Drug Delivery [1 ed.] 9781620815502, 9781613245385

Citation preview

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

BIOTECHNOLOGY IN AGRICULTURE, INDUSTRY AND MEDICINE

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

DRUG DELIVERY

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

BIOTECHNOLOGY IN AGRICULTURE, INDUSTRY AND MEDICINE Additional books in this series can be found on Nova‘s website under the Series tab.

Additional E-books in this series can be found on Nova‘s website under the E-books tab.

BIOMEDICAL DEVICES AND THEIR APPLICATIONS Additional books in this series can be found on Nova‘s website under the Series tab.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Additional E-books in this series can be found on Nova‘s website under the E-books tab.

BIOTECHNOLOGY IN AGRICULTURE, INDUSTRY AND MEDICINE

DRUG DELIVERY

MARIA A. POPESCU

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

EDITOR

Nova Science Publishers, Inc. New York

Copyright ©2011 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers‘ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data Drug delivery / editor, Maria A. Popescu. p. ; cm. Includes bibliographical references and index. ISBN:  (eBook) 1. Drug delivery systems. I. Popescu, Maria A. [DNLM: 1. Drug Delivery Systems. QV 785] RS199.5.D714 2011 615'.6--dc23 2011014475

Published by Nova Science Publishers, Inc. †New York

CONTENTS Preface

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Chapter 1

vii The Influence of Particle Physicochemical Properties on Delivery of Drugs by Dry Powder Inhalers to the Lung Ali Nokhodchi, Waseem Kaialy and Martyn D. Ticehurst

1

Chapter 2

Pharmaceutical Dosage Forms: Past, Present, Future Mohammad Amin Abolghassemi Fakhree and Somaieh Ahmadian

51

Chapter 3

Drug Delivery through Multifunctional Polymeric Nanoparticles Romila Manchanda and Anthony J. McGoron

91

Chapter 4

Targeted Liposomal-Based Chemotherapeutics David R. Khan

Chapter 5

Erythrocytes as Pharmacological Carriers for Corticosteroids and Other Drugs in Patients with Inflammatory Bowel Diseases Luigia Rossi, Francesca Pierigé, Angelo Andriulli and Mauro Magnani

Chapter 6

Chapter 7

Chapter 8

Index

Recollections of 45 Years in Research: From Protein Chemistry to Polymeric Drugs to the EPR Effect in Cancer Therapy Hiroshi Maeda A Novel Transdermal Drug Delivery System Mediated by ArginineRich Intracellular Delivery Peptides Betty Revon Liu, Yu-Wun Hou, Ming-Huan Chan, Hwei-Hsien Chen and Han-Jung Lee Stability of Drug Delivery PLGA Nanoparticles: Calorimertric Approach Tamaz Mdzinarashvili, Mariam Khvedelidze,Tamar Partskhaladze, Mark Schneider, Ulrich F. Schaefer, Noha Nafee and Claus-Michael Lehr

125

135

147

177

189

207

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

PREFACE In drug delivery, active pharmaceutical ingredient (API) is delivered to the patient through different methods and shapes which are called pharmaceutical dosage forms. Each API has specific physicochemical and pharmaceutical properties which require a suitable pharmaceutical dosage form to be delivered to the body. In this book, the authors present current research from across the globe in the study of drug delivery. Topics discussed include pharmaceutical dosage forms; drug delivery through multifunctional polymeric nanoparticles; targeted liposomal based chemotherapies; the stability of drug delivery PLGA nanoparticles and the influence of particle physicochemical properties on delivery of drugs by dry powder inhalers to the lung. Chapter 1 - Drug delivery by inhalation has been routinely used for the treatment of localized diseases such as asthma and COPD. In addition to local delivery the pulmonary route has more recently been found to be a suitable for delivering of drugs for the treatment of systemic diseases, such as diabetes. Pressured metered dose inhaler (pMDI) have historically been the main device platform for delivering to the lung, however in the last two decades the dry powder inhaler (DPI) has become much more popular. This increase in popularity for the DPI has lead to a wide range of DPI devices being commercially available. A high quality DPI needs to demonstrate reproducibility of dose delivery to the site of action, ease of processing and stability. In order to achieve these characteristics a well designed DPI (device and formulation) is required. This review focuses on the formulation design aspects of the DPI product demonstrating how the physicochemical properties of carrier and drug such as particle shape, flow, surface area, surface texture, density and the presence of the third components in DPI formulation affect the delivery of drugs from DPI to the lung. Chapter 2 - In drug delivery, active pharmaceutical ingredient (API) is delivered to the patient through different methods and shapes which are called pharmaceutical dosage forms (PDFs). Each API has specific physicochemical and pharmaceutical properties which require a suitable pharmaceutical dosage form to be delivered to the body. Pharmaceutical dosage form is important in drug delivery, compliance, pharmacokinetic, transportation, distribution, production, shelf life, effectiveness of therapy, and many other processes which can influence the final outcome of drug therapy. Every PDF provides unique properties, advantages, and disadvantages which result in different dosage forms for one API. For example Ibuprofen is available in tablet, capsule, suppository, syrup, suspension, oral drop, parenteral, cream, and gel formulations.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

viii

Maria A. Popescu

Pharmaceutical dosage forms make an active pharmaceutical ingredient administrable. Mankind has implemented different substances as remedy, various types of dosage forms or drug delivery methods had been used, some of which were such applicable and effective that has been modified to this date based on the needs of formulators, and some others were useful just in their time and non applicable for present time and has been removed from choices of formulators. Also some new dosage forms or delivery routes are being developed for fulfilling the needs of present/future. Usually the PDFs contain excipients in addition to the APIs. Excipients can alter pharmacokinetic of medicine and affect the final outcome of drug therapy. In some cases, the physicochemical/pharmacokinetic profile of an API/PDF is not desirable. Therefore some modifications including change of excipients/matrix or coating are applied. The act of formulation is to find a suitable combination of the mentioned modifiers. These modifications considered as generations of dosage forms. Pharmaceutical dosage forms can be categorized based on their physical state or route of administration. The PDFs have one of the following physical forms: gaseous, liquid, semi solid, and solid. Depend on route of administration PDFs are placed in one of the following groups: per oral, sublingual-buccal, ocular, otologic, nasal, urogenital, rectal, alveolar, dermal, and parenteral. All of these routes can cause systemic or local pharmacological (whether desirable or undesirable) effects. The pharmaceutical dosage forms are provided based on properties of active pharmaceutical ingredient, the needs of formulator, manufacturer, administrator, and patient. In this chapter, it has been tried to present a comprehensive data about properties, advantages, disadvantages, and employments of pharmaceutical dosage forms according to needs of past, present, and future in pharmaceutical sciences and drug delivery technology. Chapter 3 - In the modern history of medical science, chemotherapy is most widely accepted for treating multiple types of cancers. The accumulated dose of many chemotherapy drugs, and therefore their therapeutic effect, is limited by irreversible non-target tissue toxicity. Recent advances in nanotechnology using polymeric materials as drug carriers have gained increased importance and have led to the discovery of new therapeutic agents and novel materials for the treatment of cancers. Polymeric nanoparticles composed of PLGA and chitosan have emerged as potential polymers of choice because of their biodegradability and biocompatibility. They successfully increase the dosage and residence time in the body while reducing side effects by offering a sustained and tunable release profile. Polymeric nanoparticle chemistry has numerous research possibilities among which the field of multifunctional nanoparticles has taken precedence in recent times. Multifunctional nanoparticles bring the advantages of combining co-delivery, drug targeting and imaging of tumors in a single delivery system, enhancing the available repertorire of tools in the fight against cancer. This chapter will present an overview of the drug delivery strategies employing polymeric nanoparticles, in light of some recent scientific advances in the area of multi-functional nanoparticles for drug delivery and cancer therapeutics. Chapter 4 - Liposomes were first described in the 1960s and have long been used as drug delivery vehicles for chemotherapeutics in cancer therapy. However, liposomes themselves do not possess targeting capabilities, and future work seeks to confer targeting capabilities to these nanocarriers. In general, targeted drug delivery involves coupling a targeting ligand with a cytotoxic agent in order to improve the colocalization between the drug and the cancer cell. This allows for a more guided form of delivery by delivering the chemotherapeutic preferentially to cancer cells. However, conjugation of drugs directly to the targeting ligand

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Preface

ix

can negatively affect the targeting molecule in a manner that disrupts receptor/ligand recognition and may alter the cytotoxicity of the drug. Therefore, the use of nanocarriers such as liposomes in this form of delivery is particularly attractive as surface modifications made to them involving targeting ligand incorporation eliminates the need for direct conjugation between the targeting ligand and chemotherapeutic. This overall drug design would presumably allow for decreased side effects as the drug is safely encapsulated within the interior of the liposome, while the targeting ligand allows for the delivery of an effective dose of the drug to cancerous cells. The targeting ligand utilized in these constructs is generally based on its selectivity for uniquely overexpressed receptors attributed to various types of cancer with respect to noncancerous cells. Various strategies used to confer targeting capabilities to liposomes have included surface coating them with lipids, peptides and proteins (including antibodies), as well as carbohydrates. In an attempt to even further improve the overall efficacy of these targeted liposomal-based drugs in cancer therapy, multiple functionalities can also be incorporated into them. Generally, this is done in order to further improve the colocalization between the drug and cancer cells, enhance cellular uptake of the liposomal-based chemotherapeutic, or to facilitate drug escape from the nanocarrier. In addition, the coencapsulation of more than one anticancer agent in order to exert therapeutic effects in different ways allows for the construction of liposomes with multiple functionalities that do not involve surface modification beyond targeting ligand addition. This chapter is mainly focused on the recent advances in the development of targeted liposomal-based chemotherapeutics, and also explores novel concepts such as liposomes designed to contain multiple functionalities. Chapter 5 - For patients with inflammatory bowel diseases (IBDs), corticosteroids are usually employed to cut the active phase and induce long-lasting remission. However, either short- and long-term use of corticosteroids carriers adverse events, so that in principle they need to be formulated in a way to be released in low and effective doses for prolonged periods of time. Aim of the review is, at first, to reassume preliminary clinical data on safety and efficacy of administering dexamethasone 21-phosphate entrapped into red blood cells (RBCs) in IBD patients. It is known in fact that, owing to the capability of red blood cell membranes to be opened and resealed under appropriate conditions, RBCs can be loaded with therapeutics and act as pharmacological carriers to distribute them throughout the body. In particular, the un-diffusible corticosteroid analogue dexamethasone 21-phosphate was entrapped into IBD patient‘s erythrocytes which, once re-infused into original donor, were able to work as a slow delivering system for dexamethasone. After each reinfusion in fact, thank to the ability of resident enzymes to remove the phosphate group from the phosphorylated pro-drug, the active diffusible dexamethasone was released in circulation where remained detectable for up to 28 days permitting the withdrawn of oral steroids and maintaining clinical remission. Moreover, since engineered erythrocytes can be modified to target new and conventional drugs to pathological sites, working hypotheses about the feasibility of loading RBCs with other non-diffusible drugs, peptides and oligonucleotides for this target population will be here presented. Surely, the feasibility of this novel approach might be expanded and merits further clinical investigations. Finally, the availability of an apparatus that permits the encapsulation of drugs into autologous erythrocytes has made this technology available in clinical settings and competitive with other drug delivery systems.

x

Maria A. Popescu

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Chapter 6 - This article describes the lifelong research experience of a scientist, from the

beginning studies of protein chemistry to development of a protein drug (neocarzinostatin, NCS) to the invention of the first polymer conjugate drug—poly(styrene-co-maleic acid (SMA) conjugated to NCS, －called SMANCS. The author, having acquired knowledge of proteases and inhibitors, pioneered investigations of microbial proteases in the pathogenesis of bacterial infection. The author‘s group, using a polymer-conjugated enzyme (superoxide dismutase), discovered an enormous burst in the generation of superoxide anion radical (O2・－) during influenza virus infection by the generation of xanthine oxidase. O2・－ was found to be the major cause of the pathogenesis of this viral infection, which progressed even after the virus was eradiated. These events can be interpreted as advancing beyond the boundary of Robert Koch‘s postulates, that is, viral disease occurring in the absence of virus. Also, the importance of endogenous free radicals, now referred to as reactive oxygen species (ROS) and reactive nitrogen species (RNS), during the microbial infections. Role of ROS and RNS in human disease and health became clear, in that they were crucial factors for development of (eg. drug-resistant mutant) formation of mutant microorganisms in chronic and acute infections as well ass carcinogenesis. In additional studies of the pathogenesis of infections of bacterial and fungi, activation of the kallikrein-kinin cascade and thus bradykinin generation at the site of infection were found to result in pain and enhancement of vascular permeability (edema). Because no potent inhibitors of bacterial proteases exist in the human body, such proteolytic activity is detrimental to the host. The intense enhancement of vascular permeability of bacterial infection or inflammation was later found to be analogous to the situation in cancer tissues. That finding led to the discovery of the EPR (enhanced permeability and retention) effect of macromolecules (>40 kDa) in solid tumors. This EPR effect can be utilized for targeting of macromolecular anticancer drugs to tumors, in the field that is today known as nanomedicine. The EPR effect is now becoming a universal guiding principle for tumor selective targeting in nanomedicine for design of drugs such as polymer conjugates, liposomes, micelles, antibodies, and DNA/carrier complexes etc. The polymer conjugate drug SMANCS made remarkable pinpoint targeting possible with unprecedented selectivity: i.e., a tumor/blood ratio of >2000 was achieved. Further enhancement, 2- to 3-fold, of the EPR effect, and thereby more tumor selective drug delivery became possible via either angiotensin II-induced elevation of blood pressure or application of nitroglycerin ointment (which produces nitric oxide in tumors). As described in the text, such interactions of multiple disciplines and of basic science and clinical problems have yielded many discoveries that will be invaluable to young scientists and future directions and development in the medical sciences. Chapter 7 - Transdermal drug delivery system (TDDS) has been improved currently and becomes popular in biological application. Recent reports indicated that arginine-rich intracellular delivery (AID) peptides can enter cells directly without receptor binding or endocytic forming, leading to a new way to overcome the impermeable properties of plasma membrane. Furthermore, AID peptides were applied in the delivery of different cargos with either covalent or noncovalent fashion. Our studies demonstrated that AID peptides and their cargos, such as peptides, insulin, collagen and proteins, can not only enter animal cells noncovalently but also penetrate skin tissues including epidermis, dermis, panniculus adiposus and hypodermis. Notably, cell viability is not influenced by

Preface

xi

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

AID peptides and their cargos. The mechanisms of the AID-mediated transdermal delivery may involve macropinocytosis and actin rearrangement. Therefore, according to our investigations, the AID-mediated transdermal transport of bioactive molecules in a noncovalent manner will be a powerful TDDS and provide a beneficial strategy in pharmaceutics, therapeutics and cosmetics. Chapter 8 - The spherical PLGA nanoparticles (NP) calorimetric investigation is presented in this paper. Such nanoparticles is used for biological active substances (drugs) encapsulating inside of them with the purpose of medicine transferring into the cell. It is clear that without determination of particle stability it is impossible their practical usage. From calorimetric study of PLGA nanoparticles with PLA/PGA ratio 70:30 it was determined the entirety conditions of such particles and the temperature interval, where the particle destructions take place. It was unambiguously shown that for noncoated PLGA NP and for chitosancoated PLGA NP the stability temperature are equal to 370C and less than physiological temperature, which exclude their practical application. Also it was determined that hermiticity destroy temperature depends on heating rate. At the same time it was established that strongly alkaline and acid area (pH2 – pH9) do not destroy noncoated PLGA NP and chitosancoated PLGA NP what gives possibility for their using orally.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

In: Drug Delivery Editor: Maria A. Popescu

ISBN 978-1-61324-538-5 © 2011 Nova Science Publishers, Inc.

Chapter 1

THE INFLUENCE OF PARTICLE PHYSICOCHEMICAL PROPERTIES ON DELIVERY OF DRUGS BY DRY POWDER INHALERS TO THE LUNG Ali Nokhodchi1,2, Waseem Kaialy1,3 and Martyn D. Ticehurst4 1

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

2

Medway School of Pharmacy, University of Kent, UK Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Iran 3 Pharmaceutical Technology Department, University of Damascus, Syria 4 Pfizer, Global R & D, Kent, UK

ABSTRACT Drug delivery by inhalation has been routinely used for the treatment of localized diseases such as asthma and COPD. In addition to local delivery the pulmonary route has more recently been found to be a suitable for delivering of drugs for the treatment of systemic diseases, such as diabetes. Pressured metered dose inhaler (pMDI) have historically been the main device platform for delivering to the lung, however in the last two decades the dry powder inhaler (DPI) has become much more popular. This increase in popularity for the DPI has lead to a wide range of DPI devices being commercially available. A high quality DPI needs to demonstrate reproducibility of dose delivery to the site of action, ease of processing and stability. In order to achieve these characteristics a well designed DPI (device and formulation) is required. This review focuses on the formulation design aspects of the DPI product demonstrating how the physicochemical properties of carrier and drug such as particle shape, flow, surface area, surface texture, density and the presence of the third components in DPI formulation affect the delivery of drugs from DPI to the lung.

2

Ali Nokhodchi, Waseem Kialy and Martyn D. Ticehurst

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

ABBREVIATIONS AFM C CAB CI D50% Dae Dgeo DPI ED FPF FT-IR GSD IGC OINDP PSD SSA T VB VT X ρB ρT ρtrue ρP α

Atomic force microscopy Cohesion force Cohesive adhesive balance Carr‘s compressibility Index Median diameter Aerodynamic diameter Geometric diameter Dry powder inhaler Emitted dose Fine particle fraction Foriour transfrom infrared Geometric standard deviation Inverse gas chromatography Orally inhaled and nasal drug products Particle size distribution Specific surface area The normal force of the particle to the slant surface Freely settled powder volume Tapped powder volume Shape factor Bulk density Tapped density True density Particle density Angle of repose

1. INTRODUCTION In order to obtain a high quality of DPI performance, the manufacturer has to meet two important requirements: good formulation design and carefully selected device (RodriguezSpong et al., 2004) (Figure 1). It has been recognized that the performance of a DPI formulation can be extensively affected by the physicochemical properties of the drug and excipient(s) (Hickey and Martonen., 1993; Atkins and Clark, 1994; Karhu et al., 2000; Harjunen et al., 2002) (Figure 1). Pharmacologically potent drugs usually display poor physicochemical properties, so formulation development is often considered challenging (Telko and Hickey, 2005). In fact, molecular properties that are responsible for pharmacological activity can also be responsible for compound‘s pharmaceutical utility limitation (Pell and Dunson, 1999; Brittain, 1999). Particle-particle (drug-drug, drug-excipient and excipient-excipient) interactions are critical to the performance of DPI formulations. These interactions are mainly dependent upon the physicochemical properties of the interacting particles. Any small change in particle physical properties may result in dramatic change in aerosol powder performance (Zeng et al., 2001a).

The Influence of Particle Physicochemical Properties …

3

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Therefore, in order to develop a high quality DPI delivery system, it is critical to have full understanding of drug and excipient physicochemical properties. Assessment of drug and excipient physicochemical properties in molecular level, particulate level, and bulk level (large assembles of particles) is necessary to fully characterize aerosol formulations. Failure to study one of these areas may lead to significant lack of understanding in terms of particles formation processes, prediction performance, batch to batch variations, particle interactions, and the overall DPI performance (York, 1994).

Figure 1. .The schematic showing some major factors affecting drug delivery from DPIs.

In case of DPI systems, the impact of changing physicochemical properties can display complex inter-relationships. For example the amount of fine carrier particles dominates over both carrier particle size and carrier surface smoothness. So, the existence of fine carrier particles will make the role of carrier particle size and surface smoothness less significant (Zeng et al., 2001b). On the other hand, introducing a small cavities or asperities on the smooth lactose surface resulted in a decrease in fine particle fraction (FPF) and dispersibility regardless of carrier particle size (Zeng et al., 2001b). Also, the type of carrier polymorph was found to dominate over carrier particle size distribution in determining DPI aerosolisation efficiency (Traini et al., 2008). Fine carrier particles have a dominating factor in determining aerosol inhalation properties over carrier mean size and carrier surface roughness (Islam et al., 2004; Young et al., 2007; Zeng et al., 2000b). Finally, it has been shown that the higher the cohesive-adhesive balance (CAB) ratio, the higher the fine particle fraction upon aerosolisation (with only limited range of CAB ratios around 1) regardless of other carrier physicochemical properties such as size, shape, rugosity, and flowability (Hooton et al., 2006; Hooton et al., 2005; Jones et al., 2008a, b). In fact, there are examples in the literature where particle-particle interactions are dependent upon a whole range of physicochemical properties

4

Ali Nokhodchi, Waseem Kialy and Martyn D. Ticehurst

of the interacting particles, such as particle size (Zimon, 1982), particle shape (Mullins et al., 1992), particle surface texture (Otsuka et al., 1988; De Boer et al., 2003), particle electrostatic properties (Bailey, 1984), particle hygroscopicity (Karra and Fuerstenau, 1977), and particle contact area within the powder (Zimon, 1982). In summary, the formulation design and physicochemical properties of the excipient can significantly affect the respiratory deposition pattern of the inhaled drug-carrier mixture (Figure 1) and small changes in particle characteristics result in unacceptable variability in aerosol performance. Furthermore there are often multiple factors in play and thus the control of any individual factor would likely be insufficient in optimizing drug delivery from inhaler devices.

2. ANATOMY AND PHYSIOLOGY OF THE LUNG Respiratory tract is an attractive delivery route due to several advantages as described below:   



Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.



Avoiding the harsh conditions of gastro-intestinal tract (Crooks and Damani, 1989). Convenient and non-invasive route of administration and it can be considered the most effective route to treat airway diseases. -Providing fast drug absorption and action due to large surface area (i.e., 126 m2, size of a tennis court) and highly vasculated tissue with close proximity to blood flow, but short lived time (Wall, 1995). -Capable to deliver the drug directly to the lungs (with no first pass metabolism) and hence minimize the effective required dose when compared to oral route. Providing less systemic side effects

For the reasons above the lung has the potential to be used for both local and systemic treatments (Jain, 2008). Two factors are considered unique variables to the pulmonary delivery which are inspiratory airflow (because of different patient inhalation mode) and physiology and anatomy of respiratory tract (Moulton and Zaworotko, 2001). The airways may be considered as a series of dividing passageways originated at the trachea and terminating at the alveolar sacs. The respiratory system is divided into upper respiratory tract, and lower respiratory tract. The upper respiratory tract includes the nose, oropharynx, larynx, pharynx, and the trachea. The lower respiratory tract includes the tracho-bronchial airways, gas conducting airways, and gas exchanging acini (Figure 2). The respiratory airways bifurcate by the following order (Figure 2): The trachea, the main bronchi, the left and the right primary bronchi, secondary primary bronchi (or lobar bronchi), tertiary bronchi (or segmental bronchi). Then the tertiary bronchi branches several times until it reaches the tiny bronchi (or the smaller bronchi), the terminal bronchioles, the alveolar duct, the alveoli (which are clusters of small thin-walled air sacs), and the alveolar sac (Phalen et al., 1995; Ross et al., 1995). The airway model is subdivided into 24 airway generation in total. The trachea was named the generation 0, and the alveolar sacs were being generation 23. This branching is not perfectly symmetrical (Hickey and Thompson, 1992). The number of airways is doubled from each generation to the next generation, as each airway divided into

The Influence of Particle Physicochemical Properties …

5

two smaller airways (daughter airways) (Weibel, 1965). According to their function, the airway passages can be divided into two parts which are the conducting zone and the respiratory zone as shown below (Adjei et al., 1996; Altiere and Thompson, 1996).

Function Regions

Conducting airway zone Has no role in gas change. Involves the airways from the trachea to the terminal bronchioles.

Respiratory airway zone Participate in gas change. Involves the respiratory bronchiole, the alveolar ducts, and the alveolar sacs.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Alveoli are the terminal airway passages of the respiratory system and the principle site in the airways where the actual gas exchange takes place (Gehr et al., 1978; Hickey and Tompson, 1992).

Figure 2. The human respiratory system.

Each lung contains approximately 100 million alveoli (Stone et al., 1992). Each alveolus is a thin walled polyhedral chamber of about 0.2 mm in diameter. The alveoli region is considered to be of great importance as targeting airway region for therapeutic inhalers due to several reasons that described above. For example, the alveolar region is the airway region where the systemic absorption is most efficient due to vast alveoli vascularised surface area (Telko et al., 2007). Also, the alveolar region is the airway region where the β-adrenergic receptors exist in most number. The luminal surface of the airways is covered with a continuously sheet of epithelium cells containing different cell types performing different functions according to the airway

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

6

Ali Nokhodchi, Waseem Kialy and Martyn D. Ticehurst

region. For example, these cells include specialized tight junctional cells (Hickey and Tompson, 1992), ciliated cells (Philip, 1981), mucus cells (Finkbeiner, 1999; Schutte and Cray, 2002), Clara cells (type I and type II) (Notter, 2000a; Notter, 2000b). The surfactant is secreted from the lamellar bodies that exists in the cytoplasm of the type II alveolar cells (Phalen, 1995). This surfactant is composed of 90 % lipids, and 10 % proteins (Fehrenbach, 2001). Aerosol particle deposition in the respiratory airways is affected by several ventilation factors including particle velocity, inspired volume, inspired time, duration of breath holding, and timing of aerosol delivery during inspiration. The ventilation particle velocity is affected by two factors which are aerosol generator and inspiratory flow. For aerosol generator different inhalation devices have different aerosol particle velocity. For example, pressurised metered-dose inhaler (pMDI) particle velocity range from 10-100 ml/sec, while current drug powder nebulisers have lower particle velocities and current jet/ultrasonic nebulisers produce relatively low particle velocities. Also, inspiratory flow has a significant role on particle velocity, which in turn has a large effect on the particle deposition in the respiratory airways. Faster inspiratory flow rates enhance deposition due to inertial impaction in the oropharyngeal and upper airways. The development of turbulence as a result of increasing inhalation velocity has its significant effect of increasing deposition by impaction in the upper respiratory tract. On the other hand slower inspiratory flow rates enhance deposition due to gravitational sedimentation and diffusion in the lower airways, and minimize pharyngeal and upper airway deposition. During quite tidal breathing, typical adult inspiratory flows are about 0.25-2 L/sec. Some dry powder systems may need faster inspiratory flows (e .g. 0.5-2 L/min) in order to be dispersed and overcome the powder aggregation in those systems. Increasing the size of the inspired volume alter the deposition profiles by affecting two factors which are increasing the total amount of aerosol particles that enter the lung and increasing the particle depth of penetration into the lung. For example, increasing tidal volume results in increasing in particle mass delivered to the alveoli (Musante et al., 2002). Tidal volume with breathing frequency parameters can affect the distribution of air within the lung. Also, particle deposition in the alveoli regions of the inspiration tract can be enhanced by quite breathing. Increasing the duration of a post inspiratory pause, such as breath holding time, can enhance the deposition in the lower lung by facilitating sedimentation and diffusion (Newman et al., 1989; Suarez and Hickey, 2000). The highest deposition in the pulmonary region of the lung was found with inhalation rate of 60 L/min and inspiratory volume of 3000 mL (Musante et al., 2002). Respiratory tract morphology may significantly differ between individual humans. For example, examining of respiratory tract anatomy has showed individual human variations in the alveolar-zone airspace size (Lippmann and Schlesinger, 1984; Martonen and Yang, 1996). Particle deposition is deeply affected by individual variations in airway morphology. For example the diameter of the airways plays an important role on particle displacement before it contacts the airway surface. Large size particles will not contact airways with smaller diameter than their diameter. Also, the cross section of the airway has a significant effect on the flow rate velocity and mixing characteristics between the tidal air and the reserve air in the lungs. In general, lower volume of aerosol delivery could be ascribed to some morphological reasons in the respiratory tract such as obstruction in the airway (which results in poor airway ventilation) and decreasing in airways compliance.

The Influence of Particle Physicochemical Properties …

7

Higher deposition in the upper respiratory tract through inertial impaction could be ascribed to some morphological reasons in the respiratory tract anatomy such as network of branching airways with sharp angles, mucus accumulation in the airway tract, and airway construction (airway narrowing). Changes in the respiratory tract morphology could be ascribed to some diseases. The most important diseases are asthma, COPD (chronic obstructive pulmonary disease), CF (cystic fibrosis), and lung cancer. These diseases could cause changes in the airway morphology such as obstruction and constriction. Obstruction may be the result of mucus accumulation due to the disease which promotes excessive production of mucus leading to poor airway ventilation.

3. DRY POWDER INHALERS Dry powder inhalers (DPI) are considered one of the important delivery devices for delivering respirable drugs to the lungs. In fact, dry powder inhalers are the result of the development of two areas, powder technology and device technology. Like other dosage forms DPIs have advantages and disadvantages and some of the important ones are summarised below. Advantages include: 

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.



  

 

DPIs can have better lung delivery than pressurised metered dose inhalers (pMDIs) (Borgstrom et al., 1996), because DPIs are usually activated by inspiratory air flow, so they require little or no coordination of actuation and inhalation (automatic coordination). So DPIs can be considered more efficient compared to pMDIs. DPIs are considered friendly to the environment because they are propellant-free. pMDIs contribute in decreasing the emission of ozon-dropleting gases such as chlorofluorocarbons (CFC), and greenhouse gases (hydrofluroalkans (HFA). With DPIs it can be easier to facilitate the delivery of macromolecules and biotechnology products DPIs are typically easier to formulate than HFA pMDIs (Ashurst et al., 2000). DPIs have lower rate of chemical degradation because they have lower energy state which also leads to a decrease in the like hood of reaction with the contact surfaces (Telko and Hickey, 2005). Pre-metered DPI can shown high reproducibility of dosing. Minimal devise retention and minimal exhaled lose.

Disadvantages include: 

DPIs are considered effort dependant and not suitable for some patients who are not able to make sufficient inspiratory effort that is required to draw the powder from the device (e.g. patients with severe condition or small age patients such as infants and young children). Higher variation in dose delivery was associated with DPIs when considering factors like age, gender, disease, and the breathing cycle of the device user. So, the deposition efficiency is more dependent on patient‘s inspiratory airflow (Ashurst et al., 2000; Newman et al., 1994; Cegla, 2004; Dunbar et al., 2000).

8

Ali Nokhodchi, Waseem Kialy and Martyn D. Ticehurst   

Some DPIs are considered not easy to use because they have many steps to accomplish before and after inhalation. Each DPI has its own specific step. DPIs can be more complex and more expensive to development and manufacture than pMDIs Low drug delivery efficiency to the lower airway regions

There have been some reports of some patients who take the DPI capsule by the mouth to the gastrointestinal tract rather than load it within the device (Tezky and Holquist, 2005). In fact appropriate training is very important in order to take the drug correctly by a DPI, and this is the mission of health providers to do what called "device education" (Melani et al., 2004). In DPI systems, DPI performance (DPI dispersion and following deposition of drug particles in the respiratory tract) is affected by three main factors which are the design of inhaler device (Dalby et al., 1996), inhaler powder formulation properties (with respect to physicochemical properties of the drug and the carrier) (Timsina et al., 1994), and patient airflow and inhalatory manoeuvre (inhaled flow rate) (Hindle et al., 1994; Frijlink and De Boer, 2004; Chan, 2006; Ashurst et al., 2000; Patton et al., 1999). The most attractive methods to improve DPI performance was to use engineered drug particles and modified excipient systems (Maa and Prestrelski, 2000; Thompson, 1998; Chan, 2003; Kaialy et al., 2010a, Kaialy et al., 2010b) as it is known now that DPI performance is most importantly affected by particle-particle interactions (Guchardi et al., 2008).

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

3.1. DPI Particle Size The effect of particle size on the aerosol clinical outcome was extensively investigated (Mitchell et al., 1987; Clay et al., 1986; Ganderton et al., 1992; French et al., 1996; Steckel and Müller, 1997). Aerosol particle size is the most important physical property of the aerosol formulation and also the most important variable factor of a DPI formulation (Pilcer, 2008; Aulton, 2007). It can be deduced from the research published in the literature, the aerosol particle size is the most important factor determining the site of aerosol particles deposition in the respiratory airways (Heyder et al., 1980; Brain and Valberg, 1979; Brain and Blanchard, 1993; Gonda, 1992; Hinds, 1999). In addition, aerosol particle size affects both the safety and the efficiency of the orally inhaled and nasal drug products (OINDP) (Adams et al., 2007). Generally, the larger the particle size, the stronger the inter-particulate forces between the particles. So it appears that the inter-particle forces between particles can simply be minimized by reducing the size of the interacting particles. However, the performance of fine particle powder is determined not only by the inter-particulate forces, but also by the gravitational forces upon these particles (Zeng et al., 2001a). Whilst Van der waals forces are directly proportional to the particle size (d), the gravitational forces are proportional to the cube of the particle size (d³), so as a result, fine particles are highly sticky, cohesive, and have poor flowability (Zeng et al., 2001a).

3.1.1. Aerodynamic Diameter Various methods could be used to determine aerosol particle size distributions which depend on various geometric features or physicochemical properties (Snow et al., 1984).

The Influence of Particle Physicochemical Properties …

9

Among these, aerodynamic diameter is the most used parameter to express aerosol particle size (Hinds, 1982). Accurate determination of aerosol particle aerodynamic diameter is critical for assessing aerosol inhalation performance. Aerodynamic diameter is used because it describes the dynamic behavior of particle and the theoretical shape of a sphere is never met by the aerosol particles. In aerodynamic diameter measurement, particle shape is included in aerodynamic size expression. Also aerodynamic diameter relates to the main mechanisms of particle deposition (which are sedimentation and inertial impaction) and as a result it is the most relevant to lung delivery and consequently therapeutic effect. For spherical particles the particle aerodynamic diameter is equal to the particle geometric diameter (Dgeo). By definition, aerodynamic diameter is the diameter of another particle which is a sphere with the same volume and a unit density. This assumes the particle is supposed to impact on the same stage of the impactor during aerosolisation or by other words have the same impaction characteristics as the real particles being measured (De Boer et al., 2002a). Aerodynamic diameter is defined by particle size, shape, and mass. Theoretical aerodynamic diameter of particles can be calculated from the particle true density and geometrical diameter (Velaga et al., 2004) Dae = Dg × (ρtrue/X) ½

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

where Dae is the aerodynamic diameter; Dg is the physical (geometrical) diameter; ρtrue is the particle true density. For non-spherical particles (especially elongated particles) shape factor (X) should be added to the equation. This theoretical aerodynamic diameter could alternatively be calculated using tapped density (ρT) instead of true density using the following equation where p1= 1 g cm-3 (Rabbani and Seville, 2005; Bosquillon er al., 2004)

(dae= dg

)

However, true density is preferred in calculating theoretical aerodynamic diameter as it is irrelevant to voids between the particles (Velaga et al., 2004). It should be noted that tap density might underestimate true density by 21% for monodisperse spheres particles (Vanbever et al., 1999). It can be seen that aerodynamic diameter can be changed by changing three factors: a) Particle size b) Particle density c) Shape factor For example, in order to decrease aerodynamic diameter, particle size and particle density can be decreased and dynamic shape factor can be increased. By definition, the particle in which the aerodynamic diameter is equal to the physical diameter is a water droplet with density of 1 g/cm³. Drug particle that has particle density more than 1 g/cm3 will have aerodynamic diameter higher than its geometric diameter.

10

Ali Nokhodchi, Waseem Kialy and Martyn D. Ticehurst

In practice, aerodynamic diameter is usually measured by the techniques that are dependent on inertial impaction (Heyder et al., 1986). Indeed, aerosol particle size distribution can be expressed in two ways. First, aerodynamic diameter could be expressed in terms of the number of particles which is called count median aerodynamic diameter. Second, aerodynamic diameter could be expressed in terms of mass which is known as mass median aerodynamic diameter (MMAD) (Clark and Borgström, 2002).

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

3.1.2. Mass Median Aerodynamic Diameter (MMAD) MMAD is used to define the central tendency of number of aerosol particles and refers to the particle size that divides the particle aerodynamic diameter in a half as a function of mass. MMAD of the aerosol particles is very important, because it determines the site of deposition of drug particles, which is deeply related to gain successful inhalation therapy. In determining aerosol particle size distribution (PSD), MMAD is more suitable than geometric mean diameter (Dg) (Schlesinger, 1995) or theoretical aerodynamic diameter (Pilcer, 2008) as MMAD reflects aerosol particles as aggregates, not single particles. Moreover, lung deposition is determined by Dae irrespective of Dg (to a certain point which is approximately 20 m). However, the total deposited mass of an inhaled aerosol cannot be predicted according to MMAD alone as particles with different aerodynamic particle size distributions (MMAD and GSD) might have similar aerosolisation efficiency (Martonen et al., 1992; Martonen and Katz, 1993). But MMAD can be used to obtain information about the manner by which the particles will deposit during inhalation (USP, 1995). For example, when comparing different drugs in DPI formulations, a linear relationship could be found between experimental drug MMAD determined by impaction method and percentage of drug particles < 5 µm in geometric size (Pilcer, 2008). 3.1.3. Geometric Standard Deviation (GSD) Particle size distribution polydispersity is important in terms of aerosol quality and efficiency. Good mass distribution is of great importance because it relates directly to the uniformity of the dose. Aerosol particle size distribution is generally described by log-normal distribution. Therefore the best way to describe the degree of dispersion in a log-normal distribution is the determining of the geometric standard deviation (GSD). Lower GSD values indicate narrower particle size distribution. Aerosol particle size distribution could be either monodisperse or polydisperse. In monodisperse pattern the distribution is characterized by uniform size and thus in this kind of distribution all the aerosols particle size is nearly the same with GSD < 1.2 m (Suarez and Hickey, 2000). On the other hand, polydisperse or heterodisperse distribution is characterized by non-uniform size and the aerosol particle sizes significantly differ from each other with GSD  1.2 m (Suarez and Hickey, 2000). Standard DPIs formulations are frequently bimodal because it contains both small drug particles and large carrier particles. Usually, aerosols employing excipients in their formulation produce GSD of around 2 (Pilcer, 2008). The value of aerosol GSD could affect its aerosolisation performance. For example, if two aerosols with the same MMAD of 2 µm are compared; increasing GSD from 1 to 3.5 will result in reduction in alveolar deposition from 60 % to 30 % (Gonda, 1981). On the other hand, aerosol particles with different GSD might have similar inhalation properties (Martonen

The Influence of Particle Physicochemical Properties …

11

et al., 1992). In general, aerosol particle with narrow size distribution are preferred in terms of deposition of particles in specific airway region (Zeng et al., 2001a).

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

3.1.4. Fine Particle Fraction (FPF, Respirable Fraction) Fine particle fraction is the percentage of particles in fine particle range which differs according to the type of drug (USP, 2003; Hickey and Martonen, 1993; Telko and Hickey, 2005). In theory, FPF refers to the percentage fraction of the drug that is pharmacologically active (Dunbar et al., 1998). However, In vitro measured respirable fraction will always overestimate the actual in vivo respirable fraction (Vidgren et al., 1991). The mass of the delivered drug, respirable particle mass, and fraction were significantly increased by increasing the flow rate of all tested DPIs as higher gas flow rates generate smaller particles (Smith et al., 1998; Clay et al., 1983; De Boer et al., 2006; Frijlink and de Boer, 2005).

3.1.5. The Effect of Aerosol Particle Size on Aerosol Mixing, Dispersion, and Inhalation Performance During mixing, the larger the carrier particles, the higher inertial and frictional press-on forces which have the potential to increase the adhesive forces in the mixture, depending on the carrier payload (Dickhoff et al., 2003. 2005a). Also, during mixing, an increase in polydispersity of carrier particle size can lead to poor uniformity of formulation blends due to enhanced percolation segregation by size and forming of drug rich areas within the DPI blend (Telko and Hickey, 2005). It has been shown that the aerosol dispersion is affected by aerosol particle size (Chew and Chan, 1999; Chew et al. 2000; Louey et al., 2004a, b) and the reduction of the particle size will generally improve the aerosolisation performance of drugs from inhalers (Ganderton et al., 1992; Steckel and Müller, 1997). For example, in case of patients with severe airflow obstruction, small particle aerosols (1.8 m) were therapeutically more efficacious than large particle aerosols (4.6 and 10.3 m) (Clay et al., 1986). At high flow rates (60-120 L/min) and for specific inhaler devices (Dinkihaler® and Rotahaler®), the FPF will decrease while increasing the particle size of the aerosol (Chew and Chan, 1999). Generally, increasing the median diameter (d50%) of the aerosol particles results in decreasing in the FPF, decreasing in the emitted dose (ED), increasing the amount of drug deposited on the inhaler wall, and increasing in the MMAD (Louey et al., 2004a, b; Steckel and Müller, 1997). It has been shown that decreasing the aerosol d50% could increase the total aerosol powder entrainment, hence FPF. Maximum FPF was obtained when aerosol d50% was about 4 m (Louey et al., 2004a, b). It should be kept in mind that different inhalers might produce different aerosol particle size distributions with the same drug resulting in variations in the final product therapeutic effect (Clay et al., 1986). For β2 agonists it should be considered that the adrenoreceptors exist in high concentrations in the small airways, mainly in the alveoli (Labiris and Dolovich, 2003; Hensley et al., 1978; Howarth, 2001). Therefore the target site of salbutamol sulphate was proved to be mostly in the lower airways (Price and Clissold, 1989). Studies on 2 agonists showed that small aerosol particles with MMAD < 2 m are preferred in the treatment of asthma (Clay et al., 1986). Other studies showed that in patients with severe

12

Ali Nokhodchi, Waseem Kialy and Martyn D. Ticehurst

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

respiratory tract airways obstruction, the optimal and most suitable particle size of a 2 agonist salbutamol sulfate and ipratropium bromide aerosol is approximately about 3 m (Zanen et al., 1996) and more generally 2-5 m (Rees and Clark, 1982). Recent studies showed that indeed there is more than one optimal β2-agonist particle size and 3 µm and 6 µm particles are more potent as bronchodilators compare to the same drug with particle size of 1.5 µm (Usmani et al., 2003). However, it should be noted that although aerosol particle size is the most important factor in determining the amount of drug deposited on the lungs of a healthy adult; in the presence of airway obstruction the effect of aerosol particle size on therapeutic effect becomes less evident (Mitchell et al., 1987). Generally, the total lung deposition will increase in the presence of airflow obstruction (Chan and Lippmann, 1980). Also, the tendency of the particles to deposit on the central airways will increase when the lung airways are narrower (Lippmann et al., 1980). Researchers have developed semi-empirical methods that correlate aerosol particle size with the deposition of drug particles in lungs which can be used as a general guide when assessing the effect of particle size on lung deposition (Rudolf et al., 1986). Lung deposition region of the aerosol is so important because it relates directly to the pharmacological effect of the drug (Figure 3).

Figure 3. Lung deposition site for aerosol particles according to their aerodynamic diameter.

On the basis of figure 3 the following points can be deduced: Few particles larger than 10 m pass the larynx (Swift and Proctor, 1982), and they are believed to be swallowed rather than reaching the lungs (Adams et al., 2007). b. Deposition is predominant on the pharynx, trachea, and upper airway regions when particles diameter is between 6 and10 m (Stahlhofen et al., 1980; Khilnani and Banga, 2008). a.

The Influence of Particle Physicochemical Properties …

13

Aerosol particles with MMAD between 4-6 m deposit mainly on the central bronchial airway (Mitchell and Nagel, 2003). d. Aerosol particles with MMAD between 2-4 m will mainly deposit on the peripheral alveolar airway (Mitchell and Nagel, 2003; Stahlhofen et al., 1980). e. Aerosol particles with MMAD less than 2 m usually penetrate deeply to the lung (expected to deposit primarily in the alveolar region of the lungs). Also, there is still a probability for these particles of being exhaled, and they may not deposit at all (Mitchell and Nagel, 2003; Agnew, 1984; Swift, 1980). f. Aerosol particles smaller than 0.5 m have two limitations. First, they keep moving by Brownian motion and as a result they settle very slowly and may not deposit at all because of their high airborne stability (Heyder et al., 1986; Bosquillon et al., 2004; Agnew, 1984). Second, 0.5 m sphere particles can carry into the lungs only 0.1 % of the mass that a 5 m sphere can carry. As a result, 0.5 m particles could be considered inefficient.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

c.

As a result, only aerosol particles with aerodynamic diameter between 1-5 m can reach the lower respiratory tract (Zanen et al., 1994; Zanen et al., 1995; Zanen et al., 1996; Elversson et al., 2003; Heyder et al., 1986; Bosquillon et al., 2004; Usmani et al., 2003; Malcolmson and Embleton, 1998).This particle size was seen to be the best even for different therapeutic agents with different diseases. It was also seen to be the optimal particle size range despite differences due to different patient lung function. However, it should be noted that the optimal particle size range of aerosol particles depends on drug being used and the precise site of action of this drug in the lungs which is still not well defined (De Boer, 2002b). There are two basic strategies by which aerosol particles could be made: In strategy 1, aerosol particles can be made to a unit density and then the particle geometric size should be between 1-5 m. In strategy 2, density of particles can be between 0.04 and 0.6 g/cm³, but mean geometric diameter of the particles should be between 3-15 m. Aerosol powders with these two characteristics (large porous particles DPI formulations) were proved to result in high percentage of respirable particles both in vitro (Musante et al, 2002; Edwards et al., 1997; Edwards and Dunbar, 2002; Maa et al., 1999; Vanbever et al., 1999; Tarara et al., 2000) and in vivo (Ben-Jebria et al., 1999; Edwards et al., 1997; Wang et al., 1999). Also, it should be noted that in case of hygroscopic particles, due to the presence of hydrophilic surfaces the particle size might increase. This increase can be ascribed to particle‘s water absorption; a phenomenon called hygroscopic growth. Hygroscopic growth of aerosol particles could happen before inhalation (if the relative humidity of the ambient air was high) and/or after inhalation (due to water vapor absorption within the lung airways). However, small drug particles have high electrostatic and cohesive forces and hence poor flow properties, poor aerosolisation performance, and high dose variability (Telko et al., 2007; Hinds, 1999; Feeley et al, 1998; Malcolmson and Embleton, 1998). As a result, carrier is added to the drug in the formulation; but it should be noted that the particle size and size distribution of the carrier itself affect particle dispersion from the formulation blends (drugcarrier) during inhalation (Podczeck, 1999; Kassem and Ganderton, 1990; Chew and Chan, 1999; Braun et al., 1996; Steckel and Müller, 1997; Kulvanich and Stewart, 1987; Karhu et al., 2000).

14

Ali Nokhodchi, Waseem Kialy and Martyn D. Ticehurst

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Typically, in drug-carrier DPI formulations, the size of carrier particles is used to be 6390 µm (Steckel and Müller, 1997, Bell et al., 2006; Byron et al., 1990). Particles below that range are too cohesive, and particles above that size range will block the perforation in the gelatin capsule and it will not pass through (Steckel et al., 2004). Nevertheless, using carrier particles with particle below 63 µm size resulted in an increase in the respirable drug fraction (Steckel and Müller, 1997; Ganderton and Kassem, 1992; Weyhers et al., 1996; Zeng et al., 2001b; Kaialy et al., 2010a; Kassem, 1990; French et al., 1996; Islam et al., 2004) (Figure 4). That could be due to the fact that larger carrier particles have higher surface rugosities (Kawashima et al., 1998; Dickhoff et al., 2003) and higher percentage of surface impurities (De boer et al., 2002b; De boer et al., 2003) per unit carrier surface area, and both have influence on drug-carrier interaction as discussed later. In fact, the type of drug and inhaler device used in the DPI formulation blends may have effect on preferable carrier size for enhanced aerosolisation performance. Carrier fractions with smaller size distributions will produce better aerosolisation performance only for turbulent shear inhalers (e.g. Diskus®, Rotahaler®, Aerolizer®, Handihaler®, Turbuhaler®, Turbulizer®) not inertial forces (e.g. AirmaxTM, TwisthalerTM and NovolizerTM).

Figure 4. FPF in relation to carrier mean diameter.

Usually carrier powders are sieved in 63-90 µm size range before blending with the drug. Theoretically, particle sieving is ideal for particle > 75 µm and is not suitable for particles 50°C) the monotonously decreasing curves indicate that the particles start to aggregate (Figure 2). Further increase of the temperature leads to particles‘ aggregate destruction (above 120°C) which appears in sharp increase of particles‘ heat capacity. This is the result of separations of the molecules forming nanoparticles having high heat capacity (contact between hydrophobic groups and water molecules causes an increasing specific heat).

194

Tamaz Mdzinarashvili, Mariam Khvedelidze, Tamar Partskhaladze et al.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Figure 3. Dependence of non coated nanoparticles‘ suspension transparency on heating temperature; PLA/PLG 70:30.

It was carried out turbidity measurements of nanoparticles with temperature (noncoated; PLA/PLG 70:30). The device of turbidity was constructed in Tbilisi State University by us, where as a source of light it is used blue- light-emitting diode (with wavelength λ=480 nm) and the detector of light is photomultiplier. The suspension of nanoparticles was placed in the glass tube with length 10 centimeter, which was heated by heater which was surrounded around tube. The measurement of temperature was carried out by mercury thermometer, which with good thermal contact was fixed on the glass tube. On the Figure 3 it is given dependence of suspension transparency changes on temperature during scanning the temperature, from which it is obvious that while increasing the temperature of nanoparticles in 15°C -35°C temperature interval the intensive suspension transparency increase takes place (heating of suspension up to higher temperatures (>50°C) was not achieved for this time due to construction of device). To our opinion obtained curve should be related with volume increase of spherical nanoparticles (in mentioned temperature interval) until it will be destroyed, as a result of this (>30 °C) the transparency of suspension is changed not considerably. We would like to underline the circumstance, that while increasing the temperature of suspension the small (not large) increase of nanoparticles‘ volume takes place, which results the decrease of concentration of nanoparticles in suspension (the number of particles in the unit of volume will be less) and consequently the increase of turbidity occurs. This experimental datum is explaining the increase of specific heat capacity of nanoparticles in the above mentioned temperature interval which takes place during calorimetric experiments. Spectrophotometric data showing that the so-called Rayleigh scattering (light intensity is proportional to λ-4) is the same for both, ―native‖ and particles after agglomerate desintegration. In other words, the absorption spectrum of the destroyed chitosan-coated nanoparticles, obtained by heating up to 150°C, did not differ from the spectrum of the ―native‖ ones (Figure 4).

Stability of Drug Delivery PLGA Nanoparticles: Calorimetric Approach

195

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Figure 4. The light absorption spectra of chitosan-coated PLGA nanoparticles (the solid line) with 1.238 mg/ml concentration and for denatured particles with the same concentration (the dash line). Solvent was bidistilled water, pH 5.0 and its temperature was 250C.

Figure 5. Dependence of the specific heat capacity of non-coated PLGA nanoparticles on temperature at different heating rates: 1 – 0.5 K/min; 2 – 1 K/min; 3 – 2 K/min; 4 – 4 K/min.

The same results were obtained for non-coated nanoparticles. To determine whether the nanoparticles melting is a kinetic process or not, the calorimetric experiments with NP suspensions at different heating speeds (0.5°/min, 1°/min, 2°/min, 4°/min) have been carried out (Figure 5). These experiments show that thermodynamic parameters such as Tm and the particle enthalpy (the area of the peak in 23°C–35°C temperature interval) depends on particle heating rate. In particular, the higher the speed of heating, the higher is the particle transition temperature Tm and their melting enthalpy (Table 1). It must be noted that the observation accuracy was increased by multiple determinations carried out.

196

Tamaz Mdzinarashvili, Mariam Khvedelidze, Tamar Partskhaladze et al.

Table 1. Dependence of transition temperature (Tm) and melting non-coated PLGA nanoparticles on different heating rates Heating rate [K/min] 0.5 1 2 4

Transition temperature Tm [0C] 26.5 27.9 29.5 31.7

H) of

Melting enthalpy H [J/g] 1.87 1.92 1.98 2.25

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

For practical application it is important to determine the storage stability of the NP. Especially, the storage in suspension for these biodegradable samples is of high interest. For this reason we carried out calorimetric experiments with nanoparticle prepared three months before and stored at 4°C in refrigerator. The result was compared with the same experiment performed with freshly prepared particles. Figure6 shows calorimetric curves for freshly prepared non-coated nanoparticles (line 1) and the same particles after 3 months (line 2). As it can be seen from this figure storage time influences only particle aggregation process, in other words, the influence of time on nanoparticles becomes apparent in an attempt to increase particle aggregation (they aggregate at lower temperature: 40-110°C range).

Figure 6. Dependence of the specific heat capacity of non-coated PLGA nanoparticles on temperature: 1 - fresh prepared nanoparticles; 2 - the nanoparticles after 3 months.

In addition, the experiments have been carried out with the so-called nanoparticle annealing by temperature, where the nanoparticles were heated only till 23°C – the temperature where the NP internal architecture is starting to modify (Figure 7). The peak is restored at lower temperature (Tm = 25°C) after particle pre-heating. The result of Figure 7 points out that the particles already change at lower temperature.

Stability of Drug Delivery PLGA Nanoparticles: Calorimetric Approach

197

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Figure 7. Dependence of the specific heat capacity of non-coated PLGA nanoparticles on temperature: first heating till 23°C; second is the totally heating up to 1500C.

Figure 8. Dependence of the specific heat capacity of chitosan-coated PLGA nanoparticles on temperature: 1 – nanoparticles in bidistilled water; 2 – nanoparticles in 10% methanol solution.

It is known that in creation of nanoparticles the existence of hydrophobic forces play an important role. Therefore, we changed the solvent‘s polarity to investigate the solvent-particle interaction. The calorimetric experiments in 10% ethanol solution lead to a decreased transition temperature Tm = 24°C (Figure8). In contrast to water, in ethanol no aggregation was observed. Moreover, because of the reduced solvent hydrophobicity no particle aggregation process was observed.

198

Tamaz Mdzinarashvili, Mariam Khvedelidze, Tamar Partskhaladze et al.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Figure 9. The microcalorimetric study of chitosan-coated PLGA nanoparticles, immersed in buffers with different acidity, ranging from pH 2 to pH 8.2. The buffer molarity was 0.02M Na2HPO4 and 0.01M citric acid. The solid line – pH 2; the short dot line – pH 3.8; short dash dot line – pH 5; dash line – pH 8.2.

As it was mentioned above, under the influence of temperature, at first nanoparticles modification (10-25°C) takes place, which is followed by the particle cracking process at Tm=30°C. Hence the particle transition temperature has to be depended on the environmental pressure in all our calorimetric experiments the samples were situated under 6-7 atmosphere pressure to avoid the solution boiling process during heating. To find out if the pressure influences on widening process, the experiments have been performed at 1.5 atmosphere pressure and without excess pressure have been carried out. No differences were obtained. Also experiments were done to determine the stability of nanoparticles in deionized water. Our results emphasize that using deionized water is not so necessary for stability of nanoparticle. For this reason other parameters such as the solvent‘s pH were investigated. Figure 9 shows microcalorimetric study of nanoparticles in buffers of different acidity ranging from pH 2 to pH 8.2. The buffer molarity was chosen not too low (0.02M Na2HPO4 and 0.01M citric acid) to obtain a sufficient buffer capacity for maintaining the solution‘s pH during the heating process in the wide temperature interval (10-150oC). These data are compared to the calorimetric data of nanoparticles suspension in pure bidistilled water.

DISCUSSION From the calorimetric results in Figure2 we can conclude that the coating of nanoparticles with chitosan did not exert an influence on the behavior of the particles. This means that thermodynamic parameters, in particular the profile of the specific heat absorption curves in dependence on temperature for non-coated nanoparticles and chitosan-coated nanoparticles were the same. Also it is clear that the calorimetric curves themselves have a complex shape

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Stability of Drug Delivery PLGA Nanoparticles: Calorimetric Approach

199

(Figure 2) which is composed out of the heat absorption peak area (23-35°C), the sharp change at T ~ 130°C, and the monotonic sections from 10 – 23°C and 35 – 130°C. Such complicated nature of the calorimetric curves indicates that the temperature has multifarious influences on the nanoparticles and causes significant modification of their structure. It should be mentioned that the influence of temperature on nanoparticles starts right at the beginning of the experiment, namely at 10°C, where an increasing heat absorption is observed which turns into a peak at 23-35°C temperature interval. At the beginning of the experiments respectively at the start of temperature scanning the increasе of particle specific heat absorption might be induced by increasing the particle volume, as it happens typically for solid bodies. We received such conclusion, owing to the calorimetry construction, because the DASM-4A calorimeter (DSC) is a device whose ampule is represented by platinum thin capillary which when it is entirely infilled, measures the sample heat effect for only the half of the filled volume. Other construction calorimeters (calorimeters, whose measuring ampules are hermetically closed) measure the whole investigated sample heat effect and are less sensitive to particle widening effect [75]. In other words, as we have mentioned above, in our case the DASM-4A calorimeter measures only part (half) of the suspension filled up in the capillary and if the volume of the particle changes in this part of the capillary, this change instantly affects the heat capacity of this volume phase. Moreover, based on aforesaid it is clear that in such calorimeters it becomes necessary to know the partial volume for measuring the sample‘s heat capacity. The partial volume was obtained from nanoparticles‘ weight, diameter and its shape and was found to be 0.59 ml/g (assuming that the nanoparticles suspended in water had spherical shape and a diameter of approximately d = 147 nm resulting in a mean weight of 2.88•10-15g). Finally it can be concluded, that at initial temperatures the growing of particle volume takes place, the particle small swelling, which at 23-350C temperature interval finishes with particle cracking. Because in this case the break in particle existing bonds takes place, the heat absorption peak is springing up. On the other hand it should be mentioned that the shape of the nanoparticles did not change even for such high temperature as 150°C. Hence, cooling them back to room temperature resulted again in the homogeneous suspension which absorption spectrum is analogous to the spectrum of non-heated nanoparticle suspensio. This is supported by spectrophotometric data showing the so-called Rayleigh scattering (the scattering intensity I ~ -4) which is the same for ―native‖ and destroyed particles (Figure 4). Moreover, the spectrum of the particles, obtained by heating up to 150°C, did not differ from the spectrum of the ―native‖ particles. This indicates that the particles (polymer composition) and they are coctostabile; otherwise they would be destroyed entirely at high temperatures. Therefore the optic spectroscopy, in particular turbodimetric method, is not able to distinguish the initial and temperature-induced changed nanoparticles from each other because both spectrums were carried out at room temperature. For increasing temperature, on the surface of the particles additional hydrophobic chemical groups appear and try to connect with the neighbouring particle surface hydrophobic groups. It betokens that particles will aggregate. From calorimetric curve we can see that after the heat adsorption peak, at higher temperature the specific heat capacity curve is decreasing approximately from 50°C to 120°C area (Figure 2), which is the typical case of aggregates appearing. A further increasing of temperature (above 120°C) leads to a sharp increase of the heat capacity curve, which in our point of view, is caused by aggregate/conglomerate dissociation perhaps to suspension of

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

200

Tamaz Mdzinarashvili, Mariam Khvedelidze, Tamar Partskhaladze et al.

nanoparticles. The hydrophobic part of torn nanoparticles falls into the contact with water and with further temperature increase the amount of aggregates raises. The enthalpy and temperature dependence on heating rate (Figure 5) may be explained by nonequilibrium of process when the interior temperature is less than its outer once and this distinction is as more as the heating rate increase. Earlier it has been shown that PLGA (50:50) nanoparticles, with inherent viscosity of 0.69 dL/g coated with PVA, have glass transition temperature (Tg) onset 38°C and endset 45°C [76]. The heating speed in those calorimetric experiments was 10°/min. Because of thermal gradients, the high heating rate caused increasing the transition temperature value. In other words, the closer we can come to equilibrium the exacter the thermal parameters can be measured. This is also supported by the so-called annealing experiments where the nanoparticles first were heated only until 23°C – the starting temperature of the particles‘ melting process (Figure 7). The significant changes in the enthalpy and transition temperature (Tm) from 30°C to 25°C in the reheating curve show that if the particles are heated till the temperature, which is required to start their internal transition, the process proceeds spontaneously - no more energy is needed to destroy them up to the end. It is clear that the existence of hydrophobic forces in creation and stability of nanoparticle emphasizes the high profile. The nanoparticles expected destruction temperature depends on the contact forces which originate during production. The main part belongs to hydrophobic forces. However, their strength depends on the solvent properties around the particles. Changing (decrease) the polarity of the solvent would have significant influence (diminution) on particle transition temperature. In other words the stability of the particles must depend on the extent of solvent‘s polarity. In Figure 8 we can see Tm of the particles‘ diminished right away (from 30°C up to 24°C) when a 10% ethanol solution is used. Moreover because of the solvent‘s hydrophobicity decrease there was no particles‘ aggregation process observed. An important parameter for future applicability of NP-based delivery systems in pharmaceutics is their stability under relevant environmental conditions to avoid their damage and prematurely drug release. Therefore, the influence of temperature, pH and various salts on nanoparticles needs to be investigated. At first, an unchanged Tm (Figure 9) indicates the stability of the NP in all investigated pH-values .The nanoparticles maintain their structure in deep acid (pH 2) as well as in alkaline (pH 8.2) conditions (heat absorption peak at 30oC, Figure 9), i.e. the particles are not destructed under these conditions. Moreover, the constant heat capacity in the acid range for T > Tm reflects the augmented stability due to electrostatic repulsion, in contrast to water and alkaline ranges. This is valid and expected for cNP. For non-coated NP this would be surprising because of the absence of any pH influence[74]. Therefore besides the particles are stable in buffer, in pH 2 (stomach pH) there is no aggregation process observed what makes them suited for oral delivery as already shown in the literature. The experiments unambiguously show that in a wide pH interval (2-8) the changes in transition temperature did not take place. These results are important for two reasons: such nanoparticles (PLA/PGA ratio in these PLGA nanoparticles is 70:30) could be used in acidic surrounding (for instance, in stomach) for drug transfer and the particles structure, stability and their other properties are less depended on either the particles were in water (bidistilled or deionized) or the suspension of particles were located in buffer (at least in buffer with low molarity).

Stability of Drug Delivery PLGA Nanoparticles: Calorimetric Approach

201

ACKNOWLEDGMENTS Authors are thankful of the collaborative program between Tbilisi State University (Georgia) and Saarland University (Germany), which allow carrying out the collaborative research.

REFERENCES [1] [2]

[3] [4] [5] [6] [7]

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

[8]

[9] [10] [11]

[12]

[13]

[14]

[15]

J. Panyam, V. Labhasetwar (2003) Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Advanced Drug Delivery Reviews 55: 329-347. R. Bejjani, D. BenEzra, H. Cohen, J. Rieger, C. Andrieu, J. Jeanny, G. Golomb, F. Behar-Cohen Nanoparticles for gene delivery to retinal pigment epithelial cells. Molecular Vision, 2005, 11, 124-132. M. Nishikawa, L. Huang Nonviral vectors in the new millennium: delivery barriers in gene transfer. Hum. Gene Ther, 2000, 12, 861-870. S. Li, L. Huang. Nonviral gene therapy: promises and challenges, Gene Ther. 2001, 7, 31-34. D. Ferber. Gene therapy. Safer and virus-free? Science 2001, 294, 1638-1642. S. Moghimi, A. Hunter, J. Murray. Long-circulating and target specific nanoparticles: theory to practice. Pharmacol. Rev., 2001, 53, 283-318. S. Douglas, S. Davis, L. Illum. Nanoparticles in drug delivery. Crit. Rev. Ther. Drug Carrier Syst., 1987, 3, 233-261. J. Kreuter, U. Tauber, V. Illi. Distribution and elimination of poly(methyl-2-14Cmethacrylate) nanoparticle radioactivity after injection in rats and mice. J. Pharm. Sci 1979, 68, 1443-1447. M. Brown, A. Schatzlein, L. Uchegbu. . Gene delivery with synthetic (non viral) carriers. Int. J. Pharm., 2001, 229, 1-21. S.De, D. Robinson. Polymer relationships during preparation of chitosan-alginate and poly-l-lysine-alginate nanospheres. J. Control Release. 2003, 89, 101-112. M. Ricci, P. Blasi, S. Giovagnoli, L. Perioli, C. Vescovi, C. Rossi. Leucinostatin-A loaded nanospheres: characterization and in vivo toxicity and efficacy evaluation. Int. J. Pharm. 2004, 275, 61-72. M. Muller, J. Voros, G. Csucs, E. Walter, G. Danuser, H. Merkle, N. Spencer, M. Textor. Surface modification of PLGA microspheres. Journal of Biomedical Materials Research. 2003, 66A, 55-61. S. Feng, G. Huang. Effects of emulsifiers on the controlled release of paclitaxel (Taxol^(R)) from nanospheres of biodegradable polymers. Journal of Controlled Release 2001, 71, 53-69. S. Feng, G. Huang, L. Mu. Nanospheres of biodegradable polymers: a system for clinical administration of an anticancer drug paclitaxel (Taxol). Ann. Acad. Med. Singapore 2000, 29, 633-639. L.Mu, S. Feng. Vitamin E TPGS used as emulsifier in the solvent evaporation/extraction technique for fabrication of polymeric nanospheres for controlled release of paclitaxel (Taxol). J. Control Release 2002, 80, 129-144.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

202

Tamaz Mdzinarashvili, Mariam Khvedelidze, Tamar Partskhaladze et al.

[16] L. Mu, S. Feng. Fabrication, characterization and in vivo release of paclitaxel (Taxol) loaded poly(lactic-co-glycolic acid) microspheres prepared by spray drying technique with lipid/cholesterol emulsifiers. J. Control Release. 2001, 76, 239-254. [17] V. Labhasetwar. Nanoparticles for drug delivery. Pharmaceutical News. 1997, 4, 28-31. [18] E. Allemann, J. Leroux, R. Gurny. Polymeric nano- and microparticles for the oral delivery of peptides and peptidomimetics. Adv Drug Del. Rev. 1998, 34, 171-189. [19] Y. Nishioka, H. Yoshino. Lymphatic targeting with nanoparticulate system. Advanced Drug Delivery Reviews. 2001, 47, 55-64. [20] K. Soppimath, T. Aminabhavi, A. Kulkarni, W. Rudzinski. Biodegradable polymeric nanoparticle as drug delivery devices. J. Control Release. 2001, 70, 1-20. [21] S. Hariharan, V. Bala Bhardwaj, I. Sitterberg, J. Bakowsky, R. Kumar. Design of estraiol loaded PLGA nanoparticulate formulations: A potential oral delivery system for hormone therapy. Pharmaceutical Research. 2006, 23, 184-195. [22] G. Mittal, D. Sahana, V. Bhardwaj, R. Kumar. Estradiol loaded PLGA nanoparticles for oral administration: effect of polymer molecular weight and copolymer composition on release behavior in vitro and in vivo. J. Control Release. 2007, 119, 77-85. [23] K. Sonaje, J. Italia, G. Sharma, V. Bhardwaj, K. Tikoo, R. Kumar. Development of Biodegradable Nanoparticles for Oral Delivery of Ellagic Acid and Evaluation of Their Antioxidant Efficacy Against Cyclosporine A-Induced Nephrotoxicity in Rats. Pharmaceutical Research. 2007, 24, 899-908. [24] H. Jeon, Y. Jeong, M. Jang, Y. Park, J. Nah. Effect of solvent on the preparation of surfactant-free poly(D,L-lactide-co-glycolide) nanoparticles and norfloxacin release characteristics. Int. J. Pharm. 2000, 207, 99-108. [25] J. Anderson, M. Shive. Biodegradation and biocompatibility of PLA and PLGA microspheres. Advanced Drug Delivery Reviews. 1997, 28, 5-24. [26] R. Jain. The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials. 2000, 21, 2475-90. [27] R. Langer. Tissue engineering: a new field and its challenges. Pharm. Res. 1997, 14, 840-841. [28] K. Uhrich, S. Cannizzaro, R. Langer, K. Shakeshelf. Polymeric systems for controlled drug release, Chem. Rev. 1999, 99, 3181-3198. [29] M. Vert, G. Schwach, R. Engel, J. Coudane. Something new in the field of PLA/GA bioresorbable polymers? J. Control. Release. 1998, 53, 85-92. [30] M. Hans, A. Lowman. Biodegradable nanoparticles for drug delivery and targeting. Curr. Opin. Sol. State Mater. Sci. 2002, 6, 319-327. [31] S. Sahoo, J. Panyam, S. Prabha, V. Labhasetwar. Residual polyvinyl alcohol associated with poly(D,L-lactide-co-glycolide) nanoparticles affects their physical properties and cellular uptake. J. Control. Release. 2002, 82,105-114. [32] I. Bala, S. Haribaran, R. Kumar. PLGA nanoparticles in drug delivery: the state of the art. Critical Reviews in Therapeutic Drug Carrier Systems. 2004, 21, 387-422. [33] S. Hyon. Biodegradable poly(lactic acid) microspheres for drug delivery systems. Yonsei. Med. J. 2000, 41,720-34. [34] S. Hanafusa, Y. Matsusue, T. Yasunaga, T. Yamamuro, M. Oka, Y. Shikinami, Y. Ikada. Biodegradable plate fixation of rabbit femoral shaft osteotomies. A comparative study. Clin. Orthop. 1995, 315, 262-271.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Stability of Drug Delivery PLGA Nanoparticles: Calorimetric Approach

203

[35] Y. Matsusue, S. Hanafusa, T. Yamamuro, Y. Shikinami, Y. Lkada. Tissue reaction of bioabsorbable ultra high strength poly (L-lactide) rod. A long-term study in rabbits. Clin. Orthop. 1995, 317, 246-253. [36] D. Mooney, K. Sano, P. Kaufmann, K. Majahod, B. Schloo, J. Vacanti, R. Langer. Long-term engraftment of hepatocytes transplanted on biodegradable polymer sponges. J. Biomed. Mater. Res. 1997, 37, 413-420. [37] P. Eiselt, B. Kim, B. Chacko, B. Isenberg, M. Peters, K. Greene, W. Roland, A. Loebsack, K. Burg, C. Culberson, C. Halberstadt, W. Holder, D. Mooney. Development of technologies aiding large-tissue engineering. Biotechnol. Prog. 1998, 14, 134-140. [38] T. Park. Degradation of poly(lactide-co-glycolide acid) microspheres: effect of copolymer composition. Biomaterials 1995, 16, 1123-1130. [39] K. Leong, R. Langer. Polymeric controlled Drug Delivery. Advanced Drug Delivery Reviews 1987,1,199-233. [40] M. Hedley, J. Curley, R. Urban. Microspheres containing plasmid-encoded antigens elicit cytotoxic T-cell responses. Nat. Med. 1998, 4, 365-368. [41] S. Lin, K. Chen, H. Teng, M. Li. In vitro degradation and dissolution behaviours of microspheres prepared by three low molecular weight polyesters. J. Microencapsul., 2000, 17, 577-586. [42] L. Brannon-Peppas. Recent advances on the use of biodegradable microparticles and nanoparticles in controlled drug delivery. Int. J. Pharm. 1995, 116, 1-9. [43] T. Görner, R. Gref, D. Michenot, F. Sommer, M. Tran, E. Dellacherie. Lidocaineloaded biodegradable nanosperes. I. Optimization of the drug incorporation into the polymer matrix. J. Control. Release. 1999, 57, 59-268. [44] F. Burkersroda, L. Schedl, A. Göpferich. Why degradable polymers undergo surface erosion or bulk erosion. Biomaterials, 2002, 23, 221-231. [45] C. Kneuer, M. Sameti, E. Haltner, T. Schiestel, H. Schirra, H. Schmidt, C-M. Lehr. Silica nanoparticles modified with aminosilanes as carriers for plasmid DNA. Int. J. Pharm. 2000, 196, 257-261. [46] C. Kneuer, M. Sameti, U. Bakowsky, T. Schiestel, H. Schirra, H. Schmidt, C-M. Lehr. A nonviral DNA delivery system based on surface modified silica-nanoparticles can efficiently transfect cells in vitro. Bioconjug Chem. 2000, 11, 926-932. [47] A. Florence, T. Sakthivel, I. Toth. Oral uptake and translocation of a polylysine dendrimer with a lipid surface, J. Control Release. 2000, 65, 253-259. [48] C. Ramaswamy, T. Sakthivel, A. Wilderspin, A. Florence. Dendriplexes and their characterization. Int. J. Pharm. 2003, 254, 17-21. [49] C. Pouton, P. Lucas, B. Thomas, A. Uduehi, D. Mikroy, S. Moss. Polycation-DNA complexes for gene delivery: a comparison of the biopharmaceutical properties of cationic polypeptides and cationic lipids. J. Control Release. 1998, 53, 289-299. [50] E. Ramsay, M. Gumbleton. Polylysine and polyornithine gene transfer complexes: a study of complex stability and cellular uptake as a basis for their differential in-vitro transfection efficiency. J. Drug Target. 2002, 10, 1-9. [51] D. Oupicky, C. Konak, K. Ulbrich, M. Wolfert, L. Seymour. DNA delivery systems based on complexes of DNA with synthetic polycations and their copolymers. J. Control Release 2000, 65, 149-171 [52] E. Wagner, C. Plank, K. Zatloukal, M. Cotten, M. Birnstiel. Influenza virus hemagglutinin HA-2 N-terminal fusogenic peptides augment gene transfer by

204

[53]

[54]

[55] [56]

[57]

[58]

[59]

[60]

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

[61]

[62] [63]

[64]

[65]

[66]

[67]

Tamaz Mdzinarashvili, Mariam Khvedelidze, Tamar Partskhaladze et al. transferrin-polylysine-DNA complexes: toward a synthetic virus-like gene-transfer vehicle. Proc Natl Acad Sci USA. 1992, 89, 7934-7938. D. Fischer, T. Bieber, Y. Li, H. Elsasser, T. Kissel. A novel non-viral vector for DNA delivery based on low molecular weight, branched polyethylenimine: effect of molecular weight on transfection efficiency and cytotoxicity. Pharm Res. 1999, 16, 1273-1279. K. Kunath, A. Harpe, D. Fischer, H. Petersen, U. Bickel, K. Voigt, T. Kissel. Lowmolecular-weight polyethylenimine as a non-viral vector for DNA delivery: comparison of physicochemical properties, transfection efficiency and in vivo distribution with high-molecular-weight polyethylenimine. J. Control Release. 2003, 89, 113-125. M. Singh, M. Briones, G. Ott, D. O‘Hagan. Cationic microparticles: A potent delivery system for DNA vaccines. Proc Natl Acad Sci USA. 2000, 97, 811-816. M. Singh, G. Ott, J. Kazzaz, M. Ugozzoli, M. Briones, J. Donnelly, D. O'Hagan. a) Cationic microparticles are an effective delivery system for immune stimulatory CpG DNA. Pharm Res. 2000, 18, 1476-1479. M. Singh, M. Vajdy, J. Gardner, M. Briones, D. O‘Hagan, Mucosal immunization with HIV-1 gag DNA on cationic microparticles prolongs gene expression and enhances local and systemic immunity. Vaccine. 2001, 20, 594-602. J. Smith, T. Wedeking, J. Vernachio, H. Way, R. Niven. Characterization and in vivo testing of a heterogeneous cationic lipid-DNA formulation. Pharm Res. 1998, 15, 13561363. C. Olbrich, U. Bakowsky, C-M. Lehr, R. Muller, C. Kneuer. Cationic solid-lipid nanoparticles can efficiently bind and transfect plasmid DNA. J. Control Release. 2001, 77, 345-355. V. Oberle, U. Bakowsky, I. Zuhorn, D. Hoekstra. Lipoplex formation under equilibrium conditions reveals a three step mechanism. Biophys J. 2000, 79, 1447-1454. R. Mahato, K. Kawabata, T. Nomura, Y. Takakura, M. Hashida. Physicochemical and pharmacokinetic characteristics of plasmid DNA/cationic liposome complexes. J. Pharm. Sci. 1995, 84,1267-1271. H. Farhood, N. Serbina, L. Huang. The role of dioleyl phosphatidylethanolamine in cationic liposome mediated gene transfer. Biochim Biophys Acta. 1995, 1235, 289-295. B. Sternberg, K. Hong, W. Zheng, D. Papahadjopoulos. Ultrastructural characterization of cationic liposome-DNA complexes showing enhanced stability in serum and high transfection activity in vivo. Biochim Biophys Acta. 1998, 1375, 23-35. O. Meyer, D. Kirpotin, K. Hong, B. Sternberg, J. Park, M. Woodle, D. Papahadjopoulos. Cationic liposomes coated with polyethylene glycol as carriers for oligonucleotides. J. Biol. Chem. 1998, 273, 15621-15627. J. Behr, B. Demeneix, J. Loeffler, J. Perez-Mutul. Efficient gene transfer into mammalian primary endocrine cells with lipopolyamine-coated DNA. Proc. Natl. Acad. USA. 1989, 86, 6982-6986. V. Torchilin, T. Levchenko, R. Rammohan, N. Volodina, B. PapahadjopoulosSternberg, G. D‘Souza. Cell transfection in vitro and in vivo with nontoxic TAT peptide-liposome-DNA complexes. Proc. Natl Acad Sci USA. 2003, 00, 1972-1977. J. Rädler, I. Koltover, T. Salditt, C. Safinya. Structure of DNA-cationic liposome complexes: DNA intercalation in multilamellar membranes in distinct interhelical packing regimes. Science. 1997, 7, 810-814.

Stability of Drug Delivery PLGA Nanoparticles: Calorimetric Approach

205

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

[68] G. Mrevlishvili, B. Kankia, T. Mdzinarashvili, T. Brelidze, M. Khvedelidze, N. Metreveli, G. Razmadze, Liposome-DNA interaction: microcalorimetric study Chemistry and Physics of Lipids, 1998, 94, 139-143. [69] Z. Cui, R. Mumper. Plasmid DNA-entrapped nanoparticles engineered from microemulsion precursors: in vitro and in vivo evaluation. Bioconjug Chem. 2002, 13, 13191327. [70] R. Kumar, U. Bakowsky, C-M. Lehr. Preparation and characterization of cationic PLGA nanospheres as DNA carriers. Biomaterials. 2004, 25, 1771-1777. [71] R. Kumar, S. Mohapatra, X. Kong, P. Jena, U. Bakowsky, C-M. Lehr. Cationic poly(lactide-co-glycolide) nanoparticles as efficient in vivo gene transfection agents. J. Nanosci Nanotechnol. 2004b, 4, 990-994. [72] J. Haas, K. Ravi, G. Borchard, U. Bakowsky, C-M. Lehr. Preparation and characterization of chitosan and trimethyl-chitosan-modified Poly-(ε-caprolactone) nanoparticles as DNA carriers. AAPS Pharm. Sci. Tech. 2005, 6, 22-30. [73] J. Luengo, B. Weiss, M. Schneider, A. Ehlers, F. Stracke, K. König, K-H. Kostka, Lehr C.-M, Schaefer U. Influence of nanoencapsulation on human skin transport of flufenamic acid, Skin Pharmacology and Physiology. Skin Pharmacology and Physiology. 2006,19,190-197. [74] N. Nafee, S. Taetz, M. Schneider, U. Schaefer, C-M. Lehr. Chitosan-. Nanomedicine: Nanotechnology, Biology and Medicine 2007, 3, 173-183. [75] P. Privalov, S. Potekchin. Scanning microcalorimetry in studing temperature – induсed changes in proteins. Methods in Enzimology. 1986, 131, 4-51. [76] S. De, D. Robinson. Particle size and temperature effect on the physical stability of PLGA nanospheres and microspheres containing Bodipy. AAPS Pharm. Sci. Tech, 2004, 5, 1-7.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

INDEX

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

A absorption, 170, 188, 194, 195, 198, 199, 200 absorption spectra, 195 accuracy, 195 acetate, 191 acetone, 40, 99 acetonitrile, 99 acid, x, xi, 27, 33, 38, 45, 60, 65, 79, 95, 97, 100, 103, 108, 111, 129, 132, 147, 149, 150, 151, 152, 155, 160, 167, 169, 170, 174, 189, 190, 198, 200, 202, 203, 205 acidic, 60, 67, 100, 190, 200 acidity, 198 activase, 82 active compound, 138 active pharmaceutical ingredient (API), vii, 51, 52 active site, 25, 26 active transport, 59 actuation, 7 acute infection, x, 147 acute leukemia, 170 acute lymphoblastic leukemia, 126, 131 acute myeloid leukemia, 105, 114 adalimumab, 72, 85 ADC, 68 additives, 25, 39 adenocarcinoma, 131, 132 adhesion, 15, 18, 19, 20, 22, 23, 24, 25, 28, 29, 34, 37, 41, 42, 43, 44, 45, 186 adhesion force, 19, 22, 23, 24, 29, 30, 45 adhesion interaction, 37 adhesive properties, 25 adhesives, 60, 65 adjustment, 62, 80 administration, 201, 202 adsorption, 27, 127, 191, 199

adult T-cell, 151 adults, 43 adverse effects, 53, 58, 67, 136, 137, 138, 144 adverse event, ix, 135, 136 aerosols, 10, 11, 32, 33, 34, 35, 36, 37, 38, 39, 41, 43, 47, 48, 49 AFM, 2, 26, 29, 34 age, 7, 118 agent, 190 agents, 190, 205 aggregates, 199 aggregation, 6, 18, 26, 28, 29, 196, 197, 200 aggregation process, 196, 197, 200 agonist, 12, 39, 49 AID peptides, x, 177, 179, 180, 181, 182, 184, 185, 186 aiding, 203 AIDS, 79, 94, 114 airflow obstruction, 11, 12, 49 airways, 4, 5, 6, 7, 8, 11, 12, 13, 15, 19, 26, 31, 33, 39, 42, 43, 47 alanine, 151 albumin, 95, 97, 102, 117, 126, 153, 156, 157, 160, 161, 171 alkaline, xi, 189, 200 alteplase, 69, 82 alveoli, 4, 5, 6, 11, 53, 57, 58, 80 alveolus, 5, 37 ambient air, 13, 157 amine, 111 amines, 110 amino, 24, 35, 97, 118, 178 amino acid, 24, 35, 97, 118, 178 amino acids, 24, 35, 97, 168 ammonia, 150, 169 amphiphilic compounds, 77 anatomy, 4, 6, 7

Index

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

208 anesthesiologist, 152 angina, 165 angiogenesis, 106, 120, 162, 164 angiography, 160, 164 angiotensin II, x, 148, 174 annealing, 196, 200 antagonists, 187 antibiotic, 53, 169, 170 antibody, 52, 68, 98, 102, 115, 129, 132 anticancer, 190, 201 anti-cancer, 171 anticancer activity, 102, 111 anticancer drug, x, 102, 107, 110, 112, 113, 120, 148, 163, 167, 168, 201 anticholinergic, 49 antigen, 68 antigenicity, 153 antihypertensive agents, 190 anti-inflammatory agents, 93, 113 antioxidant, 63, 166 antisense, 79, 117, 145 antisense oligonucleotides, 205 antitumor, 116, 130, 131, 132, 149, 152, 156, 165, 166, 167, 169, 170, 171, 172, 174, 175 antitumor agent, 167, 171, 172 API/PDF, viii, 51, 67 apoptosis, 92, 105, 175 application, xi, 189, 191, 192, 196 aqueous solutions, 62 architecture, 164, 173 arginine, x, 121, 163, 174, 177, 178, 179, 187 arginine-rich intracellular delivery (AID), x, 177, 179 arteries, 156 arterioles, 95 artery, 59, 153, 154, 155, 160, 161, 167, 170 ascites, 79, 154, 173 assessment, 84 assets, 83 asthma, vii, 1, 7, 11, 32, 43 atmosphere, 61, 69, 198 atomic force, 33, 36, 37, 39, 42, 47 atomic force microscope, 36 atoms, 31 attachment, 20, 21, 68, 102, 111, 151 Au nanoparticles, 109 autoimmune diseases, 79 autoimmunity, 140

B bacteria, 79, 156, 157, 159, 163, 171 bacterial infection, x, 140, 147, 148, 158, 159, 162

bacteriostatic, 71, 74, 75, 76, 77 Bangladesh, 157 banking, 138 barriers, 59, 68, 79, 81, 190, 201 base, 17, 27, 45, 60, 61, 64 behavior, 198, 202 behaviours, 203 benefits, 61, 132, 136, 138 bicarbonate, 60, 151 bilirubin, 166, 175 biliverdin, 166 bioavailability, 58, 59, 63, 79, 80, 95, 96, 100, 127, 137, 190 biochemistry, 144, 148, 152 biocompatibility, viii, 91, 97, 112, 115, 137, 141, 190, 191, 202 biodegradability, viii, 91, 97, 141, 190 biodegradable, 196, 201, 202, 203 biological activity, 149 biological fluids, 54, 68 biological processes, 108 biological responses, 26 biological systems, 192 biomarkers, 102, 103, 104 biomaterials, 79 biomolecules, 93, 97, 100, 107 biotechnology, 7, 62, 79, 118 bleeding, 79 blends, 11, 13, 14, 15, 18, 19, 24, 25, 28, 30, 31, 32, 45 blood, ix, x, 4, 57, 58, 65, 77, 79, 86, 95, 100, 103, 104, 106, 110, 122, 135, 136, 137, 138, 143, 145, 178 blood circulation, 57, 77, 110 blood flow, 4, 65, 164, 174 blood plasma, 148, 154 blood pressure, x, 148, 164, 172, 173 blood supply, 106 blood transfusion, 154 blood vessels, 58, 100, 103, 106, 154, 156, 162, 164 blood-brain barrier, 153 boiling, 198 bonds, 21, 65, 150, 169, 199 bone, 59, 72, 85, 139, 143, 144, 156, 173 bone marrow, 59, 156, 173 bowel, 136 bradykinin, x, 147, 156, 157, 159, 162, 163, 172, 173, 176 brain, 58, 94, 153, 167, 170 brain tumor, 94, 153, 167, 170 branching, 4, 7 breakdown, 169

Index breast cancer, 94, 102, 105, 107, 115, 116, 118, 121, 126, 129, 131 breathing, 6, 7, 46 bridges, 150 bronchial airways, 4 bronchioles, 4, 5 bronchoconstriction, 34 bronchodilator, 43, 47 Brownian motion, 13 buffer, 198, 200 burn, 186 by-products, 100

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

C calcitonin, 71, 80, 84 calcium, 106 calorimetry, 199 cancer, viii, x, 79, 91, 92, 94, 97, 98, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 125, 126, 128, 129, 130, 131, 132, 148, 150, 151, 153, 154, 158, 159, 160, 161, 162, 163, 164, 165, 166, 169, 171, 172, 173, 174, 187 cancer cells, viii, 103, 107, 111, 116, 121, 125, 128, 129, 130, 159, 166 cancerous cells, ix, 82, 125 candidates, 61, 62, 97, 110, 111, 191 capillary, 22, 26, 29, 62, 199 caprolactone, 205 capsule, vii, 8, 14, 51, 53, 54, 57, 61, 66, 67, 68 carbamazepine, 38 carbohydrate, 129 carbohydrates, ix, 125, 128 carbon, 59, 60, 109 carbon dioxide, 59, 60 carbon nanotubes, 109 carcinogen, 159, 172 carcinogenesis, x, 147, 159, 172 carcinoma, 117, 129, 132, 180 cardiac output, 109, 122 cardiomyopathy, 136 cargoes, 178, 180, 182, 185, 186 castor oil, 118 cell, xi, 187, 189, 203 cell cycle, 92 cell death, 111 cell killing, 109 cell line, 105, 109, 119, 129, 168, 169 cell lines, 105, 109, 119, 129, 168 cell membranes, ix, 78, 135 cell surface, 97, 104, 128

209

challenges, 80, 105, 106, 107, 112, 113, 118, 127, 132, 201, 202 chemical, 7, 42, 46, 53, 59, 63, 81, 97, 100, 102, 113, 115, 137, 178, 179, 183, 185, 186, 188, 190, 199 chemical degradation, 7 chemical properties, 137, 185, 190 chemical stability, 53 chemotherapeutic agent, 107, 111, 120 Chemotherapeutics, 125 chemotherapeutics in cancer, viii, 125 chemotherapy, viii, 91, 92, 99, 105, 106, 108, 109, 114, 118, 120, 126, 132, 150, 158, 165, 170, 171, 172, 174 chemotherapy drugs, viii, 91, 105 chicken, 149, 160 children, 7, 131, 139 China, 163, 164 chitin, 97 chitosan, viii, 91, 97, 98, 99, 104, 105, 106, 107, 115, 116, 117, 119, 191, 192, 193, 194, 195, 197, 198, 201, 205 Chitosan, 97, 98, 99, 115, 116, 191, 205 chitosancoated PLGA NP, xi, 189 chlorophyll, 166 cholesterol, 202 chondroitin sulfate, 128 chromatography, 2, 47, 149 chronic myelogenous, 166 chronic obstructive pulmonary disease, 7 chymotrypsin, 150 circulation, ix, 58, 61, 69, 78, 94, 95, 97, 101, 104, 109, 112, 114, 127, 135, 136, 137, 138, 141, 153, 164, 165, 166 City, 161, 163 classes, 137 classification, 54 cleavage, 100, 157 clinical application, 103 clinical oncology, 152 clinical problems, x clinical trials, 102, 105, 109, 111, 126, 127, 128, 139 clone, 168 clustering, 145 clusters, 4 Co, 192 CO2, 69 coding, 176 collage, 182 collagen, x, 72, 177, 179, 182 colocalization, viii, 125, 128, 130 colon, 122, 127, 156, 173 colon cancer, 127 colorectal cancer, 105, 106, 127, 176

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

210

Index

combination therapy, 88, 111 commercial, 96, 104, 112 community, 84, 89, 167 compaction, 30 complexity, 77, 92, 112 compliance, vii, 6, 51, 53, 58, 66 complications, 154 composition, 34, 44, 67, 97, 100, 112, 131, 137, 169, 191, 199, 202, 203 compounds, 93, 136, 141, 149, 185, 188 compressibility, 2, 15, 16 compression, 15, 38, 60, 67 computed tomography, 154 computer simulation, 170 concentration, 194, 195 condensation, 22 conference, 121 configuration, 31 conjugation, viii, 68, 110, 122, 125, 126, 131, 153, 160, 166, 167, 169, 170 consensus, 101, 140, 176 construction, ix, 7, 126, 130, 194, 199 contact time, 58 control group, 180 controversial, 178 COOH, 108 cooling, 199 coordination, 7 COPD, vii, 1, 7 copolymer, 97, 101, 107, 117, 120, 191, 202, 203 copolymers, 116, 121, 162, 190, 203 cornea, 156 correlation, 192 corticosteroids, ix, 135, 136, 137, 138, 139, 140, 144 cortisol, 139, 143 cosmetics, xi, 177, 186 cost, 16, 53, 60, 61, 66, 77, 80, 103, 112, 167, 168 coughing, 61 covering, 54, 59, 80, 191 cracking, 193, 198, 199 crystal growth, 21, 41 crystal structure, 38 crystalline, 31, 36, 45, 64 crystalline solids, 45 crystallinity, 31 crystallisation, 21 crystallization, 22, 36, 47 crystals, 21, 40, 41, 47 CSF, 72, 73, 85, 86 CT scan, 161 culture, 169 curcumin, 99, 117 cure, 136

cures, 122 currency, 78 cyclooxygenase, 173 cyclosporine, 106, 140 Cyclosporine A, 202 cystic fibrosis, 7, 44, 80, 139, 143 cytoplasm, 6 cytotoxic, 203 cytotoxic agent, viii, 106, 125, 126, 127, 128 cytotoxic agents, 106 cytotoxicity, ix, 105, 107, 119, 125, 126, 169, 185, 204 Czech Republic, 162

D database, 118, 142 deacetylation, 97 deaths, 92 debulking surgery, 108 decoration, 111 defence, 140 deformation, 42 degradable polymers, 203 degradation, 52, 58, 59, 61, 62, 63, 66, 67, 69, 79, 80, 94, 95, 97, 100, 140, 144, 145, 149, 150, 151, 152, 153, 167, 170, 175, 191, 203 degradation rate, 95, 100 dehydration, 64 delivery, 186, 187, 190, 191, 200, 201, 202, 203, 204 dendrimers, 191 density, 192 deposition, 4, 6, 7, 8, 9, 10, 12, 19, 22, 23, 25, 29, 33, 34, 35, 37, 38, 39, 40, 41, 42, 43, 45, 46, 47, 49, 156 depth, 6 derivatives, 33, 95, 103, 109, 140, 149, 169, 171, 191 dermis, x, 58, 59, 78, 177, 181, 182, 184, 186 destruction, 106, 193, 200 detachment, 20, 21, 22, 25, 29, 31, 36, 46 detectable, ix, 135, 138, 140, 192 detection, 103, 121, 149, 180, 184 detoxification, 105, 175 dexamethasone, ix, 102, 135, 136, 138, 139, 141, 143, 144 diabetes, vii, 1 dialysis, 98 diaphragm, 68 diffraction, 36, 186 diffusion, 6, 38, 68, 97, 99, 100, 159, 191 diffusion process, 68 diluent, 71, 73, 74 dimethylsulfoxide, 99

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Index diseases, vii, 1, 4, 7, 13, 45, 66, 113, 136, 141 dislocation, 179 disorder, 45 dispersion, 8, 10, 11, 13, 15, 18, 20, 21, 22, 23, 26, 28, 29, 31, 35, 39, 40, 42, 49, 57, 62, 63 displacement, 6, 25, 99, 191 dissociation, 199 distribution, vii, 2, 3, 6, 10, 11, 13, 14, 15, 31, 32, 35, 36, 43, 44, 48, 51, 53, 64, 97, 113, 136, 192, 204 divergence, 168 diversity, 187 DNA, x, 78, 80, 92, 97, 98, 99, 107, 108, 116, 120, 148, 151, 152, 153, 160, 163, 169, 170, 187, 191, 192, 203, 204, 205 docetaxel, 103, 106, 116 donors, 136 dosage, vii, viii, 7, 34, 46, 51, 52, 53, 54, 55, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 77, 79, 80, 81, 86, 91, 167 dosing, 7, 53, 54, 57, 58, 59, 61, 62, 66, 131, 167 drainage, 127 drawing, 138 drinking water, 61 drug action, 52 drug carriers, viii, 91, 94, 95, 97, 100, 113, 119 drug delivery, vii, viii, ix, x, 3, 4, 8, 15, 18, 35, 37, 38, 40, 41, 43, 44, 49, 51, 52, 53, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 78, 80, 81, 91, 92, 96, 100, 104, 105, 107, 109, 110, 111, 113, 114, 115, 116, 117, 119, 120, 121, 122, 125, 126, 127, 128, 130, 131, 132, 136, 137, 141, 143, 148, 151, 155, 160, 161, 164, 165, 174, 177, 178, 186, 190, 201, 202, 203 drug delivery systems, 202 drug design, ix, 125 drug interaction, 119 drug release, 69, 94, 104, 106, 111, 129, 165, 166, 200, 202 drug resistance, 119 drug therapy, vii, viii, 51 drugs, vii, viii, ix, x, xi, 1, 2, 7, 10, 11, 31, 33, 43, 53, 57, 58, 59, 60, 61, 62, 63, 65, 66, 67, 68, 77, 78, 80, 82, 86, 87, 91, 92, 93, 94, 95, 96, 97, 100, 102, 104, 105, 106, 107, 108, 110, 111, 117, 120, 125, 126, 135, 136, 137, 140, 141, 144, 145, 148, 149, 158, 160, 164, 165, 166, 167, 168, 169, 170, 171, 173, 174, 178, 182, 185, 187, 188, 189, 190, 191 dry powder inhaler (DPI), vii, 1, 58 drying, 22, 24, 37, 42, 192, 202 DSC, 199 dyes, 109, 166

211

dysphagia, 131

E edema, x, 147, 162 editors, 143 education, 8, 81 egg, 148, 160 Egypt, 165 electric current, 78 electrodes, 78 electron, 27, 28, 162, 179 electroporation, 59 elongation, 19, 20, 21, 140 elucidation, 156 emboli, 62, 63, 77 emergency, 57, 59 emission, 7, 15, 18, 38, 43, 180 emulsifier, 201 emulsions, 54, 57, 59, 63, 64, 67, 68 encapsulated, 190, 191 encapsulation, ix, 53, 93, 119, 120, 133, 136, 137, 166 endocrine, 204 endocytosis, 187 endothelium, 116, 173 enemas, 143 energy, 7, 21, 22, 25, 27, 28, 40, 64, 100, 109, 178, 200 engineering, 34, 36, 43, 67, 79, 143, 202, 203 England, 35 engraftment, 203 enlargement, 46 entrapment, 106, 113 environment, 7, 39, 66, 191 environmental conditions, 29, 40, 190, 192, 200 environmental factors, 52 enzyme, x, 93 enzymes, ix, 79, 95, 135, 190 epidemic, 157 epidermis, x, 58, 65, 78, 177, 178, 179, 180, 181, 182, 184, 186 epithelia, 63 epithelial cell, 201 epithelial cells, 201 epithelium, 5 EPR, x, 100, 101, 111, 117, 127 equilibrium, 192, 200, 204 equipment, 15, 44, 61 erosion, 100, 203 erythrocytes, ix, 135, 137, 138, 139, 140, 141, 143, 144 erythropoietin, 69, 70, 82, 83, 131

Index

212

esophagus, 131 ester, 100, 129, 132, 152 estradiol, 186 etanercept, 70, 83 etching, 22 ethanol, 22, 40, 52, 179, 180, 183, 184, 185, 197, 200 ethers, 129 ethyl acetate, 99, 191 ethylene, 97, 104, 107, 113, 114 ethylene glycol, 104, 107, 113, 114 EU, 142 evaporation, 65, 99, 191, 201 evidence, 44, 185, 187 excitation, 109, 180 excretion, 97, 153, 167, 170, 175 experimental design, 38 expertise, 112 experts, 152, 157 exporter, 105 exposure, 78, 112, 139, 159 extraction, 52, 156, 201 extravasation, 100, 101, 156, 157, 159, 160, 161, 162 extrusion, 98

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

F fabrication, 41, 201 Fabrication, 117, 202 fasting, 137 fat, 59, 62 fatty acids, 113 FDA, 47, 53, 59, 68, 79, 103, 131, 191 fiber, 108 fiber optics, 108 fibroblast growth factor, 106, 123 fibroblasts, 187 fillers, 60 films, 61, 155 filters, 21, 97 first generation, 67 fish, 149 fistulas, 139 fixation, 202 flexibility, 59, 137 flour, 53 flow, 192 fluid, 28, 35, 77, 78, 149, 156, 159, 162, 172, 173 fluorescence, 149, 180, 182 foams, 65 folate, 99, 103, 106, 107, 111, 118, 122, 123, 129 folic acid, 111, 129 follicle, 71, 84

food, 53 force, 2, 17, 19, 23, 25, 29, 33, 36, 39, 40, 41, 44, 45, 47, 68, 78 formamide, 156 formation, x, 3, 42, 63, 77, 192, 204 formula, 16, 45 fractures, 142 fragments, 102, 150 France, 43 free energy, 27, 28 free radicals, x, 147, 158, 165, 168, 172 friction, 15, 16, 17, 32, 44, 45, 60 functionalization, 104, 110, 111, 115, 119 funding, 112, 149 funds, 130 fungal infection, 65 fungi, x, 147 fusion, 179, 187 fusion proteins, 187

G gadolinium, 108, 114 gastrointestinal tract, 8, 57, 59, 167 gel, vii, 51, 53, 57, 58, 75, 79, 80 gelation, 99 gene, 191, 201, 203, 204, 205 gene expression, 107, 140, 204 gene silencing, 98 gene therapy, 97, 201 gene transfer, 201, 203, 204 genes, 105, 107, 190 genomics, 92 geometry, 22, 23, 26, 27, 28, 43, 78 Georgia, 189, 201 Germany, 150, 157, 164, 180, 189, 192, 201 glass, 194, 200 glass transition, 200 glass transition temperature, 200 glasses, 180 glioblastoma, 153 glucagon, 71, 84 glucocorticoid receptor, 138, 139 glucose, 24 glutathione, 105 glycine, 121 glycol, 73, 77, 86, 95, 97, 116, 127, 178, 179, 204 gold nanoparticles, 109, 121 grades, 41 graduate students, 156, 157 granules, 37, 48, 54, 57, 60, 61, 67, 68 gravitational constant, 17 gravitational force, 8, 17

Index gravity, 18 greenhouse, 7 greenhouse gases, 7 groups, 193, 199 growth, 13, 21, 60, 63, 64, 70, 71, 72, 79, 83, 84, 85, 91, 106, 118, 120, 129, 132 growth factor, 72, 79, 85, 106, 118, 120, 163 growth hormone, 70, 71, 83, 84 guanine, 159 guidance, 122, 154 guidelines, 112, 131, 142

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

H HA, 187, 203 half-life, 104, 108, 153, 158, 166 hanging, 193, 200 HE, 178, 180, 181 head and neck cancer, 114 healing, 53 health, x, 8, 33, 35, 43, 83, 84, 89, 112 heat, 192, 193, 199, 200 heat capacity, 192, 193, 194, 195, 196, 197, 199, 200 heat shock protein, 166, 175 heating, xi, 189, 192, 193, 194, 195, 196, 197, 198, 199, 200 heating rate, xi, 189, 192, 193, 195, 196, 200 height, 17 hemagglutinin, 203 heme, 166, 174, 175 heme oxygenase, 166, 174, 175 hepatitis, 63, 70, 74, 75, 76, 79, 83, 87, 88, 89 hepatocellular carcinoma, 155, 164, 167, 171 hepatocytes, 203 hepatoma, 154, 155, 161, 167, 171 hepatotoxicity, 140 heterogeneous, 204 high strength, 203 high temperature, 199 histidine, 74 history, viii, 91 HIV, 111, 123, 143, 187, 204 HIV-1, 143, 187, 204 HO-1, 166, 175 homeostasis, 79 homogeneity, 28, 29, 31, 37, 41, 42, 46, 49 homogenized, 192 hormone, 92, 202 hormones, 79, 190 host, x, 45, 103, 140, 148, 158, 168 hot spots, 25 house dust, 157, 171

213

human, x, 5, 6, 38, 39, 43, 46, 48, 52, 70, 71, 72, 76, 79, 80, 82, 83, 84, 85, 87, 88, 89, 105, 109, 117, 121, 141, 186, 187, 205 human body, x, 141 human immunodeficiency virus, 186, 187 humidity, 13, 29, 34, 41, 42, 45, 47, 48, 65 Hunter, 201 hydrogen, 21 hydrogen bonds, 21 hydrolysis, 63, 78, 100, 150 hydrophilicity, 95, 110, 191 hydrophobic, 193, 197, 199, 200 hydrophobic groups, 193, 199 hydrophobicity, 101, 131, 197, 200 hypersensitivity, 59 hypertension, 161, 174 hyperthermia, 99, 108, 109, 116, 129 hypodermis, x, 177, 181, 182, 184, 186 hypothesis, 160 hypoxia, 164 hypoxia-inducible factor, 164

I IBD, ix, 135, 136, 138, 140, 141, 142, 144 Ibuprofen, vii, 51, 53 id, 199, 200 ideal, 14, 60, 97, 109, 111, 126, 151, 154, 166 identification, 102, 108 image, 108, 112, 171, 181, 182, 183 images, 112, 155, 161, 162, 180, 183 immune response, 103, 145, 158 immune system, 103 immunity, 113, 204 immunization, 204 immunodeficiency, 186, 187 immunogenicity, 101, 102, 103, 153, 166 immunoglobulin, 160 immunomodulatory, 113 immunomodulatory agent, 113 immunomodulatory agents, 113 immunostimulatory, 120 immunosuppression, 153 immunotherapy, 92 impairments, 92 implants, 54, 66, 68 improvements, 97, 136 impurities, 14 in transition, 200 in vitro, 13, 18, 23, 35, 37, 38, 39, 42, 44, 46, 48, 49, 102, 105, 107, 112, 115, 116, 132, 188, 191, 202, 203, 204, 205

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

214

Index

in vivo, 11, 13, 97, 102, 103, 105, 108, 109, 111, 112, 114, 115, 116, 117, 118, 127, 129, 132, 137, 138, 151, 152, 156, 158, 161, 165, 166, 172, 173, 175, 191, 201, 202, 204, 205 indentation, 30 India, 165, 166 individuals, 57, 58, 61, 79, 139 induction, 136, 140, 144, 175 industrialization, 53 infants, 7, 60 infection, x, 111, 123, 145 inflammation, x, 54, 79, 136, 140, 143, 148, 159, 162, 163, 168, 172 inflammatory bowel disease, ix, 135, 142, 144, 145 inflammatory bowel diseases (IBDs), ix, 135 infliximab, 75, 82 influenza, x influenza virus, x infrared spectroscopy, 37 ingest, 59 ingestion, 53, 61 ingredients, 32, 52, 61, 81 inhaled therapy, 39 inhaler, vii, 1, 2, 4, 6, 8, 11, 14, 23, 24, 29, 33, 34, 35, 36, 37, 38, 39, 40, 42, 43, 44, 45, 47, 48, 54, 58 inhibition, 102, 108, 128, 129, 140, 144, 145, 152, 166, 170, 175 inhibitor, 106, 120, 127, 156, 162, 166, 167, 173, 174, 175 injection, 201 injections, 62, 77 injuries, 53, 185 injury, 78 insertion, 67, 78 instability, 191 insulin, x, 69, 71, 72, 73, 74, 79, 80, 82, 84, 85, 86, 106, 150, 177, 179, 182 integrins, 128, 129 interaction, 191, 192, 197, 205 intercalation, 204 interface, 41, 47 interferon, 40, 69, 70, 71, 72, 75, 76, 77, 82, 83, 84, 85, 88, 131, 149, 153 interferon gamma, 69, 82 interferons, 79 internalization, 103, 111, 187 interval, xi, 189, 193, 194, 195, 198, 199, 200 intervention, 140 intestinal tract, 4 intestine, 59, 68 intramuscular injection, 63, 69, 70, 71, 74, 75, 76 intravenously, 62, 114, 158, 161

inversion, 121 investors, 84 ions, 78, 190 Iran, 1, 51, 81 iron, 60, 108, 121 Islam, 3, 14, 26, 40 isolation, 169 isothermal, 186 issues, 80, 112, 118, 142 Italy, 135, 145

J Japan, 39, 147, 148, 150, 151, 152, 154, 158, 159, 161, 162, 165, 168, 172 jaundice, 154, 175

K keratin, 65 kidney, 109, 150, 156 kidneys, 97 kinetics, 36, 41, 122, 143, 162

L LA, 190, 194 lactic acid, 97, 100, 190, 202 lactose, 3, 20, 22, 26, 27, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 48, 49 lanthanum, 114 laparotomy, 154 larynx, 4, 12 lead, vii, 1, 3, 11, 21, 27, 29, 31, 65, 92, 106, 197 leadership, 176 leakage, 94, 102, 126, 156, 162, 164 lens, 66 lesions, 159, 160, 185 leucine, 24, 25, 44, 174 leukemia, 114, 130, 133, 150, 151, 153, 166, 175 liberation, 156 Lidocaine, 203 life expectancy, 154 life sciences, 148 ligand, viii, 102, 103, 125, 126, 127, 128, 129, 130, 132, 171 light, viii, 60, 65, 67, 91, 108, 109, 111, 194, 195 limitation, 191 limitations, 186 lipid, 187, 202, 203, 204 lipids, ix, 6, 78, 93, 125, 128, 132, 151, 159, 191, 203

Index lipophilic, 191 liposome, 204 liposomes, viii, x, 64, 68, 69, 77, 92, 93, 94, 95, 100, 102, 104, 105, 107, 113, 114, 115, 116, 119, 120, 125, 126, 127, 128, 129, 130, 131, 132, 133, 137, 148, 160, 163, 191, 204 liquid chromatography, 150 liquids, 31, 54, 61, 63, 77, 111 liver, 94, 97, 104, 106, 109, 114, 116, 132, 144, 154, 155, 164, 167, 171, 178 liver cancer, 106, 164, 167, 171 liver cells, 114 L-lactide, 202, 203 localization, 92, 116, 173 locus, 92 low molecular weight, 203, 204 lubricants, 60 lung cancer, 7, 102, 107, 114, 176 lung disease, 143 lung function, 13 Luo, 121 lymph, 151, 155 lymph node, 151, 155 lymphatic system, 151, 154, 155 lymphocytes, 115, 140 lymphoid, 169 lymphoma, 105, 118, 119, 150, 169 lysine, 111, 145, 151, 160, 201

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

M mAb, 98, 99 macromolecules, x, 7, 78, 79, 80, 137, 148, 151, 155, 160, 163, 164, 173, 178, 187, 190 macrophages, 97, 104, 140, 143, 153 macular degeneration, 103, 118 magnesium, 22, 25, 38 magnetic, 192 magnetic properties, 108 magnetic resonance, 122 magnitude, 109 man, 45, 110 management, 104, 142 mandatory retirement, 165 manipulation, 132, 140 mannitol, 20, 24, 27, 35, 40 manufacturing, 60, 61, 66, 77, 112, 116, 152, 202 mapping, 42 marketing, 152, 167 masking, 60, 62, 67, 81 mass, 9, 10, 11, 13, 15, 35, 38, 53, 185 mass media, 10

215

materials, 33, 44, 45, 53, 63, 65, 67, 78, 95, 100, 112, 185, 191 matrix, viii, 51, 65, 66, 67, 68, 95, 100, 131, 163, 173, 190, 191, 203 matrix metalloproteinase, 131, 163, 173 measurement, 9, 22, 33, 36, 43, 47, 108, 109, 122, 194 measurements, 15, 16, 26, 28, 33, 35, 44, 192, 194 measures, 199 mechanical properties, 29 media, 86, 88, 184 median, 10, 11, 22 mediation, 131, 140 medical, viii, x, 42, 43, 49, 62, 79, 91, 112, 178, 179, 182, 185, 186 medical science, viii, x, 91 medication, 57, 59, 60, 102 medicine, viii, xi, 33, 34, 47, 51, 52, 57, 58, 59, 63, 64, 65, 79, 83, 86, 92, 108, 113, 114, 137, 178, 189 melanoma, 117, 128, 130, 162 melting, 195, 196, 200 melts, 66 membranes, 68, 78, 81, 93, 97, 204 mentor, 148, 162 mercury, 43, 194 MES, 103, 109 metabolic, 187 metabolism, 4, 44, 58, 61, 63, 65, 66, 79, 80, 136, 164 metal ion, 190 metal ions, 190 metal nanoparticles, 92 metalloproteinase, 131, 156 metals, 38 metastasis, 92, 132, 151 metastatic cancer, 117 methanol, 99, 197 methodology, 16 Miami, 91 mice, 106, 109, 111, 116, 117, 122, 128, 130, 158, 160, 161, 166, 170, 171, 172, 174, 179, 201 micelles, 148, 160, 165, 166, 174 microcalorimetry, 186, 192, 205 microcirculation, 174 microemulsion, 205 microheterogeneity, 148 micrometer, 80 microorganism, 63, 64 microorganisms, x microparticles, 202, 203, 204 microscope, 162, 180, 181, 183 microscopy, 2, 33, 37, 39, 42, 47, 186

Index

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

216

microspheres, 44, 63, 64, 92, 113, 115, 191, 201, 202, 203, 205 mild asthma, 49 miniature, 41 Ministry of Education, 168 mission, 8 misuse, 43 mixing, 6, 11, 24, 28, 29, 31, 32, 33, 36, 39, 40, 41, 48, 52 mobility, 192 modelling, 35, 143 models, 103, 120 modification, 148, 151, 160, 166 modifications, viii, 38, 51, 60, 67, 80, 82, 130, 137 moisture, 15, 26, 29, 60, 61, 64 moisture content, 15, 64 molecular biology, 46 molecular mass, 151, 185 molecular weight, 61, 65, 97, 100, 101, 110, 117, 171, 173, 191, 202, 203, 204 molecules, xi, 21, 41, 43, 63, 77, 78, 92, 95, 97, 102, 103, 111, 118, 129, 137, 141, 159, 172, 177, 178, 186, 193 monoclonal antibody, 103, 116 monomers, 100 morphology, 6, 7, 18, 21, 22, 25, 26, 34, 41, 43, 49, 64 morphometric, 38 mortality, 43 Moscow, 167, 172 mouse, 187 MRI, 108, 111, 121, 122 mRNA, 107 mucosa, 61, 136, 140 mucus, 6, 7 Multifunctional nanoparticles, viii, 91 multiple factors, 4, 163 multiplication, 158 mutagen, 172 mutant, x, 147 mutation, 159, 168, 172 mutations, 92 myocardial infarction, 165

N NaCl, 82 nanocarriers, viii, 64, 125, 126, 127, 129, 130, 131 Nanocarriers, 126, 130 nanocrystals, 108 nanomaterials, 108, 112, 137 nanomedicine, x, 148, 161 nanometer, 80, 96

nanometers, 23, 77, 80 nanoparticles, vii, viii, xi, 37, 62, 68, 82, 91, 92, 95, 96, 97, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 111, 112, 113, 115, 116, 117, 119, 120, 121, 122, 163, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205 nanoparticulate, 191, 202 nanorods, 109, 121 nanostructures, 109 nanotechnology, viii, 66, 91, 110, 112, 113, 131, 190 National Institutes of Health, 149 natural, 190 natural killer cell, 153 natural polymers, 97 NCS, x, 147, 149, 150, 151, 152, 153, 158, 160, 166, 167 nebulizer, 58, 63, 75, 80 neck cancer, 94 neovascularization, 162 nerve, 78 neurotoxicity, 127, 131 neutral, 97 next generation, 4 NH2, 99 NIR, 108, 109 nitric oxide, x, 148, 159, 172, 173, 175 nitric oxide synthase, 173 nitrogen, x, 27, 147 nitrogen gas, 27 NMR, 167 noncoated PLGA NP, xi, 189 nonequilibrium, 200 nonirritant, 62 non-polar, 21 nontoxic, 204 norfloxacin, 202 normal distribution, 10 North America, 113, 119 novel materials, viii, 91 NRP, 129 N-terminal, 203 nucleic acid, 79, 123, 137, 140, 145, 159, 172 nucleus, 137 nuisance, 186 null, 139 nutrient, 69, 106 nutrients, 62, 159, 162, 164

O obstruction, 6, 7, 12 occupational health, 112 oil, 57, 62, 63, 64, 77, 159, 172

Index

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Oklahoma, 161 oleic acid, 178, 179, 183 oligonucleotides, 191, 204, 205 omeprazole, 60 operations, 44 opportunities, 92, 100, 108, 110 optical, 186, 187 optical microscopy, 186 optical properties, 121 optimal performance, 97 optimization, 54 oral, 200, 202 oral drop, vii, 51, 53 organ, 92, 109, 169 organelles, 137 organic, 191, 192 organic solvent, 191, 192 organic solvents, 191 organism, 137 organs, 94, 140, 190 osmotic pressure, 164 osteoporosis, 136 osteotomies, 202 ovarian cancer, 94, 103, 114, 118 ovarian tumor, 103 oxidation, 59, 60 oxidative stress, 158, 172 oxide nanoparticles, 108, 121 oxygen, 53, 57, 61, 115, 159, 162, 164, 165, 172, 174

P paclitaxel, 68, 77, 97, 100, 102, 106, 115, 116, 117, 118, 120, 121, 126, 129, 132, 201, 202 pain, x, 52, 53, 147, 156, 162 palivizumab, 76, 89 paradigm, 172 parallel, 159 parameter, 191, 192, 200 parathyroid, 75, 87 parathyroid hormone, 75, 87 particle mass, 6, 11, 17, 30 particle morphology, 38, 39, 46 particles, xi, 189, 191, 192, 193, 194, 195, 196, 198, 199, 200 pathogenesis, x, 147, 158, 171, 172 pathogens, 158 pathologist, 150 pathology, 37 pathophysiology, 164 pathways, 190 PCT, 33

217

pegfilgrastim, 73, 86 peptide, 98, 128, 129, 132, 140, 145, 178, 179, 183, 185, 186, 187, 188, 204 peptides, ix, x, 48, 79, 80, 125, 128, 135, 136, 137, 140, 145, 169, 177, 179, 180, 181, 182, 184, 185, 186, 187, 190, 191, 202, 203 percolation, 11, 15 perforation, 14 performance, 168 peripheral blood, 78 peritoneal cavity, 59 permeability, x, 54, 65, 78, 100, 117, 118, 147, 153, 159, 160, 162, 163, 165, 171, 173, 174, 175 permeation, 65, 79, 179 permission, 161 peroxynitrite, 159, 172, 173 pertussis, 74, 87 PET, 108, 121 PGA, xi, 189, 190, 200 pH, 52, 58, 59, 60, 62, 64, 66, 67, 79, 100, 122, 129, 132, 151, 165, 190, 191, 192, 193, 195, 198, 200 phagocyte, 115 phagocytosis, 103 pharmaceutical, vii, viii, 2, 19, 23, 32, 33, 34, 35, 36, 37, 38, 39, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 59, 62, 65, 68, 80, 81, 97, 115, 130, 131, 190 pharmaceutical dosage forms (PDFs), vii, 51 pharmaceuticals, 118, 152, 166 pharmaceutics, xi, 32, 33, 34, 35, 36, 37, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 81, 177, 186, 200 pharmacogenomics, 132 pharmacokinetic, 204 pharmacokinetics, 33, 112, 118, 126, 132, 151, 152, 153, 162, 166, 167, 169 pharmacology, 33, 41, 45, 46, 48, 152, 175 pharynx, 4, 12 phenylalanine, 24 Philadelphia, 33, 81 phosphate, ix, 107, 135, 136, 144, 178, 179 phosphatidylethanolamine, 204 phospholipids, 93, 128 phosphorylation, 144 photobleaching, 109 photon, 192 photons, 108 physical activity, 78 physical characteristics, 34 physical chemistry, 42 physical properties, 2, 28, 34, 43, 44, 46, 202 physicochemical, 204 physicochemical characteristics, 111 physicochemical properties, vii, 1, 2, 3, 4, 8, 15, 18, 25, 30, 31, 32, 53, 65, 81, 100, 204

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

218

Index

physico-chemical properties, 190 physicochemical/pharmacokinetic profile, viii, 51, 67 physiological, xi, 189 physiological factors, 41 physiology, 4, 37, 38, 39, 44, 47, 140, 164 piezoelectric crystal, 64 pigs, 34, 156, 171 placebo, 142 plasma levels, 139 plasma membrane, x, 78, 177, 178 plasma proteins, 156 plasmid, 187, 203, 204 platform, vii, 1 platinum, 199 play, 197 PLGA, xi, 189, 190, 191, 192, 193, 195, 196, 197, 198, 200, 201, 202, 205 PM, 86, 144 PNA, 140, 145 pneumonia, 157, 172 polar, 21, 27, 65, 93 polar groups, 21 polarity, 21, 191, 197, 200 poly(lactic-co-glycolic acid), 202 polydispersity, 10, 11, 38 polyesters, 203 polyethylene, 204 polyethylenimine, 204 polymer, x, 65, 66, 92, 95, 100, 101, 102, 104, 107, 110, 116, 126, 147, 148, 151, 152, 153, 158, 161, 166, 167, 169, 170, 171, 172, 175, 191, 199, 202, 203 polymer chain, 65 polymer chains, 65 polymer materials, 100 polymer matrix, 191, 203 polymeric chains, 114 polymeric materials, viii, 91 polymeric matrices, 63 Polymeric nanoparticle chemistry, viii, 91 polymers, viii, 62, 66, 67, 91, 97, 100, 105, 110, 112, 115, 151, 162, 173, 190, 191, 201, 202, 203 polymorphism, 43, 45 polypeptide, 170 polypeptides, 80, 203 polysaccharide, 97 Polysaccharides, 113 polyvinyl alcohol, 202 polyvinylalcohol, 99 population, 32, 92, 142 porosity, 30, 31 pranlukast, 41

precipitation, 99 precision engineering, 116 preparation, 48, 52, 62, 93, 96, 97, 100, 104, 115, 187, 201, 202 preservative, 63, 72 pressure, 198 Pressured metered dose inhaler (pMDI), vii, 1 prevention, 123 principles, 33, 34, 45, 63, 81 prior knowledge, 160 probability, 13, 31 probe, 29, 47 proctitis, 142 prodrugs, 114, 131 product market, 66 production, 200 program, 201 pro-inflammatory, 140 project, 142, 149, 150, 152, 157 proliferation, 92 propagation, 159 protease inhibitors, 148, 159 proteases, 147, 148, 156, 157, 158, 165, 171 protection, 34, 63, 66, 191 protein, 186, 187, 188 proteins, ix, x, 6, 48, 70, 78, 79, 80, 83, 94, 95, 97, 125, 128, 137, 148, 153, 156, 158, 159, 160, 166, 167, 170, 172, 177, 179, 180, 181, 182, 185, 186, 187, 190, 205 proteolysis, 145 proteolytic enzyme, 170 proteomics, 92 prototype, 167, 170, 174, 175 Pseudomonas aeruginosa, 156 pulmonary route, vii, 1 pumps, 66 purines, 159 purity, 149 PVA, 98, 99, 192, 200

Q quality of life, 104, 112 quantification, 33, 40, 184 quantum dot, 99, 108 quantum dots, 99, 108 quaternary ammonium, 102 quercetin, 100

R radiation, 92, 108, 128

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Index radicals, 158, 172 radio, 92, 156 radiologists, 160 radiotherapy, 92, 108, 114 range, 196, 200 rats, 201 raw materials, 48 Rayleigh, 194, 199 reactions, 59, 63, 78, 79, 168 reactive nitrogen species (RNS), x, 147 reactive oxygen, x, 147, 167 reactive oxygen species (ROS), x, 147 real time, 108 reality, 22, 112 receptor/ligand recognition, ix, 125, 126 receptors, ix, 5, 97, 103, 104, 125, 128, 129 recognition, ix, 95, 111, 112, 125, 126, 157 recombinant DNA, 70, 73, 79, 83 recommendations, 53, 157 rectum, 66, 67 recurrence, 136, 154 red blood cells, ix, 135, 136, 138, 141, 144 red blood cells (RBCs), ix, 135, 136 redistribution, 32 referees, 160 rehydration, 59 relationships, 201 relatives, 151 relevance, 137 relief, 52, 160 remission, ix, 135, 136, 138, 139, 140, 142 renal cell carcinoma, 119, 164 replication, 143 reproducibility of dose delivery, vii, 1 reproduction, 157 repulsion, 200 requirements, 2, 31, 53, 97 RES, 94, 95, 127 researchers, 18, 27, 93, 95, 102, 104, 106, 107 residues, 149, 152, 178, 191 resistance, 19, 57, 77, 104, 105, 107, 117, 119, 120, 175 resolution, 108, 176, 192 resources, 84, 149 response, 16, 17, 39, 45, 48, 92, 95, 96, 103, 111, 132, 136 retinitis, 79 retirement, 157, 165, 171 rheumatoid arthritis, 144 risk, 57, 62, 77, 112, 118, 127, 136, 137, 139 risk factors, 112 risks, 123 rituximab, 103, 118, 119

219

RNA, 80, 103, 107, 116, 118, 121 RNAs, 107 room temperature, 138, 179, 192, 199 roughness, 3, 16, 22, 23, 37, 41, 42, 44, 46, 49 routes, viii, 51, 52, 53, 54, 57, 59, 62, 66, 79, 80, 95 Royal Society, 40 Russia, 192 Russian, 192

S safety, ix, 8, 57, 111, 112, 115, 116, 118, 135, 138, 139, 142, 186, 190 saliva, 61 salmon, 71, 84 salmonella, 174 salts, 59, 114, 192, 200 sample, 199 saturated fat, 22 saturated fatty acids, 22 saturation, 25, 26 scattering, 194, 199 science, x, 33, 41, 42, 43, 47 screening, 149, 168 secrete, 173 sedimentation, 6, 9 segregation, 11, 15, 33 selectivity, ix, x, 113, 125, 140, 148 semi-empirical method, 12 semi-empirical methods, 12 sensation, 63 sensitivity, 149, 192 sequencing, 106, 149, 150 serine, 157 serum, 94, 95, 102, 103, 138, 204 serum albumin, 102 shape, vii, 1, 3, 9, 15, 16, 18, 19, 20, 21, 26, 28, 29, 30, 38, 44, 45, 48, 52, 60, 100, 104, 112, 137, 192, 198, 199 shear, 14, 22, 24, 34, 37 shelf life, vii, 51, 53, 54, 60, 77 shock, 175 showing, 3, 109, 194, 199, 204 sialic acid, 95 side effects, viii, ix, 4, 58, 59, 65, 69, 91, 92, 100, 104, 125, 126, 127, 136, 138, 139, 140, 167 signaling pathway, 159 silica, 203 silicon, 67 simulation, 170 Singapore, 201 siRNA, 98, 99, 105, 107, 111, 116, 120, 121, 130, 133, 191

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

220

Index

skin, x, 54, 58, 59, 62, 64, 65, 66, 78, 79, 121, 156, 161, 177, 178, 179, 180, 181, 182, 183, 185, 186, 187, 188, 205 small intestine, 60 SMANCS, x, 147, 148, 151, 152, 153, 154, 155, 160, 161, 163, 164, 166, 167, 169, 170, 171, 172, 174, 175 smooth muscle, 164 smoothing, 22, 35, 37, 48 smoothness, 3, 22, 23 sodium, 35, 48, 70, 71, 73, 75, 76, 77, 79, 86, 89, 118 software, 180, 183 solid state, 53, 54, 62 solid tumors, x, 101, 132, 148, 156, 160, 161, 163, 164, 168, 171, 172 solubility, 24, 57, 62, 63, 64, 65, 67, 68, 77, 78, 95, 100, 190 solution, 54, 57, 58, 62, 63, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 80, 82, 180, 192, 193, 197, 198, 200 solvent, 191, 193, 197, 198, 200, 201, 202 solvents, 21, 62, 66, 100, 191 sorption, 47 sorption kinetics, 47 space, 151, 156, 164 species, x, 147, 167, 178 specific heat, 192, 193, 194, 195, 196, 197, 198, 199 specific surface, 26, 27 specifications, 151 spectrophotometric, 192, 199 spectroscopy, 192, 199 spectrum, 194, 199 speed, 195, 200 spin, 59 spleen, 94, 104, 156 sponge, 72 sponges, 203 spore, 82 SSA, 2, 27 stability, vii, xi, 1, 13, 26, 30, 31, 46, 53, 57, 59, 60, 61, 62, 63, 65, 94, 95, 103, 111, 131, 179, 189, 191, 192, 196, 198, 200, 203, 204, 205 stabilization, 52 standard deviation, 2, 10 starch, 95 state, viii, 7, 19, 31, 34, 51, 53, 54, 55, 58, 64, 136, 137, 142, 202 states, 47, 54, 87, 89 stent, 113 sterile, 57, 58, 60, 62, 63, 64, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79 steroids, ix, 135, 136, 138

stomach, 58, 60, 68, 131, 200 storage, 34, 66, 93, 94, 95, 113, 115, 191, 196 strategies, 186 strategy, 151, 153, 172 strength, 200, 203 structure, 21, 97, 100, 193, 199, 200 style, 122 styrene, x, 147, 151, 152, 153, 169, 170, 174 subcutaneous injection, 63, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 151 subcutaneous tissue, 121 subgroups, 139 substances, xi, 189 substrate, 29, 44, 46, 140, 145 success rate, 92 sucrose, 62 sulfate, 12, 39, 40, 41, 60, 132 sumatriptan, 188 Sun, 107, 120 supervision, 149 support services, 150 suppository, vii, 51, 53 suppression, 137, 139 surface area, vii, 1, 2, 4, 5, 14, 16, 26, 27, 28, 42, 43, 64, 77, 95, 110 surface energy, 24, 27, 28, 33, 35 surface modification, ix, 26, 40, 95, 125, 126, 128, 130, 191 surface properties, 16, 22, 29, 37, 47, 97 surface tension, 64 surface treatment, 36, 39, 44 surfactant, 6, 44, 77, 115, 202 surfactants, 64, 77, 112 surgical resection, 154 surgical technique, 79 survival, 106, 112, 145, 158, 166, 185 susceptibility, 94 suspensions, 54, 57, 62, 63, 64, 79, 195 swelling, 68, 95, 100, 191, 193, 199 Switzerland, 40 syndrome, 136 synergistic effect, 106, 108, 109 synthesis, 37, 144, 150, 151, 152, 170 synthetic polymeric materials, 107 synthetic polymers, 95, 97, 137 Syria, 1

T T cell, 153 Taiwan, 177, 179, 186 tamoxifen, 98, 99, 105, 116

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Index target, viii, ix, 11, 53, 68, 91, 92, 94, 95, 97, 100, 102, 103, 106, 108, 110, 114, 126, 130, 135, 136, 138, 140, 141, 145, 201 target population, ix, 135 Taxol, 201, 202 Tbilisi, 189, 194, 201 T-cell, 203 technetium, 70, 73, 83, 86 techniques, 10, 18, 26, 29, 32, 33, 42, 52, 92, 191, 202 technologies, 54, 68, 203 technology, viii, ix, 7, 18, 28, 33, 36, 38, 39, 42, 43, 46, 48, 52, 66, 67, 68, 70, 77, 78, 79, 80, 83, 113, 136, 141, 187 teeth, 61 temperature, xi, 21, 22, 29, 37, 78, 109, 179, 189, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 205 temperature dependence, 200 tension, 64 tensions, 64 testing, 35, 46, 118, 204 testosterone, 186 tetanus, 74, 87 textbook, 45 texture, vii, 1, 4, 15, 22, 29 therapeutic agents, viii, 13, 79, 91, 118, 137, 190 therapeutic approaches, 92, 136 therapeutic effects, ix, 116, 117, 121, 126, 129 therapeutics, viii, ix, xi, 79, 91, 103, 104, 105, 107, 117, 135, 143, 152, 161, 172, 173, 174, 177, 186 therapy, vii, viii, 10, 34, 41, 47, 51, 53, 59, 79, 92, 94, 97, 98, 104, 106, 107, 108, 109, 110, 111, 112, 113, 115, 116, 118, 121, 122, 125, 131, 132, 136, 139, 142, 153, 154, 174, 175, 201, 202 thermal expansion, 193 thermodynamic, 191, 192, 195, 198 thermodynamic parameters, 195, 198 thrombin, 75, 79, 88 thyrotropin, 76, 89 tics, 49 time series, 43 tincture, 52 tissue, viii, 4, 59, 61, 79, 91, 92, 97, 100, 101, 108, 109, 111, 140, 143, 151, 154, 155, 156, 159, 160, 161, 162, 164, 165, 167, 170, 173, 201, 203 tissue engineering, 203 TNF, 140, 145 TNF-alpha, 145 TNF-α, 140 topology, 34 toxic, 190 toxic products, 137

221

toxicity, viii, 53, 91, 92, 100, 101, 110, 111, 112, 116, 166, 174, 175, 201 toxicology, 45 trachea, 4, 5, 12 trafficking, 116 training, 8 trans, 186 transcription, 140 Transdermal drug delivery system (TDDS), x, 177, 178, 186 transducer, 78 transduction, 178, 185, 187, 188 transfection, 107, 191, 203, 204, 205 transfer, 200, 201, 203, 204 transferrin, 103, 130, 132, 133, 160, 204 transformation, 40, 132 transfusion, 137 transition, 193, 195, 196, 197, 198, 200 transition temperature, 193, 195, 196, 197, 198, 200 translocation, 187, 203 transmission, 79 transparency, 194 transplantation, 118 transport, xi, 47, 58, 78, 101, 177, 178, 179, 182, 186, 187, 205 transportation, vii, 51, 53, 54, 78, 129, 190 treatment, vii, viii, 1, 11, 32, 44, 60, 65, 79, 80, 91, 92, 93, 101, 102, 103, 105, 108, 109, 113, 114, 115, 118, 119, 120, 126, 127, 130, 131, 133, 136, 137, 138, 139, 140, 142, 144, 180, 184, 185, 187 treatment methods, 92 trial, 102, 113, 114, 117, 118, 138, 139, 143 triggers, 158 trypsin, 150, 162 tumor, x, 68, 100, 101, 102, 103, 104, 106, 107, 108, 111, 115, 116, 117, 119, 120, 121, 122, 123, 126, 127, 128, 129, 131, 132, 142, 148, 149, 150, 153, 154, 155, 159, 160, 161, 162, 164, 165, 166, 168, 170, 171, 172, 173, 174, 175, 187 tumor cells, 104, 122, 128, 132, 164, 166, 168, 175 tumor growth, 108, 128, 129, 159, 162, 164 tumor necrosis factor, 142, 163 tumors, viii, x, 91, 100, 101, 103, 104, 106, 108, 111, 112, 120, 121, 122, 127, 128, 132, 148, 153, 154, 160, 161, 162, 163, 164, 165, 168, 173, 174 tumour growth, 175 tumours, 175 turbulence, 6 tyrosine, 159

U UK, 1, 33, 161, 164, 174, 192

Index

222 ulcer, 79 ulcerative colitis, 136, 138, 139, 141, 142, 143, 144 ultrasound, 78 ultrastructure, 38 UN, 180, 183 uniform, 10, 28, 29, 57, 62, 97, 100, 145 United, 47, 48, 92, 118, 122, 142 United States, 47, 48, 92, 118, 122, 142 upper airways, 6 upper respiratory tract, 4, 6, 7 urea, 150 urethra, 66 urinary bladder, 153 urine, 160 USA, 39, 91, 122, 125, 143, 179, 180, 192, 204

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

V vaccine, 63, 70, 71, 73, 74, 75, 76, 83, 84, 85, 87, 88, 89, 113 vagina, 66, 67 valuation, 205 values, 200 variable factor, 8 variables, 4, 43, 101 variations, 3, 6, 11, 178 vasculature, 100, 104, 106, 107, 111, 127, 162, 164, 174 vector, 82, 97, 129, 140, 204 vehicles, viii, 52, 68, 100, 125, 127 vein, 59 velocity, 6, 31, 167 ventilation, 6, 7 versatility, 104 vessels, 78, 106, 162, 164 vibration, 64 Vietnam, 149 violence, 149 viral diseases, 172 viral infection, x, 147, 158

virus, 186, 187, 201, 203 virus infection, 147, 158, 159, 172 viruses, 79 viscose, 77 viscosity, 62, 64, 200 vision, 70 vitamins, 97 vomiting, 58

W warts, 65 water, 9, 13, 22, 40, 47, 52, 53, 57, 59, 60, 61, 62, 63, 64, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 93, 108, 111, 179, 180, 192, 193, 195, 197, 198, 199, 200 water absorption, 13, 108 water structure, 40 water vapor, 13 wetting, 22, 60 withdrawal, 138 workers, 110 worldwide, 92

X X-ray, 154, 155, 167, 171 X-ray diffraction, 186

Y yield, 29, 108, 126

Z zinc, 166, 174, 175