Nasal Drug Delivery: Formulations, Developments, Challenges, and Solutions 3031231112, 9783031231117

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Yashwant V. Pathak Hemant K. S. Yadav   Editors

Nasal Drug Delivery Formulations, Developments, Challenges, and Solutions

Nasal Drug Delivery

Yashwant V. Pathak  •  Hemant K. S. Yadav Editors

Nasal Drug Delivery Formulations, Developments, Challenges, and Solutions

Editors Yashwant V. Pathak Taneja College of Pharmacy University of South Florida Tampa, FL, USA

Hemant K. S. Yadav School of Pharmacy Suresh Gyan Vihar University Jaipur, Rajasthan, India

ISBN 978-3-031-23111-7    ISBN 978-3-031-23112-4 (eBook) https://doi.org/10.1007/978-3-031-23112-4 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To the loving memories of my parents and Dr Keshav Baliram Hedgewar, who gave proper direction to my life, to my beloved wife Seema who gave positive meaning and my son Sarvadaman who gave a golden lining to my life. I would like to dedicate this book to the loving memories of Ma Chamanlaljee, Ma Lakshmanraojee Bhide and Ma Madhujee Limaye who mentored me selflessly and helped me to become a good and socially useful human being. Yashwant V. Pathak I would like to dedicate this book to my Parents Shri. B S Yadav and Kamla Yadav for making me what I am today, to my strength and companion my wife Sharmishtha, my daughter Khyati who made both of our life complete and my teachers who always kept me motivated. Hemant K. S. Yadav

Preface

In recent years, interest in using nasal passage as drug absorption site has received increased attention from formulation scientists. The nasal passage, even though offering a small surface area of the body as compared to other absorption passages such as the gastrointestinal tract or skin, still shows significant possibility of drug absorption at a quicker rate. Another application is the possibility of delivering drugs to the brain using this passage. Nasal delivery has come up as a promising approach to deliver diverse therapeutic agents from small drug molecules to biomacromolecules like peptides and proteins and genes to treat various disorders of the central nervous system including depression, epilepsy, migraine, schizophrenia, Parkinson’s disease, Alzheimer’s disease, and brain tumor. Different approaches have been studied in order to facilitate the delivery of different drugs into the brain; among all these approaches, intranasal administration has gained special interest. Nose-to-brain delivery provides a direct pathway of drug delivery to the brain without the need to permeate the BBB, potentially avoiding adverse effects that could occur when the drug is systemically absorbed. The book comprehensively covers the anatomy and physiology and pharmacology of the nasal passage and its use as a drug absorption site. It discusses various drug delivery systems and polymeric applications for nasal drug delivery. It provides in-depth information on nasal drug delivery and predicts a potential market in the global scenario. It describes challenges and approaches to overcome drug absorption via the nasal route. The volume also covers various formulations like nanosuspensions, niosomes, and vaccines, which effectively deliver drugs via the nasal route. This book, Nasal Drug Delivery: Formulation and Development, Challenges and Solutions, contains 19 chapters written by academicians and researchers from the USA, India, UAE, Italy, Turkey, Korea, Belgium, Ghana, Brazil, South Africa, West Indies, and Serbia. We are extremely indebted to all the authors who took lot of efforts to complete the chapters on time and ensure that all the aspects related to nasal drug delivery

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formulation and challenges are covered comprehensively in their respective chapters. We are extremely thankful to Ms. Carolyn from Springer for encouraging and helping us to edit this book, as well as other Springer employees who supported this book, and the printing press employees who helped to get this book in the print book form. We would like to state the support of our family members during the editing of the book. We would certainly appreciate our readers’ feedback, which will help us in future projects. Tampa, FL, USA Jaipur, Rajasthan, India

Yashwant V. Pathak Hemant K. S. Yadav

Contents

1

An Overview of the Anatomy and Physiology of Nasal Passage from Drug Delivery Point of View��������������������������������������������    1 Hemant K. S. Yadav, Allyson Lim-Dy, and Yashwant V. Pathak

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Pharmacological and Clinical Problems with Special Focus on Nasal Drug Delivery����������������������������������������������������������������   15 Misha Mathur and Yashwant V. Pathak

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Drug Absorption via the Nasal Route: Opportunities and Challenges ����������������������������������������������������������������������������������������   25 Seth Kwabena Amponsah and Ismaila Adams

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 Factors Affecting the Design of Nasal Drug Delivery System��������������   43 Jéssica Bassi da Silva, Maria Vitoria Gouveia Botan, and Marcos Luciano Bruschi

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Challenges in Targeting Nasal Passage and Nose-to-Brain Delivery via Nanoemulsions��������������������������������������������������������������������   59 Shiv Bahadur and Kamla Pathak

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 Potential Targeting Sites to the Brain Through Nasal Passage������������   83 Mershen Govender, Sunaina Indermun, Pradeep Kumar, and Yahya E. Choonara

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 Biomedical Applications of Nanocarriers in Nasal Delivery����������������  101 Namdev Dhas, Soji Neyyar, Atul Garkal, Ritu Kudarha, Jahanvi Patel, Srinivas Mutalik, and Tejal Mehta

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 Delivery of Vaccines via the Nasal Route ����������������������������������������������  127 Seth Kwabena Amponsah and Emmanuel Boadi Amoafo

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 Overview on Nanocarriers for Nasal Delivery��������������������������������  141 An Sunita Dahiya and Rajiv Dahiya

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10 Nose-to-Brain  Delivery of Peptides and Proteins����������������������������������  169 Meltem Ezgi Durgun, Gamze Çamlık, İsmail Tuncer Değim, and Yıldız Özsoy 11 Novel  Mucoadhesive Polymers for Nasal Drug Delivery����������������������  189 Ljiljana Djekic 12 Novel  Approaches in Nasal In Situ Gel Drug Delivery ������������������������  235 Cinzia Pagano, Luana Perioli, and Maurizio Ricci 13 Nasal  Delivery of High Molecular Weight Drugs: Recent Trends and Clinical Evidence ����������������������������������������������������������������  253 Emine Kahraman, Sevgi Güngör, and Yıldız Özsoy 14 Niosomes-Based  Drug Delivery in Targeting the Brain Tumors Via Nasal Delivery����������������������������������������������������������������������  279 Mahmoud Gharbavi, Sepideh Parvanian, Milad Parvinzad Leilan, Shabnam Tavangar, Maedeh Parchianlou, and Ali Sharafi 15 Nanosuspension  – A Novel Drug Delivery System via Nose-to-Brain Drug Delivery������������������������������������������������������������������  325 Hemant K. S. Yadav and Raghad Zain Alabdin 16 Nasal  Delivery of Micro and Nano Encapsulated Drugs����������������������  339 Muhammad Sarfraz, Sara Mousa, Ranim Al Saoud, and Raimar Löbenberg 17 Different  Strategies for Nose-to-Brain Delivery of Small Molecules ����������������������������������������������������������������������������������  361 Smita P. Borkar and Abhay Raizaday 18 Is  There a Global Market and Opportunities for Nasal Drug Delivery? Recent Trends in Global Nasal Delivery Market ������  381 Abdullah Abdelkawi, Jean Pierre Perez Martinez, and Yashwant V. Pathak 19 Nasal  Drug Delivery System: Regulatory Perspective��������������������������  393 Sudhir Sawarkar and Julie Suman Index������������������������������������������������������������������������������������������������������������������  417

Contributors

Abdullah Abdelkawi  Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA Ismaila Adams, PhD  Department of Medical Pharmacology, University of Ghana Medical School, Accra, Ghana Raghad  Zain  Alabdin, PhD  Department of Business Development, Gulf Pharmaceutical Industries (Julphar), Ras Al Khaimah, UAE Department of Pharmaceutics, College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE Ranim Al Saoud, PhD  College of Pharmacy, Al Ain University, Al Ain Campus, Al Ain, United Arab Emirates Emmanuel  Boadi  Amoafo, B Pharm  Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA Seth  Kwabena  Amponsah, PhD  Department of Medical Pharmacology, University of Ghana Medical School, Accra, Ghana Shiv  Bahadur, PhD  Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India Smita  P.  Borkar  College of Pharmacy, JSS Academy of Technical Education, Noida, Uttar Pradesh, India Arvind Gavali College of Pharmacy, Jaitapur, Satara, Maharashtra, India Maria Vitória Gouveia Botan, PhD  Department of Pharmacy, State University of Maringa, Maringa, PR, Brazil Marcos  Luciano  Bruschi, PhD  Department of Pharmacy, State University of Maringa, Maringa, PR, Brazil Gamze  Çamlik, PhD  Department of Pharmaceutical Technology, Faculty of Pharmacy, Biruni University, Istanbul, Turkey xi

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Yahya E. Choonara, PhD  Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa Rajiv  Dahiya, PhD  School of Pharmacy, Faculty of Medical Sciences, The University of the West Indies, St. Augustine, Trinidad and Tobago Sunita Dahiya, PhD  Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico - Medical Sciences Campus, San Juan, PR, USA Jéssica Bassi da Silva, PhD  Department of Pharmacy, State University of Maringa, Maringa, PR, Brazil İsmail Tuncer Değim, PhD  Department of Pharmaceutical Technology, Faculty of Pharmacy, Biruni University, Istanbul, Turkey Namdev Dhas, PhD  Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, MAHE, Manipal, India Ljiljana Djekic, PhD  University of Belgrade-Faculty of Pharmacy, Department of Pharmaceutical Technology and Cosmetology, Belgrade, Serbia Meltem Ezgi Durgun, PhD  Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey Atul  Garkal, Ph  Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India Mahmoud Gharbavi, PhD  Nanotechnology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Mershen Govender, PhD  Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg, Gauteng, South Africa Sevgi  Güngör, PhD  Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul, Türkiye Sunaina Indermun, PhD  Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa Emine  Kahraman, PhD  Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul, Türkiye Ritu Kudarha  Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, MAHE, Manipal, India

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Pradeep  Kumar, PhD  Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa Milad Parvinzad Leilan, PhD  Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran Allyson  Lim-Dy  Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA Raimar  Löbenberg, PhD  Faculty of Pharmacy and Pharmaceutical Sciences, Katz Centre for Pharmacy & Health Research, University of Alberta, Edmonton, AB, Canada Jean  Pierre  Perez  Martinez  Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA Misha  Mathur  University of South Florida, Taneja College of Pharmacy, Tampa, FL, USA Tejal  Mehta, PhD  Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India Sara  Mousa, PhD  College of Pharmacy, Al Ain University, Al Ain Campus, Al Ain, United Arab Emirates Srinivas  Mutalik  Department of Pharmaceutics, Pharmaceutical Sciences, MAHE, Manipal, India

Manipal

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of

Soji  Neyyar, PhD  Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, MAHE, Manipal, India Yıldız  Özsoy, PhD  Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey Cinzia  Pagano, PhD  Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy Maedeh  Parchianlou, PhD  Zanjan Pharmaceutical Biotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran Sepideh  Parvanian, PhD  Faculty of Science and Engineering, Åbo Akademi University & Turku Bioscience Center, Turku, Finland Jahanvi Patel, PhD  Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India Kamla Pathak, PhD  Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Saifai, Etawah, Uttar Pradesh, India Yashwant  V.  Pathak, PhD  Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia

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Luana  Perioli, PhD  Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy Abhay  Raizaday  College of Pharmacy, JSS Academy of Technical Education, Noida, Uttar Pradesh, India Maurizio  Ricci, PhD  Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy Muhammad  Sarfraz, Ph.D.  College of Pharmacy, Al Ain University, Al Ain Campus, Al Ain, United Arab Emirates Sudhir Sawarkar, PhD  QRServes Global LLC, Sharjah, United Arab Emirates Ali Sharafi, PhD  Zanjan Pharmaceutical Biotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran Julie Suman  Next Breath, Halethorpe, MD, USA Shabnam  Tavangar, PhD.  Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran Hemant K. S. Yadav, PhD  School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Jaipur, Rajasthan, India

Chapter 1

An Overview of the Anatomy and Physiology of Nasal Passage from Drug Delivery Point of View Hemant K. S. Yadav, Allyson Lim-Dy, and Yashwant V. Pathak

Abstract  This chapter covers the anatomy and physiology of the nasal passage with special focus on utilizing the nasal passage for delivering drugs for disease treatment. The total length of the nasal cavity is 120–140 mm and the total surface area is about 160 cm2. Also, the total volume is nearly 15 ml. The flow of air and particles in the cavity is controlled by structures within it. The sense of smell is controlled by the nasal cavity’s olfactory area. Nasal blood flow can be affected by a variety of causes. The vasomotor response of the nose is influenced by a variety of stimuli, both locally and generally. Changes in ambient temperature and humidity, topical application of vasoactive medications, external compression of major veins in the neck, trauma, and inflammation are all examples of local factors. This chapter discusses further details about how this nasal passage can be sued for drug delivery and as an absorption surface for the drugs whether small molecules or macro molecules. Keywords  Nasal · Drug Delivery · Intranasal · Targeting and physicochemical

1 Introduction 1.1 Nasal Drug Delivery Systems [1] There are many attractive reasons to introduce a drug via the nasal route of administration as a convenient accessible route which achieves localized and systemic actions rapidly and manageably. Some of these reasons, that made many pharmaceutical companies and researchers investigate further about this route of administration, are: the rapid onset of drug action potential, hepatic and gastrointestinal H. K. S. Yadav (*) School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Jaipur, Rajasthan, India A. Lim-Dy · Y. V. Pathak Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_1

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metabolism avoidance, noninvasiveness and ease of access, no sterilization requirements compared to parenterals leading to lower costs, non-irritative, and can be used for prolonged periods. The most attractive part in this route of administration is the olfactory region, which is considered as a direct physiological link to the central nervous system. Thus, the nasal route of administration has a high level of potential for administering the drugs to effectively treat many diseases such as Alzheimer’s disease, epilepsy, brain tumors, and many others. To appreciate this potential and digging deeper into a clear picture of the idea of locally, systemically, and nose-to-brain drug administration, it is very important to review the physiology and anatomy of the nasal route, nasal route applications, challenges, and the factors affecting the formulations and drug absorption via the nasal route. 1.1.1 Nasal Anatomy and Physiology The total length of the nasal cavity is 120–140 mm and the total surface area is about 160 cm2. Also, the total volume is nearly 15 ml. By the nasal septum, the nasal cavity is divided into two and extends posteriorly to the nasopharynx. The nasal vestibule is the first part of the nasal cavity which opens to the face through the nostril (Fig. 1.1) and it is the narrowest part with an area of 30 mm2 and it contains vibrissae (hairs) that filter the inhaled particles that are larger than 10 μm. The atrium is an intermediate region between the vestibule and the respiratory region. The respiratory region, the nasal conchae, or turbinates are convoluted projections from the nasal septum dividing it into three sections: the superior, middle, and inferior nasal turbinates. These folds provide the nasal cavity with a very high surface area compared to its small volume. The epithelial cells in the nasal vestibule are pseudostratified columnar epithelium with ciliated, non-ciliated, basal, and mucus-secreting goblet cells. Hundreds of motile cilia which are located on each of the ciliated cells and the serous and seromucous glands are providing the mucus support and nasal secretions. Olfactory region is located at the top of the turbinates and its area is about 12.5 cm2 composed of nonciliated pseudostratified columnar epithelium traversed by 6–10 million olfactory neurons that are passing from the nasal cavity through the cribriform plate to the olfactory bulb of the brain. Figure 1.1 is a schematic diagram of a sagittal section of human nasal cavity.

2 Physiology of the Nose The flow of air and particles in the cavity is controlled by structures within it. The sense of smell is controlled by the nasal cavity’s olfactory area. The following factors should be considered when describing the functions of the nose: airway, olfaction, effects on speech, air conditioning, reflex functions, and other common factors.

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Fig. 1.1  Schematic diagram of a sagittal section of human nasal cavity showing lateral wall of the nasal cavity (a), and cross-section through the middle of the nasal cavity (b), the respiratory epithelium (c), and the olfactory epithelium [1]

2.1 Airway One of the most essential components of airflow resistance is the nose. It has been estimated that it provides between 30% and 50% of total resistance to inspiration. Because the anterior nares’ cross-sectional diameter is much smaller than the posterior choana’s, inspiratory air currents differ significantly from expiratory air currents. The former is directed upward into the nasopharynx, crossing the superior surface of the inferior turbinate and the main surfaces of the middle turbinate. The horizontal position of the front nares, the smooth anterior ends and surfaces of the turbinates, and the form of the septum all contribute to this upward movement. The expiratory airway differs in that it starts at a bigger posterior choana close to the nasopharynx and travels through the nose to a relative constriction of the anterior nares. This forms a huge central eddy or recurrent stream that flows into the inferior meatus before joining the main nasopharyngeal stream. The airflow pattern used to induce olfaction is slightly different. Sniffing starts the process. The air is redirected superiorly into the olfactory cleft, where it stimulates the neuroepithelial

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membrane. The olfactory area of the human nose is restricted to the roof of the nasal cavity, the superior section of each superior turbinate in the lateral wall of the nose, and the upper one-third of each nasal septum.

2.2 Olfaction The olfactory area of the human nose is restricted to the roof of the nasal cavity, the superior section of each superior turbinate in the lateral wall of the nose, and the upper one-third of each nasal septum. The membrane has the histologic appearance of a thick, pseudostratified, columnar nonciliated epithelium. Supporting cells, basal cells, and olfactory receptor cells are the three types of cells found there. The receptor cells are found in the vicinity of the supporting cells. Their population is believed to be between 10 and 20 million people. They are oval in shape and operate as both peripheral sensory receptors and neuronal cell bodies with processes. Each olfactory cell’s central elongated end functions as a continuous strand or thick axon that is encased by the basal cells. As an unmyelinated nerve axon, the filaments breach the foundation membrane and become immediately continuous. The fibers of the olfactory nerve are formed by these axons, which eventually terminate in the glomeruli of the olfactory bulbs.

2.3 Effects on Speech Vocal resonance is provided by the nose. It is self-evident that nasal blockage can alter a person’s voice for any reason. The medical word for nasal resonance caused by a nasal obstruction is rhinolalial clausa. When the vibrating air column moves from the larynx to the pharynx, mouth, and nose, rhinolalial aperta occurs. This is most typically seen in those who have a cleft palate. The vibrating air column of air flowing from the larynx through the nose produces only the nasal consonants M, N, and NC.

2.4 Air Conditioning One of the most well-known functions of the nose is to humidify and heat the air that is inhaled. The volume and rate of airflow, as well as the specific vascular nasal mucosa, are critical in keeping the temperature of the inspired air within a narrow range from the portal of entrance to the alveoli. Because the inspiratory air comes into contact with a moist and warm nasal mucous membrane, the process of conditioning this air changes very quickly. This quick change is due to the high temperature and water vapor pressure gradients. Expiration is, in some ways, the inverse of

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inspiration. Some of the air that has been cooled by the preceding inspired air is ejected from the dead space in the tracheobronchial tree and passes across the mucosa of the pharynx and nose. This membrane absorbs the heat and moisture from the air. In a 24-hour period, a healthy adult living in a temperate climate would lose between 300 and 400 mL of water and between 250 and 350 kcal in expired air. These values will rise as a result of increased physical activity and living in dry, chilly settings. The humidification of the air happens at the same time as the heating of the inspired air. Moisture is mostly obtained through the physical process of fluid transudation through the mucosal epithelium. A lower volume is provided by epithelial gland secretions and goblet cells in the nasal membrane. The actual volume of fluid required to achieve this high level of saturation will be influenced by the ambient air’s temperature and relative humidity. The daily volume of secretion and transudate from the nose is estimated to be 1000 cc. Three-quarters of this is thought to be used to saturate the inspired air, with the remaining going to the ciliary mechanisms that clean and purify the air [2].

2.5 Reflex Functions The nose is the source of a plethora of reflex functions. They are divided into two groups: those begun by the sense of smell and those initiated by trigeminal nerve ending terminals. Reflexes connected to digestive movements are a common example of olfactory group functions. The olfactory centers stimulate the salivary, gastric, and pancreatic glands reflexively. Changes in the lower respiratory tract, particularly the larynx, trachea, and tracheobronchial tree, variations in the heart rate, changes in pulmonary ventilation, and reflex sneezing are all examples of fifth nerve reflexes.

2.6 Common Factors Nasal blood flow can be affected by a variety of causes. The vasomotor response of the nose is influenced by a variety of stimuli, both locally and generally. Changes in ambient temperature and humidity, topical application of vasoactive medications, external compression of major veins in the neck, trauma, and inflammation are all examples of local factors. The natural mucous membrane of the nose reacts to keep the nasopharynx and tracheobronchial airway in a homeostatic state. Congestion of the nasal mucous membrane and restricted airflow are caused by para-­ sympathomimetic medications, which also increase the volume of nasal secretions. Cocaine causes considerable contraction of these erectile regions through constriction of the capillaries and contraction of the cavernous tissue in the nose. On the other hand, sympathomimetic medications that have been administered locally to the mucosa will cause shrinking. Depending on the medicine, this impact can last

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anywhere from 1 to 3 hours. Adrenaline and ephedrine are common medicines that cause this reaction. Nasal blood flow is affected by a variety of elements, which have been recognized for a long time. In their monograph on the nose, Holmes et al. explain the emotional factors that are associated with nasal symptoms. Fear elicited a “sympathetic” reaction from the nasal mucous membrane, but frustration, shame, and anxiety engorged the mucous membrane and elicited a “parasympathetic” response. They demonstrated these effects by comparing emotional tone to biopsies of the inferior turbinate mucosa taken from people who had been through various stages of emotional conflict [3].

3 Nasal Airflow The human nose’s physiological activities, such as filtering and conditioning inhaled air, respiratory feedback, and the perception of smell and discomfort, all require adequate airflow. The anatomical structures of the nose, as well as the respiratory situation, determine nasal airflow patterns. Human nasal anatomy varies substantially from person to person, which is unsurprising. Furthermore, nasal illnesses such as inflammation, allergies, sinusitis, and polyps can all obstruct nasal airflow [4]. On the other hand, due to its position and the anterior nasal valve, air flows superiorly into the nares. The airstream then passes into the nasopharynx, turning roughly 90° posteriorly. After passing via the pharynx and larynx, the airstream rotates inferiorly 90° and passes through the trachea, eventually reaching the lungs. The anterior nasal valve is the narrowest part of the upper airway, positioned 1.5–2 cm posterior to the anterior nares. The upper airway’s narrowing allows for close contact between the airstream and the mucosal surfaces. Evaporation of fluid from the mucosal blanket causes humidification. The humidity level in the air is between 75% and 80%. Contact between air and the abundant blood supply of the nasal membranes, particularly the inferior turbinate mucosa, warms inspired air to 36 °C. Adults condition about 14,000 liters of air per day, which necessitates over 680 g of water, or around 20% of our daily water intake. Sniffing is also an important aspect of nasal airflow because it forces air into the superior nasal vault, where it can better contact the olfactory mucosa [5].

4 Abnormal Nasal Physiology Inhaled irritants and environmental allergens are the leading causes of nasal membrane inflammation, for example, various chemicals, perfumes, cigarette smoke, and other noxious odorants. Nonallergic rhinitis, also known as vasomotor rhinitis, is caused by autonomic nervous system dysfunction or alterations in blood flow caused by iatrogenic or

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drug-related factors. Increases in blood flow or parasympathetic tone, as well as decreases in sympathetic tone, cause nasal congestion and discharge. Nasal congestion and discharge are reduced when blood flow is reduced, the parasympathetic system is suppressed, and the sympathetic system is stimulated. Nasal systems may be affected by supplemental female hormones or hormonal changes induced by pregnancy or menstruation. Nasal physiology may be affected by medicines used to treat hypertension or heart malfunction [6]. Nasal physiology is also influenced by anatomical abnormalities, which can impact congestion, drainage, and olfaction in different ways. Airflow into the nasal cavity can be affected by septal deviation and increased turbinates, changing it from a laminar to a turbulent pattern (see the images below). Turbulent airflow irritates nasal membranes even more, resulting in increased nasal discharge and congestion [6]. The most frequent cause of transient loss of smell is turbinate hypertrophy, which can occur as a result of an upper respiratory infection (URI) or an allergic reaction. The sense of smell is vital for quality of life, taste, and detecting smoke and other potentially life-threatening odorants. The primary sources of nitric oxide in the upper airways are nasal cavities and paranasal sinuses (NO). Although the specific function of NO in nasal physiology is unknown, it is assumed to be involved in host defense, ciliary motility, and a better ventilation-perfusion ratio in the lungs through auto-inhalation. Low NO concentrations have been found in illnesses including primary ciliary dyskinesia, cystic fibrosis, and acute and chronic maxillary sinusitis, whereas high NO concentrations have been found in upper airway infection, allergic rhinitis, and nasal polyposis [6].

5 Tests of Nasal Physiology Tests of nasal physiology include studies of airflow, ciliary function, and olfaction. Nasal Endoscopy Fiber optic cables and a light source are used in nasal endoscopy to see the nasal and sinus cavities, which would otherwise be hard to see. Visualization is the best approach for assessing a wide range of medical issues affecting the nose and sinuses since it is less intrusive. A nasal endoscope is used to perform a variety of typical surgical operations in the nose cavity [7]. Rhinomanometry During exclusive nasal breathing, rhinomanometry aims to measure nasal airflow and total nasal area. A nasal catheter is inserted into the nasopharynx to acquire differential pressure readings. Nasal resistance testing evaluates all resistive components of the nasal airway, from the anterior nares to the nasopharynx, and is sensitive to even minor changes in airway diameter. This approach has been proven to be effective in recording changes in nasal patency as a result of pharmaceutic or surgical treatments. It’s a somewhat invasive procedure that takes a long time to execute and needs patient’s help [7].

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Acoustic Rhinometry Acoustic rhinometry is a relatively recent method of determining the cross-sectional area of the nose and the volume of the nasal cavity by analyzing incident and reflected sound during a brief pause in nasal breathing. This method has also been verified and may be used to document changes in nasal patency as a result of pharmaceutic or surgical treatments. It is a minimally invasive procedure that takes only a few minutes to complete and requires little patient participation [7]. In a variety of clinical settings, rhinomanometry and acoustic rhinometry can be used to assess nasal patency. Either test can be used to assess nasal airflow in general and to compare premorbid circumstances to changes that may occur following medicinal or surgical treatment. Furthermore, these tests can be used to compare nasal passageways in order to plan medical or surgical procedures [7]. Clement et al. conducted a critical study and found that among the three tests— active anterior rhinomanometry (AAR), four-phase rhinomanometry (4PR), and acoustic rhinometry—AAR is the best way of objectively evaluating nasal patency. While acoustic rhinometry, which evaluates different characteristics than AAR, has limits and cannot be used in substitute of AAR, the researchers found that it may be used as a supplementary test. Furthermore, Clement and colleagues claimed that while 4PR may be capable of providing extra data, the open technical and mathematical issues associated with it have yet to be fully resolved [7]. CT/MRI Congenital, inflammatory, benign, and malignant diseases in the sinonasal area are best evaluated using CT. CT and MRI offer the benefit of revealing anatomic features that would otherwise be hidden, as well as displaying exquisite anatomic detail [7]. Saccharin Test The saccharin test is used to determine the mucociliary clearance time in the nose. A drop of saccharin is put behind the inferior turbinate and brushed back into the nasopharynx. As the cilia sweep the saccharin posteriorly, the patient should detect a pleasant flavor. Poor ciliary function is indicated by delayed taste perception [7]. UPSIT There are several olfactory tests available, but the most popular is the University of Pennsylvania Smell Identification Test (UPSIT). The test consists of 40 questions, each of which releases a distinct odor when scratched. The patient is asked to identify the odor that has been emitted by the examiner. This test can help with the diagnosis of a variety of diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and others [7]. Nitric Oxide Exhaled nitric oxide measurements may be useful as non-invasive objective techniques for the assessment and management of normal nasal physiology and nasal and sinus diseases in the future, according to a recent study.

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Computational fluid dynamic studies of nasal airflow and physiology have increased knowledge of the complicated nasal architecture and the consequences of illness and surgery on physiology, according to research by Leong et al. and Liu et al. [7].

6 Factors Affecting Intranasal Delivery Intranasal delivery includes numerous benefits like non-invasiveness, convenient self-administration, and quick absorption. Nevertheless, diverse factors influence the restrictions and potency of IN drug delivery. Some include volume, permeability, absorption, and mucus. Volume and Permeability The volume that can flow through a human’s nasal cavity is limited. Only 25–200 μL of drugs is permitted [8]. This small amount hinders drugs from being efficiently transported. Permeability is also crucial for the drug to enter the blood or brain. However, the limited volume prevents drugs from having ample permeability in the nasal cavity. Mucus and Absorption Mucus or nasal secretion performs a significant role in absorption. When mucus is swallowed, it may carry the drug’s molecules to the gastrointestinal tract [9]. This would prevent the drug from reaching the CNS. Hence, the drug must pervade the mucus to be properly transported. Mucus promotes absorption if the drug remains longer in the nasal cavity and is not inadequately transported.

7 Nasal Passage Targeting the CNS The intranasal route functions as a direct passageway from the nasal cavity to the brain. Drug(s) travel this route via olfactory or trigeminal nerves during IN delivery. Molecules of a drug proceed along these nerves to their corresponding origins in the brain: the cerebrum and pons. Subsequently, the drug disseminates in the brain through the intranasal route’s two pathways, intracellular and extracellular. The intracellular pathway carries drugs to the olfactory bulb with olfactory neurons and various cells. The olfactory bulb directly connects and transfers the drug to the central nervous system (CNS). The extracellular pathway transports drugs from the nasal epithelium to the lamina propria until it externally travels along the axon. The drug eventually reaches the CNS and fluid movement helps it to incrementally disperse. Altogether, both pathways allow efficient transportation for nose-to-brain drug delivery [9, 10].

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8 Barriers to Drug Transport from Nose to Brain Three important barriers that influence intranasal drug delivery and formulations are the nasal epithelium, blood-brain barrier (BBB), and blood-cerebrospinal fluid barrier (B-CSF-B). The latter two barriers can potentially be bypassed by IN drug delivery. Nasal Epithelium The nasal epithelium is a crucial barrier to comprehend for nose-to-brain drug delivery. Its natural leaky behavior allows for swift absorption. However, the epithelium’s compact junctions can restrict a drug’s impact due to the limited permeation of the membrane [9]. Permeation enhancers can be utilized to overcome this barrier and promote drug delivery to the CNS. Blood-Brain Barrier (BBB) The blood-brain barrier is a sensitive barrier that contains the basal lamina and endothelial cells. Its limited access protects the central nervous system from xenobiotics or neurotoxic substances. This restriction defends the brain yet limits the direct delivery of drugs to the CNS. Thus, many CNS drugs have been ineffective due to the BBB. Drug transport from the nose to brain can bypass the barrier via the intranasal route and molecular diffusion [9, 11]. Blood-Cerebrospinal Fluid Barrier (B-CSF-B) Another determining barrier in CNS drugs is the blood-cerebrospinal fluid barrier (B-CSF-B). It consists of cerebrospinal fluid (CSF) that encompasses the brain. B-CSF-B protects the brain from detrimental substances by regulating the movement of CSF. Like BBB, numerous drugs cannot pervade, and drug delivery via the nasal cavity can avoid the B-CSF-B barrier.

8.1 Mucociliary Clearance Mucociliary clearance is a defense mechanism in the lungs that can affect IN drug delivery. Gravity and absence of cilia in the olfactory mucosa cause mucociliary clearance to arise [12]. It also varies with environmental conditions and certain illnesses. Mucociliary clearance rate determines the absorption of drugs, with a lower rate being more optimal. Mucoadhesive agents can be employed to lower the rate. Adding these agents to standard nanoemulsions can enhance the absorption and distribution of a drug in the brain. Mucoadhesive substances like chitosan allow for better retention time and affect the mucus in the nasal cavity. Furthermore, the viscosity of mucus and clearance rate are indirectly proportional. Increasing the viscosity of mucus or drug formulation can decrease clearance rate. Drug formulations with high viscosity such as gels are effective at assisting drug absorption. It provides longer retention time with the nasal mucosa, which can help increase absorption.

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8.2 Physico-Chemical Properties of the Drugs Proper drug formulations are necessary for efficacy and preventing irritation. There are diverse forms of IN drugs—liquid, gels, nasal sprays—but they must maintain standard properties. Several components include pH level, temperature, solubility, and particle size. pH Level and Temperature pH levels and temperature can alter the mucus layer when the drug travels intranasally [13]. The pH level must range from 5.0 to 6.5 to prevent irritation in the nasal mucosa [10]. Temperature is another property that maintains drug stability and potency. Mucociliary clearance rate can be influenced if the nasal cavity’s temperature is not within the range of 5–50 °C [13]. Solubility Solubility can also affect drug absorption. Drugs travel quickly in the nasal cavity; thus, there is insufficient time for a drug to be dissolved and effectively absorbed [9]. This occurs because nose-to-brain drug delivery bypasses several phenomena: dilution and first pass effect. Pires and Santos suggest a formulation strategy that can improve low soluble and less potent drugs. They express that these drugs require formulations and systems that strengthen bioavailability and brain-targeted delivery. Using nanotechnology like nanosystems is part of their strategy. Nanosystems can carry the drugs to certain cells and tissues that may promote solubility through enhancing agents [10]. Particle Size Particle size is an important property since the volume the intranasal route can carry is limited. Particle sizes of a nanoemulsion can determine the drug’s retention time and permeation in the nasal cavity and brain. A study by Ahmad et al. illustrated that nanoemulsion (NE) particles approximately the size of 100 nm or smaller remained longer in the nasal cavity. These 100 nm particles could travel through the intracellular pathway, but only a particular amount. 900 nm NE particles were also tested; they were able to move along the intranasal route yet were hindered by mucociliary clearance and diffusion [14]. Particle sizes affect the drug potency but must be minuscule to prevent irritation and poor absorption.

9 The Sensitivity of the Nasal Mucosa as a Limiting Factor The nasal mucosa’s rapid clearance and tight junctions limit absorption and permeability. Therefore, the sensitivity of the nasal mucosa acts as a guide for creating drug formulations. Ideal formulations must have permeation and mucoadhesive enhancing agents, higher viscosity, and certain pH levels. Nevertheless, fundamental characteristics of a drug can hinder exemplary formulations. For example, lipophilic drugs offer better bioavailability than certain hydrophilic drugs (peptides)

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[13]. The latter exhibits low permeability along the nasal mucosa. If drugs cannot be efficiently absorbed, they can easily be eliminated by mucociliary clearance. Enzymatic degradation in the nasal mucosa is another concerning factor with peptides. This degradation reduces the original dosage’s effect on the brain. Implementing enzyme inhibitors can assist the peptides. It will not alter the peptides’ bioavailability but can partially defend them from proteolytic enzymes [13]. The sensitivity of the nasal mucosa establishes various limitations, but alternatives and enhancers are available.

10 Impact of Delivery Instructions, Patient Compliance, and Body Position Instructions and delivery systems can heavily affect patient compliance and drug efficacy. Many common delivery systems like nasal sprays and drops require certain steps and body positions. In an observational study by Rollema et al., they interviewed 64 patients to determine how many accurately followed the patient information leaflet (PIL) for intranasal corticosteroid sprays (INCS). Six percent of patients followed all, while less than half had proper positions. These observations show that instructions were either disregarded, unclear, or improperly instructed. Another study by Trabut et al. illustrates their findings regarding body positions during self-­ administration. Body positions are crucial because they can target specific areas of the nasal cavity. They proposed that several positions—Lying Head Back and Lateral Head Low—provide better alternatives to traditional ones like Head Down and Forward. Head Down and Forward is unfavored because it causes higher discomfort and poorly targets the middle meatus or middle turbinate. Results from both studies exhibit the importance of instructions and body positions. Patients should be properly advised since efficacy can be influenced by these factors [15, 16].

11 Conclusion Intranasal drug deliveries are convenient, effective, and constantly improving with new formulations and research. The easy accessibility through the intranasal route implements IN drug deliveries as an appealing alternative to invasive administrations. Administrating via this route allows drugs to bypass common, intricate barriers and phenomenon: blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (B-CSF-B), and first-pass effect. Although there are many advantages, numerous limitations hinder substantial efficacy. Major limitations include nose anatomy and physiology, nasal inflammation, permeability, absorption, and mucociliary clearance. New drug delivery formulations and systems should be constructed around these diverse factors. Nasal tests and assessments should also be conducted to

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ensure a patient receives optimal treatment. Non-invasive administrations display higher patient compliance; however, patients should be fully informed of the recommended instructions and positions for self-administration. Clinicians must be responsible for providing this information and any applicable alternatives. Overall, nose-to-brain drug delivery is a promising approach that can help alleviate various illnesses.

References 1. Aulton ME, Taylor KMG. Aulton’s pharmaceutics; the design and manufacture of medicines. 5th ed. Elsevier Ltd.; 2018. p. 671–89. 2. Nathan Geurkink MD, Hanover NH, et al. Nasal anatomy, physiology, and function. J Allergy Clin Immunol. 1983;72(2):123–8. 3. Holmes TH, Goode H, Wolf S, Wolff HG. The nose. Springfield: Charles C Thomas; 1950. 4. Zhao K, Jiang J. What is normal nasal airflow? A computational study of 22 healthy adults. Int Forum Allergy Rhinol. 2014;4(6):435–46. 5. Naclerio RM, Pinto J, Assanasen P, Baroody FM.  Rhinology. 2007;45(2):102–11. (ISSN: 0300-0729) 6. Archer SM.  Nasal Physiology: Overview, Anatomy of the Nose, Nasal Airflow (medscape. com), 2021. 7. Freeman SC, Karp DA, Kahwaji CI. Physiology, Nasal. 2022 May 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 30252342. 8. Gao H.  Progress and perspectives on targeting nanoparticles for brain drug delivery. Acta Pharm Sin. 2016;6(4):268–86. 9. Erdő F, Bors LA, Farkas D, Bajza Á, Gizurarson S. Evaluation of intranasal delivery route of drug Administration for Brain Targeting. Brain Res Bull. 2018;143:155–70. 10. Pires PC, Santos AO. Nanosystems in nose-to-brain drug delivery: a review of non-clinical brain targeting studies. J Control Release. 2018;270:89–100. 11. Crowe TP, Greenlee MHW, Kanthasamy AG, Hsu WH. Mechanism of intranasal drug delivery directly to the brain. Life Sci. 1973;(195):44–52. 12. Jain H, Prabhakar B, Shende P. Modulation of olfactory area for effective transportation of actives in CNS disorders. J Drug Deliv Sci Technol. 2022;68:103091. 13. Dholakia J, Prabhakar B, Shende P. Strategies for the delivery of antidiabetic drugs via intranasal route. Int J Pharm. 2021;608:121068. 14. Ahmad E, Feng Y, Qi J, Fan W, Ma Y, He H, Xia F, et al. Evidence of nose-to-brain delivery of nanoemulsions: cargoes but not vehicles. Nanoscale. 2017;9(3):1174–83. 15. Trabut S, Friedrich H, Caversaccio M, Negoias S. Challenges in topical therapy of chronic rhinosinusitis: the case of nasal drops application – a systematic review. Auris Nasus Larynx. 2020;47(4):536–43. 16. Rollema C, van Roon EN, de Vries TW.  Inadequate quality of administration of intranasal corticosteroid sprays. J Asthma Allergy. 2019;12:91–4.

Chapter 2

Pharmacological and Clinical Problems with Special Focus on Nasal Drug Delivery Misha Mathur and Yashwant V. Pathak Abstract  The production of medications has seen many advancements. More diseases can now be managed or even treated and a variety of symptoms can be eliminated. While these options exist, many come with a long list of side effects with a range of severity. Furthermore, many diseases still do not have treatment options, such as neurodegenerative diseases like Alzheimer’s. A method that has shown to be successful in addressing these concerns is nasal drug delivery. Due to the manner in which it is introduced to the body, it decreases the chance of many metabolic side effects such as nausea and vomiting. Furthermore, the proximity of the nose to the brain would allow certain drugs to cross the blood-­ brain barrier and enter the brain to address neurodegeneration. The nasal cavity was also very beneficial in testing for COVID-19. It provided a convenient and non-­ invasive way to test for COVID-19. However, there are certain constraints on drugs that can be delivered nasally, depending on their properties. Yet, there have been parallel developments on absorption enhancers, components mixed with the medication that can increase the absorption. Overall, introducing medication through the nose has demonstrated a variety of benefits such as a decreased chance of side effects, lower cost, and higher bioavailability. Keywords  Nasal passageway · Drug delivery · Blood-brain barrier · COVID-19 · Absorption enhancer · Bioavailability · Nasal to brain delivery

1 What Is the Nasal Passageway? The nasal cavity, the nose, has two openings called external nares, commonly known as nostrils. The internal nares are the open area between the nasal cavity and pharynx. The nasal passage specifically is a subset of sinuses, which are hollow spaces around the nose, cheek, and forehead. These three regions have four sinus cavities. M. Mathur · Y. V. Pathak (*) University of South Florida, Taneja College of Pharmacy, Tampa, FL, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_2

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Firstly, the frontal sinuses are located at the base of the forehead, closely above the eyebrows. The sphenoid sinuses are on the back of the head, close to the optic nerve. The largest sinus is the maxillary sinuses which are on both sides of the nose under the eyes. Ethmoid sinuses have three layers topped on each other. This tends to be the location of the noticeable effects of a sinus infection. Understanding the sinuses is a major part of understanding the nasal passageways since anything breathed in will travel through all the sinuses. Furthermore, blockage of any part of the sinuses will result in obstructed airflow [19]. The cells that line the nasal cavity possess tiny hair, called cilia. The goblet cells also produce mucus in the nose. The mucus traps certain pathogens and the cilia are responsible for clearing them from the nose [6].

2 What Is the Blood-Brain Barrier? The information that humans and animals perceive and the actions they do are under the control of the nervous system. One part of the nervous system, the central nervous system, consists of the brain and the spinal cord and is known as the processing center [2]. Since this is such a vital part of the body, the movement of materials such as ions, molecules, and cells is tightly regulated by the cerebral endothelial cells [20]. This is referred to as the blood-brain barrier. The endothelial cells in the central nervous system form tight junctions to not allow large molecules in, such as drugs and other solutes which have been quantified by the blood-brain barrier’s high trans-endothelial electrical resistance [20]. The cerebrospinal fluid is hydrophobic. Since hydrophobic and hydrophilic substances cannot interact, the blood-brain barrier places an extra emphasis on blocking hydrophilic compounds from entering the brain tissue [3]. Trials demonstrated successful delivery of these particles through the blood-brain barrier when the particles were dissolved  in an aqueous phase [21]. While the exact mechanism is not fully understood, it has been determined that if medication is delivered to the olfactory region of the nares, the medication can travel to the brain.

3 Properties of Nasal Passages In terms of drug delivery, the nasal passageway can be categorized into the respiratory and the olfactory area. The respiratory area is located low in the nostrils, while the olfactory area is located higher up in the nares. The epithelium in both categories is able to absorb molecules. While the exact mechanism is not fully understood, it has been determined that if medication is delivered to the olfactory region of the nares, the medication can travel to the brain by the olfactory neurons. From what is understood, this is done by the trigeminal nerves [21]. By observing the movement of stained dye that is administered nasally, it has been shown that the dye travels through the middle concha, the maxillary sinus, and the choana, prior to reaching

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the trigeminal nerve. Overall, the dye was seen to reach the brain within 10 minutes [8]. The steps of mucosal absorption are drug release, penetration, permeation, and absorption [15].

4 Current Relevance with COVID-19 The connection between the nasal passageway with the rest of the body has been extremely emphasized recently by SARS-CoV-2, the virus responsible for COVID-19. In this virus, the primary point of entry was the nasal cavity. From there, the virus had the ability to spread to the lungs which potentially developed into more serious and even fatal conditions, such as pneumonia. The theory that the nasal cavity is the point of origin can be explained due to ACE2, a cell surface receptor utilized by the virus to get into cells, being present in larger quantities in the nasal lining than in the lower airway cells. Research on the mechanism of this virus has also highlighted the importance of TMPRSS2, a transmembrane protease that allows the virus to reach the cells in the airway. Overall, these findings have demonstrated that the upper airway is more susceptible to outbreaks [7]. The fact that the nasal passageway housed the markers that were needed to detect COVID-19 was extremely beneficial. In nasal cavity swabbing, the swab goes to the anterior nasal cavity which was important because this technique was quick, painless, and could be done with basic medical training [10]. At the start of the pandemic, some people reported injury to the base of their skull. However, it has been demonstrated that the individual swabbing will be able to successfully swab if they go in the anterior nasal cavity at an angle of less than 30° while the patient’s head is tilted back [12]. It was important to understand that the rapid antigen test which was done after a swab was submitted was a successful strategy in testing individuals in resource-poor countries [10]. Overall, the nasal passageway allowed for an easily accessible and non-invasive route for COVID-19 detection (Fig. 2.1).

5 Benefits of Utilizing the Nasal Passageway There are multiple options by which medications can be delivered to individuals, such as intravenous, intramuscular, and many more. The oral passage is one of the most common ways. However, there are certain circumstances in which the utilization of the nasal passageway would be a more effective form of delivery than ingestion. The nasal cavity allows direct access to the bloodstream via the vascular network for substances that can cross mucous membranes. This method allows for rapid onset because the medication is directly absorbed into the systemic circulation. Some medications can reach the brain from the nasal mucosa in less than 10 minutes. On the other hand, a medication taken orally must first go through the liver and get metabolized to a certain degree prior to entering the bloodstream. The

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Fig. 2.1  Ideal route of nasal swab for COVID-19 testing [12]

metabolism of the medication would not allow the proper dosage to enter the bloodstream so physicians may have to prescribe higher dosages to account for the metabolism of the drug. Additionally, the process of metabolism takes many hours which means that the medication would not reach the bloodstream for a couple of hours. In contrast, since delivery via the nasal cavity is easily absorbed and does not have to follow the longer absorption process that oral medications must, a smaller dosage would suffice because the ingested amount would not have to be increased to take metabolism into account. In turn, a smaller dose will result in less cost of the medication and a decreased chance of unintentional consequences to the body because a higher dosage is correlated with a higher probability of developing side effects. The nasal passageway is also effective at delivering medication across the blood-­ brain barrier due to the proximity of the two regions, which results in a faster impact of the medication administered [17]. Devices like nebulizers and mucosal atomization devices (MAD), also known as nasal sprays, are extremely efficient at quickly getting the medication absorbed into the bloodstream because these devices expel a soluble mist in the mucosa [23]. These delivery methods are straightforward and

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non-invasive, making them more convenient than other delivery methods. This convenient nature of the sprays leads to higher compliance in long-term therapy [18]. Many diseases that medicine does not have cures for are neural degeneration diseases. This is largely due to the difficulty of delivering medication to the brain since the delivery is blocked by the blood-brain barrier. Given that certain medications, such as macromolecules and low molecular weight drugs are delivered via the olfactory and trigeminal nerve pathways through the nasal passageway, they can easily enter the blood [14]. Furthermore, research shows that the proximity of the nose and the brain is pertinent in explaining how this passageway can bypass the blood-brain barrier and deliver medication to cerebrospinal fluid [11]. Utilization of these passageways has prospective implications for finding treatments to neural diseases, such as Alzheimer’s disease. Researchers have been able to reverse neurodegeneration in a mouse model with Alzheimer’s disease [5] (Fig. 2.2). Overall, medication delivered via the nasal passageway is easy to deliver, non-­ invasive, and has decreased side effects. For example, there is a lower chance of vomiting if the medication was delivered orally due to a lower dosage. Delivery via the nasal passageway also demonstrates rapid onset. For example, nanoparticles delivered via the nasal passageway had reached the nasal bulb in under 5 minutes [21].

Fig. 2.2  Flow of medication via nasal spray delivery [9]

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It also allows for higher bioavailability and cost-effectiveness because fewer products being used correlate with lower prices.

6 Possible Barriers to the Utilization of the Nasal Passageway While there are many benefits of utilizing the nasal passageway, it is not the most ideal delivery mechanism for all scenarios. Instead, the reason for delivery and the medication being delivered highly influences the preferred route of administration. In instances where it is pertinent to get the medication in the bloodstream right away, intravenous delivery is more effective since it would have a 100% bioavailability, which is a measure of the amount of medication that reaches the bloodstream divided by the amount administered, which is also understood as the proportion of the administered dose that enters the bloodstream and is available to the site of action [23]. Furthermore, the nasal lining has a thick layer of mucus, which is often composed of many enzymes. This may degrade the medication which would result in an ineffective cure [21]. It is also imperative to ensure that the cilia, and thus the nasal cavity, is not irritated by the drug. The nasal passageway also doesn’t allow a large amount of medicine to be administered when compared to taking something by mouth. Magnetic resonance imaging (MRI) has determined that the average adult nostril opening is 357.83  ±  108.09  mm2 and the average nasal volume of an adult is 16,449.81 ± 4288.42 mm3 [21]. This small area and volume tend to only allow the entry of nanoparticles. Even particles of 900 nm were not successful in reaching the brain. On the other hand, a dosage too small like 100 nm results in a very small amount reaching the brain [21]. However, in cases where the medication has a large molecular size, has poor membrane permeability, or is likely to be degraded by aminopeptides, absorption enhancers and enzyme inhibitors may be utilized. These work by increasing the solubility of the drug, decreasing the surface tension of the mucus, and decreasing enzymatic activity so that the medication is not broken down. The first possible barrier is during absorption because medication would have to go through many layers, such as the mucus layer, epithelial layer, interstitium, and capillary endothelium [4]. The nasal tract has a thinner and more permeable mucus layer than the respiratory tract which allows the medication to be more readily absorbed. Hydrophobic molecules can cross the epithelial cell membrane via a concentration gradient but hydrophilic molecules would require a transport system to cross the bilayer. Once the medication has traveled across this physical barrier, there are other obstacles that must be overcome as well. Surfactants provide support to the body by acting as absorption enhancers. Specific examples include fatty acids, non-ionic surfactants, and bio-surfactants, which assist the medication in crossing the epithelial layer during nasal absorption [4].

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Another obstacle that a medication must overcome is enzyme degradation. The nasal passageway has enzymes such as proteases and nucleases that may degrade the medication before it can be absorbed. Protease inhibitors have been effective in animal trials, especially when it was delivered alongside absorption enhancers, such as sodium glycocholate. A study was conducted on rats to demonstrate this relationship in terms of insulin absorption through the lungs. Protease inhibitors enhanced the absorption between 24.0% and 66.7% for a 90-minute timeframe [4]. Overall, these mechanisms allow a higher bioavailability of the drug in the patient, which will allow it to be more successful [15].

7 Properties of an Effective Nasal Delivery Drug While the nasal passageway is a beneficial route of drug delivery, it is not always feasible or necessary due to the characteristics of the drug. One important characteristic to consider is size. When comparing the nasal passageway and the nose to other common delivery pathways such as oral intake, there is a stark difference in the amount of liquid that each can hold. Thus it is only feasible to use intranasal delivery when the particles are less than 10 nm, ideally 25–200 μL [23]. This is similar to the characteristic that the quantity of the administered drug should be of low molecular weight. To take this idea a step further, it is important to be cognizant that if the delivered amount is smaller, the smaller amount should be more potent to compensate for a lack of quantity. More specifically, medications that are capable of being potent in nanomolar quantities are ideal for intranasal delivery. Some examples of therapeutics that have been successfully delivered intranasally are neutrophils, neuropeptides, cytokines, and polynucleotides [5] (Fig. 2.3). The nasal passageway has been determined to be an effective manner in delivering mRNA. One application of this idea is seen in tumor vaccinations to cure cancer. Since mRNA rapidly degrades, this delivery system is only effective if the mRNA is encapsulated in nanoparticles. This idea has already been successful in mice. The survival rates were 14.5–23 days for mice that were intranasal immunized while it was only 7–13 for mice that had mRNA delivered in a naked form. Furthermore, 2 out of 10 ended the 40-day study while still being tumor-free [16]. When analyzing which medications are fit to be delivered intranasally, it is also important to consider the physical properties. One property would be the solubility of the medication. The nasal mucosa and the blood-brain barrier are cell membranes with a lipid bilayer. Thus, for a medication to pass the membrane, it must be able to dissolve. In other words, the medication must be lipophilic [23]. It is also noteworthy to consider the pH.  When looking at the pH of the nose, there are different measurements necessary for the anterior and posterior nasal cavity. However, the pH of these regions varies depending on the individual. Thus, a study was done in which the original pH of the participant’s nose was measured, and then the pH is measured again after nasally administering different pHs of liquids. The average pH of the anterior nose is 6.4, while the average pH of the posterior of the nasal cavity

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Fig. 2.3  Characteristics of a successful nasal delivery drug [15]

is 6.27. The nasal anterior pH is much more sensitive than the posterior nasal cavity pH [22]. For example, when a spray that has a pH of 7.2 is used, the average anterior pH of 6.4 increased to 7.06 while the pH in the posterior of the nose did not change. Ideally, nasal sprays are made to mirror the slightly acidic pH of the nose. Some nasal sprays are manufactured without maintaining this ideology which leads to some sprays having a high pH. However, a high pH can result in fungal infections, stinging, and a decrease in the effectiveness of steroids [13]. Overall, the chemical properties of the medication contribute to whether or not the medication will be well tolerated, adequately absorbed, or effective [23].

8 Conclusion Over the past decades, technology has greatly improved and has allowed for the synthesis and production of a variety of medications. However, the increase in the number of medications has consequently seen an increase in side effects and there

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are still many diseases that have no cure. The nasal passageway has the ability to overcome both of these obstacles in healthcare. Medications delivered via the nasal route have lower dosages which decrease the chances of many side effects. Furthermore, the proximity of the nose to the brain allows certain medications to cross the blood-brain barrier. This opens a door to further research in neurological diseases for which there is no way to deliver medication to the brain.

9 Future Trends As described by COVID-19, a virus that originated in the nasal cavity can spread to the lungs. Thus, studies in the future can extrapolate and assume that medication administered through the nose could also make it to the lungs and be beneficial [1]. While the general idea of utilizing nasal passageways to administer some types of medication seems extremely effective, it is more challenging to fully gauge if any of the medication delivered this way would result in detrimental side effects. Various trials have been done in mice but due to the varying physiology between humans and various animals is very profound so it is unclear to assume a direct correlation of results [15]. However, once this is better understood, another possibility is working on ensuring that medication delivered via the nasal passageway remains at the nasal mucosal surface so that it can eventually penetrate the blood-brain barrier. More research and discovery on this may shed some light on cures for neurological disorders [21].

References 1. Boucher R, Baric R.  Researchers map how coronavirus infection travels through cells of nasal cavity and respiratory tract. UNC Gillings School of Global Public Health. 2 June 2020. Retrieved March 18, 2022, from https://sph.unc.edu/sph-­news/researchers-­map-­how-­ coronavirus-­infection-­travels-­through-­cells-­of-­nasal-­cavity-­and-­respiratory-­tract/ 2. Central nervous system: Brain and Spinal Cord. Queensland Brain Institute. 17 July 2018. Retrieved March 13, 2022, from https://qbi.uq.edu.au/brain/brain-­anatomy/central-­ nervous-­s ystem-­b rain-­a nd-­s pinal-­c ord#:~:text=Broadly%20speaking%2C%20the%20 nervous%20systemhttps://qbi.uq.edu.au/brain/brain-­anatomy/central-­nervous-­system-­brain-­ and-­spinal-­cord#:~:text=Broadly%20speaking%2C%20the%20nervous%20system,of%20 membranes%20known%20as%20meninges.,of%20membranes%20known%20as%20 meninges 3. Daneman R, Prat A.  The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015;7(1):a020412. https://doi.org/10.1101/cshperspect.a020412. 4. Ghadiri M, Young PM, Traini D. Strategies to enhance drug absorption via nasal and pulmonary routes. Pharmaceutics. 2019;11(3):113. https://doi.org/10.3390/pharmaceutics11030113. 5. Hanson LR, Frey WH 2nd. Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci. 2008;9 Suppl 3(Suppl 3):S5. https://doi.org/10.1186/1471-­2202-­9-­S3-­S5.

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6. Hayes K. Anatomy of the nasal cavity. Verywell Health. 9 April 2021. Retrieved March 17, 2022, from https://www.verywellhealth.com/nasal-­cavity-­anatomy-­5097506 7. Jian L, Yi W, Zhang N, Wen W, Krysko O, Song WJ, Bachert C. Perspective: COVID-19, implications of nasal diseases and consequences for their management. J Allergy Clin Immunol. 2020;146(1):67–9. https://doi.org/10.1016/j.jaci.2020.04.030. 8. Johnson NJ, Hanson LR, Frey WH. Trigeminal pathways deliver a low molecular weight drug from the nose to the brain and orofacial structures. Mol Pharm. 2010;7(3):884–93. https://doi. org/10.1021/mp100029t. 9. Kapoor M, Cloyd JC, Siegel RA.  A review of intranasal formulations for the treatment of seizure emergencies. J Control Release. 2016;237:147–59. https://doi.org/10.1016/j. jconrel.2016.07.001. 10. Lee S, Widyasari K, Yang H-R, Jang J, Kang T, Kim S. Evaluation of the diagnostic accuracy of nasal cavity and nasopharyngeal swab specimens for SARS-COV-2 detection via rapid antigen test according to specimen collection timing and viral load. Diagnostics. 2022;12(3):710. https://doi.org/10.3390/diagnostics12030710. 11. Merkus FW, van den Berg MP.  Can nasal drug delivery bypass the blood-brain barrier?: questioning the direct transport theory. Drugs R&D. 2007;8(3):133–44. https://doi. org/10.2165/00126839-­200708030-­00001. 12. Mistry SG, Walker W, Earnshaw J, Cervin A. Covid-19 swab-related Skull Base injury. Med J Aust. 2021;214(10):457. https://doi.org/10.5694/mja2.51082. 13. Nasal pH of saline spray and nasal gel results in less stinging and steroid compatibility. Rhinase. n.d. Retrieved March 12, 2022, from https://rhinase.com/pages/nasal-­ph 14. Pardeshi CV, Belgamwar VS. Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood-brain barrier: an excellent platform for brain targeting. Expert Opin Drug Deliv. 2013;10(7):957–72. https://doi.org/10.1517/17425247.2013.790887. 15. Pathak V. Nasal delivery - a promising route of drug delivery to the brain. Drug Development and Delivery. 13 August 2018. Retrieved March 18, 2022, from https://drug-­dev.com/ nasal-­delivery-­a-­promising-­route-­of-­drug-­delivery-­to-­the-­brain-­scientific-­considerations-­2/ 16. Phua KKL, Staats HF, Leong KW, Nair SK. Intranasal mRNA nanoparticle vaccination induces prophylactic and therapeutic anti-tumor immunity. Nature News. 4 June 2014. Retrieved February 13, 2022, from https://www.nature.com/articles/srep05128 17. Sliva S, Barton E. Intranasal use of drugs in the emergency room and Pre-Hospital Arenas. Medscape. 8 October 2010. Retrieved March 17, 2022, from https://www.medscape.com/ viewarticle/730093 18. Stanford R, Meltzer E, Nathan R, Derebery J, Stang P, Campbell U. Nasal spray device and formulation attributes may contribute to stopping treatment with prescription nasal sprays. J Allergy Clin Immunol. 2007;119(1):S228. https://doi.org/10.1016/j.jaci.2006.12.264. 19. Understanding your nasal passages. ADVENT Knows. 2 September 2021. Retrieved March 17, 2022, from https://adventknows.com/blog/navigating-­your-­nasal-­passages/#:~:text=Your%20 nasal%20passages%2C%20also%20referred,as%20passages%20for%20mucus%20drainage 20. Villabona-Rueda A, Erice C, Pardo CA, Stins MF. The evolving concept of the Blood Brain Barrier (BBB): from a single static barrier to a heterogeneous and dynamic relay center. Front Cell Neurosci. 2019;13. https://doi.org/10.3389/fncel.2019.00405. 21. Wang Z, Xiong G, Tsang WC, Schätzlein AG, Uchegbu IF. Nose-to-brain delivery. J Pharmacol Exp Ther. 2019;370(3):593–601. https://doi.org/10.1124/jpet.119.258152. 22. Washington N, Steele RJ, Jackson SJ, Bush D, Mason J, Gill DA, Pitt K, Rawlins DA.  Determination of baseline human nasal pH and the effect of intranasally administered buffers. Int J Pharm. 2000;198(2):139–46. https://doi.org/10.1016/s0378-­5173(99)00442-­1. 23. WRHA professionals. Intranasal medication administration. Winnipeg Regional Health Authority. November, 2017. Retrieved February 13, 2022, from https://professionals.wrha. mb.ca/old/extranet/eipt/files/EIPT-­055.pdf

Chapter 3

Drug Absorption via the Nasal Route: Opportunities and Challenges Seth Kwabena Amponsah and Ismaila Adams

Abstract  Drug administration via the nasal route appears to be another reliable way of getting drugs into systemic circulation. The nasal route has easy access, large surface area, is well vascularized, and circumvents first-pass metabolism. Currently, there is a lot of attention on nasal delivery of drugs. This route has been found to aid rapid absorption of drugs into systemic circulation. The mucosa found in the nasal cavity has been shown to aid absorption of bioadhesive drug delivery devices. Microspheres, liposomes, and gels expand readily when they come into contact with the mucosa in the nasal cavity. Furthermore, to enhance absorption of drugs, a number of methods have been used to extend residence time in the nasal cavity. However, prospects of using the nasal route as a means of getting drugs into systemic circulation face a number of challenges. Some of which include barriers in the mucosa and toxicity which may be associated with the excipients used. Drug absorption enhancers are currently being explored to improve intranasal drug delivery. Drug absorption via the nasal route (opportunities and challenges) is discussed in this chapter. Keywords  Absorption · Challenges · Enzyme inhibitors · Nasal route · Surfactants

1 Introduction Over the years, nasal administration of drugs has had several systemic applications. Some of the applications include management of pain, allergy, infections, osteoporosis, and sexual dysfunction [1, 2]. The nasal route also serves as a topical site for administration of drugs in the management of nasal congestion associated with allergic rhinitis [3]. Decongestants and antihistamines are examples of drugs administered topically in the treatment of rhinitis [4, 5]. S. K. Amponsah (*) · I. Adams Department of Medical Pharmacology, University of Ghana Medical School, Accra, Ghana e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_3

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A number of studies have explored the nasal route in the administration of drugs for cardiovascular indications [6]. In individuals with angina pectoris, administration of propranolol via the nasal route has been found to improve tolerance during exercise [7]. Patients with perioperative hypertension and hypertensive crises have been treated with intranasal nifedipine [7]. Nitroglycerin given intranasally has been proven to reduce hypertensive episodes after endotracheal intubation [8]. Intranasal administration of drugs for cardiovascular diseases, according to the aforementioned studies and others, might be used in clinical settings when fast and intermittent therapeutic effects are needed, and could possibly replace parenteral drug administration [9, 10]. In 1991, it was discovered that it was possible to deliver drugs to the central nervous system (CNS) via the nasal route [11]. Subsequently, there has been a surge in nasal drug delivery systems, particularly nose-to-brain delivery [12]. Therapeutic proteins currently exist for some CNS diseases [8]. These agents have the potential to improve efficacy while minimizing adverse effects [8]. Additionally, intranasal drug delivery systems have been employed in the management of diabetes-mediated cerebral degeneration and Alzheimer’s disease [9, 10]. Glioblastoma is currently being managed with anticancer drugs administered via the nasal route [13, 14]. Several other drugs could be administered through the nasal route. Indeed, administration of peptide hormones (calcitonin, desmopressin, insulin, and glucagon) is also possible via the nasal route [15, 16]. Inhaled insulin is currently available on the market [17]. Analgesics and some rescue drugs (e.g., naloxone) depend on rapid absorption via the nasal mucosa [18]. In addition, intranasal triptans have been used for migraines, fentanyl for pain, and ondansetron for nausea [19–21]. Vaccines may benefit from intranasal administration as well [22]. Intranasal vaccination can provide wider protection because of lymphoid tissues found in the nasal cavity [23]. Intranasal vaccination can bring about mucosal and systemic immunity [24]. Furthermore, the nasal route provides cross-protection against different types of viruses, such as influenza, which might help with the creation of “universal vaccinations” [25]. The nasal route has also been linked with possible vaccination for hepatitis B [26]. The anatomical position and physiological features (surface area, innervation, and blood supply) of the nose make it an external conduit to the lungs, and an appropriate route for the topical and systemic administration of drugs [27–30]. When systemic distribution is required, intranasal administration provides excellent bioavailability. The nasal route has some advantages over the oral route. These include rapid onset of drug action, fast attainment of therapeutic drug levels, and the fact that small drug doses can achieve required therapeutic effect [31]. Despite its advantages, administration of drugs via the nasal route could be plagued by mucociliary clearance, metabolic obstacles (peptides/proteins), and inadequate drug deposition to the targeted site [32]. As a result of the aforementioned, there has been minimal progress with new drug candidates for nasal route administration [15, 33].

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2 Challenges Associated with Absorption of Nasal Drug Delivery Systems There are a number of challenges that could potentially affect the use of the nasal route for systemic drug delivery. Some of these challenges include barriers against mucosal drug absorption and toxicity associated with intranasal administrations.

2.1 Barriers Against Mucosal Drug Absorption Absorption of the active pharmaceutical ingredient (API) of a drug would require that it moves across a number of barriers before reaching circulation. These barriers include mucus layer (surfactant), epithelial layer, basement membrane, and capillary endothelium [34], as shown in Fig. 3.1. Administered drugs usually get deposited on the first barrier: mucus layer [35]. There could be ciliary action that can remove the drug from the absorption site [36]. Thus, knowledge of the thickness of the mucus layer and clearance is important in the development of drug delivery systems [37–39]. The nasal tract has a thin mucus layer. This layer is highly permeable compared to other mucosal surfaces [40, 41]. Drug clearance from the nasal cavity, which is determined by nasal mucociliary clearance, is required for drug absorption via the nasal route. The second barrier is the epithelial layer. This layer is made up of pseudostratified columnar cells that are linked together by tight junctions [42]. A number of drugs are absorbed primarily through transcellular diffusion, which occurs when they pass through the epithelial cell membrane. A concentration gradient allows small hydrophobic molecules to partition across biological membranes. To cross the lipid bilayer, hydrophilic molecules usually require a selective transport system. Paracellular mechanism can aid the absorption of large and polar drugs, and the

Fig. 3.1  Barriers against mucosal drug absorption via the nasal route

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tight junctions usually act as barriers [43]. Absorption across the capillary endothelium is necessary for APIs that have to reach systemic circulation. Strategies to overcome these aforementioned barriers to improve absorption are thus relevant.

2.2 Toxicity Associated with Intranasal Applications When developing a pharmacological formulation for intranasal administration, safety is paramount. Usually, large molecules (peptides and proteins) would require absorption enhancers. Other excipients serve as mucoadhesives which can extend contact time with the nasal mucosa. Excipients can greatly reduce the safety of the final therapeutic product [44–46]. Therefore, the toxicological implications of a drug formulation must also be examined in vivo. Benzalkonium chloride, which is used in cosmetics and various nasal formulations, is a good illustration of the toxicological importance of preservatives [47]. The safety of benzalkonium chloride is debatable. Some research report that benzalkonium chloride has no harmful impact in vivo [47]. The use of benzalkonium chloride in medical products for nasal use is between 0.02 and 0.33 mg/mL; occasionally cilia toxicity in vitro and in vivo has been reported [47–49]. For CNS conditions such as epilepsy, psychosis, and glioma, the use of nanotechnology-­based drug delivery systems has to be done with caution [50, 51]. Oxymetazoline is a nasally administered sympathomimetic that is used as an anesthetic and in the treatment of epistaxis. It is noteworthy, however, that the unfavorable side effects of intranasal oxymetazoline are independent of the route of administration [52].

3 Drug Absorption Enhancers as Opportunity for Improving Nasal Drug Delivery There are a number of permeation enhancers that are known to improve nasal and pulmonary drug administration. Some of these include surfactants, tight junction modulators, protease inhibitors, cyclodextrins, and cationic polymers [36, 53, 54].

3.1 Surfactants Surfactants are amphiphilic molecules with lipophilic and hydrophilic residues [55]. Surfactants can improve absorption by disrupting the cell membrane through membrane protein leaching, opening tight junctions, and can prevent degradation of drugs by enzymes [56]. Surfactants that can be used as absorption enhancers include

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phospholipids, bile salts and their derivatives, fatty acids, non-ionic surfactants, and alkyl glycosides [57–59]. 3.1.1 Phospholipids Natural pulmonary surfactant could be a mixture of about 90% phospholipids and 10% proteins [60]. The primary function of this surfactant is to reduce surface tension [61]. Phospholipids have also been shown to improve absorption of drugs [60]. Dipalmitoylphosphatidylcholine (DPPC), for example, is a major component of lung surfactant [62]. DPPC has been used to improve absorption of parathyroid hormone from the lungs [63]. Phosphatidylcholines, sphingomyelin, phosphatidylinositol, phosphatidylglycerol, and neutral lipid have also been used as absorption enhancers [35, 64]. In a diabetic rat model, phospholipid hexadecanol tyloxapol (PHT) was tested as an absorption enhancer for recombinant human insulin in the lungs [65]. To further investigate its absorption potential, PHT was tested in vitro on Calu-3 ALI (air-liquid culture) cells [66, 67]. The recombinant human insulin was found to permeate the cell layer more efficiently in vitro [66, 67]. It can be postulated that PHT interacted with tight junctions and enhanced absorption via the paracellular route [35]. 3.1.2 Bile Salts and Their Derivatives Bile salts and their derivatives have the ability to enhance drug absorption. Glycodeoxycholate, salts of cholate, taurodeoxycholate, and taurocholate have been investigated as absorption enhancers for nasal and pulmonary drug administration [57, 68–70]. One of the most commonly used bile salts that has the ability to enhance bioavailability, particularly insulin, is sodium taurocholate [71, 72]. Despite the fact that bile salts and derivatives have shown promise as absorption enhancers, their safety is a major concern. The impact of inhaled bile salts as absorption enhancers on surfactant function has been studied in vitro and in vivo. Bile salts were found to impair surfactant function in vitro and caused lung irritation in vivo [70]. 3.1.3 Fatty Acids Polyunsaturated fatty acids (PUFA) have been studied as nasal and pulmonary drug absorption enhancers [73, 74]. PUFA has tight junction modulatory action and improves drug penetration across epithelial cell barriers [75, 76]. Although the specific mechanism is uncertain, research has shown that PUFA may affect membrane permeability by increasing membrane fluidity or act via Ca2+-dependent tight junction processes [77–79]. Absorption of fluorescein isothiocyanate was improved when arachidonic acid was added [80]. Often, medium-chain fatty acids like capric and lauric acid are used as absorption enhancers [81, 82].

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3.1.4 Non-ionic Surfactants Non-ionic surfactants are relatively non-toxic in nature [83]. Alkylglycosides (AGs) are non-ionic surfactants that include groups like glucose, sucrose, and maltose that are linked to alkyl chains of varying lengths [84]. The two most widely used AGs are N-lauryl-b-d-maltopyranoside and tetradecyl maltoside [85, 86]. At extremely low doses, these two agents have demonstrated significant nasal absorption augmentation characteristics [54]. Also, AGs could be used to improve insulin, calcitonin, and glucagon absorption via the nasal route [87]. The exact mechanism behind these in vivo absorption-boosting actions of tetradecyl maltoside is unknown. AGs may have direct effect on epithelial cells, most likely through the paracellular route [88]. Despite their ability to improve absorption, AGs are toxic to airway epithelial cells, most likely due to a membrane-damaging action [89]. Another non-ionic surfactant, poloxamer 188, has been extensively studied for its role in intranasal drug delivery [90]. Addition of poloxamer 188 to nano-cubic vehicles for intranasal administration has been shown to affect their flexibility [91]. An insulin formulation that contained sucrose cocoate (0.5%) was found to increase plasma insulin level [92]. The non-ionic surfactants cremophor EL and laurate SE have been evaluated as intranasal absorption enhancers in rats [56]. Cremophor EL was found to open Caco-2 cell tight junctions when used as an excipient in taxol infusions, ritonavir oral gelatin capsules, and oral solutions [93], hence, could be a good intranasal drug absorption enhancer. 3.1.5 Biosurfactants Biosurfactants are surface-active chemicals produced by living organisms like bacteria, fungus, and yeast [94]. Biosurfactants are non-toxic, ecologically friendly, and biodegradable in most cases [95]. Previously, biosurfactants were studied as medication absorption enhancers. Rhamnolipids are a kind of biosurfactant that have been studied extensively [96]. Rhamnolipids have been shown to affect epithelial permeability across Calu-3 and Caco-2 cells [97]. 3.1.6 Animal-Derived Surfactants There have been a number of studies that have used animal-derived surfactants to aid drug absorption. Gentamicin and polymyxin E were delivered into the lung of a newborn rabbit using poractant alfa, an animal-derived surfactant [98]. The bactericidal activities of gentamicin and polymycin E were enhanced in vivo [98]. At resting transpulmonary pressures, poractant alfa decreased surface tension at the air-liquid interface on alveolar surfaces during breathing and stabilized alveoli against collapse [99].

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3.2 Enzyme Inhibitors A significant number of enzymes are found in airway surfaces (fluids and mucus), which may destroy active constituents of drugs before absorption [100]. Aminopeptidases and proteases account for the majority of enzymes found in the nasal pathway and lungs [101, 102]. Drugs that are peptides, proteins, and nucleic acids are particularly susceptible to this metabolism. Thus, methods to protect drugs against breakdown by these enzymes within nasal cavities may be required. Bacitracin, leupeptin, soybean trypsin inhibitor, bestatin, and phosphoramidon are some of the protease inhibitors that have been explored as absorption enhancers in nasal or pulmonary medication delivery systems [103, 104]. Rats were given insulin with a protease inhibitor by intratracheal injection during a trial [105]. The hypoglycemic and hypocalcemic response of insulin from the lungs was examined. Within 90 minutes of administration of insulin, the plasma concentration of glucose reached a minimum baseline (24.0–66.7%) in the presence of the protease inhibitors [105]. Bacitracin (20 mM) has also been shown to be effective in increasing insulin pulmonary absorption [35]. Neutrophil-specific serine proteases, neutrophil elastase (NE), are released into the lung lumen during infection or inflammation [106]. It is hypothesized that excessive NE builds up in the pulmonary fluid of individuals with persistent lung infection, and this has the tendency to reduce inhaled drug absorption [107]. A rapid-acting NE inhibitor, EPI-HNE-4, has been used in patients with cystic fibrosis [108].

3.3 Cationic Polymers Cationic polymers usually have cationic substances integrated into their side chains [109]. Examples of cationic polymers include cationic gelatins, cationic pullulans, polyethylenamine, chitosan, and poly-L-arginine [110]. Negative-charged insulin in neutral fluids can interact with cationic polymers and improve insulin absorption [111]. A good contact can assist insulin to get to the cell surface; conversely, a bad interaction can prevent insulin from getting to the cell surface [112]. Polyethylenamine, a cationic polymer, has shown promise as a drug carrier in the nasal cavity [113]. Polyethylenamine is known to improve insulin absorption in the lungs of rats [114]. Another cationic polymer, spermined dextran (SD), has been investigated as an absorption enhancer for drugs intended for pulmonary administration [115]. SD was found to boost insulin absorption and FD-4 permeability through Calu-3 cells [115]. The mechanism of action of SD is unknown, however, it is thought that the molecule causes the opening of tight junctions, allowing water-­ soluble drugs to pass between cells [116]. Cationic polyelectrolytes such as chitosan can also enhance absorption [117]. Chitosan and its derivatives have been employed in the development of

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mucoadhesive polymers because of their biocompatibility, biodegradability, and low toxicity [118]. They are ideal as pharmaceutical excipients due to the aforementioned properties. Chitosan has mucoadhesive characteristics because it interacts electrostatically with mucin chains that are negatively charged [119]. This mucoadhesion increases API absorption by prolonging the period of residence of the drug. On the other hand, chitosan derivatives at physiological pH are poorly soluble in water and this restricts their use [120]. Due to the fact that chitosan has good mucoadhesive capabilities, various derivatives have been created to address solubility problems [121]. Chitosan oligomers, for example, have high water solubility than normal chitosan and have been studied for their ability to improve absorption via the nasal route or lungs [122]. A 0.5% (w/v) chitosan hexamer seemed to be more efficient than other chitosan oligomers at the same concentration in increasing interferon pulmonary absorption when compared to control. O-palmitoyl chitosan, which is made from chitosan and palmitoyl chloride, has been shown to have better mucoadhesive and absorption-boosting characteristics [123, 124]. In rats, sperminated pullulans have been found to improve insulin pulmonary absorption [125]. When a 0.1% (w/v) solution of sperminated pullulans was administered with insulin concurrently in  vivo, insulin absorption improved [125]. Pulmonary delivery of salmon calcitonin in rats was investigated using both positively and negatively charged gelatin microspheres [126]. The pharmacological impact of salmon calcitonin was considerably greater in the positively charged gelatin microspheres than the negatively charged ones [126]. Subsequently, salmon calcitonin was administered in positively charged gelatin microspheres, and this lead to a greater pharmacological effect.

3.4 Polyamines Polyamines have also been studied for their ability to improve drug absorption [127]. In mammalian cells, the polyamines spermine and spermidine are abundant [128]. Reports suggest that polyamines, notably spermine and spermidine, may significantly enhance absorption of insulin and other water-soluble agents without causing tissue membrane injury [129, 130]. The opening of epithelial tight junctions is thought to be responsible for the absorption-enhancing action of spermine [36]. In rats, sperminated dextrans enhanced insulin pulmonary absorption and FD-4 penetration across Calu-3 cell monolayers in vitro [131].

3.5 Tight Junction Modulators Tight connections decrease gaps between neighboring epithelial cells [132]. Drug absorption via the paracellular route can be improved by modulating tight junctions. Large macromolecules cannot be transported by paracellular transport, which is

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limited to substances with molecular radii of less than 11 nm [133]. Nonetheless, low-molecular-weight hydrophilic drugs have limited bioavailability [134]. Some peptides, including thyrotropin-releasing hormone, desmopressin, and octreotide, have been found to be absorbed in between tight junctions [135, 136]. Tight junction modulators that target tight junction proteins like claudin are 400 times more effective than other treatments in opening these tight junctions [137].

4 Conclusion Intranasal drug formulations may have local and systemic indications. Suitability of the nasal route for local and systemic drug delivery is based on its rich blood supply, large surface area, and avoidance of pre-systemic drug metabolism. Drugs could be administered via the nasal route for the management of rhinitis and pain, among others. Over the last few years, there has been an interest in intranasal drugs for Table 3.1  Absorption enhancers and their potential mechanisms of action Absorption enhancers Phospholipids

Example(s) Phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine

Bile salts and derivatives Fatty acids

Deoxycholate, glycocholate, glycodeoxycholate Capric acid

Non-ionic surfactants

Poloxamer 188, tetradecylmaltoside

Biosurfactants

Rhamnolipids

Animal-derived surfactants Enzyme inhibitors

Poractant alfa

Cationic polymers

Poly-L-arginine, Cationic pullulans, chitosan, polyethylenamine Spermine, sperminated dextran Claudin

Polyamines Tight junction modulators

Nafamostat mesilate, aprotinin, bacitracin

Possible mechanisms May interact with tight junctions and enhance absorption via the paracellular route Modulation of tight junctions Contraction of actin microfilaments and dilatation of tight junctions Direct effect on the epithelial layer, most likely through the paracellular route Enhance epithelial permeability across Caco-2 and Calu-3 monolayers Decrease surface tension at the air-liquid interface Prevent enzymatic breakdown within nasal cavity Alteration of tight junctions

References [53, 138, 139]

Open tight junctions Open tight junctions

[115, 128] [75]

[100, 138] [78, 79]

[84, 140]

[97]

[99] [103, 105]

[120, 136, 141]

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diabetes, cardiovascular, and CNS diseases. Despite its merits, administration of drugs via the nasal route could be affected by barriers against mucosal drug absorption, and inadequate drug deposition to the targeted site. To improve absorption via the nasal route, surfactants, protease inhibitors, cationic polymers, cyclodextrins, and tight junction modulators (as summarized in Table 3.1) can be used.

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101. Oliveira P, Fortuna A, Alves G, Falcao A. Drug-metabolizing enzymes and efflux transporters in nasal epithelium: influence on the bioavailability of intranasally administered drugs. Curr Drug Metab. 2016;17(7):628–47. 102. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol [Internet]. 2003 [cited 2021 Oct 21];56(6):588–99. Available from: /pmc/articles/PMC1884307/. 103. Morimoto K, Yamaguchi H, Iwakura Y, Miyazaki M, Nakatani E, Iwamoto T, et al. Effects of proteolytic enzyme inhibitors on the nasal absorption of vasopressin and an analogue. Pharm Res An Off J Am Assoc Pharm Sci [Internet]. 1991 [cited 2021 Oct 21];8(9):1175–9. Available from: https://pubmed.ncbi.nlm.nih.gov/1724082/. 104. Morimoto K, Yamaguchi H, Iwakura Y, Morisaka K, Ohashi Y, Nakai Y. Effects of viscous hyaluronate–sodium solutions on the nasal absorption of vasopressin and an analogue. Pharm Res An Off J Am Assoc Pharm Sci. 1991;8(4):471–4. 105. Yamamoto A, Umemori S, Muranishi S. Absorption enhancement of intrapulmonary administered insulin by various absorption enhancers and protease inhibitors in rats. J Pharm Pharmacol [Internet]. 1994 [cited 2021 Oct 21];46(1):14–8. Available from: https://pubmed. ncbi.nlm.nih.gov/7515417/. 106. Dittrich AS, Kühbandner I, Gehrig S, Rickert-Zacharias V, Twigg M, Wege S, et al. Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis. Eur Respir J [Internet]. 2018 [cited 2021 Oct 22];51(3). Available from: https://erj.ersjournals. com/content/51/3/1701910. 107. Demkow U, Van Overveld FJ. Role of elastases in the pathogenesis of chronic obstructive pulmonary disease: implications for treatment. Eur J Med Res [Internet]. 2010 Nov 4 [cited 2021 Oct 22];15(2):27–35. Available from: /pmc/articles/PMC4360323/. 108. Delacourt C, Hérigault S, Delclaux C, Poncin A, Levame M, Harf A, et al. Protection against acute lung injury by intravenous or intratracheal pretreatment with EPI-HNE-4, a new potent neutrophil elastase inhibitor. Am J Respir Cell Mol Biol [Internet]. 2002 [cited 2021 Oct 22];26(3):290–7. Available from: https://pubmed.ncbi.nlm.nih.gov/11867337/. 109. Pan Y, Xia Q, Xiao H.  Cationic polymers with tailored structures for rendering polysaccharide-­based materials antimicrobial: an overview. Polymers (Basel) [Internet]. 2019 Aug 1 [cited 2021 Oct 22];11(8):1283. Available from: https://www.mdpi. com/2073-­4360/11/8/1283/htm. 110. Farshbaf M, Davaran S, Zarebkohan A, Annabi N, Akbarzadeh A, Salehi R. Significant role of cationic polymers in drug delivery systems. Artif Cells, Nanomedicine Biotechnol [Internet]. 2018 [cited 2021 Oct 22];46(8):1872–91. Available from: https://www.tandfonline.com/doi/ abs/10.1080/21691401.2017.1395344. 111. M. A. Oral delivery of insulin: novel approaches. Recent Adv Nov Drug Carr Syst [Internet]. 2012 [cited 2021 Oct 22]. Available from: https://www.intechopen.com/chapters/40267. 112. Fargion S, Dongiovanni P, Guzzo A, Colombo S, Valenti L, Fracanzani AL. Iron and insulin resistance. Aliment Pharmacol Ther Suppl [Internet]. 2005 [cited 2021 Oct 22];22(2):61–3. Available from: /pmc/articles/PMC1204764/. 113. Kichler A, Chillon M, Leborgne C, Danos O, Frisch B.  Intranasal gene delivery with a polyethylenimine-­PEG conjugate. J Control Release. 2002;81(3):379–88. 114. Dong Z, Hamid KA, Gao Y, Lin Y, Katsumi H, Sakane T, et  al. Polyamidoamine dendrimers can improve the pulmonary absorption of insulin and calcitonin in rats. J Pharm Sci [Internet]. 2011 May 1 [cited 2021 Oct 22];100(5):1866–78. Available from: http://jpharmsci.org/article/S002235491532178X/fulltext. 115. Morimoto K, Fukushi N, Chono S, Seki T, Tabata Y.  Spermined dextran, a cationized polymer, as absorption enhancer for pulmonary application of peptide drugs. Pharmazie. 2008;63(3):180–4. 116. Seki T, Hamada A, Egawa Y, Yamaki T, Uchida M, Natsume H, et al. Evaluation of the effects of absorption enhancers on Caco-2 cell monolayers by using a pore permeation model involving two different sizes. Biol Pharm Bull. 2013;36(11):1862–6.

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133. Laksitorini M, Prasasty VD, Kiptoo PK, Siahaan TJ. Pathways and progress in improving drug delivery through the intestinal mucosa and blood-brain barriers. Ther Deliv [Internet]. 2014 [cited 2021 Oct 22];5(10):1143. Available from: /pmc/articles/PMC4445828/. 134. Craik DJ, Fairlie DP, Liras S, Price D. The future of peptide-based drugs. Chem Biol Drug Des [Internet]. 2013 [cited 2021 Oct 22];81(1):136–47. Available from: https://onlinelibrary. wiley.com/doi/full/10.1111/cbdd.12055. 135. Karsdal MA, Riis BJ, Mehta N, Stern W, Arbit E, Christiansen C, et al. Lessons learned from the clinical development of oral peptides. Br J Clin Pharmacol [Internet]. 2015 [cited 2021 Oct 22];79(5):720–32. Available from: /pmc/articles/PMC4415709/. 136. Thanou M, Verhoef JC, Verheijden JHM, Junginger HE. Intestinal absorption of octreotide using trimethyl chitosan chloride: studies in pigs. Pharm Res. 2001;18(6):823–8. 137. Günzel D, Yu ASL.  Claudins and the modulation of tight junction permeability. Physiol Rev [Internet]. 2013 [cited 2021 Oct 20];93(2):525–69. Available from: /pmc/articles/ PMC3768107/. 138. Morales JO, Peters JI, Williams RO. Surfactants: their critical role in enhancing drug delivery to the lungs. Ther Deliv. 2011;2:623–41. 139. Reno FE, Normand P, McInally K, Silo S, Stotland P, Triest M, et al. A novel nasal powder formulation of glucagon: toxicology studies in animal models. BMC Pharmacol Toxicol [Internet]. 2015;16(1):29. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26502880. 140. Li Y, Li J, Zhang X, Ding J, Mao S.  Non-ionic surfactants as novel intranasal absorption enhancers: in vitro and in vivo characterization. Drug Deliv [Internet]. 2016 [cited 2021 Oct 13];23(7):2272–9. Available from: https://www.tandfonline.com/doi/abs/10.3109/1071754 4.2014.971196. 141. Lemmer HJ, Hamman JH. Paracellular drug absorption enhancement through tight junction modulation. Expert Opin Drug Deliv [Internet]. 2013 [cited 2021 Oct 11];10(1):103–14. Available from: https://pubmed.ncbi.nlm.nih.gov/23163247/.

Chapter 4

Factors Affecting the Design of Nasal Drug Delivery System Jéssica Bassi da Silva, Maria Vitoria Gouveia Botan, and Marcos Luciano Bruschi

Abstract  Over the recent years, many strategies have improved the delivery of bioactive agents to the brain, improving the treatment of several pathologies. Nonetheless, the design of new formulations is highly dependent on the capacity of the drugs to permeate the blood-brain barrier (BBB) and reach a significant effect on the neurological disorders. Therefore, different approaches have been studied in order to facilitate the delivery of different drugs into the brain; for instance, intranasal administration has gained special interest. The nose-to-brain delivery provides a direct pathway of drug delivery to the brain without the need to permeate the BBB, potentially avoiding adverse effects that could occur when the drug is systemically absorbed. Although it may overcome BBB, there are alternative barriers that have to be circumvented for nose-to-brain route and different strategies have been massively studied. This chapter provides a comprehensive overview of factors related to the physiology of nasal cavity, the drug, and the formulation that can affect the development of formulations for nose-to-brain drug delivery. Keywords  Design of nasal drug delivery · Blood-brain barrier · Nasal cavity · Drug formulation · Nasal absorption · Nose-to-brain drug delivery

1 Introduction The drug administration by nasal route has been used for more than three decades aiming at the therapy of systemic and local diseases, such as perennial and allergic rhinitis, inflammations, pains, and also microbial infections [1, 2]. Nowadays, the

J. B. da Silva · M. V. G. Botan · M. L. Bruschi (*) Department of Pharmacy, State University of Maringa, Maringa, PR, Brazil e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_4

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use of this pathway for the delivery of challenging bioactive compounds is of great interest among the scientific community and in the pharmaceutical industry [3, 4]. During the last two decades, this administration route has been used for systemically acting bioactive agents that are difficult to deliver via routes other than parenteral and for nose-to-brain drug delivery. Moreover, the nasal administration of vaccines and other preparations for prevention against infections constitute an important and efficient strategy [5], which is being highlighted with the COVID-19 pandemic, for example. The nasal administration constitutes an important strategy for the rapid onset of drug action. Many characteristics of nasal region synergically enhance the permeation of bioactive agents administered by this route, such as the relatively large surface area (high number of microvilli), the presence of a porous endothelial membrane, and a highly vascularized epithelium [4]. Conventional relatively lipophilic low-molecular–weight bioactive agents can be absorbed with improved degree of efficiency across the different regions of nasal cavity, resulting in suitable availability at the action site. The nasal route enables to achieve similar blood level profiles for many bioactive agents compared to the intravenous administration [1]. In this context, the nasal drug delivery can enable many possibilities [2, 3]: • • • • •

Local delivery for the treatment of nasal allergy, congestion, and/or infection. Systemic delivery for crisis treatments when a rapid onset is necessary. Systemic delivery for long-term therapy (daily administration). Systemic delivery of peptides and proteins (when difficult to administrate). Vaccine delivery using antigens (whole cells, split cells, surface antigens, and others) and DNA. • Central nervous system access for reaching local receptors and/or to circumvent the blood-brain barrier. The function and physiology of the nasal cavity, the metabolism (e.g., the presence of cytochromes P-450, especially in the epithelium of the olfactory region), and the patient’s pathological state must be deeply understood during the development of nasal formulations. Physicochemical characteristics of drug (e.g., charge, molecular weight, and lipophilicity), anatomical and physiological variables (e.g., membrane transport, deposition, enzymatic degradation, and mucociliary clearance), and also formulations characteristics (e.g., pH, osmolarity, viscosity, concentration, volume and type of dosage form) constitute important factors that impact the design of nasal drug delivery system. Conventional relatively lipophilic low-molecular-weight bioactive molecules have been shown to be efficiently absorbed across the nasal cavity. However, large hydrophilic molecules (e.g., peptides and proteins) often display less efficient absorption by this route of administration. Therefore, compounds of hydrophilic nature, large molecular size, enzymatic degradation, and fast nasal mucociliary clearance (movement away from the absorption site in the nasal cavity) are challenges for the development of nasal drug delivery formulations [1]. Therefore, many physicochemical and technological strategies have been used for overcoming these drawbacks. The modification of the permeability of nasal

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membrane using absorption enhancers (e.g., bile salts, surfactants, cyclodextrins, phospholipids, and fatty acids), the use of micro and nanostructured systems, and mucoadhesive and/or environmentally responsive systems are some examples [1]. This chapter provides a comprehensive overview of the factors that can affect the development of formulations for nasal drug delivery. The factors related to the physiology of nasal cavity, the drug, and the formulation are discussed. In addition, the design, optimization, and challenges are also considered.

2 Factors Related to Nasal Anatomy and Physiology The development of new medicines for nasal application with the aim of delivery drugs is a challenge, given that the nasal cavity and the body have mechanisms able to hinder the absorption of biologically active agents administered at this place. Among the factors related to physiology that may impair the absorption there are mucociliary clearance, blood flow, enzymatic degradation, and the physical condition of the nasal mucosa [4, 6]. The ciliary mucosa present in the nasal cavity is responsible for mucociliary clearance. This process works for the protection and maintenance of the physiological environment, constituting the main defense mechanism against foreign bodies (i.e., bacteria, dust, and other types of allergens) that can settle in the nasal cavity; however, they can also remove the formulation administered in this location. When a preparation is administered through the nasal route, the mucociliary clearance eliminates around 50% of it in 15–30 min, fostering a shorter contact time of the drug with the mucosa, which considerably reduces its absorption [7, 8]. The nasal blood flow also plays a great role in drug absorption. The nasal mucosa is highly vascularized and the blood flow will depend on vasoconstriction and vasodilation of the blood vessels. Better blood circulation makes it easier for drugs to be absorbed and distributed through the system [9, 10]. Although intranasal administration has the advantage that the drugs do not undergo the first-pass effect, considering the molecules are absorbed by trigeminal pathways present in the nasal cavity or by the systemic route, directly reaching the bloodstream,  some drugs can still suffer due to the presence of metabolizing enzymes present in the nasal mucosa. For instance, proteins and peptides can suffer alteration by proteases and aminopeptidases. Meanwhile, the cytochrome P450 is responsible for the metabolization of some drugs, such as progesterone, cocaine, and decongestants [6, 11, 12]. Finally, changes in the physical conditions of the nasal cavity can also change drug absorption. Colds, allergies, and nasal infections can impair absorption because in these cases the mucociliary clearance is increased, which reduces the time the formulation remains in the mucosa. Inflammation or irritation of the mucous membrane causes swelling and also changes the conditions of drug absorption. Still related to nasal secretions, the circadian rhythm influences them. Some studies have revealed that the secretion and clearance rates of nasal cavity are reduced at night,

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thus altering the permeating of drugs. In addition, some diseases can change the pH of the mucosa and the viscosity of the mucus as well [4, 10–12].

3 Factors Related to the Biologically Active Agent The physicochemical characteristics related to the biologically active agent also influence the development of a formulation. The three main characteristics involved in the passage of bioactive agents through the nasal mucosa are molecular weight, lipophilicity, and degree of ionization. Regarding molecular weight, molecules up to 400 Da are still freely and easily transported; however, larger molecules are more difficult to absorb. Generally, drugs with molecular weight above 1000 Da exhibit low ability to penetrate the physiological barrier. A high molecular weight limits the paracellular passage of a drug through tight junctions. In these cases, the best alternative is to use special drug delivery systems, such as permeation enhancers, for example, cyclodextrins and surfactants, or nanosized systems, in order to improve the bioavailability of the drug [7, 8]. The partition coefficient of the biologically active agent is another factor that impacts drug absorption. Due to the lipophilic nature of the biological membranes, the more a molecule is lipophilic, the more easily it will pass through physiological barriers. However, a massive lipophilicity makes the drug difficult to dissolve in the aqueous environment of the nasal cavity. Thus, the drug must have an ideal lipophilic and hydrophilic balance to be absorbed correctly. Lipophilic molecules freely cross the mucosa, while hydrophilic ones need to use the paracellular route for this. An example of a lipophilic drug that has good nasal absorption and about 80% bioavailability is fentanyl, in addition to its rapid absorption, very similar to its intravenous administration. Other studies have shown that other hydrophobic drugs such as naloxone, buprenorphine, and testosterone are highly absorbed nasally in animals’ models [5, 6, 8, 13]. The pKa is also an important parameter that must be considered in the biologically active agent. In the case of weak electrolytes, the absorption is dependent on the degree of ionization and it is greater for non-ionized species. However, for polar drugs, the partition coefficient is the major factor that influences the permeability through the nasal mucosa, and there is a quantitative relationship between this parameter and the nasal absorption constant. In this context, several studies have shown that the drug concentration on cerebrospinal fluid (CSF) rises with the increase of the lipophilicity or of the partition coefficient of the drugs [4, 6]. The polymorphism of the biologically active agent is also a factor that should be also considered, as it affects the rate of dissolution and solubility of drugs, which affect their absorption. This is because polymorphs have different solubilization profiles in body fluids. Thus, drugs that exhibit many polymorphisms will have different absorption profiles due to varying rates of solubilization and absorption across biological membranes. It is suggested to study this characteristic of the active

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ingredient so that there are no surprises in the development of a formulation intended for nasal application [11, 13]. The drug’s solubility is also critical and, since nasal secretions are aqueous in nature, it is important that the drug has sufficient aqueous solubility for adequate dissolution. Furthermore, it not only limits the drug absorption itself, but it can also limit the ability to develop a product if the drug is not sufficiently soluble in the desirable vehicles. Considering that formulations intended for nasal administration are, in most cases, solutions and that it is not possible to administer high dose volumes, drugs with low solubility end up becoming an obstacle in the treatment. It is also important to consider the water activity of the nasal surface during the absorption of the bioactive agent, since this can result in the water-bioactive agent interaction that conduces to an improved solubility [6, 9, 11].

4 Factors Related to the Formulation The World Health Organization (WHO) has reported central nervous systems disorders, such as depression, migraine, Alzheimer’s, and Parkinson’s disease as the most debilitating in humans [14, 15]. Over the recent years, many strategies have improved the delivery of therapeutic agents to the brain [16]. However, the design of new formulations is highly dependent on the ability of the drugs to adequately permeate the BBB to reach a significant concentration on the brain; therefore, intranasal administration has gained special interest in this field [17]. As the main barriers avoid the entrance of external substances into the brain, there are the BBB and the blood-cerebrospinal fluid barrier (BCSF). When a biologically active compound is administered through oral or intravenous route, it firstly needs to cross the BBB to reach the brain [7]. The blood capillaries on the BBB are covered with endothelial cells tightly connected among themselves by tight junctions, which constitute a strong barrier to the passage of plenty of compounds and make many studied drugs to fail on treating brain disorders in preclinical studies [7]. The nose-to-brain delivery enables a direct pathway of drug delivery to the brain without the need to cross the BBB. Therefore, adverse events that usually occur when the bioactive agent is systemically absorbed can be avoided. Despite to overcome BBB, there are alternative barriers that have to be circumvented for nose-to-brain drug delivery systems. The critical factor in this field is the ability of the drug to achieve the upper and posterior nasal regions, such as the olfactory region [15, 18]. Furthermore, a tiny amount of a drug administered via intranasal route can reach the brain (ca. 0.1 to 1%) [19, 20], which is often related to the small volume that can be applied in the nasal cavity (ca. 25 to 200 μl) [7]. Thus, strategies and technologies to improve nose-to-brain drug delivery have been massively studied. Considering there are two pathways for this delivery, [1] indirect pathway: from respiratory mucosa evolving blood capillaries, systemic circulation, and BBB passage; and [2] the direct pathway: from trigeminal nerve and olfactory epithelium, there are different strategies aiding to enhance both (Fig. 4.1). Promising

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Fig. 4.1  Potential pathways for the nose-to-brain drug delivery (BBB blood-brain barrier)

properties for nose-to-brain formulations are often related to their ability to get into contact with the mucosal surfaces, can pass through the mucus barrier, and to improve the extracellular/paracellular diffusion or intracellular absorption. For example, the strategy of using protein inhibitors, surfactants, or even nanosized vehicles may improve the nose-to-brain delivery [15, 18]. Herein, we will discuss the most used strategies and their applications in this field.

4.1 Strategies and Technologies 4.1.1 Permeation Enhancers Permeation enhancers are compounds used to facilitate the permeation of drugs across biological membranes. Although lipophilic drugs are able to easily permeate nasal mucosa, some hydrophilic substances (i.e., peptides) frequently find it difficult to permeate. Therefore, permeation enhancers may contribute to the permeation of drugs that cannot effectively permeate biological surfaces by themselves [21]. Among the constituents of this class, the surfactant agents are frequently used due to their ability to disrupt the nasal barrier, which involve irritative effects to the mucosa in some cases [7]. Non-ionic surfactants such as Cremophor EL, poloxamer 188, and laurate sucrose esters have been used in nose-to-brain preparations [22, 23]. Horvát and collaborators successfully facilitate the permeation of a hydrophilic molecule of high molecular weight (dextran – 4.4 kDa) by using sodium hyaluronate and Cremophor RH40. Combining mucoadhesive polymer and a surfactant agent, the system prolonged the contact time of the preparation with the mucosa, and enhanced the drug permeation [22]. Moreover, cyclodextrins, lipids, and different polymers have also been reported enhancing the permeation of different drugs across nasal mucosa [7, 19]. For instance, chitosan presents the ability of opening tight junctions in the nasal epithelium. Rassu and collaborators mixed chitosan with β-cyclodextrin for the

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development of nose-to-brain microparticles objecting the delivery of deferoxamine mesylate [15, 24]. Besides the chitosan effect, β-cyclodextrin has demonstrated the ability to disrupt the lipid bilayer by creating inclusion complexes with the lipids in the mucosa membrane, increasing fluidity and enhancing permeation [19, 24]. Strategies improving the penetration are particularly interesting when the drug is absorbed via direct pathway. Besides the use of permeation enhancers, which favor extracellular/paracellular diffusion, cell-penetrating peptides may be added to the formulations in order to improve intracellular absorption. These peptides, also known as protein transduction domains, have been reported as small sequences of amino acids able to cross the biological membranes and help drug internalization [25]. In a nose-to-brain drug delivery system, Kamei and collaborators successfully improved the delivery of insulin administering it with penetratin, mainly through the olfactory bulb way. While L-penetratin leads to high insulin levels in the plasma, D-penetratin demonstrated to increase insulin delivery to the brain, with low systemic absorption [26]. Moreover, the delivery of a siRNA and dextran in rats were also demonstrated via nose-to-brain by polymeric micelles coated with a cell-­ penetrating peptide known as TAT.  This cell-penetrating peptide is derived from HIV-Tat and modified amphiphilic block copolymers of poly (ethylene glycol) and poly (ε-caprolactone), which have demonstrated high ability to form stable complexes with pDNA and siRNA [27]. Eutectic mixtures are known for their ability to enhance drug transportation across biological membranes [28]. For instance, Li and collaborators developed a mixture of borneol/menthol to enhance the permeation of cobrotoxin via olfactory epithelium. Interestingly, they demonstrated cobrotoxin could not permeate through this pathway out of the eutectic mixture [29]. Moreover, aiding migraine treatment, Khan and co-workers described the intranasal administration of zolmitriptan using a eutectic system, which achieves high levels of brain delivery in comparison to intranasal instillation of the drug powder and intravenous injection of the drug solution [28]. 4.1.2 Protein Inhibitors (Enzyme and Glycoprotein) Several enzymes may be found in the nasal cavity, being able to promote drug degradation. For instance, CYP450 isoforms, transferases, and carboxylesterases are reported to constitute the nasal environment and their inhibition has improved the stability of the compounds topically applied. Therefore, the use of these agents increases the amount of drugs available to be effectively delivered to the brain [7]. The inhibition of proteases, by α-aminoboronic acid derivatives, has avoided the degradation of peptides, albeit its real impact on nose-to-brain delivery is not completely known [30]. Dhamankar and Donavon have shown the enhancement of the permeation of melatonin via nasal administration, when it is formulated with fluvoxamine, a CYP450 inhibitor [31]. There are P-glycoproteins in the BBB, nasal mucosa, and olfactory epithelium that can act as membrane transporters. When a drug is the substrate of this

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transporter, it performs the efflux of the drug from the brain, losing nose-to-brain delivery property. In order to overcome this, Shingaki and collaborators used cyclosporine A and the inhibitor or the P-glycoproteins, improving the permeability of verapamil, a known substrate of this protein [32]. Graff and co-workers also demonstrated the P-glycoproteins effect on the transportation of diazepam, verapamil, and antipyrine drugs to the brain [33]. As P-glycoproteins inhibitors, the properties of pantoprazole and elacridar have been reported, Hada et  al. demonstrated this mixture enhancing imatinib mesylate delivery to the brain [34]. 4.1.3 Nanostructured Systems Nanostructured pharmaceutical platforms have been extensively utilized in the nose-to-brain delivery of drugs. Many studies have proposed nanoparticles covered with some additives, trying to overcome the limitations of this route of administration. Lectin has been used for coating nanoparticles for increasing the affinity with mucin and improving the residence time of the system in the nasal cavity [35]. Bioactive agents displaying polar characteristics and high molecular weight usually display a low nasal permeability, and the use of micro/nanoencapsulation has been shown to successfully increase the drug permeation with this type of profile [24]. Even considering their small diameter, for nose-to-brain delivery, the relatively large size (ca > 100 nm) of the nanoparticle preparations is often a disadvantage, since it could exceed the diameter of the filia olfactoria, fostering low transportation through the olfactory pathway [36]. If the nanoparticles are fully transported to the brain via olfactory epithelium or if the bioactive agents released from the nanostructures can diffuse into the brain is not totally comprehended [15]. However, many investigations have used nanosized materials to improve nose-to-brain delivery. For instance, Gao and colleagues used wheat germ agglutinin on the surface of poly(ethylene glycol)-poly (lactic acid) nanoparticles to enhance the delivery of a vasoactive intestinal peptide and fluorescent probe to the brain [35]. They reported the nanoparticles reached the brain’s levels 5- to seven-fold higher than the administration of the raw drug in solution [35]. Recently applied in the nose-to-brain field, the lipid particulates and liposome systems are also nanostructured preparations. For instance, Singh and co-workers demonstrated higher bioavailability of rizatriptan via intranasal than via intravenous route by using solid lipid nanocarriers [37]. Moreover, increased haloperidol brain/ blood levels have been observed when it was intranasally administered using lipid nanocarriers [38]. Liposomes ranging from 40 to 10,000 nm have been explored for nose-to-brain delivery, the majority of them prepared with phosphatidylcholine and cholesterol [39]. Besides solid, colloidal nanoparticles have also been recently studied to drive the drugs on this route. Polymeric micelles are colloidal structures composed of surfactant copolymers. With a diameter lower than 100 nm, they are able to cross BBB [40] and to carry drugs of different polarities, self-assembling in a hydrophobic core and a hydrophilic shell [41]. Pokharkar and collaborators explored the poloxamer

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407 micellar-based system for neurotherapeutics nose-to-brain delivery. When entrapped in micelles, the bioactive agent lurasidone could reach the brain tissue crossing through the BBB via trigeminal and olfactory and nerves [42]. 4.1.4 Mucoadhesive and Mucus-Penetrating Formulations The cilia in the nasal and respiratory regions act as a barrier to the entrance of external particles. They are motile and perform the movement of the mucus from the nose to the oropharynx, with a clearance of 10–15 min [43]. When a drug enters into the nasal cavity, they are trapped in the cilia and mucus secretions, tending to be eliminated after a few minutes [44]. Therefore, some approaches have been described to overcome this inconvenience, trying to increase the retention time of the preparation in the nasal mucosa. For instance, there are dosage forms containing inhibitors of the mucociliary clearance or composed of mucoadhesive or mucus-­ penetrating polymers. Although some classes of drugs (i.e., α-adrenergic agonists) have been explored regarding the reduction of the cilia beat frequency, in an attempt to delay the mucociliary clearance [45], mucoadhesive polymers are the most used in this way. When Horvát and colleagues reported dextran nose-to-brain delivery by a mucoadhesive and permeation enhancer formulation, they did not demonstrate by which pathway the delivery occurred. Although alone the excipients could not increase the delivery of dextran to the brain, together they massively enhanced the drug availability in the olfactory bulb and frontal cortex. The authors linked the observation to the mucoadhesive property of the sodium hyaluronate [22]. In another study, the mucoadhesive property of chitosan, covering microparticles, was responsible for increasing the residence time of a drug in the mucosal surface, increasing also its permeation [24]. Although most of the mucoadhesive polymers are not selective for the olfactory epithelium, and could be dispersed in other mucosal surfaces (e.g., olfactory mucosa, respiratory mucosa) [35], the use of mucoadhesive materials has been related to the inhibition of the mucociliary clearance. Since they increase the viscosity and adhesive profile of the formulations, they improve adhesiveness to the mucus and delay mucociliary clearance [15, 46, 47]. Moreover, mucoadhesive polymers can consolidate the adhesion of pharmaceutical formulations to the mucosa with chemical and physical interactions. Therefore, hydrogen-bonding, electrostatic and ion-dipole interactions between excipients and mucosa play great role on the increased period of time of the formulation on the surface of the mucosal membrane together with polymer chain interpenetration into the mucus gel [48]. In pursuit of this, the use of chitosan, poly (acrylic acid) derivatives, cellulose derivatives, and other mucoadhesive polymers facilitate nose-to-brain delivery when incorporated to new drug delivery systems [49]. Performing mucociliary inhibition, the use of thermoresponsive polymers, such as poloxamers, has also been described in the literature. They constitute liquid preparation during storage and application and become gel once in contact with nasal

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mucosa [50], increasing the local viscosity and, consequently, inhibiting mucociliary movements. Mucoadhesive dosage forms are typically designed using cationic and anionic polymers capable of interacting with the mucosal surfaces [49]. Meanwhile, mucus-­ penetrating dosage forms are able to effectively penetrate the mucus barrier and subsequently be accumulated in the epithelial surface [51]. Therefore, PEGylated dosage forms, that contain poly (ethylene glycol) (PEG) on the surface, have been described to optimize transmucosal drug delivery, besides they increase systemic circulation time of nanoparticles. They are often prepared through the use of block-­ copolymers containing PEG as one of the blocks [52], or through the use of agents as poloxamers [53] or functionalized phospholipids that generates PEGylated liposomes [54]. For instance, Porfiryeva and collaborators studied mucoadhesive (Eudragit®) and mucus-penetrating PEG nanoparticles for nose-to-brain haloperidol delivery and found that the non-mucoadhesive PEGylated nanoparticles demonstrated more pronounced in vivo effects than the mucoadhesive carriers [49]. 4.1.5 Other Strategies Vasoconstrictor drugs have been used as an additional tool to limit the systemic absorption of drugs applied in the nasal mucosa, enhancing their retention at the site of application. Dhuria and colleagues, for example, added 1% phenylephrine hydrochloride to systems containing two neuropeptides (hypocretin-1 or L-Tyr-D-Arg). By this, the drug concentration into the plasma was reduced by 65% and 56%, respectively, after 30 min of intranasal administration in comparison to the administration of the drug alone [55]. However, when ephedrine was co-administered with an angiotensin agonist, no reduction of systemic absorption was observed [16]. Besides chemical additives, physical methods also have been demonstrated to improve nose-to-brain drug delivery controlling the localization of the drug. The technology based on applying of a magnetic force to drive magnetic particles to a target site of the body (magnetophoresis) can be used for the development of nasal drug delivery systems [56]. Xi and collaborators, in nose-to-brain field, have increased the efficiency of the drugs crossing the olfactory region and being straightly transported to the brain by using ferromagnetic microspheres [20]. Another physical strategy was used by Chen and colleagues who used focused ultrasound sonication in rats to study its effect on the transport of brain-derived neurotrophic factor to the brain. The same method was previously used to facilitate the BBB permeation for drugs administered via intravenous pathway [57]. The comparison between intranasal drug administration with and without ultrasound application demonstrated improvement of the localization of the drug in a specific area of the brain [57].

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5 Design and Optimization The controlled drug delivery field has its origin in the 1960s to 1980s, and a high number of systems, carriers, and devices were developed to be administered by different routes and for different purposes [58]. The concept and technology of nasal drug delivery systems improved during the last three decades. Different strategies have been applied for the development of improved nasal medicines [59]. Biologically active agents of natural and synthetic origin have been investigated for nasal delivery in each more specialized formulation with the aim to control the delivery, reduce the adverse effects, increase the safety and patient compliance, and improve the therapeutic. A considerable knowhow and information have been obtained from scientific and technological studies. The development of new nasal delivery carriers and innovations has been used for system design and efficient clinical translation to nasal products [2]. Therefore, aiming for the efficient design of nasal delivery systems, innovative strategy approaches for specific bioactive agents are being investigated. They are composed of new nasal enhanced delivery technologies, design of carriers for avoiding the drug enzymatic degradation, modulation of system’s physicochemical properties, and also systems for nose-to-brain drug delivery [2, 19]. The investigation of potential advantages and limitations of nasal route is a fundamental step during the design of a system for nasal drug delivery. Among the main variables, the ones described below should be highlighted [4]: • The degradation of drug in the gastrointestinal tract (by acidic or enzymatic degradation) and/or the hepatic first pass can be avoided. • It is possible to acquire rapid absorption and onset of drug effect. • Higher bioavailability can be reached and using lower doses of drug. • It is a route of easy access and non-invasive, which can improve the patient adherence to the treatment. • It is possible the direct transport into systemic circulation and central nervous system. • Offers lower risk of overdose. In this context, we can also conclude that the design of nasal systems does not have any complex formulation requirement. However, some limitations can turn it into an endeavor. The volume of formulation that can be delivered by this route is limited to 25–200 μl, and molecules of high molecular weight cannot be delivered through the nasal route (mass cut off ~1 kDa). Irritation of mucosa and pathological conditions can affect the nasal region and also the drug delivery. The intrinsic defense mechanisms, such as mucociliary clearance, ciliary beating, and the enzymatic barrier, can affect the residence time of the system and the drug permeability. Therefore, for a biologically active agent to be successfully administered through the nasal cavity, these challenges should be overcome. A better understanding of permeation pathways is necessary for the formation scientist. An effective

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correlation must be established between the physicochemical properties of the bioactive and formulation with that of permeation rate. It is also necessary to perform extensive research for alternatives at the molecular level for the increase of the drug permeation through the nasal mucosa without compromising normal function [4]. This process will lead to the optimal design of formulation for nasal drug delivery and can cut down the experimental efforts involved as well. Therefore, for achieving safe and efficient intranasal drug medicines, some strategies to overcome nasal delivery barriers should be considered. In the design of a nasal formulation, three main cooperative points should be taken into consideration [2]: • The bioactive agent (chemical structure, chirality, molecular size, potency, lipophilicity, solubility, and ionization). • The physicochemical characteristics of the carrier (pH, components, enhancers, viscosity, charge and solubility) and dosage form (nano or microparticulate systems, solution, powder, emulsion, gel, etc.) • The administration device (single or multi-dose, simple or sophisticated). During the development of nasal products, it is fundamental to think about the quality of the process. The ability to identify and control the variables of the pharmaceutical formulation can ensure this objective and the utilization of the pharmaceutical Quality by Design (QbD) is fundamental. QbD is a systematic approach for development. It begins with predefined aims and emphasizes product and process understanding and process control, based on sound science and quality risk management [60]. QbD constitutes a culture shift from knowledge exchange to knowledge integration, and it can improve the safe assurance, effective drug supply to the consumer, and also ensures significant improvement of manufacturing quality performance [58]. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has the pharmaceutical development guideline Q8 (Q8r2 is the updated version) and it can enable the application of scientific approaches and quality risk management for development of nasal products and its manufacturing process [61]. Over the design of a nasal drug delivery system, it is necessary to achieve the aim of developing a quality formulation and its manufacturing process to consistently deliver the intended performance of the formulation. Thus, the use of tools that can provide information from pharmaceutical development studies constitutes a basis for quality risk management [58]. In this context, the use of experimental design constitutes an important strategy for formulation of nasal products. The more important statistical activity is the planning of the experiments where the data is obtained for analysis. The suitable way to plan an experiment leads to significant and trusted numbers from which it is possible to get conclusions [62]. The essence of good experimental design is to plan an experiment in such a way that it can provide exactly the kind of information that the formulation researcher is looking for. Therefore, the factors affecting the development must be considered in

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full and the more advantageous techniques should be used. In this context, the first step is to accomplish a trial and discard non-significant variables, so as not to waste time and resources with them in the laboratory. The use of Design of Experiment (DoE) is a good strategy to achieve this goal. DoE enables the determination of the influence of one or more variables on another variable of interest. For example, the composition and type of polymeric material can directly influence the mucoadhesive and rheological properties of a semi-solid nasal delivery system [2, 62]. Thus, during the planning of any nasal formulation development, the first thing that must be done is to decide what factors and responses are of interest. With the answers indicating which were the statistically significant and the most influential variables, it will be possible to achieve an optimized nasal drug delivery formulation.

6 Concluding Remarks Considering the many advantages, benefits, and interest in nasal drug delivery, it was observed an increased interest for the development of formulations and a high number of novel nasal products have reached the market. Most of these products comprise formulations designed for crisis treatments, sleep disorders, acute pain, panic attacks, nausea, heart attacks, and Parkinson’s disease. Furthermore, medicines for the treatment of long-term illnesses (i.e., diabetes, growth deficiency, osteoporosis, fertility treatment, and endometriosis) for nasal administration are also available in the market. The research and development of nasal delivery systems have gained higher evidence with the strategy of nose-to-brain drug delivery and important progress has been observed. It enables the bioactive agents to achieve a rapid and efficient concentration in the central nervous system, since this route is able to circumvent the blood-brain barrier. Besides the treatment of several neurological diseases, many formulations have also been applied to prevent and the treat infectious diseases. Therefore, considering the growth interest in this area and the development of novel nose-to-brain formulations, factors that affect their design must be considered in order to overcome physiological/drug conditions that could impair the availability of the carried drug into the brain.

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Chapter 5

Challenges in Targeting Nasal Passage and Nose-to-Brain Delivery via Nanoemulsions Shiv Bahadur and Kamla Pathak

Abstract  Nasal drug delivery has been considered an important approach for brain targeting since the last decade. The intranasal route has gained attention as a potential route of drug administration for the treatment of CNS disorders. The intranasal route can be more effective than other conventional routes for the treatment of CNS disorders. Presently, several strategies with novel approaches have been used to get nose-to-brain delivery of drugs. The management of neurological disorders is still challenging despite the enormous development of various strategies for drug delivery. The main limiting factor for drug therapeutics is the blood-brain barrier (BBB). Nanoemulsion has shown a promising formulation tactic among other nanocarrier-­ based drug delivery systems which can deliver the higher drug to the brain through the intranasal route compared to the conventional drug delivery systems. Nanoemulsions consist of emulsions and stabilized with surfactants and co-­ surfactants having small droplet size and large surface area. Hence, nanoemulsion can be an alternative drug delivery to oral to avoid some constraints such as enzymatic degradation, low solubility of drugs and low bioavailability. There are several nanoemulsion-based formulations that have been explored for brain targeting and results indicate the significant enhancement of bioavailability of various drugs for CNS diseases. Therefore, the present review highlights the several aspects of nanoemulsion as a potential carrier for brain targeting through intranasal administration. Keywords  Nanoemulsion · Nose-to-brain delivery · CNS disorder · Alzheimer’s disease · Parkinson’s disease

S. Bahadur Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India K. Pathak (*) Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Saifai, Etawah, Uttar Pradesh, India © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_5

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1 Introduction The brain is the most complex organ in the body which is protected by the skull and separated from the blood circulatory system [26]. There are two major types of cells in the brain such as neurons and glia. Neuron cells have the most important function in the brain. Hence any disruption or imbalance in neuronal cell function may cause neurological diseases in the brain [1]. The death of the neuron due to any region is most commonly known as neurodegenerative disease [55]. The functions of neuronal cells get disturbed due to neurodegenerative disease. Various symptoms are associated with these diseases such as losses in memory and thinking ability, difficulty in body movement and intelligence of individuals [90]. The neurodegenerative disease could be from different areas of the brain such as the cerebellum, brainstem and hippocampus. The most commonly known neurodegenerative disorders are Alzheimer’s and Parkinson’s diseases [81]. The nanotechnology-based drug deliveries have shown various potential advantages over other delivery systems [80]. Higher concentration of drugs may be reached to the predetermined site of action through targeted drug delivery. Unwanted adverse effects can be also minimized by targeted drug delivery system. BBB has been considered as a potential barrier for drug delivery to the brain. Therefore, several approaches have been applied for the drug targeting to the brain such as physiological approach (e.g., pseudonutrients, chimeric peptides, ligand binding proteins), pharmacological approach (e.g., chemical drug delivery, liposomes, nanoconjugates, nanoparticles) and invasive approach (e.g., intracerebral implants, BBB disruption) [46, 77]. These strategies play a very significant role not only in the treatment of CNS diseases but also in the diagnosis of various diseases. Nanotechnology can be seen as a potential problem solver for the therapy and diagnosis of several CNS diseases like epilepsy, AD, psychosis, migraine and PD [3, 53]. Nose-to-brain delivery system has been most widely explored since the last decades. Drugs can be directly delivered to the brain through the nasal cavity. Hence, nasal administration can be a choice of route for drug delivery to the brain in the treatment of several CNS disorders. Implications of novel drug delivery systems have added several advantages for the nose to brain targeting [53, 77]. Nanoemulsions (NEs) are nanosized which are most commonly used for the targeting of drugs to get the maximum concentration of drug at the desired site of action with minimum adverse effects [49]. Several research reports showed the various benefits of NEs which are most efficient drug delivery systems for nose-to-­ brain [13]. The globule size of NEs ranges from 100 to 200 nm [83]. NEs are thermodynamically stable and no gravitational separation occurs due to kinetic stability. NEs have small globule size due to reduced attractive force between the small-sized droplets [65]. The drug transport pathways from nose-to-brain delivery have been depicted in Fig. 5.1. The NEs are stable for the physical and chemical variations such as pH and temperature because less amount of surfactants are required for the formulation

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Fig. 5.1  Drug transport pathways from nose-to-brain delivery

development. Hence, NEs are most appropriate due to having several applications. Nanoemulsification is known to protect and increase the bioavailability of bioactive compounds and has been observed in several studies. Further, NEs have significant encapsulation efficiency for both lipophilic and hydrophilic compounds [15]. The present chapter highlights on NEs as a significant drug delivery system for treatment of neurodegenerative diseases through intranasal administration. Further several research reports have been discussed along with the related challenges and future prospects.

2 Composition of Nanoemulsion for Nasal Administration NEs are composed of two immiscible liquids in which one is lipophilic and second is aqueous with an emulsifier. In the aqueous phase, the lipophilic component is distributed. The core-shell structure is present in both the o/w and w/o nanoemulsions. In an o/w nanoemulsion system, the amphiphilic shell is made up of surface-­ active molecules, whereas the lipophilic core is made up of non-polar molecules. Monoacylglycerols, diacylglycerols, triacylglycerols, and free fatty acids make up the oleaginous phase of a nanoemulsion [13]. The oily phase may also be constituted of non-polar essential oils, lipid substitutes, mineral oils, waxes, oil-soluble vitamins, weighting agents, and various other lipophilic components. The physical properties of the oil phase components, such as density, refractive index, viscosity, interfacial tension, and phase behaviour, influence the formation, stability, and functional qualities of nanoemulsions [4]. However, because of their low cost, availability, and functionality, long-chain triacylglycerols are favoured for NE formation. A polar solvent and a cosolvent compose the aqueous phase of a NE. The polarity, rheology, phase behaviour, interfacial tension, and ionic strength of a nanoemulsion

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are all determined by this factor. Water is the most common polar solvent, while carbohydrates, protein, alcohol, and polyols are utilized as cosolvents. Ostwald ripening (increase in mean droplet size over time), flocculation, coalescence, and gravitational separation can cause the aqueous and oil phases to separate. A stabilizer agent can be added to nanoemulsion to prevent this. The stabilizers can form a monolayer, multilayer, or solid particulate nanoemulsion depending on how they are distributed on the particle. Emulsifiers, weighting agents, ripening retarders, and texture modifiers are just a few of the stabilizers that are used [15].

2.1 Surfactants Surfactants are one of the most significant components of NE, as they help to reduce surface tension, and prevent globule coalescence, and phase separation. Surfactants should have the ability to dissolve maximum amounts of drug(s). Further, they help in stabilization of NE formulations and small globule size. As a result, surfactants can impact medication penetration through the nasal mucosa, either by changing the fluidity or by disrupting the epithelial layers’ tight junction. Several studies report that the globule size decreases on increasing the surfactant concentration [29]. The lower the globules size, the higher will be permeation and ultimately higher drugs will be delivered to the brain. The type and concentration of surfactant have significant effects on the drug permeation on the nasal mucosa. The changes in the structural integrity of nasal mucosa by surfactants are critically questionable for the toxicity issues. Hence, as a result, surfactant concentrations are kept as low as feasible in order to maintain a balance between medication penetration and harmful effects [13, 43].

2.2 Co-surfactant Surfactants employed in nanoemulsion formulations are often single-chain surfactants that may not reduce desirable interfacial tension [89]. Hence, co-surfactants are substances that aid the surfactant in lowering surface tension [12]. By entering into the hard layer of surfactants, co-surfactants provide flexibility to the interfacial layer, breaking interfacial layers and imparting fluidity, which aids in the emulsification process as well as formulation stability. For the development of stable NE, combinations of surfactant and co-surfactant have a very significant role [2]. The ternary phase diagram is a widely used method for determining the working range and optimum concentrations of oil, surfactant, and co-surfactant. When the concentration of co-surfactant is increased, the globule size decreases, and the drug concentration rises. These are some most commonly used co-surfactants such as polyethylene glycol (PEG), Transcutol-P® and ethanol in NE formulation for intranasal drug delivery permeation [13, 89].

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2.3 Oil The solubility of novel chemical compounds is a crucial issue, as it impacts the pharmacokinetic and pharmacodynamic aspects of medications. Hence drugs are usually solubilized in the lipid phase of the NE and the solubility of drugs increases with increase in the lipophilicity of oils [73]. The solubilizing capacity of oils decreases in the order of vegetable oils > medium-chain triglycerides > medium-­ chain mono and diglycerides [86]. The solubilization capacity is determined not only by the oils, but also by a delicate balance with the oil’s emulsification zone as determined by phase diagram studies. Generally, the globule size of NE increases with increase in oil concentration in the formulation [17]. Higher globule size of NEs reduces drug permeation from nasal mucosa. Thus, optimal concentration of oils has to be selected to get sufficient solubility of drugs. Some oils have permeation-­ enhancing properties and they increase the drug permeation through the nasal mucosa. In the study, it was found the polar lipids are present in butter oil which have the key role in the permeation of quetiapine fumarate through nasal mucosa by transcellular and paracellular pathways [36].

3 Factors that Influence Nanoemulsion Transport from Nose to Brain NE offers better permeation through nasal mucosa compared to the other conventional drug delivery [16]. Surfactants and co-surfactants have a permeation-­ enhancing effect aside from that; there are some other characteristics of nanoemulsion which have significant role in the transport of drugs to the brain. NEs may be a viable option for nose-to-brain delivery because they meet all of the desirable NE characteristics [13].

3.1 Globule Size The globule size of nanoemulsion is one of the most important features for drug permeation from the nasal mucosa. The most common pathway for nose-to-brain drug transport is through either trigeminal or olfactory pathways. The typical diameter of an olfactory axon in different species is about 200 nm; however, it varies from 100 to 700 nm in humans [13, 67]. As a result, the size range of new formulations should be less than 200 nm to allow drug absorption across transcellular channels. Ahmad et  al. [8] reported that quercetin loaded mucoadhesive NE having 100 nm typical globule size was found to be higher rate and extent of drug absorption than the typical globule size of 700 nm reaching the olfactory bulb via the olfactory and trigeminal nerve. However, NEs having globule size more than 200  nm

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have also shown the efficient transport of drugs into the brain by intranasal administration. Further, the retention time on the nasal mucosa is also affected by droplet size, which is an important factor for drug delivery to the brain. The less retention time resutls the lowers the drug absorption. The larger droplet size can be cleared out from nasal mucosa more easily by mucosal clearance. NEs having average globule size >200 nm were cleared from the nasal mucosa after 4 h of intranasal administration, whereas formulations having globule size 80 and 200 nm showed more retention time 16 and 12 h respectively on nasal mucosa. As a result, the globule size of NE plays an important role in medication targeting the brain via intranasal delivery [7, 8, 13].

3.2 Zeta Potential The zeta potential of NE is linked with the stability of formulations. A zeta potential value of 30 mV indicates stability [93]. Several investigations have found that zeta potential is also essential in medication retention on nasal mucosa. The positively charged globules get firmly attached to the nasal mucosal layer which contains negatively charged mucin [84]. However, the majority of the reported NEs for nose-to-­ brain transport have a negative zeta potential. The mechanism of NE adherence on nasal mucosa in relation to electrical charge has not been considered enormously. Therefore, the effects of zeta potential on drug permeation across nasal mucosa need to be considered for the development of formulations for nose-to-brain drug delivery [13].

4 Methods of Preparation of Nanoemulsion The presence of multiple nanoscale droplets in the NEs increases the surface area. Therefore, a significant quantity of energy is required to generate additional surface area. Thus, NE creation is not self-sustaining and necessitates the application of energy [7, 8]. The amount of energy required to produce nanoemulsions (ΔG) is determined by the following equation:

G   A  T  S

(5.1)

where ΔA denotes a rise in the interfacial area, γ denotes surface tension, and TΔS denotes dispersion entropy. NEs can be made using either high or low energy processes (Fig. 5.1). The size of the globule is determined by the constituents, operating conditions, and technique of manufacture. Mechanical devices are used in high-­energy methods to disturb the oil phase, allowing it to interact with the water phase and create smaller oil droplets. The mechanical device’s enormous tension interrupts the oil phase. The

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Fig. 5.2  Different methods of preparation of nanoemulsion

NEs are created using low-energy methods by changing the temperature or composition of the oil-water system, with the energy input coming from the chemical potential of the ingredients. The low-energy methods involve minimal energy generation, and hence are appropriate methods for preparing NEs of heat-labile actives [20]. The methods of preparation of NE have been depicted in Fig. 5.2. The traditional nanoemulsification formulation entails the breakdown of bigger droplets or the inversion of solvents. New emulsification technologies are being developed at an increasing rate in order to broaden the range of material formulations and operating conditions while simultaneously lowering manufacturing costs. To manufacture nanoscale emulsions, a bottom-up strategy based on condensation has been developed. The technique is simple, quick, scalable, and energy-efficient, and it has the potential to be used in processed meals [49]. The vapour condensation method was used to create Pickering nanoemulsions. Pickering eliminates the issues associated with surfactant desorption and Ostwald ripening [54].

5 Intranasal Delivery of Nanoemulsion for CNS Disorders The several NE formulations have been developed for the nose-to-brain delivery. The NE formulations for intranasal administration of drugs are usually O/W emulsions. Several preclinical studies showed that CNS administration via the nasal mucosa outperforms intravenous administration. NE can be created in a variety of ways, including the use of oil, surfactants, co-surfactants, and water [13]. The major components of the NEs have significant role in drug penetration through nasal mucosa.

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Intranasal NE has been recognized as a potential drug delivery system for direct nose-to-brain delivery. NEs with enhanced retention time on nasal mucosa are able to drug targeting to brain bypassing BBB. Safety and toxicity of NE are one of the major issues that should be considered for long-term uses. Several intranasal NEs have been researched for the therapy of CNS illnesses such as migraine, Alzheimer’s disease, and Parkinson’s disease. Thus, several fundamental studies need to be considered in the creation of NE for administration from the nose to the brain. The several characteristics of nanoemulsion make them more appropriate for nose-to-­ brain transfer. Mucoadhesive agents reduce the mucociliary clearance in the nasal mucosa. Table  5.1 shows several examples of intranasal NEs and their potential effects for neuronal diseases. Nasal medication administration may be an option to oral therapies for brain targeting. NEs have several characteristics for nose-to-brain delivery for CND diseases. Several studies suggest that intranasal route NEs led to better results than intravenous administrations. However, clinical trials of NE formulations are still needed to show that they are appropriate for clinical use. Hence, there is utmost requirement of clinical study of NEs for intranasal drug delivery for CNS diseases [6, 13]. NEs in the field of nanomedicine, formulations are becoming increasingly significant. Their properties (high-surface nanodroplets) make them ideal for nose-to-­ brain administration. To impede nasal clearance, mucoadhesive polymers might be added to their formula. Because it is mucoadhesive and has penetration-enhancing characteristics on nasal mucosa, the introduction of chitosan as an extra excipient serves a dual purpose. Nasal administration of NEs is a promising technique for nose-to-brain medication delivery and CNS targeting for neurodisease treatment. Clinical trials of these formulations, however, are still needed to demonstrate their efficacy in clinical practice. To improve the performance of NEs, a lot of work needs to be done. The use of other excipients may be considered in the future [15]. The primary obstruction in drug delivery to the brain is the BBB that does not allow the drug to attain therapeutic levels in the brain leading to a significantly low CNS bioavailability. Consequently, several strategies are being approached for the local delivery of active therapeutics to the brain including many invasive methods that are risky and induce neurotoxic effects. While many of them cannot be considered appropriate for chronic treatments, there is a pressing need for methods that can bypass BBB. Of the several methods, one significant approach is nose-to-brain delivery [9]. For many systemic medications and vaccinations, nasal delivery has gained popularity as an alternative to injections and oral administration. The nasal mucosa, which is highly vascularized and immunogenic, may provide advantages in terms of speed of action, bioavailability, and patient compliance. Migraine, smoking cessation, acute pain alleviation, nocturnal enuresis, osteoporosis, and vitamin B12 deficiency are among the conditions for which the method is now used. Cancer therapy, epilepsy, psychosis, rheumatoid arthritis, neurological disease, and insulin-­ dependent diabetes are some of the other therapeutic areas where nasal administration has potential. Because of the high total blood flow, porous endothelium membrane, and vast surface area, intranasal delivery has been shown to carry

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Table 5.1  Recent report of nanoemulsion-based therapeutics for nose-to-brain delivery through in-vivo and in-vitro Drug Donepezil

Therapy for Alzheimer’s disease

Rivastigmine

Alzheimer’s disease

Resveratrol

Parkinson’s disease

Selegiline

Parkinson’s disease

Letrozole

Epilepsy

Study model(s) In vitro drug diffusion study Ex vivo drug permeation study Tolerability study through in vitro and in vivo models

Relevant therapeutic outcomes The permeation of donepezil was found to be significant through intranasal NE. The polymers can be used as an effective strategy to improve the bioadhesion and drug penetration through nasal mucosa, which enhances the bioavailability of donepezil In vitro drug release Rivastigmine-loaded NE showed significantly higher study drug concentration in the brain Ex vivo diffusion than the solution. The study optimized formulation was In-vivo pharmacokinetic and devoid of nasal ciliotoxicity biodistribution study in the rat Nasal ciliotoxicity studies in goat nasal mucosa In vitro drug release Diffusion controlled release of resveratrol was till 6 h with flux study of 2.86 mg/cm2 h through sheep Ex vivo diffusion study nasal mucosa. The drug level in In vivo drug the brain from intranasal biodistribution study resveratrol mucoadhesive NE in Wistar rat’s brain was higher than the resveratrol solution. Bioavailability was seven times higher through this approach In vitro drug release Selegiline NE showed 3.7-fold more penetration than the drug study solution. Haloperidol-induced Ex vivo diffusion Parkinson’s disease in animals study with selegiline intranasal NE Behavioural showed significant activities of Parkinson’s disease improvement in behavioural activities in comparison to in Wistar rats conventional drug delivery In vitro and ex vivo Intranasal administration of NE showed the prolonged drug drug release study. release profile as compared to The behavioural seizure, biochemical suspension. High concentration of drug was found in the brain and histopathological study were performed

Ref. [39]

[48]

[52]

[37, 38]

[78]

(continued)

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Table 5.1 (continued) Drug Amiloride

Therapy for Antiepileptic

Study model(s) In vitro drug release study Ex vivo diffusion study In vivo pharmacodynamic and pharmacokinetic study in Wistar rats In vitro mucoadhesion study Ex vivo drug permeation studies In vivo pharmacokinetic and biodistribution studies

Relevant therapeutic outcomes Ref. [69] Bioavailability and brain-­ targeting efficiency with efficacy of developed amiloride NE was enhanced through nasal administration

Zolmitriptan mucoadhesive NE showed higher permeability coefficients than the solution through the nasal mucosa. In vivo study of zolmitriptan mucoadhesive NE showed higher AUC0–8 and shorter Tmax in the brain in comparison to intravenous and nasal solution Ex vivo drug diffusion defined Rizatriptan Migraine In vitro drug controlled release with 86% in diffusion study 4 h. Brain targeting through Nasal irritation study on sheep nasal intranasal NE (AUC = 302.52 μg min/g) was mucosa. In vivo more than intranasal gel brain targeting (AUC = 115 μg min/g) and potential intravenous route (AUC = 109.63 μg min/g) The brain/blood ratios of Cyclosporine-A Neuroprotective In vitro drug cyclosporine-A by intranasal diffusion study In vivo brain uptake and intravenous were found to be 4.49 and 0.01, respectively. study Cyclosporine-A NE can be used for direct nose-to-brain delivery bypassing the BBB. The drug concentration through Kaempferol Neuroprotective Ex vivo diffusion intranasal NE was found to be and anti-tumour study 4–5 fold higher than solution. In vivo drug biodistribution study Ex vivo permeation and in vivo biodistribution studies showed in Wistar rats higher drug concentration in the brain with chitosan NE through intranasal administration compared to NE and kaempferol solution

Zolmitriptan

Migraine

[5]

[44]

[80]

[47]

(continued)

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Table 5.1 (continued) Drug Ziprasidone hydrochloride

Therapy for Antipsychotic

Quetiapine

Antipsychotic

Study model(s) Ex vivo diffusion study In vivo pharmacodynamic study in Wistar rats Nasal ciliotoxicity studies in goat nasal mucosa In vitro dissolution study In vivo drug distribution study in Wistar rats

Relevant therapeutic outcomes Ref. [14] Higher drug diffusion of ziprasidone NE than solution was found. Pharmacodynamic study revealed the superiority of mucoadhesive NE than NE in locomotor activity and paw test. Formulation was devoid of acute nasal ciliotoxicity Higher drug transport efficiency [45] (DTE%) via intranasal NE

Reproduced from Bahadur et al. [15] Abbreviations: GS Globule size; PDI Polydispersity Index; ZP Zeta potential; DC  diffusion coefficient

medications noninvasively from the nose to the brain in minutes. Intranasal medication administration can deliver a wide range of therapeutic substances (small molecules and macromolecules) to the CNS. When delivered nasally, several CNS-active drugs are more efficacious and provide therapeutic effects in lower dosages. It does not necessitate any therapeutic agent change, nor does it necessitate the medicine being paired with any carrier [6, 13].

5.1 Nanoemulsion in the Treatment of Alzheimer’s Disease Alzheimer’s disease (AD) has become the most common and progressive form of dementia; 60–80% reports of dementia are due to Alzheimer’s disease. As the ageing population is increasing the occurrence of this disease has also been rising for decades which ultimately results in the financial and emotional burden for society and family [91]. While ageing is one of the important correlations with the AD, in the last 30 years researchers are focusing on the role of genetics and other agents. They discovered many factors beyond keeping the age as the factor. Intranasal drug delivery has been accounted as one of the promising routes for drug delivery system for targeting brain disorders. The nasal mucosa is directly connected to the brain parenchyma and CSF.  Delivery through the brain via the intranasal route transported the drug through various mechanisms such as olfactory transport and regimental transport [33]. NEs have several significant applications in bioavailability and solubility enhancement, and could be delivered by various routes such as oral, parenteral, nasal and ocular [11]. NEs of two polyphenols namely resveratrol and curcumin have demonstrated enhanced drug concentration in the brain through

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intranasal administration [52, 85]. NEs have garnered great attention in dosage design due to favourable features such as optical clarity, increased surface area, ease of preparation, etc. There are two major problems in the conventional drug delivery such as low bioavailability and non-compliance. To overcome these disadvantages NEs have been used as a carrier for CNS drug delivery in AD, stroke, neurodegeneration, etc. [35]. Alzheimer’s disease (AD) is a neurological condition that causes psychological and behavioural problems. Several drugs like acetylcholinesterase inhibitors usually fail due to poor solubility and inability to cross BBB which ultimately leads to lower bioavailability. Novel drug delivery systems (NDDS) include design, production and characterization in the nanoscale delivery system. These NDDS include nanoemulsion, solid lipid nanoparticles, nanospheres, etc. which can be a potential method for delivering drugs to the brain via various routes especially intranasal route [89]. Ahmad et al. [7, 8] studied NE of coumarin-6 for intranasal administration. The particle size of about 100 nm results in longer retention of time and lower mucociliary clearance than the other conventional delivery. NE with more than 900 nm cannot be transported through the olfactory region. With the help of confocal microscopy the translocation of 100 nm in the nasal cavity was assured, that was followed by trigeminal nerve with depleted intensity [7, 8, 34].

5.2 Nanoemulsion in the Treatment of Parkinson’s Disease Parkinson’s disease (PD) has surpassed Alzheimer’s disease (AD) as the second most common chronic and progressive neurological disease. PD has a high impact both socially and economically on the suffering population [41]. Dopamine synthesis decreases as dopamine neurons in the ventral tegmental region and substantia nigra of the brain degenerate. There are a variety of clinical symptoms linked with Parkinson’s disease patients, including motor, non-motor, and mixed motor symptoms. Among them non-motor is the most significant are rigidity, tremor and bradykinesia [88]. Several researches have reported nanoformulations such as NEs for improvement of drug delivery for PD [71]. NEs have been very well recognized for extended drug delivery from nose to brain by olfactory pathway. Mustafa et al. in 2012 developed ropinirole loaded and studied different parameters. The developed formulations were evaluated for several physiochemical parameters including particle size and viscosity. Further, ex-vivo, in vitro, and in-vivo experiments were also conducted, and the concentration of ropinirole was found to be greater in the brain than conventional formulation [68]. Kumar et al. [37] developed selegiline-­loaded NEs by using principles of QbD. The behavioural investigation in rat model with intranasal injection of selegiline NE revealed a considerable improvement in selegiline concentration in the brain [37, 38].

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5.3 Nanoemulsion in the Treatment of Migraine Migraine is a headache illness defined by moderate to severe intensity of pain attacks, which results in many autonomic dysfunction disabilities such as nausea, vomiting, gastric stasis, effort, small bowel, photophobia, and so on. Because of the many symptoms associated with migraine disorder, such as vomiting and nausea, oral medication delivery is not appropriate. For migraine treatment, parenteral and nasal medication delivery are the best options. The innovative medication delivery is in the form of a spray of sumatriptan (OptiNoseTM), which is being tested in a phase II clinical trial for migraine therapy. The delivery has a quick commencement of action since it is deposited in the olfactory region and subsequently travels through the nose to the brain. A measured dose actuated pump is used to measure the dose. This device is inhaled from the nasal cavity by activating the nozzle, which releases the medicine into the olfactory area and then to the action site [82]. Migraine can be treated with a variety of natural and synthetic medications. Natural drugs such as ergot derivatives, alkaloids, and synthetic pharmaceuticals such as analgesics and anti-inflammatory drugs are examples of natural and synthetic drugs. These drugs have been demonstrated to be effective in the treatment of migraines. Abdou et al. [5] has studied the zolmitriptan-loaded intranasal nanoemulsions. In vivo pharmacokinetic and biodistribution experiments revealed that the solution had higher permeability coefficients than the nasal mucosa.

5.4 Nanoemulsion in the Treatment of Psychosis Our study group provided one of the earliest examples in the literature of the use of NEs for intranasal administration, in which NEs were used to convey risperidone. This medication is available in oral formulations (tablets and oral solutions), although it has a low bioavailability due to first-pass hepatic metabolism. Risperidone NEs were synthesized with Capmul MCM as the oily phase and Tween 80 as the surfactant. In addition, mucoadhesive NE was created by combining NEs with chitosan [57]. In vivo investigations in Swiss albino rats using technetium (99mTc) labelled formulations revealed faster and bigger drug transport into the CNS following intranasal delivery of the mucoadhesive NEs compared to plain NE delivered intranasally, intravenously, and as a solution [50]. Analogous results were obtained for NEs loaded with olanzapine. The positive results were attributed to the increased nasal retention duration caused by the presence of chitosan [50, 51, 56, 57]. Another study created buffered mucoadhesive NEs filled with ziprasidone hydrochloride. Mucoadhesive NE had a 1.79 times higher diffusion coefficient than ordinary NE. The pharmacodynamic trials, which were free of acute nasal toxicity, produced remarkable results in the locomotor activity test and the paw test. Thus, a safe and effective NE for intranasal delivery of ziprasidone was created, despite the fact that pharmacokinetic and biodistribution studies would have provided proof of evidence in this situation. Intranasal NE of the drug is justifiable as it is commercially

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available as oral capsule formulation (Geodon® and Zeldox®) that exhibits low bioavailability due extensive first-pass metabolism of drug [14]. Quetiapine fumarate is an atypical antipsychotic medication that is taken orally as tablets. Due to weak water solubility and a significant first-pass effect, quetiapine oral treatment has a low bioavailability (5–15%) [45]. Hence, different formulations are preferable. Following nasal delivery, O/w NEs were created to target the medication directly into the brain. In an in vivo tissue distribution study in Wistar rats, post-intranasal delivery of quetiapine fumarate-loaded NE resulted in a lower T max than intravenous administration. Because of its higher drug transport efficiency, NE appears to be a potential method for brain-targeted delivery of quetiapine fumarate [75].

5.5 Nanoemulsion in the Treatment of Epilepsy Presently most of the antiepileptic drugs prescribed are orally in different dosage forms such as tablet, solution, suspension, capsule and controlled release tablet and capsule. For the rapid action, there is only one choice for the parenteral routes. While several routes have been explored such as buccal, rectal and sublingual but they have various limitations for the fast action. One report suggests that one-third of epileptic patients have resistant to the presently marketed formulations of antiepileptic drugs [22]. This resistance may be due to not achieving desired drug concentration in the brain. There may be several regions for not reaching drug to the brain such as hepatic drug metabolism, high plasma protein binding, efflux transporters in GIT and BBB, drug-drug interaction, etc. These factors may be responsible for the restricting effective transport of antiepileptic drugs and lower concentration of therapeutic agents in the brain [72, 92]. The patients having drug resistance are treated by intracerebral or intracerebro-ventricular delivery system for the management of epilepsy [31]. Various studies have been performed with modern technologies for the treatment of epilepsy such as nanoformulations through transdermal and intranasal routes [27, 32]. Some research reports showed that intranasal NEs can be an alternative drug delivery system for antiepileptic drugs. The nanoemulsion of phenytoin was prepared and evaluated for biopharmaceutical parameters such as nasal toxicity and drug release profile. The developed formulation showed that NEs were stable having globule size of less than 20 nm. Release study showed 100% drug was released within 48 h. The nasal toxicity study was performed with optimized formulation and found to have safe. The formulations can be sterilized by filtration method through 0.22 μm [54]. Further, preclinical studies are required to validate safety and efficacy of nose-to-brain delivery. Jain et al. have developed amiloride-loaded NEs for nose-to-brain delivery. The globule size of NEs was found to be in the range of 9.41 ± 1.23 to 10.71 ± 1.09 nm. The toxicity study of mucoadhesive NE was performed in sheep nasal mucosa and found to be safe [70]. Hence, intranasal NEs can be an alternative drug delivery system for the management of epilepsy.

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6 Recent Patents on Nose-to-Brain Delivery for CNS Disorders Nanocarrier-based drug delivery system has been most widely explored for the treatment of several neurological diseases. Various patents have been reported on nanocarriers such as nanoparticles, nanoemulsion, solid lipid nanoparticles, liposomes, and multiple dosage forms (Table  5.2) [74]. Improvement in therapeutic interventions for the treatment of individuals with CNS disease should be emphasized by clinicians and pharmaceutical industries. Therefore, significant clinical data should be collected and investigated for the development of products [75, 79].

7 Current Challenges and Future Prospective for Intranasal Nanoemulsion Intranasal NE may be an effective strategy for the drug targeting to the brain. Nasal mucociliary clearance has been considered as one of the major limiting factors but it can be resolved by developing mucoadhesive formulations of NEs. There are some other challenges which can create obstacles for the successful product development. Generally, in labs nanoemulsions are prepared by addition of excipients along with sonication and these methods cannot be used for the large-scale production of nanoemulsions. But fortunately, some new techniques have been explored for the preparation of nanoemulsion formulation at industrial scale like high-­ amplitude ultrasound, high-pressure homogenization, high shear mixing, etc. Marketed NE formulations (Limethasone®, Vitalipid®, Diprivan® and Ropion®) are evident of these methods but still not explored for nose-to-brain targeting [76]. Apart from issues of preparations of formulations, nasal irritation and chances of nasal mucosa damage which can be appeared by repeated administration of NEs have been considered as major limitation for nasal drug delivery. Several studies showed that surfactants have efficient permeation properties but they also can damage the structural integrity of nasal mucosa [62]. The repetitive administration of formulation on nasal mucosa may cause irritation and bleed [87]. Several researches have been reported on the NEs for the nose-to-brain delivery and they show significant results. Hence NEs can be the most suitable drug delivery systems for the treatment of CNS disease through intranasal administration [40]. In various researches, toxicity study has been performed either as short-term duration (2–4  h) or single dose study in nasal mucosa for animals. Although, no toxicity was found in several short-term studies by intranasal NEs [58]. While for treatment of CNS diseases like as epilepsy, PD, AD, therapy is required for long time [23]. Hence, long-term toxicity studies are required in animals on intranasal NE. Surfactant concentration should be selected minimum which can be another approach for the reduction of toxicity. There are so many surfactant and co-surfactants which are not approved by USFDA but most commonly being used in the

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Table 5.2 Patents for various nanotechnology-based dosage forms for treatment of Alzheimer’s disease

Patent no. US 2013 8349293B2 US 2014 8877207B2

Active ingredient/ composition Metallic ions

Centre point/main outcome Metal NPs for diagnosing AD using magnetic resonance imaging (MRI) Cerium oxide Polymeric NPs of cerium oxide with antibody specific for amyloid β embedded for better targeting in AD US 2009 Nutritional Food supplement, nutritional mixture for 0252796 A1 supplement improving the status of AD disease manufactured using microfluidizers US 2011 Multiple Nanoemulsion can improve the 0045050A1 therapeutic bioavailability for vast therapeutic agent segment EP 2550020 Metal ions and Reverse micelle system for improved B1 lipids targeting using metal ions and various lipids US 2015 Model drug Liposomes with specific lipids that can 0017235A1 reduce amyloid b plaques in AD WO 2009 Model drug Liposomes with specific lipids content 150686A1 that high binding capacity to reduce amyloid b plaques in AD WO 2014 Model drug Peptide conjugated liposomes for 076709A1 targeting in AD CA 02203513 Selegiline Selegiline liposome for better targeting by parenteral route and improved permeation in case of transdermal delivery for treatment of AD US 2015 Curcuminoid The formulation makes the curcuminoid 9192644B2 SLN stable at basic pH and improves the concentration in AD patient brain US 2006 Cholinesterase Delivery of cholinesterase inhibitors via 0018839A1 inhibitors various dosage forms through nasal and ophthalmic route to improve the targeting in AD and ocular disorders US 2014 Pharmaceutical CNS agent complexed with transport 0100282A1 CNS agent moiety for effective transport through intranasal route in neurological disease US 2015 NSAIDS Intranasal NSAIDS for improved 0086616A1 neuro-protection in case of AD using various nano-dosage forms EP 2332570 Glatiramer Proteosomes and nanoemulsion for GA A1 acetate (GA) through nasal route and parenteral route to improve neuroinflammation in AD 267/ Glatiramer Proteosomes and nanoemulsion for GA KOLNP/2007 acetate (GA) through nasal route and parenteral route to improve neuroinflammation in AD Reproduced from Pathak et al. [75]

Publication year/granted 2013

Ref. [19]

2014

[18]

2009

[64]

2011

[21]

2015

[63]

2015

[60]

2009

[61]

2014

[10]

2001

[66]

2015

[24]

2006

[30]

2014

[94]

2015

[42]

2011

[25]

2007

[59]

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development of NE formulations [13]. Thus, for the development of intranasal NE, we need to select approved surfactant and co-surfactants along with considering their concentration limits. These approaches can be very helpful in the commercialization of intranasal NE for nose-to-brain delivery [37, 38]. Several products have been approved by FDA for various pathologies through intranasal administration which has been represented in Table 5.3 [28].

Table 5.3  FDA-approved intranasal products for various pathologies [28] Proprietary name DDAVP

Active ingredient Desmopressin acetate

Tyzine

Tetrahydrozoline hydrochloride

Beconase Synarel

Beclomethasone dipropionate monohydrate Nafarelin acetate

Nicotrol

Nicotine

Astelin

Azelastine hydrochloride

Imitrex

Sumatriptan

Nasonex

Mometasonefuroate

Migranal

Dihydroergotamine mesylate

Cromolyn sodium

Cromolyn sodium

Butorphanoltartrate

Butorphanol tartrate

Flunisolide

Flunisolide

Ipratropiumbromide Ipratropium bromide Nascobal

Cyanocobalamin

Omnaris

Ciclesonide

Dosage form Applicant holder Solution Ferring Pharmaceuticals Inc Solution Fougera Pharmaceuticals Inc Metered GlaxoSmithKline spray Metered Pfizer Inc spray Metered Pfizer Inc spray Metered Mylan Specialty spray LP Metered GlaxoSmithKline spray Metered Merck Sharp and spray Dohme Corp Metered Bausch Health US spray LLC Metered Bausch and Lomb spray Pharmaceuticals Inc Metered Mylan spray Pharmaceuticals Inc Metered Bausch and Lomb spray Pharmaceuticals Inc Metered Bausch and Lomb spray Inc Metered Endo spray Pharmaceuticals Inc Metered CovisPharmaBv spray

Approval Year 1982

1982

1987 1990 1996 1996 1997 1997 1997 2001

2001

2002

2003 2005

2006 (continued)

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Table 5.3 (continued) Proprietary name Patanase

Calcitoninsalmon Sprix Lazanda Qnasl

Zomig Nasacort allergy24 hour Natesto

Flonase allergy Relief Rhinocort allergy Narcan Onzetraxsail Kovanaze Xhance Tosymra Spravato

Nayzilam Baqsimi Valtoco Gimoti

Dosage form Applicant holder Metered Novartis spray Pharmaceuticals Corp Calcitonin salmon Metered ApotexInc spray Ketorolac tromethamine Metered Zyla Life Sciences spray US Inc Fentanyl citrate Metered BtcpPharma LLC spray Beclomethasonedipropionate Metered Teva Branded monohydrate aerosol Pharmaceutical Products R and D Inc Zolmitriptan Metered AstraZeneca spray Pharmaceuticals LP Triamcinolone acetonide Metered Sanofi Aventis US spray LLC Testosterone Metered Acerus gel Pharmaceuticals Corp Fluticasone propionate Metered GlaxoSmithKline spray Budesonide Metered AstraZeneca spray Pharmaceuticals Naloxone hydrochloride Metered Adapt Pharma spray Operations Ltd Sumatriptan succinate Powder Currax spray Pharmaceuticals Oxymetazoline hydrochloride; Metered St Renatus LLC tetracaine hydrochloride spray Fluticasone propionate Metered Optinose US Inc spray Sumatriptan Spray Upsher Smith Laboratories LLC Esketamine hydrochloride Spray Janssen Pharmaceuticals Inc Midazolam Spray UCB Inc Glucagon Powder Eli Lilly and Co Diazepam Metered NeurelisInc spray Metoclopramide Metered Evoke PharmaInc hydrochloride spray Active ingredient Olopatadine hydrochloride

Approval Year 2008

2008 2010 2011 2012

2013 2013 2014

2014 2015 2015 2016 2016 2017 2019 2019

2019 2019 2020 2020

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8 Conclusion and Future Prospective The present chapter covers the various aspects of intranasal drug delivery of nanoemulsion in the management of several neurological disorders. Due to the limited entry of therapeutic agents into the brain, drug delivery to the brain has become a challenging task. NEs are composed of two immiscible liquids with surfactantSurfactants and co-surfactants having low globule size with thermodynamic stability. NEs have unique feature to increase the solubility and stability of drugs along with their good interaction with the endothelial membrane of the brain. NEs have been found to be a favourable delivery system for the brain targeting of drugs through intranasal administration. While clinical data with robust studies are required for the validation of in-vivo data. Several in-vivo studies indicate that NEs may be an encouraging approach for drug delivery for brain targeting by intranasal administration for the treatment of CNS diseases. Hence, intranasal drug delivery could be an alternative route of drug administration for the management of neuronal diseases. Several research reports showed that better drug concentration in the brain was found through intranasal NEs. The intranasal Nanoemulsions can be used as alternative drug delivery system for the management of neuronal diseases. Hence, further extensive researches are required for the confirmation of safety, efficacy and toxicity of NEs formulations through clinical studies for commercialization. NEs could be most suitable for the treatment of neurological disease through intranasal administration. They have ability to cross the BBB and desired drug concentration may be achieved in the brain. Various studies showed significant indications that nose-to-brain products are likely to emerge commercially included for several neurodegenerative diseases.

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Chapter 6

Potential Targeting Sites to the Brain Through Nasal Passage Mershen Govender, Sunaina Indermun, Pradeep Kumar, and Yahya E. Choonara

Abstract  Delivery to the central nervous system (CNS) has posed a major challenge in both therapeutics and diagnostics. Although nose-to-brain delivery has gained momentum as a result of the advantages it provides, it is not without its shortcomings. Anatomical positions, delivery formulation constituents and cellular targeting have been determined to be important considerations in optimal nasal drug delivery. This chapter seeks to highlight the numerous anatomical challenges that face nose-brain drug delivery platforms and will discuss the pathways that have been effectively utilized for targeted CNS delivery through the nasal cavity. Keywords  Intranasal · Nose-to-Brain Delivery · Central Nervous System Targeting · Blood Brain Barrier · Nasal Pathways

1 Introduction Disorders such as epilepsy, multiple sclerosis, cerebrovascular diseases, Parkinson’s disease, Alzheimer’s disease and brain tumours have been noted to affect the peripheral and central nervous system (CNS) in multiple ways [1]. Although many treatments and therapies exist for CNS disorders, some are complex and sometimes ineffective in eliciting an appropriate pharmacological response. Effective interventions such as oral, topical, and intravenous treatments, deep brain stimulation, surgeries and rehabilitation therapies each come with their own disadvantages and limitations. Furthermore, invasive strategies such as catheter infusions; M. Govender · S. Indermun · P. Kumar · Y. E. Choonara (*) Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_6

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mini-pump-­assisted intracranial delivery; electromagnetic force-field techniques; precise ultrasound methods; and intracerebroventricular or intraparenchymal injections are acute treatment options which pose many risks and have the potential to induce neurotoxic effects at the site of delivery [2]. Even though there are numerous advances in the drug delivery and neuroscience fields, drug delivery to the CNS is still eluded by the microvascular blood-brain barrier (BBB), thus rendering a cure elusive. The BBB, which is critical in the maintenance of CNS homeostasis, is formed by the tight junctions that join specialized CNS endothelial cells [3–5]. These cells are positioned at the blood-nervous tissues interface as well as between the blood and the cerebrospinal fluid, where the blood-­ cerebrospinal fluid barrier (BCSFB) is formed [6–8] (Fig. 6.1). BCSFB cells are composed of choroid plexus epithelium cells, as well as the arachnoid epithelium, which line the cerebral ventricles and the brain vasculature in the subarachnoid space, respectively [8]. In comparison to the BCSFB, the BBB has a larger surface area as well as a faster blood flow rate, and as a result is considered to be the primary obstacle to brain permeability [7]. A continuous, non-fenestrated basal lamina is conferred by the endothelial cells in addition to interacting with several perivascular elements such as pericytes, astrocytes, and perivascular macrophages which contribute to the barrier [6]. The tight junctions that are present in the paracellular space between adjacent cells are imperative in determining the BBB’s properties [5]. Hydrophilic molecules and drugs have limited permeability due to the junctions consisting of several specific transmembrane proteins such as junction adhesion molecules, claudin and occludin [9]. Low pinocytic activity, an enzymatic barrier as well as several drug efflux mechanisms, including transmembrane proteins expressed by the specialized CNS endothelial cells and other multidrug resistance proteins, further support the physical barrier between the CNS and the blood and is responsible for the removal of exogenous substances such as micro-organisms and toxic compounds from the brain circulation [10]. These specialized CNS endothelial cells also function to prevent fluctuations in the bloodstream, thereby ensuring that synaptic transmission is maintained [6]. Either circumventing the BBB or optimizing systemic drug delivery has therefore been the primary focus of CNS drug delivery. Permeation of approximately 100% of macromolecules and 98% of low molecular weight drugs have been estimated to be hindered by the BBB even though low molecular weight drugs not exceeding 400  Da, along with high lipophilicity, are typically considered as favourable permeation factors [11]. Molecular physicochemical properties such as the molecular mass, lipid solubility and charge further govern transportation across the BBB. Since the cell membrane is unionized and consists of anionic phospholipids, which confer a negative charge, basic molecules are favoured over acidic molecules. The preferred drug molecule should possess an octanol: water partition coefficient (log p) value near 2 (1.5–2.7) and have a molecular weight of less than 400–500 Da. Notably, for each polar functional group or pair of hydrogen bonds that the drug molecule possesses, the permeability across the BBB is reduced by one log unit

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Fig. 6.1  The three main barriers in the central nervous system (CNS), namely the meningeal or arachnoid barrier, the choroid plexus barrier and the blood-brain barrier (BBB). The arachnoid and choroid plexus barriers separate the blood from the cerebrospinal fluid (CSF), and the BBB separates the blood from the interstitial fluid (ISF). At each site, the barrier is mainly formed by tight junctions that seal off the paracellular space. The blood-brain barrier possesses an intricate architecture of basement membrane, mural and glial cells that work in synergy to maintain the barrier’s integrity and regulate its permeability in response to neuronal needs. (Reproduced from Razzak et al. [8] © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/))

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with the cumulative number of hydrogen bonds for appreciable permeability being less than 8–10 [12]. Consequently, nose-to-brain delivery has been explored as a feasible drug delivery route to the brain utilizing the nasal passages and tissue. This delivery pathway allows for simplified administration, a fast onset of action, patient compliance and a reduced systemic exposure of the delivered agent [4, 13, 14].

2 Drug Delivery Pathways Understanding the morphological and structural properties of the potential targeting sites in the nasal cavity is pertinent in the engineering of nose-to-brain delivery systems. The nasal cavity, as the starting of the respiratory system, is vital in olfaction processes, dust and particulate filtration, as well as the regulation of the temperature and humidity of inhaled air [4].

2.1 The Nasal Cavity The nasal cavity is longitudinally bisected by the nasal septum and extends from the nostrils to the nasopharynx [13, 15] (Fig. 6.2). It has a length of 12–14 cm [13, 16, 17] and is 5  cm in height [16] with a reported surface area of between 150 and 200 cm2 [13, 18–20] and a total volume of 13–25 ml [13, 17, 18, 21]. The highly vascularized nasal mucosa lines three turbinates, i.e., the superior, middle and inferior nasal turbinates, which extend laterally from the wall of each nasal compartment, functioning to warm, filter and humidify inhaled air [13, 19]. The turbinates furthermore have an approximate surface area of about 160 cm2 [15]. Each half of the nasal cavity consists of three regions: the vestibule (∼0.6 cm2) [22], which is located immediately at the nostril, extending from the nostrils to the inferior turbinate [15, 23]; the olfactory region (2–12.5 cm2) [13, 19, 22]; and the respiratory region. The vestibule region contains stratified squamous epithelium, and its mucosa contains hairs, sweat and sebaceous glands [15]. Non-ciliated transitional epithelium separates the squamous cells from the respiratory epithelium and the respiratory epithelium from the olfactory epithelium, respectively [15]. The relatively small surface area of the vestibule region, as well as the non-ciliated cell surfaces, makes this a poor drug absorption site [24] with the respiratory and olfactory mucosa an intended drug absorption site [15]. The nasopharynx-associated lymphoid tissue (NALT), containing immune cells, is interconnected to the tonsils and the local lymph nodes [15]. During inhalation, air enters the nostrils, flows into the flexible nasal valve via the nasal vestibule and into the main chamber [16, 19, 25]. Despite the nasal cavity’s high vascularization and large surface area, its anatomic configuration results in only 15–20% of inhaled air reaching the olfactory region [25, 26].

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Fig. 6.2  Anatomy of the human nasal cavity. Squamous mucosa (green) is located at the frontal parts of the nasal vestibules. The three turbinates (inferior, middle and superior) humidify and warm the inhaled air. The area covered predominantly with respiratory mucosa is labelled in blue. The olfactory mucosa (yellow) is located next to the cribriform plate at the skull base down to the superior turbinate. Nasally transmitted substances can cross the cribriform plate via different pathways to enter the brain. Nasopharynx-associated lymphatic tissue (NALT) is located in close proximity to the tonsils at the nasopharynx. (Reproduced from Gänger and Schindowski [15] © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http:// creativecommons.org/licenses/by/4.0/))

2.2 The Respiratory Region and Epithelium The respiratory region accounts for the largest area of the nasal cavity, occupying a total surface area of approximately 80–90% or ~130 cm2 due to its ciliated pseudostratified columnar epithelium lining [13, 21, 22, 24]. Its high degree of vascularization, along with a large microvillus- covered surface area, renders the respiratory region a major site for systemic drug absorption [21, 25, 27]. Furthermore, blood supply is received from the maxillary artery via an arterial branch and is innervated by the trigeminal nerves, a potential targeting pathway for nose-to-brain delivery [27]. Four distinct cell types comprise the respiratory epithelium, viz. the ciliated and non-ciliated columnar cells, the goblet cells and the basal cells [4]. These cells function in facilitating intracellular water and ion exchange, mucus secretion and clearance and mucosal humidity regulation, in addition to the coordinated cilial sweeping motion with an approximate frequency of 1000 S/min [20, 22, 25].

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A double-layered viscoelastic mucus gel covers the respiratory epithelium, comprising of a network of mucins, water, salts, proteins and some lipids. Its viscoelastic and adhesive properties confer protective abilities against inhaled irritants and particulates [28, 29]. The sweeping motion of the epithelial cilia tips together with continuous mucus secretion allowing for the entrapped inhaled irritants, particulates and microbes to be transported along the nasal passage and pharynx, at an approximate rate of 1–30  mm/min [19], until enzyme- and acidmediated lysis in the stomach occurs. This pathway refers to the process of mucociliary clearance [20, 21, 25]. The respiratory mucus layer is additionally estimated to be renewed every 1 to 20 min [17].

2.3 The Olfactory Region and Epithelium The olfactory region is situated under the cribriform plate, which is the horizontal bone that separates the brain and the nasal cavity, occupying 2 ~ 12.5 cm2 or approximately 1.25–10% of the nasal cavity [13, 19, 22, 24, 25]. This highly perforated structure allows for nerve endings to enter the nasal cavity and is thus recognized extensively as a viable nose-to-brain drug delivery route for various CNS disease treatments [22, 30]. Ciliated chemosensory pseudostratified columnar epithelium furthermore lines the olfactory region of the nasal cavity (Fig. 6.3). The olfactory mucosa, which is surrounded by the respiratory epithelium, is located on the surface of the superior turbinate. The olfactory mucosa is also located bilaterally on the nasal septum [4]. The ophthalmic artery branches provide the blood supply to this region [27] and the olfactory epithelial cilia is longer (over 50 μm) than that of the respiratory epithelium and is non-motile [22]. Mucus clearance occurs as a result of continuous mucus secretion by the Bowman’s glands, gravitational and mechanical forces, and the solvent drag effect, with the mucus turnover being over several days [19, 20]. The olfactory mucosa is also highly innervated, containing the autonomic nerve fibres, the olfactory axon bundles and the maxillary branch of the trigeminal nerve. The olfactory epithelium has been noted to consist of several distinct cell types including the sustentacular cells which is the most abundant olfactory epithelium cell type. These are microvilli-possessing columnar cells that function to provide both mechanical and metabolic support to the olfactory epithelia, whilst also functioning to regulate the ionic environment of the overlying mucus [4, 13, 22]. These cells also function to catabolize inhaled xenobiotics as they exhibit high enzymatic activity [19]. The small, conically shaped basal cells are also situated in the basement membrane and provide mechanical support to the other cells [18] and due to their ability to differentiate into other cell types, specifically olfactory sensory neurons (OSNs), function to continuously replace dead cells [13].

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Fig. 6.3  Structure and composition of the olfactory mucosa. In the posterior part of the nasal cavity, the olfactory mucosa, together with the olfactory epithelium (OE) and the lamina propria (LP), represents the first contact zone of environmental cues towards the human body. Within the OE, the mature olfactory sensory neurons (OSNm) are projecting their axons towards the olfactory bulb (OB), where they form glomeruli with the dendrites of mitral cells. The axons of OSNms are enclosed by olfactory ensheathing cells (OECs) and olfactory nerve fibroblasts (ONFs). The axons together with the OEC and ONF form the olfactory nerve bundles (ONBs) in the lamina propria. The OE further consists of sustentacular (SUS) and mucus-producing Bowman’s glands (BGs). In the middle part of the OE are the immature ORN (ORNi). The OE is surrounded by a layer of immature basal cells, the globose (GBC) and horizontal basal cells (HBCs). The lamina propria (LP) is separated from the OE by a basal lamina (BL). Further, the LP also contains blood vessels (BVs) and lymphatic vessels (LVs). (Reproduced from Keller et al. [32] © The Author(s) 2021. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/))

The terminal branches of the trigeminal nerve also consist of brush cells. The surface of these cells displays a tuft of blunt, squat microvilli (approximately 120–140 per cell) which contain filaments that extend into the cytoplasm of the cell [31]. In the respiratory system, the brush cells are characterized by the absence of the distinctive terminal situated immediately beneath the microvillous border, differentiating them from those present in the gastrointestinal system [31]. The brush cells and their associated microvilli function to provide sensory mucosal stimulation [22]. 2.3.1 Olfactory Sensory Neurons The olfactory sensory neurons (OSNs), which are interspersed between the sustentacular cells [18], are non-myelinated neurons that are enclosed by specialized ensheathing cells. The OSNs are responsible for the process of olfaction, as they are

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exposed to the inhaled air [15]. Dendrites from the OSNs also extend into non-­ motile cilia and terminate into externally exposed mucus [13]. Unmyelinated axons bundle into profuse axon bundles that are enwrapped by the olfactory ensheathing cells and nerve fibroblasts, entering the cribriform plate of the ethmoid bone through its foramina to further penetrate further into the brain [4]. Due to their inherent function, OSNs have a lifespan of 1 month. OSN systematic apoptosis protects the brain from any infections [15]. Basal stem cells further ensure tissue maintenance-related cell death or recovery of the olfactory mucosa after injury [15]. Two types of different basal stem cells are located in the olfactory mucosa that differentiate into OSNs [33]. When the OSN dies, gaps in the epithelial layer are formed until an OSN can regrow into that space, resulting in the delayed formation of tight junction during this time [34]. Beneath the epithelium layer, the Bowman’s glands (for production and secretion of mucus), axons, lymphatic vessels, blood vessels, and connective tissue are contained [35].

3 Drug Delivery Pathways/Brain Targeting Sites via the Intranasal Route Successful intranasal administration of small lipophilic compounds occurs when drugs bypass mucociliary clearance in the vestibular region and migrate to posterior regions of the nasal cavity, where they are absorbed through contact with the respiratory epithelium. Subsequent absorption into the systemic circulation via the blood or lymphatic system then occurs. However, both increased systemic exposure as well as hepatic metabolism is still necessary for BBB delivery through this transcellular delivery pathway [4, 24]. Direct drug transport to the brain occurs via the olfactory or trigeminal pathways with indirect drug transport occurring via the systemic pathway [18, 22, 24, 36] (Fig. 6.4).

3.1 The Olfactory Pathway The olfactory epithelium lends itself to three possible drug transport pathways: the transcellular pathway; the paracellular pathway; and the olfactory nerve pathway (Fig. 6.5). Passive diffusion or endocytosis governs the transcellular pathway, where the drugs move across the respiratory epithelium and the sustentacular cells in the olfactory epithelium to the OSNs and peripheral trigeminal neurons. The intracellular and transcellular transport pathways are responsible for drug delivery to the various regions of the brain. The intracellular route transports the drug from the olfactory nerve to the olfactory lobe and from the trigeminal nerves to the brain. This pathway is primarily responsible for the lipophilic drug transport and is also referred to as the intraneuronal route of drug transport. This drug

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Mucocilliary clearance First-pass metabolism Systemic circulation

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(b) Olfactory bulb Cribriform Plate

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ii) Intracellular pathway

iii) Transcellular pathway

Intranasal Administration of drugs or drug formulations

Fig. 6.4 (a) The potential drug transport routes leading to brain uptake following intranasal administration (b) Schematic representation of various possible mechanisms involved in direct nose-to-brain drug transport from the olfactory region. (Reproduced from Hong et al. [24] © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http:// creativecommons.org/licenses/by/4.0/))

transport route from the nasal cavity to the brain is relatively slow, reaching the CNS after 24 hours [37, 38]. Hydrophilic drugs are transported between the sustentacular cells via the paracellular pathway, where appreciable bioavailability is achieved with drugs having a molecular weight of 1000  Da or more. The olfactory nerve pathway involves the uptake of the drug via the neuronal cells with transport to the olfactory bulb being facilitated through intracellular axonal transport [17, 40]. The olfactory neurons also transport drugs into the olfactory bulb via the intracellular axonal channel [41]. The diameter of the olfactory axon is approximated to be 0.1–0.7 μm [4], providing a targeted size range for nanoparticles or molecules

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Fig. 6.5  Schematic overview of several molecular pathways after intranasal drug administration. CSF cerebrospinal fluid. BBB: blood-brain barrier. (Reproduced from Tashima [39] © 2020 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/))

to be appropriately delivered. Both extracellular and intracellular mechanisms govern drug transport through the olfactory pathway, with the paracellular route transporting hydrophilic drugs and passive diffusion transporting lipophilic drugs [2]. Using the olfactory pathway, wheat germ agglutinin-horseradish peroxidase was shown to be concentrated (140 nM) in the olfactory nerve and glomerular layers of the olfactory bulb [42]. Additionally, for the treatment of Alzheimer’s disease, recombinant human nerve growth factor was delivered to the brain achieving concentrations of 3400 pM and 660–2200 pM in the olfactory bulb and in other brain regions, respectively [43]. Nanogold-labelled insulin was also noted to reach the anterior regions of the olfactory bulb 30 min after administration [44].

3.2 The Trigeminal Pathway The trigeminal nerve functions to provide chemo- and thermo-sensory stimuli to the nasal, oral and ocular mucosa [45]. Since the dorsal nasal mucosa is innervated by the trigeminal nerve, the trigeminal nerve pathway is a potential delivery pathway (although not widely used) for drug delivery to the brain, particularly the frontal brain and olfactory bulb [36]. Labelled fluorescein isothiocyanate (FITC)-insulin was intranasally administered in female Sprague-Dawley rats for its distribution and delivery pathways into the brain via the trigeminal nerves [46] (Fig. 6.6). Upon excision of the nerves from the base of the skull, at the point in which the V1V2 branches exit the anterior lacerated

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Fig. 6.6  FITC-insulin was intranasally administered and imaged in the trigeminal nerve 30 min later (b, e, h). Axons in the trigeminal nerve were labelled with the pan-neuronal marker Neuro-­ Chrom (a, d, g). The merged images (c, f, i) show FITC-insulin in the perineural spaces of the trigeminal nerve. These data suggest FITC insulin reaches the CNS along perineural spaces of the trigeminal nerve. Scale bar  =  10  μm. (Reproduced from Lochhead et  al. [46] © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)))

foramen, FITC-insulin localization was observed in the endoneurium, with stronger signals detected in the perineurium and epineurium of the trigeminal nerve. In a study by Wang and co-workers [47], a self-assembling two-component supramolecular hydrogel was evaluated as a vehicle for L-DOPA delivery. The system was evaluated as a potential treatment of Parkinson’s disease using a hemiparkinsonian rat model. The gel was shown to display 4.1 times more L-dopa uptake in the brain. Additionally, more L-dopa was present in the blood (2.1 times) at 10 min after intravenous administration of an equivalent dose. Radioactivity after 10 min in various regions of the brain was evaluated following nasal administration of the hydrogel (Fig.  6.7). 3H-labelled L-DOPA was readily distributed throughout the brain with the greatest detection in the trigeminal nerve, which accounted for more than 30% of the brain’s total radioactivity.

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Fig. 6.7  Brain distribution of [3H]l-DOPA hydrogel at 10 min post intranasal administration. (a) Dorsal view of the mouse brain and dissection guidance of different brain segments, the olfactory bulbs (OB), the cerebrum (CB 1&2), the brain stem (BS), cerebellum (CE), spinal cord (SP), and trigeminal nerves (TN). (b) % of [3H]l-DOPA uptake in different brain segments. At the experimental endpoints, whole body perfusion with 0.9% saline was performed and studied tissues were dissected and proceeded for liquid scintillation counting. Results are expressed as % uptake normalized to total [3H]l-DOPA detected in these collected tissues. Data are expressed as mean ± SD, n = 3. (Reproduced from Wang et al. [47] © 2021 The Authors. Advanced Science published by Wiley-VCH GmbH. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/ by/4.0/))

3.3 The Lymphatic Pathway Olfactory nerves from the lamina propria of the olfactory region, terminating in the olfactory bulb, give rise to extracellular pathways such as the perivascular, perineural and lymphatic pathways [2, 4, 13]. In a study by Furubayashi and co-workers [48], intranasal administration of methotrexate to the cervical lymph nodes (CLNs) via the nasal mucosa was studied in Wistar rats. The study concluded that the delivery of methotrexate was attributed more to the direct nasal–CLN pathway as opposed to the direct blood–CLN pathway with a direct transport percentage of 74.3%. Although these pathways are not new, research on them are few and far between [13, 49].

3.4 The Systemic Pathway Drugs that are lipophilic with low molecular weights are most suited for delivery via the systemic pathway. This pathway avoids hepatic first-pass metabolism as drugs absorbed from the vascular epithelium membrane of the nasal mucosa and the lymphatic system are transported directly into the systemic circulation [2, 20, 26].

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Table 6.1  Overview of drug delivery pathways related to the nasal cavity Drug delivery route related to different nasal mucosa Local Predominantly squamous and respiratory administration mucosa Systemic delivery Predominantly respiratory mucosa Intranasal vaccination CNS delivery (N2B)

NALT and immune cells in all mucosal types Olfactory mucosa: olfactory neuronal bundles; Respiratory mucosa/olfactory mucosa: trigeminal nerve endings

Examples with supporting clinical data Decongestants, local anaesthetics, glucocorticoid [50, 51] Calcitonin, sumatriptan, desmopressin [52–54] Seasonal flu vaccine [55, 56] Oxytocin, insulin [57, 58]

Reproduced from [15] © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)

Table 6.1 summarizes the many nose-to-brain pathways, delivery routes and their targeting compartment.

4 Factors Affecting Nasal Absorption Although nasal delivery offers many advantages, its biggest limitation is the restriction of dose size/volume, allowing only 50–250  μL per nostril at a time, making drugs requiring high dose obsolete from nasal delivery. Molecules exhibiting weights >1000 Daltons further display poor absorption through the nasal mucosa. Alterations in nasal secretions such as tonicity and pH (generally 4.5 ~ 6.5) as a result of flu, cold, allergies and other pathological conditions pose a challenge to nasal drug delivery and may exaggerate drug effects [24, 35, 59]. Furthermore, inner nasal surface enzymes such as exonuclease and endonuclease as well as aldehyde hydrogenase, epoxide hydrolase, glutathione S-transferase and carboxylesterase contribute to protein and peptide degradation and drug metabolism [35, 60–62]. In addition to the afore-discussed physicochemical properties affecting BBB transversion, poor nasal mucosa penetration capacity and tonicity-related rapid mucociliary clearance result in poor nose-to-brain drug transport [59]. Dosage form factors of drug concentration, osmolality, surfactant type and viscosity also have an effect on nasal absorption and toxicity [63]. Preservatives such as benzalkonium chloride have further been noted to sensitize the nasal mucosa [64], while head position during nasal administration has been determined to affect the extent to which drug deposition occurs as well as localization within the nasal cavity [24, 65].

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5 Conclusion Despite the mentioned restrictions and limitations, research into nose-to-brain delivery has resulted in promising platforms with the potential to significantly improve the delivery of drug molecules to the brain. This has been achieved through the targeting of specific nasal pathways, dependent on the properties of the drug molecule and the delivery system, with effective drug delivery occurring in various parts of the brain. With research into this field of study, new and more effective systems can be developed which will seek to further enhance the treatment of CNS conditions.

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Chapter 7

Biomedical Applications of Nanocarriers in Nasal Delivery Namdev Dhas, Soji Neyyar, Atul Garkal, Ritu Kudarha, Jahanvi Patel, Srinivas Mutalik, and Tejal Mehta

Abstract  Non-invasive drug delivery is an emerging way to target a wide range of therapeutics. One of them, i.e., the nasal drug delivery has shown promising results in delivering small and large molecules, genes, peptides, and proteins. This drug delivery system targets the drug to the brain by direct nose-to-brain and/or indirect nose-to-blood-to-brain routes. Nanocarriers play a vital role in the nasal delivery system due to their small size which provides ease in targeting. Numerous strategies have been explored by researchers for the transportation of drugs from nose to target and found excellent results in therapy. It was observed that polymeric and lipidic nanocarriers have numerous applications in targeted drug delivery, gene delivery, and vaccine delivery. Moreover, they are also used for diagnostics as well as theranostics purposes. This chapter briefly summarizes the different types of nanocarriers used for nasal delivery with their characterization techniques. Further, the biomedical applications of nanocarriers via the nasal route are discussed in detail. Keywords  Nasal drug delivery · Biomedical application · Nanocarriers · Nose-to-­ Brain · Ploymers

N. Dhas Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, MAHE, Manipal, India S. Neyyar · R. Kudarha · S. Mutalik Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, MAHE, Manipal, India A. Garkal · J. Patel · T. Mehta (*) Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_7

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1 Introduction Clinical utilization of nanomaterial is turning out to be progressively significant in the treatment of several diseases and diagnostics along with theranostic applications. In medicine, nanocarriers improve the pharmacokinetics, bioavailability, and efficiency of many medicines or contrast agents by assuring greater hydrophilicity, less interaction with cellular proteins and plasma, and better accumulation in target tissues. The ability of nanoparticles to localize (or be targeted) in a precise manner to the site of action and reduce or eliminate harmful side effects is the most promising application of nanocarriers in medicine [1–4]. The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have already approved over 50 nano carrier-based formulations for intravenous, intramuscular, topical, oral, intrabronchial, subcutaneous, administration as a result of nanomaterials research. Liposomes and polymeric nanoparticles (NPs) are the most clinically authorized nanomedicines; however, the number of nanomaterials approved by the FDA for medical uses is still small [4–8]. Apealea®/Paclical®, which contains micellar paclitaxel PTX (PTX formed with the surfactant XR17) and is used to treat Fallopian tube cancer, primary peritoneal cancer, and epithelial ovarian cancer, is an example of a polymeric nanomedicine [9]. The safety and therapeutic efficacy of novel nanomaterials were recently confirmed in multiple clinical investigations, the majority of which focused on anti-cancer medication nanocarriers [10]. Another PTX nanoformulation, NK105, a “core-shell-type” polymeric micellar NPs formulation used in patients with metastatic or recurrent breast cancer, has already completed phase 3 of clinical trials. Additionally, numerous distinct nano-based systems have been created in connection with the severe acute respiratory syndrome coronavirus 2 (SARS-­ CoV-­2) pandemic that could be effective in the treatment of individuals with the coronavirus disease-19 (COVID-19) [11]. Clinical trials for a full-length recombinant SARS-CoV-2 glycoprotein NPs vaccine adjuvanted with Novavax’s saponin-­ based Matrix M (NVX-CoV2373, NCT04368988) or Remdesivir’s inhaled NPs formulation have recently begun (developed by NeuroActiva, NCT04480333, data from clinicaltrials.gov). There are consistent huge requests on new, progressed, multifunctional nanomaterials to be utilized in the eventual fate of medication. In addition, to this, these fabricated nanocarriers need to be delivered via a proper route through which an efficient pharmacological action can be obtained. For the same, route of administration also plays a significant role ineffective treatment. Each administration routes have their advantages and disadvantages. Nasal delivery has garnered more attention among conventional and non-conventional delivery routes. The nasal route exhibits numerous merits, for instance, non-invasiveness, first-pass metabolism can be avoided, the nasal route provides large surface area as a site of absorption, lesser systemic exposure, rapid and fast absorption, avoids toxicity to healthy cells to a greater extent, more specifically when the drug needs to be transported to the brain, the nasal route bypasses the blood-brain barrier (BBB) [12]. However, along with its merits, it also possesses several disadvantages, rapid

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A Frontal sinus

B

Upper nasal turbine Middle nasal turbinate

Nasal cavity

Nasal septum

Vomeronasal organ

Sphenoid sinus Lower nasal turbinate Nasal choanae

Oral cavity Tongue Nasal cavity Histology

Fig. 7.1  The anatomy of the human nasal cavity. (a) Histological section of the human nasal cavity. (b) Schematic view of the internal structure of the human nasal cavity. (Open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited) [13]

mucociliary clearance results in a short residence time of nanocarrier at the site of absorption ultimately leading to lesser bioavailability, the nasal cavity is small hence  it limits dose. Figure  7.1 illustrated the anatomy of the human nasal cavity. [13]. Although the exact mechanisms by which therapeutic moieties go from the nose to the brain are unknown, the olfactory pathway plays an important role. The pathway involves the olfactory bulb, lamina propria, and olfactory epithelium. Figure 7.2 illustrates the intranasal drug transport through the olfactory route to the CNS by intracellular and extracellular pathways [14, 15]. The second significant pathway, the trigeminal nerve pathway, enters the brainstem through the pons by innervating the nasal cavity, whereas it enters the forebrain through the cribriform plate, allowing drugs/therapeutic moieties to reach the caudal and rostral portions of the brain. This connection of the nasal route and brain opened several avenues for research and attracted several researchers to narrow down their research orientation. Figure  7.3 illustrates the trigeminal nerve pathway. Additionally, the nasal route can be significant for the delivery of nanocarrierbased systems in which several drug molecules such as peptides, nucleotides, and proteins can be entrapped through which enzymatic degradation can be avoided in the nasal cavity [16]. Nanocarrier-­based systems which are the most promising technology among the advanced technologies and controlled release systems are discussed in the present chapter.

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Fig. 7.2  Intranasal drug transport through the olfactory route to the CNS by intracellular and extracellular pathways. The drug is taken up by OSNs, which project to the olfactory bulb. The extracellular route is between the SCs, where the drug passes through the tight junctions (TJs), paracellular cleft, the lamina propria, perineural space, and ultimately to the subarachnoid space where it is transported to distal targets around the CNS. Abbreviations: SC Support cells, OSN olfactory sensory neurons, OEC olfactory unsheathing cells, ONF olfactory nerve fibroblasts. (Ref: Modified from [14, 15])

Fig. 7.3  The trigeminal nerve pathway, The initial processes at intracellular and extracellular mechanisms of intranasal drug transport to the CNS. Intracellular shows pinocytosis/endocytosis (1), trafficking of the endosome to Golgi apparatus (2), sorting with the Golgi stacks (3), and axonal transport toward olfactory bulb (4). The extracellular pathway shows the movement of the drug to the paracellular space and translocations through an absent tight junction (TJ) (6), and finally translocation to the lamina propria through the paracellular cleft (7). Abbreviations: olfactory sensory neuron (OSN), supporting cells (SC), endosome (EN), Golgi apparatus (GA), exosome (E), and tight junction (TJ). (Ref: Modified from [14, 15])

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2 Types of Nanocarriers 2.1 Polymeric Nanocarriers The polymeric nanocarriers are usually derived from natural as well as synthetic origin, with a size range from 10 to 1000  nm [17]. The polymeric nanocarriers exhibit several advantages like outstanding intracellular uptake and prolonged and controlled delivery of therapeutic moiety. In a study, uptake of PLA, chitosan, and PLGA nanoparticles (NPs) by the olfactory ensheathing cells were evaluated. The PLGA NPs showed better uptake than PLA and chitosan [18]. While treating neurological diseases like schizophrenia, the drug should be present in the brain cells for an extended duration of time to get a better therapeutic response. Some of the biological obstacles like first-pass metabolism, low bioavailability, and frequent dosing are making conventional delivery systems of less usage. Shah and his co-workers formulated quetiapine (QT)-loaded chitosan-based polymeric NPs and microemulsions for nasal delivery. The polymeric nanoparticles (PNP) were manufactured by ionic gelation and chitosan-based mucoadhesive microemulsion (MME) through the water titration technique. The loading efficiency was higher (95%) in MME compared to PNP (65%). The reason for poor drug loading in PNP could be due to pH-dependent and poor aqueous solubility of quetiapine. MME showed 1.3-folds of higher diffusion compared to PNP as it is hydrophilic. Permeation-enhancing property of chitosan in MME made them possess superior diffusion characteristics than NPs. The pharmacokinetic study in Sprague-Dawley rats showed better concentration in the brain and about 1.9-fold higher bioavailability in MME over PNPs, attributed due to bypassing of the blood-brain barrier and transporting via an olfactory route. MME (i.n.) showed 1.2–2.0-folds of blood/brain ratio than that of QTNP. The biodistribution of the formulation was evaluated using gamma scintigraphy, which is a non-invasive imaging technique. The formulations were labeled with technetium-99 m via a direct labeling approach. Thin-layer chromatography was used to confirm radiolabeling efficiency of the formulation. The formulations were then administered via i.v. and i.n. route and compared their radioactivity. MME formulation administered via i.n. route showed the highest radioactivity. Pharmacokinetic study along with gamma scintigraphy study demonstrated that brain delivery of quetiapine was notably better in MME compared to PNP. The findings of in  vivo biodistribution and imaging study confirmed the outstanding potential of MME as a candidate for the delivery of quetiapine via the non-invasive intranasal route [19]. Mucus-penetrating NPs can reach the brain via intranasal administration. Junior et al. developed PEGylated polycaprolactone (PCL) NPs loaded with bexarotene to overcome reduced epithelial permeation, enzymatic degradation, and rapid mucociliary clearance. All the formulations exhibited spherical structure and an average diameter of 100 nm, and PDI less than 2. Particle diameter and morphology were unchanged on PEGylation with different concentrations of PCL-PEG such as 1, 3, 5, and 10% w/w. 5% and 10% of PCL-PEG exhibited sufficient homogeneity and

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stability in artificial nasal mucus. 98.8% of mucus-penetrating activity was observed in 5% concentration and 99.5% in 10%. Fluorescence microscopy confirmed that the presence of PEG on the surface of NPs has no role in changing the uptake by RMPI 2650 cells. Translocation of the system into the brain was confirmed by fluorescence tomography for 5% PCL-PEG.  The concentration of drug-loaded 5% PCL-PEG in the brain was threefold higher than drug dispersion and threefold than non-PEGylated NPs. The increased distribution and retention of formulation in the brain followed by intranasal administration is expected due to enhanced mobility and stability of the 5% PCL-PEG. All these data indicate that 5% of PCL-PEG is effectively promoting permeation of NPs through the mucus, bypassing the clearance and finally increasing the concentration of drug in the brain cells [20]. In another study, Masjedi and his co-workers developed chitosan NPs loaded with sumatriptan succinate for intranasal delivery. The drug-loaded nanoparticles were prepared by the ionic gelation technique. The drug loading efficiency was relatively high due to the establishment of a hydrogen bond between drug molecules and chitosan. In vitro release study suggested more than 50% drug release in 24 h. The in vivo parameters such as drug targeting efficiency (DTE%) and drug transport percentage (DTP %) showed 493.39% and 79.79%, which indicates direct and fast delivery of sumatriptan to the brain via nasal cavity [21]. Sclachet et al. evaluated the biodistribution of polymeric nanoparticles of poly (methyl methacrylate), chitosan, and poly (vinyl alcohol) for brain delivery via intranasal (i.n.) and intravenous (i.v.) administration. The drug concentration in the off-target region was found to be less in i.n. compared to i.v. The results suggest that both delivery routes exhibited differential accumulation in the brain region and could be utilized for various medical conditions [22]. Joachim et al. explored gelatin NPs (GNPs) as a carrier for the intranasal delivery of osteopontin (OPN) for the therapy of ischemic stroke. GNPs can potentiate the neuroprotective activity of OPN on intranasal administration. The increased efficacy of OPN was attributed due to the presence of GNP which protects OPN from degradation by protease, sustained drug release, and higher concentration of drug in brain regions [23]. Muntimadugu et al. designed a poly (lactide-co-­ glycolide) (PLGA) nanocarrier for the brain delivery of tarenflurbil (TFB), which has failed in the clinical trial (phase 3) due to its poor brain penetration. The formulation showed particle size less than 200 nm, which assured the transcellular transport of the drug through the olfactory axons. In vitro drug release study confirmed the prolonged residence time at the targeting site. DTE and DTP results indicated that the drug was capable of direct transportation to the brain after the administration of polymeric nanoparticles via the olfactory pathway [24].

2.2 Lipidic Nanocarriers Lipid-based nanocarriers are one of the drug delivery systems (DDS) to be discovered and approved by the FDA. Liposomes are lipid-based nanocarriers of phospholipid spherical bilayer vesicles exhibiting a similar structure as that of the human

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cell membrane and are biodegradable and biocompatible [4, 25]. Li et al. developed flexible liposomes of galanthamine hydrobromide (GH) to check the pharmacokinetic characteristic of acetylcholinesterase inhibition via i.n. administration. Negative-stained TEM micrographs of flexible liposomes demonstrated that it is spherical and consists of multilamellar vesicles. The size distribution range of 112 ± 8 nm confirmed the homogeneity of the preparation. It exhibited a zeta potential of about −49.2 ± 0.7 mv, which indicates the stability of liposome by electrostatic repulsion which inhibits the aggregation. It showed excellent entrapment efficiency of 83.6 ± 1.8%, which is attributed due to the high lamellarity of vesicles. The cell viability on PC-12 cells confirmed the non-toxicity of the cultured cells. The acetylcholinesterase activity was determined in male SD rats using a reagent kit. The animals were administered with the liposome via i.n. at a GH dose of 3 mg/ kg. The animal which was given with GH-loaded formulation showed good permeability in the rat nasal mucosa and better anticholinesterase activity. The cerebral microdialysis technique was used to assess the pharmacokinetic properties of formulation in the brain. In this technique, analytes will move through a semi-­permeable membrane due to concentration gradient, and the perfusion fluid will be analyzed to check drug concentration by analytical methods like HPLC or microsensors. GH-loaded liposomes showed Cmax of 13.98  μg/ml and AUC of 55.42  μg  h/ml, which is notably more than other animal groups. These results suggest the deep penetration of liposomes into the nasal mucosa and efficient delivery of GH [26, 27]. Yang and his co-workers developed cell-penetrating peptide (CPP) liposomes of rivastigmine (RS) to enhance its distribution in the brain and minimize the side effects. RS transport across the BBB was time-dependent and the results suggested that the liposomes can potentiate the transmembrane effect. Bio-distribution and pharmacokinetic studies were performed in male SD rats. A higher concentration of RS was observed in the brain region by i.n. delivery compared to i.v. This study demonstrated that the intranasal delivery of liposome  increased the rivastigmine distribution. The developed CPP liposome Pharmacodynamic study demonstrated that cilia movement and hemolytic effect were the same as that of physiological saline, indicating non-toxicity of the formulation [28]. Upadhyay et al. developed nanoliposomes of quetiapine for the improved and direct delivery to the brain for treating schizophrenia. A thin film hydration technique was used to prepare liposomes with the particle size and surface charge of 139.6 nm and −32.1 mV, respectively. The maximum entrapment efficiency was observed in the 1:3 ratio of egg phosphatidylcholine (EPC):cholesterol (CH), which is attributed due to the necessity of the large amount of EPC to make the lamellar structure of liposomes and cholesterol to increase the stability. An increase in ratio resulted in the leakage of liposomes due to disruption of the liposomal membrane by CH. Scintigraphy study demonstrated that the liposome can efficiently deliver quetiapine compared to simple solution and dispersion. These results suggest the use of this platform for targeting the brain [29]. Solid-lipid NPs (SLNs) are nanocarrier systems manufactured with solid lipids and are efficient in loading high amounts of the drug that can load both lipophilic and hydrophilic agents. As the SLNs exhibit smaller particle size and lipophilicity,

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this delivery system can make use for brain drug delivery [30]. In an investigation, Bhatt et al. formulated SLNs of astaxanthin (AST) using lecithin, poloxamer 188, and citric acid to improve the brain targeting via i.n. delivery. The double emulsion solvent displacement technique was employed to prepare AST-loaded SLNs. The SLN was optimized by response surface methodology. The PDI of the formulation was +0.349 and the average particle size was about 205.85 nm, which indicates the narrow size distribution. The developed SLN showed excellent entrapment efficiency (77.42% ± 1.15%) and better loading capacity (47.63 ± 1.07%). SEM and TEM results indicated that the SLNs are in nanosize range and spherical. The in vitro drug release study showed the drug release in a controlled and sustained manner (81.40% release in 24 h). The optimized formulation was then radiolabeled with technetium-99 m (99 mTc) and the labeling efficiency was confirmed by thin-­ layer chromatography (TLC). A bio-distribution study was performed in male albino Wistar rats, and administered the SLNs via i.n. and i.v. route. The drug concentration in the brain was higher and lesser in blood followed by i.n. administration. Intravenous administration of SLNs showed higher radioactivity in the spleen, kidney, and lungs. The brain accumulation of SLNs on i.n. (1.70 ± 0.13) showed 200% more than i.v. (0.844 ± 0.12). Gamma scintigraphy was performed to visualize the brain uptake followed by i.n. and i.v. administration, which confirmed the internalization of the drug in the brain. The above results strongly suggest that the AST-SLNs can be effectively used for brain targeting [31]. Patel et al. formulated risperidone (RES)-loaded SLNs for targeted delivery to the brain via the intranasal route to cross BBB. The RES-SLNs were prepared by solvent emulsification-­ evaporation technique. It exhibited better entrapment efficiency of 59.65 ± 1.18%, the particle size of 148.05 ± 0.85 nm, and PI of 0.148 ± 0.028, which indicates the physical stability of the formulation. The zeta potential was found to be −25.35  ±  0.45  mV, negative charge is due to the surfactant and lipid used. The in vitro drug release of the formulation was 25.74% ± 0.65% and 48.90 ± 1.01% after 7  h and 24  h respectively, which demonstrates the controlled release of the drug. The pharmacodynamic study was carried out by using paw test with Perspex platform, which exhibited prolonged hind limb reaction time (HRT) on RES-SLNs administration than RES solution. These findings indicated that the SLNs delivery via nose-to-brain is an excellent technique to drug delivery [32]. Nanostructured lipid carriers (NLCs) are a novel type of nano-mediated carrier system which integrates both liquid and solid lipids. Compared with SLNs, NCLs exhibit enhanced stability and better drug loading [33]. Singh et al. formulated glycol chitosan functionalized lipid carrier (GC-NLC) for intranasal delivery of asenapine (AS). The optimized formulation of AS-NLC showed a particle size of 167.30  ±  7.52  nm, excellent entrapment efficiency of 83.50  ±  3.48%, and zeta potential of −4.34 ± 1.37 mV. GC-coated AS-NLC showed a significant increase in particle size, zeta potential, and entrapment efficiency. Increased particle size may be attributed due to the deposition of GC on the surface of AS-NLC and positive zeta potential indicates the cationic nature of GC. The dialysis bag technique was performed to evaluate in  vitro drug release, where 90% of ASM was released in 12 h. Cell viability of GC-AS-NLC was checked in A549 cells by MTT assay. They

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observed a negligible difference in the viability between ASM and GC-AS-NLC. In vivo pharmacokinetic evaluation was carried out in Charles foster rats. The systemic absolute bioavailability of GC-AS-NLC was 141.50%, which was 2.3-folds higher than ASM (59.02%) followed by i.n. delivery. To confirm the brain targeting of the formulation, the AS concentration from GC-AS-NLC was compared with pure AS on i.v. and i.n. which demonstrated the high concentration of AS from GC-AS-NLC at all the time points. The systemic bioavailability of AS in the brain, from GC-AS-­ NLC, was 407.89% and ASM was 103.31% via i.n. route. The overall result indicates that GC-AS-NLC through i.n. the route can efficiently target the brain with increased bioavailability [34]. Rajput et  al. formulated resveratrol (RES)-loaded NLCs in situ gel for i.n. administration. The emulsification-probe sonication technique was used to prepare RES-loaded NLCs. The particle size distribution of NLCs was from 70 ± 6 nm to 189 ± 109 nm. As the NLCs showed PDI less than 0.3, it is considered as uniform particle size. TEM showed that NLCs are spherical and exhibited narrow size distribution. Pharmacokinetic and biodistribution parameters were evaluated in Sprague-Dawley rats. The biodistribution study showed that a higher concentration of RES was found in the brain on NLC in situ gel administration than RES suspension, due to direct brain delivery of NLCs via olfactory lob and its enhanced lipophilicity. A pharmacokinetic study also confirmed the sufficient amount of RES in the brain. The developed formulation could be a better strategy for efficient drug delivery in Alzheimer’s disease [33].

2.3 Metallic Nanocarriers Metallic nanocarriers exhibit their outstanding application in the area of biomedical sciences and engineering. It possesses a wide variety of applications like image-­ guided therapy and targeted drug and gene delivery. The majority of imaging techniques like MRI, SERS, and ultrasound techniques need a contrast agent for proper functioning. This is the basis of the development of metallic NPs like silver, magnetic iron oxide, and gold [35–37]. Gold NPs (AuNPs) are the most used metallic nanocarrier for targeted delivery of the drug and bio-imaging. Sukumar et al. developed gold-iron oxide NPs conjugated with microRNAs (miRNA) for multimodal imaging and presensitization of glioblastoma (GBM). As biological barriers like BBB are the major challenging factors for GBM treatment, the approach was to bypass BBB via a direct nose-to-­ brain pathway. This formulation is expected to presensitize the GBM cells to deliver chemotherapeutical agent temozolomide (TMZ) and for image-guided treatment. Followed by the synthesis of gold iron oxide NPs (GIONPs), it is coated with a β-cyclodextrin-chitosan polymer and conjugated with miRNA. Then it was surface modified with PEG-T7 peptide via CD-adamantane host-guest chemistry. A partial negative potential on the GIOn surface was attributed due to the coating with cyclodextrin-­chitosan (CD-CS) polymer. The in  vivo i.n. delivery of formulation was performed in an orthoptic xenograft mice model (U87-MG GBM derived). The

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MR imaging and optical fluorescence studies suggested the better localization of Cy5-loaded miRNAs in mice administered with GIONPs. The survival rate of mice treated with the formulation was higher compared to other groups. This theranostic platform has good capability to improve the therapeutic effects of TMZ in GBM patients [38, 39]. Salem et al. developed nanoemulsion conjugated with AuNPs for the brain delivery of RES via i.n. delivery for the therapy of Alzheimer’s disease. AuNPs were synthesized by a simple reduction technique and conjugated with RES-loaded transferosomess (RES-Tr-AuNPs). The TEM images of AuNPs indicated they are uniformly distributed and spherical, having a diameter and PDI of 10.30  ±  2.4 and 0.130  ±  0.05, respectively. Micrographs showed that RES-Tr-­ AuNPs are uniform and spherical with a measured size of 94.93 ± 5.6 nm. The zeta potential of the formulation was about −28.7  ±  4.7, which confirms the uniform dispersion and enhanced stability of the system. PDI was less than 0.3, which indicates the uniform and narrow size distribution. The ex vivo penetration study demonstrated the deep penetration of RES-Tr-AuNPs via nasal mucosal layers, indicating uniform distribution and showing higher fluorescence intensity. The histopathology studies showed enhanced accumulation of AuNPs in the cytoplasm and nucleus of brain tissues. Thus the developed formulation can show an efficient brain-targeting effect and can be used for CNS diseases [40]. Betzer et al. developed non-invasive glucose-coated AuNP (G-AuNPs) system for tracking and neuroimaging of exosomes in brain structures. The G-AuNPs were loaded into exosomes via GLUT-1 glucose transporters. The optimal particle size of the formulation was about 5 nm and the administration route of i.n. intranasal administration resulted in excellent in vivo brain accumulation and efficient in vivo bioimaging. The mouse model was used to track AuNPs, which also demonstrated the specific localization of the system. These results suggested the use of this system as a potential diagnostic tool [41]. Silver nanoparticles (AgNPs) show cytotoxicity in normal lung, skin, and fibroblast cells [42]. AgNPs are broadly used in nutraceutical and consumer products due to their better antibacterial and therapeutic characteristics. It has an excellent capability to cross BBB via intranasal administration and to concentrate in the brain. Jonathan and his co-workers compare the transport and biological characteristics of i.n. administration of AgNPs with silver ion. First, they compared the antimicrobial activity of AgNPs and silver ions on the bacteria responsible for clinical rhino sinusitis. AgNPs exhibited reduced antimicrobial activity (minimum bactericidal concentration (MBC) = 15 ppm) compared to silver ions (MBC = 5 ppm). After that, they evaluated the residence time of silver in the sinus cavity followed by i.n. administration of both AgNPs and silver ions to mice, and checked the sinonasal mucosal distribution of silver. The uptake level of AgNPs via respiratory epithelium was minimal in the olfactory bulb and brain. The reduced retention and biodistribution of silver on i.n. administration suggesting the safety of AgNPs [43]. Lung et  al. loaded poorly soluble phytochemicals like chrysin and curcumin into mesoporous silica NPs (MSNs) for nose-to-brain phytochemical delivery. The formulated MSNs exhibited a spherical shape along with an average particle size of 220 nm. DSC, TGA, and FTIR techniques were used to confirm the efficient loading of

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phytochemicals into the MSNs. In vitro drug evaluation indicated the pH-dependent release of drugs at lower pH (5.5) at a better release rate of 53.2 ± 2.2% for curcumin and 9.4 ± 0.6% for chrysin over 24 h. The cellular toxicity of MSNs was evaluated in OBGF400 cells for 24 h, and MSNs were found to be non-toxic. The confocal microscopy study demonstrated that FITC-labelled MSNs showed membrane-­specific and cytoplasmic accumulation on 2 h of post-incubation. Thus the MSNs are capable of targeting and delivering drugs to the brain by bypassing BBB [44]. Magnetic nanoparticles (MNPs) are nanocarriers that show magnetic properties. It exhibits a unique property called magnet operation, in which MNPs produce pores in the cell membranes including BBB for a shorter duration of time, which enhance the targeting efficiency and delivery of drugs [45]. MNPs have potential significance as magnetic contrast agents and magnetic vectors [46]. Abbas et  al. formulated superparamagnetic iron oxide (SPION) loaded with nano lipid carrier (SLN and NLC) for the targeted clonazepam (CZ) delivery to the brain via intranasal olfactory mucosa. To enhance the efficiency of CZ delivery, lipid carriers were conjugated with mucoadhesive in situ gel. NLC formulation showed better entrapment efficiency than SLNs. All the formulations showed zeta potential above 20 mV and negative surface charge, which proved that the nanosuspensions possessed good stability and were well dispersed. The lipid nanocarriers showed a PDI below 0.5, indicating the narrow size distribution. NLC formulation showed better entrapment efficiency (59.3 ± 1.68% – 65.7 ± 1.81%) than SLNs (49.2 ± 1.55% – 52.6 ± 1.35%). NLC showed most satisfactory properties than SLNs and are conjugated with SPION to form NLC-SPION. Both NLC and SPION were then loaded into an in situ system containing sodium alginate (0.75%) and pluronic 127 (15%). The anticonvulsant activity of NLC/in situ and NLC-SPION/in situ was evaluated in Albino mice with chemically induced convulsion. The study resulted in a pronged onset of convulsion and significantly protect from its death [47, 48].

3 Characterization of Nanocarriers for Nasal Delivery Many studies proved the efficient delivery of drugs to the brain followed by the i.n. administration of the drug-loaded nanoformulation is better than free drug formulations. As the nanocarrier system offers non-invasive drug delivery, it is highly patient compliant. Surface functionalization improves the targeted delivery of drugs via i.n. route. It is better to keep particle size below 100 nm to evade opsonization for a prolonged duration. The nanocarrier systems should be biodegradable and biocompatible to keep away from an immune reaction, should show controlled release, no leakage of drugs, be able to load peptides, proteins, and drugs, cost-­ effective and reduce drug-excipient incompatibility [49]. Different mechanisms have been suggested for drug delivery to the brain. The first one is by the release of a chemotherapeutic agent into the mucus-epithelial interface or at mucus membrane by the interaction of drug-loaded nanocarrier with

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the mucus layer. The second one is by uptake of drug-loaded nanocarriers by the neurons after crossing the mucosal barrier, and then it will be moved into trigeminal or olfactory nerve axons and release the drugs. The third one is explained by the crossing of drug-loaded nanocarrier through the neuroepithelium and respiratory epitheliums that will uptake these carriers. Here the drug will be released and enter the CNS through perineural space. The above-mentioned mechanisms indicate that the delivery of drug molecules and the efficacy of the drug delivery system depend on the physicochemical properties of nanocarriers. So it is evident that surface hydrophobicity/hydrophilicity, surface charge, size distribution, composition, and surface charge will affect the activity of nanocarriers in the biological environment. These characteristics can influence the brain delivery of drugs by affecting the drug’s release kinetic profile, neuroepithelial/epithelial-mediated uptake of nanocarrier, and mucus interaction. These aspects on the properties of nanocarriers reveal that the physicochemical properties are important and to be considered while making the formulation for the effective, targeted, and safe delivery of a drug into the brain [50]. To demonstrate the influence of these physicochemical characters on the brain delivery of the drug, many researchers have evaluated in vitro as well as in vivo transport of dug-loaded nanocarriers. In recent work, Gartziandia and his co-­ workers evaluated the permeability characteristics of the nanocarriers (NLCs) as per the change in physicochemical properties. DiR (1-1′dioctadecyl-3,3,3′,3′-tetranethy lindotricarbocyanine), a fluorescent probe was conjugated with the nanocarriers to trace the drug delivery. Compared to PLGA NPs, chitosan-coated NLCs showed higher permeation. The coating of chitosan with NLCs showed a change in surface charge from negative to positive charge and enhanced transcellular transport, which is threefold higher than uncoated NLCs. Surface functionalization of nanocarriers with cell-permeating peptides such as penetration resulted in enhanced permeability [51]. Ahmad et al. evaluated the transportation of nanoemulsions (NEs) by fluorescent bioimaging techniques. They compared the residence duration of NEs in the nasal cavity of rats by administering 100 μL of NEs of different size ranges as 80, 200, 500, and 900 nm from 0.5 to 16 h. NEs with smaller droplet sizes exhibited prolonged retention time compared with larger ones. NEs having a >200 nm showed mucociliary clearance after 4 h of NE application. The remaining evaluation studies were carried out with three optimized formulations NE of particle size 80  nm (NE-80), 900 nm (NE-900, uncoated NEs) and chitosan-coated 108 nm (NEs-108, chitosan coated). The order of retention time after 1 h of nasal instillation of NEs is 108 nm chitosan-coated NEs > NE80 > NE900-uncoated NE [52]. Gabal and his co-workers evaluated the influence of surface charge of nanocarriers for the efficient delivery of a hydrophilic therapeutic agent, ropinirole hydrochloride (RPHCL) to the brain via i.n. route. They formulated both anionic and cationic NLCs optimized based on their zeta potency and particle size. Both cationic and anionic NLCs showed a particle size below 200 nm and a zeta potential of about 34 mV. These optimized formulations were loaded into poloxamer in situ gel and determined the efficacy of the formulation after administering it to rats by

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checking its behavior in the brain and plasma to measure pharmacokinetic variables. A toxicity study was performed in rats for 14  days for both cationic and anionic NLCs and gel-dispersed nanocarriers. Toxicity study showed nasal mucosal lining destruction in rats treated with cationic NLCs and nasal epithelial reversible inflammation in anionic NLCs-treated rats. Gel-loaded NLCs have not shown any histopathological changes in the treated animal. The absolute bioavailability showed by the anionic NLCs (44%) and cationic NLCs (77.3%) in situ gels were significantly larger than i.n. solution of RPHCL. The maximum drug concentration (Cmax) shown by the cationic NLCs-in situ gel was more than the anionic NLCs-in situ gel. Anionic NLCs showed a better targeting effect (158.5) which is 1.2-folds better than cationic NLCs. The poloxamer 188 showed an efficient protective mechanism to safeguard against inflammation and oxidative stress. The reduced toxicity could be attributed due to the restricted movement of NPs via gel network and reduced contact between epithelium and NPs [53]. The relation between brain distribution and peptide-based nanocarriers was evaluated by Kanazawa and his co-workers. Arginine-rich oligopeptide, which possesses excellent transmissibility and adhesiveness, was loaded with stearic acid (hydrophobic nature) or PEG-PCL block copolymer (hydrophilic nature) to make micellar formulations. The particle size of PEG-PCL-peptide (P-P-Pep) and stearate-­peptide (St-Pep) was 50 and 100 nm and zeta potential of about +15 and +20 mV, respectively. The formulations were conjugated with Alexa-dextran (AD) conjugate of molecular weight 10,000 D, a fluorescent probe for assessing biodistribution. Both St-Pep and P-P-Pep carriers showed better uptake in nasal mucosa than AD alone. The St-Pep complex showed intense fluorescence than P-P-Pep in the nasal mucosa, but St-Pep showed less fluorescence than P-P-Pep in the trigeminal nerve. The St-Pep exhibited intense fluorescence in the forebrain, but no fluorescence was observed in the hindbrain. Intranasal administration of P-P-Pep showed fluorescence in the entire brain, which confirmed the distribution of formulation on the entire brain. The study results suggest that the delivery pathways of drugs can be modified based on the characteristics of different nanocarriers [54]. Functionalization of nanocarriers with appropriate polymers could enhance the efficiency of nasal drug delivery. Several natural (gelatine and alginates), semisynthetic (cellulose derivatives), and synthetic polymers (crospovidone and polyacrylates) potentiated the nasal drug delivery [55]. The nasal formulations containing pectins and chitosan showed prolonged residence time in the olfactory area; besides that, sodium hyaluronate enhanced the brain delivery of 4 kDa dextran conjugated with fluorescein after i.n. administration to rats [56, 57].

4 Biomedical Applications of Nanocarrier in Nasal Delivery Several nanocarriers are used for drug delivery: chitosan nanoparticles, liposomes, solid lipid nanoparticles, dendrimers, polymeric nanoparticles, micelles, and nanoemulsions. The objective of nanocarrier in drug entrapment is to increase the

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effectiveness of the drug to the target cell and to decrease the toxicity of the drug to other organs. This will be advantageous in cancer treatment. An anticancer drug like paclitaxel has been investigated for the nanoparticles. It has been shown that the nanoparticles entrapped by the paclitaxel had increased sustainable therapeutic effect and also increased cytotoxic effect on cancerous cells. Due to nano-size, the nanoparticles have several advantages like they can effectively bind to the proteins and can penetrate the cell membrane. They can save from the lysosome after entering into the cell by endocytosis [58]. Along with the drug delivery to the brain, a nasal route can also be utilized for the delivery of stem cells. Several studies have been confirmed that mesenchymal stem cells, neural stem cells, and pluripotent stem cells localized in the brain after administered through the nasal route. Studies were also done on delivery of the mesenchymal stem cells to the brain which successfully treated various brain-related diseases like Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and also stroke. Radiation therapy is successfully used in the treatment of brain tumors. But the disadvantage of radiation therapy is it causes damage to the surrounding healthy tissue. To overcome this disadvantage mesenchymal stem cells were administered intranasal which showed improved neurological function [2]. Liposomes  Liposomes for drug delivery have been investigated. As liposomes can incorporate hydrophilic as well as lipophilic substances, it has extensive use in the delivery of biomedicines. The following drugs have been investigated as liposomal drug delivery system: anticancer drugs like doxorubicin, daunorubicin, cisplatin, amikacin, amphotericin B, liposomal lidocaine, annamycin, nystatin, and retinoic acid [59, 60]. Carboxymethyl chitosan nanoparticles have been prepared for the carbamazepine drug. It has been observed that the concentrations of CBZ remained higher in the brain than the plasma over 240 min. Also, sodium alginate nanoparticles were formulated for the venlafaxine to treat the depression and administered intranasally. The concentration of the drug in the brain was compared with the venlafaxine solution administered through IV and the venlafaxine solution administered intranasally. It was found that the blood/brain ratio of the VLF concentration was higher in the nanoparticles than in other formulations. These prove the prominence of the nanoparticle which directly transports the drug to the brain [4]. Solid lipid nanoparticles (SLN)  Few examples where SLN systems have been utilized for the delivery of anticancer drugs are docetaxel, doxorubicin, paclitaxel, methotrexate, and 5-fluorouracil (5-FU). Dendrimers  Doxorubicin, cisplatin, and 5 fluorouracil have been investigated in the form of dendrimers which have greater effectiveness as compared to the drug used in free form. Virus-based nanoparticles  It was investigated to deliver drugs, in gene therapy, vaccination, targeted drug delivery system. Various viruses like bacteriophage, insect virus, cowpea chlorotic mottle virus, cowpea mosaic virus, red clover necrotic mosaic virus, tobacco mosaic virus poliovirus, and adenovirus are employed in developent of

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virus-based nanoparticles. Advantages of using virus-based nanoparticles are: They are morphologically uniform in size, biocompatible, available in various sizes and shapes, Chemical and genetic alteration can be possible, greater drug entrapment efficiency. If the surface of the virus-based nanoparticle is PEGylated then the circulation time in the host cell can also increase. Carbon nanotube has been investigated for the delivery of various anticancer drugs like methotrexate, paclitaxel, doxorubicin, cisplatin, carboplatin, and mitomycin C [61]. Along with the drug delivery to the brain, the nasal route can also be utilized for the delivery of the stem cells. Several studies have confirmed that mesenchymal stem cells, neural stem cells, and pluripotent stem cells localized in the brain after administration through the nasal route. Studies were also done on delivery of the mesenchymal stem cells to the brain which successfully treated various brain-related diseases like Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and also stroke. Radiation therapy is successfully used in the treatment of brain tumors. The main disadvantage of radiation therapy is it causes damage to the surrounding healthy tissue. To overcome this disadvantage, mesenchymal stem cells were administered intranasally which showed improved neurological function [2] versus applications as shown in Table 7.1.

4.1 Targeted Delivery Parkinson’s disease, Alzheimer’s disease, glioblastoma, epilepsy, and multiple sclerosis are neurological disorders. The central nervous system (CNS) still lacks adequate medication delivery in therapeutic doses [62]. Mainly through the nasal cavity, the target organ is the brain. Nanocarriers are investigated for the delivery of the drug to the brain through the nasal cavity (nose-to-brain drug delivery system). Figure 7.4 illustrates the drug transport from nose-to-brain and systemic circulation. It is a non-invasive method to directly approach the brain by bypassing the blood-­ brain barrier. Thereby it decreases the systemic side effects. It is potentially investigated as an alternative route for administration for the delivery of the drugs which are used in CNS diseases. They also provide the controlled drug release and thereby decrease the administration frequency. NBDDS has been investigated for the treatment of glioblastoma. It is the most lethal form of brain tumor. The absorption of the drug through the nasal route depends on the nature of the drug (hydrophilic or lipophilic) and the molecular weight of the drug. Bioavailability is very less for the drug, which has M.W. greater than 1 kDa. The drug with lyophilic nature and having M.W. less than 1 kDa may have a bioavailability near to 100%. Nanoparticles are investigated for the treatment of brain-related diseases through the nasal cavity. The drug may be administered in the nanoparticle in the form of a matrix or the drug may be encapsulated into the polymer coat. Due to their small size nanoparticles are more effectively transported to the brain transcellular. The disadvantages of nasal administration are the drug is poorly penetrated through the nasal mucosa, fast mucociliary clearance, and degradation of the drug by the enzyme. Encapsulating the drug into nanoparticle will overcome these disadvantages. Besides, NP may offer improved drug delivery to the brain, since they can

Opiorphin

In situ Pain-­ mucoadhesive-­ killing thermosensitive liposomal gel

Polymer–lipid nanocarrier

Ovalbumin

Cancer

Liposomes

Systemic Tenofovir circulation disoproxil fumarate

Ovalbumin

Cancer

Liposome

Therapeutic molecule Rosu­ vastatin

Target diseases Epilepsy

Type of nanocarrier Liquid crystalline nanoparticles

Melt emulsification-­ probe sonication technique

Thin layer evaporation method

Reverse pH

Thin film hydration technique

Method of preparation Hydrotrope-­ based method

Acconon CO-7 (PEG-7 glyceryl cocoate), Carbopol 934 P

Chitosan Carbopol® 974P Chitosan, hydroxypropylmethyl­ cellulose, Poloxamer, Carbopol 239 nm

200– 250 nm 141 ± 4 nm

Dimethyl dioctadecyl 265.9 (± ammonium 51.9) nm

Particle Carrier/polymers size Glyceryl monooleate, 219.15 phenytoin, PTZ, PEG ± 8.14 nm 400, and poloxamer 407

Table. 7.1  Application of polymeric/lipidic nanocarrier in various diseases through nasal route

0.184 ± 0.024

–

–

PDI 0.24 ± 0.03

−44.16 ± 2.51 87.14%

–

–

73.15 ± 0.21% –

−5.33 mV ± 2.019 −0.62 ± 0.18

59 ± 3

70.30 ± 1.84% Female C57/ BL6 mice

56.5 (± 11.9)

Zeta potential −26.2 mv

Reference [81]

–

[85]

L-132 [82] Human lung epithelial cells Calu-3 [83] cells Nasal [84] porcine mucosa

In-vivo Encapsulation animal Ex-vivo efficiency model cell line 70.30 ± 1.84 Swiss – albino male mice

Sumatriptan Micellization

Nose-to-­ brain delivery

Micelle

Particle size 70–80 nm

Transcutol P®, 23.1 Pluronic® ± 0.4 nm F127 (PF127; poly[ethylene oxide]– Poly[propylene oxide] block copolymer)

Method of preparation Carrier/polymers Water-in-oil Poly(ethylene (w/o) emulsion glycol)polycaprolactone block polymer, ε-caprolactone

Therapeutic molecule Camp­ tothecin

Type of Target nanocarrier diseases Nano-micelles Nose-to-­ brain delivery PDI 0.4

–

Zeta potential 5.98 ± 1.32

In-vivo Encapsulation animal Ex-vivo efficiency model cell line Reference 85.7 ± 6.11 Tumor-­ Gastrin-­ [86] bearing releasing rats peptide receptor (GRPR) positive cells – Male – [87] Wistar rats

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Fig. 7.4  Illustration of drug transport from nose-to-brain and systemic circulation Table 7.2  Study on the use of various nanocarrier in nasal delivery for the treatment of glioblastoma Name of drug Bevacizumab Melatonin Temozolomide Curcumin Methotrexate Carboplatin

Nanocarrier Polymeric NPs (PLGA) Polymeric NPs (PCL) Polymeric NPs (PLGA) Nano-emulsion Nanostructure lipid carrier Polymeric nanodispersion (PLA) Polymeric NPs (PCL)

Reference [63] [64] [65] [66] [67] [68] [69]

prevent extracellular transport by P-glycoprotein (P-gp) efflux proteins localized in the olfactory epithelium and the endothelial cells that surround the olfactory bulb. Table 7.2 shows the summary of various nanocarriers, and have been investigated for the treatment of glioblastoma. Alzheimer’s disease (AD) has been managed by meloxicam (MEL). Scientists formulated poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) and solid lipid nanoparticles (SLNs) and SLN coated by the chitosan (c-SLNs). SLNs showed higher encapsulation efficacy (EE) and drug loading (DL) than PLGA NPs. When compared to a native drug, nanocarriers (c-SLNs,>SLNs> PLGA NPs) had a greater sustained release profile, permeation characteristics, and adhesion. As a result, encapsulating MEL in C-SLNs and delivering it via the intranasal route could improve its brain bioavailability [70]. Another study has been done to deliver the drug to the brain by formulating dexamethasone (DXM)-loaded, mixed polymeric micelle-based drug delivery system. Micelles formed had high water solubility due to high surface polarity and low z average. So it shows a high in vitro permeability value on polar brain

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(porcine) lipid extract .diffusion study showed the rapid diffusion through the nasal mucosa. The formulation had also sufficient mucoadhesive property [71–76].

4.2 Gene Therapy Apolipoprotein E (ApoE) gene therapy is a promising disease-modifying method for Alzheimer’s disease. ApoE can control Aβ clearance so it reduces its level and thereby prevent pathogenic plaque development. So it protects neurons. Keeping this concept scientists formulated transferrin-penetrating modified (dual functionalized) liposomes containing ApoE encoding a plasmid DNA (pDNA). The pDNA was complexed with chitosan to increase the transfection’s vitality. They confirmed that the dual-ligand liposome nanoparticles could preserve pDNA from enzymatic nuclease destruction while delivering the therapeutic gene and enhancing ApoE expression. Greater BBB penetration has been observed in the dual-functionalized liposomes than single modified (either transferrin or penetration) formulations. The authors believe that this liposomal-based gene delivery technology has a lot of promise for preventing and treating Alzheimer’s disease [77].

4.3 Vaccine Delivery Apart from the advantages of the nasal drug delivery system there are several disadvantages like permeability of the nasal mucosa for the hydrophilic drugs is less so we get less bioavailability, the dose we can apply is very low, degradation of the drug due to enzymes present in the nasal mucosa and mucociliary clearance is very high. To solve these disadvantages there were many strategies developed. Among that one of the strategies is the formulation of a nanocarrier drug delivery system. Along with the nanocarrier permeation enhancers also be used to increase the penetration of the drug into the nasal mucosa. To prevent mucociliary clearance bioadhesive polymers have been investigated. The principal location for inducing nasal immunity against given antigens is the nasal-associated lymphoid tissue (NALT). NALT consists of B cells, T cells, and a dense network of antigen-presenting cells conveniently located to improve the nasal. Another promising strategy to improve the antigen uptake at nasal mucosa is targeting the formulation for DCs or M cell capture using specific ligands or antibodies. Attenuated influenza vaccine (LAIV) FluMist® (or Fluenz® at Europe): it is the most successful nasal vaccine to date. It is used for more than 10 years in children and adults. The vaccine contains three types of LAIV. The vaccine is in suspension form administered in a specific dose with the help of an intranasal sprayer [78]. The scientist also studied the monovalent influenza subunit vaccine for nasal delivery in form of N trimethyl chitosan nanoparticles as a carrier. The vaccine was formulated by combining TMC and monovalent influenza A subunit H3N2 with a tripolyphosphate (TPP) solution. Incubation of the

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particles in phosphate buffer solution showed that greater than 75% of the protein remain connected with the nanoparticles. The vaccine was administered intranasally as well as intramuscularly. The strong hemagglutination inhibition and total IgG responses have been created in both the routes but response in intranasal (IN) administration was significantly higher than in intramuscular administration. Nanoparticles prepared from trimethyl chitosan induce greater immune responses than the other intranasal antigen formulations. It can be concluded that TMC nanoparticles are a powerful novel delivery system for influenza antigens [79].

4.4 Theranostic Application Theranostics is a combination of two terms therapeutics and diagnostics. It is a new discipline that has the potential to help with medicine delivery to the brain. Theranostics combine radiological science with the delivery of medicinal agents. As a result, customized medicine’s goals are likely to be advanced. The main principle of theranostics is it includes a nanocarrier that contains medicinal agents and imaging labels. So they functionalized as a therapeutic carrier as well as molecular imaging. It also enables real-time tracking of the drug molecule. The nanoparticles were formulated using the polylactide (PLA)–1,2-­distearoylp hosphatidylethanolamine (DSPE) coated with the polyethylene glycol. The aerosolized formulation has been administered to the rat and measured the quantity of the nanoparticles that reached the brain. The novel nano-theranostics was evaluated for quantitative temporal and spatial testing. The nanoparticles were also administered intravenously. After being administered intranasally via nasal tubing and intravenously imaging was done by PET/CT. Imaging was done for 2 h and the animals were sacrificed and different parts of the brain were isolated to compare the activity in each brain region with the corresponding PET/CT region. Greater activity in the brain was found in intranasal administration as compared to intravenous administration. This result was correlated with the ex vivo gamma counting [80].

4.5 Diagnostics Application The nanocarriers containing active moiety are labeled with the radioactive substances. Nanocarriers are administered through the nasal route. The amount of the drug accumulated at the site of action can be determined by various imaging techniques like PET, CT, SPECT, etc. A scientist has developed the chitosan nanoparticles of the zolmitriptan (ZMT) which was labeled with the technetium-99 (99mTc). The nanoparticle was prepared by the modified ionic gelation of anionic sodium triphosphate and cationic chitosan. Three formulations were investigated for the activity in the brain. Those were ZMTNP, ZMT pure drug solution administered intranasal, and ZMTNP administered intravenously all three formulations were radiolabeled with the 99mTc. The accumulation of nanocarrier into the brain was

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visualized by the single-photon emission computerized tomography (SPECT). The percentage of radioactivity in the brain was found greatest in ZMTNP administered intranasally. Therefore, nanocarrier with nasal route is the convincing drug delivery system.

5 Conclusions and Future Perspectives Drug delivery with a nanocarrier system is a viable approach for the treatment of various diseases compared to the conventional formulation. The research done so far had majorly focused on the targeting to the brain via the nasal route. Several nanocarriers were tried in research and showed efficacy. However, still there is a strong need to consider the safety  and efficacy aspects in designing nano-carrier-­based formulations. The polymeric and lipidic nanocarriers are most preferred for deliver drug to brain via nasal route. Furthermore, there is a need to examine the targeting pathway from the nose-to-brain region to understand its mechanism and thereby designing robust formulation. The pharmacodynamics and pharmacokinetic studies in higher animals and clinical proof in humans would be required for judging the nanocarriers for the therapeutic purpose. It is projected that the effective use of new tools and imaging techniques of diagnosis might help for the same in the future. Acknowledgments  The authors would like to thank Nirma University, India for providing financial assistance in the form of Nirma University fellowship-SRF to Atul Garkal (NU/Ph.D./IP/ GAD/19-20/1496). Conflicts of Interest  The authors declare that there are no conflicts of interest for this publication.

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Chapter 8

Delivery of Vaccines via the Nasal Route Seth Kwabena Amponsah and Emmanuel Boadi Amoafo

Abstract  Several methods, including novel formulations and production systems, have been proposed as ways to improve drug delivery. Nasal delivery of drugs is traditionally employed when local effects (allergies, congestion, and respiratory illnesses) and/or systemic effects (pain treatment) are required. Over the last couple of years, the nasal route has been sought as a site for vaccine delivery. Data suggests that when vaccines are administered via the nasal route, they elicit powerful immune system responses. There are a number of vaccines that have been developed for nasal administration, some of which include Nasalflu, FluMist®, and Coronavac, among others. The nasal route for delivering vaccines has many merits; however, a few drawbacks limit the use of this route. Nonetheless, scientists are still trying to exploit this route as a potential for vaccine administration. Keywords  Absorption · Liposomes · Mucociliary · Nasal delivery · Vaccine

1 Introduction Historic data suggests that smallpox killed about 375 million people throughout the twentieth century alone. However, after a successful vaccination (eradication) campaign in the 1970s, few deaths from smallpox have been recorded. Currently, more than 70 vaccines, against nearly 30 microorganisms, exist [1, 2]. Indeed, vaccination has reduced morbidity and mortality associated with infections. The history of vaccination began when Thucydide (430  BC) realized that people who survived fatal infectious diseases were not likely to contract that same disease again [3]. S. K. Amponsah (*) Department of Medical Pharmacology, University of Ghana Medical School, Accra, Ghana e-mail: [email protected] E. B. Amoafo Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_8

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Later on in the fifteenth century, people in China started to practice variolation, a method of exposing healthy individuals to air-dried pustules of smallpox. While effective, the procedure was extremely dangerous. Contemporary medicine made great advancements in vaccination when Jenner discovered that it was worth inoculating people with pustulae derived from cowpox [4, 5]. Later on, Pasteur pioneered the development of vaccines by exposing people to dead or attenuated microorganisms that mimicked the infectious agents [6, 7]. Vaccination leads to induction of an immune response from the host and this is to confer protection against infection or disease upon subsequent exposure to a pathogen. To achieve this, the vaccine should have either antigens from the causative microorganism or synthetic antigens that are components of causative microorganism [8]. Currently, vaccine design takes advantage of the principle of eliciting protective immunity against diseases by simulating immune response against a pathogen that causes the disease, without inducing disease. Additionally, it is important to consider factors that influence interaction between the host and the infectious agent at the population, individual, cell, and, more recently, genetic level [9]. Generally, licensed vaccines are administered intramuscularly (IM), however, some are also available for subcutaneous or intradermal (SC or ID) use [10]. Administration of vaccines via mucosal membranes is becoming a promising avenue to drug delivery. There are currently about 5 approved vaccines (i.e., Dukoral® given orally for cholera, Biopolio™ B1/3 given orally for poliomyelitis, Rotarix® given orally for rotavirus, Vivotif® given orally for typhoid and FluMist™ given intranasally for influenza), that are administered via mucosal membranes. There are several advantages of using mucosal routes in vaccination. For instance, mucosal tissues cover large surface area (on average 400 m2), and this makes them a point of entry for many pathogens [11]. Likewise, nearly 80% of human immunocytes are found on mucosal surfaces; therefore, vaccination via this route helps achieve both systemic and mucosal immunity, unlike parenteral vaccination which merely stimulates systemic immunity [12, 13]. Furthermore, administration via mucosal routes has other advantages over parenteral administration, and these include lower infection risks, increased patient compliance (particularly for pediatric populations), and minimal need of skilled personnel [12, 13]. It is noteworthy, however, that mucosal tissues also have their limitations. They have mucus or cell barriers and enzymes that can affect vaccine function. Nonetheless, there is a lot of effort being made to develop vaccines that can be administered to overcome these limitations [14].

2 Mucosal Delivery of Vaccines Infections of viral or bacterial origin can start at mucosal surfaces [15, 16]. Immune responses mediated by mucosal vaccination are relevant because antibodies can be released into the mucus, thereby, eliminating causative microorganisms. This approach serves as first line of protection on mucosal surfaces. Indeed, this is a big

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step in vaccine development [17]. As a needle-free method of administering vaccines, the mucosal route would address the challenge of needle reuse. Around 16 billion injections were given worldwide in 2000, with reused needles resulting in approximately 266,000 new cases of human immunodeficiency virus (HIV), two million new cases of hepatitis C, and 21 million new cases of hepatitis B [18]. Although not all injections were associated with the process of vaccination, the use of the mucosal route can help minimize needle reuse. Additionally, mucosal vaccination can reduce sharp wastes and prevent needle-stick injuries [17].

3 Nasal Route 3.1 Anatomy of the Nose Compared to the skin, the nasal mucosa does not have a highly keratinized stratum corneum; rather, it is composed of numerous microvilli and a rich vascular network [19]. Traditionally, the nasal route has been employed in the administration of drugs for local and systemic effects. In the past decade, systemic-acting drugs and vaccines have been formulated to be delivered via the nasal route [14]. The nose is divided into two symmetrical halves by the median septum; both halves open toward the face via the nostrils and reach the nasal cavity posteriorly [20]. The nasal cavity is protected by the membranous viscerocranium. The atrium occupies an intermediate area between the respiratory region of the nose and the vestibule. The respiratory region of the nasal cavity, the nasal turbinates, has three sub-sections: inferior, superior, and middle turbinates [21]. Characteristics of various portions of the nose are summarized in Table 8.1.

3.2 Physiology of the Nose The nose is involved in an array of functions, some of which include olfactory (the sense of smell), as well as filtering, humidifying, and regulating the temperature of air entering the respiratory system. The nose is also a point of entry for pathogens. Hair at the entrance of the nostrils provides the first barrier to foreign bodies, since it effectively keeps out large particles [26]. A mucus layer covers the entire nasal cavity, trapping smaller particles. The mucus produced by this layer is viscoelastic and made from mucins that are secreted by mucus sub-glands and goblet cells [27–29]. Through mucociliary clearance, cilia transport mucus blankets packed with pathogens to the back of the throat at a rate of 5–6 mm per minute in either direction, either to destroy the pathogens in the stomach or expel them via sneezing and/or coughing [30].

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Table 8.1  Characteristics of the different portions of the human nose Nasal region Vestibule

Atrium

Respiratory region

Olfactory region

Cells present (function) Nasal hair, stratified squamous and keratinized epithelial cells (support and protection). Stratified squamous cells (support). Pseudostratified cells (support). Columnar non-ciliated cells (support). Columnar ciliated cells (support and muciliary clearance). Globet cells (mucus secretion). Basal cells (progenitors of other cell types). Sustentacular cells (support). Olfactory receptor cells (olfaction perception). Basal cells (progenitors of other cell types).

Surface area (cm3) ≈ 0.6

Vascularization Permeability Low Poor

Reference [22]

Not found

Low

Reduced

[23]

≈ 130

Very high

Good

[24]

≈ 15

High

Direct access to [25] central nervous system

4 The Mucosal Immune System Mucosal surfaces have physical, chemical, and immunological defense mechanisms against infection [31]. In the mucosa of the nose are lymphoid tissues that are responsible for immunity. They are often referred to as mucosa-associated lymphoid tissue (MALT). MALT can also be found in the gastrointestinal tract, lungs, vagina, and rectum [32]. To effectively fight infection, MALT suppresses pathogen-­ specific immune responses and releases immunoglobulin A (IgA) at mucosal surfaces [31, 33]. MALT can be subdivided based on their location. One associated with the nasal route is nasopharyngeal-associated lymphoid tissue (NALT) [34].

5 Nasopharyngeal-Associated Lymphoid Tissue (NALT) Induction of nasal immunity against administered antigens via vaccines takes place primarily at NALT [35]. In simple terms, the NALT is an integrated immune system in the nasal mucosa consisting of lymphoid tissue, B cells, T cells, and

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antigen-presenting cells (APCs) which are covered by epithelia containing memory cells [36]. The Waldeyer’s ring is formed by the physical arrangement of multiple lymphoid tissues in humans, including two palatine tonsils, two tubal tonsils, an adenoid, and a lingual tonsil [37]. These lymphoid tissues sample antigens from food, water, and air and contribute to host immunity [37, 38]. Pathogens are usually identified by APCs (macrophages and dendritic cells) after going through nasal epithelium. Antigens are processed by these APCs and immunogenic features of the antigens are presented to T cells in the lymph node. As a result, the immune response cascade is activated [39]. Additionally, the NALT drains into lymph nodes, where it undergoes further antigen processing [40].

6 Drug Uptake in the Nose Once a drug dissolves in the nasal mucus, extremely vascularized surfaces and low enzymatic activity facilitate absorption [41]. Absorption of drugs from the nasal mucosa can be via transcellular and/or paracellular processes (Fig. 8.1). The mucosal lining over the turbinates or conchae is the most efficient location for absorption in the nasal cavity because it is highly vascularized [21]. By bypassing the liver, drugs administered via the nasal route avoid first-pass hepatic processing, making the nose an ideal target for low orally bioavailable drugs. There is evidence, however, that the nasal mucosa can metabolize substances such as cocaine and progesterone [42, 43].

Fig. 8.1  Drug uptake mechanism in the nasal cavity

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7 Absorption Through Nasal Route Nasal absorption of drugs can happen rapidly; with concentration versus time for nicotine and butorphanol being almost similar to that of intravenous route [44]. A nasally administered drug has to cross a mucus layer and epithelial membrane before reaching the bloodstream [45]. Vaccine administration through the nasal route can be affected by a number of factors. Two of the most important factors are nasal physiology and the physiochemical properties of the vaccine.

7.1 Nasal Physiological Factors 7.1.1 Blood Flow The nasal mucosa is well supplied with blood and has a large surface area, making it ideal for drug absorption. The sphenopalatine artery supplies the nasal septum from behind, the anterior ethmoid artery from above, and the superior labial branch of the facial artery from below. Furthermore, the palatine and ethmoid arteries supply the inferior and lateral walls of the nasal cavity, respectively, while the sphenopalatine artery supplies the remainder of the blood flow to the nasal cavity [46]. Since the absorption of drugs occurs by diffusion, blood flow plays an important role in the concentration gradient at the absorption site [47]. 7.1.2 Mucociliary Clearance Mucociliary clearance system prevents unwanted particulate material from entering the lower airways. Mucociliary clearance reduces the time during which drugs are exposed to the mucosa and thereby affects the absorption of active principles of drugs. Inhaled agents are usually eliminated by this mechanism within 15–30 min at the mucus layer. Transit times longer than 30 min may indicate mucociliary clearance abnormality [22, 23]. Mucociliary clearance is often compared to a “conveyor belt,” with cilia acting as the propeller and mucus, a sticky fluid that discards foreign particles [23]. 7.1.3 Degradation and Excretion of Nasally Administered Drugs Due to the availability of a number of metabolic enzymes in nasal tissues, drugs may be metabolized in the nasal cavity or during transit over the nasal epithelial barrier [47]. Endopeptidases and/or carboxypeptidases are present in the nasal epithelium. These enzymes are involved in the metabolism of drugs as well as the degradation of native molecules [41]. Isoenzymes of the cytochrome P450 family

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have been identified as metabolizers of pharmaceuticals (progesterone, cocaine, nicotine, and decongestants) via the nasal route [48, 49]. Aminopeptidases and proteases can affect the absorption of peptide drugs (insulin, calcitonin, and desmopressin) via the nasal route. These aforementioned enzymes may alter the pharmacokinetics and pharmacodynamics of nasally administered drugs [50, 51].

7.2 Physicochemical Properties of Drugs 7.2.1 Lipophilicity/Hydrophilicity, Molecular Weight, and Degree of Ionization Hydrophilic molecules must employ the paracellular pathway to cross the epithelium, whereas lipophilic molecules can freely diffuse across. For paracellular transit across tight junctions, high molecular weight of a drug may be a limiting factor. Nasal absorption is fast when drugs have a molecular weight below 300 Da, whereas molecules with a weight above 1 kDa are absorbed relatively slowly [22, 45, 52, 53]. Ionization is also an important factor for diffusion; hence drug absorption [53]. Physicochemical factors that can affect the absorption of the active principles of a drug are summarized in Fig. 8.2.

Fig. 8.2  Factors that affect the absorption of xenobiotics across the nasal epithelium

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7.2.2 Solubility Drug absorption is often dependent on the dissolution of the drug at the absorption site. Only molecularly dispersed forms of the drug can pass through biomembranes. For nasal absorption to occur, the drug must dissolve in the watery fluids of the nasal cavity. Thus, it is important that the drug dissolves adequately in the nasal environment to allow adequate contact with the nasal mucosa [54].

8 Types of Nasal Vaccines Studies over the years have tried to develop intranasal drug delivery systems for vaccines. When administered via the nasal route, vaccines may elicit powerful immune system responses. In order to improve the absorption of vaccines, delivery systems can comprise enzyme inhibitors, nasal absorption enhancers, or mucoadhesive polymers [47]. Examples of vaccines administered via the nasal route are summarized in Table 8.2. Some of the formulations of vaccines may include liposomes, microspheres, and nanoparticles.

8.1 Liposomes Liposomes, also known as phospholipid bilayer vesicles, have been well investigated as drug delivery vehicles [60]. Hydrophilic drugs can be entrapped in the aqueous interior of liposomes, and lipid-soluble pharmaceuticals can be integrated into the hydrophobic core of the phospholipid bilayer [61]. Liposomes are small, amphiphilic, and biocompatible, hence, offer promising delivery systems. Liposomes are identified by APCs (macrophages and dendritic cells) and then Table 8.2  Available vaccines that are administered via the nasal route Vaccine name Nasalflu FluMist® Comirnaty (BNT162b2) Ad26.COV2.S

Coronavac

Type Inactivated virosomal-subunit Live attenuated influenza vaccine mRNA vaccine (nucleoside modified) Adv serotype 26(Ad26) vector-based DNA vaccine (non-replicating viral vector) Inactivated vaccine

Potential use Influenza Influenza

Company Berna Biotech AstraZeneca

References [55] [56]

SARS-­ Pfizer, BioNtech, CoV-­2 Fosun Pharma COVID-­19 Johnson & Johnson

[57]

COVID-­19 Sinovac Biotech

[59]

[58]

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presented to other lymphoid cells for immunological responses [62]. Liposomal drug delivery systems provide several benefits, including the ability to encapsulate drug molecules with different solubility and pKa values [63]. The ability of liposomes to change the pharmacokinetics of their associated medications is a key feature that makes them useful as drug delivery systems [64, 65]. Liposomes have been found to increase membrane penetration of peptides such as insulin and calcitonin by increasing their nasal absorption [66, 67]. The Swiss Serum Institute recently launched a nasal influenza vaccine based on a liposome (virosomal) formulation of influenza virus components [68].

8.2 Microspheres Microsphere technology has been widely used in the development of nasal medications. Microspheres are small spherical particles that range from 0.1 to 200 μm in diameter and are made of biodegradable and non-biodegradable materials [69]. Microsphere-based systems have the potential to extend the half-life of active constituents, while also regulating the release of bioactive compounds [70]. Degradable starch microspheres (Spherex®) are the most utilized microsphere technology for nasal drug delivery. Usually, an emulsion polymerization approach (starch cross-linked with epichlorohydrine) is used to make these microspheres [71]. Microspheres can protect vaccines from degradation by enzymes and improve their efficacy [72].

8.3 Nanoparticles Drug delivery using nanoparticulate systems is known to improve intranasal drug delivery. Nanoparticles are natural or artificial polymers ranging in size from 1 nm to 1000 nm. Nano-biotechnology in drug delivery is to improve precision of medicine, reduce toxicity, and enhance therapeutic effect [73]. In vaccines, nanoparticles can be adjuvants in which the active agent can be dissolved, entrapped, encapsulated, adsorbed, or chemically attached [74]. Nanoparticles can protect vaccines against the hostile environment of the nasal mucosa and also aid in the activation of the immune system response [21].

9 Challenges with Nasal Vaccines Vaccines administered via the nasal route have many merits but also have some limitations. Water soluble molecules with low membrane permeability (especially those with high molecular mass), mucociliary clearance, mucus barriers, and

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enzymatic environment can adversely affect vaccine administration via the nasal route [75]. Additionally, the poor deposition of vaccines in nasal mucosa poses a challenge to the use of this route [76]. To overcome these challenges, absorption boosters and/or protease inhibitors can be added to vaccines. Cell-stabilizing and cell-penetrating agents can also be added to vaccines. The use of nanoparticulate drug delivery systems also holds promise [40, 77].

10 Conclusion Administration of vaccines via the nasal route has promise based on the research available. By using the nasal route, we could possibly solve many unmet medical needs and improve vaccination of masses due to better compliance (compared to parenteral vaccines). Furthermore, employing the nasal route avoids the risk of disease transmission via needle reuse. Also, the nasal route for vaccination can trigger powerful mucosal and systemic immune responses.

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Chapter 9

An Overview on Nanocarriers for Nasal Delivery Sunita Dahiya and Rajiv Dahiya Abstract  Nasal delivery has come up as a promising approach to deliver diverse therapeutic agents including small drug molecules to biomacromolecules like peptides, proteins and genes to treat various disorders of central nervous system including depression, epilepsy, migraine, schizophrenia, Parkinson’s disease, Alzheimer’s disease, and brain tumor. Nasal route unveils the possibility for delivering the drug directly from nose to brain, circumventing the challenging blood-brain barrier enabling their effective brain delivery. The past couple of decades have witnessed tremendous enthusiasm about exploiting nanotechnology-based approaches in the drug delivery area, specifically due to the exponential growth in research efforts employing the nanocarriers’ delivery via different administration routes including the nasal route. Nanocarrier-based nasal delivery of drugs has progressed over the years with an assumption that the use of nanocarriers would enable the drug to access tissues and organs that could otherwise not be accessed effectively by conventional nasal delivery. The present chapter sets out to discuss applications of different nanocarriers in nasal delivery along with their transportation mechanisms and toxicity concerns. Keywords  Nano carrier · Intranasal administration · Nasal delivery · Nasal toxicity · Nasal transport

S. Dahiya (*) Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico – Medical Sciences Campus, San Juan, PR, USA e-mail: [email protected] R. Dahiya School of Pharmacy, Faculty of Medical Sciences, The University of the West Indies, St. Augustine, Trinidad and Tobago e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_9

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1 Introduction The global market for nasal drug delivery is forecasted to reach US$59.2 billion by 2027 at a CAGR of 4.1% from the estimates of US$44.7  billion in 2020 [1]. Traditionally, nasal delivery is limited to topical delivery of drugs in combating nasal problems like nasal congestions, allergic rhinitis, and common cold. In recent years, an increased interest has emerged to utilize nasal route as non-invasive alternative to achieve systemic effects of drugs and vaccines over the invasive parenteral route based on its efficient and cost-effective delivery. In particular, nasal mucosa is highly vascularized and offers benefits including fast onset of action, improved bioavailability, enhanced patient acceptance, and higher immune response to favor vaccine delivery [2]. Some studies indicated that a drug delivered via intranasal route provides quicker therapeutic response than an oral mixture or tablet and the response could be achieved as fast as intravenous injection [3]. In addition, intranasal vaccination contributes to local immune protection [4]. Further, the nose is a promising route for delivery of macromolecules and biotechnology-derived multifarious proteins. Combining the nasal formulation advancements with the contemporary nanotechnology concepts may render vital benefits for the delivery of drugs and vaccines [5–7]. More efficient dosage forms not only offer patient compliance but can also get long patent periods upon their successful commercialization that help to sustain market share and revenue of pharmaceutical company under rationally limited investment. Marketed nasal formulations containing biologic macromolecular drugs and small molecule drugs are summarized in Tables 9.1 and 9.2 respectively [8, 9].

Table 9.1  Marketed nasal formulations containing biologics Therapeutic agent (Dosage form) Calcitonin (Nasal spray) Desmopressin (Nasal spray)

Molecule (MW) Peptide (3432 Da) Peptide (1183 Da)

Oxytocin (Nasal spray) Nafarelin (Nasal spray) Cyanocobalamin (Nasal spray) Live attenuated influenza vaccine (Nasal spray) Human live attenuated influenza vaccine (Nasal spray)

Peptide (1007 Da) Peptide (1321 Da) Peptide (1355 Da) Virus-based vaccine H1N1

Brand name(s) Fortical® Miacalcin® Diabetes insipidus, Hemophilia A, Minirin® Nocturnal polyuria Stimate® Noctiva™ Start or strengthen uterine Pitocin® contractions during labor Syntocinon® As part of a fertilityprogram, Synarel® endometriosis Deficiency of vitamin B12 Nascobal® Indication Osteoporosis

Influenza

FluMist®

Swine flu

NASOVAC™

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Table 9.2  Nasal delivery of small molecule drugs for systemic effects Drug Butorphenol Estradiol Fentanyl

MW (log P) 327.5 (3.7) 296.4 (4.3) 336.5 (4.1)

Indication Migraine; pain management Hormone replacement therapy Breakthrough cancer pain

Naloxone Nicotine Sumatriptan Zolmitriptan

327.4 (0.6) 162.2 (1.09) 295.4 (0.8) 287.3 (1.6)

Opioid overdose Smoking cessation Migraine and cluster headaches Migraine

Brand name(s) Stadol NS® Aerodiol® Instanyl® PecFent® Narcan® Nicotrol NS® Imitrex® Zomig®

2 Key Anatomical Regions and Functions of Nasal Cavity Three major segments of nasal cavity are nasal vestibule, respiratory region, and olfactory region, each one performs distinct functions [10]. The nasal vestibule, also known as nostril, is the area surrounding anterior external opening to the nasal cavity. Nostrils contain nose hairs that behave like baffle and performs filtration of inhaled air. The olfactory region is situated at the peak of the nasal cavity. Olfactory region is lined by olfactory cells with olfactory receptors. From this region, odorant particles are transported to olfactory epithelium and further solubilized by binding with the odorant-binding proteins, attach to olfactory receptors, and allow higher processing before entry into the brain. The respiratory region is lined by a ciliated pseudostratified epithelium and spread along mucus-secreting goblet cells. The respiratory region is the most significant segment performing the functions to humidify, warm, filter, protect, and remove debris [11]. The olfactory epithelium is located in the upper part of nasal cavity and occupies about 10% of the nose area. The olfactory region is the only site in the human body that allows direct contact of the CNS with the external environment. This region is of prime importance for the drug delivery because nasal administration can directly transport the drugs to this region which can further diffuse through the olfactory mucosa to reach the CNS through the epithelial pathway [12].

3 Nasal Delivery: Rationale and Design The delivery of drugs via nasal route has logical reasons in terms of the easy access of nasal cavity, rich vascularity that help to achieve effective drug concentrations in blood even if after topical administration, which is specifically convenient compared to the use of catheter required for the invasive intravenous route as a means of direct drug delivery to the blood [13]. Higher blood concentrations can be achieved via nasal route by employing the drug solution as fine droplets or mist rather than as larger droplets of drug solution, as larger droplets may run off and fail to be absorbed

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[14]. The rich vascularity of nasal cavity enables entry of highly permeable drug directly into the blood stream. Further, this direct systemic absorption bypasses the first pass hepatic metabolism of the drug by live enzymes which is common for several drugs administered via oral route. Thus, for the drugs undergoing extensive first-pass metabolism, nasal route offers a non-invasive way of enhancing bioavailability over oral route [15]. In addition, nasal administration of many drugs shows comparable plasma concentrations to those achieved by their intravenous route or typically better plasma concentrations that are achieved by intramuscular or subcutaneous routes [16, 17]. Nasal administration is non-invasive, painless, and readily self-administered by the patient, in contrast to the invasive intravenous administration that requires medical aid for their administration. Another advantage of nasal route is its nearby location to the brain, which may achieve higher drug concentrations in cerebrospinal fluid (CSF) and spinal cord as compared to that of the plasma [18]. Typically, small and lipophilic drug molecules permeate through the nasal mucosal membranes easily at near physiological pH [19]. However, the important concern in nasal drug delivery system is that the adequate drug concentration be present in volume as low as 0.25–3 mL which is the volume that the nasal cavity can accommodate per nostril. For intranasal administration, a drug must be concentrated to a degree that a dose can be administered in 50%. Gelling of pectins is significantly affected by degree of esterification. LMP can form gel in the presence of divalent cations, such as calcium, following a similar mechanism of gellan gum due to the formation of intermolecular junction zones by side by side association of homogalacturonic smooth regions of different chains. HMP form gel with sugar and acid. LMP gelled rapidly after administration in the nasal cavity of sheep and retained for an extended period of time [133, 134]. The example of commercially available ion responsive in situ gelling nasal drug delivery is PecFent® (fentanyl citrate) nasal spray which uses Archimedes Pharma’s patented drug delivery system PecSys™. It is the LMP-based drug delivery system designed for administration as fine mist spray which forms gel upon contact with the nasal mucosa. This system enables fast onset of action [135]. The gelling of the product prolongs

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the delivery of fentanyl in a controlled manner as well as absorption of the drug, but does not increase the bioavailability [37]. PecFent® exhibited better tolerability profile when compared with fentanyl, chitosan and fentanyl in chitosan-poloxamer 188 system, as well as superior pharmacokinetic profile compared to transmucosal oral fentanyl citrate [136]. Pectin-based liquid nasal formulations are rated as controlled drug release vehicles; however, these polymers showed low effect on drug molecules transport in cell monolayers, as demonstrated for the model substances mannitol and propranolol [11]. LMP-based liquid nasal formulations have been shown to be promising for achieving mucoadhesion in the olfactory region. Charlton et  al. [11] investigated nasal drug delivery systems prepared with LMP. It was found that all formulations were able to reach the olfactory region in the nasal cavity of human volunteers when delivered using a simple nasal drop device whereby the volunteer is in the supine position with the head tilted back. Moreover, the formulations displayed a significantly increased residence time on the olfactory epithelial surface, potentially enhancing the delivery of drugs to the brain, in contrast to a non-bioadhesive control administered with the same device. Also, the pectin formulation administered with a nasal spray system did not show an increase in residence time in the olfactory region.

2.7 Alginates Alginates are salts of anionic linear polysaccharides consisting of varying ratios of glucuronic and manuronic acid units [137]. Sodium alginate is the purified product obtained by alkaline extraction from brown seaweed. It dissolves in water, slowly forming a viscous, colloidal solution. The solution of this hydrosoluble monovalent salt undergoes sol-gel transition upon addition of divalent ions (e.g., calcium) [138]. Alginate gels with high glucuronic acid contents are more rigid and porous in comparison with gels comprising alginates with low glucuronic content, which are more randomly packed and less porous [139]. Mucoadhesiveness of alginates is relatively poor because it is based on formation of hydrogen bonds with mucin-type glycoproteins through carboxyl–hydroxyl interactions [140, 141]. It can be improved by covalent attachment of L-cysteine to the polymeric backbone. Thiomer alginate-­ cysteine exhibited a concentration-dependent cilio-inhibitory effect. The observed effect was moderate and followed by a partial recovery of ciliary beat frequency at the polymer concentration of 1%, while at 2% cilio-inhibition was severe and partially reversible [79]. In spite of promising observations, alginate thiomers have been scarcely investigated for the nasal drug delivery.

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2.8 Gelatin and Its Derivatives Gelatin is a fibrillar protein derived from collagen. The product of acidic collagen hydrolysis is gelatin A, while the product of alkaline treatment of collagen is gelatin B. The molecular weight is about 75 kDa. Gelatin dissolves in water forming thermally reversible and pH-sensitive gels. The gelation temperature is about 35 °C and may vary with the pH of the solution [34]. Morimoto et al. [142] have prepared gelatin microspheres (10.9 μm) with negative charge and microspheres (3.4–71.5 μm) with positive charge using basic gelatin [isoelectric point (IEP) value of 5.0] and acidic gelatin (IEP = 9.0), respectively. The adhesion to the nasal mucosa of positively charged gelatin (PCG) microspheres was significantly higher than that of negatively charged gelatin (NCG) microspheres. The nasal absorption of salmon calcitonin in rats was enhanced by both types of gelatin microspheres; however, the hypocalcemic effect after administration of PCG microspheres of 11.2 μm was significantly greater than that of NCG microspheres of the same size. The hypocalcemic effect of the NCM microspheres tended to appear more slowly and last longer compared to that of PCG microspheres. In order to enhance the nasal drug delivery potential of gelatin, aminated derivatives were prepared and investigated. Wang et  al. [143] prepared aminated gelatin by cationization of gelatin with ethylene diamine. Positively charged aminated gelatin can interact with negatively charged mucin, thus upgrading the mucoadhesiveness. Moreover, it showed the absorption-enhancing effect, in both liquid and powder dosage forms, for insulin and fluorescein isothiocyanate-dextran (4.4 kDa) in rats. The hypoglycemic effect was affected by the pH of the formulations and the concentration of aminated gelatin. Aminated gelatin showed a concentration-­ dependent (0.1–0.4%) but relatively small effect on the lactate dehydrogenase leaching in an in situ perfusion rat nasal epithelial membrane model. In the continuation of the research, aminated gelatin microspheres (AGM) were prepared and investigated as a nasal delivery carrier for fluorescein-labeled insulin and dextran (4.4  kDa) [144]. Insulin release from the microparticles was significantly slower than from native gelatin microspheres (GMS); however, the release of dextran from both AGM and GMS was fast, likely due to the different electrostatic interactions between the model drugs and the microspheres. The plasma glucose levels of healthy rats following intranasal administration of insulin-loaded AGM showed that AGM could significantly increase the absorption of the drug when administered in a dry powder formulation, but no significant hypoglycemic effect was observed when given in suspensions. The absorption enhancement effect was ascribed to the hydration of AGM with water from nasal mucosa resulting in a temporary dehydration of the epithelium membrane and opening of the tight junctions. Indirectly, mucoadhesiveness contributed to the absorption enhancing effect. In a similar study, sperminated gelatin (SG) also enhanced the nasal absorption of insulin in rats by modulation of the epithelial tight junctions [145]. SG was prepared by the addition of spermine, which is a small organic polyamine. In Calu-3 cell monolayer permeation experiments, SG showed significant enhancing effects on

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Table 11.2  Examples of synthetic polymers and their derivatives evaluated for nasal drug delivery Mucoadhesive polymer Polyacrylates

Miscellaneous synthetic polymers

Derivative Carbomers

Polycarbophil thiomers Polyvinylacetal diethylamino acetate Polyamidoamine (PAMAM) dendrimers

Benefit pH-responsive/sensitive polymers; swelling upon hydration; suitable for achievement of controlled (sustained) drug release; enhanced nasal bioavailability of drugs Sustained drug release and increased drug uptake by nasal mucosa pH-responsive and thermo-­ responsive gelling on the rat nasal mucosa to control the drug release Enhancement of aqueous drug solubility; transmucosal drug delivery; nose-to-brain drug delivery and cellular uptake

References [21, 26, 36, 100, 147–151]

[152–154] [155]

[156–162]

5(6)-carboxyfluorescein (CF), FITC-dextran (MW 4400, FD4), and insulin. Although the cylindrical pore radius was not changed, the pore occupancy/length ratio of the permeation pathways for water-soluble molecules in the tight junctions increases indicating that SG increase the pore number, while retaining the sieving property of the epithelial membranes.

3 Synthetic Mucoadhesive Polymers The synthetic mucoadhesive polymers offer advantages such as stability, mechanical strength, and easy production, but there are only few types that show adhesion to the nasal mucosa and sensitivity to conditions in the biological environment. Examples are given in Table 11.2. So far, in nasal drug delivery carbomers and polycarbophils have been considered the most often [36]. Their mucoadhesion is based on formation of hydrogen bonds between the functional groups of the polymer and mucosal layer. The interaction with the nasal mucus can be altered by chemical derivatization of the parent polymer. Thiomers  have been synthetized with the free thiol groups which form disulfide bonds with the cysteine-rich residues of mucin [146].

3.1 Polyacrylates Polyacrylates are polymers of acrylic acid very frequently used in liquid, semisolid, and solid dosage forms for different drug administration routes. As mucoadhesive polymers, polyacrylates attach to nasal mucosa and ensure intimate and prolonged contact between the drug delivery system and the membrane surface at the site of

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absorption. In the nasal drug delivery systems, carbomers and polycarbophils are mostly considered. Carbomers are polymers of acrylic acid that have been cross-­ linked with either allyl sucrose or allyl ethers of penta erythritol. They are hydrosoluble polyelectrolytes with pendant carboxyl side chains which are ionized at neutral pH.  Such acidic carboxylic groups get deprotonated at the basic pH and acquire negative charge. The similar charge causes electrostatic repulsion between the polymer chains, and the material expands in dimensions. At acidic pH, carboxyl groups lose their charge hence the repulsion is eliminated, and the material regains its original shape. Therefore, at acidic pH carbomers are in solution, while they form soft gel at pH 6–8, so they can be considered as pH-responsive/sensitive polymers toward nasal route of administration. Also, carbomers are powders which readily absorb water, become hydrated, and swell. The cross-linked structure and swelling behavior make them suitable for achievement of controlled (sustained) drug release mechanisms [36, 147]. Carbopol® 974 (1%, 1.5%, and 2%) was used for preparation of nasal gels for progesterone delivery in rabbits. The drug-loaded gels were prepared by dispersing polymer in distilled water followed by addition of progesterone/progesterone-beta cyclodextrin complex dissolved in propylene glycol and neutralization. The absolute bioavailability of progesterone from nasal gels was significantly increased in comparison to intravenous injection. The nasal absorption of progesterone was promoted by the beta cyclodextrin complex; however, the significance of mucoadhesion has not been assessed [148]. Carbopol® 934P gel produced a significant hypoglycemic response in rabbits, whereas no response was seen following nasal administration of the insulin solution formulation. The bioavailability of insulin from the nasal gel formulation was 20.6% higher in comparison with the intravenous injection. Although there have been no attempts to assess its mucoadhesiveness, it was concluded that the Carbopol® 934P 0.4% gel promoted the nasal absorption of insulin due to its sprayability with commercially available spray pumps [149]. Ugwoke et al. [100] investigated the residence time of apomorphine administered in rabbit nasal cavity in the form of a mucoadhesive preparation based on the oral grade carbomer (carboxypolymethylene (Carbopol® 971P)) or carboxymethyl cellulose. The drug clearance from the nasal cavity to the stomach and intestine was evaluated and compared by gamma scintigraphy. Although apomorphine itself inhibited nasal mucociliary clearance, the lowest drug clearance percentages (3% and 12% at 30 min and 3 h post insufflation, respectively) were observed in the presence of Carbopol® 971P. The use of Carbopol® 971P increased the nasal residence time and provided sustained nasal delivery of apomorphine and achievement of its peak plasma concentration while the formulation was still within the nasal cavity. Another study of Ugwoke et al. showed that the Tmax of apomorphine delivered by the Carbopol® 971P-based formulation was 52.21 min, that is, 5-fold higher in comparison with that of the lactose-containing formulation. Simultaneously, the Cmax of the Carbopol® 971P-containing formulation was lower than that of the lactose-­containing formulation [150]. Nandgude et  al. [151] demonstrated pH-­ responsive gelation caused by deprotonation of Carbopol® 934 at nasal pH. This in situ gelling formulation comprising 0.4–0.5% w/v of carbomer enabled sustained

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release and enhanced bioavailability of salbutamol sulphate. Sustained release of drugs results in a more stable blood concentration-time curve [21]. The study of Abd El Haamed and Kellaway [26] showed that Carbopol® 934P-based microspheres had superior mucoadhesiveness compared to those made from chitosan, polyvinyl alcohol, and HPMC.

3.2 Polycarbophils Polycarbophils are polyacrylic acid-based polymers cross-linked with divinyl chloride. Thiolated polycarbophils were used to study the nasal delivery enhancement potential of leu-enkaphlin and human growth hormone [152, 153]. The results showed that the thiomers of polycarbophils provide sustained release and diminish the risk for the degradation of leu-enkaphlin, while the drug uptake by nasal mucosa was increased by 80-fold [152]. Gel based on thiolated polycarbophil effectively improved the nasal delivery and plasma level of human growth hormone [153]. Greimel et al. [154] used polycarbophil thiomer (polycarbophil-cysteine) for development of microparticles (up to 100 μm) for nasal administration. The thiomer was synthesized by the covalent attachment of L-cysteine to neutralized polycarbophil via formation of amide bonds between the primary amino group of cysteine and the carboxylic acid group of the polymer. The microparticles provide controlled release of the model compounds sodium fluorescein and fluorescein isothiocyanate-­dextran, while their transport through the freshly excised bovine nasal mucosa was increased 1.70-fold and 2.64-fold, respectively, in the presence of permeation mediator glutathione. Evaluation of ciliary beat frequency of human nasal epithelial cells excluded the risk of ciliotoxicity caused by thiolated polycarbophil.

3.3 Miscellaneous Synthetic Polymers Aikawa et al. [155] developed pH-responsive polyvinylacetal diethylamino acetate (PDA) hydrogel and evaluated its potential for nasal delivery of chlorpheniramine maleate and tetrahydrozoline hydrochloride. PDA forms transparent solution at pH 4, while abrupt formation of porous hydrogel occurred in vitro, in phosphate buffer at pH 7.4 at 37 °C. In vivo formation of the hydrogel on the rat nasal mucosa was visually confirmed. The gelling phenomenon included shrinkage of the pores due to increase in the temperature from 25 to 37 °C at pH 7.4, which was related with the hydrogel potential to control the drug release. The higher the PDA concentration, the lower drug release rate was observed. The in vitro drug release profiles from dialysis tubes showed a rapid and a slow phase, with an inflection point, at which hydrogel formation occurred. Dendrimers are three dimensional, highly ordered, branched polymeric molecules with unique structural architecture. Polyamidoamine (PAMAM) dendrimers have gained attention for nasal drug delivery due to their capacity for enhancement of aqueous

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Fig. 11.2 (a) Synthesis schematics for the PAMAM dendrimer nanocomposites. (a) Synthesis of pegylated PAMAM dendrimer (mPEG-PAMAM G5.NH2); (b) synthesis of mPEG-PAMAM G5. NHAc by the addition reaction between anhydride and the amino group; (c) paeonol (PAE) loading in the cavities of mPEG-PAMAM G5.NHAc; (d) the FITC tracer was used to label PAMAM to observe the nasal brain transport of PAMAM dendrimer nanocomposite in vivo; (b) Transmission electron microscopy (TEM) images of nanocomposites. (a) PAMAM G5.NH2; (b) PAE/mPEG-­ PAMAM G5.NHAc; (c) high-resolution image of a single PAE/mPEG-PAMAM G5.NHAc; (d) the image of PAE/mPEG-PAMAM G5.NHAc based DGG (deacetylated gellan gum) in situ gel [158]

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Fig. 11.2 (continued)

drug solubility, transmucosal drug delivery, and cellular uptake as well as the nose-tobrain drug delivery [156, 157]. PAMAM dendrimers are biocompatible, biodegradable, and low-immunogenic spherical molecules with internal cavities and peripheral functional groups available for modification to encapsulate drugs. The core of PAMAM dendrimers is usually ethylenediamine, to which methyl acrylate and ethylenediamine are repeatedly added according to the desired number of generations G0, G1, G2, G3, G4, and also generation called G5 obtained by terminating the reaction sequence after addition of methyl acrylate that leads to terminal carboxylate groups (Fig.  11.2). Superficial branches of PAMAM molecule could be terminated by amino-, hydroxyl-, aldehyde-, methoxycarbonyl-, tert-­butyloxycarbonyl-, methyl-, or -COONa groups. The amino group is typically employed in intracellular delivery of genetic material [158–160]. PAMAM dendrimers were evaluated for enhancement of solubility and nose-to-­ brain delivery of haloperidol. Nasal administration of PAMAM-based formulation enabled achievement of the same behavioral response by 6.8-fold lower doses as the one induced by the intraperitoneal injection [161]. Kamei et  al. [162] attached siRNA onto PAMAM dendrimers to target against high mobility group box 1 (HMGB1). Upon intranasal administration, siRNA was distributed in different regions of brain and depleted the target gene in peripheral cortex and striatum. PAMAM dendrimers also had potential diagnostic applications on neurological

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biomarkers in mouse brain by nasal route, although it is not clear whether the brain delivery realized through systemic circulation or via olfactory pathway [163].

4 Mucoadhesive Copolymers Synthetic copolymers as well as copolymers obtained by covalent conjugation of natural polymers with synthetic polymers find application in the design of mucoadhesive nasal drug delivery systems with sensitivity to temperature and/or pH in the nasal cavity. Copolymer formation allows the expansion of excipients performances, such as increased water solubility, amphiphilicity, increased molecular weight and mucoadhesiveness, and/or extended drug release [22, 164]. Examples of copolymers considered so far for nasal drug delivery are: poloxamers, poly(N-­ isopropylacrylamide) (PNiPAAm), PNiPAAm-co-polyacrylamide, PEGylated chitosan, alginate polyethylene glycol acrylate, poly lactic-co-glycolic acid (PLGA), PEGylated PLGA, lectin conjugates of PLGA, and PEG-PLGA (Table 11.3). Poloxamers are nonionic poly(ethylene oxide)-poly(propylene oxide)poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymers. The hydrophobic polypropylene oxide segment connects two hydrophilic polyethylene oxide segments. Poloxamers are commonly named with the letter “P” (for poloxamer) followed by three digits. The first two digits × 300 give the approximate molecular mass of the polyoxypropylene core, and the last digit × 10 gives the percentage polyoxyethylene content [41, 165, 166]. In aqueous solutions poloxamers show amphiphilic character and form micelles at concentrations above the critical micellar concentration (CMC). An increase in the polymer concentration leads to arranging of the micelles in various liquid crystalline phases such as lamellar, cubic, and hexagonal. An increase in temperature causes desolvation (i.e., the rupture of the hydrogen bonds present between the hydrophilic polyoxyethylene chains and solvent) as well as the enhancement of the hydrophobic interactions among the polyoxypropylene chains that induce formation of cubic structure and formation of gel [167, 168]. Poloxamers are thermo-responsive polymers whose aqueous solutions exhibit in situ gelling (sol-gel transition) upon exposure to the nasal temperature. Their thermoreversible gelling properties depend on the copolymer concentration, molecular weight, and ratio of molecular weight of hydrophilic core to molecular weight of hydrophobic core [169, 170]. Poloxamer 407 is frequently used in drug delivery systems and its lower critical solution temperature (LCST) varies between 25  °C and 37  °C as a function of the copolymer concentration. Aqueous solutions of poloxamer 407 at the polymer concentration of 16–18% exhibited thermoresponsive gelling at the temperature of 32 ± 2 °C, which is close to the nasal temperature [171, 172]. It was demonstrated that poloxamers in concentrations below CMC may increase the transnasal drug delivery, but this was not observed at concentrations above CMC [173]. The study of Na et  al. [95] reported better permeation enhancing effect of poloxamer 188 in comparison with hydroxypropyl-beta-cyclodextrin and chitosans of different molecular weight, for

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Table 11.3  Examples of mucoadhesive copolymers and achieved benefits for nasal drug delivery Mucoadhesive copolymers Poloxamers

Poloxamer/carbomer graft-copolymers Poly(N-isopropylacrylamide) (PNiPAAm) and (PNiPAAm)-co-polyacrylamide Acrylated Eudragit® E PO

PEGylated chitosan

Alginate polyethylene glycol acrylate Poly lactic-co-glycolic acid (PLGA) Wheat germ agglutinin-conjugated PLA-PEG Solanum tuberosum lectin-­ conjugated PLGA Solanum tuberosum lectin-­ conjugated PEG-PLGA nanoparticles

Benefit In situ gelling upon exposure to the nasal temperature Permeation enhancing effect for intranasal absorption of drugs Inhibition of drug efflux transporters in olfactory region and at the BBB Thermogelling property and enhanced mucoadhesion Thermosensitive gelling in nasal cavity

References [169–172]

Enhanced mucoadhesiveness due to covalent linkages between acrylated groups and mucins Aqueous solubility at alkaline pH; pH-dependent permeability enhancing effect; enhanced nasal absorption Gelling properties with strong mucoadhesion; controlled drug release rate Design of nanoparticles for brain targeted delivery via olfactory neurons Nanoparticles for improved nose-to-brain absorption Nanoparticles suitable for rapid absorption and higher brain targeting efficiency Nanoparticles for achievement of enhanced brain bioavailability of nasally administered peptides; protection of peptide and protein-based drugs from peptidase degradation in nasal cavity

[179]

[95] [174] [175, 176] [177, 178]

[180–182]

[184, 185] [186, 187] [189] [190] [194, 195]

intranasal absorption of isosorbide dinitrate in rats. In addition to thermo-sensitivity and permeation enhancement ability, poloxamers have been attributed the ability to inhibit the drug efflux transporters, such as Pglycoprotein, that are present throughout the nasal cavity, in olfactory region, and at the BBB [174]. Despite these favorable characteristics, uncharged poloxamer molecules are considered weak mucoadhesive agents. Mucoadhesion can be enhanced by graft-copolymerization of the hydrophobic segment of poloxamers with a suitable polyelectrolyte segment having ionizable groups. The example is poloxamer 407/carbomer copolymer consisting of a thermosensitive polymer and a pH-sensitive mucoadhesive polymer, respectively. The copolymer has shown thermogelling property and enhanced mucoadhesion at low concentrations due to the presence of carboxylic groups in carbomer. Also, the carboxylic groups get deprotonated at the basic pH and acquire negative charge that causes repulsion between the copolymer molecules leading to their expansion and gelling of the system. Relevant studies reported the enhancement of the viscosity for

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10–103 fold for 1–5% w/v solution of the poloxamer/carbomer (1:1) graftcopolymers and increase in the residence time for fluorescent labels in rat nasal cavity, while the physical mixture and/or random copolymer of the thermosensitive and the pH-­ sensitive polymer loses its thermosensitivity and shows only pH-sensitivity [175, 176]. Poly(N-isopropylacrylamide) (PNiPAAm) and (PNiPAAm)-co-polyacrylamide are examples of copolymers which aqueous solubility significantly changed around their LCST due to rapid hydrophobic and hydrophilic interactions between the polymeric chains and the aqueous media. At the temperatures lower than the LCST the copolymer is soluble in water and hydrophilic interactions between the copolymer and water are dominant, but at the temperatures higher than the LCST, hydrophobic interactions between the copolymer chains become stronger [177]. The LCST of PNiPAAm and (PNiPAAm)-co-polyacrylamide is 30–32 °C, so they can enable localization of the drug delivery system in the nasal cavity. Thermosensitive gel based on (PNiPAAm)-co-polyacrylamide was evaluated for nasal delivery of insulin in rats [178]. The linear cationic terpolymer obtained by copolymerization of N,N-dimethylaminoethyl methacrylate with methylmethacrylate and butylmethacrylate is a commercially available pharmaceutical excipient Eudragit® E PO (EPO), which is freely soluble in water only under acidic conditions (Evonik technical notes, 2018). EPO’s molecule is convenient for chemical modification using acryloyl chloride, which results in the formation of acrylated polymers with enhanced mucoadhesive properties due to the formation of covalent linkages between the acrylated groups and thiols present in mucins. Biocompatibility of the prepared EPO’s acrylated derivatives was demonstrated by the slug mucosal irritation test. Liquid formulations were prepared using EPO and its acrylated derivatives. The formulations were loaded with sodium fluorescein as a model compound. The formulations prepared with acrylated derivatives exhibited superior mucoadhesive effect and greater retention of sodium fluorescein on freshly excised sheep nasal mucosa in comparison with those prepared with EPO [179]. The formation of a positively charged copolymer of chitosan and macrogol (PEGylated chitosan) provided solubility at alkaline pH values, while permeability-­ enhancing effect was pH-dependent at pH 6 and higher in comparison with unmodified chitosan [180, 181]. Zhang et  al. [182] reported that PEGylated chitosan nanoparticles (150–300  nm), with insulin loading efficiency of 20–39%, enabled the plasma drug concentration maximum of 350 μU/ml after 30 min and subsequent reduction of the initial glycemia by 60% after 90 min in rabbits. The nasal absorption of insulin from the nanoparticles was better in comparison with the physical mixture of insulin and the PEGylated chitosan. Alginate polyethylene glycol acrylate (alginate-PEGAc) is an anionic copolymer comprising an alginate backbone with acrylated polyethylenglycol groups attached to it. This copolymer combines strength and gelling properties of alginates with strong mucoadhesion which is the result of the penetration of polyethylene glycol into the mucus surface and binding with sugar moieties on glycosylated proteins by hydrogen bonds, while the acrylate group binds with the sulphide group of glycoproteins present in the mucus and β-d-mannuronic acid moiety binds to the

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glycoproteins in the mucus through carboxyl–hydroxyl interactions. The introduction of acrylic acid compensated the erosion of alginate in neutral pH, but also controlled the release rate of drugs and improved its adhesive properties. Addition of PEG increased the viscosity of the resulting copolymer, retarding its disintegration and removal from the mucosal surface [183]. Poly lactic-co-glycolic acid (PLGA) is a biocompatible and biodegradable synthetic copolymer of polylactic acid and polyglycolic acid [184, 185]. It has been used for preparation of nanoparticles to study their uptake on olfactory ensheathing cells. Higher level of rhodamine-incorporated PLGA nanoparticles was observed in olfactory cells than that of nanoparticles prepared from polylactic acid or chitosan. PLGA nanoparticles are considered more promising for brain-targeted delivery via olfactory neurons [186]. For example, the brain uptake efficacy of olanzapine loaded in PLGA nanoparticles increased by 10.86-fold after intranasal administration and 6.35-fold for intravenous administration compared with free drug solution. Md et al. [187] reported enhanced brain uptake of PLGA nanoparticles for nose-to-brain delivery of donepezil. Coupling PEG and/or lectins with PLGA or poly(lactic acid) (PLA) is a useful strategy to upgrade the polymer performance to target the brain via nasal mucosa. Lectins are structurally diverse proteins that are usually extracted from gorse, soybean, peanut, and lentil. They are promising for use in nasal delivery due to low ciliary irritation risk and high permeability. They have shown specific and reversible binding to the mucosa due to their capability to identify and bind to specific sugar moieties like those present in the mucus layer. Depending on the number of carbohydrate-recognizing domains (CRD), lectins are classified into: merolectins (1 CRD), hololectins (≥2 crd), and chimerolectins (with additional unrelated domains). Conjugates of lectins with synthetic polymers are considered promising excipients for development of nose-to-brain drug delivery systems. Wheat germ agglutinin is a biorecognitive ligand-lectin which was used for conjugation with PLA-PEG nanoparticles in order to improve their nose-to-brain absorption by specifically binding to N-acetyl-D-glucosamine and sialic acid moieties, both of which were abundantly observed in the nasal cavity particularly in the olfactory mucosa [188–192]. The lectin-conjugated nanoparticles were prepared by incorporating maleimide in the PLA-PEG molecule so that its thiol group binds 2-iminothialane thiolated wheat germ agglutinin. The nasal toxicity of the nanoparticles was negligible. The brain uptake of wheat germ agglutinin-functionized nanoparticles was about two-fold higher in different brain tissues compared with the unmodified ones [189]. Solanum tuberosum lectin (STL) was used for conjugation of PLGA nanoparticles (STL-nanoparticles). The in vitro uptake study in Calu-3 cells showed markedly enhanced endocytosis of STL-nanoparticles compared to unmodified PLGA nanoparticles and significant inhibition of uptake in the presence of inhibitor sugar (chitin hydrolysate). Following nasal administration, a marker coumarin-6 carried by STL-nanoparticles was rapidly absorbed into blood and brain segments (olfactory bulb, cerebrum, brainstem, and cerebellum) achieving 1.89–2.45 times higher brain targeting efficiency than unmodified NP.  Mild cytotoxicity and negligible cilia irritation demonstrated safety of STL-nanoparticle [190]. Moreover, Zhang et  al. [193] developed SLT-conjugated PEG-PLGA

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nanoparticles with entrapped fibroblast growth factor (I-bFGF). After intranasal administration nanoparticles exhibited significantly higher area under the concentration time curve (AUC) in different parts of the brain than intravenously administered STL-conjugated nanoparticles and nasal drug solution. Hence, lectin conjugated nanoparticles may protect peptide- and protein-based drugs from peptidase degradation in nasal cavity. Conjugation of PEG-PLGA nanoparticles by lactoferrin enabled targeting of lactoferrin receptors which are present on the respiratory epithelium cells and neurons in nasal cavity [194]. It was reported by Yan et al. that lactoferrin-modified nanoparticles delivered higher concentration of the antiparkinsonian drug rotigotine in olfactory bulb, striatum, and other brain regions compared to unmodified nanoparticles [195].

5 Mucoadhesive Polymer Blends Many published studies have focused on combining two or more mucoadhesive polymers with different physicochemical properties in order to integrate their properties relevant for nasal drug delivery and possibly achieve synergy that would expand functionality (mucoadhesion, thermo-sensitivity, pH-sensitivity, ion-­ sensitivity, and/or solubility) and enhance drug delivery potential of the nasal formulation. Polymer combinations are mostly physical mixtures when there is no chemical bond between the polymers. The possibility of physical and chemical cross-linking of polymers in order to create a carrier with improved mucoadhesive properties and drug release kinetics, in comparison with the starting molecules, has been also considered.

5.1 Physical Blends In physical polymer, blends often use poloxamers to provide thermoreversibility of the formulation, as well as chitosan and carbomers to emphasize mucoadhesion and/or to introduce pH-sensitivity. Selected examples, which are commented on in this subchapter, illustrate the potential of this strategy. Poloxamers are responsible for in situ gelling; however, their mucoadhesiveness is weak due to their nonionic character and relatively low molecular weight. The combination of poloxamers with other mucoadhesive polymers, such as carbomers, polycarbophils, and PEGs, has been allowed for the tuning of the residence time in the nasal cavity and sol-gel transition temperature as well as to control the in vitro drug release. Thermoresponsive nasal gel of Nardostachys jatamansi with poloxamer 407 and PEG 4000 [196] showed an increase in the gelling temperature as the concentration of the PEG 4000 increases. PEG 4000 is a nonionic, hydrophilic compound, which may establish intermolecular hydrogen bonding with poloxamer chains and water and thus delay gelation time and increase the gelation temperature,

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during which these hydrogen bonds weaken and hydrophobic interaction between poloxamer chains becomes dominant leading to gel formation. Addition of mucoadhesive polymers such as carbomers, chitosan, and cellulose derivatives reduces the gelling temperature of the poloxamers [41, 197]. Srivastava et al. prepared thermoreversible and mucoadhesive in situ gels by combining xanthan gum, HPMC, or carbomer, in different concentrations (0.5, 1, or 1.5% w/v), with poloxamer 407 (10% w/v), with an aim to improve the antioxidative and anti-inflammatory effect of polyherbal (Moringa olifera and Embelia ribes) extract in the treatment of allergic rhinitis. After administration into the nasal cavity, formulations rapidly transformed into viscous hydrogels. The combining of poloxamer 407 with the mucoadhesive polymers increased the gel strength, so the formulations prepared with high concentrations of xanthan gum, HPMC, or carbomer exhibited better mucoadhesiveness than poloxamer 407 itself. The pH values of the formulations ranged between 5.2 and 5.9 and their spreading ability was from 7.6 ± 0.21 to 11.7 ± 0.65 cm. Investigated in situ nasal herbal gels did not exhibit nasal redness, edema, inflammation, and irritation in mice. Poloxamer 407-based thermoreversible formulation for intranasal delivery of fexofenadine included 0.1–0.3% (w/v) of chitosan [167]. Besides the increased nasal residence time, the presence of chitosan increased the nasal permeability and drug bioavailability in rabbits of about 18-folds. The nasal permeation activity of chitosan was confirmed also in  vivo, where the Cmax increased from 52.96 ± 9.43 ng/ml to 78.25 ± 21.25 ng/ml, employing 0.1% and 0.3% of this polymer, respectively. Shelke et al. [198] developed thermoreversible intranasal gel with zolmitriptan-loaded nanoethosomes (171.67  nm) with entrapment efficiency of 66%. Thermoreversible gel vehicle with phase transition temperature at 32–33 °C was prepared by using varying concentrations of poloxamer 407, Carbopol® 934, and HPMC.  In vitro drug release from the optimized formulations followed Korsemeyer-Peppas model indicating non-Fickian release profiles. The gels were non-toxic on columnar epithelial cells. The study of Perez et al. [199] demonstrated enhancement of nose-to-brain delivery of siRNA dendriplexes from in situ mucoadhesive gels comprising a blend of poloxamer 407 with mucoadhesive chitosan or carbopol 974P NF. In situ gel maintained the stability of dendriplexes and enhanced their uptake by olfactory neurons in comparison with intravenously administered dendriplexes and intranasally administered naked siRNA within gel vehicle. Chitosan has been used often in combination with other synthetic and natural polymers due to its mucoadhesiveness and permeation enhancer effect. There is an interest for thermosensitive chitosan-based formulations since they may be suitable for application in nasal cavity as liquids which transform into gel of increased mucoadhesiveness resulting in prolonged residence as well as with potential for increased drug absorption. Agrawal et al. [200] incorporated insulin in thermosensitive gel formulation based on chitosan (3%) and polyvinyl alcohol (PVA) (2%). Formulation showed thermoresponsive gelling, high swelling index, and the potential of controlling the blood sugar level for 6 h. PVA is a water-soluble polyhydroxy polymer. At room temperature, the intermolecular hydrogen bonds exist between hydroxyl and amino groups of chitosan and hydroxyl groups of PVA as well as between water and PVA.  These hydrophilic interactions lead to dissolution of

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chitosan chains. At nasal temperature, intermolecular hydrogen bonding gets ruptured, and thus chitosan chains’ mobility enhances, surrounding water molecules are removed, and hydrophobic chitosan chains associate with each other to form gel. Thermosensitivity of the formulation was dependent on the polymers mass ratio. Temperature sensitive in situ gelling property does not occur if PVA/ chitosan ratio exceeded 10:1 [201]. Al-Ghananeem et  al. [202] promote nasal absorption of Δ9 -tetrahydrocannabinol (THC) by formulation of a mucoadhesive gel spray based on chitosan (2% w/v) and PEG 400 (10% w/v). Although no significant difference between the absolute bioavailabilities of the THC solution (13.3  ±  7.8%) and the chitosan-based gel (15.4  ±  6.5%) was observed, the THC delivered with the chitosan-­based gel reached the higher Cmax (31  ±  4  ng/ml) in contrast to the drug solution formulation (20 ± 3 ng/ml). Jose et al. [203] reported the sustained release of lorazepam over 24  h from mucoadhesive chitosan microspheres loaded in a thermosensitive poloxamer-based gel formulated for noseto-brain delivery. For comparison, lorazepam-loaded microspheres in phosphate buffer solution pH 6.2 and lorazepam powder loaded in poloxamer gels showed a release profile over 9 h and 15 h, respectively. Zafar et  al. [204] aimed to formulate the microspheres by using chitosan and ethyl cellulose for the systemic delivery of domperidone via the nasal route. In vivo study for optimized DOM-Microsphs (F1) formulation was performed on Wistar rats for the evaluation of bioavailability and pharmacokinetic parameters after nasal administration and compared to nasally administered DOM solution (DOM-Sol), and orally administered DOM-Sol and commercially available tablet formulation (ComTab). The optimized microspheres were spherical with 21.12 ± 0.51 μm particle size, 84.79 ± 1.39% entrapment efficiency, 50.68 ± 0.96% drug loading, and 81.2 ± 6.75% drug release in 8 h. Domperidone-loaded microspheres demonstrated 2-folds ex vivo permeation higher than commercial tablet formulation. The relative bioavailability of optimized microsphere formulation administered nasally was superior 3.75-fold, 2.61-fold, and 1.77-fold in comparison to the drug solution and tablets administered orally, and solution administered nasally, respectively. Gavini et al. [205] prepared zolmitriptan-loaded microspheres from chitosan and HPMC of different molecular weights. Microparticles in the form of powder were administered nasally to rats. The nasal bioavailability of zolmitriptan was around 35%; however, the concentrations of the drug in the CSF after 1 h were similar for the intravenous injection and the nasal chitosan microsphere formulation, albeit they had shown different plasma concentrations. Nasal gel based on chitosan and HPMC blend provide 8.5 times higher concentration in brain of a dopamine D2 agonist ropinirole, than nasal drug solution [38]. Jose et al. [203] formulated poloxamer-­ based thermosensitive gel loaded with mucoadhesive microspheres prepared from chitosan. This drug delivery system, upon nasal administration in rats, provided sustained release of lorazepam over 24 h. The microspheres in phosphate buffered saline (pH 6.2) and lorazepam-loaded poloxamer gels released drug over 9 h and 15 h, respectively. The chitosan-based gels undergo a slow sol-gel transition at physiological pH [25], while chitosan derivative TMC retains the key characteristics of the parent

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polymer, but presents improved aqueous solubility and thermosensitivity, enhanced mucoadhesiveness, and a significant absorption enhancing effect over a wide pH range [206, 207]. In addition, combinations of TMC with other mucoadhesive polymers were considered. Nazar et al. [59] synthesized thermosensitive in situ nasal gel from TMC with PEG 4000 which provided additional sites for hydrogen bonding and allows the formation of more extensive gel network. TMC, synthesized from chitosans of three different average molecular weights, have been co-formulated with PEG 4000 into stable thermosensitive liquid formulations suitable for administration via nasal spray or drops. The hydrogels derived from TMC with a low degree of quaternization and high or medium average molecular weight exhibited relatively short sol-gel transition time at physiologically relevant temperatures, good water-holding capacity, and strong mucoadhesive potential. TMC of medium average molecular weight and low degree of quaternization (3.6% w/v) with 5.8% w/v PEG 4000 and 2.5% w/v glycerophosphate undergo thermal gelation at 32.5 °C within 7  min [208]. In a study of Wu et  al. [206], thermosensitive hydrogel was formulated using N-[(2-hydroxy-3-trimethylammonium)propyl] chitosan chloride (HTCC) and PEG 4000 with a small amount of α, β-glycerophosphate. Negatively charged moieties of glycerophosphate may interact with various bioactive components [200]. HTCC is a water soluble, mucoadhesive derivative of chitosan which retains absorption enhancement effect on nasal mucosa. After being administered into the nasal cavity, the solution transformed into viscous hydrogel at body temperature, which decreased nasal mucociliary clearance rate and drug release rate. The hydrogel enabled insulin retention and absorption, while blood glucose concentration was drastically decreased (almost 40–50% of initial glycemia for at least 4–5  h) after administration in male Sprague–Dawley rats [206]. Introduction of alginate into chitosan/tripolyphosphate nanoparticles was used to design a hybrid carrier for nasal delivery of insulin (5 IU/kg) in rats [209]. This hybrid nanocarrier had a high positive surface charge (ζ N + 41 mV). Alginate molecular weight was related with the duration of the hypoglycemic response. Although the chitosan/tripolyphosphate system showed higher reducing capacity of the glucose level (35%) compared to the hybrid system (30%) after 1 h, the glucose level reduction (20%) from the hybrid nanocarrier was prolonged up to 5 h. Blend of pH-responsive chitosan and thermo-responsive pNIPAAM has been used for the formulation of dual responsive hydrogels for effective nasal delivery of pilocarpine hydrochloride [210]. Intranasal gels comprising PEGs and carbomer (Carbopol® 934) were evaluated for insulin in vitro release, and its bioavailability was compared with an intranasal solution and subcutaneous injection in rabbits. Increasing the molecular weight of PEG and Carbopol® 934 concentration increased the gel viscosity and affected the drug release mechanism. A lower viscosity gel was prepared by applying heat and it was suitable to achieve a higher insulin release. A stronger and longer hypoglycemic effect with 1.7-fold and 3.1-fold higher maximum decrease in glycemia and AUC, respectively, were provided by the gel, when compared with the subcutaneous injection [211].

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5.2 Polyelectrolyte Complexes Polyelectrolyte complexes are formed by establishing noncovalent interactions between anionic and cationic polymers at pH in the vicinity of pKa interval of the two polymers. In this way, various polyelectrolyte complexes of chitosan with polyanions such as xanthan gum, pectin, and hyaluronic acid were obtained and considered for use in nasal drug delivery. The chitosan/xanthan polyelectrolyte complex was assessed by Dehghan and Kazi [212] for design of the mucoadhesive nasal insert for treatment of motion sickness by promethazine hydrochloride. The complexation of the oppositely charged polyelectrolytes enabled the formation of a three-dimensional network with a capacity to control the release of the incorporated drug. The study focused on evaluation of the effect of concentration of the parent polymers on viscosity of polyelectrolyte complex solution, water uptake of nasal inserts (at pH 2, 5.5, 7.4), bioadhesion potential, and in-vitro drug release at Q6h. The higher content of xanthan gum in polyelectrolyte complexes retarded in vitro drug release. The polycation/polyanion concentration as well as pH of the medium strongly influenced the water uptake behavior of nasal insert and formation of a mucoadhesive gelled system. Luppi et al. [213] suggested the preparation of chitosan/hyaluronic acid polyelectrolyte complexes with mucoadhesive properties for nasal delivery of vancomycin and insulin in the form of nasal inserts. In vitro swelling, mucoadhesion, and drug release were evaluated. The selection of suitable conditions for preparation of the polyelectrolyte complexes was of significant importance for modulation of swelling behavior and prolonged drug release from the inserts during 6 h. The same group investigated capacity of chitosan/pectin polyelectrolyte complexes in the form of nasal inserts for improvement of bioavailability of an antipsychotic drug chlorpromazine hydrochloride [214]. Chitosan/pectin polyelectrolyte complexes (Fig.  11.3a) were prepared at pH 5.0 from citrus peel pectin (Mr 30,000–100,000; esterification degree 60%; pKa 4.0) and chitosan (Mr 150,000; deacetylation degree 97%; pKa 6.3). The selection of suitable chitosan/pectin molar ratio during complex preparation allowed the modulation of insert water uptake behavior and drug release and permeation across sheep nasal mucosa. The higher amount of pectin in the complexes, with respect to amount of chitosan, produced a more porous nasal inserts, improving water uptake ability (Fig.  11.3b) and mucoadhesion capacity (Fig.  11.3c). Also, pectin interacted with the drug inducing the formation of less hydratable inserts and sustained drug release and permeation.

5.3 Cross-Linked Polymers The use of cross-linked polymers in the development of nasal drug delivery systems of various types has not been intensively considered so far. A representative example is the thermo-responsive gels formulated by using chitosan, cross-linked by

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Fig. 11.3 (a) Scanning electron micrographs of the different chitosan/pectin complexes; (b) water uptake ability of nasal inserts in different pH conditions (n = 5, the SD did not exceed the 5%); (c) mucoadhesive capacity (expressed as detachment force, mean ± SD, n = 3) of chitosan hydrochloride, pectin, and chitosan/pectin complexes at pH 5.5. (With permission from Ref. [214])

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glutaraldehyde, and poloxamer which interpenetrated gels. These gels were evaluated as carriers for nasal delivery of insulin in diabetic rats. The in vitro release of insulin from the gels followed a Fickian diffusion model, and it was for about six times longer than release from poloxamer gels. Also, hyperglycemic effect was prolonged and pharmacological efficiency significantly improved in vivo [60]. Another example is the study of Deutel et  al. [215] which was focused on utilization of interpolymer complex formed between poly(vinyl pyrrolidone) (PVP) and poly(acrylic acid) (PAA) or poly(acrylic acid)-cysteine (PAA-Cys) for preparation of microparticles for nasal delivery of insulin. The mean particle size of PAA/PVP/ insulin and PAA-Cys/PVP/ insulin microparticles was 2.6 ± 1.6 μm and 2.8 ± 1.7 μm, respectively. A strong network based on formation of intra- and intermolecular disulphide bonds between thiomer/polymer and insulin was established. Nasal safety of formulation and native compounds was confirmed in in vitro ciliary beat frequency test. The release of insulin from the microparticles at pH 7.4 occurred within the first 60 min likely due to swelling process, the maximum was reached after 120 min, while the release amounts detected after 6 h were 52.3 ± 18.9% and 37.0  ±  10.7% regarding formulations containing the thiomer and the polymer, respectively. There was no significant difference between the microparticles; however, thiomer-based microparticles then showed a lower release likely due to a greater stabilization as a result of disulphide bond formation within the thiomeric network. The release of insulin was hindered by electrostatic and hydrophobic drug/polymer interactions as well as steric effect and hydrogen bonds.

6 Conclusion and Future Perspectives Nasal drug delivery strategies based on the mucoadhesive polymers have been intensively researched for achievement of local and systemic immune response, systemic drug delivery, and nose-to-brain drug delivery. The absorption of polar drugs and macromolecules through the nasal mucosa is a permanent challenge, thus the enhancement of intranasal retention time and trans-nasal bioavailability could be particularly exciting prospects. Contemporary chemical engineering techniques enable the synthesis of derivatives of natural polymers, copolymers, polyelectrolyte complexes, and cross-linked polymers with improved solubility, mucoadhesiveness, and drug release kinetics in response to unique physiological conditions (temperature, pH, ions, or enzyme) in the nasal cavity, thus providing significant improvements in the bioavailability of both small molecules and macromolecular active substances. Novel stimuli responsive polymers can be optimized in accordance with the nasal temperature and pH value. Also, by combining thermo-responsive and pH-­ responsive polymers, dual (thermo-/pH)-responsive nasal drug delivery systems can be formulated. Functionalization of polymers by special molecules, such as lectins, enables the targeted delivery to specific receptors in the olfactory region, which is promising for improving generally low direct transport of drugs into the CNS. The increasing number of more complex and fragile molecular drugs, which can be

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applied exclusively by injection, will expand the future development of the nasal drug delivery systems and the role of the mucoadhesive polymers. However, there are a number of limitations and challenges that need to be overcome. Natural polymers are available from renewable sources; however, to obtain safe excipients of satisfactory functional characteristics, a high degree of purity and/or chemical treatment are required. Further work is needed to characterize the various types of the polymers available on the market, including a variety of molecular weights, degree of chemical treatment, and/or chemical derivatization. The data published so far on the strength of mucoadhesion of different polymers, both intrinsic and in nasal formulations, are inconsistent and sometimes contradictory. Safety aspects of mucoadhesive polymers, especially neurotoxicity, as well as their potential for enhancing the intranasal absorption of macromolecular drugs, mechanisms and dynamics of the polymer phase transitions in the nasal environment, the polymer-mucus interactions, the drug release, and trans-nasal delivery, have not been sufficiently investigated. Of particular importance could be studying these aspects of nasal drug delivery under disease conditions which can significantly affect mucus production and/or ciliary movement.

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188. Mythri G, Kavitha K, Kumar MR, Singh SJ. Novel mucoadhesive polymers-a review. J App Pharm Sci. 2011;01(08):37–42. 189. Gao X, Tao W, Lu W, et al. Lectin-conjugated PEG-PLA nanoparticles: preparation and brain delivery after intranasal administration. Biomaterials. 2006;27(18):3482–90. 190. Chen J, Zhang C, Liu Q, et al. Solanum tuberosum lectin-conjugated PLGA nanoparticles for nose-to-brain delivery: in vivo and in vitro evaluations. J Drug Target. 2012;20(2):174–84. 191. Smart JD, Nicholls TJ, Green KL, Rogers DJ, Cook JD. Lectins in drug delivery: a study of the acute local irritancy of the lectins from Solanum tuberosum and Helix pomatia. Eur J Pharm Sci. 1999;9(1):93–8. 192. Andrews G, Laverty T, Jones D.  Mucoadhesive polymeric platforms for controlled drug delivery. Eur J Pharm Biopharm. 2009;71(3):505–18. 193. Zhang C, Chen J, Feng C, et al. Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat Alzheimer's disease. Int J Pharm. 2014;461(1–2):192–202. 194. Hu K, Shi Y, Jiang W, Han J, Huang S, Jiang X.  Lactoferrin conjugated PEG-PLGA nanoparticles for brain delivery: preparation, characterization and efficacy in Parkinson's disease. Int J Pharm. 2011;415(1–2):273–83. 195. Yan X, Xu L, Bi C, et al. Lactoferrin-modified rotigotine nanoparticles for enhanced nose-­ to-­ brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects. Int J Nanomedicine. 2018;13:273–81. 196. Jadhav PP, Jadhav NR, Hosmani AH, Patil S.  Development and evaluation of in situ thermoresponsive nasal gel system for Nardostachys jatamansi. Pharm Lett. 2013;5:113–25. 197. Srivastava R, Srivastava S, Singh SP.  Thermoreversible in-situ nasal gel formulations and their pharmaceutical evaluation for the treatment of allergic rhinitis containing extracts of Moringa olifera and Embelia ribes. Int J App Pharm. 2017;9(6):16–20. 198. Shelke S, Shahi S, Jalalpure S, Dhamecha D. Poloxamer 407-based intranasal thermoreversible gel of zolmitriptan-loaded nanoethosomes: formulation, optimization, evaluation and permeation studies. J Liposome Res. 2016;26(4):313–23. 199. Perez AP, Mundina-Weilenmann C, Romero EL, Morilla MJ. Increased brain radioactivity by intranasal P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels. Int J Nanomedicine. 2012;7:1373–85. 200. Agrawal AK, Gupta PN, Khanna A, et al. Development and characterization of in situ gel system for nasal insulin delivery. Pharmazie. 2010;65:188–93. 201. Zao J. Chitosan-based gels for the drug delivery system. In: Yao K, Li J, Yao F, Yin Y, editors. Chitosan-based hydrogels: functions and applications. 1st ed. CRC Press; 2011. p. 263–314. 202. Al-Ghananeem AM, Malkawi AH, Crooks PA. Bioavailability of Δ9-tetrahydrocannabinol following intranasal administration of a mucoadhesive gel spray delivery system in conscious rabbits. Drug Dev Ind Pharm. 2011;37:329–34. 203. Jose S, Ansa CR, Cinu TA, et al. Thermo-sensitive gels containing lorazepam microspheres for intranasal brain targeting. Int J Pharm. 2013;441:516–26. 204. Zafar A, Afzal M, Quazi AM, et al. Chitosan-ethyl cellulose microspheres of domperidone for nasal delivery: preparation, in-vitro characterization, in-vivo study for pharmacokinetic evaluation and bioavailability enhancement. J Drug Deliv Sci Technol. 2021;63:102471. 205. Gavini E, Rassu G, Ferraro L, et  al. Influence of polymeric microcarriers on the in  vivo intranasal uptake of an anti-migraine drug for brain targeting. Eur J Pharm Biopharm. 2013;83:174–83. 206. Wu J, Wei W, Wang LY, Su ZG, Ma GH. A thermosensitive hydrogel based on quaternized chitosan and poly(ethylene glycol) for nasal drug delivery system. Biomaterials. 2007;28:2220–32. 207. Wu J, Su ZG, Ma GH.  A thermo- and pH-sensitive hydrogel composed ofquaternized chitosan/glycerophosphate. Int J Pharm. 2006;315:1–11. 208. Chenite A, Chaput C, Cpmbes C, Selmani A, Jalal F. Temperature-controlled pH-dependant formation of ionic polysaccharide gels. US Patent 6344488. 2002. https://pubchem.ncbi.nlm. nih.gov/patent/US6344488.

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Chapter 12

Novel Approaches in Nasal In Situ Gel Drug Delivery Cinzia Pagano, Luana Perioli, and Maurizio Ricci

Abstract  The nasal cavity represents a suitable administration route both for local and systemic treatments. Conventional nasal formulations (liquid, solid, semisolid) show a limited residence time responsible for an incomplete drug absorption with consequent impaired therapeutic efficacy. In situ nasal gels represent a suitable formulative strategy able to overcome this problem. These formulations are liquid at room temperature, making an easy administration, and become gel once in the nasal cavity. This is possible thanks to the use of polymers able to form a viscous gel under specific stimuli as temperature, pH, ions in the nasal fluid. The chapter illustrates the evolution from conventional nasal formulations to innovative in situ gel delivery systems and the advantages of such formulations. It presents also recent approaches, based on the combination of in situ gels with nanocarriers, useful to protect the drug either improve the biopharmaceutical properties and promote a controlled release. The safety aspects have been examined as well. Keywords  Nasal formulations · Residence time · In-situ gelification · Polymers · Nanocarriers · Safety

1 Introduction According to the official pharmacopoeias, “nasal preparations” are classified as “liquid (solutions, suspensions and emulsions), semi-solid or solids (powders) intended to be administered in the nasal cavity to obtain a systemic or local affect” [1, 2]. The nasal cavity is a useful administration route especially for drugs subjected to first-pass metabolism as the absorption through the nasal mucosa allows to C. Pagano (*) · L. Perioli · M. Ricci Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_12

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reach the systemic circulation bypassing the liver [3]. This route is also interesting for the administration of biological drugs and biotherapeutic products, such as recombinant proteins, peptides, and vaccines as antibodies, which generally have a high molecular weight and a complex structure. Biological molecules are extremely sensitive to the physical and chemical conditions of the gastrointestinal environment and their permeability across the intestinal mucosa is extremely poor [4]. For these reasons they are currently administered parenterally and, more recently, by intranasal route as a valuable alternative to perform systemic treatments. Moreover, nasal formulations represent a useful tool for the treatment of “special” patients such as newborns, infants, elderly, and unconscious patients that often are non-cooperative and/or presenting swallowing difficulties with risks of suffocation in case of oral therapy. Nasal formulations are noninvasive, safe, easy to administer, and characterized by a short onset time, useful to obtain a rapid effect included the case of emergency treatments [5] as a valid alternative to intravenous route when it is not possible to obtain venous access. The drugs mainly administered intranasally in emergency rooms are fentanyl, morphine, naloxone, midazolam, flumazenil, ketamine, lidocaine, glucagon, haloperidol, and dexmedetomidin [3, 5–7]. Conventional nasal formulations are mainly represented by instillations (solutions, suspensions), applied in the nasal cavity by means of proper dispensers as dropper, and ointments (semisolid) spread on the nasal mucosa by the finger or using cotton swabs. Recently the tubes have been provided by special cannula-tips in order to perform a better and precise dosing in the nasal cavity. The main limitations of this kind of formulations are the small dose that can be administered and the low residence time responsible for an incomplete absorption of the administered drug. Generally, most of the drug delivered in the nasal cavity are physically removed in less than 80 min [8, 9]. In addition, the application of drops or ointments produces nasal discharge with loss of drug, discomfort, and the necessity to perform many daily administrations for an efficacious treatment [3]. The nasal discharge represents the main factor responsible for therapy failure. It depends on two main factors: physiological, mainly due to patient orthostatic posture and nasal mucociliary clearance (mechanisms having the objective to protect the respiratory system from damage by inhaled substances) [9], and formulative. The development of formulations compatible with nasal cavity anatomy and physiology could allow to perform a safe, standardized, and effective therapy [3]. The nasal products available on the market are conventional formulations intended both for local and systemic treatments (Table 12.1). The local treatments are generally performed by solutions of small and water-soluble drugs as decongestants, antihistaminics, and fluidifying agents and suspensions, generally used for the nasal administration of poorly water-soluble corticosteroids. In regard to systemic therapies, commercially available products are solutions administered by sprays containing small molecules that can be easily absorbed through the nasal mucosa such as benzodiazepine (e.g., diazepam) for the treatment of seizures in epilepsy, alkaloids such as dihydroergotamine mesylate and zolmitriptan for migraine treatment, hormones as estradiol hemihydrate for menopausal syndrome treatment,

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opioids as fentanyl for severe pain treatment, and nicotine for smoking cessation. In addition, few other intranasal formulations are available on the market as powders (Table 12.1). In order to better exploit the nasal route, new nasal drug delivery systems are expected to be on the market in the near future considering that the success of a nasal therapy mainly depends both on the suitable formulation and device. The formulation should offer advantages in terms of high drug bioavailability with consequent reduced daily administrations and thus decrease of the total amount of daily administered drug (reduced side effects). At the same time, increased patient compliance and improved adherence to therapy can be achieved. A suitable device offers advantages in terms of easy, precise, and reproducible dosing and thus therapeutic efficacy [10]. Table 12.1  Examples of conventional nasal dosage forms for drug administration available on the market Formulation Drug Solutions Decongestants: For example, oxymetazoline hydrochloride (e.g., Oxywell® nasal drops, Otrivin®oxy nasal spray), xylometazoline hydrochloride (e.g. Otrivin® nasal drops, Otrivin® nasal spray), naphazoline (e.g. Naprisol® nasal drops, Privine® nasal spray), phenylephrine (e.g. NTR® nasal drops, Equate™ nasal spray), silver (Argotone® nasal drops, Rinosilver® nasal spray) Antihistaminics: azelastine (Rinazina® nasal spray), tramazoline hydrochloride (Rinogutt® nasal spray), levocabastine (Levoreact® nasal spray) Fluidifying agents: For example, acetylcysteine (Rinofluimucil® nasal spray) Solutions Benzodiazepine (diazepam – Valtoco®) Opioids (naloxone-hydrochloride – Narcan®, fentanyl-PecFent® and Instanyl®, butorphanol tartrate – Stadol®) Antidepressants (esketamine – Spravato®) Antiemetic (metoclopramide – Gimoti®) Alkaloids (dihydroergotamine mesylate – Trudhesa™) 5HT1-receptor agonists (zolmitriptan – Zomig®, sumatriptan – Imitrex®) Hormones (estradiol hemihydrate – Aerodiol®) Polypeptides (calcitonin – Miacalcin™) Vaccines (virus strains: an A/H1N1 strain, an A/H3N2 strain and two B strains – FluMist®) Suspensions Corticosteroids: For example, fluticasone propionate (Flixonase® nasal spray), mometason furoate (Nasorex® nasal spray), beclomethasone dipropionate (Rinoclenil® nasal spray), triamcinolone acetonide (Nasacort® nasal spray), budesonide (Benacort® nasal spray) Semisolids Antimicrobial agents (mupirocin – Bactroban® ointment; chlorhexadine + neomycin – Naseptin® cream) Powders 5HT1-receptor agonists: sumatriptan (ONZETRA™ Xsail) Peptidic hormone: For example, glucagon (Baqsimi™) Steroids: For example, beclomethasone dipropionate (QNASL™)

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2  In Situ Nasal Gel The hydrophilic semisolid nasal formulations (gels) available on the market are medical devices, intended only for nasal mucosa hydration, mainly represented by hydrogels based on saline solutions, aloe vera, and hyaluronic acid, while no hydrogels intended for drug administration can be found. In fact, the gel administration in the nasal cavity could be difficult (applicator blockage due to gel drying) with low dosing precision and discomfort for the patient. Nasal in situ gel forming drug delivery systems represent the formulative answer to the limitations of conventional gels and, in general, to the problem of the low residence time of conventional nasal dosage forms. The rationale for the development of such kind of formulations is based on the idea to obtain a formulation liquid at room temperature able to increase its viscosity once in the nasal cavity where it forms a gel. The liquid form at room temperature allows an easy administration/ dosing (e.g., by spray), being very practical to use and with high patient compliance. In situ gel formation takes place thanks to polymers that, once in the nasal cavity, gel after specific stimuli, such as temperature, pH, ions in the nasal fluid [11–18] (Table 12.2).

2.1 Temperature-Induced In Situ Gel System Temperature is the most commonly used physical stimulus and is based on the fact that at room temperature (20–25 °C) the formulation is in a liquid state while undergoes a rapid sol-gel phase transition when in contact with body fluids (35–37 °C) Table 12.2  Examples of in situ nasal gels Drug Lamotrigine

Fluticasone

In situ gelling agent Gellan and xanthan gum Poloxamer 407/ deacetylated gellan gum Gellan gum

Docetaxel Piribedil

Pluronic F127 Methyl cellulose

Ropinirole Influenza virus nucleoprotein Breviscapine

Pluronic F-127 Pluronic F127 and F68 Gellan gum

Rufinamide

Xyloglucan

Timosaponin BII

Stimulus for gelification Nasal fluid ions

Disease Epilepsy

Reference [13]

Temperature/ nasal fluid ions

Alzheimer

[14]

Nasal fluid ions

Nasal inflammatory disorders Brain tumor Parkinson’s

[15]

Parkinson’s Influenza

[23] [26]

Cerebrovascular and cardiovascular Epilepsy

[27]

Temperature Temperature/ nasal fluid ions Temperature Temperature Nasal fluid ions Temperature

[16] [17]

[28]

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Fig. 12.1  Schematic representation of temperature-induced gelification of poloxamer

(Fig. 12.1). This type of behavior is characteristic of polymers, which can be synthetic such as poloxamers; semi-synthetic such as methylcellulose (MC), hydroxypropyl methyl cellulose (HPMC), and ethyl (hydroxyethyl) cellulose (EHEC); or natural such as xyloglucan and gellan gum. Among them, poloxamers are widely used in pharmaceutics as thermo-­responsive gelling agents (as well as non-ionic surfactant) [19–23]. They are synthetic, A-B-A type, linear, tri-block co-polymers made of hydrophilic end-groups of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) hydrophobic core group [(PEOx-­ PPOy-­PEOx)]. They are commercially known with the trade names Pluronics®, Lutrol®, Kolliphor®, Antarox®, and Synperonics®. Although the exact gelation mechanism is not yet fully elucidated, it seems to be correlated to the following steps. In water, the copolymers, due to their amphiphilic character, self-aggregate into micelles with an inner core formed by PPO hydrophobic blocks and an outer shell constituted by PEO hydrophilic units. With the rising of temperature, a packing and entanglement of the micelles, with concomitant dehydration of the PPO block and the expulsion of water from the micelle core, is observed [24] resulting in gelation of the system.

2.2 pH-Triggered Systems The gelation process triggered by changes in pH is typical of polymers containing pendant acidic or basic groups that either accept or release protons in response to changes in environmental pH. These polyelectrolytes behave differently toward pH, depending on whether they are anionic or cationic polymers. In the case of anionic polymers, gelation occurs with the increase of the external pH, while the opposite is observed with cationic polymers. The polyacrylic acid (Carbopol®) is the most representative of the pH-­responsive polymers. The Carbopol®-based formulations are initially maintained at a pH value

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Fig. 12.2  Schematic representation of pH-induced gelification of polyacrylic acid. Neutralization with a base creates negative charges along the backbone of the polymer. These repulsive forces uncoil the polymer into an extended, highly swollen structure

between 4 and 5 and when in contact with nasal cavity, where the pH is approximately 6.2, the polymer changes conformation resulting in sol-gel transformation (Fig. 12.2). At low pH values, approximately 3.5, the carboxylic acid groups are protonated and thus no effective charge is present in the molecule. This results in limited polymer-solvent interactions, leading to a collapsed conformation of the polymer with low hydrodynamic volume [25]. As the pH increases the carboxylic groups are deprotonated, exhibiting a negative charge along the backbone. These repulsive forces uncoil the polymer into an extended, highly swollen structure, with a significant increase in viscosity of the aqueous solutions.

2.3 Ionic Gelation Some polymers are ion-sensitive, undergoing a phase change in the presence of various ions such as K+, Ca2+, and Na+. These ions are found in the nasal fluid representing another stimulus useful to induce the gelification of ion-sensitive polymers. For example, in the case of the carrageenan (polysaccharide formed by galactose and 3,6-anhydro-D-galactose units), water-soluble biopolymers obtained from red algae, the type k-carrageenan is able to form rigid and brittle gels mainly in presence of K+ ions while iota(ι)-carrageenan forms elastic gels in the presence of Ca2+ ions. The anionic polysaccharide gellan gum, obtained from cultures of Sphingomonas elodea, gels with both mono- and divalent cations, including Ca2+, Mg2+, K+, and Na+. The linear polysaccharide sodium alginate, obtained from brown algae, undergoes ionic gelation in the presence of multivalent counterions Ca2+ and Mg2+, due to cross-linking reaction between bivalent ions and guluronic acid block in alginate chains forming hydrogels with a characteristic structure called “egg-box” (Fig. 12.3). All the above-mentioned polymers are often combined with others having a bioadhesive capacity (e.g., cellulose derivatives, polyvinylpyrrolidone), that is, the

12  Novel Approaches in Nasal In Situ Gel Drug Delivery

-OOC

OH

HO HO -OOC -OOC HO HO

-OOC

O OH OH O

M

O HO

OH

O HO

O

OH

-OOC

M

G

O OH

OH

-OOC

G

HO O -OOC

O OH

-OOC O HO

HO

O OH

Ca++

-OOC O

O

O

OH

-OOC

OH OH

OH O

OH

O

Ca++

-OOC O

-OOC O

O

O

OH

O

HO O -OOC HO O

OH

O

241

OH OH O

OH

-OOC O HO

O

O

OH -OOC

OH O

M

HO O -OOC

OH HO

O

M

Ca2+

G: 1,4-α-L--Guluronic acid M:1,4-β-D-Mannuronic acid Fig. 12.3  Gelification mechanism of alginate in the presence of ions

ability to interact with mucin chains on the nasal mucosa, thus prolonging dosage form residence time. This can allow a greater absorption of the drug and longer lasting protective effect of the nasal mucosa, if needed. Bedford et al. [26] developed an in situ gel for vaccine nasal administration using a mixture of pluronic F127 and F68 combined to the mucoadhesive polymer chitosan loaded with the model antigen ovalbumin. In vivo studies performed on mice highlighted that a prolonged retention and a better absorption of the antigen in the nasal upper respiratory tract are observed using the in situ bioadhesive gel compared to the same formulation without the thermosensitive polymers (pluronic). Moreover, the number of antigen-positive cells resulted 6.7-fold more as well. These results confirm the advantages derived from the use of thermo-responsive polymers in the formulation. The same authors observed a better protection against a respiratory virus infection loading the in situ gel with influenza virus nucleoprotein. Mice, previously infected by a heterologous influenza A virus, treated with the in situ gel vaccine formulation showed a reduction of virus growth 100-fold in comparison to mice treated with the same formulation without thermo-responsive polymers. Moreover, the virus was not detected in the lung of 80% of mice [26]. As an alternative to pluronic, polymers from natural sources have been employed to obtain the in situ gelification. For example, Chen et al. [23] prepared a nanosuspension of the poor soluble molecule breviscapine in 0.5% of gellan gum (m/v), a polysaccharide produced by the bacterium Sphingomonas elodea, which forms an in situ gel, thanks to the interaction with the cations present in the nasal fluid. In vivo studies performed on rats showed that, after intranasal administration, the formulation increases the drug retention time in the nasal cavity resulting in an improved concentration in cerebrum, cerebellum, and olfactory bulb tissues compared to i.v. administration. For example, the AUC0–8h measured in the cerebrum was

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3194.833  ±  501.745  μg/L·h vs 139.603  ±  33.691  μg/L·h for intranasal and i.v. administration, respectively. Moreover, evaluating the intranasal administration of breviscapine in comparison to the oral administration, a higher absolute bioavailability was measured resulting 57.12% vs 0.40%, respectively. The tmax of intranansal administration resulted low (0.167  ±  0.000  h), indicating the rapid drug absorption from nasal mucosa [27]. Dalvi et al. [28] used xyloglucan as an in situ gelling agent. It is a tamarind seed polysaccharide in which galactose residues were removed to obtain the thermo-­ reversible form. The in situ gel, loaded with the anti-epileptic drug rufinamide, allowed to obtain a preferential accumulation of the drug in the brain compared to the aqueous suspension of the drug administered intranasally. In fact, the bioavailability resulted enhanced as testified by the AUC values (AUC0  →  tlast) measured resulting 201.8  min·μg/g vs 104.28  min·μg/g for in situ gel and drug suspension, respectively [28]. Recently, the nasal route is under investigation for a new nasal gel for COVID-19 respiratory infections treatment. In fact, on April 2021 a clinical trial started (still ongoing) to evaluate the efficacy of a nasal gel loaded with the antiviral drug LTX-109 for the treatment of severe acute respiratory syndrome SARS-CoV-2 [29].

3 Recent Approaches Despite the use of film-forming and bioadhesive polymers solves the problem of the low residence time, however the nasal absorption of molecules showing poor biopharmaceutical properties (solubility and/or permeability) and/or stability problems (e.g., chemical and enzymatic) is still a challenge. Therefore, new approaches involve the incorporation of nano- and microcarriers into the in situ nasal gel in order to protect the drug, improve the biopharmaceutical properties, and control the release (if needed) [30–32] (Table 12.3). This technological approach was investigated both for local and systemic therapies [33]. In particular it represents a more valuable platform for a nose-to-brain delivery promoting the drug absorption via the olfactory neuroepithelium in order to improve the bioavailability of drugs used in the treatment of central nervous system (CNS) diseases [34, 35] as well as alternative for brain cancer therapy [36]. Among the carriers used for this application, liposomes [37, 38], niosomes, nanostructured lipid carrier (NLCs) [39], dendrimers [40], and β-cyclodextrin [41], properly customized, are the most useful. Liposomes are versatile carriers that, due to their structure, can entrap both hydrophilic and lipophilic drugs, improving their absorption through the nasal mucosa [37]. Mura et al. [42] used PEGylated liposomes for nasal administration of the analgesic opiorphin that, due to its peptidic nature, is susceptible to degradation.

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12  Novel Approaches in Nasal In Situ Gel Drug Delivery Table 12.3  Examples of in situ nasal gel combined to nanocarriers In situ Stimulus for gelling agent gelification Gellan gum Nasal fluid ions Carbamazepine Poloxamer Temperature 407 (P407) and poloxamer 188 (P188) Ondansetron Poloxamer Temperature 407 Donepezil Poloxamer Temperature 407 and poloxamer 188 Apixaban Poloxamer Temperature 407 and poloxamer 188 Sumatriptan Poloxamer Temperature succinate 407 and poloxamer 188 Buspirone Carbopol pH hydrochloride 974P and poloxamer 407 Teriflunomide Carbopol-­ pH-nasal gellan gum fluid ions Resveratrol Gellan gum Nasal fluid ions Disulfiram Deacetylated Nasal fluid gellan gum ions Duloxetine Pluronic Temperature F127 and PF68 Paeonol Gellan gum Nasal fluid ions Clonazepam Poloxamer Temperature 407 Drug Voriconazole

Nanocarrier Disease Nanotransferosomes Nasal fungal infection NLC Epilepsy

Reference [33]

Niosomes

Cancer

[36]

Liposomes

Alzheimer’s

[38]

Ethosomes

Thromboembolic [43] disorders

[35]

Nanotransferosomes Migraine and [45] cluster headaches

Niosomes

Anxiety disorders

[46]

NLC

Glioma

[51]

NLC

Alzheimer’s

[53]

Nanoemulsion

Glioblastoma

[54]

Cubosomes

Depressive disorders

[55]

PAMAM dendrimer Parkinson’s

[56]

Cyclodextrins

[58]

Seizures, panic disorder, and akathisia

Liposomes were loaded and then dispersed in a mixture of poloxamer 407 (as thermo-responsive polymer) and carbopol 934P (as bioadhesive polymer) able to form a gel at 34 °C with a rapid gelation time (10 s). Ex vivo studies performed on nasal porcine mucosa showed a considerable enhancement of opiorphin permeation from the thermosensitive hydrogel containing liposomes (Papp 14.3·10−4  cm/min)

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compared to the same formulation containing the drug in free form (Papp 2.5·10−4 cm/min). El-Shenawy et  al. [43] developed a formulation based on a thermosensitive-­ bioadhesive gel associated to ethosomes loaded with the anticoagulant drug apixaban, a molecule characterized by low permeability (class III of the Biopharmaceutics Classification System, BCS). Ethosomes were prepared using lecithin, cholesterol, and ethanol and dispersed in a mixture of poloxamer 407/ poloxamer 188 (thermosensitive polymers) and carbopol 934 (bioadhesive polymer). In vivo studies on rabbits showed that this formulation is able to produce high plasmatic concentrations improving drug bioavailability (Cmax 0.618  ±  0.073  μg/ml, AUC0–6h 2.078  ±  0.084  μg  h/ml) compared to the nasal solution of the drug (Cmax 0.298 ± 0.04 μg/ml, AUC0–6h 0.710 ± 0.04 μg h/ml). A further study showed that the in situ gel exhibits a bioavailability 5.5 times more than the oral solution of apixaban [43]. Hosny et al. [44] prepared a nasal formulation for fungal sinusitis treatment containing the antimicotic agent amphotericin loaded in nanotransferosomes prepared using soybean lecithin and clove oil, which were dispersed in a gellan gum base. Amphotericin is a molecule that, due to its physico-chemical properties, is not able to cross the membranes. The use of nanotrasferosomes showed an improved penetration as testified by ex vivo studies performed on goat nasal mucosa (permeability coefficient 3.101 × 10−3 cm/min vs 0.411 × 10−3 cm/min of aqueous suspension). Omar et  al. [45] developed an in situ gel, for migraine and cluster headaches treatment, based on thermosensitive polymers (mixture of poloxamer 407 and poloxamer 188) and the bioadhesive carrageenan containing nanotransferosomes loaded with sumatriptan succinate. As this drug molecule has a low oral bioavailability (15%), the choice of intranasal administration route appeared to be advantageous. In vivo studies performed on two rabbit groups, one treated with an oral solution of the drug and the other one treated intranasally with the developed in situ gel, showed differences in the bioavailability. The AUC0–12 resulted low for the rabbits treated orally, 186.81  ng·h/mL plasma; 158.95  ng·h/mL in the brain vs. 723.65 ng·h/mL plasma and 742.37 ng·h/mL brain for the group treated with the developed in situ nasal gel. Abdelnabi et al. [46] developed an in situ gel for the intranasal administration of buspirone hydrochloride, an anxiolytic agent, characterized by limited oral bioavailability (4%) as subject to first-pass metabolism and short half-life (2–3 h). The drug was loaded into niosomes then formulated in carbopol 974P solution able to form a gel in situ at the nasal fluid pH value. In vivo studies highlighted that the intranasal administration of drug in situ gel is more advantageous than the oral one. In fact, the bioavailability measured as AUC0–24 resulted higher for the in situ gel (141.86  ±  13.15  ng·ml−1·h) in comparison to oral administration (67.54 ± 7.12 ng·ml−1·h). The study performed on animals treated with the developed nasal in situ gel highlighted a further improvement of AUC0–24 value (462.95 ± 10.15 ng·ml−1 h), suggesting the advantage in the use of a formulation able to remain in the application site for a prolonged time allowing better drug absorption.

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In situ nasal gels were developed in combination to lipid carriers mainly employed to treat diseases affecting the central nervous system (CNS) as Alzheimer’s [39, 47, 48], Parkinson’s [49], and glioblastoma [50]. In fact, due to their nature, the lipid nanocarriers are able to cross the blood-brain barrier, allowing a preferential drug accumulation in the brain [39, 51]. Rajput and Butani [52] formulated the poor soluble and unstable (susceptible to enzymatic degradation) molecule resveratrol in nanostructured lipid carrier (NLCs) dispersed in a mixture of the polymer gellan gum combined to xanthan gum (polysaccharide gum produced by the microorganism Xanthomonas campestris) [53]. In vivo experiments were performed on rats divided into two groups: the first one submitted to intranasal administration of the in situ gel loaded with NLC-resveratrol and the second one treated with a resveratrol suspension (control). The plasmatic curves obtained showed a rapid (Tmax 0.5 h) and higher localization of resveratrol in the brain in comparison to the control. In fact, the AUC values (AUC0 → 8) measured in the brain were 2572 ± 338 ng·h/ml vs. 1809 ± 206 ng·h/ml obtained from a nasal suspension. Qu et al. [54] investigated an ion-sensitive nanoemulsion in situ gel formulation for disulfiram nasal administration to perform a more effective treatment of glioblastoma. Disulfiram, characterized by low solubility and high instability, was loaded in the lipophilic phase of a nanoemulsion. In vivo studies performed on glioma-­bearing rats demonstrated that the intranasal administration of the ion-­ sensitive nanoemulsion is able to promote the localization of the drug in the tumor cells compared to a saline solution administered intranasally used as control. The measured median survival time resulted 1.6 folds higher than the control group. Recently “cubo-gels”, a combination of the cubosomes and a thermosensitive hydrogel, were prepared for the nasal delivery of duloxetine, a drug used for the treatment of depressive disorders [55]. In vivo experiments were performed on Swiss albino rats divided into three groups. The first two were administered intranasally with in situ “cubo-gel” and drug solution, respectively. The third one was administered intravenously. The plasmatic AUC0–72 measured for the three different groups highlighted that the “cubo-gel” was able to produce higher values (457.96  ±  4.53  ng·h/mL) compared to the other two control formulations (243.14 ± 8.16 ng·h/mL and 301.04 ± 9.03 ng·h/mL for intranasal solution and i.v., respectively). The brain bioavailability was evaluated as well, and the obtained results confirmed the best results for rats treated with “cubo-gels” measuring higher AUC values (179.62  ±  6.30  ng·h/mL) compared to intranasal solution (109.27 ± 5.3 ng·h/mL) and i.v. administration (106.32 ± 3.7 ng·h/mL). Another kind of carrier, combined to thermosensitive polymer, is represented by polyamidoamine (PAMAM) dendrimers. Xie et al. encapsulated paeonol, a neuroprotective agent useful for Parkinson’s disease treatment, in the hydrophobic cavities of polyamidoamine (PAMAM)modified dendrimer [56]. The obtained complex was dispersed in a mixture of deacetylated gellan gum (0.45% w/w) and HPMC (0.30% w/w) able to form a gel in the presence of ions (Na+, K+, and Ca2+). In vitro studies demonstrated that the molecule is released by a sustained mechanism within 12  h. The developed

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formulation (containing a fluorescent molecule) was administered in the nasal cavity of 25 rats in order to evaluate the nasal brain transport. A comparison was carried out with the loaded dendrimer alone. The fluorescence images collected at established times (0 h, 2 h, 6 h, 12 h, and 24 h) showed that the administration of the complex by the in situ gel allows to obtain a better and higher localization of the drug in the brain tissue than the loaded dendrimer alone. This result has been explained considering that the latter is easily cleared from the nasal cavity while the in situ gel is able to prolong the contact time with the nasal mucosa allowing a better release and absorption. Ahmed et al. [57] prepared an in situ gel based on gellan gum in which were dispersed micelles loaded with the poor soluble molecule raloxifene hydrochloride intended for the treatment and prevention of osteoporosis. In vivo studies performed on rats showed a higher bioavailability (AUC) of the drug obtained from both the in situ gel containing the micelles (11.26 ± 2.53 μg·h/ml) and the in situ gel containing the drug in free form (2.34 ± 1.93 μg·h/ml) compared to oral tablets of raloxifene hydrochloride (0.83  ±  0.47  μg·h/ml), suggesting the advantages in the use of nasal route. Cirri et al. developed a nasal thermosensitive and mucoadhesive gel to perform clonazepam (anti-epileptic drug) intranasal delivery in order to overcome the problems associated with both oral and parenteral administration of this drug [58]. Poloxamer was employed as thermosensitive polymer and chitosan glutamate and sodium hyaluronate as mucoadhesive and permeation enhancer, respectively. In addition, a randomly methylated β-cyclodextrin was used to improve diazepam solubility. In consideration of all the variables of the formulation, including the drug-cyclodextrin ratios, the authors used a screening DoE for a systematic evaluation of the formulation composition on gelation temperature and gelation time and prepared many loaded gels at different clonazepam-cyclodextrin concentrations. All selected formulations showed properties suitable for an in situ mucoadhesive thermosensitive gel formulation, and they demonstrated that the gel formulations were significantly more effective in the improvement of clonazepam permeation than the drug solution. In vitro permeation studies showed that the complex clonazepam-­ methylated β-cyclodextrin formulated as an in situ gel allows to obtain an improved permeability of clonazepam (Papp ~ 9 × 10−5 cm/s) in comparison to clonazepam solution (Papp ~ 2 × 10−5 cm/s).

4 Safety Aspects Recently nasal drug delivery has widely increased, especially for peptides and proteins, mainly due to rapid absorption to the systemic circulation and good bioavailability of drugs, advantages offered by the particular anatomical structures of the nasal cavity. In fact, the site of absorption offers a high contact area presenting only two cell layers separating the nasal lumen from the dense blood vessel network in the lamina propria, which is probably the main reason for the rapid absorption of

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drugs via this route. On the other hand, it is very important to take into account that the administration of nasal formulations could cause damage to this thin and delicate epithelium [59]. For this reason, safety is a key issue when an innovative and effective drug formulation, as nasal in situ gel, is planned. Total safety and not only that of the active ingredient must be considered when developing a new product. In fact, in this kind of formulation the excipients play a very important role and particular attention must be paid to the penetration enhancers, eventually used, and to the polymers (mucoadhesive and film-forming) which prolong the contact time with the nasal mucosa. Their action could in fact significantly reduce the safety of the final medicinal product [60]. With regard to local effects on the nasal mucosa, the tolerability of the medicinal product depends on many factors and differs, obviously, from individual to individual. In fact, environmental aspects (temperature, local humidity), presence of infections or inflammations, and previous illnesses or allergies can influence the interactions between the nasal mucosa and the applied formulation. The blood flow of the nasal mucosa is the factor most responsible for the regulation of temperature and humidity of the inhaled air, and some nasal administered drugs can both decrease blood flow (e.g., vasoconstrictors) and increase it (histamine, albuterol, isoproterenol, and fenoterol). These variations, together with the presence of polymers able to bind the mucin chains present on the mucosa, can cause irritation, especially in case of continuous use. Rare side effects such as nosebleeds and the onset of perforation of the nasal septum have only rarely been observed [60]. Particular attention must be paid to the penetration enhancers, largely used in intranasal gels, generally able to improve the transport of drug molecules through the nasal epithelium and mucosa due to the opening of the tight junctions, the alteration of the mucus layer, and the inhibition of proteolytic enzymes. In turn, those functions can have a disruptive character and thus lead to adverse side effects, thereby significantly reducing the safety of the final pharmaceutical product. In fact, this approach is very useful for drugs that possess low permeability, but the penetration enhancers alter the natural nasal barrier function damaging epithelial cells, mucus, or the cilia. Thus, the barrier function may be lost. The boundary between the irritant (dryness, irritation, sneezing, itching) and the toxic (rhinitis medicamentosa, congestion, nasal lesion) activity depends on the mechanism of action exerted but above all on the local exposure time. In this perspective it is possible to believe that these substances and compounds act as irritants to the nasal mucosa but are non-damaging [59, 60]. Most nasal formulations, as hydrogels, are formulated as multidose preparations requiring a preservative to prevent the growth of microorganisms upon repeated use. The effects of various preservatives on mucociliary transport rate have been in vitro studied in order to investigate their influence on the safety characteristics of the final product. Methyl-p-hydroxybenzoate (0.02% and 0.15%), propyl-p-­hydroxybenzoate (0.02%), and chlorbutol (0.5%) halted mucociliary transport. The ciliostatic effect of methyl-p-hydroxybenzoate and propyl-p-hydroxybenzoate was reversed after

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rinsing with normal saline solution, whereas in the case of chlorbutol (0.5%) and methyl-p-hydro-xybenzoate (>0.15%) the reverse of the inhibiting effect was variable [59]. Benzalkonium chloride exhibits surfactant properties that can destroy the ciliary membrane and thus might be expected to be toxic to cilia. In contrast, nasal administration of 0.01% bezalkonium chloride in humans was well tolerated and did not change nasal clearance after a single administration. Long-term administration of 0.02% benzalkonium chloride (6 weeks) in humans did not change the nasal clearance rate without changes in mucosal morphology [59]. Ethylenediaminetetraacetic acid (EDTA) halted mucociliary transport irreversibly by disruption of ciliated epithelium. Due to its chelating ability, EDTA causes expansion of the intercellular spaces and therefore could permit an increase in the permeability of the tissue to various molecules [59]. The human nasal mucosa has an average physiologic pH of 6.3 (slightly acidic), and the maintenance of the pH value in the mucus ensures the function of the ciliary clearance. Therefore, the pH of nasal hydrogels should be within a pH range from 4.5 to 6.5 to avoid nasal irritation [60]. Not only the pH but also the osmolarity has an influence on the mucus rheological properties and on the ciliary beat contributing to local toxicological considerations [61, 62]. These aspects must be taken into consideration in the case of nasal hydrogels based on filming and mucoadhesive polymers whose action derives from the ability to establish numerous bonds, mainly hydrogen bond and van der Waals forces, with water and biological structures [63]. Although the residence time in the cavity is considerably increased for polymeric formulations that absorb water, when in contact with the mucosa to form a film, it is not the only factor in the increased absorption of drugs. It has been suggested that the gels swell by taking water from the mucus layer and the underlying epithelial cells, resulting in a temporary widening of the tight junctions. Also the osmotic pressure of the nasal hydrogels is an important parameter to keep under control because hypotonic or hypertonic gels can have different effects on the nasal mucus rheology and clearance [64]. Rossi et al. [65] demonstrated that hypertonic formulations cause a weak interaction with the biological structures. Most of the studies carried out to evaluate the toxicity of nasal formulations focused mainly on acute drug-induced or short-term effects. In vitro techniques often provide a good screening method for identifying substances with potential deleterious effects on the nasal mucosal structure although a good correlation with in vivo use is not observed. Moreover, to make accurate and reliable evaluations of the potential side effects of nasal gels, researchers have to determine the effects of its long-term use in animals and humans [59, 60]. Despite the fact that in situ nasal gels represent a promising therapeutic tool, pharmacovigilance data will be useful to perform a deep analysis of the safety aspects. Finally, patient compliance must be considered for an optimal nasal formulation. In this respect, gel strength should be considered as an important physical parameter in order to improve patient adherence to therapy. In fact, a gel strength in the range

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25–50  sec is recommended [66]. A less strong gel hardly maintains its integrity while a stiff gel could be responsible for irritation and consequent discomfort.

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Chapter 13

Nasal Delivery of High Molecular Weight Drugs: Recent Trends and Clinical Evidence Emine Kahraman, Sevgi Güngör, and Yıldız Özsoy

Abstract  In recent years, the nasal route has been a promising administration for systemic drug delivery. However, the nasal epithelial barrier hinders high molecular weight medications, especially hydrophilic drugs, while low molecular weight drugs are rapidly absorbed through the nasal mucosa. Additionally, enzymatic degradation and mucociliary clearance in the nasal cavity negatively affect the bioavailability of these drugs in the peptide-protein structure. As a result of the limitations, the nasal bioavailability of these drugs is generally less than 1%. Thereby, the recent studies have been  focused to increase the nasal bioavailability of high molecular weight drugs, using various strategies such as particulate drug delivery systems, mucoadhesive/thermosensitive polymers, absorption enhancers, and enzyme inhibitors. In this chapter, the recent advances that developed to improve nasal bioavailability of high molecular weight drugs have been reviewed in the light of literature studies and preclinical and clinical trials. Keywords  High molecular weight drugs · Macromolecular drugs · Nasal delivery · Peptide-protein drugs · Absorption enhancers

1 Introduction The nasal drug delivery has been used for therapeutic reasons for centuries. Nowadays, it is commonly utilized for the treatment of local inflammation, common rhinitis, and allergic rhinitis, with active ingredients such as glucocorticoids and antihistamines [1]. In recent years, the nasal delivery of the drugs into the systemic E. Kahraman · S. Güngör · Y. Özsoy (*) Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul, Türkiye e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_13

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circulation has gained a great importance as an alternative approach to oral and parenteral drug administration because of its many advantages such as rapid drug absorption resulting in a quick onset of action, prevention of the hepatic first-pass metabolism, reduced adverse effect, increased patient compliance, and low costs [2]. Besides these advantages, the nasal delivery of high molecular weight drugs has some limitations including enzymatic barriers for peptide-protein drugs and low permeability of the nasal epithelia. Thus, the nasal bioavailability of high molecular weight drugs is low and variability is high, while the bioavailability of low molecular weight drugs is relatively high and variability is low in comparison with injections [3]. Thereby, the recent studies have been focused to increase the nasal bioavailability of high molecular weight drugs, especially peptide-protein drugs, by using various strategies such as particulate drug delivery systems, mucoadhesive/thermosensitive polymers, absorption enhancers, and enzyme inhibitors. In this chapter, the recent advances that developed to improve nasal bioavailability of high molecular weight drugs have been reviewed in the light of literature studies and preclinical and clinical trials.

2 High Molecular Weight Drugs The high molecular weight drugs (also referred as macromolecules) are defined as compounds having a number of average molecular weight that are greater than or equal to 1000 Da. These molecules having mostly peptide-protein structures have rapidly grown with development of biotechnology over the past 20 years [4]. Herein, nasal delivery of peptide-protein drugs which are commercially in another dosage forms (e.g., injection) on the market is intensively highlighted in this section.

2.1 Insulin Insulin is a peptide hormone composed of 51 amino acids with a molecular weight of 5778  Da. Since its discovery in 1922, it has been used in the management of diabetes mellitus, which is a chronic disease characterized by elevated levels of blood glucose [5, 6]. Nowadays, insulin has been subcutaneously administered with side effects such as possibility of hypoglycemia episodes, weight gain, and inadequate post-meal glucose control [7]. Kupila et al. [8] reported that short-term use of intranasal insulin was well tolerated with minimal hypoglycemia risk and no local irritation. Moreover, Schmid et al. [9] reviewed safety of intranasal insulin using articles published between 1999 and 2017. This retrospective review on the intranasal insulin presented that no hypoglycemia episode or severe adverse effect were reported after administration of intranasal insulin. However, further data are needed to ensure long-term safety of chronic insulin administration. In addition to the management of diabetes mellitus, many studies including preclinical and clinical

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indicate that intranasal insulin might improve cognition and memory in the patients with age-related cognitive impairments such as Alzheimer’s and Parkinson’s disease [3, 10–12]. Over the years, numerous formulations have been developed to improve absorption of intranasal insulin. However, no approved formulation of intranasal insulin is currently available on the market, with being the most studied molecule in the formulation development [3].

2.2 Desmopressin Desmopressin is a synthetic analogue of the natural antidiuretic hormone arginine vasopressin, which has a molecular weight of 1069 Da [6]. It has been clinically used to treat nocturnal enuresis, central diabetes insipidus, and congenital bleeding disorders including hemophilia A and von Willebrand diseases over 40 years [13– 15]. On the market, it is available in several dosage forms including injection, oral tablet, fast-dissolving tablet, sublingual tablet, nasal spray, and nasal drops [5, 16, 17]. Bypassing the intestinal first-pass effect, nasal spray has the higher bioavailability (5–10%) than sublingual and oral tablets, but it exhibits high variation in its bioavailability, which could lead to severe adverse effects such as hyponatremia [18].

2.3 Salmon Calcitonin Calcitonin is a peptide hormone composed of 32 amino acids with a molecular weight of 3432 Da [6], which acts in the calcium homeostasis, regulating intestinal calcium absorption and renal calcium reabsorption and inhibiting osteoclast activity [19]. Calcitonin, which is commercially available as salmon calcitonin, has been used in the treatment of osteoporosis and Paget’s disease. In 1995, its nasal spray (Miacalcin®, Novartis) was approved by the Food and Drug Administration (FDA), but its nasal absorption was very low (3%) [5].

2.4 Oxytocin Oxytocin is a peptide hormone with a molecular weight of 1007  Da [6], which normally plays a role in social bonding, labor, and post-partum period in the human body. On the market, it is available in two pharmaceutical forms: injection and nasal spray. Its parenteral form is intravenously used for labor induction, abortions, and control of post-partum bleeding as nasal spray is used for stimulation of post-­partum milk ejection [3]. Additionally, some studies have indicated in the recent years that

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intranasal oxytocin has created positive results on psychiatric disorders, social behavior, autism, and obesity [20–22].

2.5 Glucagon Glucagon is a peptide hormone composed of 29 amino acids with a molecular weight of 3483 Da [6], which is used in the treatment of severe hypoglycemia that could be life threatening. Since 1960, there have been only injectable preparations on the market despite lack of ability to administer in the emergency conditions [23]. In 2019, nasal powder glucagon (Baqsimi®, Eli Lilly) was approved by FDA, to meet the unmet medical need for an easily administrated glucagon [24].

2.6 Human Growth Hormone The major isoform of human growth hormone is a protein composed of 191 amino acids with a molecular weight of approximately 22 kDa [6]. It is used in the treatment of growth hormone deficiency, Turner syndrome, Prader–Willi syndrome, chronic kidney failure, and idiopathic short stature in children [25]. Its nasal delivery can greater simulate the normal endogenous pulsatile human growth hormone secretion pattern when compared to a subcutaneous injection, but there has been only its injection preparation on the market.

2.7 Teriparatide (Recombinant Human Parathyroid Hormone) Teriparatide is a form of parathyroid hormone consisting of the first (N-terminus) 34 amino acids, which is the bioactive part of the hormone [26]. The drug, which is a peptide with a molecular weight of 4118 Da [6], was approved by the FDA for parenteral treatment of osteoporosis in postmenopausal women and in men with idiopathic or hypogonadal osteoporosis that are at high risk for fractures [27]. There has been still commercially no nasal form, despite several formulation are being under development.

2.8 The Miscellaneous Beside aforementioned macromolecules, there have been some molecules (interferon-­beta, basic fibroblast growth factor, glial-derived neurotrophic factor, etc.) which are only under preclinical and clinical studies for the nasal delivery.

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Table 13.1  The molecular weights and indications of high molecular weight drugs

Molecule Insulin

Molecular weight (Da)a 5778

Structure (Peptide/protein) Peptide

Desmopressin

1069

Peptide

Salmon calcitonin Nafarelin Buserelin Leuprolide

3432

Peptide

1323 1239 1209

Peptide Peptide Peptide

Goserelin

1269

Peptide

Oxytocin

1007

Peptide

Glucagon

3483

Peptide

Teriparatide

4118

Peptide

Interferon-beta

1663

Peptide

Octreotide

1019

Peptide

Insulin-like growth factor-I (IGF-I) Orexin A Exenatide

7649

Peptide

3561 4186

Peptide Peptide

Hirudin-2

6892

Peptide

Indication The management of diabetes mellitus The treatment of nocturnal enuresis, central diabetes insipidus, and congenital bleeding disorders The treatment of osteoporosis and Paget’s disease The treatment of endometriosis and fertility The treatment of endometriosis, prostate cancer, and central precocious puberty The treatment of breast and prostate cancer The stimulation of post-partum milk ejection The treatment of severe hypoglycemia The treatment of postmenopausal and idiopathic osteoporosis The management of multiple sclerosis The management of acromegaly, diarrhea, and flushing caused by carcinoid tumors and vasoactive intestinal peptide-secreting adenomas The treatment of growth failure and short stature in children with severe primary IGF-I deficiency The treatment of narcolepsy The adjunctive treatment of diabetes type 2 The prophylaxis and treatment of heparin-induced thrombocytopenia, venous and arterial thrombosis, and shunt thrombosis or treatment of disseminated intravascular coagulation

Reference [28] [13–15]

[19] [29] [30] [31]

[32] [33] [24] [27] [34] [35]

[36]

[37] [38] [39]

(continued)

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Table 13.1 (continued) Molecular weight (Da)a ca 22,000

Structure (Peptide/protein) Protein

Erythropoietin

ca 34,000

Protein

Basic fibroblast growth factor

In range of 16,000 and 18,500 ca 15,000

Protein

Protein

ca 36,000

Protein

ca 140,000

Protein

Molecule Human growth hormone

Single-domain antibody Glial-derived neurotrophic factor Nerve growth factor (NGF)

Indication The treatment of growth hormone deficiency, Turner syndrome, Prader–Willi syndrome, chronic kidney failure, and idiopathic short stature in children The treatment of anemic patients with insufficient erythropoietin production The treatment of brain trauma, ischemic stroke, and neurodegenerative diseasesb The treatment of severe pneumoniab The treatment of several neurodegenerative disorders including Parkinson’s diseaseb The treatment of spermatogenesisb

Reference [25]

[40]

[41]

[42] [43]

[44, 45]

www.pubchem.com Non-approved by no regulatory authority, only under preclinical and clinical trials

a

b

Further, only few studies have been to improve the nasal absorption in the literature. Hence, information on these molecules is summarized in Table 13.1.

3 Superiorities and Limitations of Nasal Administration for High Molecular Weight Drugs 3.1 Nasal Blood Flow When compared to other biological membranes, the nasal mucosa is a relatively porous, thin, and highly vascularized epithelial membrane. Also, it comprises a large absorption area (150  cm2) with microvilli in epithelial cells. As a result of these characteristics, the nasal mucous membrane is well supplied with blood. The greater blood circulation, the easier it is for the drugs to be absorbed and distributed in the system. Hence, the nasal administration ensures fast absorption of drugs, rapid onset of action, and low risk of overdose [46].

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3.2 Enzymatic Activity Enzymes such as carboxylesterases, epoxide esterases, glutathione S-transferases, epoxide hydrolases, aminopeptidases, endopeptidases, and exopeptidases exist in the nasal cavity. They negatively impact stability of nasally applied peptideprotein drugs. These drugs might be degraded by peptidase and proteases. The endopeptidases and exopeptidases can cleave internal peptide bonds and peptides at their N, C termini, respectively. This results in decreased nasal bioavailability [2].

3.3 Mucociliary Clearance The nasal mucosa is covered with 5 μm of thick mucus which has a viscous gel on the upper part and an aqueous sol layer on the lower part. The nasal mucus renews itself approximately every 10–15 min at a speed of 5–6 mm/min. This occurs with ciliary activity to clean the nose from foreign particles and pathogens. All foreign bodies in the air inhaled are enclosed by the mucous layer and pushed from the nasal cavity to nasopharynx to be thrown into the gastrointestinal tract. This movement of mucus is named “mucociliary clearance”, which is the main defense mechanism of the body against foreign particles and pathogens. Therefore, the retention time of drugs is limited in the nasal cavity. Particularly, hydrophilic drugs are readily soluble in the mucus and quickly removed from the nasal cavity by mucociliary clearance, resulting in poor nasal absorption. Also, the mucociliary clearance being affected by external factors (air pollution, smoking, lung diseases, etc.) might cause variation in the nasal absorption [5, 47].

3.4 Nasal Absorption Nasal absorption can be described as diffusion of a drug into the circulation via the nasal mucosa. The physicochemical characteristics (ionization, lipophilicity, etc.), surface charge, and especially the molecular size of drug affect its nasal absorption, and then bioavailability. Low molecular weight drugs are well absorbed through the nasal mucosa. However, the nasal mucosa is an obstacle for absorption of high molecular weight drugs, especially for more than 1000 Da in size. Thus, the nasal bioavailability of particularly hydrophilic peptide-protein drugs is mostly less than 1% [5].

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3.5 Physical Condition of Nose The constant nasal administration is a challenge in the cold season because the physiological change that is based on a disease in the nasal mucosa affects nasal drug absorption. In the case of a disease, the mucous membrane swells after inflammation or irritation, leading to decreased drug absorption. Moreover, itching and sneezing during the disease intensify this effect [48].

4 Recent Trends in Nasal Delivery of High Molecular Weight Drugs Intranasal drug delivery is not complicated, hence all types of preparations (solution, powder, spray, gel, suspension, ointment, insert, etc.) could be administrated for the nasal delivery of high molecular weight drugs as well as small molecular weight drugs. However, it has some limitations for high molecular weight drugs, as explained in Sect. 3. Thereby, several strategies have been used to enhance the nasal bioavailability of high molecular weight drugs, including improvement in the half-­ life of drugs, higher mucoadhesion and retention time, protection from degradation of enzymes in the nasal cavity such as aminopeptidases and endopeptidases, and use of absorption agents that enable delivery through tight junctions of nasal epithelium.

4.1 Particulate Drug Delivery Systems 4.1.1 Microparticulate Systems Microparticulate systems including microparticles and microspheres are matrix carriers where the drug is dispersed in a polymeric material, with diameter in the range of 1 μm and 1000 μm. These systems are fabricated by different encapsulation methods including mostly spray-drying, emulsification solvent evaporation, and phase separation [5]. The microparticulate systems which are produced using mucoadhesive polymers such as chitosan and alginate could protect the peptide-protein drug from degradation and ensure prolonged drug release via nasal mucosa into the systemic circulation [49]. Mostly, these nasally applied systems are insoluble in water, but absorb water into the matrix, resulting in swelling of the microparticles/ microspheres and formation of gel [50]. Chitosan is one of the most used polymers to prepare these microparticulate systems. As a result of a combination of chitosan and microparticle properties, the microparticles provide controlled drug  delivery while the chitosan increases the residence time in the nasal cavity and enhances drug absorption by opening the tight junctions between the epithelial cells. Hence, drug absorption through the nasal mucosa has shown a great extent as also reported

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by Varshosaz et  al. [51]. Further, the bioavailability of thiolated chitosan microspheres (7.24 ± 0.76%) was 3–4 times higher than that of chitosan microspheres (2.04  ±  1.33%) [52]. When thiolated chitosan microspheres are utilized, they increase the bonds with the mucin protein because of their enhanced interactions with the cysteine residues of the mucus glycoprotein, resulting in a longer retention time in the nasal cavity [53]. Similarly, increased positive charge of aminated gelatin microspheres and thiomer polycarbophil-cysteine microparticles contributed to insulin and human growth hormone absorption through the nasal mucosa, respectively [54, 55]. Nema et al. [56] revealed that thiolated microspheres loading insulin showed greater reduction in the blood glucose level than that of non-thiolated microspheres in the streptozotocin-induced diabetic rabbits. Additionally, some studies are available about thiolated microparticles and microspheres, as seen in Table 13.2. Differently, Balduci et  al. [92] formulated desmopressin microparticles as chimera agglomerates to improve nasal drug bioavailability. In vitro permeation studies indicated that permeation of desmopressin in the novel formulation through nasal mucosa was significantly higher than that of commercial liquid nasal spray. In rats, it induced a significant reduction in urine production. In another study, Serim et al. [59] produced spray freeze-dried lyospheres® with diameter in the range of 190 μm and 250 μm for nasal administration. Because of their low density, 90% or greater of lyospheres deposited in the nasal cavity, resulting in the nasal bioavailability of insulin of 7.0 ± 2.8%. 4.1.2 Nanoparticulate Systems Nanoparticulate systems with diameter in the range of 20  nm and 200  nm have become attractive as a promising administration for nasal delivery in recent years. Despite complicated preparation process and paradoxical effectiveness reports, they improve drug permeation through the nasal mucosa, protect peptide-protein drugs from enzymatic degradation in the nasal cavity, increase delivery of vaccines to the lymphoid tissue in the nasal cavity with an adjuvant activity, and offer a way for peptide-protein drug delivery particularly into the brain and systemic circulation. Moreover, these systems could be targeted for nose-to brain delivery of drugs and decrease adverse effects of the drugs [49, 50, 93]. Generally, polymeric nanocarriers (nanoparticles, nanocomplexes, dendrimers, nanogels, etc.) and lipid-based particles (liposomes, solid lipid nanoparticles, nanostructured lipid carriers, etc.) have been reported to be used for nasal delivery of high molecular weight drugs (Table 13.2). Chitosan and chitosan derivates have been widely used in the preparation of the nanoparticles for the nasal delivery, because of their mucoadhesive and absorption-enhancing characters, being safety polymers. Zhang et al. [61] revealed that intranasal administration of PEG-g-chitosan nanoparticles in the rabbits resulted in a greater insulin absorption through the nasal mucosa in comparison with insulin-PEG-g-chitosan suspension and control insulin solution. In other studies, insulin-loaded PEGylated trimethyl chitosan nanocomplexes and ­chitosan/

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Table 13.2  The examples of particulate drug delivery system, mucoadhesive/thermosensitive polymer, and absorption enhancer used to improve the nasal delivery of high molecular drugs Polymer/others Thiomer polycarbophil-­ cysteinea Poly (acrylic acid)-cysteinea Poly (acrylic acid)-cysteine-poly (vinyl pyrrolidone)a Thiolated carbopol cysteinea Polyvinylpyrrolidone Poly (L-aspartic acid) and chitosan Polyethylene glycol (PEG)-grafted chitosan Chitosan/sodium alginate Starch Chitosan-N-acetyl-Lcysteinea Chitosan/ cyclodextrin derivativesb Lectins modified PEG-polylactide-­ polyglycolide Phenylboronic-acid-­ functionalized dextran Chitosan–ZnO PEGylated trimethyl chitosan Amine-modified poly (vinyl alcohol)-graft-­ poly(L-lactide)a

Molecule Delivery system Human growth Microparticles hormone

Absorption enhancer –

Reference [55]

Exenatide

Microparticles

–

[57]

Insulin

Microparticles

–

[58]

Insulin

Microspheres

–

[56]

Insulin

Lyospheres

[59]

Insulin

[60]

Insulin

Submicron capsules Nanoparticles

Sodium taurocholate or cyclodextrins – –

[61]

Insulin

Nanoparticles

–

[62]

Insulin

Nanoparticles

Insulin

Nanoparticles

Na glycocholate or [63] Lysophosphatidylcholine – [64]

Insulin

Nanoparticles

–

[65]

Basic fibroblast growth factor Insulin

Nanoparticles

–

[66]

Nanoparticles

–

[67]

Insulin Insulin

Nanocomposites – Nanocomplexes –

[68] [69]

Insulin

Nanocomplexes

[70]

–

(continued)

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13  Nasal Delivery of High Molecular Weight Drugs: Recent Trends and Clinical… Table 13.2 (continued) Polymer/others Chitosan, glyceryl distearate, caprylic/ capric triglyceride, poloxamer 188 Tween 80b

Molecule Glial cell–derived neurotrophic factor

Gelatin, poloxamer 188, Tween 80b

Basic fibroblast growth factor Chitosan, cholesterol, Leuprolide dicetyl phosphate, acetate stearyl amine, hydrogenated soya phosphatidylcholineb Soybean Salmon phosphatidylcholine, calcitonin cholesterol, sodium deoxycholateb Alginate, propylene Insulin, epidermal glycol, magnesium growth factor, salt, phospholipidb oxytocin Lauroyl proline Human growth hormone, erythropoietin, and salmon calcitonin Polyamidoamine Insulin, (PAMAM) calcitonin Poly(N-vinyl Insulin pyrrolidone) Chitosan Insulin

Carbopol

Insulin

Carbopol/ hydroxypropyl methylcellulose Gelatin

Insulin

Basic fibroblast growth factor

Delivery system Chitosan-coated nanostructured lipid carriers with surface modified transactivator of transcription (TAT) peptide Nanostructured lipid carriers

Absorption enhancer –

Reference [71]

–

[72]

Liposomes with chitosan

–

[73]

Ultraflexible liposomes

–

[74]

Phospholipid vesicles (Phospholipid Magnesome) Protein-­ lipoamino acid complexes

–

[75]

–

[40]

Dendrimer

–

[76]

Nanogel

–

[77]

Mucoadhesive gel

[78] Saponin, sodium deoxycholate, ethylendiamine tetra-acetic acid (EDTA), lecithin – [79]

Mucoadhesive gel Mucoadhesive gel Mucoadhesive gel

–

[80]

–

[81]

(continued)

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Table 13.2 (continued) Polymer/others Chitosan/hyaluronate polyelectrolyte complexes Hydroxypropyl methylcellulose Carbopol/Starch

Molecule Insulin

Delivery system Insert

Absorption enhancer –

Reference [82]

Insulin

Insert

–

[83]

Powder – Salmon calcitonin, human growth hormone Insulin Thermosensitive – N-[(2-hydroxy-3-­ gel trimethylammonium) propyl] chitosan chloride, poly (ethylene glycol), a-b-glycerophosphate Chitosan, poly vinyl Insulin Thermosensitive – alcohol gel Glyceryl Insulin Solution – monocaprylate-­ modified chitosana Sperminated gelatina Insulin Solution – Aminated gelatina Insulin Solution – Chitosan Insulin Solution EDTA, Tween 80, cyclodextrins Chitosan Hirudin-2 Solution Glycyrrhizic acid monoammonium salt, azone, hydroxylpropyl-­ beta-­cyclodextrin, lecithin, EDTA, sodium dodecylsulfate, Brij35, Tween 80, menthol

[84]

[85]

[86] [87]

[88] [89] [90] [91]

Cationized polymers to increase the mucoadhesion At least one component of the delivery system is an absorption enhancer

a

b

cyclodextrin nanoparticles showed 34–47% and ˃35% reduction in the blood ­glucose concentration, respectively [65, 94]. In contrast to these results, Dyer et al. [95] reported that chitosan powder for the nasal insulin delivery (bioavailability of 17.0%) was more effective in reducing the blood glucose concentration than chitosan nanoparticles and chitosan solution (bioavailability of 1.3% and 3.6%, respectively). Besides chitosan derivates, phenylboronic acid-functionalized glycopolymers (3-acrylamidophenylboronic acid-r-N-acetyl glucosamine, 2-lactobionamidoethyl methacrylate-random-3-acrylamidophenylboronic acid, phenylboronic-acid-­ functionalized dextran, etc.) have recently attracted attention because of their mucoadhesive and enzyme-inhibitory properties [67, 96, 97]. Lipid-based particles have been mostly applied by coating/incorporating a mucoadhesive polymer into the nasal mucosa. In recent years, glial cell–derived

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neurotrophic factor was encapsulated into chitosan-coated nanostructured lipid carriers with surface-modified transactivator of transcription (TAT) peptide for treatment of Parkinson’s disease in the study of Hermando et  al. [71]. Similarly, Akel et  al. [98] indicated that chitosan-coated solid lipid nanoparticles had superiority in comparison with native insulin for management of Alzheimer’s disease.

4.2 Polymers 4.2.1 Mucoadhesive Systems The mucoadhesive polymer  approach has been developed to enhance nasal drug absorption, extending formulation’s intimate contact time with the nasal mucosa by attaching to the mucus layer’s surface. This is achieved by several drug delivery systems including microspheres, powders, gels, inserts, using mucoadhesive polymers such as chitosan, poly (acrylic acid) (Carbopol), hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, and gelatin [54, 80, 99, 100]. This approach has low toxicity, and the most promising method, especially when combined with absorption enhancers [50]. Chitosan is the most used polymer of mucoadhesive systems for nasal delivery of high molecular weight drugs. It has positive charge at slightly acidic pH due to its glucosamine residues. Because of its ionization, chitosan is soluble in water at pH˂6, and it becomes water insoluble at more than 6 of pH. As a result of this, it could be utilized as a viscosity agent in the acidic medium [101]. More importantly, it exhibits a strong adhesion ability to mucosal tissues consisting of anionic sialic acid groups in the nasal cavity, owing to its cationic amino groups. Additionally, solvent-drag mechanism of chitosan leads to widening the tight junctions, and then high molecular weight drugs transports through the nasal mucosa into the blood capillary, enhancing nasal absorption [50]. Further, it has a high loading capacity of drug molecules, owing to interactions with peptide-­ protein drugs of hydroxyl and amino functional groups in the chitosan [102]. It is a promising mucoadhesive polymer for nasal delivery of high molecular weight drugs. Hinchcliffe et al. [103] reported that relative bioavailability of salmon calcitonin from the chitosan solution was increased twofold in comparison with marketed nasal product in animal studies. Additionally, most of the studies demonstrated that nasal bioavailability of peptide-protein drugs increased greater than that of only chitosan formulations when chitosan and chitosan derivates were combined with absorption enhancers [78, 90, 91]. Apart from chitosan, carbopol, hydroxypropyl methylcellulose, starch, gelatin, and their combinations with/without absorption enhancers were widely studied to improve nasal absorption of several peptide-­ protein drugs by numerous of research groups (Table 13.2).

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4.2.2 Thermosensitive Systems The thermosensitive systems which would be herein called as in-situ gelling systems form gel from solution state in specified temperature conditions. In the solution state, they may be readily dropped or sprayed into the nasal cavity and spread on the nasal mucosa. Following the formulation into the nasal cavity, the solution could transform into viscous gel at body temperature. As a result, the rate of nasal mucociliary clearance reduces, and drug release gets slower. Poloxamers are widely used for the preparation of thermosensitive gels [50, 104]. In recent years, Bahmanpour et al. [105] have developed a novel thermosensitive hydrogel consisting of chitosan, chitosan quaternary ammonium salt, and gelatin for intranasal insulin administration. This novel formulation exhibited low gelation time, uniform pore structure, and desirable swelling rate, which resulted in adequate encapsulation and prolonged release of insulin over 24 h. Similarly, Wu et al. [85] and Agrawal et  al. [86] had separately optimized thermosensitive gels consisting of N-[(2-­ hydroxy-­3-trimethylammonium) propyl] chitosan chloride, poly (ethylene glycol), a-b-glycerophosphate and chitosan, poly vinyl alcohol to improve nasal insulin absorption, respectively.

4.3 Absorption Enhancers The use of absorption enhancers is the most common and effective strategy to enhance absorption of high molecular weight drugs through the nasal mucosa. The absorption enhancers increase the permeability of epithelial cell layer based on various mechanisms, by improving drug solubility or stability, inhibiting enzyme activity, reducing mucus viscosity or elasticity, decreasing mucociliary clearance, and opening tight junctions between the cells. Ideally, they are compatible with drugs in the formulation, reversibly rapid-acting on the absorptive properties without systemic absorption. They provide predictable and reproducible absorption enhancement degree. Although they are mostly safe, some of the mechanisms can lead to severe irritation and damage to the nasal mucosa at concentrations required to effectively promote nasal absorption, especially in case of chronic nasal administration [50, 104]. Generally, absorption enhancers are mainly subdivided into six groups: (i) bile salt and its derivatives, (ii) surfactants also composing of fatty acid and its derivatives, (iii) chelators such as ethylendiamine tetra-acetic acid (EDTA), (iv) cationized polymers, (v) cyclodextrins, and (vi) cell-penetrating peptides. The bile salts (sodium deoxycholate, sodium taurodihydrofusidate, etc.) are conjugates of bile acids with taurine or glycine residues. They are utilized in the formulation alone [106] or in combination with other absorption-enhancing methods such as mucoadhesive polymers and particulate drug delivery systems [59, 63, 78]. The surfactants (lysophosphatidylcholine, dodecylmaltoside, tetradecylmaltoside, tetradecylsucrose, dodecanoylsucrose, Laureth-9, sucrose cocoate, soybean-­derived sterol, sterol glucoside, etc.) can exhibit detrimental effect on the nasal membrane

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at concentrations required to effectively promote nasal absorption, especially for chronic nasal administration. Thereby, they have been evaluated over the years in animal models [50, 107, 108]. The esters of hydroxystearic acid have recently been of great interest because of its low systemic toxicity and negligible local toxic effect on the nasal mucosa [109–112]. Williams et al. [110] indicated in rat models that Cmax (13.7 ± 1.6 ng/mL) of human parathyroid hormone with polyethylene glycol (15)-hydroxystearate (Solutol® HS15) was equivalent to Cmax (14.8 ± 8 ng/mL) in subcutaneous injections. Additionally, Wang et al. [109] reported that polyethoxylated 12-hydroxystearic acid (Kolliphor® HS15) was effective and biosafe as a permeation enhancer in the intranasal formulation of human parathyroid hormone. The cationized polymers (thiolated chitosan, sperminated gelatin, aminated gelatin, etc.) (Table  13.2) are the most effective and safest materials to increase nasal absorption of high molecular weight drugs. Besides strong mucoadhesion properties, as  explained in Sect. 4.2.1, they lead to an ionic interaction with the luminal surface of nasal mucosa, and then induce signals which open tight junctions, resulting in intercellular permeation [50]. The cyclodextrins are oligosaccharides which is widely used in the pharmaceutical area. In the nasal formulations, they could effectively utilize as absorption enhancer and solubilizer [113]. Among cyclodextrin derivatives, dimethyl-ß-­cyclodextrin is the most effective absorption enhancer, especially for the powder formulations. The absolute bioavailability of insulin with dimethyl-ß-cyclodextrin powder was 13  ±  4% in rabbits [114]. However, hydroxypropyl-ß-cyclodextrin and randomly methylated-ß-cyclodextrin exhibit lower toxicity than dimethyl-ß-­ cyclodextrin [115]. Principally, they increase the nasal absorption, by decreasing affinity of peptide-protein drugs to the physical and/or metabolic barriers. Hence, (i) they protect the peptide-protein drugs against enzymatic as well as chemical degradation. (ii) The hydrophilic cyclodextrins could remove some lipids through nasal mucosa via the formation of rapid and reversible inclusion complexes. (iii) They could interact with the hydrophobic chain of peptide-protein drugs, altering its intrinsic aggregation or permeability through the phospholipid bilayer. (iv) They might change distribution of tight junction proteins, thereby opening the tight junctions between epithelial cells [50]. The cell-penetrating peptides (D, L-penetratin, D, L-octaarginine, transactivator of transcription (TAT), etc.), which are also known as “protein transduction domains,” are novel high-capacity delivery vectors for various hydrophilic macromolecules. They effectively internalize various molecular cargoes of the drugs through plasma membranes, without altering their activities [116–118]. L-Penetratin, which is characterized by a high density of basic amino acids (Arg and Lys) and by the presence of hydrophobic residues (importantly Trp), is one of the most promising cell-penetrating peptides as a universal vector for various high molecular weight drugs including insulin, glucagon-like peptide-1 (GLP-1), exendin-4, and interferon-­ß [119–121]. L-Penetratin ensured that nasal bioavailability of insulin was 50.7% relative to subcutaneous administration, without causing detectable damage to the integrity of cells in the nasal respiratory mucosa [119].

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Besides aforementioned absorption enhancers, tight junction modulating peptides (zonula occludens toxin, clostridium perfringens enterotoxin, etc.), tight junction modulating lipids (glycosylated sphingosines, oxidized lipids and ether lipids, etc.), nitric oxide donors (S-nitroso-N-acetyl-DL-penicillamine, etc.), and N-acetyl-­L-cysteine at a high concentration (20%) have been also studied to improve nasal absorption of high molecular weight drugs [50, 122–124].

4.4 Enzyme Inhibitors The enzyme inhibitors (soybean trypsin, bacitracin, nafamostat mesilate, phosphoramidon, aprotinin, bestatin, etc.) protect the peptide-protein drugs from enzymatic degradation in the nasal cavity. Namely, the enzyme inhibitors cannot dramatically improve the nasal bioavailability, but they improve stability of peptideprotein drugs at the absorption area by restricting enzymatic activity and reducing degradation rate of the drugs [104]. For example, camostat mesilate, an aminopeptidase and trypsin inhibitor, improved the nasal delivery of vasopressin and desmopressin because of protecting the drugs from enzymatic activity in the nasal cavity [125]. However, they are not very effective to improve nasal absorption of peptide-protein drugs. Additionally, they might affect the normal metabolism of body, and then lead to severe adverse effects [50].

4.5 The Miscellaneous The other strategies are chemical modification of primary peptide structure or preparation of pro-drugs and use of deep eutectic solvents to improve absorption of peptide-protein drugs. The chemical modification protects peptide-protein drugs from enzymatic degradation or improves absorption characteristics of the drugs. In the first condition, chemical modifiers such as for polyethylene glycol (PEG), poly styrene-maleic acid copolymer, albumin, and dextran are used to protect the peptide-protein drugs. However, this might not be feasible for the nasal delivery of hydrophilic large peptide-­protein drugs because of making it more hydrophilic and larger, which reduced nasal absorption of peptide-protein drugs. In the second condition, the drug’s absorption across the nasal mucosa improves owing to the increased lipophilicity, because the preparation of pro-drug makes the drug more lipophilic. However, it can cause to decrease pharmacological activities of parent peptides [50, 104]. Due to these limitations, there are no examples of chemical modification for nasal administration of peptide-protein drugs. The use of deep eutectic solvents is a novel strategy, which is rarely used to improve nasal absorption of macromolecules. The deep eutectic solvents are mixtures  of compounds having lower melting points than melting points of the

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compounds individually. They exhibit as greater solubilization as higher viscosity properties. Additionally, they could readily interact by hydrogen bonds, electrostatic forces, and van der Waals forces. These could lead to increased nasal absorption of the macromolecules [104]. Li et al. [126] demonstrated that choline chloride and maleic acid eutectic mixture increased solubility and release rate of insulin. Also, increased viscosity of the formulation improved the residence time of insulin in the nasal mucosa, and then its nasal absorption.

5 Clinical Evidence on Nasal Delivery of High Molecular Weight Drugs In recent years, the number of high molecular weight drugs administered nasally has progressively increased on the market, despite temporarily or permanently stopping the production of some molecules. Additionally, clinical studies of novel nasal formulations of high molecular weight drugs are ongoing. The information about marketing status and clinical studies of these molecules are presented in Table 13.3. Presently, a range of nasal peptide formulations on the market exhibits very low bioavailability (less than 1%). However, these drugs are intended for non-parenteral administration considering clinical superiorities and development costs [5]. The marketed formulations generally contain none of efficient nasal absorption strategies, because of the poor nasal tolerability of the most known absorption enhancers [112]. However, recently a commercial product (Baqsimi®, Eli Lilly) and a few clinical studies have emerged. Baqsimi® dry powder formulation (commercial product) which contains synthetic glucagon utilizes phospholipid dodecylphosphocholine as surfactant and absorption enhancer, and beta-cyclodextrin (β-CD) as filler/bulking agent and absorption enhancer [127]. Additionally, dodecyl maltoside (Intravail™ Technology, Aegis Therapeutics) and cyclopenta decalactone (azone, CPE-215) have been in development as the nasal delivery systems of teriparatide and insulin (Nasulin, CPEX Pharm), respectively [93].

6 Future Directions and Conclusion The nasal route is a promising administration for drug delivery into the systemic circulation because it offers large absorption area, relatively porous, thin, and highly vascularized epithelial membrane. However, the nasal epithelial barrier constitutes an obstacle for drugs greater than 1000 Da. Thereby, high molecular weight drugs, particularly those which are hydrophilic (e.g., peptide-protein drugs), cannot transport through the nasal mucosa. Further, enzymes in the nasal cavity are a hurdle for stability of high molecular weight drugs with peptide-protein structure. Numerous strategies have been developed to overcome these issues. Among these, absorption

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Table 13.3  The high molecular weight drugs administered via intranasal delivery on the market and under clinical trials

Molecule Desmopressin acetate

Marketing status Prescriptiona Discontinuedb Discontinuedb Discontinuedb

Buserelin acetate Nafarelin acetate Interferon alfa-2b Glucagon

Prescription

Oxytocin

Discontinuedb

Salmon calcitonin Recombinant salmon calcitonin Insulin

Discontinuedb

Prescription Prescription Prescription

Discontinuedb

Phase 2 Phase 2

Oxytocin

Phase 2

Phase 2 Teriparitide

Phase 1

Somatotropin

Phase 1

Dosage form Spray, metered Spray, metered Spray, metered Spray, metered Spray, metered Spray, metered Spray, metered Powder

Commercial Strength name Company 0.01 mg/ Minirin Ferring spray 0.01 DDAVP Ferring mg/spray 0.15 mg/ Stimate Ferring spray 0.15 mg/ Octostimc Ferring spray 0.1 mg/ Suprefactc Sanofi-Aventis spray 0.2 mg/ Synarel Pfizer spray 500 IU/ Genferond Biocad spray 3 mg/ Baqsimi Eli Lilly dose Solution 40 USP Syntocinon Novartis units/mL Spray, 200 IU/ Miacalcin Mylan metered spray Spray, 200 IU/ Fortical Upsher Smith metered spray Labs

FDA approval date 2002 1978 1994 2018 – 1990 2011 2019 1960 1995 2005

Spray, 100 IU/ metered dose Solution 40 IU/ dose Solution 24 IU/ dose

Nasulin

CPEX Pharm

–

–

Beth Israel

–

–

–

Solution 24 IU/ dose Solution 90 mcg/ dose

–

Massachusetta General Hospital TriGemina

–

Solution n.d.

–

Nottingham University Hospital Critical Pharm

–

–

–

Cold storage formulation b If generic versions of this product have been approved by the FDA, there may be generic equivalents available c Approved by Canadian and EMA authorities d Approved by Russian authority a

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enhancer method is the most common and effective strategy to enhance absorption of high molecular weight drugs through the nasal mucosa, which is used in a commercial product (Baqsimi®, Eli Lilly). In light of recent studies, ongoing preclinical and clinical trials, it is asserted that novel nasal formulations containing high molecular weight drugs and absorption enhancers will become gradually available on the market in the next decades.

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Chapter 14

Niosomes-Based Drug Delivery in Targeting the Brain Tumors Via Nasal Delivery Mahmoud Gharbavi, Sepideh Parvanian, Milad Parvinzad Leilan, Shabnam Tavangar, Maedeh Parchianlou, and Ali Sharafi

Abstract Targeting tumors has always been a herculean task. Moreover, the presence of blood brain barrier (BBB) acts as a physical barrier and restricts the transportation of therapeutic molecules across the brain. Targeted delivery of the therapeutic payload across the blood brain barrier has gained widespread attention over the past few years. Intranasal route offers delivery to the brain via the trigeminal and olfactory route surpassing BBB. It also offers various other advantages such as surpassing biotransformation, and systemic absorption increasing the efficacy. Over the last few decades, several novel drug delivery systems such as liposomes and other lipid nanoparticles targeting brain, have gained widespread attention. The Niosomes are vesicular nanoparticle flatforms comprised of non-ionic surfactants, which are biodegradable, more stable than liposomes. This current review discusses the potential use of niosomes as a delivery vehicle for targeting brain tumors via the nasal route. Keywords  Niosomes · Nasal route · Blood brain barrier · Nanoparticles · Tumours

M. Gharbavi Nanotechnology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran S. Parvanian Faculty of Science and Engineering, Åbo Akademi University & Turku Bioscience Center, Turku, Finland M. P. Leilan · S. Tavangar Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran M. Parchianlou · A. Sharafi (*) Zanjan Pharmaceutical Biotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_14

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1 Introduction Chemotherapy, radiation therapy, and targeted drug therapy play a significant role in the treatment of glioblastoma and central nervous system (CNS) diseases to decrease the mortality rate [1]. The main problem is the inability of drugs to cross the blood-­ brain barrier (BBB) to reach the brain tissue in sufficient quantities to achieve therapeutic levels. It is estimated that the BBB prevents intrusion of approximately 98% of low molecular weight drugs and about 100% of macromolecules drugs leads to poor bioavailability for drug delivery to the CNS [2]. Different strategies including intracerebroventricular or intraparenchymal injections, mini-pump-assisted intracranial delivery, catheter infusions, accurate ultrasound methods, or electromagnetic force-field are used to deliver active drug agents. However, these methods are aggressive and dangerous for patients [3]. BBB is the first limiting factor to the delivery of drugs to the brain through systemic circulation [1]. Several studies are underway to cross the BBB through the nose-to-brain approach. Intranasal delivery is a promising alternative approach compared to the invasive methods mentioned above for drug delivery to the brain, because the nasal cavity has so many arteries that provide a high absorption level for the prescribed drug. It also allows this pathway to bypass the BBB and provide fast and direct drug delivery to the brain [4]. Also, this route (delivery through the nose) limits unnecessary drug systemic exposure and reduces systemic toxicity [5]. As the olfactory nasal segment cavity extends to the cranial cavity, nasal drug delivery can provide direct access to the brain [3]. At present, nanotechnology-­ based drug delivery systems provide a great opportunity for intranasal drug delivery to the brain. Nano-drug delivery systems have been widely studied in the last decades as a new strategy to solve the problem of poor bioavailability of various drugs [6]. Successful delivery of the drug to the brain through liposomes, dendrimers, microspheres, nanoemulsions, carbon-based nanoformulations, microspheres, and dendrimers has been reported in different studies [7]. The major goal of vesicular structure development is to change distribution profiles, control drug release over time, and deliver drugs to target sites. Vesicular systems can handle high amounts of drugs and generate an appropriate surface for targeting. It enables the drugs to carry both hydrophilic and lipophilic components. The non-ionic surfactant vesicles (Niosomes), systems with the advantages of liposomes and the permeability of membranes, are created in the aqueous phase from non-ionic surfactants. The integrity of niosomes in biological fluids is a critical requirement for their function as a medication carrier. Niosomes are to circulate in the body while simultaneously protecting the medicine for a certain period, connect with the target site, and convey their contents into the target cells as a carrier. Niosomes are preferred in comparison to other bilayer structures, because of chemical stability, biodegradability, biocompatibility, low production cost, low toxicity, and easy storage and handling. Niosomes have been used by different delivery routes, such as oral, intramuscular, intravenous, transdermal, and so on. In this chapter, we will discuss and suggest the niosomes as versatile nasal formulations for brain targeting of drugs.

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2 Nasal Drug Delivery Route 2.1 The Blood-Brain Barrier (BBB) and Targeted Drug Delivery to the Brain Despite advances in the treatment of brain diseases, the blood-brain barrier (BBB) is a major barrier to the delivery of drugs to the central nervous system (CNS). Crossing BBB barrier is a challenging problem for most of the effective drugs on central nervous system diseases such as neuropeptides, proteins, chemotherapeutic agents, monoclonal antibodies, recombinant proteins, and antisense or gene therapy agents. The BBB is made up of tight junctions between the brain capillaries endothelial cells with low endocytic activity. This structure leads to a capillary wall that, like the lipid bilayer of the cell membrane, prevents the passage of polar and insoluble substances across the BBB. With significant advances in nanotechnology, several strategies have been developed for drug delivery to the CNS. Some strategies, such as modifying the drug itself, binding it to the transcytosis vector, and using appropriate carriers, increase the capacity of therapeutic agents to cross the BBB. One of the current challenges is to develop a targeted drug delivery system that can effectively cross the BBB barrier while the drug agent remains intact [8, 9].

2.2 Transmitting to the Brain Through Nasal Passages Understanding the anatomy and physiology of the nasal cavity is essential to the success of nasal drug delivery systems. The nasal cavity can be divided into three areas: the olfactory area, respiratory area, and vestibule. The respiratory area is rich in blood vessels; thus, it can provide systemic absorption of the drug after intranasal administration and subsequent indirect delivery of the drug to the brain. The vestibule is a small area and the drug absorbed through this area is very low [10, 11]. The respiratory area is suitable for the delivery of the vaccines by the intranasal route. The olfactory area also plays an important role in the direct delivery of drugs to the brain and cerebrospinal fluid (CSF) [1, 12]. The main purpose of these drug delivery routes is to deliver the desired drug concentration to the drug activity site. Due to the permeability of the nasal epithelium, high overall flow, porous endothelial membrane, large surface area, and evading of the first passage metabolism cause the drug to be rapidly absorbed into the brain. Methods of drug delivery through the nasal route can transfer a wide range of therapeutic agents (small molecules and macromolecules) to the CNS. Several studies have shown that, when administered nasally to the CNS, the drug offers effective therapeutic effects in lower doses (Fig. 14.1). The transmission of therapeutic agents from nose to brain is described below.

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Fig. 14.1  Schematic of the niosomal nasal delivery route for brain targeting

2.2.1 Olfactory Pathway The olfactory area at the top of the nasal cavity is known as the possibility of drug delivery through the nose to the brain for the treatment of various CNS diseases [13]. Drugs can pass through the olfactory epithelial space through the tight interstitial space with passive diffusion, or through transmission through cell membranes with endocytosis, or neuron transfer [5, 14]. Most drugs that deposit in the olfactory area are extracellularly transported between cells. Various studies on drug delivery through the nose have suggested the role of P-glycoprotein in this pathway. In addition, a study was performed to test the penetration and transfer of the drug in the three-dimensional culture of these cells (3D MucilAir) as a model of nasal structure [15]. The olfactory neurons play an important role in targeting drugs to the brain through the nasal path [16]. The path of the drugs for transmission is from the intracellular axon to the olfactory bulb and then to the brain [17]. The diameter of the olfactory axon in humans is about 0.1–0.7 micrometers, indicating that molecules that have a diameter in this range can easily deliver their pharmaceutical agents through this route. Since nanosystems used in drug delivery are usually nano sized, they seem to be suitable for transmission through this pathway [7].

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Drug delivery through the epithelium is faster than axonal transport. Drug delivery from the olfactory pathways occurs through extracellular and intracellular mechanisms. Most lipophilic drugs are transported through passive diffusion, while most hydrophilic drugs are transported through the paracellular pathway. The hydrophilic and molecular weight of drugs has a significant effect on drug absorption. Drugs with high lipophilicity are usually absorbed through the transcellular pathway [5]. 2.2.2 Trigeminal Pathway The trigeminal pathway for drug delivery from the nose to the brain has been less studied. The main function of the trigeminal nerve is to transmit chemical and thermal information to the nose, mouth, and ocular mucosa [18, 19]. The trigeminal nerve pathway can be an important site for drug delivery to the brain through the nasal route. For example, insulin-like growth factor 1 was transmitted to the brain through the trigeminal and olfactory pathways [20]. 2.2.3 Lymphatic Pathway Drugs can be transferred through several extracellular pathways such as perineural, perivascular, and lymphatic channels in the olfactory region. These extracellular pathways are connected to the olfactory bulb of the brain by olfactory nerves [7, 21]. Therefore, the lymphatic pathway also plays an important role in drug delivery from the nose to the brain. 2.2.4 Systemic Pathway The systemic pathway is an indirect transmission from the nose to the brain and can be a promising approach for low molecular weight lipophilic drugs [22, 23]. Drugs are absorbed by the vascular regions of the epithelial membrane of the nasal mucosa and lymphatic system and then are transported to the systemic circulation to avoid the first-pass metabolism of the drug [22, 24].

2.3 Advantages and Disadvantages of the Nasal Drug Delivery Route Targeted drug delivery through the nasal route to the brain reliably, effectively, non-­ invasively, and directly transmits drug agents to the CNS via neural connections between the nose and the brain [25]. The nasal cavity has high blood vessels that are

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also highly permeable and therefore one of the best places to prescribe drugs [10, 26]. The following are some of the unique benefits of nasal transmission: 1. Has a large surface area for drug absorption. 2. Facilities and patients are comfortable. 3. In this method, the level of drugs in the bloodstream rises rapidly. 4. Drugs penetrate this pathway well, especially low molecular weight lipophilic drugs. 5. Circumvent difficult conditions of absorption through the intestine. 6. Circumvent hepatic metabolism, which is the first-line metabolism for drugs that are absorbed from the intestine. 7. It is possible to transfer the drug directly to the brain through the olfactory nerves. 8. This pathway is adjacent to the lymphatic tissue; the vaccine is administered through the nasal route directly to the lymphatic tissue. 9. This route is suitable for people who are undergoing long-term drug treatment. 10. Suitable for prescribing drugs that have low fluid stability. In the nasal uptake pathway, drug agents reach the olfactory bulb and brainstem after passing through the surface of the nasal epithelium, and through the pulsating current, that spaces around the cerebral blood vessels and contributes to drug absorption, drug agents spread to other areas of the CNS. In some cases, nasal transmission is almost equivalent to intravenous injection because there is a unique connection between the nasal cavity and brain [27–29]. Nasal administration is the only way to administer directly to the brain without non-invasive methods [22]. Because proteins, peptides, nucleic acids, and even stem cells can be transported through the nasal passage, this route has received considerable attention for drug delivery. In addition, via the nasal passage drugs can be administered both locally and systematically. Drugs in the form of suspensions, solutions, gels, surfactants bases, and emulsions can be administered through the nose, and administration through this route increases the efficiency of targeted delivery and decreases the side effects of systematic administration [30–33]. Some factors that affect nasal absorption are as follows: 1. Some physicochemical properties of drugs: including drug or nanocarriers containing drug size, molecular weight, hydrophilic or lipophilic, and resistance to enzymatic degradation 2. Nasal condition: rate of mucociliary clearance, nasal pH condition, and endothelial cell permeability 3. Including drug formulation, drug solubility, and viscosity [34–37] For example, a drug with low molecular weight, lipophilic, and resistance to enzymatic degradation with high endothelial permeability and low clearance of the nasal cavity is well absorbed from the nasal route. The anatomy of the nasal cavity and the condition of the nasal mucosa can affect the process of drug absorption such as  enzymatic degradation, mucociliary clearance, nasal cavity blood flow, nasal health conditions [38–45].

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2.4 Mechanism of Drug Absorption from the Nasal Route The main step in absorbing drugs from the nasal cavity is to cross the mucus. Large particles find it relatively hard to pass through the mucus layer, but small particles pass easily [46]. The nasal mucosa contains mucin, a protein that can bind to solutes, and the presence of this mucin affects the absorption process. Environmental or physiological changes cause structural changes in the mucosal layer, and this influences the rate of absorption through the nose [47]. After the drug passes through the mucosa, there are several mechanisms for absorption through the mucosa. These include simple diffusion from the membrane, transcellular transcytosis by vesicular carriers across the cell, and paracellular transmission between cells. Among the several mechanisms mentioned, paracellular and transcellular pathways are predominant [48]. Transmission from the paracellular pathway is slow and passive. The lower the molecular weight of the drug or nanocarriers containing the drug, the faster it is absorbed through nasal passages. In contrast, low bioavailability has been reported for drugs with molecular weight above 1000 Daltons [46]. Lipid drugs are often transported through a lipoid pathway, also known as the intercellular process; the transfer of this pathway depends on the lipophilicity of the drug. Other drug routes include passing through the cell membrane through active transport facilitated by the carrier and passing through the opening of tight junctions [48]. Barriers to drug absorption are potential metabolism before reaching systemic circulation and improper length of stay in the nasal cavity [49]. Many water-soluble drugs are poorly absorbed through the nose and therefore do not have sufficient bioavailability. Penetration enhancers are often used to increase the absorption and bioavailability of such drugs [50]. The mechanism of action of penetration enhancers is that they increase the rate of drug absorption by making reversible changes in the structure of the nasal epithelial barrier [49]. Researchers have been drawn to investigate the intranasal drug delivery method based on the findings so far. Nonetheless, it is critical to comprehend medication uptake across the nasal mucosa. The nose is a complex organ from a kinetic standpoint since three separate processes, such as drug disposal, clearance, and absorption, occur simultaneously inside the nasal cavity. Understanding the nasal anatomy and related physiological aspects is critical for optimal drug absorption across the nasal mucosa.

2.5 Nasal Anatomy and Physiology of the Nose The human nasal cavity is separated into two nasal cavities by the septum and has a total volume of 16 to 19 mL and a total surface area of 180 cm2 [51]. Each cavity has a volume of around 7.5 mL and a surface area of about 75 cm2 [52]. A solute can be deposited in one or more of three anatomically distinct locations following medication administration into the nasal cavity: the vestibular, respiratory, or olfactory regions. The vestibular area is responsible for filtering airborne particles and is

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located at the entry of the nasal passages [53, 54]. When it comes to medication absorption, it is thought to be the least essential of the three zones [55]. The respiratory system is the largest and most vascularized, and it is primarily responsible for drug absorption. The olfactory region has a surface area of around 10 cm2 and is important for drug delivery to the brain and CSF. In the nasal cavity, there are three main anatomical zones. A mucus layer covers the epithelium of the nose canal, trapping particles. Cilia clean the mucus layer from the nasal cavity, which is replenished every 10 to 15 min [56]. Mucosal secretions have a pH of 5.5 to 6.5 in adults and 5.0 to 6.7 in children [57], which retains particles and allows cilia to remove them from the nasal cavity. The mucus moves through the nose at an approximate rate of 5 to 6 mm/min resulting in particle clearance within the nose every 15 to 20  minutes [58, 59]. Numerous enzymes [51], for instance, cytochrome P450, enzyme isoforms [60] (CYP1A, CYP2A, and CYP2E), carboxylesterases, and glutathione S-transferases are found in the nasal cavity [61, 62].

2.6 Brain Targeting Through the Nasal Route Because of the BBB’s poor distribution into the CNS, the development of numerous potentially interesting CNS therapeutic candidates has been hampered for some time. The intranasal route can deliver therapeutic drugs to the brain without passing through the BBB because of the unique connection between the nose and the CNS [63]. A unique characteristic and superior choice is the capacity to transfer therapeutic drugs to the brain via drug absorption across the olfactory region of the nose [58]. When drugs were administered nasally to rats, some drugs produced significantly higher CSF and olfactory bulb drug levels than when administered intravenously [25]. Many scientists have identified evidence of nose-to-brain transfer [64]. Many previously abandoned potent CNS medication candidates with intranasal delivery have the potential to become successful CNS therapeutic drugs. Thus, several nasal intranasal injection formulations were developed for the treatment of disorders such as epilepsy, migraine, MS, depression, and erectile dysfunction [65].

2.7 Drugs for Glioblastoma Treatment Administered Intranasally Several studies have been carried out to discover the optimal intranasal treatment for glioblastoma (GBM) utilizing monotherapy or in combination with other drugs, including natural and/or synthetic agents. The research that was done to develop a viable treatment for this aggressive brain tumor is summarized here. Intranasal delivery of curcumin, as a natural compound, combined with a glioblastoma-­specific antibody was suggested by Mukherjee et  al. The targeted

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curcumin-CD68 Ab conjugate was intranasally administered to mice in which glioma GL261 cells were xenografted in the brain. Adult male C57BL/6 mice were given a curcumin-CD68 Ab solution in PBS intranasally every 72 h ten days after GL261 cells were xenografted, whereas another set of animals got an intraperitoneal injection of a commercially available lipid-complexed form of curcumin, that is, Curcumin Phytosome. Curcumin-CD68 Ab conjugate intranasal delivery and Curcumin Phytosome intraperitoneal injection both caused GL261 brain tumor remission in 50% of mice, confirming that CD68 Ab could be delivered to the brain via the intranasal route and that CD68 Ab had a targeted therapeutic effect after intranasal delivery. Furthermore, on day 90, 70% of the animals given curcumin­CD68 Ab intranasally and 60% of those given Curcumin Phytosome intraperitoneal were still alive, whereas all the control group animals, that is, vehicle-treated mice, were already dead. As the obtained results, intranasally delivered curcumin-targeted conjugates can directly kill GBM cells and also lead to repolarizing tumor-­associated microglial cells (TAMs) to a tumoricidal state [66]. Rhein (4, 5- dihydroxyanthraquinone-2-carboxylic acid) is a natural compound with anti-inflammatory, antioxidant, anti-fibrosis, neuroprotective, and anti-tumor properties [67]. The CD38 enzymatic activity is inhibited by rhein, which leads to attenuating glioma progression. To demonstrate this, Blacher et  al. conducted a study while using a syngeneic mouse glioma progression model (CD38-deficient C57BL/6J (CD38-/-) mice) [68]. Glioma cells (GL261) were intracranially implanted into the mice’s brains after 24 h, and vehicle or rhein was administered three times each week for 22 days. Rhein can suppress CD38 enzymatic activity, which leads to reduced microglia activation that is supportive of tumor progression. The intranasal administration of rhein suppressed the glioma progression significantly in WT mice, showing that CD38 is a therapeutic target in the tumor microenvironment and that small-molecule inhibitors of CD38 could be a potential treatment for glioma [68]. Furthermore, Shingaki et al. evaluated the direct brain uptake of 5-fluorouracil (5-FU) from the nasal cavity, as well as whether the inhibition of CSF secretion by choroid plexus could lead to increased brain concentration of the free drug [69]. In this study, male Wistar animals were administered 5-FU intravenously or nasally in the presence or absence of intravenous infusion of acetazolamide (AZA). AZA (25 mg/kg) was injected for 15 min before initiating the nasal perfusion of 5-FU in the n groups of co-treatment. CSF secretion by choroid plexus epithelial cells is inhibited by AZA. The active transport of Na+ ions is connected to CSF secretion in these cells, and AZA significantly reduces the activity of the Na/K ATPase [70]. The results found that intravenous administration of AZA increased the CSF content of nasally given 5-FU by 200–300% when compared to 5-FU nasal perfusion without pre-treatment with AZA.  By reducing CSF secretion from the choroid plexus and so maintaining the concentration of the nasally administered drug in the CSF, AZA was able to improve nose-to-brain drug transport [69]. It was concluded that co-administration of therapeutic agents to treat neurological diseases with drugs that reduce CSF secretion from the choroid plexus could be an interesting alternative to treating diseases of the brain, such as GBM, because the concentrations of therapeutic agents in the brain are improved.

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In another report, the same group found a similar effect in male Wistar rats after methotrexate (MTX) administration by nasal injection [71]. MTX is a folic acid antagonist that inhibits the enzyme dihydrofolate reductase and has been used in treating a variety of cancers [72]. Because MTX has a poor penetration across the BBB, therapeutic options for GBM via oral administration are limited [73]. In the study, MTX was administered nasally with sodium carboxymethyl cellulose (CMC) added to improve the nasal residence time of the formulation, and AZA was given orally 30 min later. The amount of MTX measured in the CSF was higher than that measured in plasma 15 minutes after intranasal injection, indicating that MTX was transported directly from the nasal cavity to the CSF. When compared to the concentrations found in the CSF following intraperitoneal administration, plasma had a greater concentration. Simultaneously, the effect of oral AZA 30 min before nasal MTX administration was investigated, and it was shown that the co-treatment enhanced the concentration of MTX in CSF by 195% [71]. In another research, MTX-loaded chitosan microspheres were prepared by spray-­ drying technique. In this way, different molecular weights of chitosan were used to fabricate chitosan microspheres owing to promote the nose-to-brain delivery of the MTX.  The animals were given MTX solution, and MTX-loaded chitosan microspheres were intranasally administered. According to the obtained results, a higher concentration of MTX in rat brain tissues was shown after intranasal administration of the MTX-loaded chitosan microspheres when compared to the MTX solution, which was attributed to the presence of chitosan. In fact, chitosan is known to be a safe mucoadhesive polymer that could effectively improve the brain hydrophilic drug delivery, like MTX, via intranasal administration [74]. Another study [75] suggested that temozolomide (TMZ) be delivered by the nose. After oral administration, TMZ is efficiently absorbed and is available in capsule form. TMZ has also shown good penetration via the BBB and an acceptable toxicity profile [76]. However, a significant increase in overall survival was observed in multimodal treatment with TMZ and radiotherapy group as compared to the radiotherapy alone group. This study suggested that 60–75% of patients with GBM present no clinical benefit from treatment with TMZ [77]. Based on these findings, a rat model with orthotopic C6 glioma xenografts was employed to investigate the therapeutic efficacy of intranasal administration of TMZ to take benefit of the drug’s brain-targeting capabilities. In fact, it was proposed that TMZ be administered intranasally to restrict systemic exposure to the drug and therefore reduce toxic effects on healthy organs. During the 40-day experiment, the rats were given saline solution or TMZ via three distinct delivery routes: intravenous, oral, or intranasal, and tumor size, rat survival time, and pathological changes were evaluated. When compared to all other groups, including controls, magnetic resonance imaging revealed a significant reduction in the volume of glioma xenografts in the intranasal TMZ group (p   500 nm) [88].

3.2 Advantages and Disadvantages of Niosomes-Based Drug Delivery Systems Niosomes have several advantages over other nano-carriers: 1. Surfactants used for synthesis niosomes are non-immunogenic, biocompatible, and biodegradable. 2. The method used to produce niosomes does not involve very toxic solvents.

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Fig. 14.2  Schematic typical vesicle size of niosomes

3. The chemical stability of niosomes components is high, so their storage and transportation do not require special conditions. 4. By changing the structural composition and production method of niosomes, their physicochemical properties such as size, shape, and fluidity can be easily changed. 5. Niosomes can carry large amounts of drugs. 6. Niosomes can be used to deliver unstable and sensitive drugs because they protect drug ingredients against heterogeneous conditions inside and outside the body. 7. Niosomes improve the therapeutic function of drug molecules because they have high circulation time and limit the effects of the drug on the target cell. 8. Niosomes can be administered in a variety of ways, such as topical, oral, and injectable. 9. Niosomes have different drug formulations: semi-solid, powder, and suspension. 10. Niosomes increase the bioavailability of insoluble drugs when used orally. 11. Niosomes increase the penetration of drugs when used for skin delivery. 12. Niosomes-based drug delivery formulation leads to better patient compliance compared to free oil forms. 13. To regulate the rate of drug release from the structure of the niosomes, becoming an aqueous phase, it can be emulsified in the non-aqueous phase. In contrast, niosomes have disadvantages including aggregation, physical and chemical instability, decomposition of vesicles, and leakage encapsulated drugs. Also, the methods required to prepare multilayer vesicles are time-consuming and require specialized equipment [89, 90].

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3.3 Formulation Components of Niosomes 3.3.1 Non-ionic Surfactants Non-ionic surfactants are a group of surfactants that have no charge in the structure of their head group. Non-ionic surfactants have high stability and biocompatibility compared to positive, negative, and amphoteric surfactants. Non-ionic surfactants have an amphiphilic structure, that is, they have a distinct hydrophilic part and a distinct hydrophobic part [91]. Non-ionic surfactants play a major role in the structure of niosomes and are the most abundant factor in the structure of niosomes. Non-ionic surfactants used in niosomes synthesis have an amphipathic structure and these include polysorbates [92], terpenoids [93], spans [94], alkyl oxyethylene [95], and so squalene belongs to the group of terpenes, a natural lipid, used in the synthesis of niosomes. The advantage of squalene in niosomes synthesis is that it stabilizes the structure of niosomes and is also slightly toxic in vivo and in vitro [93]. Polysorbate is another group of non-ionic surfactants used in the structure of niosomes; for example, niosomes synthesized with 80 Polysorbates are an excellent vector for gene delivery because they have a polyethylene glycol (PEG) group in their structure. Niosomes with a structure of Span 60/Tween 60/cholesterol are a carrier with a high percentage of drug encapsulation because the interaction is established between the acyl group of 60 Span and the drug [94]. 3.3.2 Cholesterol Steroids are an important part of cell membranes, and their presence affects membrane fluidity and permeability. Cholesterol is the most important steroid that is often used to synthesize niosomes. Cholesterol binds to non-ionic surfactants using a hydrogen bond. Although cholesterol may not play a role in lipid formation, it plays a role in stabilizing and controlling the properties of niosomes nanostructures. The addition of cholesterol to niosomes formulation affects the properties of the nanosystem, such as lipid layer permeability, rigidity, increased drug encapsulation efficiency, easier hydration of frozen niosomes, and increased biocompatibility of nanocarriers. Cholesterol reduces leaky niosomal nanocarriers by inhibiting phase shifts from gel to liquid [96]. 3.3.3 Charge Inducer Molecules In the synthesis of niosomes, charge inducer molecules may also be added. Charge inducer molecules, by inducing positive or negative electrostatic charges on the surface of niosomal vesicles, maintain the suspension state of nanocarriers, prevent aggregation, and ultimately increase stability. Negative inducers of electric charge include diacetyl phosphate (DCP) and phosphatidic acid. Stearylamine (STR) and

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stearyl pyridinium chloride are negatively charged inducer molecules. For niosomes synthesis, a percentage of charge-inducing material of 2.5–5 M is acceptable; adding more than this amount prevents synthesis [97].

3.4 Types of Niosomes 3.4.1 Proniosomes Proniosomes is a new vesicle system for delivering medication to the skin and ocular. Proniosomes overcome a variety of disadvantages of previous structures, such as physical stability, aggregation, and leaking. Proniosomes are suitable for drug delivery because they have no first-pass hepatic metabolism, no adverse effects on oral delivery, and no gastrointestinal tract (GIT) [98]. Proniosomes are composed of non-ionic surfactants whose outer part is hydrophobic and the inner part is hydrophilic. Because peroxisomes increase the permeability of the skin layers, they are very suitable for transporting drugs through the skin. Proniosomes are dehydrated niosomes that become niosomes with the absorption of water. Proniosomes are more stable than other carrier vesicles [98]. Proniosomes are inactive and must be transformed to the active form, niosomes, to function. The proniosomes become niosomes by passing through the skin layer or adding an aqueous solution. When proniosomes are administered to the skin, they hydrate in the skin and form one-side concentration on the outer surface of the skin, which increase the permeability of the skin. When niosomes lysis into the endosomes of subcutaneous tissue, encapsulate drugs  are released [99, 100]. Non-ionic surfactants used in the synthesis of niosomes are also used to synthesize proniosomes. These non-ionic surfactants are used in combination with cholesterol and lecithin, a structure-stabilizing phospholipid. To hydrate the lipid layer, hot water, phosphate buffer with pH = 7.4, and 1% glycerol are used to synthesize proniosomes [100]. Proniosomes have been successfully used as a carrier for better delivery of various drugs, including Roxithromicin, Tazarotene, α-Mangostin, Tolterodine tartrate, and so on [98]. 3.4.2 Ethosomes Ethosomes were first introduced by Touitou et al. in 1997 [101]. Ethosomes arose from the modification of liposomes and were composed of phospholipids, high concentrations of ethanol, and water [102]. Ethosomes nanocarriers compared to liposomes have (1) reduced particle size, (2) negative zeta potential, (3) higher drug encapsulation percentage, and (4) are more stable [103]. However, to develop a more efficient delivery system, a new generation of ethosomes, that is, binary ethosomes, and transethosomes developed. Zhou et al reported different form of ethosomes such as binary ethosmes by adding alcohol to the conventional form [104]. In the formulation of binary ethosomes, in addition to ethanol, another alcohol is usually propylene glycol (PG), and isopropyl alcohol is also present [103, 105, 106].

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PG increases permeability, low toxicity, low skin irritation, high viscosity, as well as greater stability than ethanol [103, 107]. This specificity of PG causes the drug to increase its affinity to the skin and also the drug to accumulate into deeper levels of the skin. Adjusting the ratio of PG and ethanol is very important to achieve proper penetration of the drug into the skin [105, 108]. Sung et al. introduced a new generation of ethosomes in 2012. The advantages of this new generation autosome were the same as those of previous generation ethosomes and liposomes [109]. Transethosomes are identical to ethosomes in composition, but they also contain a penetration enhancer (surfactant) [109]. Evidence suggests that transethosomes are smaller in size, more elastic, and have more permeability to the skin – the “more permeability to skin” probably due to the synergistic effect between ethanol and surfactant [110]. 3.4.3 Bola-Surfactant Niosomes Bola surfactant is used to synthesize bola niosomes. Surfactants of this type were initially discovered in the membrane of Archaebacteria in 1980. These surfactants have two hydrophilic heads that are connected by one or two lipophilic bonds. In 2010, Zakharova et al. showed that bola surfactants have low critical micelle concentrations, high surface tension, high self-assembly, and high tolerance in vitro and in vivo compared to conventional surfactants [111, 112]. 3.4.4 Aspasomes Vesicles synthesized by supramolecular amphiphiles that have antioxidant properties, such as aspartic acid and its derivatives, are used therapeutically for diseases in which active oxygen species are produced. Ascorbyl palmitate (ASP) combination with cholesterol and a negative charge inducer can be used to synthesize bilayer lipid of niosomes. Aspasomes are prepared by film hydration method and then hydration with aqueous solution along with sonication is synthesized. Gopinath et al. introduced the nanoparticle formulation of aspasomes (ASC-P) [113]. Submicron-sized aspasomes are synthesized by thin layer hydration. A lipid film is synthesized with ascorbyl palmitate and cholesterol (27.63 to 72.18) and dicetyl phosphate at 10% mol of total lipid and hydrated with phosphate saline buffer (PBS, pH  7.4). For example, for hydration of zidovudine (AZT) hydrophilic drug, it is first dissolved in PBS and then the solution is hydrated on a thin layer. Then the prepared suspension is sonicated in an ultrasonicator to obtain AZT-­ encapsulated aspasomes. In a study for zidovudine (AZT) encapsulation in aspasomes, adding cholesterol to the lipid layer showed no change in size, zeta potential, and zidovudine (AZT) encapsulation percentage. But release rate of zidovudine (AZT) varied with the presence of cholesterol. The antioxidant property of ascorbyl was maintained even after ascorbyl palmitate was converted to aspasomes. Aspasomes also showed increased skin penetration and AZT preservation properties [114].

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3.5 Methods of Preparation The qualities of niosomes can vary widely depending on how they are synthesized. In this chapter, different approaches were reviewed: 3.5.1 Thin-Film Hydration (TFH)/Handshaking Method (HSM) These two methods are mostly put into one category for the similarities they have (although some articles have separated them to be two different methods) [115]. Based on the research and the lab practices done, they seem to be the most common technique to prepare niosomes: need a round bottom flask, a volatile organic solvent like diethyl ether or chloroform, etc. (for dissolving surfactant), cholesterol, and charge inducers (rotary evaporator). Using TFH/HSM, the solvent will be evaporated at room temperature which creates a thin dry film of dissolved components, and then the dried film must be hydrated, so an aqueous phase will be added with gentle agitation [116]. As can be seen in Fig. 14.3, depending on the structure of the drug (hydrophilic or hydrophobic) decide where the aqueous phase must be added: ( A) Aqueous phase if it is hydrophilic (B) Organic solvent if it is hydrophobic 3.5.2 The “Bubble” Method An organic solvent won’t be used for this method, but a three-neck flask will be needed (fabric must be glass) to be in a water bath for maintaining the temperature. The first neck flask must be able to place the thermometer, the second one is used to pass the nitrogen, and the third (last) one is attached for the water-cooled reflux. So, using this method first cholesterol, then surfactant, and finally, phosphate buffer is mixed together and then these particles are dispersed at 70 °C. Afterward, a high-­ shear homogenizer will be used for 15 s and afterward, nitrogen gas will be immediately supplied to the mixture (bubbling of the nitrogen gas must be at 70 °C). The vesicles produced this way are large and unilamellar [89]. 3.5.3 Ether Injection Method (EIM) In this method, an aqueous solution is used so that the solution of cholesterol and surfactant dissolved in diethyl ether (volatile organic solvent) will be injected with the help of a 14 gauge needle, and then they must be put into preheated warm water (maintained at 60 °C). Finally, niosomes are formed by vaporization of diethyl ether (volatile organic solvent) using a rotary evaporator. These single-layered niosomes can have a diameter varying from 50 to 1000 μm [115–117].

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Fig. 14.3 Schematic non-ionic surfactant vesicles (niosomes) formation by lipid layer hydration method

3.5.4 Sonication Method It is one of the conventional methods; sonication is used to prepare niosomes. In this method, solution of the drug in the buffer must be prepared so that afterward surfactant and cholesterol can add up [118]. The next necessary step to produce multilamellar vesicles is probe sonication (they require high levels of energy) at 60 °C for 3 min. It’s possible to produce unilamellar vesicles if it would be a further ultrasonicator. So, the ability to control niosomes particle sizes can be achieved by sonication of the mixture at a particular frequency, temperature, and time [116].

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3.5.5 Reverse Phase Evaporation Method (REV) In this method, an organic solvent will be used like ether and chloroform, and then surfactant and cholesterol (as the aqueous drug solution) will be mixed in (taken in the ratio 1:1 ratio) [116] and then the mixture will be added to aqueous phase containing the drug afterward resulting in a two-phase system, then they must be homogenized so that organic phase is evaporated under negative pressure to form niosomes. Now large unilamellar vesicles are formed [91]. To form a semi-solid gel of large vesicles this emulsion must be dried in a rotary evaporator at 40 C. To form small stable uniform vesicles small quantities of the buffer will be added and the semi-solid form is sonicated at 4–5 C [118]. REV can be the ideal method for creating niosomes of hydroxychloroquine, isoniazid, ellagic acid, and bovine serum albumin due to: high % EE, large particles size with a small variation to encapsulate large hydrophilic macromolecules with relatively higher EE than other methods [97]. Keep in mind that if the structure of the used drug is deformed (for being in temperatures greater than 50 °C or in organic solvents), direct entrapment method cannot be used [115]. 3.5.6 Micro-Fluidization Method This method is based on the submerged jet principle. Surfactants and the drug solution are pumped through an interaction chamber under the pressure of 100 ml/ min, and a cooling loop is required to remove the heat produced from before the micro-­fluidization. Using this method, it is possible to create different forms of niosomes with greater uniformity, small size, unilamellar vesicles, and better reproducibility of niosomes [91]. 3.5.7 Trans-Membrane pH Gradient (Inside Acidic) In this method, multilamellar vesicles are produced; so to create niosomal suspension,a round bottom flask is being used. Firstly, the surfactant and cholesterol must be mixed so they can dissolve together in chloroform, and then the mixture must be put under pressure to evaporate chloroform. The mixture should be vortex with 300 mM and citric acid (pH 4.0) to hydrate film. But still, the job is not done; an aqueous solution containing 10 mg/ml of the drug must be added to the solution and vortex. Set the pH of the final solution to 7.0–7.2 by adding 1 M disodium phosphate. Finally heat the mixture at 60 °C for 10 min [116].

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3.5.8 Single-Pass Technique This is a patented technique for creating niosomes within the range of 50–500 nm. It has also been mentioned as a multiple membrane extrusion. In this method, a lipid-containing drug suspension must be passed through a porous device and then through a nozzle. Finally, the uniform-sized niosomes are prepared [89]. 3.5.9 Heating Method (HM) The heating method was introduced by Mozafari et al. [119, 120] in 2005. In this method, surfactants and cholesterol were hydrated in PBS (pH = 7.4) separately at room temperature for one hour under a nitrogen atmosphere. The solution then is stirred and heated up to 120 °C to dissolve cholesterol. At the next level, the temperature must reach 60  °C.  Afterward, surfactants and other additives should be added to the buffer while stirring (meant for cholesterol) continues for another 15 min and after all niosomes nanocarriers were designed. At the end stage, created niosomes must be kept at room temperature for 30 min, and then for future needs, they will be stored at 4–5 °C in a nitrogen atmosphere [115]. 3.5.10 Freeze and Thaw Method (FAT) This method enables us to create frozen and thawed multilamellar vesicles (FAT-­ MLVs). First, niosomes are prepared with the TFH method (thin-film hydration), then niosomal suspensions are frozen in liquid nitrogen for 1 min and are thawed in a water bath at 60 °C for 1 min [121]. 3.5.11 Microfluidic Hydrodynamic Focusing This method provides better-sized niosomes for distribution compared to a conventional method. Lo et  al. created niosomes out of two miscible liquids via diffusive mixing based on microfluidic hydrodynamics [122, 123]. Hence, a rapid and controlled manner is required to mix the miscible liquids in microchannels. The following are the factors that can affect the assembly of niosomes: (a) Microfluidic mixing conditions. (b) Chemical structure of the surfactant. (c) Material: the micro-channels fabrication, for example; large-sized niosomes will be produced If we use aider micro-channels for it and increase the diffusive mixing time & hence. (d) Low-rate ratio: This factor can affect the size of the produced niosomes, for example, if the rate increases it will be decreasing diffusive mixing time. So, the manufactured niosomes will be small-sized [89].

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3.5.12 Dehydration-Rehydration Method The initiator of this method was Kirby and Gregoriadis in 1984 [124]. In this method, vesicles must first be prepared by the thin-film hydration method. Next, liquid nitrogen should be used to frizz vesicles and then it should be freeze-dried overnight; this will form powder niosomes, and then phosphate buffer saline (pH 7.4, at 60 °C) should be used for hydration. 3.5.13 Supercritical Carbon Dioxide Fluid Method (scCO2) The advantages are: (a) One-step production (b) Easy scale-up Manosroi et al. designed this method for creating niosomes [125, 126]. To sum up, Tween 61, cholesterol, glucose, PBS, and ethanol must be added into the view cell and the CO2 gas should be introduced into the view cell, next equilibrium must be reached through magnetic stirring, and after this level, the pressure should be released and finally, niosomal dispersions can be found (Niosomes created by this method will be in the range of 100–440 nm) [91]. So, keep in mind that this method requires solvents that are non-inflammable, non-toxic, and volatile. 3.5.14 The Handjani-Vila Method In this method, the aqueous solution of the drug must be mixed with cholesterol and surfactant. Then, ultracentrifugation or agitation should be used to homogenize the mixture at a controlled temperature [127].

3.6 Characterization of Niosomes The parameters that characterize niosomes are as follows: 3.6.1 Size, Morphology, and Size Distribution of Niosomes Light microscopy, coulter counter, photon correlation spectroscopy, electron microscopic analysis, SEM (scanning electron microscope), TEM (transmission electron microscope), freeze-fracture replicator, light scattering, and zetasizer can be used to determine the size and morphology of niosomes. Because the two methods use different measurement concepts, the particle size determined by the transmission electron microscope is smaller than the dynamic light scattering (DLS) [115, 128–130]. Rinaldi et al. [131] investigated the size, shape, and size distribution of the niosomes sample using atomic force microscopy.

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3.6.2 Entrapment Efficiency It can be computed by subtracting the total amount of drug added from the amount of unloaded drug [84]. Exhaustive dialysis, filtration, gel chromatography, and centrifugation can all be used to determine the unloaded drug [131]. By dissolving niosomes in 50% n-propranolol or 0.1% Triton X–100, the concentration of loaded medicines can be measured [132]. The percent entrapment efficiency can be calculated using the calculation below [115]. %Entrapment Efficiency 

Quantity of drug  loaded in the niosomes 100 The total quantity of drugs in the suspension



3.6.3 Charge on Niosomes and Zeta Potential Because of the charge on them, niosomes repel one other. By inhibiting aggregation and fusion, electrostatic repulsion keeps them stable [133]. The zeta potential is used to determine the charge on niosomes. The zeta potential is determined using a zeta potential analyzer, mastersizer, microelectrophoresis, pH-sensitive fluorophores, high-performance capillary electrophoresis, and a DLS apparatus [134]. Henry’s equation is the formula for calculating zeta potential [135, 136].



£

 E 

where £ = zeta potential, μE = electrophoretic mobility, η = viscosity of medium, and Σ = dielectric constant. Because of electrostatic repulsion between particles, Bayindir and Yuksel [122] employed dicetyl phosphate (DCP) to give the surface charge on niosomes and found that a negative zeta potential in the range of 41.7 to 58.4 mV is enough to keep the system stable. Manosroi et al. [137] used two different charges to manufacture gallidermin niosomes (anionic and cationic). They noticed differences in niosomes size because, in anionic vesicles, the charge was neutralized by the positive charge of gallidermin, resulting in small niosomes, whereas in cationic vesicles, the charge was neutralized by repulsion between the cationic charges, resulting in big niosomes. 3.6.4 Number of Lamellae The number of lamellae can be determined using a variety of techniques such as AFM, NMR, small-angle X-ray spectroscopy, and electron microscopy [138, 139]. Small-angle X-ray scattering combined with in situ energy-dispersive X-ray diffraction can be utilized to characterize the thickness of bilayers [140, 141].

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3.6.5 Membrane Rigidity The mobility of a fluorescent probe as a function of temperature can be utilized to evaluate membrane stiffness [142]. Fluorescence polarization can be used to determine the micro-viscosity of the niosomal membrane to better understand its packing structure [125]. The membrane characterization of pentamidine niosomes was done by Rinaldi et al. DPH and pyrene were utilized because DPH indicates lipid order and pyrene indicates lateral diffusion inside the bilayer [143]. The fluorescent measurements (ʎ = 350–425 nm) were made with a luminescence spectrometer, and the fluorescence anisotropy (r) was calculated using the equation below: Fluorescence Anisotropy  r  

 IVV  GIVH   IVV  2GIVH 

3.6.6 In Vitro Release The dialysis membrane method is used to investigate in vitro release. Niosomes are placed in a dialysis bag, which is then placed in a container with dissolving media, usually buffer, in this procedure. This entire assembly is kept at a constant temperature of 37 °C on a magnetic stirrer. A sample is obtained from the receptor compartment at specific time intervals, and drug concentration is measured using any method described in the literature [136, 137, 144]. The dialysis approach was used to release temozolomide niosomes [145], benazepril hydrochloride niosomes [146], paclitaxel, curcumin cationic PEGylated niosomes [147], and diltiazem niosomes [148]. Aboul Einien [129] studied the release of ascorbic acid derivative from aspasomes using a cellophane membrane (mol. Wt. cut off = 500–1000) soaked in glycerin: water (1:3) for 15 min; 0.5 g of aspasomes were packed in this membrane, firmly knotted, and placed in a USP dissolution apparatus I. The experiment was carried out in 250 mL of phosphate buffer (pH 7.4) at 32 °C ± 0.5 °C temperature and 50 rpm speed. At a predefined time interval, the samples were spectrophotometrically examined. To investigate the diffusion of morusin from niosomes, Agarwal et  al. [149] utilized a different approach. They dispersed 15 mg of preparation in 15 ml of phosphate buffer between pH 4.5 and 7.4. This sample was taken in 15 Eppendorf tubes. These tubes were revolved at a constant speed of 130 rpm and a temperature of 37 °C for 9 days. The tube is removed at a predetermined time interval and centrifuged at 15000 rpm for 30 min. The drug concentration of the resulting supernatant was determined using spectrophotometry.

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3.6.7 Tissue Distribution/In Vivo Study The method of delivery, drug concentration, effect, and present time of the drug in tissues such as the liver, lung, spleen, and bone marrow all influence in vivo investigations for niosomes [115, 133]. Animal models can be used to investigate a drug’s tissue distribution. Animals must be sacrificed, and various tissues such as the liver, kidney, heart, lungs, and spleen must be taken, washed with buffer, homogenized, and centrifuged to investigate the distribution pattern. The drug content of the supernatant is determined [136]. Onochie et al. [150] studied the bioavailability of benzyl penicillin niosomes in albino rats in vivo. The intubation tube was used to administer each formulation (0.1  ml) orally. Blood samples were taken at predefined intervals for 24 h using the retro-orbital puncture method, and the supernatant was utilized to measure serum drug concentration. 3.6.8 Stability Studies On storage, the drug may leak from the niosomes, because of aggregation and fusion [115]. Kopermsub et al. [151] performed the stability studies of niosomes by exposing the preparation to different conditions of temperature (4°, room temperature, and 45°) for 2 months. Niosomes are also exposed to various humidity and light (UV) conditions. During stability studies, parameters like size, shape, and entrapment efficiency are evaluated periodically. In the same manner stability of green tea extract niosomes [152], lornoxicam niosomes [153], cefdinir niosomes [154], and Ginkgo biloba [154] niosomes have been performed. Bayindir and Yuskel [122] studied the effect of gastrointestinal enzymes on the stability of niosomes. This study was performed by exposing the drug and drug-loaded niosomes in different gastrointestinal enzymes like pepsin, trypsin, and chymotrypsin and found that niosomes protect the drug from degradation by gastrointestinal enzymes.

3.7 Routes of Administration Drug-loaded niosomes can be supplied via a variety of routes, depending on the condition, drug characteristics, and the site of administration. These administration paths are briefly described below. 3.7.1 Intravenous Intravascular delivery of niosomes is possible. The advantage of injecting the medicine is that it enters the systemic circulation immediately; also, the niosomes improve the drug’s stability and prolong its time in the blood. With minimal changes,

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the drug can also be administered to a specific location. Many medications’ niosomes are delivered using the intravenous method [87, 155]. Niosomes of morin hydrate were produced by A. Y. Waddad et al. [156] for intravascular injection. To increase the stability and bioavailability of phenol, He et  al. [157] developed PEGylated niosomes. PEGylated niosomes can block uptake from the mononuclear phagocytic system, allowing to improve circulation time. 3.7.2 Intramuscular Niosomes can also be given via the intramuscular method. Jitender Singh Wilkhu [158] fabricated niosomes for the oral and intramuscular administration of subunit influenza antigen. 3.7.3 Dermal and Transdermal In the event of skin problems, the dermal route is employed to deliver drugs locally. It is solely employed for local activity. This approach has the advantage of preventing the medicine from entering the systemic circulation, resulting in fewer side effects. The medicine enters the systemic circulation via transdermal distribution; however, drugs confront a barrier in the form of the skin. The vesicular system is extremely useful in enhancing medication delivery via both dermal and transdermal routes [139]. Niosomes operate as a drug reservoir, allowing the drug to penetrate deeper into the body. To avoid gastrointestinal problems, NSAIDs are delivered by a transdermal administration method [84]. Clomipramine is provided encapsulated in niosomes to reduce first-pass metabolism and increase bioavailability [159]. Manosroi et  al. [137] produced gallidermin niosomes for transdermal administration. They demonstrated improved transdermal medication delivery with increased drug accumulation in the skin and no systemic adverse effects. Patel et  al. [160] improved lopinavir transdermal administration from niosomal gel. They compared the niosomal gel to the ethosomal gel of the same medication and discovered that the ethosomal gel deposition was better using ex vivo permeation experiments. Niosomes were found to be safer than ethosomes in histopathological investigations and their in vivo bioavailability was substantially higher than the oral suspension of lopinavir. A papain-loaded elastic niosomal gel with a molecular mass of 23.5 kDa was effectively developed for scar therapy by transdermal application [161]. Sandeep et  al. [162] produced a fluconazole proniosomal gel for topical use. Ex vivo skin penetration and permeation experiments revealed that a large amount of drug has collected in the skin, improving local drug delivery for a longer period. Abdelbary et al. [163] developed methotrexate niosomes for topical administration of methotrexate to patients with psoriasis. This preparation has the highest proportion of drug deposition in the skin (22.45%). To achieve continuous medication delivery, Narayana Charyulu R et al. [164] combined penetration enhancers with methotrexate. Junyaprasert et  al. [165] used different

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surfactants (Span 60 and Tween 60) and solubilizers to make ellagic acid niosomes (propylene glycol 400, propylene glycol, and methanol). The niosomes size, entrapment efficiency, and drug permeability were all modified by the formulation. Junyaprasert et  al. [166] investigated the effects of chemical penetration enhancers on ellagic acid skin permeability. The penetration enhancer has altered the permeation of ellagic acid from niosomes at 24  hours, according to in  vitro skin permeation tests in the human epidermis. The DMSO niosomes have the highest drug concentration in the epidermis, while N-methyl-2pyrrolidone niosomes have the highest concentration in the acceptor compartment. This research shows that DMSO niosomes are effective for epidermal distribution of ellagic acid, while N-methyl 2-pyrrolidone (NMP) niosomes are effective for dermal delivery. Niosomes of the following drugs are also made and evaluated: ascorbic acid derivative (topical delivery) [129], green tea extract (transdermal) [152], diacerein (topical) [89], etodolac (topical) [167], celecoxib (transdermal) [168], baclofen (topical) [169], and resveratrol (topical) [170]. For transdermal drug delivery, phenol ethosomes [130] and pentazocine proniosomes [171] are also created. 3.7.4 Oral As the oral route is the preferred approach for drug administration, niosomes are also given this way. The acidic environment and digestive enzymes, which may degrade the medication, are a difficulty in the oral distribution of the medicine [122]. However, niosomes have been demonstrated to successfully carry the medication to the gastric mucosa [172]. To improve oral bioavailability, niosomes containing tenofovir disoproxil fumarate [173], cefdinir [154], paclitaxel [122], and Ginkgo biloba extract are produced. To improve the oral activity, microbiological activity, and duration of action, Onochie et  al. [150] developed benzylpenicillin niosomes. Lornoxicam niosomes were developed to prolong the drug’s action when taken orally [153]. Samyukta Rani et al. [174] made orlistat niosomes from proniosomes to improve solubility, regulate release, and length of action. To improve insulin penetration through the intestinal membrane, Moghassemi et al. [175] produced trimethyl chitosan (TMC)-coated niosomes of insulin. 3.7.5 Ocular When a medicine must be given in the anterior location of the eye, topical ocular administration is usually preferred [115]. Drugs delivered in conventional forms have a bioavailability of just 1–3%, and they are subject to precorneal loss due to tear production and insufficient residence time in the conjunctival sac [176, 177]. To distribute naltrexone via the ocular pathway, Abdelkader et  al. [178] produced controlled release niosomes and discomes. They discovered that anionic niosomes

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outperform neutral niosomes in improving naltrexone penetration across the cornea. By covering tacrolimus niosomes with mucoadhesive hyaluronic acid, Zeng et al. [179] created tacrolimus niosomes. Because of its high lipophilicity and molecular weight, tacrolimus has a poor corneal penetration (822.5 D). The hyaluronic acid– coated niosomes improve corneal permeability and ocular contact time. Abdelkader et al. [180] also created unique nano-sized elastic niosomes for ocular delivery of prednisolone acetate and sodium phosphate. They tested for ocular irritation, bioavailability, and anti-inflammatory properties, as well as compared the results to those of traditional eye drops (both suspension and solution). Using a modified Draize test, researchers discovered that both forms of prednisolone have good ocular tolerability and bioavailability. A side effect elevation in intraocular pressure created by prednisolone was greatly reduced by niosomes preparations. 3.7.6 Pulmonary The pulmonary route of administration of niosomal drugs has various advantages, including enhanced mucus permeability, sustained drug delivery, targeting, and superior therapeutic outcomes. The interaction of niosomes for pulmonary glucocorticoid administration with human lung fibroblasts is created and tested. At all incubation durations, these niosomes showed no appreciable toxicity in the concentration range of 0.01 to 1 M. Vesicular carriers have been discovered to be located in the cytoplasm using confocal laser scanning (site for glucocorticoid receptors). These vesicles were shown to significantly increase drug absorption by human lung fibroblasts as well as drug activity [181]. 3.7.7 Nasal Administration Nasal delivery is an excellent option for medicines with a high first-pass metabolism. Diltiazem is rapidly absorbed from the mouth, although its bioavailability is only 30–60% due to substantial hepatic first-pass metabolism by cytochrome P450 enzymes. Nasal administration has some drawbacks, such as a short residence time in the nasal cavity due to mucociliary clearance, airflow restriction, and nasal mucosa sensitivity, all of which impair drug penetration and systemic bioavailability. Nasal niosomal diltiazem has been demonstrated to have higher absorption and less elimination [148].

3.8 Applications of Niosomes Niosomes can be employed as a delivery device for a range of pharmaceutical reasons. Table  14.1 provides a summary of some of the prior studies on the application of niosomes in a tabular format.

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Table 14.1  Recent studies in drug delivery using niosomes and applications Application Surfactant Protein delivery Tween 60

Anticancer drugs delivery

Carrier for hemoglobin Treatment of HIV-AIDS

Method Lipid layer hydration Span 60 Lipid layer hydration Brij 92 Lipid layer hydration Span 60 Lipid layer hydration Span 40 Lipid layer hydration Span 60 Lipid layer hydration Span 60 Lipid layer hydration Span 60 Lipid layer hydration Span 80 Sonication Bola Lipid layer surfactant hydration Span 60 Lipid layer hydration Span 60 Lipid layer hydration Pluronic Lipid layer P123 hydration Tween 80 Lipid layer hydration Tween-100/ Lipid layer span 80 hydration Span 60 Ethanol injection Tween 80 Lipid layer hydration Tween 80 Lipid layer hydration Span 60 Lipid layer hydration Span 60 Lipid layer hydration Span 60 Ether injection Span 60 Lipid layer hydration Span 80 Ether injection

Route Therapeutic agent administration Glutathione In vitro

Reference [182]

Insulin

In vitro

[175]

Insulin

Oral

[183]

Insulin

Oral

[184]

N-acetyl glucosamine Bovine serum albumin Cisplatin

Topical

[185]

Oral

[186]

5-Flourouracil

Topical

[188]

Curcumin 5-Fluorouracil

Intravenous

[188] [111]

5-Fluorouracil

Topical

[189]

Flutamide

Oral

[190]

Doxorubicin

In vitro

[191]

Curcumin

Vein injection

[192]

Curcumin

In vitro

[193]

Gambogenic acid In vitro

[194]

Paclitaxel and curcumin Doxorubicin and curcumin Hemoglobin

In vitro

[147]

In vitro

[195]

Intravenous

[196]

[187]

Lamivudine

[197]

Stavudine Stavudine

[198] [199]

Zidovudine

[200] (continued)

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Table 14.1 (continued) Application Surfactant Vaccine and Span 60 antigen delivery Span 20 Span 60 Span 60/ Span 85 Management of psoriasis

Span 60 Free surfactant Span 60

Treatment of leishmaniasis

Span 40/ Tween 40 Span 40/ Tween 40

Method Lipid layer hydration Lipid layer hydration Lipid layer hydration Reversed phase evaporation Lipid layer hydration Lipid layer hydration Lipid layer hydration Lipid layer hydration Lipid layer hydration

Route Therapeutic agent administration Tetanus toxoid

Reference [201]

Newcastle disease vaccine Ovalbumin

Parenteral

[202]

Bovine serum albumin

Topical vaccine

[204]

Methotrexate

Topical

[163]

Methotrexate

Topical

[205]

Acitretin

Topical

[206]

Selenium and glucantime Amphotericin B and glucantime

In vitro

[207]

intramuscularly

[208]

[203]

3.8.1 Delivery of Proteins and Peptides Protein and peptide medications have long been challenging to deliver orally due to their degradation by the acidic environment and enzymes of the gastrointestinal tract. Niosomes, on the other hand, shield these drugs from protolithic enzymes [84, 132]. Moghassemi et al. [153] developed bovine serum albumin niosomes (BSA). The formulation was tuned for loading and release as a function of cholesterol to span 60 M ratios, and an inverted light microscope was utilized to monitor the position of protein in the vesicle. To improve insulin penetration, niosomes of trimethyl chitosan-coated insulin are also produced for oral delivery [175]. 3.8.2 Delivery of Anticancer Drugs Niosomes can deliver anticancer drugs to a specific organ. This targeting could be passive [209] (deposition of niosomes within the tumor due to unique properties of tumor cells not found in normal cells) [210], physical (delivery based on specific environmental conditions such as pH or magnetic fields) [118], or active [209] (delivery based on specific environmental conditions such as pH or magnetic fields) (active uptake of niosomes by the tumor cell). Active targeting can be accomplished by altering the surface’s structural features or by binding the ligand to the niosomes. Curcumin, which is hydrophobic, and doxorubicin hydrochloride, which is hydrophilic, were encapsulated in niosomes for anticancer treatment in this study. They

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observed two distinct release phases: doxorubicin release during the first 2 days, followed by curcumin release for 7  days. Against HeLa cell lines, the cytotoxic impact was amplified (synergistic). For the co-administration of curcumin and paclitaxel, Alemi et al. [147] developed cationic PEGylated niosomes. The improved synergistic anticancer effects of these niosomes were reported. Agarwal et al. [149] created the morusin niosomes for anticancer therapy potentiation. He noticed that the drug was released in a dependent manner. The release of morusin from niosomes was lower at pH 7.4 than it was at pH 4.5. In acidic settings (pH 4.5), drug release was 58.1% after 120 hours, but it was only 43.3% at physiological pH 7.4. It suggests that in the acidic environments of cancer cells, significant drug release can be achieved. 3.8.3 Delivery of Vaccine and Antigen Wilkhu et al. [211] developed bilosomes for vaccine administration orally. Bile salt is incorporated into the bilayer of vesicles to manufacture bilosomes. The antigens are protected by these bilosomes from being degraded by enzymes found in the gastrointestinal system (GIT). 3.8.4 Carrier for Hemoglobin Because of their strong oxygen absorptive capabilities, niosomes can also be used as a hemoglobin carrier in the blood [212]. 3.8.5 Treatment of HIV-AIDS Niosomes can be used to deliver drugs for sustained delivery in AIDS patients. The low efficacy and toxicity of these drugs pose an issue in their delivery, which could be solved by constructing a niosomal system. Due to dose-dependent hematological toxicity, significant first-pass metabolism, short biological half-life, and poor absorption, zidovudine is an anti-HIV drug with limited therapeutic efficiency [146, 213]. Niosomes have been reported to solve zidovudine issues [199]. Lopinavir is an HIV protease inhibitor that is reversible. Because of its low aqueous solubility, high log P value, cytochrome P450 3A4 sensitivity, and susceptibility to P-glycoprotein efflux transporters, its systemic bioavailability via the oral route is limited. Transdermal niosomes were created and compared to the ethosomal gel to address these concerns. Ex vivo skin permeation experiments revealed that the ethosomal gel deposition of a drug into the skin was higher than the niosomal gel, but niosomes permeated deeper through the skin and had a better drug release profile [160]. Kamboj et al. developed niosomes to improve the oral bioavailability of tenofovir disoproxil fumarate [173]. They discovered a twofold increase in bioavailability and a considerable improvement in the drug’s mean residence time, indicating a

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longer drug release time. Stavudine niosomes were manufactured by Shreedevi et al. [214] for targeting and controlled release. 3.8.6 Management of Psoriasis Psoriasis is an inflammatory skin condition that lasts for a long time. It has been reported to affect joints and is recurring [180, 215]. Topical treatment is often used for mild to moderate psoriasis [173]. When more than 20% of the patient’s body is affected, systemic therapy is recommended. Emollients, keratolytic agents, coal tar, anthralin, calcipotriene, and corticosteroids are some of the topical treatments for psoriasis. Phototherapy may be combined with systemic therapy. Systemic therapy for psoriasis includes methotrexate, cyclosporine, corticosteroids, and etretinate [152]. Nausea, diarrhea, dizziness, and mouth ulcers are all common side effects of systemic methotrexate treatment [133, 216]. Hematological and liver damage are potentially possible side effects [217]. Topical methotrexate may help prevent these issues. For better psoriasis care, Abdelbary and AbouGhaly [163] created and optimized niosomes containing methotrexate for topical application. In comparison to the oral solution, the niosomes were optimized using the Box-Behnken design and reported to have a much higher area under curve and skin deposition amount of drug. The safety of niosomes was proven by histopathological examinations. Hashim et al. [206] developed an acitretin nano-vesicular gel for topical use to combat the drug’s low solubility, stability issues, skin irritation, and substantial systemic adverse effects. Moghaddam et al. [89] used topical application to prepare the diacerein niosomes for targeted distribution. 3.8.7 Treatment of Leishmaniasis Because niosomes are taken up by the reticuloendothelial system and accumulate there, they can be used to treat disorders like leishmaniasis [87, 218]. Niosomes have also been utilized to treat malignancies that have spread to the liver and spleen [132]. The Leishmania parasite primarily infects the liver and spleen. Antimonial (drugs used to treat leishmaniasis) might affect the liver, kidneys, and other organs [219]. The niosomal formulation can increase the drug’s absorption in the liver, reducing the drug’s negative effects on other organs [132]. Positively charged niosomes entrapped with autoclaved Leishmania major against cutaneous leishmaniasis had a moderate effect and successfully delayed the formation of lesions in BALB/c mice, according to Pardakhty et  al. [220]. For Leishmania tropica, Mostafavi et al. [207] produced selenium niosomes with glucantime. In vitro testing revealed that selenium niosomes combined with glucantime have effective antileishmanial action and improved potent lethal activity. For Leishmania tropica, Parizi et al. [207] investigated the immune-modulatory and antileishmanial action of benzoxonium chloride niosomes. They discovered that as the concentration of the drug was increased, the expression of interleukin IL-10 decreased while that of interleukin-12 increased.

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3.8.8 Diagnostic Imaging Niosomes have the potential to be employed as a carrier for radiopharmaceuticals, making them valuable in diagnostic imaging of organs such as the liver and spleen. For imaging, 99mTc labeled DTPA is utilized [136, 221]. Iobitridol (diagnostic agent) is utilized with niosomes for x-ray imaging [222]. Gadobenate dimeglcemine in a conjugated niosomal formulation with [N-palmitoylglucosamine (NPG)], PEG 4400, and both PEG and NPG have been found to increase tumor targeting of an encapsulated paramagnetic drug as measured by MR imaging [138, 223]. By adding contrast agents or dyes (near-infrared) in the inner aqueous or non-aqueous compartment or conjugating onto the surface of niosomes, A.  Massotti [224] created unique biconjugate niosomes for imaging. Gd (EDTA) 2- may be utilized as a contrast agent for incorporation [225]. Optical imaging combined with magnetic resonance imaging is also a useful method for tumor diagnosis [226–228]. In vivo imaging can be achieved by combining polyethylene amino groups with near-­ infrared probes [229]. 3.8.9 Enhancement of Bioavailability Drug bioavailability can be improved with niosomes. To improve oral bioavailability, niosomes of paclitaxel [122], cefdinir [154], benzylpenicillin [150], and tenofovir disoproxil fumarate [173] are produced. Diltiazem niosomes were developed for nasal delivery to improve bioavailability [148].

3.9 Targeted Drug Delivery Tavano et al. [209] and A. Massotti [224] prepared niosomes for targeted delivery of drugs to tumor cells. Tavano et  al. prepared to transfer conjugated pluronic niosomes of doxorubicin for delivery to tumor cells. A. Massotti prepared pH-sensitive niosomes for delivery of a drug to hepatoblastoma. Targeting was done using surface modification and no pH-sensitive molecule was used. These niosomes undergo protonation of amino groups present on their surface after penetration into the cell and release their cargo by “sponge effect.”

3.10 Brain Targeting As illustrated above, niosomes can entrap lipophilic or hydrophilic drugs and deliver the drug molecules to the target site in a sustained and/or controlled way [75, 115]. Drug organ distribution and metabolic stability have been reported to be affected by niosomes. Surface modification of niosomes has been shown to improve target

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selectivity for cancer drug delivery systems [118]. De et al. reported that modification of temozolomide-loaded niosomes with chlorotoxin, a target-specific peptide, significantly improved the temozolomide glioma targeting efficacy [145]. In comparison to the intranasal solution of the drug, surface-modified niosomes containing olanzapine (an atypical antipsychotic medicine) demonstrated a three-fold increase in olanzapine concentration in the brain [230]. Pentamidine is an antiprotozoal drug, also having an anti-inflammatory and neuroprotective effect in Alzheimer’s disease [231–233]. Its clinical efficacy is limited due to poor permeability across blood-brain-barrier and high hepatotoxicity. To overcome these issues chitosan-­ glutamate coated pentamidine niosomes were prepared for intranasal drug delivery to reach the brain. Approach to the brain via intranasal delivery bypasses the first-­ pass hepatic metabolism and blood-brain barrier [11, 17, 22].

4 Summary Despite the great advances in drug discovery, still, neurologic diseases are the second cause of death around the world [234]. Conventional drug delivery methods such as peripheral routes including oral and parenteral administrations are one of the most common routes for drug delivery whenever systemic effects are intended [235]. Besides the fact that the parenteral route is usually painful and also requires technical assistance, conventional methods also showed other major drawbacks in the efficient delivery of therapeutic agents to the brain. First of all, due to the presence of the blood-brain barrier (BBB), the drug administered via conventional routes results in dramatically lower drug concentration in the brain [5]. Secondly, systemic clearance as well as first-pass metabolism and enzymatic degradation hinder the efficacy of the drug and significantly reduce the drug bioavailability [236]. There are two barriers between blood and brain extracellular fluids: BBB and the blood-cerebrospinal fluid barrier (BCSFB) which mediate communication between the central nervous system (CNS) and the periphery [237, 238]. The BBB consists of a tight layer of endothelial capillary cell junctions which are surrounded by astrocyte foot processes. The BBB plays a key role in regulating CNS homeostasis and function by protecting the CNS from pathogens, toxins, inflammation, and injury. It is a highly regulated barrier that allows highly selective transport of essential molecules to the brain [239]. BBB loss or dysfunction by various diseases such as brain traumas, stroke, multiple sclerosis (MS), and neurodegenerative disorders could result in neuronal dysfunction and degeneration. Although the BBB is a critical component of CNS, it is a significant barrier for drug transport from the blood to the brain, and just the drugs with molecular weight less than 400 Da, high polarity, and not multicyclic can across the BBB successfully [234, 240]. All of these factors trigger the hunt for an alternative delivery system that directly reaches the brain. Different strategies that are mostly invasive such as intraventricular, intraparenchymal, and intrathecal delivery (disruption of the BBB) have been investigated for this purpose [240]. Over the past decades, several studies have described the

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nose-to-brain route as a promising approach that could offer an opportunity to serve as a noninvasive direct route to the CNS.  The concept of the nose-to-brain drug delivery, for the first time, was introduced by W. H. Frey II in 1989 (William H, Frey I.  Inventor Neurologic Agents for nasal administration to the brain. US1991 1990-12-04). This method previously was often used for brain targeting of insulin or insulin-like growth factor and later was developed for delivery of larger molecular weight substances like proteins, peptides, and bioactive [236]. As previously mentioned, nose-to-brain drug delivery is an invasive alternative and patient-friendly route over the traditional and invasive drug administration routes which could provide faster onset of action, high blood flow, and porous endothelial membrane to absorb drugs efficiently while circumventing the hepatic first-­ pass metabolism, BBB, and potentially lowering the systemic exposure, which enables the easy and self-administration possibilities. Furthermore, this route is optimal for drugs that are susceptible to enzymatic degradation and gastrointestinal tract acidic environment [239]. Generally, there are two main pathways for drugs to reach the brain from the nasal cavity: (1) neuronal pathway as the major route and (2) crossing the BBB through systemic circulation as the minor route. Desired drugs could be located in the deeper region of the nasal cavity which is firstly absorbed by olfactory and trigeminal neurons, and then through cellular transport can reach the olfactory bulbs [235, 236]. The nasal cavity includes three main regions: vestibular, respiratory, and olfactory regions. After a drug enters the nasal cavity, it encounters mucociliary clearance and then moves forward to reach respiratory and olfactory regions. From these regions, depending on the formulation, physiological condition, and the administration device, the drug can be transported to the brain by several mechanisms such as trigeminal nerve pathway, lymphatic and vascular pathway, olfactory nerve pathway, and cerebrospinal fluid. When the drug reaches the brain, it is distributed throughout the CNS by perivascular transport [235]. Although the nasal to brain route is a promising method for fast, easy, efficient, and targeted drug delivery, some limitations must be acknowledged when developing new therapeutics to be administered via this route. First of all, this route can be used just for potent drugs with a dose volume of 100–250 ml for liquids and 20–50 mg for powders [235]. Secondly, there is a possibility of poor drug permeation through the nasal mucosa due to the low drug retention caused by mucociliary clearance and enzymatic degradation. For this reason, drugs to be delivered by this route should be protected from degradation [236]. Thirdly, due to high vascularization, there is a possibility of peripheral side effects through systemic absorption which also reduces the drug concentration in the brain [236]. Finally, there is a need to use the proper nasal delivery device to install the right amount of drug correctly in the nasal cavity [234]. However, different approaches such as permeation enhancers, protective drug capsulation and colloidal carriers, suitable mucoadhesive system, controlled delivery system, and other novel approaches have been employed to improve the drug delivery through the nasal to brain route [236]. Niosomes are non-ionic surfactant vesicles fabricated by hydrating synthetic non-­ ionic surfactants, either with or without cholesterol or lipids. They’re vesicular structures that appear similar to liposomes and can transport both amphiphilic and

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lipophilic medicines. Niosomes are a viable vehicle for drug administration because of their non-ionic nature and are biodegradable, biocompatible, non-immunogenic, and structurally flexible. For the treatment of cancer, viral infections, and other microbial diseases, niosomes have been extensively studied for controlled release and targeted administration. Niosomes can entrap both hydrophilic and lipophilic drugs, allowing them to circulate in the body for a prolonged period. Encapsulation of a drug in the vesicular system is expected to prolong its presence in the systemic circulation and improve penetration into a target tissue, perhaps reducing toxicity if selective absorption is possible. This chapter focuses on the nasal drug delivery route, advantages and disadvantages of niosomes, types of niosomes, methods of preparation, characterization, routes of administration, and applications of niosomes.

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Chapter 15

Nanosuspension – A Novel Drug Delivery System via Nose-to-Brain Drug Delivery Hemant K. S. Yadav and Raghad Zain Alabdin

Abstract  Nanosuspension administration via the nasal route of administration appears to be an effective pathway of nose-to-brain drug delivery. The nasal cavity is highly vascularized and innervated by nerves, making it an attractive route of administration that bypasses many oral or parenteral limitations and challenges, thus having more advantages and being an effective treatment choice, especially for neuronal diseases. Nanosuspension was found to be an enhancer of drug absorption though the nasal route of administration due to its small particle size and its capability of optimizing the hydrophilic drugs within it to increase its solubility. Intranasal nanosuspensions are currently being investigated to improve nose-to-brain drug delivery. Nose-to-brain drug delivery and nanosuspension application (insight for nose-to-brain drug delivery) are discussed in this chapter. Keywords  Nanosuspension · Drug absorption · Brain and intranasal

H. K. S. Yadav (*) School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Jaipur, Rajasthan, India R. Z. Alabdin Department of Business Development, Gulf Pharmaceutical Industries (Julphar), Ras Al khaimah, UAE Department of Pharmaceutics, College of Pharmacy, RAK Medical and Health Sciences University, Ras Al khaimah, UAE © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_15

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1 Introduction Brain is the most important organ that is considered as a complex organ, and the deaths due to neuronal diseases are considered the seventh leading cause of death globally [1]. There are several limitations to the therapeutic effects of neuronal medications, such as the presence of blood-brain barrier. The blood-brain barrier blocks more than 95% of the molecules used for the treatment of neuronal diseases [1]. In this regard, many research works were conducted to find solutions to enhance the bioavailability at the central nervous system. Nanosized molecules and the nasal route of administration are the most attractive solutions to pass the blood brain barrier and achieve the best therapeutic effect of the neuronal medications due to its many favorable characteristics which include better patient compliance, non-invasiveness, and ease of administration. Intranasal delivery has also been used for systemic delivery for other diseases treatments or preventions such as flu vaccines and other areas. Formulations such as nanosuspensions not only solve many issues related to the solubility and bioavailability of molecules, but they also enhance penetration through the blood-brain barrier and the blood-cerebrospinal fluid barrier. This chapter focuses on intranasal nanosuspensions intended for nose-to-brain delivery.

2 Nanosuspension Nanosuspension is a colloidal suspension where the particle size of molecules is less than 1 micrometer. Nanosuspension has many advantages such as solubility and bioavailability enhancement, suitable for both hydrophilic and hydrophobic molecules, better drug loading than other nanoparticles, the possibility of dose reduction, physical and chemical stability enhancement, and the possibility of passive drug targeting [2]. There are two methods of nanosuspension preparation, bottom-up and top-down technology. Bottom-up technology involves the processes of microemulsion, precipitation, and melt-emulsification. In the bottom-up technology, the drug is first dissolved in an organic solvent and then it is precipitated while the antisolvent is added in the presence of a stabilizer. This technique includes various adaptations, which are solvent-anti-solvent method, supercritical fluid processes, spray drying, and emulsion-solvent evaporation. Top-down technique is majorly dependent on the reduction of the particle size of larger drug particles into smaller drug particles and this process is accomplished by using various milling techniques such as media milling, microfluidization and high pressure or shear homogenization [3]. Nanosuspension has promising efficacy and several therapeutic applications due to its properties and several merits and due to the fact that it can be administered through different routes. Based on that, many drugs in the form of nanosuspensions are intended for different routes of administrations for different therapeutic areas and some of them are presented in Table 15.1 [2, 4].

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Table 15.1 Nanosuspensions intended for different routes of administrations for different therapeutic areas Route Oral route Intravenous Ophthalmic Pulmonary Intrathecal Topical

Drugs Triglide® (fenofibrate) Abraxane® (paclitaxel) Hydrocortisone Budesonide Busulfan Silver

Company/Author Sciele Pharma/Skyepharma Abraxis Bioscience/Astrazeneca M. A. Kassem Jerry Z. Yang Skyepharma Nucryst

3 Nose-to-Brain Drug Delivery To understand the concept of nose-to-brain drug delivery, it is crucial to know the anatomy of the nasal cavity and the different pathways of drug absorption through it. It is well known that the nose has two functions, olfaction and respiration. The nose has two parts, the external and the internal nose. Bones and cartilages are the components of the external nose and are located in the center of the face. As for the nasal cavities, they are composed of three regions, the vestibular, the olfactory, and the respiratory regions. The outermost part of the nasal cavity is the smallest region, which is called the vestibular region. This region is composed of nasal hair and sebaceous glands. Due to the structural features of this region, this region is not suitable for drug absorption. However, the nasal septum contains a small opening to the vomeronasal organ where the drug can be absorbed directly into the brain via the terminalis nerve [5]. The respiratory region forms 80% of the nasal cavity and it is composed of three turbinates. This region is very attractive to be targeted for drug absorption because of its high surface area. It is highly vascularized and it is supplied by the branch of the maxillary artery, which is innervated by the trigeminal nerve, which contributes to the nose-to-brain drug delivery [6]. Lastly, the superior part of the nasal cavity is the olfactory region, that is surrounded by the olfactory neural cells, which are bipolar neurons providing direct portal between the nose and the central nervous system. Specifically, their unmyelinated axons are covered by the olfactory cells and nerve fibroblasts, which are in continuity with meninges and subarachnoid space [7]. Crowe et  al. classified the mechanisms of nose-to-brain drug delivery into two pathways  – intracellular and extracellular. Intracellular mechanism is preferred when the drug is internalized by an olfactory neuron and traffics the endocytic vesicle within the cell to the projection site of the neuron by exocytosis. As for the extracellular mechanism, it is where the drug crossing the nasal epithelium to the lamina propiato, the neurons and then gets transported externally along the length of the axon via bulk flow process which finally lead into the central nervous system where the drug is distributed via fluid movement. It is crucial that the drug’s ability to cross the blood-brain barrier and the blood-CSF barrier is determining the drug penetration. Thus, the drug properties, characteristics and formulation parameters may determine the drug absorption pathway from the nasal cavity [8]. The different pathways of drug absorption through the nasal route of administration are demonstrated in Fig. 15.1.

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Mucociliary Clearance Nose

Respiratory Region

Olfactory Region

Trigeminal nerve

Blood

BBB

Olfactory nerve

Axonal transport

Brain Stem

Olfactory Bulb

Transcellular transport

Paracellular transport

Subarachnoid space

CSF

Brain

Clearance

Fig. 15.1  Different pathways of drug absorption through the nasal route of administration

There are many advantages of the intranasal route of administration such as non-­ invasiveness, avoidance of BBB, avoidance of first pass and gastrointestinal degradation, high bioavailability, and the direct connection to the central nervous system. However, the small surface area, mucociliary clearance, enzymatic degradation, the possibility of nasal toxicity, and the poor permeation are the limitations of this route of drug administration.

4 Permeation Enhancer Techniques Through the Nasal Route of Drug Administration Different techniques were studied to enhance drug penetration through the nasal route of administration to achieve best solutions for different disease treatments. Some of these techniques use the drug in the form of solutions as small lipophilic

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molecules can easily penetrate the tissues and blood-brain barrier. Nanoparticle formulations include nanosuspensions in which their small particle size makes them an optimum choice to enhance the drug penetration. Also, Mucoadhesive agents can be used in the formulations to increase the residence time and reduce the nasal clearance. Different polymers can be used as mucoadhesive agents in the formulations. Some of these polymers are discussed below.

5 Types of Polymers Used in the Formulation of Nanosuspensions 5.1 Chitosan It is a biodegradable and non-toxic polymer which is obtained from hydrolysis reaction of chitin, a natural polysaccharide that is a major component of crustacean exoskeleton. Unmodified chitosan is soluble in acidic medium and has great mucoadhesive properties. The size of chitosan nanoparticles depends on its concentration, molecular weight, and surface charge [9, 10].

5.2 Gelatin It is formed by either alkaline or acidic hydrolysis reaction of collagen. It has a triple helical structure and high content of proline, glycine, and hydroxyproline residues. Gelatin formed by the alkaline treatment of collagen has a lower isoelectric point and more carboxyl groups than that formed by the acidic hydrolysis reaction. [9, 10]

5.3 Sodium Alginate Sodium alginates are unbranched and linear polymers which consist of ß-(1-4) linked mannuronic acid and residues of α-(1-4) linked guluronic acid which are arranged in blocks, also called G blocks or M blocks, and they can alternate with each other. The nature of this polymer is hydrophilic, anionic, and has different molecular weights. This polymer is unable to reswell in an acidic environment, which helps in the incorporation of acidic drugs into the bead, which protects it from gastric juice [9, 10].

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5.4 Albumin Human serum albumin is the most prominent plasma protein which consists of nearly 585 amino acids and has an α-helical tertiary structure. Some of albumin’s properties are that it is positively charged and multifunctional as it is involved in transportation, enzymatic activities, and ligand binding [9, 10].

5.5 Tamarind Tamarind, scientifically called “Tamarindus indica,” and known as “Imli,” is a member of the dicotyledonous family Leguminosae. Tamarind seeds consist of 20–30% of the outer coat (testa) and 70–80% of the kernel that also called “endosperm.” It consists of crude fibers which have higher carbohydrate percentage in the form of sugars. Tamarind seeds are used as raw materials in the manufacture of different materials such as tamarind seed kernel powder (TKP), polysaccharide, adhesive, and tannin. Tamarind seeds and the gum extracted from them are also used for other purposes and the gum is currently gaining importance in pharmaceutical manufacturing such as in the preparation of mucoadhesive formulations [11, 12].

6 Characterization and Evaluation of Nanosuspensions for Nose-to-Brain Drug Delivery Identification of nanoparticle properties is required to design the nanoparticles to be suitable for different applications. In general, determination of particle size is the most important characteristic as it not only determines the efficacy of the products but it can also lead to irritation if the particle size is large. There are many available tools to measure particles smaller than 1 μm. For example, light scattering (LS), also called photon correlation spectroscopy, is a rapid method for determining the particle size, size distribution, and polydispersity index. This technique is well adapted for routine measures. Electron microscopes use electromagnetic radiations of shorter wavelengths and provide magnification that can disclose details with a resolution of up to approximately 0.1 nm. Scanning electron microscopy (SEM) allows for a resolution between 3 and 5 nm and even 1 nm in some advanced microscopes. Images of the sample are taken; hence, it is possible to study the external morphology of the particles along with the determination of their size. Nanoparticles prepared using different methods can produce particles of various morphologies. The internal morphology of substances as well as their particle size can be measured using Transmission Electron Microscopy (TEM). TEM and high-resolution TEM are more powerful than SEM in providing details at the atomic level and can yield information regarding the crystal structure, quality, and grain size. Potentiometric techniques are used to characterize the phenomenon of

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counter condensation, the nature of interactions with oppositely-charged surfactant molecules, and the stoichiometry of polyelectrolyte complexes. Zeta potential measurements are useful to detect the absorption of polyelectrolytes on the particle surface.

6.1 Fourier-Transform Infrared Spectroscopy (FT-IR) and Differential Scanning Calorimetry (DSC) FT-IR spectra is the study where compatibility is investigated by using IR spectrophotometer. Firstly, the solid pellet is prepared using KBr at room temperature and then analyzed. FTIR study can be performed on pure polymers, pure drugs, and formulations. It is also important to study the dynamic DSC studies to determine the resulted molecule’s nature and confirm its compatibility [13].

6.2 Particle Size Analysis, Zeta Potential, and Polydispersity Index The average particle size distribution, zeta potential, and polydispersity index of the resulting nanoparticles can be determined using zeta potential analyzer. Prior to testing the samples, the nanoparticle dispersion should suitably diluted [13].

6.3 Scanning Electron Microscope (SEM) It is also critical to study the size and morphology of nanoparticles, which can be done by scanning electron microscope (SEM) or transmission electron microscopy (TEM). Nanoparticles should be suitably diluted with a solvent prior to placing the sample [13].

6.4 Encapsulation Efficiency The amount of encapsulated drug in nanoparticles can be determined by different methods. One of these methods is to dissolve a known amount of the prepared nanoparticles in a few milliliter of methanol and diluted using distilled water. Methanol action is to lyse the nanoparticles and release the drug into the solution. The released amount of the drug can be determined by UV spectrophotometer. The amount of the encapsulated drug can be determined by dividing the amount

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encapsulated by the amount of the drug added and then multiplying by 100 to get the percentage encapsulated [14]. Encapsulation efficiency was calculated as:



Encapsulation efficiency%   Amount of encapsulated drug / Amount of added drug  100.



6.5 Stability Testing The nanosuspension should be studied for physical and chemical stability under several conditions for a known period to determine the proper storage conditions and shelf life of the product. Also, it is very critical to study the stability of the product to determine the suitable packaging, instructions of use, and other factors [15].

6.6 Testing Direct Nose-to-Brain Delivery Different models to test nose-to-brain drug delivery as described by Franciska Erdo are summarized below: 6.6.1 In Vivo Models Mouse and rat models are the most useful models for the purposes of the preliminary studies of drug absorption. However, it does not always correlate with humans because of the physiological and anatomical differences. The study is based on administering the drug into the nostril by using a micropipette and keeping the animal in supine position to allow the drug to reach the olfactory region. The olfactory region in mice or rats covers 50% of the nasal the cavity, but in humans, it is only 10%, which is similar in monkeys. The structure of the conchae also is different, where human and monkeys only have a single scroll conchae but the nasal epithelium of monkeys has a smaller surface area than the nasal epithelium of humans. Thus, animal studies cannot be that accurate to determine the intranasal drug administration [8, 16]. 6.6.2 In Vitro Models The drug transport can be studied more clearly and controlled through the in vitro studies. The major studies are described below: A. RPMI 2650 – a cell culture model of nasal barrier. RPMI 2650 is extracted from the human nasal epithelial tissue, specifically, a human nasal squamous cell carcinoma of the nasal septum. It is suitable for

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testing nasal metabolism and toxicity assays. RPMI 2650 in ALI cultures can be used as a screening tool for cytotoxicity and permeability in pre-clinical studies [17]. B. CaCo-2 cell line. CaCo-2 cell line is extracted from the human colon carcinoma and separated into different monolayers. It is used to study drug absorption through the nasal route of administration as it is the most suitable model for this purpose [18, 19]. 6.6.3 Ex Vivo Models This model is used to study a drug’s permeability through the nasal cavity using Ussing chamber. It is also useful for quantifying the active transport, passive diffusion efflux transport, and identifying the carrier-mediated transports. It is a useful model to compare drug transport through respiratory and olfactory pathways [20]. Different preclinical and clinical studies are discussed below in the coming sections of this chapter.

7 Different Drugs Used and Current Research There is a criterion for the selection of the drug in the formulation of nanosuspensions, that is, when formulating the nanosuspension, the API should have one of the following characteristics: • The drug should be water insoluble but which are soluble in oil (having high Log P), API which are insoluble in both water and oil, drugs in crystalline form with reduced tendency to dissolve, regardless of the solvent. • Potent APIs. There are many drugs which have been studied for nose-to brain delivery wherein researchers conducted several studies on these molecules viz. Valproic acid, Duloxetine, Artemether,Temozolomide, Curcumin, Asenapine and Embedin. These are used in treatment of different central nervous system diseases as shown in Table 15.2 [21]. As noticed, most researchers target the smallest possible particle size of the formulation to enhance drug penetration through the nasal cavity. The different drugs and diseases which were targeted by different scientists through the nasal route of administration are explained below. Valproic acid nanostructured lipid carrier was developed by Eskandari et al. by the solvent diffusion and ultrasonication method and it was characterized for different parameters. Eskandari observed that the ratio of the plasma concentration was higher when the drug was administered intranasally to rats compared to when it was administered intra-peritoneally. Thus, it proved to be a better seizure therapy as a preliminary evaluation [22].

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Table 15.2  Different drugs used for nose-to-brain delivery Selected drug Valproic acid Duloxetine Artemether Temozolomide Asenapine Cytokine intereferon-­ beta-­1 b Rosuvastatin

Targeted disease Epilepsy Depression Cerebral malaria Brain tumour Schizophrenia Multiple sclerosis Pentylenetetrazole (PTZ) induced seizures

Particle size of the formulation (nm) 154 100 124.3 100 167.3

219.15

Duloxetine nanostructured lipid carrier formulated by Alam et al. using homogenization and ultrasonication method was evaluated for the in vivo nasal infusion study. It was observed that the permeability was only 2.5 times higher in case of intranasal administration as compared to the drug solution [23]. Artemether nanostructured carriers were developed by Jain et al. using microemulsion method. It was studied for understanding the brain-to-blood ratio for different routes. It was observed that the intranasal route of administration has a higher targeting efficiency and drug penetrating ability to the brain [24]. Temozolomide nanostructured lipid carriers were developed and studied by Khan et  al. It was observed that the particle size was less than 100  nm and the entrapment efficiency reached up to 81.64%. The in vivo studies and the scintigraphy images showed high concentrations of the drug in the mouse brain and higher brain-to-blood ratio [25]. Asenapine nanostructured lipid carriers were developed and studied by Singh et al. It was observed that the particle size was 167.3 nm and the entrapment efficiency reached up to 83.5%. The biodistribution study showed a higher drug concentration peak. As for the behavioural study, it was observed that the intranasal treatment promised a better choice for schizophrenia treatment where the extra-­ pyramidal side effects were reduced and the anti-psychotic effects were increased [26]. Cytokine intereferon-beta-1 b was investigated by Ross et  al. for the nose-to-­ brain delivery. Intranasal administration of cytokine intereferon-beta-1 b showed higher brain concentrations when compared to the intravenous administration [27]. Intranasal rosuvastatin liquid crystalline nanoparticle was developed by Mohammad Zubair Ahmed for the treatment of pentylenetetrazole-induced seizures, increasing current electroshock (ICES) induced seizures, and PTZ-induced status epilepticus. It was observed that intranasal rosuvastatin at lower dose was more effective than the oral and intraperitoneal administration of rosuvastatin. The nanoparticles were developed by hydrotrope method using glyceryl monooleate as the lipid phase. The Transmission electron microscopy revealed that the formed nanoparticles were cubic in shape and multivesicular with a mean size of 219.15  ±  8.14  nm. The entrapment efficiency of 70.30  ±  1.84% was achieved.

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Table 15.3  Different clinical trials investigating the nose-to-brain drug delivery for the treatment of different central nervous system diseases Drug Oxytocin Clonazepam Insulin INSULIN ASPART Oxytocin

Pharmaceutical form Nasal spray, suspension Nasal spray Nasal spray, solution Nasal spray Nasal spray

Medical condition Benzodiazepine withdrawal and craving Recurrent acute repetitive seizures (ARS) Phelan-McDermid syndrome

Clinical trial status Ongoing, 2020

Early Alzheimer’s dementia (eAD) Psychotic disorders

Prematurely Ended, 2015 Completed & Favorable, 2014

Ongoing, 2007 Ongoing, 2012

Intranasal administration of rosuvastatin nanoparticles showed that there was a significant increase in latency to PTZ-induced seizures and ICES seizure threshold compared to control and intranasal rosuvastatin solution [28].

8 Clinical Trials Investigating the Nose-to-Brain Drug Delivery A lot of clinical trials are investigating the treatments of central nervous system diseases by using the nose-to-brain drug delivery. Some of these clinical trials are shown in Table 15.3 according to the EU Clinical Trials Register [29].

9 Recent Clinical Trials of Nanosuspensions Use of ivermectin mucoadhesive nanosuspension as nasal spray was investigated for the management of early covid-19. The clinical trial was completed on February 2021 and as per EMA revision, it was concluded that the available data did not support its use for COVID-19 outside well-designed clinical trials due to the much higher ivermectin concentrations than those achieved with the currently authorized doses [29, 30].

10 Conclusion Intranasal route of administration is a promising route of administration for nose-to-­ brain drug delivery. It has many advantages like non-invasiveness, avoidance of BBB, avoidance of first pass and gastrointestinal degradation, high bioavailability,

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and the direct connection to central nervous system. However, the small surface area, mucociliary clearance, enzymatic degradation, the possibility of nasal toxicity and the poor permeation are the limitations of this route of drug administration. One of the effective solutions to overcome these challenges and limitations of the nasal route of administration is administering nanosuspensions. Nanosuspension can be considered the most suitable formulation choice for hydrophobic drugs which are restricted by molecular weight, high log P, and melting point. Also, nanosuspension method of formulation and preparation is simple and has scope for scaling up. Intranasal nanosuspension is a very attractive choice for the administration of drugs targeting the central nervous system by passing the blood-brain barrier, which makes it an attractive area for investigation by several pharmaceutical companies and researchers.

References 1. Lee D, Minko T. Nanotherapeutics for nose-to-brain drug delivery: an approach to bypass the blood brain barrier. Pharmaceutics [Internet]. 2021 [cited 10 November 2021];13(12):2049. Available from: https://doi.org/10.3390/pharmaceutics13122049. 2. Agrawal Y, Patel V. Nanosuspension: an approach to enhance solubility of drugs. J Adv Pharm Technol Res. 2011;2(2):81. 3. Verma S, Gokhale R, Burgess D. A comparative study of top-down and bottom-up approaches for the preparation of micro/nanosuspensions. Int J Pharm. 2009;380(1–2):216–22. 4. Verma S, Lan Y, Gokhale R, Burgess D.  Quality by design approach to understand the process of nanosuspension preparation. Int J Pharm [Internet]. 2009 [cited 5 December 2021];377(1–2):185–98. Available from: https://doi.org/10.1016/j.ijpharm.2009.05.006. 5. Erdő F, Bors L, Farkas D, Bajza Á, Gizurarson S. Evaluation of intranasal delivery route of drug administration for brain targeting. Brain Res Bull [Internet]. 2018 [cited 7 December 2021];143:155–70. Available from: https://doi.org/10.1016/j.brainresbull.2018.10.009. 6. Cassano R, Servidio C, Trombino S. Biomaterials for drugs nose–brain transport: a new therapeutic approach for neurological diseases. Materials [Internet]. 2021 [cited 10 December 2021];14(7):1802. Available from: https://doi.org/10.3390/ma14071802. 7. Veronesi M. Imaging of intranasal drug delivery to the brain. Am J Nucl Med Mol Imaging. 2020 [PubMed] [cited 4 December 2021];10(1):1–31. Available from: https://www.ncbi.nlm. nih.gov/pmc/articles/PMC7076302/. 8. Crowe TP, Greenlee MHW, Kanthasamy AG, Hsu WH. Mechanism of intranasal drug delivery directly to the brain. Life Sci. 2018;195:44–52. https://doi.org/10.1016/j.lfs.2017.12.025. 9. Hasnain S, Nayak A. Natural polysaccharides in drug delivery and biomedical applications. San Diego: Elsevier Inc.; 2019. p. 2–152. 10. Bhatia S.  Natural polymer drug delivery systems; nanoparticles, plants, and algae. Springer International Publishing Switzerland; 2016. p.  95–118. https://doi. org/10.1007/978-­3-­319-­41129-­3. 11. Sahoo R, Sahoo S, Azizi S. Tamarind seed polysaccharides and their nanocomposites for drug delivery: an economical, eco-friendly and novel approach. MJMS. 2017;2(2):32–40. 12. Shao H, Zhang H, Tian Y, Song Z, Lai PFH, Ai L.  Composition and rheological properties of polysaccharide extracted from tamarind (Tamarindus indica L.) seed. Molecules. 2019;24(7):1218. https://doi.org/10.3390/molecules24071218. 13. Goel S, Sachdeva M, Agarwal V. Nanosuspension technology: recent patents on drug delivery and their characterizations. Recent Pat Drug Deliv Formul. 2019;13(2):91–104.

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14. Piacentini E. Encapsulation efficiency. In: Encyclopedia of membranes; 2016; pp. 706–7. 15. Database.ich.org. 2021. [online] Available at: https://database.ich.org/sites/default/files/ Q1A%28R2%29%20Guideline.pdf. Accessed 12 Feb 2021. 16. Westin U, Piras E, Jansson B, Bergström U, Dahlin M, Brittebo E, Björk E. Transfer of morphine along the olfactory pathway to the central nervous system after nasal administration to rodents. Eur J Pharm Sci. 2005;24:565–73. https://doi.org/10.1016/j.ejps.2005.01.009. 17. Gonçalves VSS, Matias AA, Poejo J, Serra AT, Duarte CMM.  Application of RPMI 2650 as a cell model to evaluate solid formulations for intranasal delivery of drugs. Int J Pharm. 2016;515:1–10. https://doi.org/10.1016/j.ijpharm.2016.09.086. 18. Qian S, He L, Wang Q, Wong YC, Mak M, Ho CY, Han Y, Zuo Z.  Intranasal delivery of a novel acetylcholinesterase inhibitor HLS-3 for treatment of Alzheimer’s disease. Life Sci. 2018;207:428–35. https://doi.org/10.1016/j.lfs.2018.06.032. 19. Dolberg AM, Reichl S.  Expression of P-glycoprotein in excised human nasal mucosa and optimized models of RPMI 2650 cells. Int J Pharm. 2016;508:22–33. https://doi.org/10.1016/j. ijpharm.2016.05.010. 20. Cho HJ, Termsarasab U, Kim JS. In vitro nasal cell culture systems for drug transport studies. J Pharm Investig. 2010;40:321–32. https://doi.org/10.4333/kps.2010.40.6.321. 21. Selvaraj K, Gowthamarajan K, Karri VVSR. Nose to brain transport pathways an overview: potential of nanostructured lipid carriers in nose to brain targeting. Artif Cells Nanomed Biotechnol. 2018;46(8):2088–95. https://doi.org/10.1080/21691401.2017.1420073. 22. Eskandari S, Varshosaz J, Minaiyan M, et  al. Brain delivery of valproic acid via intranasal administration of nanostructured lipid carriers: in  vivo pharmacodynamic studies using rat electroshock model. Int J Nanomedicine. 2011;6:363–71. 23. Alam MI, Baboota S, Ahuja A, Ali M, et al. Intranasal infusion of nanostructured lipid carriers (NLCS) containing CNS acting drug and estimation in brain and blood. Drug Deliv. 2013;20:247–51. 24. Jain K, Sood S, Gowthamarajan K. Optimization of artemether loaded NLCS for intranasal delivery using central composite design. Drug Deliv. 2015;22:940–54. 25. Khan A, Imam SS, Aqil M, et  al. Brain targeting of temozolomide via the intranasal route using lipid-based nanoparticles: brain pharmacokinetic and scintigraphic analyses. Mol Pharm. 2016;13:3773–82. 26. Singh SK, Dadhania P, Vuddanda PR, et al. Intranasal delivery of asenapine loaded nanostructured lipid carriers: formulation, characterization, pharmacokinetic and behavioural assessment. RSC Adv. 2016;6:2032–45. 27. Ross TM.  Intranasal administration of interferon beta bypasses the blood–brain barrier to target the central nervous system and cervical lymph nodes: a non-invasive treatment strategy for multiple sclerosis. J Neuroimmunol. 2004;151(1–2):66–77. https://doi.org/10.1016/j. jneuroim.2004.02.011. 28. Ahmed M, Khan U, Haye A, Agarwal N, Alhakamy N, Alhadrami H, et al. Liquid crystalline nanoparticles for nasal delivery of rosuvastatin: implications on therapeutic efficacy in management of epilepsy. Pharmaceuticals. 2020;13(11):356. 29. EU Clinical Trials Register - Update [Internet]. Clinicaltrialsregistereu. 2022 [cited 9 January 2022]. Available from: https://www.clinicaltrialsregister.eu/. 30. Evaluation of ivermectin mucoadhesive nanosuspension as nasal spray in management of early covid-19 - Full Text View - ClinicalTrials.gov [Internet]. Clinicaltrials.gov. 2022 [cited 9 January 2022]. Available from: https://clinicaltrials.gov/ct2/show/nct04716569.

Chapter 16

Nasal Delivery of Micro and Nano Encapsulated Drugs Muhammad Sarfraz, Sara Mousa, Ranim Al Saoud, and Raimar Löbenberg Abstract  Drug encapsulation in nanoparticles and microparticles has been shown to be a promising application for nasal drug delivery. Drug encapsulation and surface modification of nano and microparticles can enhance drug bioavailability by controlling drug release, decreasing mucociliary clearance, and enzymatic degradation. The drug particle size, the nature of the polymer, and the surface decoration on the polymer play key roles in overcoming the physiological challenges of nasal drug administration. This chapter cites several polymers used to formulate nanoparticles and microparticles for nasal drug delivery. It describes techniques used to modify the surface of polymers to improve physiochemical properties such as swelling, gelling, wetting, mucoadhesiveness, and permeation. Polymer surface modifications can achieve safer drug delivery. Unlike other means of drug delivery, nasal drug delivery can be effective at low concentrations. Several candidates that have demonstrated effective intranasal drug delivery are described. Keywords  Drug encapsulation · Polymers · Surface modification · Drug delivery

1 Introduction The nasal drug delivery approach has conventionally been confined to local or topical acting therapeutic agents that address minor nasal problems. However, in recent years, the nasal route of drug administration has emerged as an alternative to oral and parenteral drug delivery. The therapeutic effects of drugs applied through the nose have some physiological challenges [1]. Enzymatic drug degradation in the nasal mucosa, low drug retention times, mucociliary clearance, poor permeability of nasal mucosa, and nasomucosal toxicity are the factors that limit the application of intranasal drug delivery [1–3]. In contrast, intranasal drug delivery provides M. Sarfraz (*) · S. Mousa · R. Al Saoud College of Pharmacy, Al Ain University, Al Ain Campus, Al Ain, United Arab Emirates e-mail: [email protected] R. Löbenberg Faculty of Pharmacy and Pharmaceutical Sciences, Katz Centre for Pharmacy & Health Research, University of Alberta, Edmonton, AB, Canada © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_16

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enhanced patient compliance and offers a greater potential for targeted drug delivery, a faster onset of drug action, and accessibility to the central nervous system (circumventing the first pass effect). These advantages make the nose an attractive route for drug administration [1, 3]. The nose is a complex organ designed to provide filtered respiration, a sense of smell, and protection against environmental threats [4]. Drug delivery formulations must meet the challenging task of avoiding the disruption of these complex functions while providing the necessary medication. The response of ciliated cells exposed to a nasal drug formulation can provide a test for functional disruption. A dose at which the cilia continue to beat, i.e., ciliary beat frequency (CBF), at a constant rate and the ciliated cells are not affected by the drug or formulation is considered to be a compatible dose. Disruptions of ciliary function by altering the beat frequency or by increasing exfoliation have a negative impact on the body’s immune system and can lead to mucosal irritation [5]. The status of cilia can be determined by the in vitro cilia beat frequency or it can be measured with a confocal laser scanning microscope or an electron microscope [6]. The presence of mucosal irritation is another indicator of bio-incompatibility. In large species, such as a beagle dog, mucosal irritation can be observed visually [7]. In smaller species, the visualization of mucosal irritation is difficult, so histopathological methods must be utilized [8]. To overcome some of these physiological challenges, researchers use absorption enhancers in nasal formulations and study its influence on mucosal irritation, enzymatic activity, and to clear nasal passages [9]. Absorption enhancers facilitate the transport of the drug through the nasal epithelium and lower the effective drug exposure. As absorption enhancement can change the optimal drug exposure, judicious adjustments are required [9]. Other researchers have tried to use the appropriate mucoadhesive systems—such as hydrogel [10], viscous formulations [11], mucoadhesive polymers [12], in situ gelling [13]—that can improve the drug retention time and decrease mucociliary clearance. Drug encapsulation into a nanoparticle system is a precaution that must be taken to prevent enzymatic degradation [14, 15]. However, the clinical success of intranasal therapy is limited by the dose provided and the frequency of dosing. The characteristics of a drug and its excipient (an inactive substance that serves as a vehicle or medium for a drug) need to be taken into account. Direct delivery to the delicate nasal epithelium of non-biocompatible, unprotected drugs, and certain excipients like preservatives can upset the nasal homeostasis and result in nasal irritation. Drug formulations must be compatible with nasal physiology if the nasal route of administration is to be used successfully. In contrast to other routes of drug administration, the nasal cavity permits a limited amount (25–200 μL) [15] of drug in a single dose per nostril. Therefore, only the use of potent drugs is favored for intranasal drug delivery. Drug excipients should be biocompatible and odor and taste-free to enhance patient compliance [16]. As the drug is absorbed primarily in the nasal mucosa, pH, viscosity, and tonicity must also be considered in intranasal formulations [10]. If the challenges described above can be overcome, the intranasal route can provide remarkable advantages over oral and parenteral routes of drug administration.

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This chapter briefly describes different procedures used to develop effective and successful intranasal drug delivery with the help of micro and nanoparticulate systems. At present, several drugs are being investigated and clinically developed for intranasal delivery. Intranasal drug delivery is a promising approach to treat central nervous system (CNS) diseases because of its potential to deliver drugs across the blood-brain barrier (BBB).

2 Polymers Used to Encapsulate Drugs Nasal drug formulations can be encapsulated in micro or nano particles. The size of the drug particles plays an important role, as it influences the interaction and transport of particles across mucosal surfaces. Studies have shown that a particle size of 10 μm deposited in front of the nose, moreover the particle size of 1 μm can efficiently cross intra-mucosal barriers [17]. To target the blood-brain barrier (BBB) using the nasal drug delivery system, the particle size should be less than 100 nm [18]. The surface of drug particles—the surface charge and the hydrophobic or hydrophilic nature of the particle surface—affects their interactions with the biological environment. By encapsulating the drug with a polymer, we can control the drug release from the polymer and achieve a low concentration of the drug in the nasal epithelium, which eventually leads to a biocompatible formulation. The slow release of the drug and the use of absorption enhancers prevent the exposure of mucosal epithelial cells in the nasal cavity to a high concentration of the drug, as the drug is absorbed quickly as soon as it is released from the formulation. Biodegradable and biocompatible polymers that have been used extensively in nano and micro encapsulations of drugs for nasal drug delivery include chitosan and poly(lactic-co-­ glycolic acid) (PLGA).

3 Chitosan Widder and his colleagues first reported chitosan micro-particles in 1983 [19]. Chitosan is a non-toxic natural polymer made of alkaline polysaccharides; it is the second most abundant natural polysaccharide (cellulose is the most abundant natural polysaccharide) [20]. Chitosan’s properties of mucoadhesion, biodegradability, and biocompatibility make it a good candidate for nano and micro encapsulations of a wide range of nasal formulations of different drugs (Table 16.1) [21]. The positive charge of an amino acid group on chitosan interacts with a negative charge on a sialic acid in the mucous membrane in the nose, and their coupling enables a mucoadhesion for a prolonged time in the nasal cavity. This coupling can also interfere with mucociliary clearance and increase the residence time of drug [22–24]. Extensive toxicity studies have concluded that chitosan is safe in nano-­ formulations using various routes of administration [25, 26]. Attempts to modify the

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Table 16.1  Drugs encapsulated in chitosan nano and microparticles with or without surface modification for intranasal delivery Drugs Carbamazepine Rasagiline Desvenlafaxine Simvastatin Estradiol

Donepezil

Particle size 216–221 nm 153 nm 151.5 nm 200 nm 237.7– 300.9 nm 170–334 nm 224.18– 229.22 nm 212.84– 234.98 nm 410.4–467 nm

Terbutaline sulphate Cetirizine

345.5 nm 120 nm

Leuprolide Buspirone Duloxetine

Fexofenadine Risperidone

716 nm 86 nm and 132.7 nm Quetiapine fumarate 131.08 nm Selegiline 341–502 nm Rotigotine 75.37 nm Methotrexate 189 nm Bromocriptine 149.8– 164.1 nm Pramipexole dihydrochloride 292.5 nm Midazolam 144.99– 149.41 nm Catechin hydrate 93.46 nm Eugenol 224.5 nm Alpha-cyano-4-hydroxycinnamic 213–875 nm acid and cetuximab Tapentadol hydrochloride 199.7– 202.7 nm

Chitosan polymer modification strategies Carboxymethyl chitosan Chitosan glutamate PLGA/Chitosan Lecithin/chitosan Thiolated-chitosan

References [29] [30] [59] [54] [60]

Thiolated-chitosan Thiolated Chitosan

[48] [33]

Proniosomes of thiolated chitosan Liposomes dispersed into thiolated chitosan hydrogel. Lipid-chitosan hybrid Deoxycholate-chitosan-­ hydroxybutyl nanoparticles pH/thermo-responsive Chitosan-coated liposome

[34] [35] [53] [31]

[51] [36, 37] [39] [40] [41, 42] [43] [44] [45] [49] [50] [57] [36] [46]

chitosan polymer to improve its physiochemical properties, control drug release, inhibit its enzymatic degradation, and prevent its toxicological effect are outlined in the following sections.

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4 Chitosan Surface Modifications 4.1 Carboxymethyl Chitosan (CMC) Chitosan is soluble only in acidic medium, below pH  6.5 [27]. Chemical modifications such as quaternization or the introduction of hydrophilic or carboxyalkyl groups can enhance the solubility of chitosan. Carboxymethyl chitosan (CMC) is one of the most studied chemically modified derivatives, and it is easy to synthesize [28]. In an intranasal formulation, carbamazepine, an antiepileptic drug, can be loaded in CMC nanoparticles to enhance its bioavailability and enable easy and quick administration in emergencies; than conventional formulation [29].

4.2 Glutamate Chitosan Chitosan nanoparticles administered intranasally can absorb water from the mucus present in the nasal mucosa, drying the nasal passages and causing discomfort. In an attempt to improve the in  vitro dissolution rate of chitosan, chitosan glutamate nanoparticles were synthesized and loaded with rasagiline to enhance the wetting effect. The results showed that glutamate nanoparticles have a better wetting effect, decreased particle size, and enhanced bioavailability [30].

4.3 Deoxycholate-Chitosan-Hydroxybutyl Nanoparticles Chemical modifications of chitosan can promote stimuli-responsive derivatives. Deoxycholate-chitosan-hydroxybutyl nanoparticles were tested for thermo and pH-­ responsive behaviors. This system promotes quick action with a prolonged release time upon hydrolysis of the chitosan backbone [31].

4.4 Thiolated Chitosan Thiolated chitosan offers further enhanced bioadhesive properties via the formation of a covalent bond—disulfide bond—between the thiol on chitosan and the mucus, which is rich in cysteine, in the nose. Thiolated chitosan has gelling features in situ that can strengthen the stability and cohesion of the carrier. In addition to their ability to open tight junctions, thiolated polymers inhibit enzymatic activity by chelating metals essential for their activity. Thiolated polymers do not disturb the ciliary beat frequency (CBF), thus, they have no toxicological effect [32]. When buspirone

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hydrochloride was added to thiolated chitosan, a biphasic drug release was observed, starting with a burst release followed by a sustained release for 24 h [33]. Thiolated chitosan was also incorporated with other nanoformulations to enhance their properties in nasal delivery. Proniosomes of duloxetine were formulated in thiolated chitosan in a gel form that promoted the sustained release of the drug in the nose, enhancing the mucoadhesion and permeation of the drug by over 1.86 times compared to proniosomes only, and providing an optimal particle size and a high drug loading efficiency [34]. Dispersing donepezil liposomes in thiolated chitosan hydrogel increased the content of the drug in the brain up to 107% compared to oral delivery [35].

4.5 Deacetylated Chitosan The positively charged surface of chitosan enables its compartmentalization and conjugation with different molecules, conferring a targeting effect. Chitosan oligosaccharide is a shorter and deacetylated chain of chitosan. This derivative offers higher solubility and lower viscosity than chitosan. The higher conjugation capacity of chitosan oligosaccharide was proposed to act as a targeting ligand for encapsulated drugs. Alpha-cyano-4-hydroxycinnamic acid was encapsulated in chitosan oligosaccharide nanoparticles when the chitosan oligosaccharide surface contained the covalently conjugated monoclonal antibody cetuximab as targeting ligand. This delivery system provided a nose-to-brain delivery that has significantly reduced the cytotoxicity and antiangiogenic effects of the drug in patients with glioblastoma [36].

5 Drug Encapsulation with Chitosan Derivatives The nasal delivery system has been widely used to enhance the bioavailability of a wide range of drugs. Chitosan is an attractive candidate for nasal delivery as compared to conventional formulations. The conventional formulations of chitosan lack the ability to deliver the required amount of drug to the brain due to multiple challenges. Table 16.1 shows drugs that are encapsulated in chitosan to overcome different challenges.

5.1 Risperidone The extensive first pass metabolism and the lipophilicity of risperidone make it an attractive drug candidate for researchers to encapsulate risperidone using chitosan. Risperidone-loaded chitosan nanoparticles were delivered with a higher yield than

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risperidone alone [37]. Risperidone encapsulated in chitosan nanoparticles had a particle size of 86 nm, when formulated by ionic gelation method using poloxamer 188 as a stabilizer. Risperidone-loaded chitosan nanoparticles had better pharmacokinetic and pharmacodynamic properties than risperidone alone [37]. Moreover, risperidone loaded in lipid-based chitosan nanoparticle escapes mucociliary clearance due to its bioadhesive properties [38].

5.2 Quetiapine Fumarate The Box-Behnken experimental design was developed to encapsulate quetiapine fumarate in chitosan nanoparticles; this increased its bioavailability around two-­ fold and conferred a prolonged retention time [39]. Pharmacokinetic studies showed a high brain-targeting efficiency. These advantages resulted from chitosan’s ability to pass through tight junctions, which increased its brain-targeting delivery via the intranasal route [39].

5.3 Selegiline Selegiline, a medication used for Parkinson’s disease, showed optimized bioavailability with in vitro and ex-vivo studies. In addition, when formulated in chitosan nanoparticles, selegiline offered more than 90% drug loading [40]. Compared to oral administration, selegiline concentrations increased around 20-fold in the brain and 12-fold in the plasma after the intranasal administration of selegiline in chitosan nanoparticles.

5.4 Rotigotine The 1% bioavailability of rotigotine limits its physiological effectiveness. Intranasal approaches using rotigotine formulated in chitosan nanoparticles showed promising in vivo results [41], which were further confirmed by the results on cell lines and in animal models. Pharmacokinetic studies suggest that the intranasal route is the best route for direct transport of rotigotine to the brain [42].

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5.5 Methotrexate Encapsulations of drugs in chitosan-based formulations enhance their bioavailability through their high drug loading efficiencies. Methotrexate-loaded chitosan-­based hydrogel nanoparticles resulted in a drug-loading efficiency of 72.03 ± 0.85% and produced a significantly higher brain concentration of methotrexate compared with simple solution [43].

5.6 Bromocriptine Encapsulation of bromocriptine in chitosan-based formulations to treat Parkinson’s disease achieved 84.2% ± 3.5% drug loading efficiency [44]. Moreover, pramipexole dihydrochloride-loaded chitosan nanoparticles showed a drug-loading efficiency up to 91 ± 0.95%, with adequate particle size and better in vivo activity compared to the conventional formulation [45].

5.7 Tapentadol Hydrochloride Nasal delivery is a promising approach for centrally-acting analgesics that are quickly metabolized. Tapentadol hydrochloride acts centrally with a half-life of 4 h; it requires frequent administration because it is extensively metabolized into inactive moieties that are rapidly eliminated, and its hydrophilic nature decreases its concentration in the central nervous system (CNS). Nasal delivery of tapentadol hydrochloride encapsulated in chitosan nanoparticles provided a quick onset of drug action, increased the time of tapentadol bioavailability compared to the intravenous route, and avoided the bitter taste associated with oral formulations [46].

5.8 Estradiol A significant increase in hormonal drug bioavailability was achieved when the drugs were loaded onto chitosan nanoparticles and administered nasally. Estradiol loaded into chitosan nanoparticles and delivered nasally achieved higher plasma and tissue concentrations than corresponding oral formulations. Leuprolide loaded onto thiolated chitosan demonstrated a —two to five fold enhanced bioavailability and a prolonged half-life [47, 48].

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5.9 Midazolam Midazolam loaded onto chitosan nanoparticles and administered intranasally was superior in brain-targeting efficiency to a midazolam solution (IV) formulation, offering a non-invasive approach to treat life-threatening seizures in status epilepticus [49].

5.10 Catechin Hydrate Catechin hydrate was formulated in chitosan nanoparticles to test its anticonvulsant effect. This formulation delivered promising in  vivo results for the treatment of epilepsy as a result of its enhanced nose-to-brain delivery and a sustained release of over 24 h [50].

5.11 Fexofenadine Allergic rhinitis was treated with fexofenadine in liposomes coated with chitosan and administered nasally. There were few systemic side effects, and the formulation offered a prolonged release of the drug that can reduce the dosing frequency [51].

5.12 Astragalus Polysaccharides Encapsulation of astragalus polysaccharides (APS) as microspheres in chitosan provided a local extended release in the nasal delivery of the anti-inflammatory drug for severe asthma, and alleviated allergic symptoms over an extended period [52].

6 Drug Encapsulation with a Lipid Polymer Hybrid 6.1 Terbutaline Sulphate Terbutaline sulphate, a drug used to relieve bronchial asthma, was hybridized with chitosan, a linear polymer saccharide, to enhance the mucoadhesive properties of the drug’s formulation. The hybrid was formulated as a phospholipid coated with chitosan/pectin (CS/PC) nanoparticles which offer a prolonged residence time [53].

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6.2 Simvastatin Simvastatin-loaded lecithin/chitosan nanoparticles were prepared in an attempt to develop a new formulation for statins that would promote their use in neuro-­ degradative diseases. Conventional formulations of statins do not guarantee the delivery of the drug to the brain [54].

6.3 Lorazepam A benzodiazepine derivative used for status epileptics, lorazepam was encapsulated with a chitosan polymer to offer safer, more effective, and more convenient delivery, especially for children. Microspherical hydrogels made of chitosan and pluronic moieties and loaded with lorazepam offered thermo-sensitive properties. They become viscous at 37 °C, allowing the microspheres to disperse before instillation. This approach showed a sustained release over 24  h. Further in  vivo studies are needed to establish the efficacy of this formulation and its superiority over conventional formulations [55].

7 Vaccine Encapsulation with Chitosan Derivatives Recently, the nasal delivery of vaccines has attracted the attention of many research groups. Polymeric nanoparticles have been investigated as carriers for different antigens. Besides the advantages of chitosan and its water-soluble derivative, trimethyl chitosan (TMC), as carriers, they could act as adjuvants, making this class a polymer of choice. In an attempt to study nasal polymeric vaccines, inactivated PR8 influenza virus was loaded into trimethyl chitosan (TMC) nanoparticles and coated chitosan (CHT) nanoparticles respectively. Both TMC and CHT nanoparticles were coated with sodium alginate (ALG) to study immune-stimulation potential after intranasal administration. PR8-TMC-ALG formulation showed significantly higher immunostimulatory response, compared with PR8-CHT-ALG and PR8 virus alone [56].

8 Drug Encapsulation with Co-polymers 8.1 Eugenol Many reports indicate that eugenol is effective in the treatment of cerebral ischemia. However, eugenol is volatile and susceptible to oxidation, which affects its stability and contributes to its low bioavailability. To address these issues, eugenol was encapsulated in nanoparticles and administered intranasally to improve its

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bioavailability. Chitosan-coated poly(ε-caprolactone) nanoparticles loaded with eugenol were prepared. The encapsulation of eugenol in chitosan increased the drug concentration in the brain through chitosan mucoadhesive properties [57].

8.2 Ropinirole Ropinirole is used to treat individuals with Parkinson’s disease. In an attempt to improve the permeation of ropinirole hydrochloride through the nasal route of administration, trimethyl chitosan was co-formulated with dipalmitoylphosphatidylcholine and poly(lactic-co-glycolic acid) (PLGA) as a penetration enhancer. This mixture has been shown to enhance ex vivo nasal drug permeation by 2.35 fold compared to the 50% bioavailability of the oral form [58].

8.3 Desvenlafaxine Succinate Desvenlafaxine succinate was an antidepressant drug and attempts were made to encapsulate it in copolymer and determine its intranasal potential. Desvenlafaxine (DVF) was loaded in PLGA/chitosan nanoparticles and evaluated for in vitro and in vivo studies. In vitro results showed a biphasic release pattern with 30% (pH 7.4) and 34% (pH 6.0) drug release within 1 h which may be due to the DVF attached to the surface of the nanoparticle, followed by characteristic sustained release for more than 24 h that may be due to swelling and hydration PLGA/Chitosan nanoparticles from the core matrix. In vivo results in rodents’ models demonstrate that DVF loaded PLGA/Chitosan nanoparticles administered intranasally had higher drug concentration in brain (954.56 ± 126.63 ng/ml) in comparison with the IV administration (396.91 ± 64.34 ng/ml) [59].

9 Poly (Lactic-Co-Glycolic Acid): PLGA The first report concerning poly lactic acid (PLA) biocompatibility and biodegradability was published in 1966. Afterward, polyglycolic acid (PGA) was discovered. PLA was formulated in long-acting microparticle formulations due to its slow rate of degradation. Unlike PLA, PGA was not formulated in microparticle formulations because of its fast degradation rate and its high hydrophilicity. As a result, poly lactic co-glycolic acid (PLGA) was synthesized from PLA and PGA to develop a customizable polymer. PLGA can be customized based on the PLA:PGA ratio used to synthesize it. The PLA:PGA ratio will control whether the rate of degradation is fast or slow, and it will control the lipophilicity/hydrophilicity ratio, because PLA is lipophilic whereas PGA is hydrophilic. Moreover, the crystallinity

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of PLGA depends on the lactic acid isomers that are used. For instance, the enantiomers of lactic acid are semi-crystalline but the racemic mixture is amorphous. Since the amorphous polymers provide a homogenous dispersion of the active ingredient used, the D,L-PLGA is preferred [61]. PLGA is synthesized through ring-opening polymerization to produce a high molecular weight copolymer. It is a useful copolymer due to its biodegradability and biocompatibility. Variations in the ratio of lactic acid to glycolic acid affect the melting point, the solubility, and the glass transition temperature [62]. Mainly, PLGA is degraded in vivo by hydrolysis, but enzymatic degradation could take place due to the presence of ester bonds. Hydrolytic degradation can occur through surface degradation and bulk degradation, with or without autocatalysis. Polymer degradation can be detected by measuring changes in the molecular weight of the polymer or by evaluating changes in the physical properties of the polymer [63]. The degradation of PLGA is influenced by factors such as the PLA:PGA ratio, the hydration rate of the polymer, the crystallinity of the polymer, and the pH of the environment [64, 65]. Due to the properties of PLGA, it is widely used to form nanoparticles (NPs) [66]. PLGA NPs can be prepared using nanoprecipitation, double-emulsion solvent evaporation, and phase separation technique [67–69]. Because PLGA NPs can be used in passive or active transport to cross the blood-brain barrier, they are of great interest in the intranasal delivery of drugs targeting the brain. However, low brain uptake was observed with the passive transport of PLGA NPs. Active transport of PLGA NPs is mediated through carrier transport, adsorption, or receptor mediated transcytosis. The mode of active transport depends on the type of modification performed on the PLGA NPs. When PLGA NPs are modified with membrane permeable molecules, these molecules are transported with the PLGA NPs across the blood-brain barrier (BBB). When the surface of the PLGA NPs is modified with positively charged molecules, the positively charged molecules are adsorbed on the negatively charged surface of the neurons, resulting in cell endocytosis. Modifications of PLGA NPs using ligands specific to blood-brain barrier cell surface receptors enable the transportation of PLGA NPs into neurons through receptor-mediated transcytosis [70]. The use of PLGA NPs in intranasal formulations enhances the drug targeting efficiency (%DTE). For instance, an intranasal formulation of PLGA NPs was found to have a drug targeting efficiency of 129.81% [68]. PLGA NPs administered intranasally provide a prolonged duration of drug release in comparison to intravenous administration [67, 68, 71].

10 PLGA Surface Modifications 10.1 Pegylation To increase the penetrating ability and stability of NPs in mucus, their surface is coated with polyethylene glycol (PEG). The PEG coating prevents the charges on the surface of the NPs from forming hydrophobic or electrostatic interactions;

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consequently, mucoadhesion is decreased [72]. Specific physicochemical properties, such as low molecular weight PEG, must be met to promote the formation of a dense PEG coating [73]. Another study demonstrated that a PEG coating improved the retentivity of an intranasal formulation [74].

10.2 Lactoferrin The modification of PLGA nanoparticles with lactoferrin is useful due to the overexpression of lactoferrin receptors on the surface of respiratory epithelial cells, neurons, and capillaries in neurodegenerative diseases [74, 75]. To provide targeted brain delivery through intranasal administration, a research group successfully formulated PEG-PLGA nanoparticles modified with lactoferrin. The formulation exhibited small particle size, narrow size distribution, low cytotoxicity, and enhanced cellular accumulation due to lactoferrin [74]. PLGA nanoparticles co-modified with lactoferrin and N-trimethyl chitosan (TMC) were formulated. Chitosan was modified to TMC by reductive methylation to enhance its solubility and adhesion. The modification resulted in better cellular uptake when compared with PLGA nanoparticles. Also, a higher brain distribution was observed over a longer period of time [75]. In another study, PLGA NPs modified with lactoferrin and folic acid increased the blood-brain barrier permeability coefficient by two-fold [76].

10.3 Peptides 10.3.1 RVG29 RVG29, an amino acid derived from the rabies virus, was reported to enhance the accumulation of PEG-PLGA nanoparticles in the brain. RVG29 is attached to the surface of PLGA NPs through avidin-biotin interactions [75]. The RVG29 modified PEG-PLGA NPs exhibited higher brain distribution than unmodified PEG-PLGA [76]. In another study, RVG29 modified PEG-PLGA NPs targeted specific tissues near the trigeminal nerves [75]. 10.3.2 Octa-Arginine Octa-arginine, a cell-penetrating peptide, can increase CaCO2 cellular uptake and cell permeability when conjugated on the surface of PLGA NPs. Also, conjugation of a 12 amino acid peptide denoted by (Pep TGN i.e., bacteriophage clone for brain-­ targeted delivery) with PEG-PLGA NPs results in a two to three-fold increase in brain accumulation. PLGA NPs modified with octa-arginine can be prepared using the solvent evaporation technique. Intranasal administration of the formulation

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leads to a high cellular uptake and a high rate and extent of drug delivery. It is important to mention that the zeta potential increases due to the neutralizing interaction between the positive charge of octa-arginine and negative charges of carboxylic acid groups on the NP surfaces. Due to the hydrophilicity of octa-arginine, the enhanced wetting results in a higher burst release of the drug from the formulation. Octa-arginine modified PLGA NPs are thought to be transported through receptor-­ mediated mechanisms [77]. 10.3.3 RGD Tripeptide The RGD (Arg-Gly-Asp) tripeptide can be used as a surface modification to target cancer cells. PLGA NPs modified with the RGD (Arg-Gly-Asp) tripeptide decrease enzymatic degradation and provide higher drug targeting ability. Administering the formulation intranasally controls cancer growth and provides a localized effect, thus, it is a promising formulation to target brain diseases [78]. PLGA NPs modified with RGD were well distributed in a tumor location; their presence was accompanied by an increased inhibition of tumor cells and a higher reduction in tumor volume [69]. 10.3.4 Lectins Odorranalectin (OL), the smallest lectin discovered, has low toxicity and low immunogenicity. OL can help nanoparticles to avoid cilia clearance and enzymatic degradation, and can improve membrane permeability through binding to highly selective glycosylated receptors expressed on the nasal mucosa. OL is attached to PEG-­PLGA NPs through an interaction between the thiol group in OL and the maleimide group in PEG-PLGA. OL PEG-PLGA NPs have some toxic effects on the cilia, but no cytotoxicity was observed in intranasal administrations [79]. This modification can enhance cellular uptake, prolong the mean residence time of the drug, and increase the bioavailability of drug-loaded nanoparticles [79].

10.4 Monoclonal Antibodies Monoclonal antibodies can be used to modify the surface of nanoparticles (NPs). The anti-EPHA3 (Ephrin Type A Receptor 3) monoclonal antibody was utilized as a surface ligand in an intranasal formulation to enhance the targeting of glioblastoma multiforme. Anti-EPHA3 was attached to the nanoparticle surface by thiolation to interact with the maleimide in trimethyl chitosan (TMC). The modification is safe and provides high cellular uptake and efficient targeting. A comparison between intranasal and intravenous administrations revealed that intranasal administration delivered more drug to the brain than intravenous administration. In vivo evaluation of the antiglioma activity indicated a significant increase in apoptotic glioma cells [80].

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11 Drug Encapsulation with PLGA Derivatives 11.1 Lamotrigine To provide a targeted and prolonged drug delivery method for lamotrigine, PLGA nanoparticles encapsulating lamotrigine were prepared through a modified nanoprecipitation method. The formulation increased the accumulation of the drug in the brain at levels higher than the levels observed in intravenous administration. The formulation followed the Korsmeyer Peppas model, in which the drug release from the formulation is due to the initial swelling of the polymer followed by a gradual drug release from the matrix [68].

11.2 Haloperidol Intranasal administration of haloperidol enhanced the efficacy of this antipsychotic drug which is used to treat schizophrenia. Haloperidol was encapsulated in PEG-­ PLGA nanoparticles coated with Solanum tuberosum lectin (STL). The emulsion/ solvent evaporation technique was successful at producing Haloperidol-STL-PEG-­ PLGA nanoparticles with a high entrapment efficiency (EE) of 73–85%. The drug reached the brain at higher concentrations when administered intranasally in comparison to other routes of administration. Haloperidol loaded in STL-PEG-PLGA nanoparticles showed a positive response at a lower dose than unencapsulated haloperidol. The observed result is attributed to the selective binding of STL, which improved nasal cellular uptake [81].

11.3 Oxcarbazepine The first line treatment for focal seizures is the lipophilic drug oxcarbazepine. The free drug is effective when administered intranasally, but it requires frequent dosing. To decrease the number of doses, increase brain targeting, and prolong the drug’s effect, the drug was loaded in PLGA nanoparticles for intranasal administration. The PLGA nanoparticles provided a neuroprotective effect for a period of 16 days and more than 24-h decrease in dosing frequency. The formulation provided epileptic patients with prolonged protection against seizures [82]. Other drugs formulated for intranasal delivery include rotigotine (an enantioselective dopamine agonist), huperzine A, lamotrigine, lorazepam, curcumin (a hydrophobic drug with low oral bioavailability), doxorubicin, paclitaxel, and temozolomide. Table 16.2 contains a list of drugs encapsulated with PLGA derivatives to overcome uptake and therapeutic barriers.

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Table 16.2  Drugs encapsulated in PLGA-based nano and microparticles with surface modification for intranasal delivery Drug Rotigotine Huperzine A

Particle size 122 nm 153 nm

miR-124 Loperamide Curcumin Doxorubicin Temozolomide

204 nm 328 nm 97.1 nm 180–200 nm 145.9 nm

Haloperidol Oxcarbazepine

121 nm 256.15 nm

PLGA polymer modification strategies Lactoferrin Lactoferrin N-Trimethyl chitosan (TMC) RVG29 Octa-arginine (R8) Odorranalectin RGD tripeptide Anti-EPHA3 monoclonal antibody Trimethylated Chitosan (TMC) PEG and lectin

References [83] [84] [76] [77] [79] [78] [80] [81] [82]

12 Other Polymers Used for Intranasal Delivery 12.1 Polycaprolactone Polymers To extend its half-life and to protect it from oxidation, melatonin was formulated in polycaprolactone-based nanoparticles for intranasal delivery to treat glioblastoma. This formulation enabled a direct transport into the brain. Interestingly, the solubility of melatonin was increased ≈35-fold and its antitumor effect was demonstrated at very low doses of the formulation. These advantages were attributed to a controlled drug release over time and a high cellular uptake [85]. Carboplatin was encapsulated in polycaprolactone-based nanoparticles to treat glioblastoma. In situ nasal perfusion studies showed a better absorption of carboplatin and in vitro studies revealed a promising carboplatin antitumor effect [17]. In another study, to stabilize and enhance the mucoadhesion properties of polycaprolactone, an amphiphilic methacrylic copolymer composed of methyl methacrylate (MMA) and 2-(dimethylamino)ethyl methacrylate (DMAEMA) was synthesized, and an emulsifier was added to olanzapine polycaprolactone-based nanoparticles. This combination produced a pH-sensitive cationic coating that offered controlled release and an increased olanzapine concentration in the brain. In vivo studies strongly suggest that this formulation offers a safe and effective nose-to-brain delivery [86].

12.2 Cellulose Derivatives Cellulose derivatives are biocompatible in general. They are easily formulated and provide a cost-effective choice for nasal delivery. Several studies noted that hydroxypropyl methylcellulose (HPMC)-based microspheres delivered nasally offered a rapid onset of action, mainly due to the low viscosity of HPMC. The encapsulation of tramadol in HMPC-based microspheres provided a quick onset of action; in vitro drug release was 94% after 90 min [87].

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Table 16.3  Drugs encapsulated in polymer as nano and microparticles for intranasal delivery Drug Olanzapine Melatonin Carboplatin Tramadol Valsartan Ropinirole HCL

Particle size 327–469 nm 100–400 nm 306.9–316.3 nm 12–18 μm 10–22 μm 2.35 μm

Polymer Polycaprolactone Polycaprolactone Polycaprolactone HPMC HPMC Sodium Alginate

References [86] [85] [17] [87] [88] [89]

Valsartan formulated as HPMC-based microspheres provided a quick onset of action. Animal models showed that nasal delivery enhanced activity compared to oral formulations. Further studies are needed to establish whether hypertension can be managed by drugs delivered through the intranasal route [88].

12.3 Alginate Derivatives Ropinirole hydrochloride, an anti-Parkinson drug, was encapsulated in sodium alginate microparticles by spray drying for nasal delivery. The formulation had no toxic effect on the nasal mucosa and provided a rapid drug release. It is important to mention that the drug:polymer ratio affects the time and quantity of drug release from the formulation [89]. Table 16.3 lists a number of drugs that are encapsulated in a polymer to overcome different nasal delivery challenges.

13  Conclusion Intranasal drug administration is a non-invasive technique to deliver small drug molecules and biologicals to the central nervous system. Successful intranasal formulations require appropriate adjuvants to enhance drug absorption and decrease mucociliary clearance. To augment drug bioavailability, a drug can be encapsulated in nanoparticles. Polymeric encapsulation with chitosan, PLGA, and their derivatives helps to control drug release; encapsulation decreases enzymatic drug degradation and increases cellular uptake. This might enable low drug concentrations to be more effective compared to other routes of administration.

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Chapter 17

Different Strategies for Nose-to-Brain Delivery of Small Molecules Smita P. Borkar and Abhay Raizaday

Abstract  The intranasal (IN) route of drug administration has emerged as an alternative route over the systemic (oral and parenteral) drug delivery to the brain. The intranasal route of drug administration exhibits as a non-invasive technique to bypass the BBB for the delivery of drugs inside the brain and the CNS.  This method is helpful for those drugs that are unable to invade the BBB to show its action in the CNS and thus erase the demand of systemic delivery and shrink systemic side effects. Drug delivery from the nose to the brain/CNS takes very less time through both olfactory and trigeminal nerves. Intranasal delivery does not require the involvement of any receptor as it occurs through an extracellular route. The delivery of the drug via an IN route offers various advantages over a systemic drug delivery system as it directly delivers the drug into the brain via the olfactory route. The presence of drugs in the olfactory bulb, in turn, increases the drug bioavailability in the brain and reduces degradation as well as wastage of the drug through systemic clearance. However, there are some limitations associated with IN like poor drug permeation through the nasal mucosa and mucociliary clearance. There are many novel drug delivery strategies (nano-drug carrier system, colloidal carriers, mucoadhesive devices, controlled delivery system, pro-drug, etc.) are adapted to overcome the above-stated limitations. Nose-to-brain delivery also involves nasal-associated lymphatic tissues (NALT) and deep cervical lymph nodes. This review focuses on different strategies for nose-to-brain delivery of small molecules. Keywords  Intranasal delivery · Systemic delivery through nasal passage · Nano drug delivery for quick absorption · Mucoadhesive drug delivery for nasal passage

S. P. Borkar College of Pharmacy, JSS Academy of Technical Education, Noida, Uttar Pradesh, India Arvind Gavali College of Pharmacy, Jaitapur, Satara, Maharashtra, India A. Raizaday (*) College of Pharmacy, JSS Academy of Technical Education, Noida, Uttar Pradesh, India © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4_17

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1 Introduction Intranasal drug delivery is emerging as a reliable and promising pathway to deliver a wide range of therapeutic agents, including small and large molecules, peptides and proteins, and genes to the central nervous system for the treatment of brain diseases such as Alzheimer’s disease, Parkinson’s disease, depression, migraine, schizophrenia, and glioma. This presents non-invasive entry into the brain via direct nose-to-brain and/or indirect nose-to-blood-to-brain routes. The nasal mucosa was seen as a potential route of administration to achieve a faster and higher level of drug absorption as it is permeable to more compounds than the gastrointestinal tract. In recent years, many drugs have been shown to achieve better systemic bioavailability via the nasal route than when administered orally. The unique relationship between nasal cavity and cranial cavity tissues in anatomy and physiology makes intranasal delivery to the brain feasible. Intranasal delivery provides some drugs with short channels to bypass the blood-brain barrier (BBB), especially for those with fairly low brain concentrations after a routine delivery, thus greatly enhancing the therapeutic effect on brain diseases. In the past two decades, a good number of encouraging outcomes have been reported in the treatment of diseases of the brain or the central nervous system (CNS) through nasal administration. In spite of the significant merit of bypassing the BBB, direct nose-­ to-­brain delivery still bears the problems of low efficiency and volume for capacity due to the limited volume of the nasal cavity, the small area ratio of olfactory mucosa to nasal mucosa and the limitations of low dose and short retention time of drug absorption. It is crucial that selective distribution and retention time of drugs or preparations on olfactory mucosa should be enhanced so as to increase the direct delivery efficiency. Several nanocarrier-based strategies have been developed to transport therapeutic agents to the brain, including nanoparticles, liposomes, and exosomes following intranasal delivery. However, the multiple barriers in nose-to-brain route - including rapid mucociliary clearance in the nasal cavity, enzyme degradation, and the blood-­ brain barrier (BBB) - pose serious challenges to brain-targeted drug delivery. The potential for treatment possibilities with intranasal transfer of drugs will increase with the development of more effective formulations and delivery devices.

2 Mechanism of Nasal Absorption Several mechanisms have been proposed for absorption of drugs through the nasal route, 1. The first mechanism involves an aqueous route of transport, which is also known as the paracellular route. This route is slow and passive. There is an inverse log– log correlation between intranasal absorption and the molecular weight of water soluble compounds. Poor bioavailability was observed for drugs with a molecular weight greater than 1000 Daltons.

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2. The second mechanism, which involves transport through a lipoidal route, is also known as the transcellular process and is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity. 3. Drugs also cross the cell membranes by an active transport route via carrier-­ mediated means or transport through the openings of tight junctions.

3 Strategies for Improving Nasal Drug Delivery Various strategies used to improve availability of the drug in the nasal mucosa include: 1 . To improve the nasal residence time 2. To enhance nasal absorption 3. To modify drug structure to change physicochemical properties

3.1 Improve the Nasal Residential Time Mucociliary clearance works to remove foreign bodies and substances from the nasal mucosa as quickly as possible. One way to delay clearance is to apply the drug to the front of the nasal cavity, an effect that is largely determined by the type of dosage form used. The preparation could also be formulated with polymers such as methyl cellulose, hydroxypropyl methylcellulose or polyacrylic acid, in which the incorporation of the polymer increases the viscosity of the formulation and also acts as a bioadhesive with the mucus. Increasing residence time does not necessarily lead to increased absorption; this concept can be illustrated by considering an insulin solution with a similar viscosity containing carbopol and carboxy methylcellulose (CMC). Carbopol improves absorption where CMC solution does not improve insulin absorption. The increase in viscosity retards drug diffusion from the matrix and causes retention in absorption with CMC.  In case of carbopol, it causes an increase in absorption due to the opening of intracellular junctions. Another lucrative way to increase nasal resistance time is to use biodegradable microspheres as carriers for drug delivery. Biodegradable microspheres swell in the presence of water, thereby increasing viscosity. This phenomenon leads to an increase in the nasal residence time.

3.2 Enhancing the Nasal Absorption The term “absorption enhancer” generally refers to an agent whose function is to increase absorption by improving membrane permeation rather than by increasing solubility. Thus, these agents are sometimes referred to more specifically as

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permeability enhancers, wherein the drug passes through the nasal mucosa, altering in some way the structure of the epithelial cells (permeation enhancers). This must be accomplished without causing damage or permanent changes to the nasal mucosa. In general, absorption enhancers can act through one of the following mechanisms: (a) Open tight junctions (b) Decrease mucociliary clearance (c) Inhibit enzyme Activity (d) Reduce mucus viscosity or elasticity The mechanism of action of the absorption enhancer increases the rate at which the drug passes through the nasal mucosa. Many activators work by altering the structure of epithelial cells in one way or another, but they should do so without causing damage or permanent changes to the nasal lining. The general requirements of an ideal penetration enhancer are as follows: (a) This should lead to an effective increase in the absorption of the drug. (b) It should not cause permanent damage or tissue damage. (c) It should be effective in small amounts. (d) It must be non-irritant and non-toxic. (e) The enhancing effect should occur when absorption is required. (f) The effect must be temporary and reversible. It must be compatible with other excipients. Types of penetration enhancers: (a) Solvents (b) Alkyl methyl sulphoxides (c) Pyrrolidones (d) Dodecyl azacycloheptan-2-one (e) Surfactants Mechanisms of penetration enhancers: (a) Increasing cell membrane permeability by opening tight junctions and formation of intracellular aqueous channels (b) Increasing lipophilicity of the charged drug by forming ion pairs (c) Inhibiting proteolytic activity

3.3 To Modify the Structure of the Drug to Change the Physicochemical Properties Modifying the structure of the drug without altering the pharmacological activity is a lucrative method of improving nasal absorption. Here, the modification of physicochemical properties such as molecular size, molecular weight, PKa, and solubility are favorable for nasal absorption of the drug.

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4 Nose-to-Brain Delivery Nose-to-brain delivery poses a big challenge. In fact, a large number of neurological diseases require therapies in which the drug must reach the brain, avoiding the difficulties due to the blood–brain barrier (BBB) and the problems connected with systemic administration, such as drug bioavailability and side-effects. For these reasons, the development of nasal formulations able to deliver the drug directly into the brain is of increasing importance. The blood–brain barrier (BBB) separates the central nervous system (CNS) from the systemic circulation. The barrier characteristics of BBB depend on the properties of the brain endothelial cells that constitute the walls of the blood vessels. There are many neurological diseases such as neurological infections, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, age-related neurodegenerative diseases, and cerebral ischemia that require a therapy in which the drug must reach the brain. Furthermore, many of these diseases need chronic therapies. Drug targeting to the brain poses a big challenge because many of these drugs cannot cross the BBB. Therefore, many efforts must be made to design strategies to solve this problem. The use of the nose-to-brain delivery route is an important and non-invasive method of drug delivery to bypass the BBB. In fact, it is well-known that there is an intranasal direct anatomical connection between the nasal cavity and the CNS, which suggests the development of nasal formulations for brain targeting of drugs. Different strategies have been developed for nose-to-brain drug delivery and involve nanomedicine with different kinds of nanocarriers: polymeric nanoparticles, nano-­ emulsions, dendrimers, and nano-micelles. The development of new nasal systems poses a great challenge in the field of controlled drug targeting and delivery.

5 Factors Relating to the Rate and Capacity of Drug Transport from Nose to Brain 5.1 Physicochemical Properties of the Drug The rate and capacity of drug transport from the nasal mucosa to the brain depends primarily on the drug’s physicochemical properties, especially its molecular weight, lipophilicity, and degree of dissociation. 5.1.1 Relative Molecular Weight Most small molecular weight ( Inhalation and nasal medication products  informational generalities and testing of product quality [44] • USP chapter Performance Quality Tests for Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders [44]

2.9 Middle East/GCC (a) Central Registration The GCC Area’s consolidated procedure outlines the possibilities of registering pharmaceutical items within the region. The Cooperation Council for the Arab States of the Gulf, often known as the “Gulf Cooperation Council” (abbreviated “GCC”), was established on May 25, 1981. The original member states are the United Arab Emirates, the Kingdom of Saudi Arabia, the Sultanate of Oman, Qatar, Bahrain, and Kuwait. To initiate the centralized procedure, the applicant must submit an application for registration for each production location that is not GCC-DR-­ accredited. In addition, the applicant must submit one application for product marketing authorization for each intended manufacturing line together with the registration application. The applicant must submit an application for registration for each production site that has not been accredited by the GCC-DR in order to initiate the centralized procedure. In addition to the previously indicated application for registration, the applicant must submit one application for product marketing authorization for each anticipated manufacturing line to the appropriate regulatory body. A product dossier, created in compliance with the GCC CTD format criteria, is initially submitted with product samples to the executive office of the GCC-DR, where it is reviewed for completeness before transmission to the technical review committees of the member states. Individual member-state evaluations are conducted initially, followed by a discussion of the received comments at the subsequent committee meeting. The authorities will contact the applicant if more information is requested. In such a case, the Committee will repeatedly reexamine the submitted responses until they are complete and acceptable. Beginning in February 2019, all submissions must be done solely through the GHC Electronic Gateway in e-CTD format. To assist applicants with the submission procedure, GHC has released many documents, including a tutorial on “How to Register for the GHC Web Client,” the “GHC Electronic Submission Portal-Naming Convention

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Files,” and the “Web Client User Guide.” The region-specific Module 1 must be produced in compliance with the “GCC Module 1 Specification and the Baseline eCTD Submission Requirements” per the December 2018 directive. After receiving a favorable decision on the product application from the Central Committee, the applicant sends samples, procedures, and materials for testing to a Central Committee-accredited laboratory (MAA). If the committee reaches a positive decision, the executive office contacts the applicant and issues registration certificates for the product as well as the manufacturing firm or location. The applicant may seek an appeal within 2 months after obtaining notice of the judgment. (b) Registration requirements in the leading GCC nations Despite the fact that the registration procedure for medications in Gulf Cooperation Council (GCC) nations is centralized and relatively similar, the regulatory requirements of a few big countries, such as Saudi Arabia and the United Arab Emirates, are separate. This regulation’s framework is identical to that of the centralized product registration system, which covers nasal medicines. In each nation, classification, site registration, and product registration are conducted differently. These nations have a well-established regulatory structure as well as enforcement measures: (1) Saudi Arabia (2) Bahrain (3) Qatar (4) Kuwait (5) United Arab Emirates (6) Oman (7) Qatar.

2.10 Indian Perspective The Drugs and Cosmetic Act of 1940 and Drugs and Cosmetic Rules of 1945 oversee drug registrations, import, production, distribution, and sale in India. This act also established the Central Drugs Standard Control Organization (CDSCO) and the Drug Controller General of India’s office (DCGI). For its functions, the CDSCO has six zonal, four sub-zonal, eleven port/airport, and six laboratories. DCGI has not established any particular guidelines for evaluating the effectiveness and safety of orally inhaled products. The CDSCO has developed “Guidelines for bioavailability and bioequivalence studies” for generic medication applications. Guidelines/rules such as Rule 122A to E of the Drugs and Cosmetics Act Schedule Y of the Drugs and Cosmetics Act and Rules thereunder (Amended in 2005), Good Clinical Practice (GCP) guidelines issued by CDSCO, and Ethical Guidelines for Biomedical Research Involving Human Subjects govern all clinical trials in India. When evaluating the regulatory procedure for registering a second-entry orally inhaled product in India, the following categories are significant. (a) The reference drug is not approved in India If the reference product has not been authorized in India, the second-entry orally inhaled product would be designated as a novel drug since it would be deemed the

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first market entry of the drug substance. Other instances that the Substances and Cosmetics Act classifies as novel drugs include the following: Drugs that have been approved by the DCGI but are now intended to be marketed for other indications; and fixed-dose combinations of two or more drugs that have been individually approved but are now proposed to be combined in an unapproved ratio.

All new medications must undergo clinical testing to assess their safety and efficacy for Indian patients. If India is participating in a worldwide clinical trial, no more than 20% of the total number of participants can be recruited from Indian locations. These tests are required for both domestically produced and imported pharmaceuticals. For approval of all strengths of a second-entry medicine or a novel drug with multiple strengths, the following requirements must be met: The qualitative content of the respective strengths is virtually identical. b. The ratio of active components to excipients is basically the same across all strengths. c. The manufacturing process is generally same, and all strengths are produced by the same producer. d. Where relevant, a suitable research has been conducted on at least one of the formulation’s strengths. e. It has been demonstrated that the pharmacokinetics of systemic availability are linear across the therapeutic dosage range. (b) The reference drug is approved in India Bioequivalence based on pharmacokinetics alone is unsuitable for orally breathed medications [non-solution pharmaceutical products] that are intended to operate locally in the lungs; comparative clinical trials or PD studies are essential to show equivalence. In India, the idea of PK bioequivalence for orally inhaled medicines is not well-established, as the correlation between systemic levels and lung deposition is still growing. No precedent exists for the approval of a second-entry orally inhaled medication based only on PK bioequivalence. However, since additional research demonstrates a strong link between Cmax and AUC0-t and lung deposition, PK bioequivalence studies are widely recognized as adequate for establishing the equivalence of orally inhaled drugs. The pulmonary accessible dosage is indicated by the AUC0-t measurement, whereas the regional deposition is shown by the Cmax measurement. With sufficient rationale, then, an evaluation of “interchangeability” utilizing “pharmacokinetic equivalence” or “PK bioequivalence” between the second entry medicine and the reference product may serve as an alternative to clinical trials. When the second entry medicine is an inhalation aqueous solution containing the same active substance(s) in the same concentration and virtually the same excipients in comparable concentrations as the reference product, bioequivalence is self-­ evident and no further in  vivo investigations are necessary. The gadget could or might not be comparable to the standard model. To establish equivalent device performance between the reference inhalation product and the second-entry medication product, more in vitro testing is necessary.

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2.11 China’s Perspective (a) Regulatory Framework for Generic Drug Registration in China The China Food and Drug Administration (CFDA) regulates and approves drugs sold in China. Formerly known as the State Food and Drug Administration (SFDA), the CFDA reports directly to the State Council. It consists of 19 departments and bureaus and 18 affiliates, some of which are directly involved in drug regulation and approval processes, including the Center for Drug Evaluation (CDE), National Institute for Food and Drug Control (NIFDC), Center for Certification of Drugs (CCD), Chinese Pharmacopeia Commission (CPC), and Center for Medical Device Evaluation (CMDE). The Provisions for Drug Registration (PDR) were issued by the CFDA in 2007 to establish the regulatory framework for drug registration in China. A revised draft of the PDR, released for public comment in March 2014, integrates the recent reorganization of the CFDA and proposes considerable revisions. As detailed on the CFDA website, applications for respiratory products follow the same registration process, regulatory criteria, and review and approval schedule as all other chemical products. In some situations, breathing equipment must be individually registered in accordance with the application procedure for medical devices. The CFDA’s 2006 “Principles and Technical Guidelines for the Research of Chemicals with Existing National Standards” must be followed for generic medicine applications. CFDA/CDE also released/published a number of specific guidelines and articles for orally inhaled products, including the Technical Guideline for Research on Quality Control of Inhalation Products in 2007, the Technical Requirements for Inhaled Drug Research in 2009, and the Clinical Trial Considerations for Inhaled Drugs for Asthma and COPD in 2009. The CFDA has not yet set clear development standards for generic orally breathed medicines. Therefore, businesses must work closely with the CFDA/CDE to define the strategy and requirements for their specific applications. (b) Bioequivalence Requirements in China In 2008, the CFDA convened professionals and academics (both local and international) from fields such as medicine, pharmaceutics, pharmacology, and toxicology. CDE published two articles in 2009, providing for the first time the detailed technical requirements for inhaled formulations (with the main emphasis on the switch from CFC to HFA propellant) and clinical aspects of technical requirements for the development of generic orally inhaled drugs for the treatment of asthma and/or chronic obstructive pulmonary disease (COPD). The requirements were derived from the then-draft EMEA guidance and the agency’s experience with inhaled medication development and clinical trials. The regulations are applicable to both imported and domestically manufactured generic medications. The CDE papers discuss fundamental principles but offer little specifics about the criteria. The CFDA/CDE bioequivalence standards involve evaluations of both pulmonary

19  Nasal Drug Delivery System: Regulatory Perspective

deposition and systemic drug exposure using pharmacodynamics (PD), and/or clinical trials (CT).

411

pharmacokinetics

(PK),

2.12 Nasal Vaccines and Regulations In recent years, nasal vaccines have become frequent; nevertheless, while choosing a device for nasal administration, it is essential to keep in mind that the administration volume is rather small. An efficient spraying apparatus will lower the amount of antigens required for successful protection. It is a question of preference whether the immunization is delivered by one or both nostrils. Patients tend to have more confidence in the second alternative, which will boost its acceptance. The initial packaging of the vaccine (dried powder or liquid) must be optimized for easy, automated filling (of both small and large volumes) and dependable storage and transport protection. Single-dose devices will provide the maximum level of vaccine protection, but their fillings will necessitate the use of highly sophisticated technologies. These systems are only suitable for nations with a well-developed infrastructure because of their high cost and size. Liquid vaccines may be packaged with multi-dose spray pumps if microbial contamination of the bottle’s contents can be prevented during use. This need may be met by so-called “preservative-free pump systems,” which are also extremely cost-efficient. Disposable sleeves or protective caps can successfully limit the transfer of diseases from one patient to another. Following are the major regulations which regulate vaccines, including nasal vaccines. (a) All vaccines type (i) EMA: Note for Guidance on Preclinical Pharmacological and Toxicological Testing of Vaccines (1997) (ii) Worldwide: WHO Guidelines on Nonclinical Evaluation of Vaccines (2005) (iii) China: State Food and Drug Administration, China Technical guidelines for preclinical research on preventive vaccines. Notice No. 140 (April 2010) (iv) Japan: Japanese Guideline for Non-clinical Studies of Vaccines for Preventing Infectious Diseases, (PFSB/ELD Notification No. 0527-1, May 27 2010) (v) India: Drug and Cosmetics Act, 1940 and Drug and Cosmetics Rule, 1945 (2005) (b) Vaccines for pregnant women and WCBP (i) FDA: Guidance for Industry. Considerations for Developmental Toxicity Studies for Preventative and Therapeutic Vaccines for Infectious Disease Indications (2006) (c) Adjuvants (i) EMA: Guideline on Adjuvants in Vaccines for Human Use (2005)

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(d) DNA vaccines (i) FDA: Guidance for Industry. Considerations for Plasmid DNA Vaccines for Infectious Disease Indications (2007) (ii) WHO: Guidelines for Assuring the Quality and Nonclinical Safety Evaluation of DNA Vaccines (2005) (e) Recombinant DNA vaccines (i) FDA: DRAFT Points to Consider in the Production and Testing of New Drugs and Biologicals Produced by Recombinant DNA Technology (1985) (f) Viral vectored vaccines (i) Guideline on Quality, Nonclinical and Clinical Aspects of Live Recombinant Viral Vectored Vaccines (2010) (g) Combination vaccines (i) EMA: Note for Guidance on Pharmaceutical and Biological Aspects of Combined Vaccines (1998)

2.13 Digital Medical Devices for Nasal Drug Delivery The Internet of Things (IoT) – simply described as a system of internet-connected gadgets that gather and send data over a wireless network – has altered the healthcare industry, from electronic health records and patient portals to telemedicine. The launch of 5G wireless technology of the next generation in 2019 is advancing the immense potential of digital health technology. Many medical equipment may now communicate with and connect to other devices and systems. FDA-approved, permitted, or cleared devices are gaining digital capabilities. New types of devices with these features are being researched. Participators in digital health activities include patients, health care practitioners, researchers, conventional medical device sector enterprises, and firms new to FDA regulatory norms, such as mobile application developers. The FDA’s Center for Devices and Radiological Health (CDRH) is enthusiastic about these developments and the convergence of networking and consumer technologies with medical devices [45]. The FDA has endeavored to provide clarification on the following issues within the digital health business, employing pragmatic approaches that balance benefits and risks: • Software as a Medical Device (SaMD) • Artificial Intelligence and Machine Learning (AI/ML) in Software as a Medical Device • Wireless Medical Devices • Cybersecurity • Device Software Functions, including Mobile Medical Applications

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• • • •

413

Health IT Medical Device Interoperability Medical Device Data Systems Telemedicine

CDRH has established the Digital Health Center of Excellence, which aims to enable digital health stakeholders to advance health care as another critical step in fostering the progress of digital health technology. (a) Benchmark Regulations for Digital Health [46] Following is an overview of major laws and rules of three federal agencies: • Act on the Portability and Accountability of Health Insurance (HIPAA) • The Office for Civil Rights (OCR) of the United States Department of Health and Human Services is responsible for enforcing the HIPAA standards, which protect the privacy and security of some health information and require some firms to provide breach notifications (HHS). • Act Concerning Food, Drugs, and Cosmetics (FD&C Act) • The FDA enforces the FD&C Act, which controls the safety and efficacy of medical devices, including some mobile medical applications. The FDA focuses its regulatory oversight on a small subset of health applications that represent a bigger danger if they malfunction. • Act of the Federal Trade Commission (FTC Act) • The FTC is responsible for enforcing the FTC Act, which prohibits deceptive or unfair acts or practices in or affecting commerce, including those involving privacy and data security as well as false or misleading statements about the safety or performance of mobile applications. • The Health Breach Notification Rule of the FTC • The FTC is responsible for implementing the FTC Act, which prohibits deceptive or unfair acts or practices in or affecting commerce, such as those involving false or misleading claims about an app’s safety or performance.

3 Summary Patient safety is of utmost importance to all regulatory agencies around the globe, with the USFDA, EMA, and Canada Health leading the way in the development of legislation. These nations are also members of ICH, which guarantees regulatory uniformity. These rules are adapted by developing nations in Asia and the Middle East, either as-is or with revisions based on their needs. Regulations pertaining to nasal drugs center on New Drug Applications, Bioequivalence, and Medical Devices. These constitute most of the traditional drug systems. The USFDA, the EMA, and the ICH have created ingredient- and delivery-device-specific recommendations for nasal medication delivery devices. Clinical trials and equivalency

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studies are also crucial components of nasal medication approval. Regulation mandates three-phased research on the efficacy of all medications and dosage formulations. Vaccinations administered by nasal route are also strictly controlled by rules and standards. With the emergence of IoT, AI, and augmented reality, there have been significant advances in nasal medication delivery systems & medical devices/ equipment. Developed nations are also focused on smart gadgets, which provide unique issues owing to a combination of software technology, data protection, and complicated software and device component combinations. In the United States and Europe, the regulation of medical devices is undergoing significant changes. This is a very dynamic sector that requires quick extra regulatory attention and utilization of data by technology businesses to help patients with better options.

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Index

A Absorption, 9, 17, 26, 44, 90, 102, 131, 144, 171, 190, 235, 255, 280, 340, 362, 384 Absorption enhancers, 20, 21, 28–33, 45, 134, 144, 176, 192, 194, 196, 199, 202, 254, 262–269, 271, 340, 341, 363, 364, 376 Alzheimer’s disease (AD), 60, 69, 70, 73, 74, 118, 181, 183 B Bioavailability, 11, 12, 20, 21, 26, 29, 33, 46, 50, 53, 61, 66–72, 74, 91, 102, 103, 105, 109, 113, 115, 118, 119, 142, 144, 146–148, 150–153, 157, 160, 170, 171, 173, 176, 177, 179–181, 184, 190–192, 194–197, 199, 201, 202, 205, 206, 208–210, 214, 218–221, 223, 237, 242, 244–246, 254, 255, 259–261, 264, 265, 267–269, 280, 285, 289, 291, 302–305, 308, 310, 311, 326, 328, 335, 343–346, 348, 349, 352, 353, 355, 362, 365, 372, 376, 384, 386, 388, 397, 398, 408 Biomedical applications, 102–121, 158 Blood-brain barrier (BBB), 10, 12, 16, 18, 19, 21, 23, 44, 47–52, 55, 60, 66, 68, 70, 72, 77, 84, 85, 90, 92, 95, 102, 105, 107–111, 115, 119, 147, 148, 153, 155, 157, 160, 170, 171, 173–175, 180, 182, 183, 190, 205, 214, 245, 280, 281, 286, 288, 311, 312, 328, 335, 341, 350, 351, 362, 365, 368–370, 372, 373, 375, 376, 394 Brain, 2, 16, 47, 60, 83, 102, 143, 170, 190, 242, 261, 280, 326, 344, 362, 385, 394

C Challenges, 2, 27–28, 44, 45, 53, 60–77, 95, 129, 135, 136, 149, 160, 171, 223, 224, 242, 260, 281, 336, 339, 340, 344, 355, 362, 365, 370, 375 CNS disorders, 60, 65–69, 73, 74, 83, 148 CNS targeting, 66 Coronavirus disease-19 (COVID-19), 17, 18, 23, 44, 102, 134, 242, 335, 386, 394 D Design of nasal drug delivery, 43–55 Digital technology, 412, 413 Drug absorption, 2, 10, 11, 25–34, 45–47, 63, 86, 87, 132–134, 144, 145, 149, 152, 174–183, 195, 218, 242, 244, 254, 260, 265, 283–286, 305, 327, 328, 332, 333, 355, 362, 367, 368, 373, 384, 386, 387 Drug delivery, 9, 16, 26, 44, 84, 106, 128, 142, 170, 191, 236, 254, 280, 339, 362, 382, 394 Drug encapsulation, 157, 292, 293, 340, 344–349 Drug formulations, 10, 11, 28, 33, 111, 149, 247, 284, 291, 340, 341 E Enzyme inhibitors, 12, 20, 31, 33, 134, 159, 173, 254, 268 G Global market trends, 381–389

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 Y. V. Pathak, H. K. S. Yadav (eds.), Nasal Drug Delivery, https://doi.org/10.1007/978-3-031-23112-4

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418 H High molecular weight drugs, 179, 253–271, 366 I In situ gelification, 241 International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), 54, 395–396, 402, 405, 413 Intranasal, 9, 21, 26, 45, 62, 95, 103, 134, 170, 205, 236, 254, 280, 326, 339, 362, 386, 394 Intranasal administration, 26–28, 30, 45, 47, 49, 52, 61, 64, 65, 67, 68, 70, 71, 73, 75, 77, 90, 91, 94, 105, 106, 110, 113, 120, 144, 148, 149, 151, 153–155, 157, 158, 180–183, 202, 207, 212, 216, 217, 241, 242, 244, 245, 261, 281, 287–289, 334, 335, 345, 348, 351–353, 366–368, 370, 371, 374 Intranasal delivery, 9, 21, 64–69, 71, 106–108, 148, 150, 156–158, 198, 205, 218, 246, 270, 280, 286, 287, 326, 341, 342, 350, 353–355, 362, 373, 375, 376, 397 Intranasal drug administration, 52, 92, 355 L Liposomes, 50, 52, 60, 73, 74, 102, 106, 107, 114, 119, 134, 135, 146, 150–152, 154, 180, 194, 198, 242, 243, 261, 263, 280, 293, 294, 312, 342, 344, 347, 362, 371–375 M Macromolecular drugs, 142, 224 Mucoadhesives, 10, 11, 28, 32, 45, 48, 51, 52, 55, 63, 66–69, 71–73, 105, 111, 119, 134, 146, 150, 152, 155, 159, 190–224, 241, 246–248, 254, 260–266, 288, 305, 312, 329, 330, 335, 340, 349, 368, 369, 376, 385 Mucociliary, 8, 10–12, 26, 27, 44, 45, 51–53, 66, 70, 73, 88, 90, 95, 103, 105, 112, 115, 119, 129, 132, 135, 144, 145, 149, 153, 155, 156, 171, 172, 176, 178, 179, 191, 209, 220, 236, 247, 248, 259, 266, 284, 305, 312, 339–341, 345, 362–364, 367–369, 387

Index N Nanocarriers, 50, 73, 102–121, 145–147, 150–152, 154–160, 171, 180, 181, 184, 200, 220, 243, 245, 261, 284, 285, 290, 292, 293, 298, 365, 368, 371, 375, 376, 387 Nanoemulsions, 10, 11, 60–77, 110, 112, 113, 146, 152–154, 243, 245, 280, 375, 387 Nanoparticles, 19–21, 50, 52, 60, 70, 73, 91, 102, 105, 106, 111, 113–115, 118–120, 134, 135, 146, 152, 156, 157, 159, 180, 182, 183, 191, 194–200, 202, 205, 214–217, 220, 261, 262, 264, 265, 289, 294, 326, 329–331, 334, 335, 340, 342–355, 362, 365, 368–371, 375, 386, 387 Nanosuspension, 111, 241, 326–327, 329, 333, 335, 336, 375 Nanotechnology, 11, 60, 142, 150, 184, 281, 289, 375, 383, 385–387, 389 Nasal, 2, 15, 25, 44, 60, 86, 102, 129, 142, 171, 190, 235, 254, 280, 339, 362, 382, 394 Nasal absorption, 20, 30, 46, 95, 132–135, 150, 158, 175–181, 184, 191, 192, 194–199, 207, 209, 214, 215, 219, 242, 255, 258, 259, 265–269, 284, 362–364, 367 Nasal cavity, 2–4, 7–12, 15–18, 20–23, 26, 27, 31, 33, 44–47, 49–51, 53, 60, 70, 71, 86–91, 95, 103, 106, 112, 115, 129, 131, 132, 134, 143–145, 149, 154, 155, 172–177, 179, 190, 191, 193, 195–197, 199, 200, 204–206, 209, 213–218, 220, 223, 235, 236, 238, 240, 241, 246, 259–261, 265, 266, 268, 269, 280–288, 305, 312, 327, 333, 340, 341, 362, 363, 365, 367, 368, 376, 383–387 Nasal delivery, 21–22, 53–55, 66, 72, 95, 102, 105, 118, 119, 142–160, 175, 191, 196, 198, 204, 207, 209, 210, 215, 216, 220, 221, 223, 245, 253, 254, 256, 260–270, 282, 305, 310, 312, 339–355, 370, 382–389 Nasal drug delivery, 1–2, 15–23, 28–33, 44, 45, 53–55, 73, 95, 113, 135, 142, 144, 190, 192–195, 197, 205–208, 212–214, 217, 221, 223, 224, 246, 253, 280–290, 313, 339, 341, 363–365, 382–388, 394, 395, 412–413 Nasal drug delivery system, 26–28, 43–55, 119, 144, 159, 191, 193, 196, 206, 209,

Index

419

213, 221, 223, 224, 237, 281, 341, 382–389, 394–414 Nasal formulations, 28, 44, 54, 55, 113, 142, 147, 178, 199, 200, 203, 206, 217, 224, 236, 238, 244, 247, 248, 267, 269, 271, 280, 340, 341, 365, 375 Nasal passageways, 8, 15–21, 23 Nasal pathways, 31, 96, 175, 176 Nasal route, 1, 2, 23, 25–27, 30, 32–34, 43–45, 53, 74, 102, 103, 114–117, 120, 121, 127–136, 142–147, 151, 156, 160, 170–173, 178, 190, 200, 209, 213, 219, 237, 242, 246, 269, 281, 283, 284, 327, 328, 333, 336, 339, 340, 349, 362, 369, 372, 373, 385, 394, 414 Nasal toxicity, 71, 72, 179, 216, 328, 336 Nasal transport, 148, 149 Natural, 5, 10, 29, 53, 71, 105, 113, 135, 154, 156, 157, 177, 183, 190, 192–195, 200–202, 213, 218, 223, 224, 239, 241, 247, 255, 286, 287, 292, 329, 341, 370, 372, 374, 385 Niosomes, 242–244, 280, 290–313 Nose-to-brain, 2, 9–11, 13, 26, 44, 47–53, 55, 60, 61, 63–70, 72–75, 77, 86–88, 91, 95, 96, 108–110, 115, 118, 121, 147–149, 151, 153, 156, 157, 160, 170, 171, 180, 181, 183, 184, 190, 191, 194, 195, 197–199, 205, 208, 212, 214, 216, 218, 219, 223, 242, 261, 281, 286–289, 326, 334, 335, 344, 347, 354, 362, 365–369, 371, 372, 375–376 Nose-to-brain delivery, 47–51, 86, 87, 116–117, 147–149, 153, 156, 157, 160, 170–184, 190, 191, 194, 198, 199, 212, 216, 218, 219, 261, 332–333, 362–376, 385 Nose-to-brain drug delivery, 44, 47–49, 52, 53, 55, 88, 96, 171, 184, 191, 208, 212, 223, 312, 326–336, 387

P Parkinson’s disease (PD), 47, 48, 55, 60, 66, 67, 70, 73, 83, 93, 114, 115, 182, 190, 245, 255, 258, 265, 345, 346, 349, 362, 365, 369, 370, 375, 387, 409, 411 Peptide-protein drugs, 254, 259, 261, 265, 267–269 Peptides, 11, 12, 26, 28, 31, 33, 44, 45, 48–50, 60, 74, 95, 103, 107, 109, 111, 112, 117, 133, 135, 142, 144, 145, 147, 148, 150, 151, 158, 160, 170–184, 190, 191, 194, 195, 197, 198, 201, 214, 236, 246, 254–257, 259, 263, 265–269, 284, 307, 311, 312, 351–352, 362, 366, 369–374, 376, 385, 387 Physicochemical, 44, 46, 53, 54, 84, 95, 112, 133, 134, 145, 154, 155, 158, 159, 171, 177, 193, 217, 259, 284, 291, 351, 363–367, 384 Polymers, 28, 31–34, 48, 51, 52, 66, 67, 109, 113, 115, 117, 119, 134, 135, 146, 150, 151, 155, 156, 158, 159, 181, 190–224, 238–248, 254, 260–267, 288, 289, 329, 331, 340–343, 347–350, 353–355, 363, 368, 369, 372, 373, 376 Proteins, 26, 28, 29, 31, 33, 44, 45, 48–50, 60, 62, 72, 84, 88, 95, 102, 103, 111, 114, 118, 120, 142–145, 147, 148, 151, 160, 170–184, 190–195, 207, 215, 216, 236, 246, 256–258, 261, 267, 281, 284, 285, 288, 306, 307, 312, 330, 362, 369, 371, 372, 374, 376

O Olfactory, 2–6, 8–10, 16, 19, 44, 47, 49–52, 63, 69–71, 86–92, 94, 95, 103–106, 109–113, 118, 129, 130, 143, 147–149, 153, 170, 172–176, 180, 181, 190, 191, 206, 213, 214, 216–218, 223, 241, 242, 280–286, 312, 327, 332, 333, 362, 366–371, 373, 386, 394

S Safety, 28, 29, 53, 66, 72, 77, 102, 110, 121, 145, 159, 203, 205, 217, 223, 224, 246–249, 254, 261, 309, 368, 395, 399, 402–405, 408, 409, 412, 413 Spreadability, 155, 191 Surface modification, 157, 310, 342–344, 350–352, 354, 368, 372

R Regulatory, 258, 394–414 Residence time, 50, 51, 53, 103, 106, 110, 113, 149, 154, 157, 192, 195, 197, 200, 204, 206, 209, 215, 217, 218, 236, 238, 241, 242, 248, 260, 269, 288, 304, 305, 308, 329, 341, 347, 352, 363, 368–369

420

Index

Surfactants, 20, 27–30, 33, 34, 45, 46, 48, 50, 60, 62, 63, 65, 71, 73, 75, 95, 102, 108, 152, 155, 156, 159, 181, 239, 248, 266, 269, 280, 284, 290, 292–299, 304, 306, 307, 312, 331, 364

336, 344, 345, 350, 352, 353, 365, 368–370, 373–376, 386 Tumors, 2, 21, 83, 114, 115, 148, 190, 238, 245, 257, 286–289, 307, 310, 334, 352, 370, 385

T Targeting, 60, 64, 66, 68, 69, 73, 74, 77, 86, 87, 95, 96, 106–109, 111, 113, 119, 121, 147–149, 153, 154, 170, 171, 180–183, 190, 214, 216, 217, 280, 282, 305, 307, 309–312, 333, 334,

V Vaccines, 26, 44, 95, 102, 119–120, 127–136, 142, 145, 146, 154–156, 158, 190, 192, 196, 201, 236, 237, 241, 261, 281, 284, 307, 308, 326, 348, 386, 394, 411–412