Handbook of Space Pharmaceuticals 3030055256, 9783030055257

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Yashwant V. Pathak Marlise Araujo dos Santos Luis Zea Editors

Handbook of Space Pharmaceuticals

Handbook of Space Pharmaceuticals

Yashwant V. Pathak • Marlise Araujo dos Santos • Luis Zea Editors

Handbook of Space Pharmaceuticals With 99 Figures and 57 Tables

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

Marlise Araujo dos Santos InnovaSpace Ltd London, UK

Faculty of Pharmacy Airlangga University Surabaya, East Java, Indonesia Luis Zea BioServe Space Technologies University of Colorado Boulder Boulder, CO, USA Universidad del Valle de Guatemala Guatemala City, Guatemala

ISBN 978-3-030-05525-7 ISBN 978-3-030-05526-4 (eBook) ISBN 978-3-030-05527-1 (print and electronic bundle) https://doi.org/10.1007/978-3-030-05526-4 © Springer Nature Switzerland AG 2022 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To the loving memories of my parents and Dr. Keshav Baliram Hedgewar, who gave proper direction to my life, to my beloved wife Seema who gave positive meaning, and to my son Sarvadaman who gave a golden lining to my life. I would like to dedicate this book to the loving memories of Ma Chamanlaljee, Ma Lakshmanraojee Bhide, and Ma Madhujee Limaye who mentored me selflessly and helped me to become a good and socially useful human being. Yashwant V. Pathak I would like to dedicate this book to my mother, Noemy Araujo dos Santos and to my husband, Arno Kieling Steiger for always being by my side and believing in me. Marlise Araujo dos Santos To Maria, Julia, and Amelia, the shining stars in my night sky. Luis Zea

Foreword

The presence of gravity on Earth has played an integral part in the development of life over billions of years, shaping the anatomy and physiology of human beings. The removal of this gravitational force, as when exposed to the microgravity of space, is known to have an effect on our entire body. It causes numerous alterations, such as important cardiopulmonary changes, disturbances of the neurological system, decreases in bone and muscle mass, and impairment of the immune function. These physiological responses to microgravity can lead to undesirable health consequences and even to operational difficulties, especially considering clinical situations and medical emergencies. A further factor of great concern is the exposure of humans to the increased levels of radiation present in space, which can cause significant damage to the body and mind, potentially leading to sickness and difficulties during and post spaceflight. Disease and disease prevention is an inherent part of our lives here on Earth, and the role of the pharmacist in maintaining health is significant. This equally applies to the human presence in space, and indeed, because there are still many unknown factors regarding this unique environment, the importance of space pharmacy in medication management and research is even magnified. Until now, visitors to space have in general been professional astronauts, in good health and having undergone a considerable period of training and monitoring. The advent of space tourism will see greater numbers of private citizens being sent into Earth’s orbit by space companies, likely at older ages and having existing health issues that would previously have precluded them from travelling into space. Moreover, the emergence of plans for Lunar habitats and long-duration voyages to Mars will require more thought and planning when preparing medical kits, factoring in the additional effects of greater radiation exposure and the longer periods of time spent in reduced gravity environments. The Handbook of Space Pharmaceuticals comes into print at this unique moment in space exploration, providing a major reference work of the current knowledge and research linked to off-Earth pharmaceuticals use. The emerging dynamic space era will see an expansion of commercial space and space agency activities in a fastmoving industry, imposing new medical challenges for space doctors, pharmacists, and scientists. This handbook presents an extremely comprehensive collection of chapters related to the physiological and psychological adaptation of humans to the vii

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hostile environment of space, together with works that discuss specific aspects related to the development and use of medications applied to the area of human space exploration. The use of medication in space missions began in 1961, with the first human flight into Earth’s orbit by cosmonaut Yuri Gagarin. Pharmacological kits have been carried onboard spacecraft ever since, trying to anticipate the range of illnesses and injuries that could occur during missions and ensuring the availability of suitable medicinal remedies. However, 50 years later, there remains a deficiency in knowledge regarding the pharmacodynamics and pharmacokinetics of medication use in space. The physiological modifications induced by weightlessness also act on the drugs administered during spaceflight, with possible pharmacological and toxicological consequences. Accordingly, the relationship between dosage regime and the circulating concentration, as well as medication effects and drug concentration, is not fully understood. For example, oral drug absorption is altered in microgravity secondary to a wider dispersion of the medication in the stomach and changes in gastrointestinal motility. Drug distribution, on the other hand, might be affected by the headward shift of blood and body fluids that happens in microgravity, which in turn influences blood supply to tissues and plasma protein concentration. Clearly, much more research is needed in this area. The Handbook of Space Pharmaceuticals is not intended to answer all the open questions related to medication use in space; however, it does provide the reader with a comprehensive review of the existing literature and research findings, from a broad interdisciplinary viewpoint and with chapters written by leading experts from around the world. Furthermore, it can serve to highlight the numerous areas in space pharmacy that require more investigation if humankind is ever to reach Mars in good health. Overall, it is an absorbing resource directed at health professionals, researchers, professors, and students, who can discover more on topics like pharmacogenomics in spaceflight, drug delivery systems in microgravity, nutrition and homeopathy as treatment for astronauts, how protein crystalizes without gravity, the benefits of using melatonin in space missions, 3D printer use for space pharmaceuticals, or the effect of microgravity on microemulsions and nanoemulsions. These and many more topics linked to the current knowledge in space pharmaceuticals are presented through the chapters of this handbook. I hope it inspires and motivates present and next generations of health professionals and space enthusiasts to contribute to the space knowledge and the success and safety of future crewed missions to Earth’s orbit, the Moon, Mars, and beyond. Prof. Thais Russomano, MD, MSc, PhD

Preface

Since the onset of human spaceflight in 1961, just a little over 600 people have flown to space. Nevertheless, access to lower Earth orbit (LEO) continues to increase for people of different nationalities and backgrounds. Additionally, programs for human spaceflight beyond LEO, namely to the Moon and Mars, are now in full motion, and some of these missions will likely extend beyond the typical approximately 6-month stay on the International Space Station (ISS). In fact, human missions to Mars will take years as the correct alignment between the two planets and the Sun is needed to minimize fuel requirements and cruise time on each of the two trips. However, the first 60 years of human spaceflight have shown that there are direct and indirect effects of microgravity, space radiation, living in an isolated confined environment (ICE), and other hallmarks of space missions on human health. Medicines have been part of space exploration since 1963, but so far, many questions have not been answered. Do drugs used in space have the same pharmacological effect as when they are used on Earth? What types of effects on human health, pathogenic processes, the spacecraft’s microbiome, and pharmaceuticals can we expect based on our current knowledge? Can we use these changes to find novel solutions to medical problems on Earth? Considering the high cost of space missions, what type of analogs can be used to simulate microgravity on Earth? We have put together this Handbook of Space Pharmaceuticals to help prepare the current and next generation of space medicine and pharmaceutical specialists, life science researchers, project managers, and engineers, so that space programs – may they be commercial, national, or international – can be ready for inevitable medical needs of the crew in space. To do so, and acknowledging that to overcome these challenges a multidisciplinary approach is needed, the handbook is structured in a fashion that enables non-specialists to understand the basic concepts of the different fields needed. The handbook begins with a part titled “Principles of Pharmaceuticals,” where the current basis of knowledge is explained in general terms as well as within the context of spaceflight. The part “Effects of Spaceflight on Human Physiology and Its Consequences on Drug Treatment” describes what we have learned so far of changes to each of the human body systems as a result of spaceflight, and their consequences for drug treatments. The parts “Model Organisms for Pharmaceutical Research in Space” and “Simulated Microgravity for Pharmaceutical Research” provide insight into what kind of studies have been ix

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performed on orbit in vitro, and what can be done in labs on Earth to replicate some aspects of spaceflight for further research, respectively. In “Translating Knowledge from Spaceflight Research to Earth Applications,” details are provided on how space has been used for drug discovery, vaccine development, and protein crystallization for their potential use on Earth. Finally, “Nutritional and Alternative Approaches to Treatment in Space” includes chapters that cover fields from homeopathics to the use of nutraceuticals for reducing the effects of radiation. The comprehensiveness of this handbook in terms of the fields being covered – which is needed to provide a complete overview of the challenges and potential solutions – was possible thanks to the experts who wrote each of the chapters. Research leaders across the world on pharmacology, microgravity research, and spaceflight medicine kindly contributed to this handbook by sharing their respective expertise, writing it in a fashion that is easy to understand for non-specialists. It is our hope that this handbook serves as a guide in the field of pharmaceuticals and drug treatments in space, and ultimately results in as safe human spaceflight missions as possible. Yashwant V. Pathak Marlise Araujo dos Santos Luis Zea

Acknowledgments

Zea Luis Zea was in part supported by the National Aeronautics and Space Administration Grants No. 80NSSC17K0036, 80NSSC18K1468, and 80NSSC19K0708, as well as by BioServe Space Technologies and Universidad del Valle de Guatemala. dos Santos I would like to thank my partner Arno and my mother Noemy who unconditionally supported me in developing this work. Thank you God for blessing me!

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Contents

Part I

Principles of Pharmaceuticals

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1

1

Introduction to Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . Keshav S. Moharir, Vinita V. Kale, Abhay M. Ittadwar, and Yashwant V. Pathak

3

2

Understanding the Routes of Administration . . . . . . . . . . . . . . . . . Deepak Gupta, Sheeba Varghese Gupta, and Ningning Yang

23

3

Physicochemical Basic Principles for Solid Dosage Forms . . . . . . . Pradeep Kumar, Priyamvada Pradeep, Sunaina Indermun, Mershen Govender, Yahya E. Choonara, and Viness Pillay

49

4

Physicochemical Basic Principles for Liquid Dosage Forms Pooja Kiran Ravi and Sheeba Varghese Gupta

.....

69

5

Solid Dosage Forms: Formulation and Characterization . . . . . . . . Shambhavi Borde, Dhirender Singh, Navneet Sharma, Dunesh Kumari, and Harsh Chauhan

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6

Pharmaceutical Liquid Dosage Forms in Space: Looking Toward the Future by Learning from the Past . . . . . . . . . . . . . . . . Ashim Malhotra

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7

Nano Drug Delivery Systems for Space Applications . . . . . . . . . . . Jayvadan Patel and Anita Patel

8

Basic Principles of Biopharmaceutics and Pharmacokinetics During Spaceflight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Yichao Yu, Christoph N. Seubert, and Hartmut Derendorf

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Medications in Microgravity: History, Facts, and Future Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Joan Vernikos

165

9

113

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10

11

12

Contents

Evaluation of Physical and Chemical Changes in Pharmaceuticals Flown on Space Missions . . . . . . . . . . . . . . . . . . . Tekilanand Persaud and Yashwant V. Pathak

179

Implications of Microgravity on Microemulsions and Nanoemulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aditya Grover and Yashwant V. Pathak

209

Three-Dimensional Printing (3DP) for Space Pharmaceuticals . . . Viness Pillay, Samson A. Adeyemi, Pradeep Kumar, Lisa C. du Toit, and Yahya E. Choonara

Part II Effects of Spaceflight on Human Physiology and its Consequences on Drug Treatment . . . . . . . . . . . . . . . . . . . . . . . .

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Neuro-ocular Effects of Spaceflight Karina Marshall-Goebel

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Effects of Spaceflight on the Vestibular System . . . . . . . . . . . . . . . Torin K. Clark

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15

Endocrine Effects of Space Flight . . . . . . . . . . . . . . . . . . . . . . . . . . Timothy G. Hammond and Holly H. Birdsall

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16

Effects of Space Flight on Bone and Skeletal Tissue Alamelu Sundaresan, Vivek Mann, and Elvis Okoro

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323

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Effects of Spaceflight on the Immune System . . . . . . . . . . . . . . . . . Cora S. Thiel, Beatrice A. Lauber, Liliana E. Layer, and Oliver Ullrich

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Space Motion Sickness Adrian Macovei

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19

Effects of Space Radiation on Mammalian Cells . . . . . . . . . . . . . . Sharef Danho, Joelle Thorgrimson, and Joan Saary

371

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Pharmacogenomics in Spaceflight . . . . . . . . . . . . . . . . . . . . . . . . . . Michael A. Schmidt, Caleb M. Schmidt, and Thomas J. Goodwin

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Therapeutic Applications of Biophotonics in Space . . . . . . . . . . . . Philippe A. Souvestre and Diana L. Pederson

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Sleep in Space Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poornima Ramburrun, Shivani Ramburrun, and Yahya E. Choonara

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Physicochemical Stability of Space Medicines Priti J. Mehta and Dhara Bhayani

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Functional and Neuromuscular Aspects of Spaceflight Flávia Porto and Jonas Lírio Gurgel

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Effects of Spaceflight on the Nervous System . . . . . . . . . . . . . . . . . Chrysoula Kourtidou-Papadeli

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Health and Hygiene of Skin, Hair, Nails, and Teeth in the Space Environment: Daily Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . Marlise Araujo dos Santos, Lucíria de Freitas Correa, and Graziela Heberlé

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Mitigating Radiation Effects on Humans During Space Travel: Recent Developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gayatri Gopal Shetgaonkar and Lalit Kumar

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Structural Brain Changes Associated with Space Stephen McGuire

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611

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Impact of Space Pharmaceuticals on Cardiovascular System . . . . Rakesh Sharma, Madhvi Trivedi, and Arvind Trivedi

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Part III Model Organisms for Pharmaceutical Research in Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Space Experiments Using C. elegans as a Model Organism . . . . . . Noriaki Ishioka and Akira Higashibata

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Rodents as a Model for Research in Space . . . . . . . . . . . . . . . . . . . April E. Ronca and Moniece G. Lowe

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Fish as a Model for Research in Space . . . . . . . . . . . . . . . . . . . . . . Masahiro Chatani and Akira Kudo

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Yeast in Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Timothy G. Hammond and Holly H. Birdsall

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Fungal Experiments in Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sheila Nielsen and Rylee Schauer

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Nutraceutical and Nutrients Development for Space Travel . . . . . Catalano Enrico

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Utility of Drug Delivery Systems in Space Travel . . . . . . . . . . . . . . Maxime A. Ahouansou, Luke Robert Ely, Branden Tyler Alsbach, and Jerry Nesamony

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Part IV 37

Simulated Microgravity for Pharmaceutical Research . . . .

Ground-Based Simulators of Microgravity for Pharmaceutical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ilaria Cinelli and Jaykumar Modi

Part V Translating Knowledge from Spaceflight Research to Earth Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

783

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Vaccines in Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Timothy G. Hammond and Holly H. Birdsall

39

Harnessing the Space Environment for the Discovery and Development of New Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . Phoebe Ryder and Martin Braddock

823

Future of Drug Development in Space: Unmanned Satellites and Vehicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Yair Glick and Sara Eyal

859

40

41

Protein Crystallization in Space and Its Contribution to Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mitsugu Yamada, Kiyohito Kihira, Momi Iwata, Sachiko Takahashi, Koji Inaka, Hiroaki Tanaka, and Izumi Yoshizaki

Part VI Nutritional and Alternative Approaches to Treatment in Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

43

Nutraceuticals for Reducing Radiation Effects During Space Travel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sweta Kulkarni, Dipal Gandhi, and Priti J. Mehta Nutritional and Alternative Approaches to Treatment in Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Akash Kumar, Nandani Goyal, Jhilam Pramanik, Bhupendra Prajapati, and Jayvadan Patel

44

Homeopathy as a Therapeutic Option in Space . . . . . . . . . . . . . . . Manish P. Patel and Jayvadan Patel

45

Ayurvedic and Herbal Nutritional Supplements for Space Travellers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Purabi Das, Dhritiman Bhargab, Sujata Paul, and Hemanta Kumar Sharma

805

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913

915

935

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Contents

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47

Plant Behavior and Metabolic Response to the Space Environment as an Alternative Food and Therapeutic Source Marlise Araujo dos Santos, Beatriz Andrade de Souza, and Everton da Silva Paz

xvii

...

991

Melatonin: A Promising Drug to Ameliorate Main Human Space Exploration Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015 Santiago Andrés Plano, Víctor Demaría Pesce, Daniel Pedro Cardinali, and Daniel Eduardo Vigo

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1029

About the Editors

Dr. Yashwant V. Pathak has over 13 years of versatile administrative experience in an Institution of Higher Education as Dean (and over 30 years as faculty and as a researcher in higher education after his Ph.D.) and now holds the position for Associate Dean for Faculty Affairs and tenured Professor of Pharmaceutical Sciences. Dr. Pathak is an internationally recognized scholar, researcher, and educator in the areas of healthcare education, nanotechnology, drug delivery systems, and nutraceuticals. His major achievements from 2015 to 2020 in international area include: 1. Fulbright Senior Scholar Core Fellowship Award 2015–2016 for Indonesia (visiting Ubaya University, Surabaya, Indonesia, from January till July 2017) 2. Endeavour Executive Fellowship by Australian Government in 2015 in collaboration with Deakin University to work on siRNA delivery 3. Prometeo Fellowship award from Ecuador Government, 2015 4. CNPQ Brazil Government Fellowship, visiting PUCRS in Porto Alegre every year for one month from 2015 till 2017 working on space pharmaceuticals and microgravity impact on stability of drug delivery systems 5. Outstanding Achievement Award for Global Engagement by the University of South Florida, a unique award given to only one faculty/administrator annually 6. Fellow of NSF I-Corps USF 2016 xix

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About the Editors

7. Outstanding Faculty Award from USF March 2017 8. Fulbright Specialist Fellowship 2019 for South Africa 9. Outstanding Faculty Award from the University of South Florida 2020 10. Elected as fellow of American Association for the Advancement of Sciences (FAAAS) in 2021 He has published extensively with over 50 edited volumes in the area of nanotechnology, drug delivery systems, artificial neural networks, conflict management, and cultural studies. Elsevier, John Wiley and Sons, Springer, Taylor and Francis, and many other international publishers publish his books. He has published over 300 research papers, reviews, and chapters in the books and presented in many national and international conferences. He is also actively involved in many nonprofit organizations, to mention a few, Hindu Swayamsevak Sangh, USA, Sewa International USA, International Accreditation Council for Dharma Schools and Colleges, International Commission for Human Rights and Religious Freedom, and many more. Marlise Araujo dos Santos, Ph.D., holds a degree in Pharmacy from the Federal University of Rio Grande do Sul (1988), a master’s in Pharmacy from the Federal University of Rio Grande do Sul (1993), and a Ph.D. in Drug Delivery and Absorption where she worked in development of formulating a nasal formulation for Space Motion Sickness and a system to assess the permeability of drugs in cells grown in simulated microgravity – Kings College London, University of London (2006). She coordinated the Joan Vernikos Aerospace Pharmacy Laboratory at PUCRS for 10 years. She was invited Professor at the Space Physiology & Health MSc Program at Kings College for 8 years. She has 21 years of research experience in Aerospace Pharmacy, working mainly on the following topics: simulated hypergravity, simulated microgravity, involving cell culture, drug synthesis, medicinal plants, and pharmaceutical technology (nanotechnology). She is the Board of Advisor Member for Aerospace Pharmacy and Telepharmacy at the British company InnovaSpace – Space without Borders (https://www.innovaspace.org/). She holds three patents in the area, is author of several scientific articles, and has

About the Editors

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received two international awards. She gives lectures and courses in the Aerospace Pharmacy area at universities and conferences in different countries (India, Portugal, Trinidad Tobago, the United States, Italy, Poland, Germany, Turkey, Romania). She is a member of the Space 4 Women international group, part of the Space & Extreme Environment Research Center at UFCSPA (https://spacecenterufcspa.org/). She is a volunteer evaluator for NASA postdoctoral projects in the area of Space Life Science. She is a member of the International Society for Telemedicine and eHealth and Founder of MyDigicare, a startup that provides remote pharmaceutical care, an area that she has 10 years of experience. Dr. Luis Zea is an aerospace engineer and gravitational microbiology scientist who has been fortunate of having worked on over 20 scientific experiments performed on the Space Shuttle and/or the International Space Station and has served as Principal Investigator of projects going to lower Earth orbit and on an upcoming mission around the Moon, in NASA’s Artemis I mission. His scientific work is based on the use of microgravity to find novel solutions to medical problems on Earth as well as to enable safe, long-term human spaceflight, including via biological in situ resource utilization. Luis served as the Co-Director of Guatemala’s first satellite, Quetzal-1, a Universidad del Valle de Guatemala student- and faculty-developed CubeSat. He has seen first-hand the benefits that space research and development has on societies, for which he is passionate of the democratization of access to space for peaceful purposes, international collaboration, and the academic preparation of the next generation.

Contributors

Samson A. Adeyemi Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, School of Therapeutic Sciences, University of the Witwatersrand, Johannesburg, South Africa Maxime A. Ahouansou College of Pharmacy and Pharmaceutical Sciences, University of Toledo HSC, Toledo, OH, USA Branden Tyler Alsbach College of Pharmacy and Pharmaceutical Sciences, University of Toledo HSC, Toledo, OH, USA Dhritiman Bhargab Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India Dhara Bhayani Department of Pharmaceutical Analysis, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India Holly H. Birdsall Cell Spinpod LLC, Durham, NC, USA Durham Veterans Affairs Medical Center, Durham, NC, USA Space Policy Institute, Elliot School of International Affairs, George Washington University, Washington, DC, USA Departments of Otolaryngology, Immunology, and Psychiatry, Baylor College of Medicine, Houston, TX, USA Shambhavi Borde Creighton University, Omaha, NE, USA Martin Braddock Newton’s Astronomical Society@Woolsthorpe, Woolsthorpe Manor, Water Lane, Woolsthorpe by Colsterworth, Grantham, Lincolnshire, UK Science4U.co.uk, Radcliffe-on-Trent, Nottinghamshire, UK Daniel Pedro Cardinali Faculty of Medical Sciences, Pontifical Catholic University of Argentina (UCA), Buenos Aires, Argentina Masahiro Chatani Department of Pharmacology, School of Dentistry, Showa University, Tokyo, Japan Harsh Chauhan Creighton University, Omaha, NE, USA xxiii

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Contributors

Yahya E. Choonara Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, School of Therapeutic Sciences, University of the Witwatersrand, Johannesburg, South Africa Ilaria Cinelli Aerospace Medical Association, Alexandria, VA, USA Torin K. Clark Bioastronautics Laboratory, Smead Aerospace Engineering Sciences, University of Colorado-Boulder, Boulder, CO, USA Everton da Silva Paz School of Health and Life Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil Beatriz Andrade de Souza School of Health and Life Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil Sharef Danho Faculty of Medicine, University of Toronto, Toronto, ON, Canada Purabi Das Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India Lucíria de Freitas Correa Centro Universitário Ritter dos Reis – Uniritter, Porto Alegre, Brazil Víctor Demaría Pesce National Institute for Health and Medical Research (INSERM), Paris, France European Astronaut Centre (EAC), European Space Agency (ESA), Köln, Germany Hartmut Derendorf Department of Pharmaceutics – College of Pharmacy, University of Florida, Gainesville, FL, USA Marlise Araujo dos Santos InnovaSpace Ltd, London, UK Lisa C. du Toit Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, School of Therapeutic Sciences, University of the Witwatersrand, Johannesburg, South Africa Luke Robert Ely College of Pharmacy and Pharmaceutical Sciences, University of Toledo HSC, Toledo, OH, USA Catalano Enrico University of Oslo, Oslo, Norway Sara Eyal Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel SpacePharma, Herzeliya, Israel Dipal Gandhi Department of Pharmacognosy, Institute of Pharmacy, Nirma University, Ahmedabad, India Yair Glick SpacePharma, Herzeliya, Israel Thomas J. Goodwin Advanced Pattern Analysis & Countermeasures Group, Boulder, CO, USA Sovaris Aerospace, LLC, Boulder, CO, USA

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Mershen Govender Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, School of Therapeutic Sciences, University of the Witwatersrand, Johannesburg, South Africa Nandani Goyal Department of Skill Agriculture, Shri Vishwakarma Skill University, Gurugram, India Aditya Grover Morsani College of Medicine, Tampa, FL, USA Deepak Gupta Department of Pharmaceutical Sciences, School of Pharmacy, Lake Erie College of Osteopathic Medicine, Bradenton, FL, USA Sheeba Varghese Gupta Department of Pharmaceutical Sciences, University of South Florida – College of Pharmacy, Tampa, FL, USA Jonas Lírio Gurgel Federal Fluminense University, Niterói, Brazil Timothy G. Hammond Cell Spinpod LLC, Durham, NC, USA Durham Veterans Affairs Medical Center, Durham, NC, USA Nephrology Division, Department of Medicine, Duke University School of Medicine, Durham, NC, USA Space Policy Institute, Elliot School of International Affairs, George Washington University, Washington, DC, USA Graziela Heberlé Javali- Cosmetics, Lajeado, Brazil Akira Higashibata Human Spaceflight Technology Directorate, Japan Aerospace Exploration Agency, Tsukuba, Japan Graduate School of Medical and Dental Sciences, Kagosima University, Kagoshima, Japan Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan Koji Inaka Maruwa Foods and Biosciences, Inc., Nara, Japan Sunaina Indermun Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, School of Therapeutic Sciences, University of the Witwatersrand, Johannesburg, South Africa Noriaki Ishioka Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency, Sagamihara, Japan School of Physical Science, The Graduate University of Advanced Studies, Hayama, Japan Graduate School of Medical and Dental Sciences, Kagosima University, Kagoshima, Japan Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan Abhay M. Ittadwar Gurunanak College of Pharmacy, Nagpur, India

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Contributors

Momi Iwata Human Spaceflight Technology Directorate, Japan Aerospace Exploration Agency, Tsukuba, Japan Vinita V. Kale Gurunanak College of Pharmacy, Nagpur, India Kiyohito Kihira Human Spaceflight Technology Directorate, Japan Aerospace Exploration Agency, Tsukuba, Japan Chrysoula Kourtidou-Papadeli WSU, Dayton, OH, USA Aeromedical Center of Thessaloniki, Thessaloníki, Greece Akira Kudo Department of Pharmacology, School of Dentistry, Showa University, Tokyo, Japan International Frontier, Tokyo Institute of Technology, Tokyo, Japan Sweta Kulkarni Department of Pharmaceutical Analysis, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India Akash Kumar Department of Food Technology, Center for Health and Applied Sciences, Ganpat University, Mahesana, India Lalit Kumar Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India Pradeep Kumar Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, School of Therapeutic Sciences, University of the Witwatersrand, Johannesburg, South Africa Dunesh Kumari College of Saint Mary, Omaha, NE, USA Beatrice A. Lauber Institute of Anatomy, Faculty of Medicine, University of Zurich, Zurich, Switzerland Liliana E. Layer Institute of Anatomy, Faculty of Medicine, University of Zurich, Zurich, Switzerland Moniece G. Lowe Blue Marble Space Institute of Science, Seattle, WA, USA Adrian Macovei Research and Physiological Training Division, National Institute of Aerospace Medicine, Bucharest, Romania University of Medicine and Pharmacy, Craiova, Romania Ashim Malhotra Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA, USA Vivek Mann College of Science, Engineering and Technology, Texas Southern University, Houston, TX, USA Karina Marshall-Goebel Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

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Stephen McGuire University of Texas Health Sciences San Antonio, San Antonio, TX, USA Priti J. Mehta Department of Pharmaceutical Analysis, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India Jaykumar Modi Space Generation Advisory Council, Mississauga, ON, Canada Keshav S. Moharir Gurunanak College of Pharmacy, Nagpur, India Jerry Nesamony Division of Pharmaceutical and Policy Sciences, College of Pharmacy and Pharmaceutical Sciences, University of Toledo HSC, Toledo, OH, USA Sheila Nielsen Montana State University, Bozeman, MT, USA Elvis Okoro College of Science, Engineering and Technology, Texas Southern University, Houston, TX, USA Anita Patel Faculty of Pharmacy, Sankalchand Patel Vidyadham, Sankalchand Patel University, Visnagar, Gujarat, India Jayvadan Patel Nootan Pharmacy College, Faculty of Pharmacy, Sankalchand Patel University, Visnagar, Gujarat, India Manish P. Patel L M College of Pharmacy, Ahmedabad, Gujarat, India Yashwant V. Pathak USF Health Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA Faculty of Pharmacy, Airlangga University, Surabaya, East Java, Indonesia Sujata Paul Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India Diana L. Pederson DragonFly MedTech, Inc, Calgary, AB, Canada Tekilanand Persaud Department of Aeronautics and Astronautics, Purdue University, West Lafayette, IN, USA Viness Pillay Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, School of Therapeutic Sciences, University of the Witwatersrand, Johannesburg, South Africa Santiago Andrés Plano Laboratory of Chronophysiology, Institute for Biomedical Research, Pontifical Catholic University of Argentina (UCA) and National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina Flávia Porto Institute of Physical Education and Sport, Rio de Janeiro State University, Rio de Janeiro, Brazil Priyamvada Pradeep Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, School of Therapeutic Sciences, University of the Witwatersrand, Johannesburg, South Africa

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Contributors

Bhupendra Prajapati Shree S K Patel College of Pharmaceutical Education and Research, Ganpat University, Mahesana, India Jhilam Pramanik Department of Food Technology, Center for Health and Applied Sciences, Ganpat University, Mahesana, India Poornima Ramburrun Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, School of Therapeutic Sciences, University of the Witwatersrand, Johannesburg, South Africa Shivani Ramburrun Department of Pharmacy and Pharmacology, Faculty of Health Sciences, School of Therapeutic Sciences, University of the Witwatersrand, Johannesburg, South Africa Pooja Kiran Ravi University of South Florida – College of Pharmacy, Tampa, FL, USA April E. Ronca Space Biosciences Division, NASA Ames Research Center, Mountainview, CA, USA Department of Obstetrics & Gynecology, Wake Forest School of Medicine, Winston-Salem, NC, USA Phoebe Ryder Newton’s Astronomical Society@Woolsthorpe, Woolsthorpe Manor, Water Lane, Woolsthorpe by Colsterworth, Grantham, Lincolnshire, UK Joan Saary Division of Occupational Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada Rylee Schauer University of Colorado, Boulder, CO, USA Caleb M. Schmidt Sovaris Aerospace, LLC, Boulder, CO, USA Michael A. Schmidt Advanced Pattern Analysis & Countermeasures Group, Boulder, CO, USA Sovaris Aerospace, LLC, Boulder, CO, USA Christoph N. Seubert Department of Anesthesiology – College of Medicine, University of Florida, Gainesville, FL, USA Hemanta Kumar Sharma Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India Navneet Sharma Perrigo Company, Allegan, MI, USA Rakesh Sharma NMR Surgical Laboratory, Massachusetts General Hospital and Shriners Burns Institute, Harvard Medical School, Boston, MA, USA Gayatri Gopal Shetgaonkar Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India Dhirender Singh Navinta LLC, Ewing, NJ, USA

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Philippe A. Souvestre NeuroKinetics Health Services, Inc., Calgary, AB, Canada Alamelu Sundaresan College of Science, Engineering and Technology, Texas Southern University, Houston, TX, USA Sachiko Takahashi Confocal Science Inc., Tokyo, Japan Hiroaki Tanaka Confocal Science Inc., Tokyo, Japan Cora S. Thiel Institute of Anatomy, Faculty of Medicine, University of Zurich, Zurich, Switzerland Department of Machine Design, Engineering Design and Product Development, Institute of Mechanical Engineering, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany Joelle Thorgrimson Faculty of Medicine, Northern Ontario School of Medicine, Thunder Bay, ON, Canada Arvind Trivedi Government Medical College, Saharanpur, Uttar Pradesh, India Madhvi Trivedi Government Medical College, Fatehpur, Uttar Pradesh, India Oliver Ullrich Institute of Anatomy, Faculty of Medicine, University of Zurich, Zurich, Switzerland Department of Machine Design, Engineering Design and Product Development, Institute of Mechanical Engineering, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany Space Life Sciences Laboratory (SLSL), Kennedy Space Center, Merritt Island, FL, USA Joan Vernikos Thirdage llc, Culpeper, VA, USA Daniel Eduardo Vigo Laboratory of Chronophysiology, Institute for Biomedical Research, Pontifical Catholic University of Argentina (UCA) and National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina Research Group on Health Psychology, Faculty of Psychology and Educational Sciences, Katholieke Universiteit Leuven, Leuven, Belgium Mitsugu Yamada Human Spaceflight Technology Directorate, Japan Aerospace Exploration Agency, Tsukuba, Japan Ningning Yang Department of Pharmaceutical Sciences, School of Pharmacy, Lake Erie College of Osteopathic Medicine, Bradenton, FL, USA Izumi Yoshizaki Human Spaceflight Technology Directorate, Japan Aerospace Exploration Agency, Tsukuba, Japan Yichao Yu Department of Pharmaceutics – College of Pharmacy, University of Florida, Gainesville, FL, USA

Part I Principles of Pharmaceuticals

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Introduction to Pharmaceuticals Keshav S. Moharir, Vinita V. Kale, Abhay M. Ittadwar, and Yashwant V. Pathak

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Early Days of Drugs and Dosage Forms: The Heritage of Pharmacy . . . . . . . . . . . . . . . . . . . . . . . . . . . Period of Scientific Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmaceuticals in Modern Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmaceuticals as Drug Products, Drug Delivery Systems, and Therapeutic Systems . . . . . . . . Brief Introduction to Dosage Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Solid Oral Dosage Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liquid Dosage Forms: Solutions and Dispersed Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oral Solutions, Syrups, Elixirs, Spirits, and Tinctures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Topical Formulations: Semisolid Dosage Forms: Ointments, Creams, Gels, Jellies, Lotions, Pastes, and Foams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Powders and Granules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dosage Forms and Drug Delivery for Specific Routes of Administration . . . . . . . . . . . . . . . . . . Novel Drug Delivery Systems and Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Challenges in Using Pharmaceuticals in Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drugs Used During the Spaceflights for the Astronauts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of Spaceflight on the Human Body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacokinetic and Pharmacodynamic Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4 4 5 6 6 7 7 8 9 10 11 12 12 13 14 15 16 16 18 19

K. S. Moharir · V. V. Kale · A. M. Ittadwar Gurunanak College of Pharmacy, Nagpur, India Y. V. Pathak (*) USF Health Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA Faculty of Pharmacy, Airlangga University, Surabaya, East Java, Indonesia e-mail: [email protected] © Springer Nature Switzerland AG 2022 Y. V. Pathak et al. (eds.), Handbook of Space Pharmaceuticals, https://doi.org/10.1007/978-3-030-05526-4_11

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Abstract

The origin of medicine dates back to prehistoric era with use of crude, natural compounds in the beginning. Development in discoveries was gradual with increase in natural sources of medicines followed by generation of new scientific theories and principles. The chronological journey leads us today to astonishing developments in terms of new dosage forms, drug delivery systems, and surgical procedures. The further progress is predicted to occur only with extensive interdisciplinary studies and proper application of technological advances. The fields of studies in every aspect have grown in the last two centuries by leaps and bounds, and space explorations are not left behind. Once upon a time, man thought of landing on moon, and the day man landed the moon was 20 July 1969. Similarly, a day will come he will land on Mars, and maybe space tourism will flourish soon. The inevitable part here is use of medicines in space. Space environment poses different set of challenges that need extensive research. The present discussion talks about various studies for maintaining stability, efficacy, and safety and extending shelf life of medicines for astronauts working in spaceflights. We have some information on short-time space travels, but data for effects of longterm travel in space is missing. So also if a common man travels to space, the requirements will be significantly different from those of the present-day trained astronaut travel. The previous experience of astronauts and available data of these studies, both in space and simulated environment on Earth, set tone for further approaches which will give assurance of stability of medicines in space.

Introduction Medicines are indispensable part of our lives. Medicines are used since the beginning of the human civilization, although crude and natural initially. As the time passed by, so was the pursuit for better medicines and ways to deliver them. The art of “apothecary” originated with skills of preparation of medicinal materials in patient-friendly “deliverable” forms (commonly called as “dosage forms” in today’s context) that can be taken by patients in suitable, safe, efficacious, and comfortable manner. From experience, humans learned the specificity of drugs toward treatment of certain diseases; thus practice of drug therapy and choices gradually evolved with establishment of pharmacological principles.

Early Days of Drugs and Dosage Forms: The Heritage of Pharmacy In early civilization period, the cause of disease was believed to be some demonic or evil spirit effect. Accordingly, the primary methods to treat these were more spiritual and using natural surrounding materials like leaf, mud, cool water, etc.

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The first apothecary, with known record of practicing this art perhaps dating back to as early as 3000 B.C., belongs to Babylonian civilization in Mesopotamia. Georg Ebers, a renowned Egyptologist, is credited with discovery of more than 700 drugs mentioning about 800 documented formulas on Ebers Papyrus (a kind of clay containing these records named after Georg Ebers.) The traditional Chinese medicine collection Shen-nung Pen-tsao Ching is a compendium of medicinal plants that was written by the Emperor Shen Nung, who is credited as the founder of Chinese herbal medicine (2500 B.C.). The book describes 365 medications, which include dried parts of medicinal plants, many of which are still used today. On a similar note, the period 1000–1500 B.C. shows data on ancient Indian traditional medicine system Ayurveda. The Sushruta Samhita is one of the foundational texts of Ayurveda. The surviving text contains descriptions of 1120 illnesses and 700 medicinal plants, including their safety, efficacy, dosage, and benefit (Allen and Ansel 2014a). The timeline of centuries followed, describing gradual development of “drugs” in crude and raw form to standardized “medicines.” The subsequent efforts and contribution by many scholars like Hippocrates (460–377 B.C.), Theophrastus (371–287 A.D.), Dioscorides (first century A.D.), Galen (130–200 A.D.), and Paracelsus (1493–1541 A.D.) undoubtedly added value to the field of pharmaceuticals and medicines. This discussion is incomplete without naming the “Father of Chemotherapy,” Paul Ehrlich (1854–1915 A.D.), who coined the term “magic bullet,” which won the Nobel Prize in medicine for path-breaking discovery in immunology. Equally important was the contribution by Gerhard Domagk (1895–1964 A.D.), which earned Nobel Prize for antiinfective sulfonamide synthesis. Their revolutionary work led to scientific viewpoint and improving standards of medicines accompanied by well-developed therapies that we see today in the modern era (College of Pharmacy and Pharmaceutical Sciences History 2018).

Period of Scientific Research With the advent of knowledge in basic sciences, several pharmacists tapped the opportunities for discovery of new compounds, new methods, and new therapies. Not only medicinal compounds but also surgeries and allied procedures were systematically studied and investigated simultaneously (Table 1). The post-World War I era witnessed spurt in drug discoveries with use of new technologies. In the late nineteenth century, the standards and quality control norms on pharmaceutical formulations emerged gradually with United States Pharmacopeia first edition published in the year 1820. In the period following World War II, the focus of drug therapy became more outcome based and patient care oriented with the development of community pharmacy and clinical pharmacy.

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Table 1 Few representative drug discoveries Name of scientist Carl Wilhelm Scheele Friedrich Serturner Joseph Caventou and Joseph Pelletier Paul Ehrlich Jokichi Takamine Alexander Fleming

Discovery Lactic acid, citric acid, oxalic acid, tartaric acid, identified glycerin Morphine extraction from opium Quinine and strychnine Salvarsan Adrenaline Penicillin

Period A.D. 1742–1786

Country Sweden

1783–1841 1795–1877 1788–1842 1854–1915 1901 1929

Germany France France Poland Japan Scotland

Pharmaceuticals in Modern Perspective A drug is defined as an agent intended for use in the diagnosis, mitigation, treatment, cure, or prevention of disease in humans or in other animals (Food, Drug, and Cosmetic Act, India, 1938). As we enter the twenty-first century, the methods of treating diseases may vary as: 1. 2. 3. 4. 5.

Surgical intervention Psychotherapy Physiotherapy Radiotherapy Drug therapy which is commonly called as pharmacotherapy

Among all these, pharmacotherapy is the most preferred and used globally (treatment with drugs). This is because of the amazing and wonderful qualities of drugs to show diverse effects and actions on the body and versatility to treat a very broad range of diseases. In a nutshell, pharmacotherapy is continuously proving to be an acceptable alternative to those conditions which needed radical surgeries in earlier days (Banker 2002; Allen and Ansel 2014b).

Pharmaceuticals as Drug Products, Drug Delivery Systems, and Therapeutic Systems A pure form of the drugs differs in inherent physicochemical properties. They may differ in physical state (solid, liquid, or gaseous), nature of crystalline structure (polymorphic or amorphous), solubility in solvents, polarity, stereochemistry, color, particle size, dose, and many more. Thus, the drugs are rarely administered as pure chemical substances alone. The drugs are given to the patients as drug products through suitable dosage forms, drug delivery system, and route of administration. The prime objective of dosage form design is to accomplish therapeutic

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Table 2 Dosage forms available for different routes of administration Administration route Oral Rectal Topical Parenteral Respiratory Nasal Eye Ear

Dosage forms Solutions, syrups, suspensions, emulsions, gels, powders, granules, capsules, tablets Suppositories, ointments, creams, powders, solutions Ointments, creams, pastes, lotions, gels, solutions, topical aerosols, foams, transdermal patches Injections (solution, suspension, emulsion forms), implants, irrigation, and dialysis solutions Aerosols (solution, suspension, emulsion, powder forms), inhalations, sprays, gases Solutions, inhalations Solutions, ointments, creams Solutions, suspensions, ointments, creams

response which is predictable and robust enough for large-scale manufacturing with consistent product quality reproducible from batch to batch. Many dosage forms are developed in the past with continuous improvement in them. Several drug delivery systems are introduced as novel drug delivery systems (nanoparticles, liposome, niosomes, polymeric carriers, implantable polymers, and so on) which help to achieve therapeutic goals like targeted drug delivery, controlled and modified drug delivery, chrono-therapeutics (Shelley Chambers Fox 2014), etc. There are a myriad of dosage forms into which a pure drug substance can be incorporated for the safe and effective treatment of a disease. Dosage forms can be designed for administration by alternative delivery routes to maximize therapeutic response and minimize adverse effects. The following table gives glimpses of commonly used dosage forms and their corresponding routes of administration (Augsburger 1988) (Table 2). The drug substances are usually formulated into dosage forms with one or more inert substances called as excipients or adjuvants. Each type of dosage form is unique in its physical and pharmaceutical characteristics. A brief introduction of commonly used dosage forms is summarized in the following text.

Brief Introduction to Dosage Forms Solid Oral Dosage Forms The most commonly used route of drug administration is undoubtedly oral route. Among various orally administered formulations, tablets of various types make maximum share. Tablets are solid, oral unit dosage forms mainly used for oral drug delivery and then systemic drug absorption but may be intended for local application in certain cases. They are available in different shapes, sizes, weights, colors, and types. The different types of tablets include chewable tablets, hypodermic tablets,

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effervescent tablets, film-coated tablets, multilayered tablets, molded tablets, sublingual tablets, buccal tablets, rapidly dissolving tablets, etc. Advantages: • Patient compliance due to ease of convenience and safety. • Solid dosage forms show better chemical, physical, and microbiological stability over liquid and semisolid dosage forms. • Dosing is accurate. • Elegant, aesthetic, easy to carry anywhere, and cost-effective. However, tablets may pose some disadvantages as poor solubility, poor absorption, and hence poor bioavailability due to instability of drugs in gastrointestinal tract environment. Compressed tablets are prepared by compressing granules of active drug with excipients in a tablet compression machine. Alternate methods include compression followed by dry granulation and direct compression. Technological advances and research on excipients have made it convenient to manufacture multilayered, modified, extended release tablets with varied mechanisms of drug release. Coating of tablets further makes them suitable for delivery of drugs which are bitter in taste, incompatible with other drugs, sensitive to gastric fluids, and sensitive to moisture. Quality Attributes of Tablets – United States Pharmacopeia (USP 41) mentions standards and tests which should be complied with by tablets. These mainly include disintegration test, dissolution test, weight variation test, and content uniformity test. Capsules have gelatin as basic component in capsule shell with various excipients as coloring agents, antioxidants, and preservatives. Dose of the drug governs the size of capsules. Soft capsules in addition contain plasticizers to make the shell softer. Manufacturing of capsules is a skilled job as it demands strict control of temperature and humidity. Hard capsules may be filled with liquids, semisolids, powders, or pellets as final dosage form. Storage conditions for capsules are worth mentioning as excessive cold may cause brittleness and excessive heat may melt gelatin present in capsule shell (Augsburger 1988). Compendia requirements and quality control tests for capsules include disintegration test, dissolution test, weight variation test, and content uniformity test.

Liquid Dosage Forms: Solutions and Dispersed Systems Liquid dosage forms intended for oral or topical use can be in the form of solutions, emulsions, suspensions, syrups, elixirs, spirits, etc., while dispersed system in addition includes foams and carbonated beverages like effervescent salts in water. Liquid dosage forms are of prime importance for pediatric and geriatric patients, who find difficulty in taking solid oral dosage forms. Emulsions are biphasic systems (two immiscible phases) which are thermodynamically unstable (since they contain two immiscible phases). The two phases are dispersed phase (internal phase) and dispersion medium (continuous phase). Based

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on dispersion medium, an emulsion can be classified as oil in water (o/w) or water in oil (w/o) with water and oil as continuous phase, respectively. The two immiscible phases are stabilized by incorporation of suitable emulsifying agent to it. Depending on the constituents and their ratio, emulsions may be prepared as liquids or semisolids. Semisolids are used for topical/dermatological applications and liquids for oral or topical applications. Orally administered emulsions are o/w, while topical emulsions are o/w or w/o. Stability of emulsions is warranted since they frequently undergo changes when exposed to high temperature, extreme pH, or excessive shearing stress. Emulsion is to be tested for phase inversion, flocculation, creaming, coalescence, and degradation of oil phase (Florence and Attwood 2006). Advantages of emulsions include quick and efficient oral absorption of the drug as compared to solid oral dosage forms and, when applied on skin, increased drug diffusion across the skin. Suspensions are formulations containing fine-particle size drug particles dispersed uniformly throughout a vehicle, which can be aqueous or nonaqueous. Suspension formulation is stabilized by addition of suitable suspending agents, wetting agent, and surfactants in order to neutralize the electrical charge developed at solid particle-liquid interphase. An ideal suspension should re-disperse on gentle shaking, should form uniform distribution of solid particles, and should be easily pourable from the container. Drugs which are otherwise unstable in solution form are formulated as suspension, making them more stable and with greater shelf life. Suspensions should be evaluated for physical and chemical stability. Sedimentation and cake formation are two frequently encountered problems with suspensions. Crystallinity and polymorphic nature of drug may trigger excess crystal growth and loose cake formation. Temperature exposure sometimes initiates degradation pathway leading to reduction in suspension shelf life (Subramanyan 2000).

Oral Solutions, Syrups, Elixirs, Spirits, and Tinctures Solutions are homogenous mixture of two or more components, wherein water is the most common solvent. Due to its versatile nature, it can be used as oral, otic, ophthalmic, or topical solution with minor changes. As a rule of thumb, solutions always include colors, flavors, sweeteners, and preservatives to make them more palatable and acceptable by patients. Solutions have one benefit over solid oral dosage forms and suspensions: the drug absorption from solutions is faster in the gastrointestinal tract. Solutions can be used as injectable when they comply with standards for sterile formulations. Syrups are concentrated aqueous preparations of a sugar or sugar substitute with or without flavoring agents. Syrups containing flavoring agents but not medicinal substances are called non-medicated syrups. These syrups are intended to serve as pleasant-tasting vehicles for extemporaneous compounding of prescriptions containing medicines. Syrups are valuable and universally acceptable pleasanttasting formulations for disagreeable-tasting drug (Allen 2012).

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Elixirs are clear, sweetened hydroalcoholic solutions intended for oral use and are usually flavored to enhance their palatability. Non-medicated elixirs do not contain any medicinal agent but can be used as vehicles. Elixirs contain less quantity of sugar; thus they are less sweet and low in viscosity when compared to syrups. Elixirs contain 10–20% ethyl alcohol, hence do not need any preservative. Due to presence of alcohol, elixirs may cause slight drowsiness, hence less preferred by patients who avoid alcohol. Tinctures are alcoholic or hydroalcoholic solutions of chemical or soluble constituents of drugs of vegetable origin. They are mostly prepared by extraction process. Alcohol content ranges from 15% to 80% depending on preparation. Alcohol acts as self-preservative. Tinctures are stored in tightly closed containers preferably at low temperatures (Mahato and Narang 2012). Few types of solutions like aromatic waters and spirits were used earlier. Their use is nowadays limited due to drawbacks and superseded by other alternative formulations.

Topical Formulations: Semisolid Dosage Forms: Ointments, Creams, Gels, Jellies, Lotions, Pastes, and Foams Topical formulations are intended for applications on the skin and into the eyes and may also be for vaginal applications. These are used mostly for local applications and occasionally for systemic effects. Ointments are intended for external application to the skin or mucous membranes. Ideal ointments should soften the skin, melt at body temperature, spread easily on the skin, and give non-gritty feel. The effects provided by ointments can be (1) protective barrier to prevent harmful substances coming in contact with the skin, (2) emollient to make the skin surface more supple, and (3) lubricant to make the skin surface smooth. Drug and excipients are fused homogeneously with suitable ointment base(s) and mixed thoroughly. Ointments contain various excipients like antioxidants, preservatives, and emulsifying agents in some types of products. Ointments intended for ophthalmic use are sterilized terminally after final packaging. They should comply with compendia requirements like minimum fill, free from gritty particles and microbial content. Creams are semisolid dosage forms containing medicinal substances dissolved or dispersed in w/o or o/w type of emulsion. Whitish or creamy appearance of cream is due to dispersion or scatter of light from globules of dispersed phases, contrary to the ointments which are translucent. Emulsion bases with water as continuous phase (o/w) are commonly used in the form of water washable bases like in vanishing cream, while w/o bases are for emollient action like cold cream. Creams are generally provided in collapsible tubes or small jars. They have good acceptability by patients, but drawbacks include lack of dose accuracy and an “oily” feeling on the skin (Mahato and Narang 2012).

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Gels are aqueous semisolid systems thickened with gelling agents, which consist of small or large molecules dispersed in aqueous vehicle. It is formed by threedimensional structure of polymeric matrix, interlinked and cross linked with natural or synthetic polymers. Drug substances incorporated into gels along with preservatives and cosolvents. These are mostly for topical applications. Gels should be stored in airtight containers to prevent water loss and to avoid freezing (Mahato and Narang 2012). Lotions are medicated or non-medicated preparations containing finely divided solid particles dispersed in an emulsion base or aqueous vehicle. These are for topical use, to be applied on unbroken skin. Lotions can be used for the topical delivery of medications such as antibiotics, antiseptics, antifungals, corticosteroids, anti-acne agents, and soothing/protective agents (such as calamine). Lotions are specifically convenient for application on hairy areas on the skin like the scalp. Further, lotions can form thinner layer on the skin compared to creams, ointments, and gels (Mahato and Narang 2012). Pastes are thick, viscous, and stiff preparations consisting of insoluble solids mixed with nonaqueous or aqueous vehicles. They form unbroken layer on the skin. Solids in the pastes can adsorb watery solutions around them. They can form excellent barrier needed for sunscreen formulations. Certain agents can make pastes water-permeable films to prevent dehydration. Toothpaste is a common example of paste providing cleansing and abrasive contents, yet smooth and pleasant to use. Foams are preparations containing gas dispersed in emulsions or other vehicles as continuous phase, for application to the skin or mucous membrane. They are filled in pressurized containers with suitable propellant(s). Active ingredients are dispersed uniformly in a vehicle and filled under pressure in a container. Upon actuation expansion of liquid droplets takes place with formation of foam by entrapment of air. The foam can be made to stay longer on the skin or break quickly with addition of suitable excipients.

Powders and Granules Most of the drugs are in powder form at some or other stages. Many times powder itself can be a final dosage form. Powders provide better shelf life and stability of a medicinal compound when the same compound is formulated into corresponding liquid formulations. Granules are mostly intermediate products used for further processing, say for compression into tablets. Powders may be applicable for oral use, for topical use, or for further processing into some other dosage forms. Oral powders have small, uniform particle size and high surface area, the most common example being the ORS formula packaged in unit dose sachet. Powders for reconstitution are supplied in multidose containers, to be reconstituted by following the given instructions. This ensures longer shelf life of the drug in resulting solution/suspension. Topical powders are supplied as simple

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talcum powders with fragrance for beautification or as dusting powders containing antibiotics or antifungal agents. Dry powder inhalers (DPI) are devices that deliver medicament to the lungs using special device for inhalation of powders. These are commonly used for local applications in patients suffering from asthma and bronchitis. Aerosolized metered dose inhaler is an alternative to the DPI devices. All powders need to be tested for flow characteristics, particle size and size distribution, absence of gritty particles, shape, surface area, porosity, and bulk density (Yalkowsky and Bolton 1990). Granules are less commonly used as final dosage form, with few exceptions like effervescent granules and laxative granules. They are generally intermediates containing one or more active pharmaceutical ingredients having acceptable powder characteristics and good compressibility and flow properties (Narang et al. 2009).

Dosage Forms and Drug Delivery for Specific Routes of Administration Certain organs or tissues require dosage forms or formulations which can be directed toward that organ/tissue with convenience. Care is required in terms of dose, size and shape, volume to be delivered, physical nature of the final dosage form, and target organ in the question. These drug deliveries may be toward organ systems – rectal, vaginal, ophthalmic, pulmonary, nasal, otic (ears), transdermal, and wound dressings. All of these require type of formulations and drug delivery systems suitable to corresponding route of administration, for example, bullet-shaped suppositories suitably optimized with shape and size for rectal route. Physicochemical characteristics are specific for specific target organ. For example, eye drops should have optimum viscosity to stay for longer time in cul-de-sac of an eye, yet it should not blur the vision; powdered medicament targeted to bronchioles will reach the site only if its particle size is less than 10 μm. Transdermal films or patches release the drug on the skin and absorbed through the stratum corneum of the dermis. There are many such examples to understand the intricacies of drug delivery system. Parenteral formulations are also popularly known as injectable. These are administered via intravenous, intradermal, subcutaneous, intramuscular, intraarticular, or intrathecal routes. These are sterile preparations, free from particulate matter and pyrogens. Onset of action is quicker than most other dosage forms.

Novel Drug Delivery Systems and Devices New concepts in drug delivery systems are reported to have profound advantages over conventional methods of drug delivery. Advanced drug delivery systems are designed to achieve either of the following objectives:

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1. 2. 3. 4. 5. 6.

Drug targeting Controlled or modulated drug release pattern Reduction in dosing frequency Reduction in cases of adverse drug reactions Improved patient compliance Enhanced bioavailability and stability (Chien 1991)

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Different novel drug delivery systems and drug carriers include liposomes, nanoparticles, niosomes, ethosomes, phytosomes, resealed erythrocytes, microspheres, implantable devices, pseudolatices, dendrimers, transferosomes, monoclonal antibodies, osmotic pumps, iontophoresis, sonophoresis, and many more (Bhagwat and Vaidhya 2013). Among all these, liposomes and nanoparticles are promisingly used in clinical applications. Liposomes are amphipathic unilamellar or multilamellar vesicles, layers (generally phospholipid bilayers) being composed of versatile excipients which can accommodate a variety of drugs. The size of liposomes may range from few nanometers to several micrometers. Stability, efficacy, biocompatibility, and biodegradable nature are some advantages, while high cost, leakage of drug, and lipid oxidation are few disadvantages of liposomes (Akbarzadeh et al. 2013). Selective cancer cell targeting has become possible by liposomes due to their ability to preferentially gain access into tumor cells by increased cell permeability (Pathak and Thassu 2009). Nanoparticles are organic or inorganic structures ranging in size from few nanometers to few hundred nanometers (10–500 nm). Metal, organic, and polymeric nanoparticles are commonly studied and can be designed for the targeted, sitespecific delivery of drugs especially those drugs which have poor solubility and absorption. For example, conventional dosage forms or drug delivery does not carry the drug across BBB (blood-brain barrier), while nanoparticulate carriers can do it selectively. They can be biocompatible, biodegradable, and specific toward cancer cells and antibodies or used in diagnostics (Pathak and Thassu 2009; Mirza and Siddiqui 2014).

Challenges in Using Pharmaceuticals in Space Preventive medicine and acute health conditions are primary issues throughout the development of space programs in Russia and America. It is not exaggeration to say that success of the space mission largely depends on good health and psychological well-being of astronauts in space (Stewart et al. 2007). Historically, instances galore to reinforce the importance and need of medicine in space. Apollo 7 was infamous as the “10-day cold capsule” when the entire crew on board developed viral upper respiratory tract infections. The first instance of deaths during spaceflight was reported in 1971 when three astronauts died due to rapid decompression in Soyuz 11 capsule during reentry (Stewart et al. 2007) (Table 3).

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Table 3 Major clinical effects of microgravity on health of astronauts Organ system involved CVS Hematological system Endocrine system

Pathological changes observed Orthostatic hypotension, ventricular tachycardia due to stress, ECG changes Decrease in plasma volume and RBC, increase in hemoglobin Renin, angiotensin, norepinephrine, ADH, and aldosterone levels are increased

Electrolyte balance

Increased urinary excretion of sodium, potassium, and calcium

Immune system

Downregulation of cellular immunity, alterations in leucocytes, cytokine production, and NK cell activity Muscular atrophy in lower limbs, increase in vertebral column up to 7 cm, bone resorption, and lowering of bone mineral density Space motion sickness, lack of coordination in movement, visual gaze, altered circadian rhythm

Musculoskeletal system

Space adaptation syndrome, a complex phenomenon

References Martin et al. (2002) and D’Aunno et al. (2003) Johnson (1983) Huntoon and Cintron (1996) and Christensen et al. (2001) Huntoon and Cintron (1996) and Christensen et al. (2001) Talor et al. (1997)

Wing et al. (1991) and Oganov and Schneider (1996) Homick et al. (1984)

Common medical problems encountered by astronauts during spaceflight include numerous conditions like vestibular dysfunction, weight loss, increase in height, upward fluid shift, anemia, cardiovascular deconditioning, muscle atrophy, space motion sickness, sleep problems, joint pain, back pain, allergies, sinus congestion, and bone loss. Almost all of these alterations can be attributed to microgravity and few due to radiation exposure experienced in space. Some of these pathological conditions are listed below (Tavassoli 1986; Kast et al. 2017).

Drugs Used During the Spaceflights for the Astronauts Commonly used drugs are enumerated in Table 4. The common medical complaints due to changes in physiological systems or other factors may require pharmacotherapy during long-term or short-term spaceflight missions. On 94% of all flights, astronauts reported taking at least one medication (Putcha et al. 1999). Common complaints during space missions are sleep problems, pain (headache, joint pain, back pain, and muscle pain), space motion sickness, allergies, and sinus congestion (Putcha et al. 1999; Wotring 2016). Difficulty falling asleep caused by disruptions in circadian rhythm and work stress leads to frequent intake of sleep-promoting drugs during space missions. More than 70% of crew members reported the use of sleep aids on both space shuttle missions and International Space Station missions with multiple doses observed on

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Table 4 Medications currently available during spaceflight (Barratt 1999; Kast et al. 2017) Acetaminophen Ampicillin Atropine Dexamethasone Morphine Diazepam Diphenhydramine Epinephrine Erythromycin Sleep aids Ibuprofen Propofol

Cephalexin Lidocaine Meperidine Prochlorperazine Penicillin Nitroglycerine Donnatal Promethazine Tetracycline Promethazine Ciprofloxacin Enteric aspirin

17% of the nights when sleep aids were taken (Wotring 2015, 2016). The relatively large number of multiple dose administrations of sleep-promoting drugs in the same night might indicate a lack of efficacy after administration of the first dose. Drugs which are reported to be taken frequently during International Space Station missions include congestion and allergy treatments, pain relievers, rash treatments, motion sickness prophylaxis treatment, and alertness aids, with 21–55% of crew members reporting their use (Wotring 2015). Many of these medications are also likely to be used on longer exploration missions, but there is a lack of experimental evidence regarding alterations in their pharmacokinetics or pharmacodynamics in the unusual environment of a spaceflight mission. Table 4 enumerates the different drugs reported to be used in space travel. Primarily, medications taken during shuttle flights have been orally administered, although ocular, topical, rectal, and parenteral formulations are also included in the space mission operational medical kits. The preceding discussion makes it clear that need-based medicine use is imperative in spaceflights, long or short duration, deep space explorations, or low Earth orbit experiments. Be it on Earth or in space, pharmaceutical stability, safety, and efficacy of medicines play a vital role to achieve therapeutic effects. Medicines in space constantly experience microgravity, excessive vibrations, and radiation. Degradation of pharmaceuticals can result in inadequate efficacy and untoward toxic effects that could compromise astronaut safety and health. Although biological studies are carried out in the last 50 years of space programs, relatively lesser data is present to date regarding pharmaceuticals in space.

An Overview Brian Du et al. (2011) carried out comprehensive stability studies (for 28 months) on various dosage forms on board International Space Station (ISS) compared with similar ground control medicine kits on the Earth. The medicine kits (22 solid,

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7 semisolids, and 4 liquid formulations) were subjected to variable temperatures, relative humidity, and radiation. For physical characterization, weight, physical appearance, color, odor, and texture of solid dosage forms (capsule, tablet) were examined. Content uniformity, assay, hardness, and friability were determined for compressed and coated tablets, whereas caking, clumping, and drying of content were evaluated for capsules. Disintegration test and dissolution test revealed rate and extent of drug release. For semisolid (gel, cream, ointment, and suppository) formulations, physical characterization included cracking, liquefaction, drying, and phase separation. Liquid and injectable formulations were examined for presence of particulates and microbial contamination. All the tests were carried as per USP (United States Pharmacopeia) specifications. Chemical analysis as stability-indicating assay by HPLC (highperformance liquid chromatography) was determined to confirm the content uniformity. Most tablets showed discoloration, while liquefaction was observed in ophthalmic ointments. Two creams out of three formulations indicated phase separation. While most of formulations complied with dissolution test criteria of USP, content uniformity test for API was within acceptance limits of only 27% formulations (that means potency loss in more than 50% medications in spaceflights!).

Impact of Spaceflight on the Human Body Physiological changes have been observed as the astronauts are exposed to the microgravity environment. And the duration of these effects can vary widely based on how long the spaceflight is and how long the astronauts are in space ranging from fast resolution within the first days of the mission or shortly after returning to Earth, up to several years, with some permanent effects that never resolve completely (Wotring 2015, 2016). One of the major physiological changes in the human body includes cardiocirculatory fluid shifts. The phenomenon continues once the astronauts are exposed to the microgravity environment. The arterial, venous, and microcirculatory blood pressure gradients are no longer present which causes a fluid shift from the lower to the upper parts of the body and a decrease in blood volume. These fluid shifts may impact the pharmacokinetics of drugs, thus have the potential to alter overall drug safety and efficacy (Kast et al. 2017). Some other changes include musculoskeletal muscle and bone loss, changes in the immune system (Crucian et al. 2013), gastrointestinal changes, and metabolic changes (Kast et al. 2017).

Pharmacokinetic and Pharmacodynamic Changes A critical study on pharmacokinetics (absorption, distribution, metabolism, and excretion of a drug) of acetaminophen by I. V. Kovachevich et al. (2009) in longduration spaceflights was conducted using UV-HPLC method of analysis. The results concluded that bioavailability of acetaminophen in spaceflight is slightly

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lower and may be related to change in electrolyte and fluid balance and decreased absorption rate from the gastrointestinal tract. A preliminary research on impact of short-term simulated microgravity on nanoemulsion stability by Danielle Dantuma et al. (Crucian et al. 2013) concludes that there is overall insignificant change in stability of nanoemulsions, with decrease in droplet size (by up to 3%) and minimal change in zeta potential for 1-week period of study. Out of common dosage forms studied inside spaceflights, foams show remarkably high stability and foamability under microgravity. The reason for this was attributed to lack of fluid drainage from the foam and insufficiency shown by antifoaming agent, as described by Pavel Yazhgur et al. (2015). Many experimental works by researchers have used clinostat equipment to replicate and simulate the microgravity experienced in space, but it does not provide all other physical aspects experienced in space. Having said this, the experimental work results are not fully unacceptable but relevant and can be fairly extrapolated to actual conditions in space as far as microgravity is concerned (Hoson et al. 1997). Nanoemulsion stability of water-insoluble drugs in presence of simulated microgravity was evaluated using clinostat by Y. V. Pathak et al. (Dantuma et al. 2015). Appearance, pH, viscosity, and particle size distribution after 48 h did not change significantly with exception of zeta potential. Conclusion was to carry out further extensive long-term studies. As wholesome diet is not possible in spaceflights, vitamin B complex can be taken by astronauts voluntarily as dietary supplements. In one such analytical study, Monica C. Chuong (2011) performed dissolution test and content uniformity assay of multivitamin tablets as mentioned in USP-NF 10 (United States Pharmacopoeia and National Formulary). The payload (Brand #1 and Brand #2) was onboard ISS for a short period of 14–20 days. Brand #2 was on board ISS for 12–19 months. UV-visible spectrophotometer and HPLC studies of two out of six tablets in the payload indicate loss of content, while the remaining were within 90–150% labeled limits. It appears that there is a need for long-term follow-up. One step ahead, Virginia E. Wotring (2016) evaluated not only contents and stability but also impurities formed in nine medications obtained after their 550 days stay at the International Space Station. No unusual degradation products (impurities) were identified, and APIs (active pharmaceutical ingredients) were within pharmacopoeial limits even after labeled expiration date. Very limited data is available on what should be the ideal primary packaging and secondary packaging materials for medicine kit for astronauts. An elaborate write-up by Lakshmi Putcha (2011) touches this aspect. Owing to unique physical and environmental factors in space missions, like microgravity, CO2-rich environment, excessive vibrations, ambient humidity and temperature, and radiation, manufacturer’s packaging is removed and repacked in new materials with new detailed labels. Ziploc ® bags and plastic amber vials in containers with Velcro ® are found to be appropriate for medium-duration missions. Similarly, ionizing radiation resulting in chemical degradation can cause drug-excipient interaction. For future deep space explorations, longer-time protection and shelf life are required where

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Table 5 Possible approaches to assure stability of space medicine Se no 1 2

Storage Proper packaging Shielding of the pharmaceuticals

Improved technology Formulation of radiation hardy drug products Use of radio protectants

3

Use of microparticles

4

Use of nanoparticles for better pharmacokinetic and pharmacodynamic outcomes

Prediction models Accelerated stability studies in normal 1G environment Accelerated stability studies in microgravity environment Creating simulation models for impact of gravity on the stability of drug products Creating mathematical models to predict the stability in different gravity environments

Based on data from Mehta (2017)

HDPE (high-density polyethylene with tungsten, boron coating) and hydrated porous organic capillary matrices may be considered as useful alternatives. Suspensions undergo sedimentation particularly under gravitational force on the Earth. Thus, sedimentation phenomenon is not observed in microgravity. A major problem occurs in the removal of air bubble from syringe loaded with injectable. The only way out is to take prefilled air bubble removed from syringe before spaceflight takes off. Since solid dosage forms are more stable than liquids and long-term flights require longer shelf life, “powders for reconstitution” are desirable. Just an additional study on technique of powder reconstitution under microgravity will be required (Marshburn 2008). An excellent review on stability of pharmaceuticals in space by Priti Mehta (2017) sheds light on stability process as per ICH guidelines (International Conference on Harmonization, a tripartite guideline for pharmaceuticals and biologicals set for three regions – USA, Japan, and EU). How improved technology can aid in stability evaluation of pharmaceuticals in space is mentioned in Table 5. Keeping in mind the above approach, Lakshmi Putcha (2011) suggested nanostructured drug delivery systems for drug encapsulation and protection from stability problems encountered in space.

Conclusion Successful stepping of humans on moon has inculcated quest to explore the vast expanse of the universe, so much so that future awaits deep space exploration to Mars and much discussed contemporary issue of space tourism. Medicines are integral part of human life and are essential for wellness, health, and safety of space explorers. This chapter has discussed about the challenges faced to maintain safety, efficacy, shelf life, and dispensing of medications arising due to environmental and other hostile conditions in the spaceflight. It also shared representative

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examples of studies on medications expressing views of various authors to tackle earlier mentioned challenges. Medicines in various dosage forms like tablets, emulsions, suspensions, ointments, creams, foams, suppositories, and parenteral are evaluated for shelf life, stability, API content, packaging integrity, rate of drug release, pharmacokinetics and pharmacodynamics, and physical stability against backdrop of radiations, vibrations, microgravity, and temperature – humidity in spaceflight. Very few studies are actually carried out inside spacecrafts, while majority are executed on Earth under simulated conditions. These current studies primarily represent the problems faced by astronauts in the past. Observations and results available are for short-term space travels. Systematic and planned protocol is needed to address concerns of long-time space travel for deep space explorations. In conclusion, the future of the medicines in space can be improved by making intelligent manipulations in dosage forms through innovative drug delivery technologies. The answer lies in extensive data generation through experimentations and ultimately optimizing the “medicine in space.”

References Akbarzadeh A, Rezaei-Sadabady R et al (2013) Liposome; classification, preparation and applications. Nanoscale Res Lett 8(1):102 Allen LV Jr, Ansel HC (2014a) Ansel’s pharmaceutical dosage forms and drug delivery systems, 10th edn. Lippincott Williams & Wilkins, Baltimore, pp 4–7 Allen LV Jr, Ansel HC (2014b) Ansel’s pharmaceutical dosage forms and drug delivery systems, 10th edn, chapter 1. Lippincott Williams & Wilkins, Baltimore, pp 2–4 Allen LV Jr (2012) The art, science and technology of pharmaceutical compounding, 4th edn. American Pharmaceutical Association, Washington, DC Augsburger LL (1988) Instrumented capsule filling machines: methodology and application to product development. STP Pharma 4:116–122 Banker GS (2002) Modern pharmaceutics, 4th edn, chap 1. Marcel Dekker, Inc., New York, pp 1–7 Barratt M (1999) Medical support for the International Space Station. Aviat Space Environ Med 70:155–161 Bhagwat RR, Vaidhya IS (2013) Novel drug delivery systems: an overview. Int J Pharm Sci Res 4 (3):970–982 Chien YW (1991) Novel drug delivery system, 2nd edn. CRC Press, Boca Raton Christensen NJ, Drummer C, Norsk P (2001) Renal and sympathoadrenal responses in space. Am J Kidney Dis 38:679–683 Chuong MC (2011) Stability of vitamin B complex in multivitamin and multimineral supplement tablets after space flight. J Pharm Biomed Anal 55:1197–1200 College of Pharmacy and Pharmaceutical Sciences History (2018) Data from https://pharmacy.wsu. edu/documents/2018/01/history-of-the-pharmacy-profession.pdf/ Crucian B, Stowe R, Mehta S et al (2013) Immune system dysregulation occurs during short duration space flights on board the space shuttle. J Clin Immunol 33:456–465 D’Aunno DS, Dougherty AH, DeBlock HF et al (2003) Effect of short and long-duration spaceflight on QTc intervals in healthy astronauts. Am J Cardiol 91:494–497

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Dantuma D, Elmaddawi R, Pathak Y, Grenha A, de Oliveira R, Paludo C, dos Santos M (2015) Impact of simulated microgravity on nanoemulsion stability – a preliminary research. Am J Med Biol Res 3:102–106. https://doi.org/10.12691/ajmbr-3-4-4 Du B et al (2011) Evaluation of physical and chemical changes in pharmaceuticals flown on space missions. AAPS J 13(2):299–308 Florence AT, Attwood D (2006) Physicochemical principles of pharmacy, 4th edn. Pharmaceutical Press, London Homick JL, Reschke MF, Vanderploeg JM (1984) Space adaptation syndrome. Incidence and operational implications for the space, transportation system program. In: Motion sickness: mechanisms, prediction, prevention, and treatment, CP-372. Advisory Group for Aerospace Research, Williamsburg Hoson T et al (1997) Evaluation of three dimensional clinostat as a simulator of weightlessness. Planta 203:187–197 Huntoon CSL, Cintron NM (1996) Endocrine system and fluid and electrolyte balance. In: Nicogossian AE, Gazenko OG (eds) Space biology and medicine, Joint US/Russian publication in five volumes, vol 3, book 1. AIAA, Reston, pp 89–104 Johnson PC (1983) The erythropoietic effects of weightlessness. In: CDR D (ed) Current concepts in erythropoiesis. Wiley, New York, pp 279–300 Kast J, Yu Y, Seubet CN, Wotring VE, Derendorf H (2017) Drugs in space: pharmacokinetics and pharmacodynamics in astronauts. Eur J Pharm Sci 109:52–58 Kovachevich IV et al (2009) Pharmacokinetics of acetaminophen administered in tablets and capsules under long-term space flight conditions. Pharm Chem J 43(3):130–134 Mahato RI, Narang AS (2012) Pharmaceutical dosage form and drug delivery, 2nd edn. CRC Press, Boca Raton Marshburn TH (2008) Acute care. In: Barratt MR, Pool SL (eds) Principles of clinical medicine for space flight, 1st edn. Springer, New York, pp 101–122 Martin DS, South DA, Wood ML et al (2002) Comparison of echocardiographic changes after short- and long-duration spaceflight. Aviat Space Environ Med 73:532–536 Mehta P (2017) Impact of space environment on stability of medicines: challenges and prospects. J Pharm Biomed Anal 136:111–119 Mirza AZ, Siddiqui FA (2014) Nanomedicine and drug delivery: a mini review. Int Nano Lett 4:94 Narang AS, Rao VM, Raghavan K (2009) Excipient compatibility. In: Qiu Y, Chen Y, GGZ Z, Liu L, Porter W (eds) Developing solid oral dosage forms: pharmaceutical theory and practice. Elsevier, Burlington, pp 125–146 Oganov VS, Schneider VS (1996) Skeletal system. In: Nicogossian AE, Gazenko OG (eds) Space biology and medicine, Joint US/Russian publication in five volumes, vol 3, book 1. AIAA, Reston, pp 247–66 Pathak Y, Thassu D (2009) Drug delivery nanoparticles formulation and characterization, 1st edn. Informa Healthcare, New York Putcha L (2011) Biopharmaceutical challenges of therapeutics in space: formulation and packaging considerations. Ther Deliv 2(11):1373–1376 Putcha L, Berens KL, Marshburn TH, Ortega HJ, Billica RD (1999) Pharmaceutical use by U.S. astronauts on space shuttle missions. Aviat Space Environ Med 70:705–708 Shelley Chambers Fox (2014) Remington education – pharmaceutics, 1st edn, Chapters 9 and 13. Pharmaceutical Press, London Stewart LH, Trunkey D, Rebagliati GS (2007) Emergency medicine in space. J Emerg Med 32 (1):45–54 Subramanyan CVS (2000) Textbook of physical pharmaceutics, 2nd edn. Vallabh Prakashan, Delhi, pp 366–394 Talor GR, Konstantinova IV, Sonnenfeld G et al (1997) Changes in the immune system during and after spaceflight. Adv Space Biol Med 6:1–32 Tavassoli M (1986) Medical problems of space flight. Am J Med 81(5):850–854

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Wing PC, Tsang IKY, Susack L et al (1991) Back pain and spinal changes in microgravity. Orthop Clin North Am 22:255–256 Wotring VE (2015) Medication use by U.S. crewmembers on the International Space Station. FASEB J 29:4417–4423 Wotring VE (2016) Chemical potency and degradation products of medications stored over 550 Earth days at the International Space Station. AAPS J 18(1):210–216 Yalkowsky SH, Bolton S (1990) Particle size and content uniformity. Pharm Res 7:962–966 Yazhgur P et al (2015) How antifoams act: a microgravity study. npj Microgr 1(1):15004

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Understanding the Routes of Administration Deepak Gupta, Sheeba Varghese Gupta, and Ningning Yang

Contents Oral Route of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology of Epithelial Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Buccal Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Small Intestine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Large Intestine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physicochemical Properties of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dissolution and Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Absorption Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Applications and Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Parenteral Route of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intravenous (IV) Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intramuscular (IM) Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Subcutaneous (SC) Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intradermal (ID) Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Topical and Transdermal Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ophthalmic Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Buccal and Sublingual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rectal and Vaginal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inhalational . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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D. Gupta (*) · N. Yang Department of Pharmaceutical Sciences, School of Pharmacy, Lake Erie College of Osteopathic Medicine, Bradenton, FL, USA e-mail: [email protected]; [email protected] S. V. Gupta Department of Pharmaceutical Sciences, University of South Florida – College of Pharmacy, Tampa, FL, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 Y. V. Pathak et al. (eds.), Handbook of Space Pharmaceuticals, https://doi.org/10.1007/978-3-030-05526-4_12

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Abstract

Routes of administration are the key determinant to ensuring therapeutic benefits of the drug. The choice of route of drug delivery is vastly dependent on drug properties, disease states, site of action, and patient compliance. Oral route of administration is the most common route owing to its simplicity, convenience, and patient acceptance. Other routes of administration are also equally important due to their ability to deliver the drugs directly to site of action as in case of inhalational route or ensuring a quicker onset of action in case of emergency as in case of intravenous route. This chapter explains various routes of drug administration and the factors affecting choice of each route. In order for a drug to produce its intended therapeutic actions, it must first be able to reach its target site of action in the body at an appropriate concentration. The site of action of the drugs may be widespread in the body (blood pressure controlling medications or systemic antibiotics) or specific tissues (osteoporosis medications – bone is the site of action). The drug is administered in such a way that it is able to reach systemic circulation in therapeutically effective concentration. Drugs can be administered by various routes; the route of administration is widely classified as oral or enteral, parenteral, rectal, inhalational, ophthalmic topical, transdermal, and intranasal. There are advantages and disadvantages associated with each route of administration (Table 1). Choice of a particular route depends on therapeutic outcomes and the physicochemical/pharmacokinetic properties of drug. Therapeutic concerns or outcomes include onset of drug action, site of action, and patient compliance. Physicochemical properties of the drug include lipid solubility, ionization status, molecular size, and plasma concentration–time profile. Oral route is the most common and convenient route of administration for systemic delivery of the drugs. More than 60% of the currently marketed drugs are administered orally. The popularity of oral route is attributed to ease of administration, high level patient compliance, low cost of production, and no need of special skills for administration. Orally absorbed drug is required to overcome many barriers to get absorbed in the systemic circulation. Oral route being the major route of administration, this chapter will address various barriers to oral drug absorption in somewhat detail.

Oral Route of Administration As mentioned earlier, oral route of drug administration is the most acceptable and most commonly used administration route for different drug products. Most of the oral drugs are intended to produce systemic effects after absorption. Gastrointestinal tract (GIT) has several absorption sites like buccal cavity, stomach, small intestine, large intestine, and rectum for drug absorption. Nature of anatomical and physiological barrier across gastrointestinal (GI) epithelium and physicochemical

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Table 1 Advantages and disadvantages of various routes of administration Route Oral

Parenteral: 1. Intravenous (IV)

2. Intramuscular (IM)

3. Subcutaneous (SC)

Rectal

Ophthalmic

Inhalational

Advantages Most convenient Relatively safe and cost effective

Disadvantages Erratic and incomplete absorption leading to variation in absorption Extensive first-pass effect for certain drugs

No absorption losses Large volume of fluid can be administered Absorption rate can be controlled by altering the formulation properties Can be used for moderate volumes and oily vehicles Absorption rate can be controlled by altering formulation properties

High risk of complications such as embolism, infection, and anaphylaxis Not suitable for water-insoluble drugs Painful Not recommended for patients on anticoagulant therapy

Partially avoids first-pass effect Suitable for drugs unstable in GI fluids Ease of administration Less systemic side effects Better patient compliance Rapid absorption due to large surface area of the inhalational endothelium Drugs are delivered remove to directly to the site of action

Not suitable for large volume of fluids Irritant drugs can cause pain and necrosis at the site of injection Lack of patient compliance Irritant drugs can irritate rectal mucosa leading to premature elimination of the formulation Short residence time Poor bioavailability Unstable drug preparation Bioavailability is dependent on patient’s administration technique

properties of drug and its formulation determine extent of drug absorption. Dissolution, solubility, and permeability of the drug molecule are major factors that influence drug absorption from solid dosage forms.

Pathophysiology of Epithelial Barrier Buccal Cavity Epithelial lining has basement membrane, lamina propria, and underlying connective tissue rich in nerve and blood capillaries. Saliva consists of water, mucus, enzymes, and minerals and is continuously secreted and has a pH of around 6.4. Saliva and its pH are very crucial for ionization and solubility of the drug, so that it can be absorbed in limited time. Nonetheless, buccal cavity is an important site for drug absorption and to avoid first-pass metabolism. Unionized drugs tend to absorb

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in buccal cavity by passive diffusion. Lipophilic drugs tend to be absorbed by passive diffusion; however, solubility can be a limiting factor. Polar drugs tend to ionize more and have limited absorption. Sublingual tablets or films tend to dissolve fast in saliva and can be very useful in faster onset of action or to avoid first-pass metabolism (Squier and Johnson 1975). Nitroglycerine sublingual tablets are useful in treating acute onset of angina due to their faster onset of action which is even less than 1 min. Example: Fentanyl is available in different buccal formulations like lollipops, films, and effervescent tablets. Lollipops and films have limited absorption of the fentanyl free base due to predominant ionized form at salivary pH. Only 25% of the dose is absorbed while 75% is destroyed due to high first-pass metabolism. On the other hand, effervescent buccal tablets are buffered with citric acid, sodium bicarbonate, and sodium carbonate. This alters the pH of the saliva allowing both more drug dissolution and eventually more unionized form to be absorbed. This approach leads to almost twice the drug absorption than with lollipops or films. Thus, understanding saliva pH, chemistry, and composition is crucial for buccal drug absorption. Besides, lesser residence time and smaller surface area also limit drug absorption. Mucoadhesive polymers have been used to increase residence time in the buccal cavity. These polymers can slowly release the drug over a period of time. Nitroglycerine and lidocaine formulations with bioadhesive polymers provide slow release of drug for absorption over an extended period of time (Nagai and Konishi 1987).

Stomach Stomach has epithelial lining covered by thick and vascular muscle layer. Gastric secretions are rich in enzymes and hydrochloric acid to aid in food absorption. Small surface area and lesser residence time let stomach have a limited role in drug absorption. Still, some of the drugs, especially acidic drugs, start absorbing in stomach and continue to absorb in upper areas of the small intestine. These drugs tend to have relatively faster onset and significant extent of absorption. Gastric pH of empty stomach is generally below 2.0 but varies with age, gender, disease, and other genetic factors. Gastric content is one of the major determinants of its pH. The type of food or drug can have instrumental effect on altering pH, thus affecting absorption (McLauchlan et al. 1989). Drug ionization is significantly affected by stomach pH, and generally, unionized drugs tend to absorb more in stomach by passive absorption. Besides, acid labile drugs sometimes need to be protected to withstand acidic pH in the stomach. Examples include enteric-coated formulations designed for drugs to be absorbed in the intestine. Gastric emptying: Since small intestine is the principal site of absorption for many drugs; rate of emptying of stomach contents into small intestine will have influence on rate of drug absorption. Thus, residence time of the drug at the site of absorption will influence absorption. Gastric emptying is generally fast on empty

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stomach; however, presence of food slows it down. Consistency, composition, and the portion of meal affects gastric emptying (Feldman et al. 1984). Low-viscosity foods like liquids are emptied faster than solids. Besides, high-fat meals have great residence time in stomach and decreases gastric emptying (Hunt and Knox 1968). Patient’s physiological condition, pathological state, as well as drugs can also affect gastric emptying. GI diseases like pyloric stenosis, GERD (gastroesophageal reflux disease), and gastroenteritis can decrease gastric emptying. Similarly, opioids and anti-cholinergics decreases gastric emptying, while prokinetic agents like metoclopramide significantly increases gastric emptying. Understanding factors affecting gastric emptying help in designing dosage forms to achieve desired rate of drug absorption.

Small Intestine Small intestine consists of duodenum, jejunum, and ileum totaling around 6 m in length. Presence of villi, microvilli, and folds of Kerckring provides absorption surface area equivalent to the size of a tennis court. Due to such a large surface area, majority of orally administered drugs are absorbed from small intestine. Drugs absorbed are carried by portal vein to the liver and further distribution based on their physicochemical properties. Highly lipophilic drugs are also absorbed by the lymphatic system (Washington et al. 2000). Small intestine allows the absorption of weak bases as well as weak acids to a greater extent. Duodenum pH ranges from 6 to 6.5; however, pH of the microenvironment closer to the intestinal epithelium is slightly acidic (4.5–6.0) allowing absorption of weakly acidic drugs as well. pH increases going down from duodenum to jejunum and ileum. At that pH (7–8), generally weak bases are unionized more and have more absorption. Still, a fraction of drug may be lost in feces or can be degraded that can reduce drug absorption. Varying pH conditions across entire GI track may not be suitable for acid- or base-labile drugs. Besides, enzymes and efflux transporters present alongside GI lumen can either degrade the drug or efflux it out in the intestine further reducing fraction of drug absorbed. Bioavailability can be further decreased as portal vein delivers the drug to the liver and first-pass metabolism can degrade the drug before it reaches to the systemic circulation (Rowland et al. 1973) Based on drug’s physicochemical properties and its vulnerability towards enzymes and transporters present, up to 100% of the drug can reach systemic circulation or it can be as low as 500 Da, log p of >5, and has either >5 H-bond donors or >10 H-bond acceptors. This has become guiding principle to understand drug absorption and how these important physicochemical properties can have significant effect on drug absorption.

Lipophilicity–Permeability As mentioned previously, solubility is an important criterion before a drug can be absorbed. Weakly acidic or basic drugs tend to ionize to further increase solubility. However, passive absorption requires drug to be in unionized state to be absorbed. Drugs need to have a good balance of ionized–unionized fraction to allow sufficient solubility and permeability for significant drug absorption. pH partition hypothesis states that drug ionization and thus passive absorption can be estimated by understanding pKa value of the drug and pH of particular site in GIT. Acidic drugs tend to be more unionized in acidic pH and basic drugs tend to be more unionized under basic pH conditions. It is broadly assumed that weakly acidic drugs tend to be absorbed from stomach and weakly basic drugs from intestine. However, there are limitations to the theory as weakly acidic dugs can also be absorbed from intestine due to different pH of epithelial microenvironment and due to the fact that absorption and unionization are dynamic processes.

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Other Factors Dosage form (tablets, capsule, solution, suspension, emulsion, gel): Active product ingredients (API) are generally formulated in to finished dosage forms and referred as drug products. Excipients are added into drug products to maintain drugs into desired formulation until administered. They may help in delivering the drug or sometimes just to make it more appealing to the patient. For example, coloring or flavoring a table may help a patient more inclined to take it orally than a bad smelling one. Food effects: Type and amount of food can have significant effect on oral drug products. Food delays gastric emptying, raises gastric pH, and leads to increased flow of bile acids and blood (Fleisher et al. 1999). Food can affect drug stability, dissolution, permeability, as well as residence time in GI track. Drugs can have positive food effect where their absorption increases in the presence of certain kind of food; for example, lipophilic drugs tend to be more absorbed with high-fat meal. On the other hand, food can interfere with drug absorption generally by altering their solubility or increasing metabolism. This kind of negative food effect is an important determinant if a drug needs to be taken on an empty stomach or can be taken with certain foods (Custodio et al. 2008). For example, antifungal drug ketoconazole has limited solubility in GI track and food can further decrease its solubility. However, acidic drinks like soda help to increase solubility for better blood levels. All these are important factors in choosing optimal route of drug administration and suitable conditions around those routes. Site of absorption: Most of the drugs tend to be absorbed unionized by passive diffusion and their permeability varies across different GI sites (Fig. 2).

Absorption Mechanism Active and passive absorption are two important mechanisms by which most of the drugs are absorbed. Passive diffusion is the desired route of absorption by lowmolecular-weight lipophilic drugs. As per Fick’s law of diffusion, rate of absorption is proportional to drug concentration gradient and the surface area. Molecules are diffused from regions of higher concentration to lower concentration. This concentration gradient across epithelial membrane and physicochemical properties of the drugs determine the rate and extent of absorption. Besides, thickness and nature of intestinal membrane can also affect passive diffusion. Sink conditions are maintained by blood flow and basal side generally have much lower concentration allowing continuous absorption. Since most of the drugs are either weak acids or bases, unionized species represents more lipid-soluble and ready-to-be-absorbed form. Therefore, rate of passive absorption is proportional to fraction of the total drug that exists in unionized solution form (Zhu et al. 2017). Active transport is generally mediated by different types of transporters commonly known as ATP-Binding Cassette (ABC) transporters. These transporters utilize adenosine triphosphate (ATP) molecules as their source of energy. Due to

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Solubility Enhancement

Class I

Particle size reduction, soluble salt, solid dispersion, self-emulsifying system, addition of surfactant, nanoparticles, water soluble complexes, pH adjustment, salting-in

Class II

Prodrugs, Permeation enhancers, efflux inhibitors, lipid filled capsules, nanoparticles, surfactants, ion pairing

Class III

Solubility Enhancement Permeability Enhancemen t

Permeability Enhancement

BCS Prodrugs, Salt forms, cosolvents, surfactants, lipid filled capsules, nanoparticles, liposomes, lyophilisation.

Class IV

Fig. 2 Different techniques utilized to increase solubility and/or permeability of different BCS drugs to enhance absorption. (Adapted from Chapter 9, Drug Absorption and Oral Route. In: “Physicochemical Principles of Pharmacy,” 5th edn. Pharmaceutical Press)

energy consumption, drug molecules can be moved against concentration gradient. These transporters are located in different parts of GIT and help in absorption of both ionized and unionized drug molecules based on their affinity for the substrate. On contrary, some transporters like p-glycoprotein (efflux transporter) can also efflux drugs out, thus decreasing overall absorption. Different subtypes of transporters exhibit varying selectivity for endogenous as well as drug molecules. Besides, inhibitors and inducers of these transporters can significantly affect drug absorption. Moreover, structurally similar molecules also compete for the same transporter further leading to clinically significant drug interactions. Another important property of this type of transport is ability to saturate. As drug concentration at absorption site increases, there will not be further increase in drug absorption beyond a particular concentration. Another group of transporters that do not rely on ATPs are called as human solute-linked carrier (SLC) transporters. These transporters help in facilitated diffusion of the drug molecules. Well-known examples of these types of transporters are organic anion transporters (OAT) and organic cation transporters (OCT) (Bardal et al. 2011).

Applications and Examples Myriad of oral dosage forms and their countless applications in oral drug delivery is one of the most fascinating fields for researchers from diverse disciplines. Different dosage forms like tablets, capsules, solutions, powders, suspensions, aerosols, concentrate, elixirs, emulsions, films, granules, syrups, troches have found use in oral

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Fig. 3 Commonly used oral dosage forms

Tablets Films

Granules

Elixirs

Syrups

ORAL Troches or Lozenges

Emulsions

Capsules

Suspensions Solutions

Powders

drug delivery formulations and possibilities are limitless. Figure 3 describes some of the most commonly used oral dosage forms. Moreover, modified formulations like delayed release, chewable, and sustained release tablets are very useful to achieve desired therapeutic outcome if immediate release formulations are not very effective. Table 1 reflects some of the most common examples of blockbuster oral formulations.

Parenteral Route of Administration In Greek language, “para” means outside and “enteral” means intestine; therefore, parenteral route of administration broadly refers to the drug administration bypassing the intestinal route; however, in the clinical setting, it is classically used to address injectable route of administration. Parenteral route of administration is the most effective route for delivering therapeutic agents with narrow therapeutic index and poor bioavailability. It is also an effective route of drug delivery to unconscious patients. Injections are among the most common health care procedures across the world (Jin et al. 2015). Intravenous (IV), intramuscular (IM), intradermal (ID), and subcutaneous are the four common types of injections used for the delivery of therapeutic agents (Fig. 4). Intra-arterial, intra-thecal, and intra-articular injections represent less common types of injections used for drug delivery. In this section, IV, IM, ID, and SC types of injections will be addressed in detail. Regardless of the type, the common feature of all parenteral administration is that the drug is injected into the body using a hypodermic needle. The formulations intended for parenteral delivery must be sterile, nonimmunogenic, and pyrogen-free, because drug delivery by injection bypasses defense mechanisms of the body. The rate and extent of systemic availability of the drug is dependent on the type of parenteral

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Fig. 4 Routes of parenteral administration

administration and the physicochemical properties of the drug. In case of IV injections, the drug is injected into the systemic circulation directly available for immediate therapeutic action, whereas IM injections can be used to inject depot of therapeutic agents, to provide long and sustained therapeutic benefit.

Intravenous (IV) Injection This route of administration involves injecting drug into the veins of the patient; the drug reaches the heart as part of venous return, from where it is distributed throughout the body. IV drugs provide complete bioavailability and faster action as compared to other routes of administration. Because of the faster onset of action, IV route is preferred in case of emergency when a quick action is required or the patient is unable to administer the drug by other conventional route of administration. This approach has both advantages and disadvantages; the advantage is that the faster onset of therapeutic action can be lifesaving and the disadvantage is that the drug cannot be retrieved once it is administered by IV route leading to detrimental outcomes in case of medication errors. IV administration can lead to potential overdosing of the drug; therefore, the dose and the dosing intervals need to be closely monitored. Only trained health personnel should perform IV administration. The formulations intended for IV administration should be devoid of any particulate

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matter to prevent capillary occlusion, should match the pH and isotonicity of blood, and should be formulated in nontoxic, biocompatible solvents. pH, isotonicity, and physiological compatibility of the IV solvents are of crucial importance, because any imbalance of these parameters can lead to phlebitis (inflammation of vascular epithelium) and potential severe damage of the tissue surrounding the site of injection (Urbanetto et al. 2016). Irritation at the site of injection due to irritant drugs such as vancomycin can be prevented by administering the drug at a slower rate, which allows the dilution and buffering in the blood (Drouet et al. 2015). Both small and large volumes of drugs can be administered intravenously. The administration can either be a bolus or by IV infusion. In IV bolus, the entire drug volume is injected in short period of time, whereas in case of IV infusion, the drug solution is administered over a period of time at a constant rate. The infusion rate is adjusted based on the needs of the patient using a mechanical pump; the flow rates are expressed in millimeters/hour and can go up to 150 mL/h. IV infusion is generally used in hospitalized patients requiring the administration of therapeutic agents, electrolytes, or nutrition for an extended period of time. The main complication of the IV infusion is thrombus formation induced by the catheter or by the needle touching the vein (Leung et al. 2016). Thrombus can lead to embolus (circulating blood clot), which can lead to obstruction of blood vessels and can be detrimental to the patient based on the site and severity of the obstruction. IV drugs must be formulated in aqueous solutions with the exception of IV fat emulsions, which consist of soybean oil emulsified with egg yolk phospholipids in a vehicle of glycerin in water for injection. In addition to being the route of drug administration, IV route is also used for administering parenteral nutrition, blood transfusion, and removal of blood for diagnostic and donating purposes.

Intramuscular (IM) Injection IM injections provide slower onset of drug action but duration is longer as compared to IV route of administration. In IM route of administration, the drug formulation is injected into the muscular tissue. The muscles are perfused well with blood, so the injected drug is absorbed into systemic circulation. The rate of absorption from the site of injection is dependent on the physicochemical properties of the drug and the extent of perfusion of the muscle tissue. Both aqueous or oleaginous solutions or suspensions of drug substances can be administered by IM route. Drugs in solution have faster absorption than that in suspensions and aqueous solutions have better absorption than their oleaginous counterparts. The deltoid muscle is well perfused, does not have major nerves (it is away from radial nerve) or blood vessels, and is of significant size for injection. The deltoid site is preferred if faster onset of action is desired. Upper outer quadrant of the gluteus maximus is the most frequently used

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site for IM injection in adults, as injection at this site is less painful than the injection at deltoid area. In infants, the gluteal area is small and primarily composed of fat and poorly developed muscle. Any injection in that area can risk hurting sciatic nerve. Therefore, deltoid muscle of the upper arm or the midlateral muscle of the thigh are preferred. IM route is not ideal for administering large volume of fluids; the volume is limited to a maximum of 5 mL in gluteal area and 2 mL in deltoid area (Dalton et al. 1996). IM injection for drugs that tend to stain the upper tissue is administered by Z-track technique in which the epidermis and hyodermis layers are moved 2–3 cm to the side or downward with the help of nondominant hand. This technique helps the needle to gain entry in to the muscle into a zigzag shape, thereby preventing the backflow of the drug from the site of injection (Yilmaz et al. 2016).

Subcutaneous (SC) Injection SC route of administration delivers drug into the subcutaneous tissue (hypodermis), where the drug resides and undergoes absorption by blood or lymphatic capillaries and is transported into systemic circulation (Richter and Jacobsen 2014). Both lymphatic and blood capillaries drain slowly into the systemic circulation, leading to very slow and unpredicatble drug absorption. The variable absorption can cause unpredictable serum concentrations of the drug. The problem of slow and erratic absorption can be solved by formulating the drug in a sustained release dosage form; the slow release from the injection site will aid in steady concentration of the drug being absorbed in the systemic circulation. The preferred site of injection is in the loose interstitial tissue of the upper arm, the anterior thigh, or the lower abdomen. SC route is used for injecting small volume of medication. The site of injection is rotated if intended for chronic therapy as in case with insulin injections.

Intradermal (ID) Injection This route of administration is primarily used for diagnostic, sensitization (allergy testing), and immunological purposes. ID route of administration allows injection of only small volume of drugs; in fact, the volume is the smallest as compared to IV, IM, and SC routes of administration. The drug substance is injected to the more vascular layer of the skin just beneath the epidermis known as corium. The usual site of ID injection is the anterior forearm. The needle is inserted horizontally into the skin with the bevel facing up. The injection is made with just the bevel disappearing into corium. The maximum volume that can be injected by ID route is 0.1 mL. Since the ID route is used commonly for diagnostic testing, massaging the site of injection is not recommended as it can lead to false positive result (Love 2006).

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Topical and Transdermal Administration Topical drug administration is a localized drug delivery system through skin. Topical preparations are applied to the skin for surface or local effects. Sometimes the baseonly formulation can be used alone, such as emollient to sooth or protect the skin, although most cases contain active ingredients which are dispersed or dissolved in the bases. The principles to combine the active ingredients and base should reside on the physical properties of both the active drugs and the bases. Same as the topical application, transdermal administration applies the medication topically to the skin. However, different from topical dosage forms, transdermal administration is the route of delivering the active pharmaceutical ingredient through the skin for the systemic distribution. As introduced before, a pure topical application creates an effect at the administration site. The drug concentration in the blood does not change significantly. However, transdermal delivery makes the drug absorbed through the skin or mucosal membranes to reach the circulation system, which is usually performed by oral or parenteral routes. Because transdermal medications can produce effects in tissues away from the site of application, it is a very useful method to use when the patients have difficulty to swallow or are afraid of injections. Besides the patient compliance, transdermal delivery is also very important for the drugs that are significantly affected by the first-pass metabolism. This session will focus on the transdermal delivery system. The biological barrier is a big concern in transdermal delivery. The drugs administered dermally are absorbed through two major steps. First, the drugs release from the dosage forms to become available for absorption. The next step for the drugs is to diffuse through the epidermis to the dermis, where the drugs can be absorbed into the capillaries. The obstacle of drug diffusion and absorption is due in large part to the stratum corneum (Downing et al. 1987). The stratum corneum consists of corneocytes, which are mostly composed of keratin filaments. Due to its extremely low water solubility, keratin is the key structural material making up the outer layer of human skin. Keratin can protect epithelial cells from damage or stress, prevent excessive water loss and other body constituents. Stratum corneum is the primary barrier to drug absorption into skin. The lipid matrix of the stratum corneum limits the transdermal delivery of hydrophilic drugs. In addition to that, the lipid part serves as a reservoir for hydrophobic drugs. Those lipid-soluble drugs can accumulate and release slowly. The absorption rate of transdermal dosage forms is slow. Besides being slow, the absorption rate can be very variable due to different physiological and pathological conditions in skin. The skin structure, thickness, hydration, and inflammation play important roles in determination of the absorption rate. Therefore, the site of application can definitely affect the absorption rate across the skin. The topical dosage forms include many lotions and ointments, such as various antibiotics to treat skin infections. Usually, transdermal medications are recommended to be applied to the outer upper parts of arms and shoulders, the upper and lower back, the upper chest, and the lower hips. However, the development of transdermal delivery systems is a little complicated.

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Many of today’s patches are from the very original techniques, in which choosing the proper drug candidate is very critical. After that, transdermal delivery study focused more on increasing skin permeability and driving forces. Currently, the research is still in development and enables transdermal delivery of not only small molecule drugs but also macromolecules. The following parts will introduce all the development stage and their application separately. Most of the transdermal patches in clinic uses original transdermal delivery techniques. The limitation of the old techniques is that only drugs with proper characteristics, such as low-molecular weight, lipophilic and efficacious at low doses, can be used as the candidates. The proper candidates therefore can transport across the intercellular lipids in the stratum corneum through diffusion highly constrained by the structural and solubility requirements for both the drugs and the lipid bilayers. The active ingredients are formulated in the patches in most cases. Although some metered liquid sprays or gels do not have a physical patch, the topical film formed upon application can drive the diffusion of medications into the stratum corneum. The film continually serves as the drug reservoir for extended release into the viable epidermis over hours (Morgan et al. 1998). For example, testosterone gels have been in use for several years and a transdermal spray has been recently approved for estradiol delivery. The newer techniques utilize various strategies such as increasing skin permeability by reversibly disrupting stratum corneum structure or providing a driving force to facilitate the transport. Although the ideal enhancer should not do major injury to deeper tissues, some conventional chemical enhancers and the physical techniques, such as iontophoresis and noncavitational ultrasound, could induce deeper tissue damages if certain delivery efficiency is desired. Meanwhile, the second generation of delivery systems did not show significant enhancement on delivery of macromolecules (Prausnitz et al. 2004). Development of chemical enhancers made the enhanced skin permeability possible (Williams and Barry 2004). The effective permeability enhancers insert amphiphilic molecules into these highly ordered bilayers in stratum corneum to disorganize molecular packing in nanometer scale. Some chemical enhancers extract lipids using solvents and surfactants to create lipid packing defects, such as Azone (1-dodecylazacycloheptan-2-one) and SEPA (2-n-nonyl-1,3dioxolane). Besides the chemical enhancers, liposomes, dendrimers, and micro-emulsions have also been used as delivery vehicles, which can increase skin permeability, drug solubility, and partitioning into the skin (Karande et al. 2005). Another strategy is the uses of prodrugs, which can facilitate the lipophilicity and therefore ease the transportation of the prodrug across the skin (Kiptoo et al. 2006; Sloan et al. 2006). Iontophoresis is another approach for transdermal delivery by typically using a continuous low-voltage current as an electrical driving force to transport the charged drugs across stratum corneum (Kalia et al. 2004). Iontophoresis is mostly applicable to small molecules and some macromolecules up to a few thousand Daltons due to intact skin structures. The rate of drug delivery can be controlled over time to enable complex delivery profiles. The marketed iontophoresis transdermal patches include rapidly deliver lidocaine for local anesthesia (Zempsky et al. 2004), pilocarpine to

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Table 2 Examples of sonophoretic transdermal systems Drug or product Ionsys (Fentanyl) Zecuity (Sumatriptan) Acyclovir Fertility hormone

Company The medicines Teva Pharmaceuticals Transport

Status FDA approved in 2006, in market now FDA approved in 2013, but suspended in 2016 Phase 2 was completed in 2006

Vyteris/Ferring

Phase 1 was completed in 2009

Indication Postoperative pain Migraine Herpes labialis Female infertility

induce sweating as part of a cystic fibrosis diagnostic test (Beauchamp and Lands 2005) and extract glucose from the skin for glucose monitoring (Tamada et al. 1999). Besides these, there are more examples of iontophoresis transdermal patches summarized in Table 2. In the second-generation delivery systems, noncavitational ultrasound is also applied as a skin permeation enhancer and was first used to deliver anti-inflammatory agents into the skin by ultrasonic heating probes (Machet and Boucaud 2002). The current developing technology significantly disrupts the stratum corneum barrier, and thereby achieves more effective transdermal delivery but still protects deeper tissues. Cavitational ultrasound can do this work compared to noncavitational ultrasound. Besides that, novel chemical enhancers, electroporation, microneedles, thermal ablation, and microdermabrasion are concluded to new delivery systems (Arora et al. 2008) which have been shown to deliver macromolecules including therapeutic proteins and vaccines. The research of novel enhancers has a branch to examine different pairs of chemical enhancers (Karande et al. 2006). For example, a combination of sodium laureth sulfate (an anionic surfactant) and phenyl piperazine (a compound with aromatic nitrogen) can dramatically increase skin permeation with low irritation. In vivo cases have also shown that combinations of chemical enhancers could deliver macromolecules (Kling and DeFrancesco 2007). Specifically designed peptides can also serve as effective permeability enhancers. It was reported that an 11-amino acid synthetic peptide can enhance transdermal delivery of insulin in diabetic rats when combined with a surfactant chemical enhancer (Chen et al. 2006). Recently, it was reported that disulfide-cyclic peptides against keratin and cyclosporine A (CsA) are capable of enhancing transdermal CsA delivery. The selected sequences were experimentally tested and found to bind both CsA and keratin (Menegatti et al. 2016). Electroporation is another approach to use short, high-voltage pulses to deliver therapeutics. The electric pulse can reversibly disrupt cell membranes for gene transfection and other applications (Denet et al. 2004), which can be used for small model drugs, peptides, vaccines, and DNA (Zhao et al. 2006). The electric field may also affect some deeper tissues containing sensory and motor neurons though. As the name says, cavitational ultrasound can produce cavitation when the frequency of the ultrasound is low (Ogura et al. 2008). Due to the low frequency, the bubbles created at the skin surface can generate localized shock waves and liquid micro-jets to facilitate the delivery through the stratum

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corneum (Paliwal et al. 2006). The cavitational ultrasound method has been approved for enhanced transdermal delivery of lidocaine (Becker et al. 2005). Microneedles are used for transdermal delivery too (Sivamani et al. 2007). These microneedles are usually made of water-soluble polymers (Lee et al. 2008) and coated with a variety of compounds, including small molecules, proteins, DNA, and virus particles (Gill and Prausnitz 2007; Jin et al. 2015). It was reported that the naltrexone patches were administered to the skin pretreated with microneedles and the blood level of naltrexone was observed (Wermeling et al. 2008). Besides that, in vitro diffusion studies using Yucatan miniature pig skin showed Gas vesicle nanoparticles (GVNPs) permeation to be enhanced after microneedle treatment compared to untreated skin (Andar et al. 2017). Microneedles were also investigated intensively in vaccine delivery (Arya and Prausnitz 2016).

Ophthalmic Administration Ophthalmic dosage forms are designed to be instilled onto the external surface of the eye (topical), administered inside (intraocular) or adjacent to the eye (periocular). The anatomy of the human eye can be generally divided into the anterior and the posterior segments. The anterior segment includes the cornea, conjunctiva, iris, ciliary body, aqueous humor, and lens while the posterior segment comprises sclera, choroid, retina, and vitreous humor. The most commonly used ophthalmic dosage forms are solutions, suspensions, gels, and ointments. Some older topical preparations are rapidly drained away from the ocular cavity due to tear flow and lacrimal nasal drainage. The newest developed dosage forms for ophthalmic drug delivery such as gel-forming solutions, ocular inserts, intravitreal injections, and ophthalmic implants, can overcome the fast drainage. There are three major barriers for the absorption of the ophthalmic preparationsrapid solution drainage, rapid removal by the peripheral blood flow, and low corneal permeability. Rapid solution drainage is due to gravity, induced lachrymation, blinking reflex, and normal tear turnover. Rapid removal by the peripheral blood flow leads to superficial absorption of drug into the conjunctiva and sclera. Besides the poor permeability of the cornea, the inner and outer blood-retinal barrier and inability of other non-corneal structures also play a big role in making the eye exceedingly impervious to foreign substances. Because of the active pharmaceutical ingredients or the viscosity enhancement agents, most ophthalmic products cannot be autoclaved to sterilize. Almost all ophthalmic products are aseptically manufactured before the package step. The whole filling procedures are operated in containers in aseptic environments using aseptic filling-and-capping techniques. That means the containers must be sterilized before packaging. The preservatives are only used in multiple-dose eye solutions for maintaining the product sterility during use but not in unit-dose package. The ophthalmic products used in eye surgery cannot include any preservatives and must be one time use and should be packed in sterile, unit-of-use containers. If the preservatives are allowed, the most commonly used candidates are benzalkonium

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chloride generally combined with disodium edetate (EDTA), phenylmercuric nitrate, phenylmercuric acetate, phenylethanol, etc. There are many different dosage forms for ophthalmic delivery. Most common are solutions, such as ofloxacin and ciloxan, and suspensions, such as cortisporin ophthalmic suspension and neomycin and polymyxin B sulfates and hydrocortisone ophthalmic suspension. A newly developed dosage form for ophthalmic use is gel-forming solutions. The very first example is timolol maleate ophthalmic gelforming solution. Timolol maleate is a nonselective beta-adrenergic receptorblocking agent with a molecular weight of 432.50. Timolol maleate ophthalmic gel-forming solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol maleate. However, the solution changes to semisolid gel upon contact to the eye because timolol maleate has been formulated in a highly purified anionic heteropolysaccharide derived from gellan gum. Upon contact with the precorneal tear film, timolol maleate ophthalmic gel-forming solution forms a gel that prolongs contact time with corneal tissue (Adamsons et al. 1998). Ocular inserts are a novel category of ophthalmic delivery. The punctal plugs are FDA-approved ocular insert to block tear drainage. They are made with polymers and usually used for dry eye diseases. A recent research is going to study its potential usage as a sustained drug delivery vehicle to the eyes (Kompella et al. 2010; Gupta and Chauhan 2011). P-Sivida developed ophthalmic implants including Vitrasert, Retisert, and Iluvien. There are several new implants still in clinical trials (Jessen et al. 2013). Besides FDA-approved Ozudex, Allergan is also developing new implants for both posterior diseases and glaucoma.

Buccal and Sublingual In sublingual or buccal administration route, drug is placed under the tongue or between the gum and cheek for disintegration and then absorbed through the mucus membrane. The drug substance diffuses into the capillaries in connective tissue beneath the mucosa and then enters the venous circulation, which avoids the firstpass metabolism. Besides this type delivery offers quicker onset of action. The first challenge for the oral trans-mucus delivery is the presence of salivary enzymes. In addition to the enzymes, the pH, fluid volume can affect the stability of the medication. The pH and salivary compositions depend on the flow rate of saliva, which is determined by the time of day, the type of stimulus, and the degree of stimulation. The high flow rates can increase the sodium and bicarbonate concentrations and therefore the pH. According to pH partition theory, the absorption of weak electrolytes, especially weak acids, can be dramatically affected. The examples are midazolam, buprenorphine, nicotine, fentanyl, and lamotrigine (Nielsen and Rassing 2002; Mashru et al. 2005; Myers et al. 2013). Table 3 compares the various parameters between the mucosa of oral and other absorption sites.

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Table 3 Comparison between the oral and other mucosa sites Absorption site Buccal and sublingual Stomach Small intestine Colon Rectum

Relative surface area (ratio) 1 10–20 10,000–20,000 50–100 2–4

pH 6.2–7.4 1–2.8 3–4 4–6 5–6

Mean fluid volume (mL) 1

Enzyme activity Moderate

Buffer capacity Low

118 105 12 1–3

High High Moderate Low

Moderate High Low Low

The permeability of the oral cavity mucosa is another major physiological barrier. The oral mucosal thickness varies according to the sites. For example, the average thickness of buccal mucosa is 500–600 microns, but the average thickness of sublingual is much thinner, only 100–200 microns. The good part for the mucosa in buccal and sublingual area is there are no keratinized epithelia which contain no acylceramides and only small amounts of ceramides. These features make those mucosae more permeable to water than the keratinized epithelia. Besides that, the negative charges carried by the mucus network at physiological pH plays an important role during absorption. These negative charges come from mucins, a class of glycoprotein and the key macromolecular components in oral mucosa. Mucins are many basic units linked together into linear arrays and form an extended 3D network. Lipophilicity of drug definitely affects the absorption. The drug must have slightly higher lipid solubility than that required for the medications administered via GI tract. An octanol/water partition coefficient range from 40 to 2000 is considered optimal for the drugs to be absorbed through oral trans-mucus route. Besides the optimal lipid solubility, the drug should be enough soluble in aqueous saliva fluids. The mean pH of the saliva is about 6.0 which restricts the absorption of the drugs ionized under this pH value. In addition, the optimal pKa range for the drugs to effectively diffuse through the epithelial barrier is greater than two for an acid and less than ten for a base. For decades, both sublingual and buccal drug administration have been used for cardiovascular drugs, steroids, some barbiturates, and enzymes. The examples for sublingual formulation include antianginal like nitrites and nitrates, antihypertensives like nifedipine, analgesics like morphine, bronchodilators like fenoterol, certain steroids like estradiol and peptides like oxytocin. The examples for buccal medications are psychiatric like asenapine, opioid like buprenorphine, naloxone, and fentanyl, cardiovascular like nitroglycerin, and nausea like prochlorperazine. In recent studies, even many vitamins and minerals could be thoroughly absorbed through those administered routes. The extra significance is sublingual or buccal absorbed nutrition can avoid irritation to the gastric intestinal system, especially for the patients with ulcers, hyperactive gut, coeliac disease, or other digestion diseases (Al-Ghananeem et al. 2006).

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Rectal and Vaginal The rectal drug delivery has special advantage to be used for elderly, young, and unconscious patients. The rectum can be utilized for dosage forms such as suppositories or enemas. The effects can be local or systemic. However, due to the limited amount and poor buffer capacity of the fluids in the rectum, the systemic drug absorption through diffusion can be very unpredictable. The middle and inferior hemorrhoid veins enter systemic venous circulation via the internal iliac veins. This route bypasses the liver and do not undergo first-pass metabolism. Therefore, the drugs are absorbed rapidly and effectively. Vaginal administration is a route of administration where the substance is applied inside the vagina. Vaginal delivery is usually being used to treat the local conditions, such as inflammation and infections. Besides that, local effects also include administration of contraceptive agents (Hussain and Ahsan 2005). The major dosage forms include vaginal tablets, vaginal cream, and vaginal suppository. The most common drugs used include estrogens and progestogens, and antibacterial and antifungals agents. In some cases, vaginal administration can be used as an alternative to oral route in the cause of nausea or other digestive problems (Woolfson et al. 2000). The first absorption barrier is mucus layer which provides a stable pH environment. However, the mucus layer can be affected by diet, age, diseases, or drugs (de Leede et al. 1982). Movable water layer is the center of the colonic lumen to the mucosa which also plays as an absorption barrier of the rectal delivery. It is basically a layer of relatively unstirred water. Some viscous soluble dietary fibers may increase the thickness of this layer by reducing intraluminal mixing. Therefore, the diffusion efficiency of the drug molecules decreases. Some dietary fibers not only change the thickness of the movable water layer but also bind charged molecules, such as pectin and chitosan, which have cation-exchange properties and can bind to bile acids. In addition, drug molecules could be trapped within the solid matrix of the dietary fibers (Yoshikawa et al. 1984). For vaginal administration, the drug absorption can be highly variable due to epithelial and musculature thickness change during the different stages of the menstrual cycle (Fanchin et al. 1997). For both rectal and vaginal administration, optimal partition coefficient and molecular size significantly contribute to the rectal absorption. The factors leading to poor absorption include small partition coefficient, large molecular weight, charge, and high capability of hydrogen bond formation. Proper physical modification can improve the absorption of poorly absorbed drugs, such as increasing drug solubility (Abd-el-Maeboud et al. 1991) and concentration in the formulas. Certain chemical modifications, such as increasing the partition coefficient and decreasing hydrogen bond formation can improve the affinity of the compound to the bilipid layer membrane. The base itself can also affect the absorption (Kanamoto et al. 1988). Besides that, absorption-promoting adjuvants can be used to increase the compound permeability through the rectal mucosal membrane barriers (D’Haens et al. 1993). A most commonly used rectal suppository is calmol 4, which can temporarily relieve burning, pain, and itching caused by hemorrhoids. The major suppository

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base of calmol 4 is cocoa butter. Cocoa butter is one type of oleaginous base. The patient should be advised to rub those oleaginous base suppositories gently with the fingers to melt the surface to provide lubrication for insertion. Other commonly used rectal suppositories are glycerin suppositories, which can promote laxation by the local irritation of the mucous membranes. Glycerin suppositories should be moistened with water to enhance lubrication before use. Encare vaginal insert is used for the prevention of pregnancy. The major suppository base of encare is polyethylene glycol (PEG), which means suppositories should be moistened with water for lubrication before use. Canesten is a vaginal tablet or cream with clotrimazole, which is used to treat most vaginal yeast infections. Clotrimazole vaginal cream or tablets should be inserted deeply into the vagina once daily. If the vaginal tablet is used and undissolved pieces of the vaginal tablet are seen the next day, the tablet may not have been inserted high enough to completely dissolve. Treatment with clotrimazole should not continue once the patient is menstruating.

Inhalational Inhalational route of administration is utilized to treat the diseases of the respiratory tract such as asthma and chronic obstructive pulmonary disease (COPD). Drug is atomized into smaller particles and is inhaled by mouth. The smaller particle size of the drug allows deposition in the respiratory tract as compared to that of trachea. The respiratory system provides lager surface area for drug absorption. The factors affecting permeability and drug absorption is similar to that of other biological membranes. Therefore, lipophilic unionized molecules are better absorbed as compared to ionized and hydrophilic molecules. However, the pulmonary epithelium possesses high permeability for hydrophilic drugs as compared to that of gastric mucosal membrane. So, hydrophilic drugs such as sodium chromoglicate with pKa of 1.9 is absorbed from lungs. Onset of therapeutic effect is quicker as compared to the oral route. The systemic side effects of drugs such as corticosteroids are minimized when administered by inhalation because of the low doses used and direct deposition at the site of action. Drug is formulated as either an aerosol-metered dose inhaler (MDI) preparation (propellant is used to produce the fine mist containing drug particles) or dry powder inhaler (DPI) preparation (patient generates the airflow to inhale the particles). Drug deposition after aerosol administration happens by diffusion, gravitational sedimentation, and or inertial impaction. The amount of drug absorbed from the pulmonary system is dependent on the particle size of the drug. Smaller particles deposit mainly by diffusion and the larger particles are deposited by gravitational sedimentation and inertial impaction. Inhalational route can be used for local effect such as the bronchodilators for asthma or can be used for systemic effect as in case of general anesthesia and insulin delivery. Advantages of inhalational route include quick onset of action, avoidance of firstpass metabolism, delivery of peptide molecules, and patient compliance. The

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Table 4 Examples of inhalational dosage forms Generic name Beclomethasone Budesonide Fluticasone Ipratropium bromide Salmeterol xinafoate Traimcinolone acetonide Metaproterenol sulfate

Trade name Vanceril ® Beclovent ® Pulmicort ® Flovent ® Atrovent ®

Type of device MDI

Disease state/conditions Asthma

DPI MDI MDI

Asthma Asthma Bronchospasm

Serevent ®

DPI

Azamcort ®

MDI

Long-term maintenance for asthma and prevention of bronchospasm Chronic asthma therapy

Alupent ®

MDI

Bronchospasm

disadvantages include the following: drug administered and absorbed is dependent on administration techniques and therefore can cause interpatient variability. Examples of some drugs available for inhalational routes and their applications are given in Table 4.

Conclusion Choices of administration route of drugs are entirely dependent on the disease state, physicochemical/pharmacokinetic properties of the drugs, and patient preference/ compliance. Although oral route is the most commonly utilized route to deliver drugs, other route of administration is also important, given their unique role in providing desired therapeutic outcome. It is important to choose the appropriate route of administration to maximize therapeutic effects of the drugs and improve patient outcomes. This chapter provides information on all the major route of administration and the situation when a particular route is preferred.

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Physicochemical Basic Principles for Solid Dosage Forms Pradeep Kumar, Priyamvada Pradeep, Sunaina Indermun, Mershen Govender, Yahya E. Choonara, and Viness Pillay

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Polymorphism in Solid Dosage Forms: Crystalline and Amorphous States . . . . . . . . . . . . . . . . . . . . Size Matters: Particle Size Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Morphological Evaluation of Solid Dosage Forms: A Nanoperspective . . . . . . . . . . . . . . . . . . . . . . . . Solid-State Stability of the Component Actives and Excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hygroscopicity and Hydroactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Solubility Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dissolution Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future Developments in the Design of Solid Dosage Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

50 50 52 53 57 59 61 63 65 65

Abstract

To achieve an efficient solid dosage form in terms of pharmacokinetics as well as pharmaceutics, parameters such as bioavailability, manufacturability, and stability are of utmost importance. These factors in turn are influenced and/or are dependent on varied important solid-state properties. Physicochemical properties such as, but not limited to, crystalline and amorphous properties of molecular solids, fundamental properties of powders, and the relationships between solubility, permeability, partitioning, diffusion rates of dissolution, and release mechanisms play a crucial role in determining the overall characteristics of the final solid dosage form. In addition, specialized inherent (morphology) and induced (particle size) properties are central to the performance of solid dosage forms. This chapter delivers an account of basic physicochemical principles involved in P. Kumar · P. Pradeep · S. Indermun · M. Govender · Y. E. Choonara · V. Pillay (*) Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, School of Therapeutic Sciences, University of the Witwatersrand, Johannesburg, South Africa e-mail: [email protected] © Springer Nature Switzerland AG 2022 Y. V. Pathak et al. (eds.), Handbook of Space Pharmaceuticals, https://doi.org/10.1007/978-3-030-05526-4_13

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formulation and development of solid dosage forms as well as provides a critical overview of these factors affecting the final dosage forms’ production and therapeutic outcomes.

Introduction Solid dosage forms (in particular oral solid dosage forms) in the form of powders, granules, tablets, capsules, chewables, and reconstitutable powders cover the largest part of pharmaceutical market both in terms of volume and value. A recent report forecasted the growth of this basic formulation market to US$ 926.3 billion in 2027 from US$ 493.2 billion in 2017 (Market Research Report). Although recent times have seen an upsurge in biologics’ formulations, the advantages offered by oral solid dosage forms appear unsurmountable in the near future. High patient compliance with negligible caregiver support makes oral solid dosage forms the most commonly prescribed and used pharmaceuticals (Plapied et al. 2011). With no dose measurement required, availability of flavoring and taste-masking agents, option of solid-to-liquid translation (effervescent tablets), choice of varied and customized drug delivery and release profiles (ultrafast, immediate, sustained, targeted, and delayed-release tablets), and the option of several dosage forms for a given active pharmaceutical agent (API), the oral solid dosage forms have established as most promising and most complaint delivery systems (Choonara et al. 2014). Adding to this, the large-scale producibility and reproducibility make oral solid dosage forms the most cost-effective dosage form. The ease of manufacture is further augmented by fast, robust, and trouble-free packaging and transportation. Furthermore, the chemical and physical stability of the active pharmaceutical agents (APIs) is comparatively maintained for longer. With the advent, application, and introduction of 3D printing in this field, it has further enhanced the potential of this comparatively research stagnant field of pharmaceutics. Although considered as most promising and most cost-effective drug delivery systems, the solid dosage forms are not immune to challenges such as, but not limited to, non-compressibility, high filling volume, temperature sensitivity, and poor flow properties. The manufacturability, stability, and clinical performance of solid dosage forms are critically dependent on the physicochemical properties of the constituent materials including the APIs and excipients (Sharpe et al. 2014; Lopez et al. 2015). This chapter deals with the basic physicochemical principles inherent to the formulation and performance of solid dosage forms with an insight into novel drug delivery systems, nanobased formulations, and specialized 3D-printed archetypes.

Polymorphism in Solid Dosage Forms: Crystalline and Amorphous States Thermodynamic stability is a vital factor that plays a crucial role toward the stability of the solid dosage forms. Technically, solids could be divided into thermodynamically stable, crystalline form, which have a three-dimensional short-range as well as

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long-range order of molecular packing that extends throughout the crystal, and the unstable, amorphous form, with typical random atomic structure (Yu, 2001). Crystalline solids are further subdivided into polymorphs, which result from different crystalline forms of the same molecule, and multicomponent crystals such as hydrates, solvates, and co-crystals. These pseudopolymorphic forms comprising of hydrates and solvates are multicomponent adducts which contain the host molecule (active pharmaceutical ingredient or excipient) as well as the guest molecule (water in the case of hydrate or other solvents in the case of a solvate incorporated into the crystal lattice structure). A liquid crystal is also known as mesophase material and is described as having intermediate symmetry (Yu, 2001). These variations in packing order at the atomic level lead to major variations in pharmaceutical physicochemical properties such as flow, density, compression properties, rigidity, solubility, and bioavailability. For example, the solubilization of a crystalline solid encompasses of three sequential processes: (1) solvation, (2) cavitation, and (3) disruption of crystal packing. The last step involves consumption of energy which in turn is extracted from the dissolution process. On the other hand, in the amorphous systems, there is a lack of well-defined lattice structure, so it is relatively easier to break solid crystal lattice, and as a result they have higher solubility compared to the equivalent crystalline solid forms (Healy et al. 2017). Due to the presence of random atomic structure, amorphous solids are characterized to have the absence of a distinctive melting points. In order to examine the nature of an amorphous material, various thermodynamic parameters such as free volume, enthalpy, and entropy are observed with the variation of temperature. Heat content or the molar volume of an amorphous sample is plotted in respect to the increasing temperature. These variables vary smoothly until a point known as glass transition temperature (Tg), where they change sharply. Glass transition temperature (Tg) is the temperature at which an amorphous material transforms from an equilibrium supercooled state to a non-equilibrium glassy state and is demonstrated as a crucial point in the heat flow due to an abrupt change in heat capacity during the heating. Physiochemical properties of an amorphous material differ in the glassy state compared to the supercooled state, and the glass transition temperature (Tg) is a thermodynamic event demarking these two structural forms of an amorphous solid. Physicochemical properties such as hygroscopicity, solubility, surface chemistry, stability, and processability depend a lot on the polymorphic or pseudopolymorphic forms of the material, and these physiochemical properties have an influence on the dosage form design and the selection of manufacturing route being used. It is imperative to identify the appropriate solid form of APIs before being selected for formulation development prior to scale-up and clinical trials. For example, stable amorphous form of carbamazepine transforms into the dihydrate form in the presence of water vapors at 37
C or when it is cooled to form crystals from a saturated ethanol solution. The dose-dependent bioavailability of the stable anhydrous form of carbamazepine (both Cmax and AUC) is better compared to that of the dihydrate form (Kaneniwa et al. 1984; Otsuka et al. 2003). Solvent molecules and water molecules interact readily in the crystal lattice with the APIs and/or excipient molecules through the formation of hydrogen bonds and/or coordinate covalent bonds. Water molecule consists of two positive and

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two negative regions of charge, unlike most of the organic solvents, so it can form a hydrogen bond and coordinate covalent bond and van der Waals interaction including induced dipole, dipole-dipole, and dispersion forces with API(s) or excipient(s). the molecular weight of the API and excipient molecules also influences this interaction quantitatively; the smaller size of the molecule bond formation is more pronounced. An array of physiochemical properties of the hydrated APIs and excipient are influenced due to these abovementioned intramolecular interactions ranging from thermodynamic parameters, stability, free energy, solubility, dissolution rate, and bioavailability. This is due to the fact that when water molecules interact with the APIs and/or excipient molecules, the level of intermolecular interactions (internal energy and enthalpy) and the degree of crystalline disorder (entropy) change. Apart from these molecular level changes, mechanical properties and deformation processes such as tableting and grinding/milling are also influenced due to the presence of water and other solvent molecules in the solid crystal lattice. On the other hand, when an organic solvent is present in the crystal structure, the solvent molecules can either induce disorder in the crystal structure which leads to the formation of unstable system or in some cases form strong interactions in the form of hydrogen bonds with APIs, excipients, and other solvent molecules to form flexible clusters. These flexible clusters further lead to improved stability of the metastable solid forms. In some cases, solvent molecules may also act as space fillers in the crystal lattice where they are merely present physically and do not demonstrate any chemical interactions with the molecules of API or the excipient without forming any strong interactions with host molecules (Aaltonen et al. 2009; Hancock and Zografi 1997).

Size Matters: Particle Size Properties Particle size significantly influences one of the most important properties of any solid dosage form which is the rate of dissolution. Smaller particles have larger surface area compared to the bigger particles, so when the smaller particles are exposed to the dissolution medium, they show much higher rates of dissolution compared to the bigger particles. Particle size also has an important role to play in determining the uniformity of dosage which is directly proportional to the ratio of smaller particles. This factor is of high importance in the cases of highly potent drugs. As the particle size increases, the flowability of its corresponding powder increases mainly because there is little cohesivity. This aspect has a major influence on the manufacturing of the solid dosage forms. A mixture of bigger and smaller particles usually give rise to the optimum flow properties, where bigger particles flow easily through the pipes without giving any resistance, and smaller particles easily fill the pores created by the bigger particles. Particles having the size larger than 250 mm are often relatively free flowing, as compared to very fine particles which are below the size of 10 mm, and this is due to extremely cohesive nature of fine particles which resists the flow. Particle size of the drugs as well as that of the excipients plays a very important role in various pharmaceutical processes. Apart from that it is also a crucial factor in

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determining the bioavailability of the drugs. Particle size has a significant influence on the safety and efficacy of the drug product; therefore it is of utmost importance to regulate and control the particle size distribution of pharmaceutical powders. Factors influencing the drug product manufacturability such as flowability, compactibility, blend uniformity, etc. are dependent on particle sizes of powders. In addition to these pharmaceutical manufacturing aspects, drug product performance factors such as dissolution, content uniformity, and stability are also influenced by the particle size and distribution of the powders. Hence, establishing appropriate particle size specifications is of high importance in controlling of final drug product quality and manufacturing consistency (Khadaka et al. 2014). Particle size affects the bulk properties of the solid system especially the flowability of the powder during the manufacturing process when the large amount of powder is handled. It is of great importance that pharmaceutical powders can flow without much hindrance into storage containers, pipes, or hoppers of tablet and capsule-filling equipment so as to ensure a uniform packing of the final product. Too big particles provide free flow; however there is greater air entrapment in them due to higher pore size. On the other hand, small particles offer very little pore size but resist the powder flow due to cohesivity of the particles arising from van der Waals forces, electrostatic forces, and/or surface tension forces (adsorbed liquid layers and the particle surface). Therefore, it is of vital importance to optimize the particle size where a mixture of bigger and smaller particles could be taken to ensure the optimum flow properties (Szunyogh et al. 2011). Often the particle size of some raw or in-process materials is observed as the critical quality attributes (CQA) of the drug product during manufacturing processes such as mixing, granulation, milling, blending, coating, etc. To assess the drug formulation and manufacturing process, according to the Quality by Design (QbD) approach, the effect of particle size of the drug substance, excipients, and the in-process materials all play an important role in the critical quality attributes (CQA) of the final drug product and should be considered instead of just the particle size of the drug substances with low solubility.

Morphological Evaluation of Solid Dosage Forms: A Nanoperspective Morphology in solid dosage forms can be divided into two major categories: (1) morphology or shape of the particles of the constituents and (2) morphology of the finished product. Morphology of the constituent particles significantly affects the flow and carrier properties of the formulations. For example, spherical particles with smooth morphology show better flow and void filling properties but are prone to segregation. Conversely, irregularly shaped particles with rough morphology show better fit and are not so easily segregated. Another typical example is related to the shape of carrier particles for dry powder inhalers. A smooth carrier may not effectively carry the drug and will release the drug immediately. However, a rough carrier particle may carry the drug efficiently but may fail to release the drug in

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adequate time. The problem can be easily resolved by combining micronized carrier particles and large rough carrier particles. The drug can be deposited onto the micronized carrier particles which in turn can be deposited within the rough regions of the carrier particle. In this way the drug can be trapped and released efficiently and effectively (Aulton 2007). Morphological characterization is further very critical for the assessment of intermediate drug-excipient components wherein the physical and chemical estimation of the pharmaceutical powders is essential for quality of the final drug product. Raman spectroscopy combined with morphological image analysis can provide the “morphologically targeted chemical characterization” and the much needed physicochemical data to ascertain the composition of intermediate granulates. This size, shape, and chemistry information correlates to efficient mixing and hence the content uniformity (Pritchard and Warman 2011). In the modern era of therapeutics, nanoparticles and more precisely nanomedicinebased interventions are being successfully employed to treat and prevent lifethreatening ailments such as cancer and neurological disorders. These carriers mostly exist in a solid form, but due to their nanometric size, the conventional solid-state properties are often applied and described differently. The transbarrier trafficking or internalization of these carriers is significantly dependent on their shape, size, and morphology (Murugan et al. 2015). With respect to size, the most accepted size range of cellular internalization is considered to be between 50 nm and 125 nm. Particles below 50 nm are thought to leak out from the cell, while particles larger than 125 nm acquire physical resistance by the cellular surface. However, this narrow size problem can be circumvented via modulation of morphological properties of nanoparticles. Wibroe and co-workers, 2017, reported that the adverse cardiopulmonary reactions (due to the complement system and/or macrophage interactions) toward injected nanoparticles can be prevented to a large extent by formulating the nanoparticles in non-spherical shapes and by hitchhiking the nanoparticles on erythrocytes. The carboxylate polystyrene particles were fabricated into spheres, rods (prolate ellipsoidal), and disks (oblate ellipsoidal), keeping the Gaussian curvature in a comparable range (Fig. 1). The effect of different shapes on the activation of complement system was studied by measuring classical markers such as C3bc, C3a, C5a (an anaphylatoxin), and sC5b-9 (a nonlytic soluble marker). When tested in pig blood, the spherical particles showed minor (but statistically significant), while the rods and disks demonstrated robust and profound activation of complement system. This was attributed to potential change in surface structure of rods and disks as sphere stretching may have “created complement-activating surface domains due to altered polystyrene repackaging and configuration.” In the human blood, the complement activation was comparable for all the three particle types. Interestingly, when tested in vivo in pigs, the spherical particles demonstrated cardiopulmonary disturbances in terms of elevated pulmonary arterial pressure (PAP) and a concomitant decline in systemic arterial pressure (SAP). This reaction was comparable to zymosan – a potent and instantaneous activator of the complement system. Surprisingly, the rods and disks showed no such cardiopulmonary disturbances. It was further noticed that the spherical particles elevated thromboxane B2 (TxB2) – a direct consequence of interactions with pulmonary intravascular

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a

Rod D1 × D2 = 450 × 120 nm

Disk D1 × D2 = 250 × 75 nm Sphere D = 500 nm

Low curvature

High curvature Rod

Disk Sphere

Fig. 1 Graphical and scanning electron microscopy (SEM) representation of spheres, rods, and disks. (a) True relative size and shape, with colors representing Gaussian curvature (assuming rods and disks as prolate and oblate spheroids, respectively). (b–d) SEM images of spheres (b), rods (c), and disks (d). Scale bars, 500 nm (Wibroe et al. 2017, Reproduced with permission from Springer Nature © 2009)

macrophages. The cardiopulmonary disturbances were further attributed to robust removal of spherical particles or zymosan from the blood (phagocytosis by pulmonary intravascular macrophages). While the spherical particles were taken up by macrophages within 2 min of administration, the rods and disks stayed in the circulation for much longer duration probably due to their reduced localization to the liver/spleen macrophages (Fig. 2) (Wibroe et al. 2017; Champion and Mitragotri 2009). Recently, an interesting report by Li and co-workers, 2017, described the in vivo fate of nanoparticles (with different morphologies) after oral administration. The effect of nanoparticle geometry (spheres vs. rods) on the transport across and absorption into the gastrointestinal (GI) tract was studied w.r.t. gastrointestinal retention, intestinal epithelial uptake, and lymphatic transport. The study was

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Fig. 2 Circulation profile of spheres, rods, and disks following intravenous injection into pigs. Particles were injected at a dose of 1.5  1011 particles per 20 kg body weight. Spheres are cleared faster than rods and disks. Inset: magnified representation of early time points. The results are expressed as mean  s.e.m. (n = 3). P < 0.05 (non-paired two-sided t-test) for all points between 30 s and 3 min, comparing spheres with rods and disks (Wibroe et al. 2017, Reproduced with permission from Springer Nature © 2009)

developed on previously reported observation that rod-shaped nanoparticles provide better cellular internalization and transport across cell membrane in vitro as compared to spherical or discoid nanoparticles (Banerjee et al. 2016). The fluorescence resonance energy transfer molecules labeled nanorods and nanospheres were administered orally (1.5 mL) in rats and were imaged ex vivo. The nanorods showed longer stay in gastric and intestinal environment with 30% of nanorods present in small intestine after 8 h as compared to 10% in the case of spherical particles (Fig. 3). The longer stay and higher amount of nanorods in jejunum and ileum presented higher chances for intestinal absorption. With respect to intestinal epithelium retention, a small proportion of nanospheres were present at the luminal side of jejunum with a small amount attached to the mucosa. Contrarily, nanorods were largely distributed on the jenunal wall and were seen penetrated deep into the space of villi, further increasing the retention and absorption opportunities. Furthermore, the lymphatic transport results confirmed a transport efficiency of 1.75% for nanorods as compared to 0.98% in case of nanospheres. In conclusion, the geometry-dependent higher retention of nanorods was attributed to “particletissue interactions at the lumenmucusglycocalyx interface” (Li et al. 2017). The authors recently published an important study wherein the cellular internalization kinetics of five neo-geometric copper nanocrystals were studied and the

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Fig. 3 Typical pictures of gastrointestinal segments from SD rats after ex vivo imaging (a) and quantification of nanoparticles in stomach (b), duodenum and jejunum (c), ileum (d), and cecum and colon (e) based on total fluorescence after oral administration (n = 3); * represents a significant difference compared with nanospheres ( p < 0.05) (Li et al. 2017, Reproduced with permission from American Chemical Society © 2017)

effect of geometry on internalization was correlated with the volume, surface area, orientation, and colloidal stability of the particles. The most striking observation of the study was that the rods demonstrated much lower cellular uptake in opposition to the conventional hypothesis (Fig. 4). Interestingly, out of the five neo-geometric forms, cubical demonstrated highest cellular internalization and uptake which were attributed to possible recruiting of actin filaments enveloping the cubical structures. This observation was further strengthened by the higher uptake of pyramids and rods as compared to spherical structures. It is important to note that a particle rotates and orientates while after internalization and the axis of attachment of the particle to the cell playing a crucial role in cell uptake (Murugan et al. 2015).

Solid-State Stability of the Component Actives and Excipients Stability of drug products ensures that the quality, strength, purity, and identity of a drug remain within its established specifications. Stability studies also ensure that toxic by-products are not produced through chemical interactions within the formulation. Chemical instability refers to the inter- or intramolecular transitions of a formulation that may result from hydrolysis, oxidation, or photolysis. Physical

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Fig. 4 Phase-contrast images of geometric CuNP internalization over a 24-h incubation period (Murugan et al. 2015, Reproduced with permission from Elsevier B.V. Ltd. © 2015)

stability refers to the phase transitions in a formulation, affecting formulation appearance, palatability, and uniformity, and may arise due to microbiological, environmental, and processing factors. Microbiological stability refers to the sterility or lack of microbiological contamination of the drug product and may result of failure of preservative in the formulation due to interaction, degradation, or loss from the system (Darji et al. 2017). Sources of microbiological contamination include air, water, raw material, personnel, containers, as well as manufacturing or processing equipment. Environmental factors significantly contribute to drug formulation stability. The shelf life of temperature-sensitive formulations may be enhanced by storing the drug products at room (25
C), refrigerated (2–8
C), or freezing temperatures (20
C). Photolysis or light-induced degradation may be prevented primarily through storage and packaging processes. The use of amber-colored bottles,

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cardboard secondary packaging, and aluminum foil wrappers may also be utilized to prevent instability associated with light-sensitive products. Moisture or highly humid environmental conditions induce instability through hydrolysis and may affect the sterility of the product. Moisture can also promote polymorphic and pseudopolymorphic transformations within a formulation, in addition to rate dependencies on the temperature. The addition of a desiccant or glass, plastic, and sometimes aluminum foil wrapper packaging may protect the product from humidity. Oxidation can occur through two processes, reaction with molecular oxygen and reaction with other oxidizing agents present in the formulation (Waterman and Adami 2005), and may be alleviated through the addition of an antioxidant to the formulation. The varied processing and storage conditions experienced by the solid-phase components during manufacturing and transport may lead to phase transitions which may in turn affect the size profile, morphological outlook, amorphous-crystalline interchangeability, and hydration of anhydrous or dehydration of hydrous polymorphs (Zhang et al. 2004; Morris et al. 2001). In general, amorphous materials are less stable than their crystalline counterparts. This is referred to as processinduced transformations or phase transformations which occur due to thermal or mechanical stresses imposed during the manufacture process (Wikström et al. 2005). These phase transformation changes may result from solubility, melting, coagulation, or aggregation (Darji et al. 2017). Processing factors such as thermal stresses of milling, compaction, dry granulation, milling, grinding, blending, compaction, tabletting, and coating may also cause phase transformations.

Hygroscopicity and Hydroactivity Water activity (aw) can be defined as “the ratio of the water vapour pressure of the substance to the vapour pressure of pure water at the same temperature” and refers to the ability to affect reactivity, permeation, and plasticization (Waterman and Adami 2005). It influences the microbial stability, flow properties, chemical stability, hardness, compaction, and dissolution rate of pharmaceutical dosage forms. Equilibrium relative humidity (ERH) can be defined as “water activity expressed as a percentage.” Both represent the amount and indication of free water in a pharmaceutical dosage form and can be used as an indicator of supporting microbial growth (Bell and Labuza 2000). A model proposed by Naversnik and Bohanec (2008) was first used to determine the most important factors, affecting stability (Fig. 5). Hygroscopicity refers to “the ability to interact with moisture from the surrounding atmosphere,” while nonhygroscopic materials remain unaffected by water vapor. Hygroscopicity can be classified into four classes as described by Callahan and co-workers (1982): 1. Nonhygroscopic solids: No increase in water content at 80% RH is less than 50% moisture. 4. Very hygroscopic solids: moisture content increase may occur at 40–50% RH and increase may exceed 30% after storage for 1 week >90% RH. Solid-state phases exist as two types, the crystalline and the amorphous phase. The polymorph phase is a subcategory of the crystalline phase, where polymorphs containing the same ions or molecules have different packing conformations in the solid state. In addition, solvates are also crystalline phases and form when the crystal lattice contains solvent molecules. This leads to molecular adducts with the host molecules; in the case of water being the solvent, then the molecular adducts are then termed “hydrates” (Zhang et al. 2004). Contrary to the crystalline phase where there is repetitive 3-D order in the lattice, the amorphous phase possesses a highly unstructured, disordered arrangement of molecules and non-distinguishable crystal lattice. Surface adsorption, capillary condensation-induced incorporation into microporous regions, crystal hydrate formation, and even simple deliquescence are the most common ways of water interaction with crystalline structures (Airaksinen et al. 2003). The mechanism of water sorption into the solid is determined by the ability to form crystal hydrates, the water-solubility, porous structure and the crystal structure

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(Dawoodbhai and Rhodes 1989). Due to the high degree of order of the crystal lattice and close packing arrangement, crystalline excipients are typically nonhygroscopic, and most crystalline solids will not absorb water into their structures. However, water adsorption onto the surface of crystalline particles may impact powder flow and compressibility properties. Process-induced transformations such as wet granulation, particularly during wetting phase solvent and drying phase conditions, allow for alternate crystalline formation (Davies et al. 2004). Amorphous compounds are considered to be more hygroscopic than their crystalline counterparts. Amorphous regions tend to absorb significantly higher amounts of moisture, which impart plasticization or dissolution, thus increasing molecular mobility (Zhang et al. 2004; Waterman and Adami 2005). Since the internal structure of an amorphous solid absorbs water vapor, water uptake is not directly related to the specific surface area of the solid (Zografi 1988). The corresponding reactivity in solid dosage forms thus confers poorer chemical stability to amorphous compound excipients. This comparatively higher dissolution possibility makes amorphous phases more important and preferable for delivering pharmaceutical agents as compared to their crystalline counterparts (Hancock and Parks 2000).

Solubility Aspects All drug molecules have an intrinsic hydrophilicity and/or lipophilicity. The determination of this solubility is however essential to ensure that the drug is in solution to exert a therapeutic effect. A large number of factors are known to affect the solubility of a drug molecule. These factors include (Aulton 2007; Sinko 2011): • • • • • •

The molecular structure, thermal properties, and polarity of the solute The chemical nature, pH, and temperature of the solvent/cosolvents Crystal characteristics of the solute, i.e., polymorphism The particle size and conjugation of the solute The common ion effect The effect of electrolytes and nonelectrolytes in solution

Assessment of the solubility of drug molecules is also essential in determining the excipients to be used in the design of medication. Parameters evaluated during solubility analysis include (Aulton 2007): 1. Intrinsic solubility: The determination of the intrinsic solubility of a compound can be highly advantageous in determining its physicochemical properties. An increase in solubility in acidic aqueous solutions suggests that the drug is a weak base, while an increase in basic solutions suggests that the drug is a weak acid. 2. Degree of ionization/pKa: As most drug molecules can be classified as either weak acids or weak bases, these molecules dissociate to an equilibrium of ionized

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and unionized molecules. The unionized species are more lipid soluble and therefore transport across the membrane barriers by passive diffusion, while the ionized species are lipid insoluble and therefore have low permeability. 3. Partition coefficient: Partition coefficient (P), also known as distribution coefficient (D), is the ratio of unionized drug distributed between an organic phase (n-octanol) and an aqueous (water) phase at equilibrium. The distribution of a drug between hydrophilic and lipophilic phases can be highly beneficial in determining the use of excipients and the absorption and therapeutic effectiveness in the body. The partition coefficient is represented as: Po

Conc:

w¼Conc:

of drug in organic phaseequilibrium of drug in aqueous phaseequilbrium

4. Common ion effect: The common ion effect describes the effect on equilibrium that occurs when an ion that is already present in a solution (“common ion”) is added to the solution. This addition of common ion significantly reduces the solubility of a lightly soluble electrolyte by shifting the equilibrium toward the reactant and causes the solute to precipitate out of solution (“salting out”). The reverse process, known as “salting in,” arises with larger anions (hydrotropes) which increases the solubility of poorly water-soluble compounds by opening the water structure. 5. Thermal properties: Determination of the melting and degradation properties of a drug molecule can be highly beneficial in enhancing the solubility of a compound. This characterization is also beneficial in determining the varying properties between polymorphic materials. There is therefore a number of options available for the improvement of drug solubility. These include (Savjani et al. 2012): • Chemical modifications – Modification of the solvent, its pH, polarity, and temperature – Use of buffers – Formation of a drug salt – Complexation and derivatization of the solute • Physical modifications – Decreasing of the particle size – Use of polymorphic solutes – Dispersion in drug carriers • Miscellaneous methods – Supercritical fluid process – Solubilization of the incompatible phase – Addition of solubility-enhancing excipients

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Dissolution Properties Dissolution in the pharmaceutical industry is defined as “the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition.” Simply, it is the process by which a drug solid solute enters into a solution. This is of high importance as only drugs in solution can be absorbed and transported within systemic circulation. Drugs are classified into four categories based on their solubility and permeability (Fig. 6). Drug delivery design aims to enhance the properties of candidate drug molecules so that they can exhibit the properties of Class I molecules. Many factors affect drug dissolution, i.e.,: 1. Drug physicochemical properties (a) Drug solubility: All drug molecules have their own inherent hydrophilic (water solubility), lipophilic (fat-soluble), or amphiphilic (water and fat solubility) characteristics. As physiological drug release media is hydrophilic in nature, the solubility characteristics are paramount to ensure effective dissolution and absorption. (b) Particle size and surface area: Particle size has a significant effect on drug dissolution. As per the Noyes-Whitney equation, an increase in surface area of a drug to the dissolution media will increase the rate of dissolution. Therefore, the smaller the particle size, the greater the surface area for dissolution to take place. The rate of dissolution in this regard is also important as the surface area of an individual particle decreases as dissolution occurs. The Noyes-Whitney Equation is as follows: dm D ¼ A ðC s  C b Þ dt d

Class II

Class I High Sol High Perm

im

is at

io n

Low Sol High Perm

Class III

ad

O

pt

Class IV

Le

Permeability

Formulaiton Design

High Sol Low Perm

Low Sol Low Perm Solubility

Lead Optimisation

Fig. 6 A typical representation of the biopharmaceutical classification system (Pouton 2006, Reproduced with permission from Elsevier B.V. Ltd. © 2006)

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Table 1 Degree of ionization of weak acids/bases Acid/base Weak acid Weak base

Ionization at acidic conditions Unionized Ionized

Ionization at basic conditions Ionized Unionized

where dm/dt = solute dissolution rate (kg.s1), m = mass of the dissolved material (kg), t = time (sec), A = surface area of the solute particles (m2), D = diffusion coefficient (m.s1), d = thickness of the concentration gradient (m), Cs = particle surface concentration (mol/L), and Cb = concentration in the bulk solution (mol/L). (c) Degree of ionization: The degree of ionization of a drug molecule is important to ensure adequate dissolution and absorption. Drugs need to be in a unionized state to absorb by passive diffusion through the gastrointestinal tract. The degree of ionization is often represented by the pKa value of the drug molecule. The lower the pKa value of the drug, the stronger the acid and its ability to dissociate. Table 1 represents the degree of ionization weak acids and bases at acidic and basic conditions. In practice, weak bases dissolute in the stomach (pH 1.2) and absorb more effectively in the intestine (pH 6.8). Salt forms of the drug molecules can further affect dissolution rates. Salt forms have a greater ionic strength that weakens electrolytes. The greater the ionic strength, the lower the rate of dissolution (Aulton 2007; Sinko 2011). It is important to note that weak acids and bases dissociate to an equilibrium in solution. This is represented by the dissolution equilibrium equation: AH⇄A þ H þ (d) Polymorphism: Polymorphism, which is the ability of a solid to exist in different forms, influences drug dissolution. Polymorphs have the same chemical structure but have different physical properties such as hardness, compressibility, density, and solubility characteristics. Crystalline solids have greater structural stability and therefore dissolute slower. Amorphous substances are inherently less stable and therefore dissolute a faster rate. 2. Physiological factors (a) Gastrointestinal transit time: Gastrointestinal transit has a direct influence on the amount of drug that has dissolved. This is due to the varying pH across the gastrointestinal system that has a direct effect on the degree of ionization and thus influences drug dissolution. An increase in the transit time will therefore increase the dissolution of weak bases in the stomach and weak acids in the intestine. (b) Presence of food: The presence of food in the gastrointestinal tract has a significant effect on the dissolution of drug molecules. This is due to the direct effect of food on gastrointestinal pH and viscosity. A fasted stomach has a pH of 1–2 with a fed stomach having a pH of approximately 2–5 (Shekhawat and Pokharkar 2017). An increased dissolution media viscosity will also negatively affect the rate of dissolution. This is due to a decreasing of the dissolution coefficient of the drug molecule.

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Table 2 Mathematical dissolution models Model Diffusion layer Interfacial barrier Zero-order First order Higuchi Dankwerts Korsmeyer-Peppas Hixson-Crowell Weibull Baker-Lonsdale Hopfenberg

Release mechanism Diffusion Diffusion Diffusion Diffusion Diffusion Diffusion Diffusion Erosion-release Empirical model based on lifetime distribution Release from a spherical matrix Erosion-release

Many mathematical models currently exist for the prediction of dissolution. These models are based on the properties of drug molecules and can be found in Table 2.

Future Developments in the Design of Solid Dosage Forms Solid dosage forms have come a long way with respect to formulation design and constituents. From the currently available literature, it is evident that the challenges pertaining to solid dosage forms have already been overcome or circumvented. Additionally, the science and technology of determining and assessing the inherent and induced physicochemical properties is been dealt with and is mostly structured. However, it is also evident that these basic physicochemical principles are losing pace with the innovation in solid dosage forms – nanotechnology and 3D printing – with most of the established physicochemical properties’ fundamental being challenged every day. The regulatory pathway and policies for the specialized excipients and drug molecules befitting these new roles along with instrumentation capabilities are long overdue and need to be addressed urgently. Acknowledgments This work was supported by the National Research Foundation (NRF) of South Africa.

References Aaltonen J, Allesø M, Mirza S et al (2009) Solid form screening – a review. Eur J Pharm Biopharm 71(1):23–37 Airaksinen S, Luukkonen P, Jørgensen A et al (2003) Effects of excipients on hydrate formation in wet masses containing theophylline. J Pharm Sci 92:516–528 Aulton ME (2007) Aulton’s pharmaceutics: the design and manufacture of medicines, 3rd edn. Churchill Livingstone, Edinburgh

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Physicochemical Basic Principles for Liquid Dosage Forms Pooja Kiran Ravi and Sheeba Varghese Gupta

Contents Terms Used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liquid Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liquids for Internal Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liquids for External Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiochemical Properties of Active Pharmaceutical Ingredient (API) in LDFS . . . . . . . . . . . . . . . Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . pKa/Dissociation Constants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Partition Coefficient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects of Physicochemical Properties on Manufacturing Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future Directions and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

There are various types of liquid dosage forms for both oral, parenteral, and topical applications. Solubility of API is a very important parameter for liquid formulations as the ability of API to undergo solubility will dictate the applications, patient compliance, and stability. The physicochemical properties will also have effects on manufacturing process of the API. The solubility of active pharmaceutical ingredients (API) is dependent on the physicochemical properties of API. This chapter briefly addresses various types of liquid dosage forms and the basic physicochemical properties.

P. K. Ravi · S. V. Gupta (*) Department of Pharmaceutical Sciences, University of South Florida – College of Pharmacy, Tampa, FL, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 Y. V. Pathak et al. (eds.), Handbook of Space Pharmaceuticals, https://doi.org/10.1007/978-3-030-05526-4_14

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Terms Used Molarity

Molality

pH

pKa

Solubility Osmolarity

Membrane permeability

Cosolvency

Molarity defines the concentration of the solution. This can be calculated by dividing the number of moles of solute by the volume of solution. The molality is defined as the number of moles of the solute divided by the mass of the solution. pH is the measure of the hydrogen ion concentration in a solution. It is calculated by the negative log of hydrogen concentration. It is defined as the dissociation constant of the acid and measures the strength of the acid. It is the measure of the ability of a solute to dissolve in solvent. The osmotic concentration of an osmotically active substance in solution, expressed as osmoles of solute particles per liter of solution. Ability of the active pharmaceutical ingredient (API) to pass through the membrane corresponding to the site of administration. For example, for oral delivery, membrane permeability is studied through mucosal tissue. Cosolvents are substances that are added to a mixture of two or more substances that are usually immiscible, to make them miscible. Cosolvency is the phenomenon of the immiscible substances becoming miscible.

Liquid Formulations Liquids for Internal Use Liquid dosage drug formulations can be administered to the patient through many routes such as oral, otic, intravenal, etc. Each route of administration requires different compositions and physical properties to avoid harmful side effects of the

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drug. This dosage form is preferred for its faster delivery of drug due to easy absorption.

Syrups Syrups are a type of liquid dosage form that is usually made with a concentrated solution of a sugar such as sucrose which acts as a proprietary vehicle to transport the drug and masks the bitterness of the same. It is commonly used to administer drugs to pediatric patients, patients who have difficulty swallowing tablets and capsules, patients who must receive medications via nasogastric or gastrostomy tubes, and patients who require nonstandard doses that are more easily and accurately measured by using a liquid formulation (Glass and Haywood 2006). Though the most commonly used vehicle is water, depending on the ingredients, the pH, and the target, many different proprietary vehicles such as cherry syrups, chocolate syrup, etc. are added to the drug mixture. In addition to making the drug easier to swallow, they also help appeal to pediatric patients. Syrups are usually divided into two types: (a) Aromatic or adjuvant syrups which are usually used to improve the taste of a particularly unpleasant mixture. (b) Medicated syrups which are again subdivided into syrups which are made from extractive drugs and those which are made from chemicals. Extractive drugs are made with the fluid extract of the respective drugs and it is mixed with the syrup.

Elixirs Elixirs are defined as sweetened, aromatic, and hydroalcoholic compounds with one active ingredient that is intended for oral use (Montebovi 1954). The color of the elixir varies according to the compounds present in the solution, but sometimes artificial coloring agents may also be added. It is a combination medicine that is commonly used to treat cough, cold, breathing illnesses, and allergies. Water and alcohols are commonly used to increase the solubility of the main ingredient in many liquid dosage forms. The amount of alcohol used in the solution varies from 5% to 40%. This variation is due to the toxic effects of alcohol in children. Most chemical salts dissolve at 25% alcohol. While commercial elixirs have almost no alcohol content, some contain as much as 40% alcohol. A common example is Norvir ®, which is an anti-retroviral drug that contains a high concentration of alcohol. An advantage of elixirs is that the patient dosage can be easily changed by administering a different volume of liquid. Elixirs have a lower viscosity compared to syrups and have lesser quantities of ingredients dissolved in them. The difficulty in preparation occurs when a partial precipitation is observed when the hydroalcoholic solutions are diluted with aqueous media, in the presence of salts (Montebovi 1954). These are purified using powdered talc to absorb and remove the excess oils. Other different types of filtration techniques such as suction filtration can also be used. While many elixirs use sucrose to sweeten, some use sorbitol, glycerin, and/or artificial sweeteners. Note: Dry elixirs are prepared by encapsulating NSAIDs and alcohols with a water-soluble dextrin

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membrane. These microcapsules help increase the dissolution rate, solubility, and bioavailability of drugs (Ikeda and Morizono 1989).

Drops Drops are liquid preparations that are made to be administered, using a medicine dropper, in small quantities due to their high potency. To attain their desired therapeutic effect, they are administered either through the eyes, ears, nose, or mouth. They may be a solution, suspension, or emulsion, and the difference in characteristics helps in distinguishing to which body part the liquid is administered to. Any types of liquid drops are prepared under highly sterile conditions and require specific protocols and equipments to prevent contamination. • Nasal drops – These are usually aqueous and not oily drops. Nasal drops are isotonic and have a pH similar to the nasal secretions (Lee et al. 2003). They are often used for decongestion of the nasal pathway. These are different from a nasal spray that consists of fine droplets that are sprayed into the nasal cavity and inhaled. • Eye drops – Eye drops are defined as any liquid formulation that is administered by allowing it to fall into the conjunctiva. The active component is usually dissolved in isotonic saline solution, and the pH and sterility of the compound are carefully monitored (Dupuis et al. 2009). They are used to treat a variety of conditions from dry eyes to serious eye infections. The shelf life of eye drops is limited compared to other dosage forms, and it is recommended that the container is thrown away 3 months after opening to prevent contamination. • Ear drops – Otic drops or ear drops are a liquid formulation that is administered to the ear cavity via a medicine dropper to treat infections in the outer ear or the ear canal. Most ear drops, irrespective of their use, have an antimicrobial component to help prevent ototoxicity. The formulation is prepared according to the inner ear fluid pH and endocochlear potential (Ikeda and Morizono 1989). They should not be used in case the ear drum is torn. • Drops for Oral administration – These drops are used when the minimum dosage is too less to measure out in a cup or a spoon. They are mainly used for pediatric patients for reasons of convenience and stability. Oral drops are prepared with a mucosa-adhesive component with the active ingredient to help its absorption. One of the widely used forms of oral drops is for oral polio vaccine (OPV). It is still used in many parts of the world which are trying to eradicate polio through mass immunizations, and oral drops are easier to use and the more economical option.

Intravenous Solutions/Fluids Intravenous solutions or fluids are the liquids that are delivered through a vein. It is a common method of administering a drug solution or IV fluids and electrolytes. The drug solution is administered intravenously when there is a critical need for immediate response to the drug such as in the cases of heart attacks or strokes. Sometimes they are given intravenously because if given orally, the stomach might break down the active component of the drug. The solutions are clear and aqueous in nature. The

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pH and other factors such as cosolvency of the solution prepared must be as close to the physiochemical properties of the body as possible (Lee et al. 2003). Many IV fluids contain a different ratio of the two major components – saline and glucose – which are given as per the needs of the patient (Developing NICE guidelines 2015). IV fluids can be categorized into two types – replacement or maintenance fluids (Hoorn 2017). Replacement fluids are administered to patients who are depleted in volume due to hemorrhagic or nonhemorrhagic causes. These are usually replenished through an isotonic saline solution administered as required. Maintenance fluids are given to patients who cannot eat or drink for prolonged periods of time. Both hypotonic and isotonic solutions can be administered as a maintenance fluid, but their prolonged effects need to be monitored carefully as hypotonic solutions have a tendency to cause hyponatremia (Yung and Keeley 2009). Though a large number of IV fluids contain glucose, they provide very little nourishment to the patient. 0.9% Sodium chloride with or without potassium is a common example of an isotonic saline solution which can be used to replenish specific GI fluids or renal losses.

Liquids for External Use Topical dosage form is the use of medicinal liquids on the surface of the skin for the desired therapeutic effect. The main use of topical dosage form additives is to control the extent of absorption, maintain the viscosity, improve the stability as well as organoleptic property, and increase the bulk of the formulation (Garg et al. 2015). They are also easy to use and start working pretty quickly. Some of these formulations have lasted for decades and sometimes even centuries. These techniques have been proven to have a high rate of absorption of drug and very less side effects with longer shelf lives.

Liniment or Balm A liniment is a medicinal liquid or semiliquid that is applied topically to counteract the effects of skin irritation and/or pain. It is made with an alcoholic, soapy, or oily vehicle and has lesser viscosity than lotions. They can be applied directly or diluted to reduce the concentration of the active ingredients. The active ingredients can be antifungal, anti-inflammatory, and/or in some cases cannabinoid for analgesic properties without the psychotropic effects. Liniments should not be applied to broken skin since alcohol-based liniments penetrate the skin, causing excess irritation. They reduce reddishness and irritation often providing a feeling of warmth or cool in the application site. A soapy or oily vehicle is more easily applied, and oil-based liniments are more mild compared to their alcohol-based counterparts (Garg et al. 2015). Depending on the response required, agents that heat or cool the affected area are added to the liniment. Capsaicin has been an integral part of liniments for centuries and is an example of a liniment that relieves pain by warming the patch of skin where it is applied (Yung and Keeley 2009). Cooling liniments are alcohol based as the alcohol evaporates quickly and takes some of the heat with it.

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In addition to these different types of liniments, currently, there is another type of liniments known as siliniments or silicon-based liniments which have been used in the treatment of alopecia (Garg et al. 2015).

Lotion Lotions are topical medicines that are applied for their soothing and protective effects. The solid components in a lotion are finely powdered and are held in permanent suspension by the presence of suspending agents or surfactants (Pawar and Kumar 2002). Lotions are aqueous solutions that are applied onto the skin without any friction since they too have low viscosity. They are applied with a cotton or gauze and covered with a waterproof dressing to prevent evaporation (Lee et al. 2003). Body lotions are especially common form of drug delivery, and, when combined with different drug molecules, they can have various properties such as antifungal, antiseptic, anti-acne, etc. The oldest and widely used lotion in the world is the antiseptic calamine lotion which can be applied on the skin for its calming effects. It is advised that regular consumer lotions should not be taken to hospital environments as they may contain irritants that provoke an immune response from immunodeficient patients (Stark et al. 2006). Tincture Tinctures contain vegetable or chemical components that used to derive the alcoholic or hydroalcoholic solutions. Sometimes glycerine or vinegar can also be used as solvents instead of alcohol. Tinctures are commonly used as antiseptics or disinfectants. They are prepared by the process of percolation or maceration. Percolation is the technique of passing a liquid phase, such as alcohol, through a filter which also contains the drug in the form of a powder. In maceration, the drug is soaked in the liquid phase and stored in a closed container. The components are frequently mixed to ensure that a concentrated solution is obtained. Tinctures are more commonly used in herbal medicines.

Physiochemical Properties of Active Pharmaceutical Ingredient (API) in LDFS The World Health Organization defines an API as “Any substance or combination of substances used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings.” Simply put, these are the main ingredients of the drug that give it potency to combat the ailment it is being used for.

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In contrast to APIs, excipients are inactive ingredients that are intentionally added to therapeutic and diagnostic products to increase the solubility and product delivery of the drug and do not exert therapeutic effects at the intended dosage (Pawar and Kumar 2002). They also help maintain stability and osmolarity of the product. The US Pharmacopeia has over 40 categories on the types of excipients used, and these are expected to increase with development of drugs through newer drug delivery technologies.

Solubility Factors Affecting Solubility of API The solubility of an active pharmaceutical ingredient is highly important in the study of dosage forms. Not only does the API have to dissolve (in the case of solid APIs) in the solvent, they should dissociate into the required components after ingestion to prevent any unwanted side effects. The current trends of drugs in the market seem to have an overwhelming number of BCS class II drugs, i.e., drugs which have high permeability but low solubility. To help understand how to make the API more soluble, we need to understand the factors that affect it. There are many factors that affect the solubility which are mostly categorized under: • pH: pH is a measure of a compound’s acidity; pH values denote the exact acidity of the compound in question. pH is defined in terms of protons/hydrogen ion activity which is a function of effective concentration. pH ¼ log 10 AH or 10pH ¼ AH The solubility of weak acid and weak base is dependent on the pH of the environment. The monoprotic weak acid (HA) at given pH will undergo ionization, and its total concentration will be sum of the free acid (H+) and the salt form (a). conditions which will favor the formation of the salt form will increase the solubility of HA as a will be interacting with the water molecules through ionic bonding. Ka

HA $ H þ þ A Ka is the dissociation constant of the weak acid. At the maximum pH or pHmax, drug solution will be saturated with both salt and acid forms. Solution will have higher concentration of salt form as compared to the free acid, whereas the reverse is true at the lower pH. To determine the amount of drug in solution at a given pH, one of the following equations can be used.

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If the pH is below pHmax   Ka ST ¼ SA 1 þ þ H If the pH is above pHmax  ST ¼ Ss

Ka 1þ þ H



where SA = saturation solubility of free acid ST = total solubility Ss = saturation solubility of salt form • Temperature: Temperature, in typical reactions, plays a role in the rate of the reaction and the amount of API dissolved. It can help tip the scales in one direction or the other by raising or lowering the temperatures. In the human body, however, we need the reaction temperatures close to the physical temperature. To help increase solubility, and thereby increase bioavailability, different techniques are employed – addition of buffers or other compounds that react at body temperature, decreasing the size of the particles by nanoformulation, etc. • Polarity: Polarity, like temperature, is very important to the solubility of API and is dependent on it. Since many molecules in our cells is polar like some amino acids, GPI proteins which are present on the lipid layer, free radicals present in the cytoplasm, etc., the API should be chosen such that the molecule does not disturb the overall polarity of the cell.(Stark et al. 2006) • Role of excipients on solubility – surfactants, wetting agents, and viscosity modifiers: While some excipients are added to increase the volume, others can be added to increase the bioavailability of the API. Though some new excipients can be patented, they are usually kept as a trade secret. Though some excipients are used to simply bulk up the API, they are carefully selected to complement the functions of the API and help in better drug delivery. – Surfactant-type excipients are used to modulate the solubility of the API. It also increases the stability and maintains the pH and osmolarity of the solution. Due to their surfactant nature, they can also act as an emulsifier. – Wetting agents are those which are used to create a homogenous dispersion of solids using a liquid vehicle such as a nasal spray. Some agents can also help wet the API and get it into solution faster. – Viscosity modifiers can help change the texture of pharmaceutical agents. They can increase or decrease the viscosity of the liquid dosage form based on the requirement. The product will include ingredients which are thickeners, texturizers, or stiffening agents.

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pKa/Dissociation Constants pKa values give insights on the degree of drug’s ionization in the pH of the environment it is presented. Lipophilicity and ionization both affect membrane permeability (Fig. 1). Ionization influences aqueous solubility and membrane permeability of the drug; aqueous solubility will affect the formulation criteria, and membrane permeability affects absorption, distribution, metabolism, and elimination of the drugs. Therefore, pKa values can have an effect on formulation and pharmacokinetic properties of the drugs. pKa values can affect solubility of drugs and excipients at various pH; this is particularly important for liquid preparations, where mixing two preparations or

Fig. 1 Membrane permeability of lipid-soluble and neutral molecules

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adding agents that can cause changes in pH can lead to precipitation of the drugs. In case with parenteral liquids, precipitation of drug can lead to potential harmful effects. In case of oral liquids, precipitation of preservatives and other stabilizing agents can affect the stability and shelf life of the formulation. The relationship between pH and pKa can be explained by Henderson-Hasselbalch equation given as follows (Po and Senozan 2001): pH ¼ pKa þ log

½WeakAcid  ½ConjugateBase

Partition Coefficient Partition coefficient is a measure of a molecule’s lipophilic nature. If a compound is dissolved in two immiscible liquids (oil and water), it will distribute between the two liquids and reach an equilibrium. The amount of the solute getting distributed between the two liquids is dependent on the lipophilicity of the molecule. The partition coefficient can be represented by the following equation (Po and Senozan 2001): log P ¼ log

½Drugoctanol ½Drugwater

Partition coefficient of the drugs can be used to assess the membrane permeability of the drug. In order for a drug to cross lipid bilayers of biological membrane, it should possess a perfect balance of solubility and lipophilicity. Aqueous solubility and lipophilicity are inversely proportional; with increase in lipophilicity, aqueous solubility decreases (Fig. 2). Partition coefficient can also be used in purification of crude drugs, extraction of drugs from biological fluids, and assessing absorption of drugs from various dosage forms. In case of liquid formulations, partition coefficient data of excipients such as flavoring agents and taste masking agents can be used to evaluate the distribution of excipients between oil and liquid phase of emulsions. Fig. 2 Balance between lipophilicity and solubility of drugs; with increase in lipophilicity, solubility decreases

Solubility

Lipophilicity

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Effects of Physicochemical Properties on Manufacturing Processes Manufacturing processes need to be kept up to date and should ensure GMP standards throughout the facility while producing any component of the drug. For liquid dosage forms, there is an additional need to ensure that the products do not degrade over time. The drug kinetics should be unchanged for the drug to be produced in bulk. Proper equipment which does not react or equipment that has a nonreactive coating is required while processing the raw ingredients of the liquid dosage form to avoid reactions that may be oxidative, reductive, photolytic, etc. Though the reaction may alter the molecule only slightly, the worst-case scenario of its effects on the body could be toxic. Since the customer cannot usually tell the difference between a drug manufactured in compliance to Current Good Manufacturing Practices (CGMPs) and one that is not, the FDA regulated these practices to ensure that the manufactured drug is up to standard and is safe to consume. If the manufacturer does not follow the CGMPs, the drugs are considered “adulterated” under law and can even be seized if an injunction is filed in court.

Future Directions and Conclusion The future of liquid dosage forms is far and wide. It is a convenient and fast-acting method of drug delivery to provide the patient immediate relief. As discussed, it is also helpful for pediatric or geriatric patients or those patients who cannot orally ingest the drug. Though there are other different forms of drug delivery being developed, it is still not possible to deliver a large dose (as it is required in the case of IV fluids) through those methods. They also help when a small dose of drug needs to be delivered in the body. These dosage forms are also sometimes available in large variety of flavors to help mask the unpleasant taste of the drug. They undergo the same rigorous regulations required to manufacture them, and hence it is important to develop or update regulations for the manufacturing processes and ensure that the product that reaches the consumer is safe and standardized.

References Developing NICE guidelines: the manual NICE process and methods guides (2015) Dupuis A, Tournier N, Le Moal G, Venisse N (2009) Preparation and stability of voriconazole eye drop solution. Antimicrob Agents Chemother 53:798–799. https://doi.org/10.1128/ AAC.01126-08 Garg T, Rath G, Goyal AK (2015) Comprehensive review on additives of topical dosage forms for drug delivery. Drug Deliv 22:969–987. https://doi.org/10.3109/10717544.2013.879355 Glass BD, Haywood A (2006) Stability considerations in liquid dosage forms extemporaneously prepared from commercially available products. J Pharm Pharm Sci 9:398–426

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Hoorn EJ (2017) Intravenous fluids: balancing solutions. J Nephrol 30:485–492. https://doi.org/ 10.1007/s40620-016-0363-9 Ikeda K, Morizono T (1989) The preparation of acetic acid for use in otic drops and its effect on endocochlear potential and pH in inner ear fluid. Am J Otolaryngol 10:382–385 Lee YC, Zocharski PD, Samas B (2003) An intravenous formulation decision tree for discovery compound formulation development. Int J Pharm 253:111–119 Montebovi AJ (1954) The colloidal demulcents. I. Physical and chemical properties. Am J Pharm Sci Support Public Health 126:4–7 Pawar S, Kumar A (2002) Issues in the formulation of drugs for oral use in children: role of excipients. Paediatr Drugs 4:371–379 Po HN, Senozan NM (2001) The Henderson-Hasselbalch equation: its history and limitations. J Chem Educ 78:1499. https://doi.org/10.1021/ed078p1499 Stark A et al (2006) Metathesis of 1-octene in ionic liquids and other solvents: effects of substrate solubility, solvent polarity and impurities. Adv Synth Catal 348:1934–1941. https://doi.org/ 10.1002/adsc.200606174 Yung M, Keeley S (2009) Randomised controlled trial of intravenous maintenance fluids. J Paediatr Child Health 45:9–14. https://doi.org/10.1111/j.1440-1754.2007.01254.x

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Solid Dosage Forms: Formulation and Characterization Shambhavi Borde, Dhirender Singh, Navneet Sharma, Dunesh Kumari, and Harsh Chauhan

Contents Introduction and Need of Solid Dosage Forms for Space Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . The Physiological Changes in the Space and Available Solid Dosage Form as Space Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Formulation of Space Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Challenges for a Solid Dosage in Context of Stability in Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stability, Formulation, and Characterization Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison of Solid Dosage Forms with Other Dosage Forms for Space Pharmaceuticals . . . Solid Dosage Form Design for Space (Gibson 2009) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future of the Medical Treatment and the Pharmaceuticals in Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

The chapter provide introduction and need of solid dosage forms for space pharmaceuticals. It discusses various drugs and excipients which can be utilized in these solid dosage forms. The chapter further emphasis on important formulation development aspects of solid dosage forms. It discusses important analytical

S. Borde · H. Chauhan (*) Creighton University, Omaha, NE, USA e-mail: [email protected] D. Singh Navinta LLC, Ewing, NJ, USA N. Sharma Perrigo Company, Allegan, MI, USA D. Kumari College of Saint Mary, Omaha, NE, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 Y. V. Pathak et al. (eds.), Handbook of Space Pharmaceuticals, https://doi.org/10.1007/978-3-030-05526-4_15

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characterization techniques utilized in solid dosage forms. Overall, solid dosage forms are key to space travel due to long-term stability advantage it offers in space conditions.

Introduction and Need of Solid Dosage Forms for Space Pharmaceuticals To date, most of the space medications have been ingested as tablets by mouth, although topical agents, rectal suppositories, ocular preparations, and intramuscular injections are among few other medicines available onboard formulary. Parenteral route is generally not preferred, because of difficulty in self-administration and other disadvantages. Medicines needed most often on space shuttle are aspirin, oxymetazoline, acetaminophen, cyclizine, and diphenoxylate, all of which are available as tablet form, except oxymetazoline, which is available as nasal spray (Nicogossian et al. 2016). Specifically, solid dosage forms of tablets and capsules are more commonly used in space shuttle. However, the solid tablet is preferred superior to capsule due to advantages such as tamper resistance and less probability of adulteration after manufacturing (Nagashree 2015). In this current scope of book chapter, formulation preparation used in space shuttle along with associated challenge is discussed.

The Physiological Changes in the Space and Available Solid Dosage Form as Space Pharmaceuticals Human body experience many changes due to the impact of spaceflight. Most of the physiological and pathological changes are observed as the consequence of exposure to microgravity environment. Cardiocirculatory system: When astronauts sit for hours in a leg-elevated position, they are under fluid shift, which is a continuous process as the astronauts further expose to the microgravity environment. In microgravity, there is an absence of the arterial, venous, and microcirculatory blood pressure gradients, which causes a fluid shift from the lower to the upper parts of the body leading to decrease in blood volume. This ultimately results in altered pharmacokinetics and thus overall drug safety and efficacy (Hargens and Richardson 2009). Musculoskeletal system: The musculoskeletal system is remodeled in the life without gravity. As there is the reduction in workload on the muscle in a microgravity environment, both muscle mass and muscle strength are diminished during spaceflight, and this exerts less force on the body than earth’s gravity. The experienced muscle losses could impact the distribution of drugs. Even though astronauts perform regular exercise (for 2 h a day), they experience significant bone mass loss when they return to earth (Smith et al. 2005). However, recent advances in exercise and nutrition have shown that astronauts can return from

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6-month spaceflight missions without significant losses of bone mass (Smith et al. 2012). Immune system: The microgravity environment, physiological stress, isolation, radiation, disrupted circadian rhythms, and other flight-associated factors dysregulate the human immune system (Williams et al. 2009). There are some recent in-flight studies which say that there is a change in leukocyte distribution, a reduction in T-cell function, and an altered cytokine production profiles during flight. Of note, most of these immunity alterations were observed in low earth orbital flights of short duration. For longer space missions, the prolonged immune system alterations may potentially cause adverse events and even malignant diseases (Kasta et al. 2017). Gastrointestinal system: There are significant changes in gastric emptying and intestinal transit rate which results into altered absorption of orally administered drugs. Gastric emptying can also be altered by space motion sickness through the inhibition of gastric motility. In microgravity, due to the decrease of the dimensionless ratio of gravitational forces to viscous forces, there can be an increase in intestinal transit rate. These variations in gastric emptying and intestinal transit may ultimately lead to variability in drug response (Kasta et al. 2017). Metabolic system: There is a need of several enzymes for the metabolism of drugs. Variety of enzymes showed changes in the activity in animals exposed to spaceflight and simulated microgravity and hence suggested that xenobiotic metabolism in humans may also change during spaceflights. Several studies showed that intestinal digestive enzymes and hydroxymethylglutaryl-coenzyme A reductase increased during spaceflights, and microsomal cytochrome P450 is decreased in rats subjected to spaceflights. Recently, some studies have shown that spaceflight may increase hepatic triglyceride storage, altering lipid metabolic homeostasis. In addition, genetic expression of ATP-binding cassette transporters and activity of certain transmembrane proteins and ion channels have been found to change in real and simulated microgravity conditions. These changes could lead to alterations in drug metabolism which could increase or decrease drug exposure significantly during spaceflight (Kasta et al. 2017). Medication: As discussed, there are number of physiological changes or other factors that may require pharmacotherapy during spaceflight. On 94% of all flights, astronauts reported taking at least one medication (Putcha et al. 1999). Among the most common complaints during space missions are sleep problems, space motion sickness, pain (headache, joint pain, back pain, and muscle pain), allergies, and sinus congestion (Putcha et al. 1999; Wotring 2015). There are disruptions in circadian rhythm, and work stress causes difficulty in sleep leading to frequent intake of sleep-promoting drugs during space missions. Studies have found out that more than 70% of crew members use sleep aids on both space shuttle missions and International Space Station missions. Barger et al. reported sleep aids were taken with multiple doses on 17% of the nights (Barger et al. 2014; Wotring 2015). This relatively large number of multiple doses of sedative drugs in the same night might indicate a lack of efficacy after administration of the first dose. Other frequently taken drug classes during International Space Station Missions include

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Table 1 The medications used in the space, their forms, and brand names Category Antioxidants Antibacterial Antidepressant Hypothyroidism Anti-seizure Antibiotic Antifungal Diuretic Antibiotic

Compound Vitamin K Ciprofloxacin Sertraline Levothyroxine Phenytoin Cefadroxil Fluconazole Furosemide Azithromycin

Analgesic Antihypertensive Antiemetic Osteoporosis treatment Antiprotozoal Sedative CNS stimulant

Ibuprofen Metoprolol Promethazine Risedronate Metronidazole Temazepam Dextroamphetamine

Solid forms Capsules Tablet Tablet Tablet Capsule Capsule Capsule Tablet Capsule Tablet Tablet Tablet Tablet Tablet Ovules (Pessaries) Capsule Capsule

Brand name Swanson Ciplox 500 Zoloft Levothroid Dilantin Duricef Diflucan Lasix Zithromax Azodis Advil Toprol-XL Phenergan Actonel Flagyl Restoril Adderall

Categories (Du et al. 2011; Mehta and Bhayani 2017)

congestion and allergy treatments, pain relievers, rash treatments, motion sickness prophylaxis and treatment, and alertness aids; about 21–55% of crew members use these medications during spaceflight (Wotring 2015). Many of these medications are also likely to be used on longer exploration missions, but there is a lack of experimental evidence regarding alterations in their pharmacokinetics or pharmacodynamics in the unusual environment of a spaceflight mission. Table 1 lists some commonly needed and used medications and their available dosage forms in the space missions.

Formulation of Space Pharmaceuticals As listed in Table 1, most of the medications required in space travel are available in solid dosage forms either as tablet or capsules. Thus, it’s important to understand their formulation aspects especially in context with space conditions. Tablets: Tablets can be classified as solid unit oral dosage forms comprising drug substance or substances with diluents and formulated either by molding or compression method. They may differ in shape, size, and weight depending on drug’s physical characteristics, compatibility with excipients, and intended method of administration. There are certain quality attributes that a formulator must considered while developing a solid dosage form in order to withstand the harsh space environment. Tablets must be sufficiently strong enough to withstand shock and abrasion during transport and storage; the drug must be released completely and in

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a timely manner to be bioavailable; tablet must be stable and should preserve its efficacy for intended period/shelf life in the space. Tablets should also possess specific markings/trade dress to identify the medication (Chan and Chew 2002). Composition of a tablet: A tablet is a powder compact of the drug and many inert materials, known as excipients or additives. An excipient may be classified by the role it plays in the finished product. The first group of critical excipients are those which imparts satisfactory processing and compression to the tables. These include diluents/fillers, binders, disintegrants, lubricants, and glidants. The second group imparts desirable physical characteristics to the finished dosage, such as coloring and flavoring agents (Gullapalli and Gelatin 2017). Table 2 comprises the most commonly used excipients in a solid dosage form. Very limited literature is available in terms of stability/physical and chemical changes of these excipients under space conditions. Any changes in the excipients might result in decrease in overall performance of tablets. Tablet manufacturing procedure: Wet granulation – Wet granulation is a widely used process of tablet manufacturing in pharmaceutical industry. The process simply involves wetting of powder blend of drug along with other excipients using appropriate granulating liquid. Damp/wet mass is then passed through a mesh to form granules or pellets, followed by drying. Dried granules are further passed through a screen/mill to form uniform sized granules. A lubricant may be then added and mixed to improve the flow characteristics. Granules are compressed to tablet of desired size and weight. Wet granulation is expensive process relative to other methods of manufacturing, as it involves use of a granulating solvent, extensive labor time, energy, and equipment. Stability of moisture sensitive or thermolabile drug substance is another major concern that limits the use of wet granulation. Moreover, any known incompatibility between drug substance and any of excipient may be aggravated during the wetting process (Shanmugam 2015; Gullapalli and Gelatin 2017). Dry granulation: Dry granulation has fewer process stages than wet granulation. First the different ingredients are weighed and combined in the required proportions, and then the resulting mixture is compressed by roller compaction (slugging) for the first time. This results in sheets of compressed material, which are then milled into granules of exactly the agreed density, before being lubricated and compressed into the desired final form. Dry granulation is preferred method for moisture sensitive or thermolabile drug substances. However, the major downside of process is creation of more dust than wet method, which leads to more contamination. Moreover, uniformity of color is limited during dry granulation process (Shanmugam 2015; Gullapalli and Gelatin 2017). Direct compression: In direct compression method, powder blend of API and excipients are compressed directly to finished tablets without any pretreatment of powder blend. Direct compression is a method of choice, since its economical process requires lesser cost of labor and equipment. No heating or moisture is involved, so suitable for moisture-sensitive or thermolabile drug substances. Since this process requires fewer manufacturing steps, batch-to-batch variations are minimized. However, achieving blend uniformity of a low-dose drug could be challenging. Moreover, direct compression sometimes leads to unblending due to

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Table 2 Common excipients generally used in the tablets Excipient Diluents/ fillers

Function Make bulk of the tablets, specifically for a very potent drug substance which itself is unable to compact into a tablet of required shape and size

Binders, granulating agents Glidants

Bind the drug substance and other tablet’s excipients together giving form and mechanical strength Reduce adhesion and friction between particles, thus improving the flowability of powders during tablet manufacturing. Also employed as anticaking agents Aid breakdown of the tablet in the fluid of the gastrointestinal tract, releasing the drug substance and improving the dissolution Similar function of glidants; however, they may adversely slow the disintegration and dissolution due to their hydrophobic nature Protect the tablet from the harsh environment conditions such as moisture, air, and light; enhance the organoleptic properties by masking smell and taste; increase the mechanical strength; improves swallowing; assist in medication identification; can be used to modify the drug release Improve patient’s compliance, assist identification, and limit counterfeiting Improve stability of light-sensitive drugs

Disintegrants

Lubricants

Tablet coatings and films

Coloring agents

Examples Cellulosic polymers like microcrystalline cellulose, hydroxymethyl cellulose, etc. Inorganic diluents, e.g., silicates, magnesium and calcium salts, potassium or sodium chloride Sugar diluents, e.g., sucrose, lactose, glucose, sorbitol, dextrin Generally natural or synthetic polymers, e.g., sugar alcohols, sugars, starches, and cellulose derivatives For example, silica compounds and colloidal anhydrous silicon and others

Compounds which dissolve or swell in water, e.g., crospovidone, cellulose derivatives and alginates, starch For example, stearic acid and its salts (e.g., magnesium stearate), sodium stearyl fumarate, etc. For example, sugar, sucrose, and polymers such as hydroxypropyl cellulose, cellulose acetate phthalate, etc. that are insoluble in acidic are used for enteric coatings to delay release of the drug substances in the stomach

Mainly natural color and synthetic dyes

different particle size and density of components. Direct compression diluents and binders must possess good flowability and compactibility (Gullapalli and Gelatin 2017; Du et al. 2011). Table 2 shows commonly used excipients for the formulation of tablets (Chan and Chew 2002). Capsules: The use of capsules goes back to the early days of pharmacy, and since these early days, capsules have evolved significantly to meet the current needs of the patient and pharmaceutical industry. They are produced in various shapes, sizes, and materials, each capsule generally containing a single dose of active ingredient. In addition to the active drug ingredient, other excipients are incorporated into

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the fill material, including antimicrobial preservatives, fillers, flavoring agents, sweeteners, and coloring agent. In general, capsule consists of two parts, i.e., base or body, the longer part with smaller diameter, and cap with slightly larger diameter that fitted onto body, and constitutes a snug seal. Capsule products are formulated by filling drug material into the body, followed by snugging of cap over the body and sealing. Formulation of capsule can be done manually, semiautomatic to fully automatic method. Like tablets, capsule drug products must consist of uniform amount of active drug substance and assure drug release in a manner to achieve desired bioavailability and thus therapeutic effect. Gelatin is most widely used material to construct capsule shells, though new class of polymeric material, e.g., hydroxypropyl methylcellulose (hypromellose), is commonly used to construct polymeric shell (Gullapalli and Gelatin 2017; Martin et al. 2012). According to literature search carried by authors, till now, there are no studies where solid dosage forms are prepared separately for space needs.

Challenges for a Solid Dosage in Context of Stability in Space Preliminary investigation of physical and chemical changes of dosage forms in space shuttle suggests an obvious difference in potency and rate of degradation of pharmaceutical preparations stored in space when compared with same formulary on the earth (Chan and Chew 2002). However, consistent with consensus that solid dosage form is less susceptible to degradation due to temperature and humidity as compared with liquid or semisolid dosage, a recent study revealed that out of nine, only seven solid dosage forms remained potent in the post space mission analysis (Kasta et al. 2017). Despite robustness of solid dosage contrary to liquid or semisolid dosage, there are several factors that need to be focused while developing solid dosage forms for spaceflight. In general, a pharmaceutical preparation is exposed to unique environmental challenges in the space that include excessive vibration, radiation exposure, off-nominal gravity, and CO2-rich environment combined with temperature variation and humidity which may compromise the stability and thus efficacy of dosage in space (Chan and Chew 2002). Noteworthy, it is well accepted that the cumulative radiation dose, even at low scale, is much higher in space environment than that of the earth, adversely composed of heavy ions and ionizing radiation of protons. Studies have demonstrated that the radiation induces chemical degradation of active pharmaceutical ingredients. However, the impact of radiation, specifically of different ions on a specific class of drugs, has not been studied extensively; thus, the extent of space degradation as of radiation on particular class/group of medicine remains unclear (Kasta et al. 2017). Despite the number of factors governing the performance of solid dosage in the space, research and development has not invested and executed intensively to embark on preventing measures while developing dosage forms with an eye to its space uses. Nonetheless, emphasis is embarked on precise storage and transport of solid dosage to minimize the harsh environmental exposure. For example, radiation impact exacerbated when radiation passes through metal ions and formed daughter

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ions; thus, use of radiation shielding of drug substances may require use of nonmetallic and polymeric material. The uses of inert gases while packing pharmaceutical preparation may potentially improve the shelf life of medicine either by means of shielding or reducing the oxidation. Furthermore, the concept of radiation attenuation by using lightweight shielding materials such as high-density polyethylene may be employed in designing kit for drug substances storage to ensure stability during space mission (Chan and Chew 2002; Kasta et al. 2017).

Stability, Formulation, and Characterization Challenges Figure 1 shows formulation and characterization challenges in space conditions. To ensure the stability and shelf life of the commercial pharmaceutical preparations, extensive studies are carried out under earth conditions, and accordingly protective packaging and dispensing practices are followed, for example, humidity and temperature conditions for storage are specified on the basis of results from accelerated stability studies required before the product is released to the marketplace (Okeke et al. 2000; Parks 1985; Allinson et al. 2001). As for characterization, hygroscopicity, drug release pattern, hardness, dehydration, physical and chemical degradation, photosensitivity as a function of relative humidity and temperature, gas liberation tendency, product packaging material interaction, and dimensional aspects are performed in comprehensive stability studies (Weeren and Sashidharan 2008). Unlike standard dispensing practices on earth, special flight-certified containers are used for packaging and dispensing the pharmaceuticals in space. They are stored in compactly packed kits, and this packaging provides stability and shelf life of pharmaceuticals in space. However, the challenge lies in limited information available on the effect of prolonged exposure to the spacecraft environment on the

Fig. 1 The challenges for the formulation and characterization of pharmaceuticals in the space as compared to on earth conditions

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stability of pharmaceuticals. Also, very limited research has been carried out to identify differences in variables that indicate physical and chemical stability of medications between ground controls and spaceflight; chemical degradation profiles of formulations and relevant environmental variables of temperature, humidity, and cumulative radiation dose were compared for the two conditions. Overall, a spaceflight presents unique environmental challenges that include radiation enrichment, excessive vibration, and off-nominal gravity environments which might affect pharmaceutical stability in space. Looking at the challenges listed, a study performed by Brain Du et al. suggested that there may be differences with respect to potency and rate of degradation of formulations stored in space compared to those on the earth. In the study, cumulative low-dose radiation and dispensers used for solid dosages in space appear to influence stability of pharmaceuticals in space (Kasta et al. 2017). The study noted that in contrast to contributing environmental factors of stability on the ground, passive radiation dosimetry demonstrated that the cumulative radiation dose, although at a low level, was much higher in space than on earth; this radiation enrichment in space is composed of ionizing radiation of protons and heavy ions. Although gamma radiation is known to be used to sterilize pharmaceuticals in commercial environments, space radiation consists of mixed fluences of high- and low-intensity radiation (Benton and Benton 2001; National Council on Radiation Protection and Measurements (NCRP) 1989) with a lower dose rate and longer duration of accumulation in contrast to exposure for pharmaceutical sterilization that typically last for a few minutes. With respect to medications, in addition to the concern about radiation effects that can induce significant changes in the active pharmaceutical agent (API) levels or potency of the medication, it is important to determine the effect of radiation on excipients and degradants. Structure and biological activity of degradation products can cause adverse/toxic effect. It’s also important to establish toxicity limits of active degradants in a formulation. Additionally, research on new and emerging formulation and packaging technologies may enhance and ensure adequate shelf life of medications in space. It is important to characterize space-specific degradation products and toxicity limits, and one can do this by using ground-based analog environments of space that include proton and heavy ion radiation, vibration, and multiple gravity conditions. By having this information, it would be easier to facilitate research for the development of space-hardy pharmaceuticals and packaging technologies (Kasta et al. 2017). Stability studies by Brian Du et al. on different dosage forms found that liquid formulation of ciprofloxacin in sealed commercial vial remained potent beyond the expiration date in contrast to promethazine which degraded faster during flight time. Hence, the light-sensitive APIs like promethazine may not be stable or have adequate protection against radiation-rich spacecraft environment when stored in commercial vials. This warrants the need for development of space-hardy dispensing technologies (Kasta et al. 2017). Medicines included in spaceflight kits are commercially available off the selfmedications and are used commonly on the earth. They have not been tested for the use in long- and short-duration space missions. Therefore, assurance of shelf-life period for space medicine is extremely important for long-duration spaceflights.

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It is well-known that drugs in solid form are more stable than liquid form, so for a longer shelf life of parenteral medication, lyophilized/reconstituted powder form is desirable. For that, not only the understanding of how these medications can be reconstituted in microgravity but also other factors such as solvents for reconstitution, time, etc. need to be formalized. In this regard, the vacuum generally causes problems like outgassing from polymers or packaging material, evaporation of solvents or water from formulations, etc. During Apollo missions, pressure-related issues emerged in pharmaceutical packaging, and more stringent requirement needs to be enforced for space pharmaceuticals (Barbarina et al. 2001; Maggi et al. 2003; Kane and Tsuji 1983; Ahrabi et al. 1999). In long-duration space exploration, space radiation penetrating the shielding material of spacecraft or ISS has been recognized as a potential hazard for the crews, electronic devices, and other materials inside the spacecraft (Mehta and Bhayani 2017). Therefore, space radiation can be considered as a major factor affecting the stability of pharmaceuticals in space. When the medicines are exposed to any ionizing radiation, the electronic transitions take place in the drug molecules depending on the type of radiation which may lead to decomposition of drugs and excipients (Mehta and Bhayani 2017). Generated radiolytic species may react with active ingredients or excipients or both resulting in a change of physicochemical properties which leads to an alteration in pharmacological activity (Mehta and Bhayani 2017). In these types of situations, shielding/packaging material and its protective strength become very important. Sterilization of pharmaceuticals by gamma radiation (~1.5 MeV, 25 kGy) for very short period of time (ranging from seconds to minutes) is well-known. Numerous articles have reported on the evaluation of stability of pharmaceuticals after gamma radiation. However, spaceflight environment comprises of highly energetic radiation with mixed fluencies at a lower dose rate, which accumulates in higher dose throughout long-duration missions. In this regard, US FDA conducted a terrestrial study to evaluate pharmaceuticals that were stored beyond their original expiration date and evaluated for its efficacy under the shelf-life extension program (SLEP). In the study, regression analysis of real-time assay data was used to determine the shelf-life extension. It was seen that out of 122 drug products studied, 88% were extended beyond their original shelf life. SLEP study supported that many pharmaceuticals can be extended beyond their expiration date. Although the SLEP study does not specifically identify pharmaceuticals that will survive while traversing deep space environment, it can be used as a guide to select medicines that exhibit multiple shelf-life extensions (Mehta and Bhayani 2017). Another important consideration in case of space medicines is the chemical changes which can result due to breakdown/changes in the bonds of active ingredient or excipients randomly due to highly energetic space radiations. During longduration exploration missions, more rigorous conditions of radiation due to change in solar cycle are expected. This may possibly result in increased rate of bond breaking that can result in changes in potency/toxicity of exposed pharmaceuticals. Additional precautions in these cases, such as discussed previously, to prevent the radiation-induced degradation of the drugs are desired. For example, the packaging

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materials of pharmaceuticals should have radiation-attenuating properties, stable excipient selections, etc. (Putcha and Taylor 2011). In this regard, recent evaluation of radiation effects on different materials has shown that when the radiations traverse through a material with high atomic number such as aluminum, they can produce large number of neutrons and other secondary particles. While the production of secondary particles decreases with the decrease in atomic number of the material, it suggests that low atomic number materials provide effective shielding against space radiations, with hydrogen being the best and having potential in shielding space pharmaceuticals. Further, high-density polyethylene, a hydrogen-rich material, has shown good shielding property, and when it is incorporated with fillers like boron, tungsten, etc., it emerges out as a material with even more superior shielding properties. Similarly, the use of these types of low atomic number polymeric materials in packaging of space medicines might provide better shielding from space radiations (Mehta and Bhayani 2017). Another big challenge in the development of solid dosage forms for space pharmaceuticals is the analytical and in vitro release characterization using currently available official monographs such as USP I and II dissolution apparatuses. Currently, these apparatuses are suitable for the testing on the earth because the paddle, basket, and reciprocating cylinder all represent the human body conditions on the earth, but they are not simulated condition for the space environment as there are many changes in the external environment as well as inside the human body and hence cannot predict the release of the API appropriately. The release behavior studied with the help of USP apparatus would not be the correct representation of the drug release in the body in the microgravity, and this remains a challenge for the simulation of release behavior of the API in the space. Therefore, there needs to be a development/modification of the analytical apparatus which is the better representation of the space conditions. These apparatuses need to be robust enough to predict the drug release pattern in space conditions and thus should help in developing optimum space pharmaceuticals. Specific to capsule as a commonly used solid dosage form, another challenge is their storage requirement. Typically, capsules contain 10–15% moisture. Under high-humidity conditions, these capsules can absorb moisture. Above 16% moisture, they lose their mechanical strength and may become sticky. Further, storage under extreme dry conditions will result in brittle capsules due to moisture loss. Therefore, the best storage and process conditions for capsules are between 10  C and 25  C and relative humidity of 35–45%, and these suitable conditions are difficult to maintain in the space.

Comparison of Solid Dosage Forms with Other Dosage Forms for Space Pharmaceuticals Medical kits used in the International Space Station (ISS) contain hundreds of medicines in different dosage forms. For short-duration missions, medicine can be replaced before the expiration; however, resupply is not possible for long-duration missions like to Mars or any other asteroid. It is desired that different dosage forms

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maintain the shelf life throughout the space mission. As stated by Du et al., “Consistent with the general consensus on the ground that stability issues are less frequent with solid than with liquid or semisolid formulations (Kasta et al. 2017).” Lyon et al. conducted a terrestrial study to test the stability profiles of drug products extended beyond labeled expiration dates. The 122 drug products stored in their original containers were evaluated past their expiration date. The general findings showed that solid oral products exhibited the greatest longevity, whereas liquids exhibited the least longevity – suffering from numerous failure mechanisms, whereas creams and ointments exhibited mixed longevity results (Lyon et al. 2006). Du et al. examined space environment effect on the stability of 35 pharmaceuticals (present in different dosage forms) returned from ISS after in-space exposures. Seven of nine formulations that remained potent by the end of the study period (880 days) were solid dosages in spite of being repackaged in flight dispensers, and the other two stable formulations, triamcinolone cream and ciprofloxacin ointment, were flown in commercial dispensers (Kasta et al. 2017). Brian Du et al. examined three formulations (solid, liquid, and semisolid) of ciprofloxacin and promethazine and found that degradation of the formulations was slightly faster in flight than on the ground (Shanmugam 2015). Higher physical changes like discoloration, liquefaction, phase separation of clotrimazole cream and mupirocin ointment, and higher degradation rates (200%) for liquid formulations of promethazine in comparison to the control samples on earth were reported. These factors suggest that there are more impacts on the liquid and semisolid dosage forms than on the solid dosage forms. In general, the occurrence of the instability of pharmaceuticals was higher for spacecraft condition than equivalent control samples on the earth. Whereas, the results on dissolution performance of solid dosage forms indicate that no major differences exist between control and flight samples with most formulations meeting USP dissolution tolerance standards in both conditions. These results might suggest that environmental conditions unique to spaceflight may affect chemical degradation but not dissolution performance of most solid dosage forms during prolonged storage in space (Kasta et al. 2017).

Solid Dosage Form Design for Space (Gibson 2009) There are several considerations that need to be taken care during the development of solid form space pharmaceuticals which include but are not limited to physicochemical properties of the drug, therapeutic effects of the drugs, and the processing and regulation. Physical/chemical properties of drugs: Whenever the pharmaceuticals are formulated, the pattern of their dissolution, release, and log P values should be considered to predict their behavior in the body in the space. Their stability against heat, humidity, light, and radiations should be studied prior to their formulation. The radiations present in the space and the API/excipients used in the formulation do not necessarily behave like they do on the earth, and hence the compatibility studies of the API with the excipients in space conditions should be studied before the formulation. Biopharmaceuticals: As the human

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body shows several physiological changes as discussed previously in this chapter, such as bioavailability, target organ behavior, mechanism of action, permeability, and other pharmacological aspects like absorption, distribution, metabolism, and elimination, there is a need to study them in the space-simulated conditions. There are chances of variation in all these processes due to the effects of space environment on human body. Therapeutics: Therapeutic factors like clinical effectiveness, route of administration during spaceflight, nature of the disease or illness, age of astronaut, and condition of the astronaut need to be studied in detail as the environment in the space is completely different than on the earth. Processing: Future directions of designing most optimum space pharmaceuticals lie in developing/establishing their production separately. However, there are several points that need to be taken care of before the production of space pharmaceuticals. As the requirement for space pharmaceuticals in terms of quantity is limited, pilot plant studies and production scale-up become an issue. Formulations of products can become very expensive with the cost of goods; dosage form (e.g., tablet vs. hard capsule) and shape (round tablet vs. unique shaped-keyed tools); processing efficiency (number of processing steps, speed of processing, volume/ quantity at each process), failure rate, etc. Regulatory: Currently, there are no established regulations for space pharmaceuticals. As described above, most of the processes/development will require specific set of guidance/regulatory process to be unique to these formulations. These processes should be regulated via documented formula, process and packaging, active ingredients, excipients, equipment, testing methods, unit operations, in-process controls, specifications, etc.

Future of the Medical Treatment and the Pharmaceuticals in Space Currently, real-time communication has provided the medical care on the International Space Station (ISS), but this is with the limited medical data transmission. There are many medical concepts of the operation that are being developed in preparation for future missions beyond low earth orbit (LEO). These operations are to ensure adequate support during the space travel, i.e., increased distance, duration, and communication delays, impossibility of emergency returns, etc. In this regard, Operational Space Medicine group at the Canadian Space Agency (CSA) is looking toward synergies between terrestrial and space medicine concepts for the delivery of medical care and to deal with the new challenges of human space exploration. There is an increased emphasis on spin-off and spin-in effects which are supported by the cross-fertilization of space-earth research. This cross-fertilization has a potential to stimulate telehealth and space medicine innovations and to engage in the new era of human space exploration (Martin et al. 2012). In this regard, a telehealth refers to the use of information and communication technology for the delivery of health-related services. In addition to video-conferencing systems, telemedicine tools allowing the transfer of image, video, sound, and other types of data, which is generally referred to as real-time telemedicine, are commonly used.

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This certainly allows for immediate intervention, but as it requires specific technologies and needs higher communication bandwidth, it is very expensive. These technologies have a significant potential to be used in conjunction with the currently used available medication and can provide support to the astronauts in future (Martin et al. 2012). Similarly, an emergency return can cause astronauts to abort a mission due to serious medical contingencies. To avoid this consequence and in order to facilitate the management of an ill or injured patient/crew member, technologies and procedures are developed which will allow the medical personnel on-site to manage the situation. Telementoring and remote control of medical devices are two examples that could provide additional benefits to telemedicine tools already being used. Telemonitoring: Even though crew members are trained, they need an assistance in some serious and emergency situations. Telementoring of medical procedures is one potential solution when the crew needs such assistance. Telementoring consists of a physician/expert guiding the CMO or another crew member through a medical procedure. Depending on the mission phase (outbound, onsite, return) and the communications delay, ground support may be provided real time to assist the CMO. In the case of a time critical event, the medical care paradigm shifts from advanced telemedicine to medical autonomy. Remote control of ultrasound: Ultrasonography is a medical specialty that typically requires extensive training, which the CMO may not necessarily have received during their medical training. To overcome this limitation, remote control of an ultrasound machine is foreseen as a means to facilitate the use of ultrasound during telementoring session (Martin et al. 2012). Although these newly developed technologies have significant potential, available solid dosage forms of commonly used medications in providing the symptomatic relief/first treatment options stand to play an important role in the near future. However, as discussed in the chapter, it’s important to design/validate/ characterize these dosage forms in terms of space environment.

References Ahrabi SF, Sande SA, Waaler T, Graffner C (1999) Effects of thermal neutron irradiation on some potential excipients for colonic delivery systems. Drug Dev Ind Pharm 25(4):453–462 Allinson JG, Dansereau RJ, Sakr A (2001) The effects of packaging on the stability of a moisture sensitive compound. Int J Pharm 221(1–2):49–56 Barbarina N, Tilquin B, de Hoffmann E (2001) Radiosterilization of cefotaxime: investigation of potential degradation compounds by liquid chromatography-electrospray mass spectrometry. J Chromatogr A 929(1–2):51–61 Barger LK, Flynn-Evans EE, Kubey A, Walsh L, Ronda JM, Wang W, Wright KP Jr, Czeisler CA (2014) Prevalence of sleep deficiency and use of hypnotic drugs in astronauts before, during, and after spaceflight: an observational study. Lancet Neurol 13:904–912 Benton ER, Benton EV (2001) Space radiation dosimetry in low-earth orbit and beyond. Nucl Inst Methods Phys Res B 184(1–2):255–294 Chan H-K, Chew NYK (2002) Excipients: powders and solid dosage forms. In: Swarbrick J (ed.) Encyclopedia of pharmaceutical technology, 3rd ed., Informa Healthcare USA, Inc, New York 2007; 3:1646–1655

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Du B, Daniels VR, Vaksman Z, Boyd JL, Crady C, Putcha L (2011) Evaluation of physical and chemical changes in pharmaceuticals flown on space missions. AAPS J 13(2):299 Gibson M (2009) Pharmaceutical preformulation and formulation. Informa Healthcare, New York Gullapalli RP, Gelatin MCL (2017) Non-gelatin capsule dosage forms. J Pharm Sci 106 (6):1453–1465. https://doi.org/10.1016/j.xphs.2017.02.006. Epub 2017 Feb 14 Hargens AR, Richardson S (2009) Cardiovascular adaptations, fluid shifts, and countermeasures related to space flight. Respir Physiol Neurobiol 169(Suppl 1):S30–S33 Kane MP, Tsuji K (1983) Radiolytic degradation scheme for 60Coirradiated corticosteroids. J Pharm Sci 72(1):30–35 Kasta J, Yua Y, Seubertb CN, Wotring VE, Derendorfa H (2017) Drugs in space: pharmacokinetics and pharmacodynamics in astronauts. Eur J Pharm Sci 109:S2–S8 Lyon RC, Taylor JS, Porter DA, Prasanna HR, Hussain AS (2006) Stability profiles of drug products extended beyond labeled expiration dates. J Pharm Sci 95(7):1549–1560 Maggi L, Segale L, Ochoa ME, Buttafava A, Faucitano A, Conte U (2003) Chemical and physical stability of hydroxypropylmethylcellulose matrices containing diltiazem hydrochloride after gamma irradiation. J Pharm Sci 92(1):131–141 Martin A, Sullivan P, Beaudry C, Kuyumjian R, Comtois J-M (2012) Space medicine innovation and telehealth concept implementation for medical care during exploration-class missions. Acta Astronaut 81:30–33 Mehta P, Bhayani D (2017) Impact of space environment on stability of medicines: challenges and prospects. J Pharm Biomed Anal 136:111–119 Nagashree K (2015) Solid dosage forms: tablets. Research and reviews. J Pharm Anal 4:60 National Council on Radiation Protection and Measurements (NCRP) (1989) Guidance on radiation received in space activities: report no. 98. NCRP, Bethesda Nicogossian AE, Williams RS, Huntoon CL, Doarn CR, Polk JD, Schneider VS (2016) Space physiology and medicine: from evidence to practice, 4th edn. Springer, New York Okeke CC, Bailey L, Medwick T, Grady LT (2000) Revised USP standards for product dating, packaging, and temperature monitoring. Am J Health Syst Pharm 57(15):1441–1445 Parks OW (1985) Screening tests for sulfa drugs and/or dinitrobenzamide coccidiostats and their monoamino metabolites in chicken livers. J Assoc Off Anal Chem 68(1):20–23 Putcha L, Taylor PW (2011) Biopharmaceutical challenges of therapeutics in space: formulation and packaging considerations. Ther Deliv 2(11):1373–1376 Putcha L, Berens KL, Marshburn TH, Ortega HJ, Billica RD (1999) Pharmaceutical use by U.S. astronauts on space shuttle missions. Aviat Space Environ Med 70:705–708 Shanmugam S (2015) Granulation techniques and technologies: recent progresses. Bioimpacts 5(1):55–63. https://doi.org/10.15171/bi.2015.04. Epub 2015 Feb 18 Smith SM, Wastney ME, O’Brien KO, Morukov BV, Larina IM, Abrams SA, Davis-Street JE, Oganov V, Shackelford LC (2005) Bone markers, calcium metabolism, and calcium kinetics during extended-duration space flight on the Mir space station. J Bone Miner Res Off J Am Soc Bone Miner Res 20:208–218 Smith SM, Heer MA, Shackelford LC, Sibonga JD, Ploutz-Snyder L, Zwart SR (2012) Benefits for bone from resistance exercise and nutrition in long-duration spaceflight: evidence from biochemistry and densitometry. J Bone Miner Res Off J Am Soc Bone Miner Res 27:1896–1906 Van Weeren R, Sashidharan A 2008 Sensitivity profiling of solid oral doses. Pharm Process 1–5. https://link.springer.com/article/10.1208%2Fs12248-011-9270-0 Williams D, Kuipers A, Mukai C, Thirsk R (2009) Acclimation during space flight: effects on human physiology. CMAJ 180:1317–1323 Wotring VE (2015) Medication use by U.S. crewmembers on the International Space Station. FASEB J 29:4417–4423

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Pharmaceutical Liquid Dosage Forms in Space: Looking Toward the Future by Learning from the Past Ashim Malhotra

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmaceutical Formulations in Space Missions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Types of Pharmaceutical Formulations: Solid, Semisolid, and Liquid Dosage Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . General Properties of Pharmaceutical Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liquid Dosage Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmaceutical Liquid Dosage Forms: Solutions, Suspensions, Colloids, and Emulsions . . . . Pharmaceutical Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmaceutical Suspensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liquid Dosage Forms and Space Travel: Overall Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fluids and Microgravity Influence on Physical Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmaceutical Product Stability and Shelf Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical Factors Affecting Phenomena Associated with Pharmaceutical Solutions and Suspensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

The previous few decades have witnessed an unprecedented expansion of space exploration programs across the world. As the objective of spaceflight transitions from Lower Earth Orbit (LEO) and exploratory expeditions to the more ambitious interplanetary, deep space, and residential missions, the inclusion of healthcare provisions such as medications for the crew becomes an imperative consideration. However, in most cases, the different formulations of pharmaceutical products used to treat human disorders are manufactured for use in the A. Malhotra (*) Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 Y. V. Pathak et al. (eds.), Handbook of Space Pharmaceuticals, https://doi.org/10.1007/978-3-030-05526-4_16

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terrestrial environment, have not been tested in microgravity and deep space. Exposure to cosmic radiation, temperature fluctuations, microgravity, and many other special space-related characteristics may adversely affect pharmaceutical dosage forms. This is especially true for liquid dosage formulations that are considered less stable over their shelf life than the solid dosage forms. This chapter explores the effect of microgravity on the manufacture, stability, bioavailability, and shelf life of the common liquid pharmaceutical dosage formulations known as solutions and suspensions. Keywords

Suspensions · Pharmaceutical solutions · Microgravity · Liquid dosage forms

Introduction Pharmaceutical Formulations in Space Missions Space exploration missions, whether they are mid-term or long-term, Low Earth Orbit (LEO) or the futuristic deep space endeavors have a common need to include medical and pharmaceutical provisions for the care of the participating space crew and astronauts. In the terrestrial context, such care is provided by trained healthcare professionals such as physicians, pharmacists, nurses, and others. However, ready access to healthcare professionals, intervention tools, and medications can prove to be challenging on space missions. A significant component of any preventative or therapeutic regimen may include the use of drugs and other pharmaceutical compounds. While the provision of healthcare services such as advice and consultation may be facilitated from terrestrial sources through the use of modern technology, it is challenging to compound, dispense, store, and dispose of drugs and pharmaceutical compounds in space, especially on long-term or futuristic deep space or interplanetary missions. This issue is further complicated by the plethora of pharmaceutical formulations that the drugs may be available in, each of which requires specialized manufacture, storage, and use.

The Types of Pharmaceutical Formulations: Solid, Semisolid, and Liquid Dosage Forms Common pharmaceutical formulations include solid dosage forms such as tablets and capsules and liquid dosage forms such as suspensions, emulsions, colloids, solutions, tinctures, foams, and others, while semisolid dosage forms may include gels, ointments, creams, and pastes among other formulations. Of course, there are also special formulations such as controlled-release tablets and capsules or formulations that are not available and ready-made for use but need to be compounded prior to dispensing. Such diversity in pharmaceutical formulations

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poses many complicating and serious challenges to the adequate provision of highquality and standardized healthcare for space travel.

General Properties of Pharmaceutical Formulations A variety of factors associated with different aspects of the manufacture, compounding, dispensing, and the use of drugs and other pharmaceutical compounds may affect the potency, bioavailability, shelf life, and the stability of different pharmaceutical formulations. The undocumented effects of microgravity, space travel, and exposure to radiation in space may adversely affect the formulation characteristics listed above. For example, although stability testing of pharmaceutical products is mandated by US law and regularly conducted by drug manufacturers, most stability tests do not include exposure to radiation or microgravity exposure as a component of the process. This may be relevant for certain kinds of formulations such as suspensions and emulsions which may develop starkly different physical properties in environments such as space, which is different from the intended-use terrestrial environment for which the products were manufactured. Fluctuations in the physical properties of these pharmaceutical formulations may lead to the degradation of the formulation and reduction in its efficacy and, at worse, can also precipitate serious side effects. Thus, consideration of the effect of space and space-related environments on the manufacture, compounding, and dispensing of drugs is essential for their safe and efficacious use. This chapter examines the effect of the space environment on the formulation, physical properties, stability, and efficacy of the liquid dosage formulations known as solutions and suspensions.

Liquid Dosage Formulations These days drugs are available in a wide variety of liquid dosage formulations. Common liquid dosage forms include solutions, tinctures, colloids, suspensions, and emulsions (Fig. 1). Before considering the effect of space on these formulations, it is

Fig. 1 Types of Pharmaceutical Liquid Dosage Formulations with Common Examples

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important to learn about the nature, manufacture, stability, storage, and use of liquid dosage forms and to be able to distinguish one from the other.

Pharmaceutical Liquid Dosage Forms: Solutions, Suspensions, Colloids, and Emulsions Pharmaceutical Solutions Pharmaceutical solutions are homogenous formulations where the active pharmaceutical ingredient and all other components are molecularly dispersed in an aqueous medium. Calling such formulations homogenous implies that the components are equidistributed in the medium and, regardless of sampling, the concentration of the active compound will be the same. Solutions typically have particle sizes in the molecular range, less than 1 nm.

Types of Pharmaceutical Solutions From a pharmaceutical perspective, solutions may be further subclassified as tinctures, elixirs, and syrups. Typically, tinctures are extracts of crude drugs such as plant extracts to which alcohol has been added a solvent, while elixirs have a higher alcoholic content. Syrups are solutions that have been sweetened typically for oral administration. Physical and Chemical Characteristics of Pharmaceutical Solutions Generally, most solutions are prepared by dissolving drugs and other components, and thus drug solubility characteristics are an important consideration for solution formulation. All physical and chemical factors that regulate aqueous solubility of solutions such as temperature, pH, ionic states, and other factors become relevant for the stability consideration of most pharmaceutical solutions. However, since solutions have molecularly dispersed solutes, at less than saturation conditions, most solutions are regarded as the most stable type of liquid formulations, as opposed to, for instance, suspensions and emulsions. Although solutions are the most stable of the liquid dosage forms, in terms of stability consideration, solutions may have a number of components, any of which may fail during space flight or upon exposure to deep space radiation. For example, in addition to the vehicle which may be water, hydroalcoholic mixtures or sweetened aqueous vehicles, and the dissolved solute, solutions may contain myriad excipients and adjuncts such as (1) chemical stabilizers, the most common of which are antioxidants and reducing agents; (2) flavors such as aromatic waters, licorice liquid extract, lemon spirit, orange syrup, and glycerol, among others; and (3) preservatives such as chloroform or benzoic acid (Carter 2008). The Medical Use of Pharmaceutical Solutions The diversity of the available pharmaceutical adjuncts underlines the ubiquitous nature of their use in the formulation of liquid dosage forms such as solutions and

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suspensions. Medicated solutions may be for (1) oral use such as mouthwashes or (2) instillation into body cavities such as douches, enemas, ear drops, and nasal drops.

The Effect of Space on the Stability of Solutions A variety of factors can affect liquid dosage forms in space. Although suspensions and emulsions are considered as more complex liquid dosage forms and therefore are more prone to physical and chemical degradation, solutions are not entirely free from the deleterious effects of space travel. Mechanism of Space-Based Degradation of Pharmaceutical Solutions Radiation-induced Free Radical Formation in Aqueous Solutions. Interestingly, it is assumed that the most common reason for the possible degradation of solutions in space is exposure to radiation due to heavy charged particles such as those comprising the galactic cosmic rays (GCRs), which result in the formation of free radicals from the excipients present in the pharmaceutical solutions. Not only has direct radiation been postulated as a source for such free radical formation, a variety of other radiation exposures such as the off-nominal source of charged particle radiation due to solar-powered events (SPE) where particles are ejected from the surface of the sun may also be involved. As space missions evolve from Lower Earth Orbit (LEO) to interplanetary missions and deep space exploration, exposure of the intravehicular space to radiation is expected to further increase. Thus, radiation-induced free radical formation in aqueous media constitutes an important mechanism for the degradation of many pharmaceutical solutions (Blue et al. 2019). For example, Daniels et al. demonstrated that exposure of different pharmaceuticals to 0.1 to 50 Gy doses of protons or iron monoenergetic beams caused a dose-related degradation of the active pharmaceutical ingredient (API) clavulanate and promethazine. Although the authors noted that, even in deep space and on prolonged exposure to radiation, the dose may not be as significantly high as in their experiment, their work provided empirical data to support the hypothesis of radiation-dependent loss in drug potency due to its chemical degradation (Daniels et al. 2018). In addition to direct degradation of active pharmaceutical ingredients or pharmaceutical excipients, radiation exposure may also result in local changes to the pH of the solution which may result in the breakdown of the solute or other chemical agents used in the formulation (Wotring 2012). This is particularly important since most drugs in use today are either weak acids or bases and are very sensitive to pH changes. Alterations in the pH of the environment may not only affect shortand long-term stability of the drug but may also affect the ionization of the weak acid or weak basic drug, which in turn may change the drug bioavailability, affecting the pharmacokinetics and pharmacodynamics of the drug in the human body. An interesting strategy for manufacturing some pharmaceutical solutions depends on the phenomenon known as co-solvency. Used for solutes that have limited or ameliorated solubility in the vehicle of choice, co-solvency works

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by dissolving solutes in the solvent in which they are soluble, provided that subsequently these miscible solvents are mixed together to produce the final pharmaceutical solution. Ethanol, sorbitol, glycerin, and a variety of polyethylene glycol polymers may be used as vehicles for co-solvency. Interestingly, for pharmaceutical solutions prepared by this approach, both direct and indirect radiations constitute prominent sources of product degradation. This is because radiation has been shown to cause cross-linking of some polymeric systems, which changes the chemical and physical structure of the pharmaceutical formulation, and may induce insolubility (Hasanain et al. 2014).

Pharmaceutical Suspensions Suspensions are liquid dosage formulations that are considered to be heterogeneous systems containing a “dispersed phase” and a “dispersion medium.” In the case of solid or particulate suspensions in aqueous systems, the solid or the particulate material is considered to be the dispersed phase, while the solvent, more appropriately the medium or the vehicle, is considered to be the dispersion medium. Thus, the dispersion medium forms a continuous channel in which the discontinuous medium is dispersed. The chief characteristic that distinguishes a suspension from the solutions described above is its particle size. Typically, most pharmaceutical suspensions have particle sizes where the diameter of the particulate matter exceeds 0.5 μm. Although suspensions with a considerably smaller particle size are also used in pharmacy and medicine, these may fall closer to being colloidal dispersions than suspensions (Martin 1961). Particle size is an important determinant of a suspension’s stability, particle interaction, and therefore its bioavailability and pharmacological potency. As is well-known, the main difference between pharmaceutical suspensions and solutions is that suspensions tend to “settle” over time due to the effects of gravity on earth, while solutions, being of molecular particle size, remain true to form. This settling-down behavior is anticipated for suspensions on earth, and therefore during their manufacture, a variety of excipients are added, and careful physical consideration is expended in their formulation. This is further explained below in the section on the physical and chemical properties of suspensions. Interestingly, altered gravity may have important implications for various physical properties of suspensions, including but not limited to settling, stability, interparticle interaction, flow properties, and viscosity.

Types of Pharmaceutical Suspensions Theoretically, a variety of physical states may be mixed to produce suspensions. The most familiar home product, of course, is where the dispersed phase is a solid and the dispersion medium is a liquid vehicle. However, for pharmaceutical products, solid/solid and solid/air dispersions are not uncommon. Interestingly, aerosols and foams are also included under suspensions.

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Physical and Chemical Characteristics of Pharmaceutical Suspensions A. Surface Tension and Indiffusible Solids. It is a significant fact that many APIs exhibit high surface tension in aqueous media. This may be both a blessing and a curse – it may be helpful in preventing the particles from interacting among themselves and clumping and precipitating as is common for many suspension systems. However, on the other hand, high surface tension and interface energy may cause the particles to become unevenly distributed in the suspension, such that random sampling of any part of a suspension may yield heterogeneous doses of the API. This is obviously a significant challenge. Table 1 provides examples of well-known APIs that may present diffusibility challenges. A common solution to overcome this issue is the addition of “thickening agents” to the suspension which will increase its viscosity. The increase in viscosity impedes settling and prevents the breakdown of suspension systems. Table 2 lists common thickening agents that may be used during the formulation of suspensions. B. Wettability. For aqueous pharmaceutical suspensions, the first step in manufacture or compounding invariably involves wetting the solid with the vehicle. This may not be as easy as it sounds since a plethora of pharmaceutical excipients and APIs are hydrophobic in nature. Thus, the formulation of pharmaceutical suspensions may include the use of a variety of wetting agents such as alcohol in tragacanth mucilage, glycerin, and glycols in sodium alginate, and for oral and parenteral (not given by the oral route) suspensions, surfactants known as polysorbates. It is important to consider that although these wetting agents may be Table 1 Examples of APIs that exhibit high surface tension in aqueous media Internal Use Suspension Aspirin Phenobarbitone Succinylsulphathiazole Sulphadimidine

External Use Suspension Hydrocortisone Triamcinolone acetonide Precipitated sulfur Zinc oxide

Adapted from Carter 2008

Table 2 Examples of thickening agents used in the formulation of suspensions to increase viscosity and impede sedimentation Polysaccharides Acacia Tragacanth Starch Sodium alginate Methylcellulose Hydroxyethylcellulose Carboxymethylcellulose Microcrystalline cellulose Adapted from Carter 2008

Inorganic agents Bentonite Aluminum-magnesium Silicate Hectorite Aluminum hydroxide

Synthetic agents Carboxyvinyl polymer Colloidal silicon dioxide

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present in the suspension in limited amounts, exposure to radiation and/or the effect of microgravity has not been extensively examined, raising the possibility of the breakdown of the suspension system because of possible shift in the interparticle interaction if such agents are reduced or their effect is lost. C. Sedimentation, Stokes’ Formula, and Caking. The formulation stability of suspensions depends on a variety of factors, prime among which is particle size and the interaction among those particles. Sedimentation in suspensions is well documented and expected, with the particle size related to the degree of sedimentation over time. In general, smaller particles tend to sediment into compact layers called cakes that are difficult to resuspend. On the other hand, coarser particles form loser assemblies upon sedimentation due in large part to the type of compaction occurring. These layers may be easier to resuspend, which can be achieved through simply shaking the container, leading to the famous “shake well before use” label. Stokes’ law governs the rate of sedimentation for a dilute suspension comprising of uniform, nearly spherical particles that settle in the absence of turbulence.
g  ρp  ρw  d 2 vs ¼ 18  μ where vs ¼ particle settling velocity, m∙s-1, g ¼ acceleration due to gravity, 9.81 m∙s2, ρp ¼ density of the particle, kg∙m3, ρw ¼ density of the fluid, ~1000.0 kg∙m3 @ 20  C, d ¼ diameter of the particle, m, μ ¼ dynamic viscosity, 1.002  103 Pa∙s (¼ kg∙m1∙s1) @ 20  C Thus, particle size and density are directly proportional, while medium viscosity is inversely proportional to the rate of sedimentation for suspensions. Since overall particle size is determined during the manufacturing process, and parameters such as density are fixed, viscosity becomes the important determinant of suspension stability. There may occur a substantial difference in the viscosity of suspension when compared between the terrestrial and space environments which will affect not only the overall stability of the suspension but also properties such as flow and, as a consequence of the latter, the distribution of the API in the suspension. From the Stokes’ equation, it may be deduced that a reduction in particle size will result in a lower sedimentation rate and therefore greater stability of the suspension. While this is theoretically true, as the particle size is reduced and very fine particles are used to make suspensions, these small particles tend to settle slowly, but once they settle, they form a hard cake at the bottom of the vessel. This cake is usually challenging to resuspend by shaking the container, and even if resuspended, the new particle size after shaking may result in loss of

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API uniformity in the suspension. Thus, caking should be generally prevented. One strategy to achieve this goal is explained in the section on flocculation below. D. Particle Charge, Nernst Potential, and Zeta Potential. For most suspensions, the development of charge on the particles occurs through an interesting process. Many solid particles used for the formation of suspensions may be hydrophobic and electroneutral. However, in aqueous vehicles, the dipolar nature of water allows the adsorption of ions on the surface of the particles. This creates an electric charge on the particles. There may also be ionic substances in the suspension that cause the particle surface to become charged. This is interesting because such anionic (negative) surface charge distribution results in an accumulation of cationic charges around the negatively charged particles. In essence, the particles in the suspension acquire a “double coat” of charge. This is called the “Stern layer.” The potential difference between the surface charge and the electrically neutral bulk is called the Nernst potential. The potential difference between the Stern layer and the bulk is called the electrokinetic or zeta potential. The zeta potential influences the stability of the suspension such that the reduction in zeta potential causes a decrease in electrostatic repulsion of the particles, enhancing their attraction and coalescence. The primary forces responsible for the increased interparticle interaction are the van der Waals forces, which at low zeta potentials overcome the potential energy of the repulsion of the particles allowing particle coalescence. Coalesced particles may sediment with greater ease, breaking down the suspension system. E. Flocculation, Deflocculation, and Related Excipients. Flocculation is a phenomenon that results in the formation of loose aggregates of particles in suspensions. Typically, when the zeta potential is high, the particles in a suspension remain separate and suspended for a long time due to the forces of repulsion. However, changes, such as the addition of electrolytes to the suspension, can destroy the zeta potential allowing the particles to loosely aggregate in flocs. Flocculated suspensions show rapid sedimentation but form loose cakes that can be resuspended by shaking. On the other hand, although deflocculated suspensions settle slowly and are more stable over time, the sedimented cakes are more compact and harder to resuspend. Flocculation may be managed in such a way as to allow a certain amount of it to occur. This can be achieved by (1) particle size manipulation, (2) adjustments to the viscosity of the dispersion medium, and (3) the use of flocculating agents. Table 3 lists some examples of flocculating agents used in the preparation of pharmaceutical suspensions.

The Medical Use of Pharmaceutical Suspensions In general, suspensions are useful for a variety of purposes. Being a liquid dosage form, oral suspensions may be preferable for use in the very young (infants and children) and the geriatric population when compared to solid dosage forms such as tablets and capsules. In the context of space missions, some adults may find tablets and capsules less palatable than suspensions. Further, suspension formulation may mask the bitter or unpleasant taste of the APIs or the excipients. Suspensions

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Table 3 Examples of flocculating agents used to stabilize pharmaceutical suspensions Electrolytes Acacia Tragacanth Starch Sodium alginate Methylcellulose Hydroxyethylcellulose Carboxymethylcellulose Microcrystalline cellulose

Surfactants Bentonite Aluminum-magnesium Silicate Hectorite Aluminum hydroxide

Polymers Carboxyvinyl polymer Colloidal silicon dioxide

may also improve the shelf life of products that contain APIs that are chemically unstable. The use of pharmaceutical suspensions in medicine is widespread. There are oral, rectal, and sustained release suspensions and dry powders that need to be suspended in the vehicle through extemporaneous compounding. Common subcategories of oral suspensions include antacids, anthelmintics (remove flatworms), antibiotic and non-antibiotic antibacterials, antidiarrheal, antifungal, antiprotozoal, antipsychotic, sedative, antiemetic, diuretic, psychotropic, and nonsteroidal antiinflammatory suspensions, to name a few. Thus, as can be gleaned from this extensive list, a variety of human diseases are treated by the administration of suspensions. Such ubiquitous use of suspensions makes it imperative to consider the effect of short-term and long-term exposure to space flight conditions because it is plausible to assume that at least some drugs in the space-flight arsenal will be provided in the suspension form.

The Effect of Space on the Stability of Suspensions There are many special formulation requirements for suspensions, complicated by the use of a whole host of different agents used for stabilizing and extending the shelf life of pharmaceutical suspensions. Since suspensions are composed of multiple phases, such as the dispersed phase and the dispersion medium, the absence of gravity may affect a variety of physical characteristics including fluid flow and dynamics, which generally translates to rheology for suspensions, especially in consideration of fluid flow in specialized containers such as pipes and other contained environments. Other associated and relevant fluid phenomena include phase separation, microdynamics due to local effects, aggregation and coalescence behaviors of multiphase fluid mixtures, and interfacial and surface tension considerations, especially where particulate solutes are dispersed in aqueous dispersion media as would be the case for most of the pharmaceutical suspensions. Furthermore, in the context of pharmaceutical suspension formulations, interfacial tension will be a consideration of primacy and includes physical phenomena such as wettability and capillary-driven fluid flows in addition to aggregation and

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coalescence. These forces may be significantly altered in a microgravity environment. A detailed discussion of the underlying physics for most of these phenomena is beyond the scope of this chapter, but a brief introduction and interpretation for pharmaceutical systems are presented in the last section of this chapter. Thus, exposure to microgravity, Low Earth Orbit, deep space, or the ISS may lead to a variety of changes that incrementally increase the possibility of a breakdown of the suspension. Keeping this in mind, NASA has continued to invest in a variety of groundbreaking studies that test the properties and behaviors of liquid mixtures that contain miscible and immiscible phases or dispersed phases. Over the years, such experiments have undergone a series of expansions that have yielded robust and meaningful partnerships between pharmaceutical companies, avant-garde material science researchers, and chemical and physical engineers to identify and resolve the complex issues associated with suspension formulation. For example, in 2019, NASA continued its Advanced Colloids Experiment (ACE) laboratory aboard the ISS, a multi-organization partnership between NASA, the ISS National Laboratory, Harvard University, Case Western Research and ZIN Technologies, and the pharmaceutical giant, P&G. The ACE laboratory is invested in examining the effect of the microgravity environment on liquid, mostly pharmaceutical formulations such as phase mixtures and suspensions. In 2019, ACE conducted experiments to test the influence of microgravity in six distinct areas related to phasic mixtures and suspensions, as outlined in Table 4. Table 4 NASA’s Advanced Colloids Experiment (ACE) laboratory examines the effect of microgravity on phase mixtures and suspensions ACE laboratory ACE-M-1

ACE-M-2 ACE-M-3

ACE-T-1

ACE-T-6

ACE-T-7

Name Advanced Colloids Experiment-Microscopy-1 Advanced Colloids Experiment-Microscopy-2 Advanced Colloids Experiment-Microscopy-3 Advanced Colloids Experiment-Temperature Control-1 Advanced Colloids Experiment-Temperature Control-1 Advanced Colloids Experiment-Temperature Control-1

Experimental approach Behavior of microscopic particles in liquids, gels, and creams, including keeping stabilizers from clumping and sinking Phase separation of liquids and gases in microgravity Design and self-assembly of complex 3-D structures from small particles suspended within a fluid medium Fundamental behaviors of colloids, including selfassembly in space temperature Microscopic behavior of colloids in gels and creams, including those with varied particle size, in space temperature Continued investigation of design and selfassembly of complex 3-D colloid structures

Adapted from International Space Station Benefits for Humanity, 3rd ed. 2020

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Some of the experiments included in the above series are directly relevant to the dissection and delineation of the specific physical phenomena and underlying physics applicable to multiphase fluid systems such as pharmaceutical suspensions.

Liquid Dosage Forms and Space Travel: Overall Considerations Fluids and Microgravity Influence on Physical Systems A deeper understanding of how liquid formulations such as pharmaceutical solutions and suspensions may be affected by space comes from examining the physics of fluid dynamics and phase mixtures in the absence of gravity. This consideration is important since gravity is an all-encompassing force that influences many properties of pharmaceutical solutions and suspensions and significant deviations in fluid dynamics in its absence can adversely affect multiple liquid formulation characteristics. From this perspective, perhaps the most significant difference between terrestrial and space fluid physics may be the differences in the applicable physics. For liquid formulations, this implies effects on fluid flow and fluid dynamics, viscosity, and homogeneity. An intriguing instance of the application of space-related differences in fluid behavior is that in the absence of gravity, some properties related to multiphasic mixtures may become enhanced. One such property is crystal growth in fluids that may be augmented by the microgravity environment such as that exists aboard the ISS. An interesting application of this phenomenon can be found in the 2019 NASA publication, International Space Station Benefits for Humanity, 3rd edition, in which mention is made regarding a study of enhanced crystal growth in fluids in the space environment for the creation of advanced, high-quality crystalline suspensions of antibodies. Antibody drugs are the mainstay of modern chemotherapy for the treatment of many aggressive cancers. Typically, antibodies are challenging to manufacture in solution form due to insolubility. Currently available antibody formulations have to be administered to patients in slow infusions. But the ideal formulation for cancer patients would be injectables. To overcome the challenges in manufacturing antibody solutions and suspensions, scientists from Merck conducted a study aboard the ISS where they investigated crystal formation in antibody solutions in the microgravity environment and showed that microgravity allows the creation of high-quality, concentrated but uniform antibody solutions. In the following sections, we describe some of the techniques and experiments conducted in space (Including Shuttle and Station, ISS) relating to fluids and crystal growth (International Space Station Benefits for Humanity, 3rd ed. 2020).

Pharmaceutical Product Stability and Shelf Life Interestingly, in their report to NASA, Jaworske and Myers suggested that solid and semisolid dosage forms were much more stable in space than most liquid dosage forms (Jaworske and Myers, 2016). In 2006, the US Food and Drug Administration

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published the now-famous Shelf Life Extension Program (SLEP) study to investigate the extent to which active pharmaceutical ingredients (APIs) remained active and usable beyond their labeled expiry dates. This was of interest to NASA since many pharmaceutical formulations need to be provided to the International Space Station (ISS) or to Low Earth Orbit vehicle missions. In fact, projecting into the future, similar formulations will most likely be included in missions to Mars. The SLEP study examined 122 pharmaceutical products for stability beyond the labeled expiry dates to explore whether the actual shelf life of these products varied from the manufacturer-indicated dates. Performance cutoff was established at 90%, which is the typical pharmacopeia-stated requirement during stability testing for most APIs. This meant that if the API was found to be degraded to less than 90%, the product would fail the test. Importantly, the SLEP study found that 88% of the pharmaceutical products tested could be used well beyond the labeled expiry dates since the APIs remained usable and not much degradation was noticed. This is important because extended shelf life may be a cost-effective mechanism for enhancing the continued availability of some formulations, especially liquid dosage forms that may be less stable when compared to solid dosage formulations. The SLEP study is also of significance to pharmacopeias and pharmaceutical manufacturers in the context of accelerated stability testing to determine the shelf life of pharmaceutical products. Although the SLEP study identified specific formulations that retain potency and avoid product degradation beyond the currently established expiry dates, it was a terrestrial study that examined pharmaceutical products on earth. Thus, the effect of space was missing. Since short- and long-term space missions may require the storage and use of pharmaceutical products beyond their expiry dates since it will be difficult to have a line for continuous supply, Du et al. employed an intriguing approach to compare product stability of pharmaceutical compounds and drugs on earth and in space. Their experimental design addressed the important question of whether there were differences in the stability of drug products in their original packaging in a series of increasing space exposure. Du et al. included 33 drugs in their original packaging, where the controls were kept in a terrestrial environment and the samples that were identical to the controls were flown and transported on the space shuttle to the International Space Station (ISS). Once at the ISS, the pharmaceutical compounds were kept for an increased duration of time, anywhere from 13 days to 2.5 years, before being returned to earth. Subsequently, comparisons were drawn between the terrestrial and space-exposed pharmaceutical formulations. This case study was made relevant and interesting by the inclusion of drugs in a variety of formulations. For instance, the authors included 22 solid dosage forms and 7 semisolid and 4 liquid dosage formulations in their study. These drugs were delivered to the ISS in four “payloads.” Table 5 below summarizes the number of pharmaceutical products that showed changes in their physical and chemical characteristics. The authors hypothesized a variety of reasons for the changes in the physical and chemical properties of the pharmaceutical formulations. Some physical and chemical changes also occurred in the earth controls, especially for the long-range time points. However, the space samples were, in general, more altered.

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Table 5 Characterization of the changes in physical and chemical properties of pharmaceutical formulations compared between terrestrial and space exposure Payload 1 2 3 4

Number of formulations showing physical change 0 7 6 6

Number of formulations showing loss of chemical potency 2 11 17 24

The most common physical change included discoloration of the liquid formulations, which may affect their cosmetic appeal and therefore patient compliance. It was assumed that the chemical degradation of the products may have been a consequence of space radiation. In fact, the authors surmised that if this were so, the problem would be a significant challenge for deep space travel such as the futuristic human exploration missions to Mars. The proposed physics behind the radiation-induced chemical degradation was considered to be the relevant lack of shielding from radiation as the distance from the earth’s magnetic field increased, which would be negligible in deep space. To protect pharmaceutical products from radiation-induced degradation, researchers have proposed a number of approaches. Some examples include the use of multiple shielding containers and devices, such as water-filled shielding solutions.

Physical Factors Affecting Phenomena Associated with Pharmaceutical Solutions and Suspensions The development of the field of study of applications for complex fluid dynamics and physics through empirical studies at NASA could probably be divided into two historical stages. Starting in 1991, with the establishment of the NASA Research Announcement and the fluid physics program, NASA became heavily invested in investigating the physics of fluids in space and microgravity environments. However, up until the first decade of the twenty-first century, resources were primarily allocated to investigating the properties of propellent fluids, which was plausible cause. However, gradually a number of studies have been added where different types of multiphase liquids have been examined in microgravity environments to delineate the specific forces and physics involved. Many of these discoveries find direct and ready application to pharmaceutical liquid dosage forms such as suspensions, emulsions, and specialty formulations. A deeper understanding of the physics governing the manufacture, transport, stability, and shelf life of pharmaceutical biphasic and multiphase fluid systems when compared in terrestrial and microgravity environments will facilitate the development of the much-needed field of specialization in pharmaceutical technology for space and space-related efforts.

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Multiphase flow dynamics and heat transfer are two important areas of active research that impact multiple areas of need for any space program. The physics and mathematics of complex fluids that include multiphase fluid systems such as the two-component pharmaceutical suspensions started garnering attention in the first two decades of the current century. For example, many areas of complex fluid physics that directly or indirectly affect multiphase fluid dynamics, including (1) miscible and immiscible interface dynamics, (2) droplet dynamics, (3) bubbly flows, (4) phase separation, and (5) atomization such as would occur in specialized suspensions such as aerosols, foams, and sprays, and other multiphase fluid systems needed a qualitative and quantitative exploratory and mechanistic comparison between the ground and space environments. Similarly, heat transfer is important during fluid flow in containers especially when considering the differences in streamline versus turbulent flow and may impact the (1) viscosity of the suspension, (2) the local distribution of the suspended drug, and (3) other stability parameters by affecting physical features such as shear forces for suspensions and other fluid mixtures exhibiting rheology and memory flow. More attention is needed for understanding the mechanisms and mathematics of heat transfer for multiphase systems exposed to different earth and space environments.

Conclusion The first 20 years of the current century have witnessed a concerted effort to better our understanding of complex fluid systems in space and microgravity environments. This is especially significant for delineating the effect of space on the physical and chemical properties, stability and shelf life, and bioavailability and efficacy of liquid dosage pharmaceutical formulations that are considered to be less stable than their solid dosage counterparts. Nevertheless, more research is needed to fully characterize the effect of space on liquid formulations.

References Blue RS, Chancellor JC, Antonsen et al (2019) Limitations in predicting radiation-induced pharmaceutical instability during long-duration spaceflight. NPJ Microgravity 5:15. https://doi.org/ 10.1038/s41526-019-0076-1 Carter SJ (2008) Cooper and Gunn’s Dispensing for Pharmaceutical Students, 12th edn. CBS Publishers & Distributors, Delhi, India Daniels V, Bayuse T, McGuire K, Antonsen E, Putcha L (2018) Radiation impact on pharmaceutical stability: retrospective data review. Tech. Report No. 09940. Proceedings of the NASA Human Research Program Investigator Workshop Hasanain F, Guenther K, Mullett W, Craven E (2014) Gamma sterilization of pharmaceuticals–a review of the irradiation of excipients, active pharmaceutical ingredients, and final drug formulations. PDA J Pharm Sci Technol 68:113–137

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International Space Station Benefits for Humanity, 3rd ed. Available on the Internet at https://www. nasa.gov/sites/default/files/atoms/files/benefits-for-humanity_third.pdf. Last accessed 15 Jan 2020 Jaworske DA, Myers JG (2016) NASA/TM – 2016-218949. Available on the Internet at https://ntrs. nasa.gov/archive/nasa/casi.ntrs.nasa.gov/20160003684.pdf. Last accessed 15 Jan 2020 Martin AN (1961) Physical-chemical approach to the formulation of pharmaceutical suspensions. J Pharm Sci 50:513–517 Wotring V (2012) Space pharmacology. Springer: International Space University, New York

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Nano Drug Delivery Systems for Space Applications Jayvadan Patel and Anita Patel

Contents Biopharmaceutical Challenges of Therapeutics in Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Necessity for Nanoparticle-Based Drug Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nanotechnology Approach for Space Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Innovative Means for Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Constant Drug Delivery Nanotechnologies for Space Exploration . . . . . . . . . . . . . . . . . . . . . . . . . . . . Applications of Nano-Gland for Space Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bionano Scaffolds (BNS) as a Space Nanomedicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nanomedical Devices for Loss of Bone Density and Mass Under Microgravity . . . . . . . . . . . . . . Carbon Nanotubes for Cardiac Function and Muscle Atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dendrimeric Nanodevice for Detection of Cellular Damage in Astronauts . . . . . . . . . . . . . . . . . . . Targeted Nanoparticles to Alleviate Microgravity-Induced Ocular Anomalies . . . . . . . . . . . . . . . . Polymeric Nanofiber Scaffolds to Prevent or Counteract the Deleterious Effects of Microgravity on the Brain and DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Quantum Dots for Diagnostic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Grapheme-Based Nanocomposites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gold Nanoparticles for Biomedical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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J. Patel (*) Nootan Pharmacy College, Faculty of Pharmacy, Sankalchand Patel University, Visnagar, Gujarat, India e-mail: [email protected] A. Patel Faculty of Pharmacy, Sankalchand Patel Vidyadham, Sankalchand Patel University, Visnagar, Gujarat, India e-mail: [email protected] © Springer Nature Switzerland AG 2022 Y. V. Pathak et al. (eds.), Handbook of Space Pharmaceuticals, https://doi.org/10.1007/978-3-030-05526-4_18

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Abstract

From the outset of the space epoch, the expansion of new technologies most suitable for habitat and adaptation in extreme habitats has equally helped life on Earth. For long-duration space journey, ionizing linear energy transfer radiation is one of the most noteworthy defies that can lead to probably severe illness. As well, the microgravity has been found to cause bone loss in addition to muscle atrophy, whereas the loss of regular day/night cycles in space can unhelpfully impact the body’s circadian rhythms, inducing sleep loss and related decline in mental along with physical performance. Though challenging to the human body, the constant microgravity of space also offers a sole ecological condition that can therefore be browbeaten, by nanotechnology and regenerative medical approaches, for the analysis of pathologies and tissue regeneration. As such, one can learn the progress of targeted drugs and vaccines or else of molecular transport properties as well as drug delivery vehicles through fluids and cells. Novel means for drug delivery and nanoscale screening tools will soon help astronauts projecting to Mars and places beyond, whereas the space laboratory will promote progresses in nanotechnologies for diagnostic and therapeutic tools to assist our patients here on Earth. In this chapter we try to emphasize key areas of ongoing and future exploration of nanotechnologies and chosen regenerative medical approaches that will help equally space and earthly medicine. These studies target important areas of human ailment such as osteoporosis, diabetes, radiation injury, and many others. Keywords

Nanotechnology · Microgravity · Space medicine · Diagnostic testing

Biopharmaceutical Challenges of Therapeutics in Space When in space, astronauts live and work in an antagonistic environment that consists of microgravity (μG), cosmic radiation, confinement, and isolation. The intense nature of the space environment has been found to unfavorably influence the mental and behavioral health of individuals in space. During their first few days in space, astronauts experience conditions, for example, fluid shift, space motion sickness, and sensory deprivation. As the increasing length of the stay, astronauts’ health risks turn out to be more prominent. The physiological risks include bone mass loss resultant from calcium loss, compromised immune system, disruption of biological rhythms, muscle atrophy, and longer exposure to space radiation. For the duration of past five decades of human spaceflight, probable illnesses and astronaut health troubles often brought about by physiological changes during missions have been recognized and treated. The Gemini flight experiences pointed out that, even though humans could stand exposure to the space environment well, declines in bone mineral density, erythrocyte mass, and plasma volume take place. An added concern was the chance of incidence of a contagious disease that could negatively affect mission victory (Taddeo and Armstrong 2008).

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All medications contained in the flight kits are commercially accessible off-theshelf formulations used for management of diseases on Earth. However, unique physical and environmental factors of space missions, for example, ambient radiation, too much vibration, multigravity, and a CO2-rich environment collective with humidity and temperature differences, may be causative factors to the stability of pharmaceuticals in space. Consideration has recently been turned to the effect of the distinctive environment of low Earth orbit (LEO) on the stability of medications planned for use during space missions, and early warning are that pharmaceutical product degradation may restrict the value of a few medications that are presently packed in onboard pharmaceutical kits (Du et al. 2011; Putcha et al. 2011). It is remarkable that in contrast with causative environmental factors of stability on Earth, outcomes from passive radiation dosimetry express that the cumulative radiation dose, even though at a low level, is much higher in space than on Earth; this radiation fortification in space is composed of ionizing radiation of protons along with heavy ions (Benton and Benton 2001). Investigations of radiation effects on pharmaceuticals on ground are not intended to understand or estimate the effect of fragmentation ions on stability; so, the degree of damage caused by different daughter ions to each class of medications is unidentified. With regard to medications, as well as the concern about radiation effects that can bring momentous alters in the levels of the active pharmaceutical ingredient or efficacy of the medication, it is significant to find out the structure and biological activity of degradation products and set up toxicity restrictions of active degradants in a formulation. These possibly will pretense a greater risk of toxicity than effectiveness regarding the therapeutic index of a formulation degraded in space (Putcha et al. 2011). Clinical conditions recorded during space shuttle flights comprise sensory-motor disturbances manifesting generally as space motion sickness; this was the most frequent illness, happening in nearly 40% of shuttle crew members, after that digestive system disturbances (9%) and the respiratory or urinary tract infections. During the first 33 US space shuttle missions, a number of medication were taken during flight by 94% of the astronaut with more than 500 individual doses of 31 different medications taken orally (Tietze and Putcha 1994). Of the doses taken by crews during flight, 47% were for space motion sickness, 45% for sleep disturbances, and smaller percentages for backache, headache, and sinus congestion (Putcha et al. 1999). Although most examples of pharmaceutical use by these astronauts indicated that the medications were well tolerated and assumed effectual, about 8% of all treatments during flight were reported as “non-efficacious” (Putcha et al. 1999). Additionally, it is highly expected that changes in human physiology (Baker et al. 2008) and the composition of the microbial flora of human mucosal surfaces, recognized to be influenced by extreme environments including microgravity (Taylor 1974; Nefedov et al. 1971), will have an effect on therapeutic effectiveness by influencing absorption, distribution, metabolism, and elimination of medications in space. Microbial infections pretense a sensible risk during and after LEO missions, but this risk is liable to increase considerably on exploration space missions. Microbes from the commensular flora of the astronaut will unavoidably colonize the spacecraft; microbial contamination from onboard cultivation of plants as a source of food

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or else a part of a bio-regenerative life-support system will also add to the complexity of the microbial population within the closed environment of the spacecraft (Taylor and Rosado 2007). Flight-induced changes in the commensular bacterial flora of the astronaut and the increased chances of scratches and open fractures necessitate prophylactic administration of antibiotics, and the depressing impact of space travel on immune function will provide likelihoods for microbes to set up foci of infection (Ball and Evans 2001). It is so extremely expected that long-duration space missions will result in a noteworthy increase in usage of anti-infective agents in comparison to LEO missions. Space agencies are working strongly to shove the present boundaries of human spaceflight by sending astronauts deeper into space than ever before, counting missions to Mars and asteroids. Spaceflight changes human physiology because of fluid shifts, immune system dysregulation, muscle and bone loss, and alterations in the gastrointestinal tract and metabolic enzymes. These changes may alter the pharmacokinetics and/or pharmacodynamics of medications used by astronauts to treat sleep disturbances, allergies, space motion sickness, pain, and sinus congestion and afterward might impact drug efficiency and safety. These medications are administered under the assumption that they perform in a similar manner as on Earth, an assumption that has not been examined scientifically up till now. Additionally to pharmacokinetic/pharmacodynamic alterations, reduced drug and formulation stability in space could also influence efficiency and safety of medications. These changes together with physiological changes and their resultant pharmacokinetic and pharmacodynamic effects must be considered to find out their final impact on medication efficacy and safety during spaceflight (Kast et al. 2017).

Necessity for Nanoparticle-Based Drug Formulations There are a range of reasons why using nanoparticles for therapeutic and diagnostic agents, as well as advancement of drug delivery, is imperative and much desirable. One of them is that, conventional drugs available currently for oral or injectable administration are not always manufactured as the best formulation for each product. Products holding proteins or nucleic acids need a more innovative type of carrier system to increase their effectiveness and protect them from unwanted degradation (Vo et al. 2012). It is remarkable that the competence of most drug delivery systems is directly related to particle size (excluding intravenous and solution). Owing to their tiny size and large surface area, drug nanoparticles show enhanced solubility and as a result enhanced bioavailability, added aptitude to cross the blood-brain barrier (BBB), enter the pulmonary system, and be absorbed through the tight junctions of endothelial cells of the skin (Kohane 2007). Distinctively, nanoparticles made from natural and synthetic polymers (biodegradable and non-biodegradable) have gained more concentration as they can be personalized for targeted delivery of drugs, improve bioavailability, and offer a controlled release of medication from

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a single dose; through adaptation the system can stop endogenous enzymes from degrading the drug (Zhang and Saltzman 2013). Secondly, the progress of new and innovative drug delivery systems is providing one more benefit for pharmaceutical sales to branch out. Though these new formulations will be valuable to the patients, it will also make an influential market force, driving the development of even more successful delivery methods (Emerich and Thanos 2007).

Nanotechnology Approach for Space Medicine Microgravity imparts manifold harmful effects on human physiology, which must be resolved as a requirement for enabling humans to engage in extended space expeditions. An outline of these negative impacts on a variety of physiological systems is listed in Table 1. Nanomedicine might have the capability to prevent or offset the effects of microgravity (e.g., bone loss, detrimental ocular conditions, neurological damage, and soft tissue degradation), to facilitate humans to undergo prolonged missions to Mars and beyond, and to further reaches of deep space (Blaber et al. 2010). Alternatives to standard oral formulations that comprise sustained and targeted delivery technologies for defensive healthcare in space will be a welcome addition to the space formulary and may well comprise controlled-release topical, subcutaneous, inhalation, and intranasal dosage forms. Leveraging operational needs of NASA for space exploration by partnership with the marketable space industry, the Department of Defense and pharmaceutical vendors can make easy productive growth of novel pharmaceuticals that will improve chronic clinical care capacities. The use of nanotechnology, a discipline in which biological, chemical, and physical phenomenon are studied and manipulated at the molecular scale (i.e., nanoscale systems) headed for the development of medical diagnostic as well as therapeutic Table 1 Physiological impacts of microgravity (Blaber et al. 2010) System Musculoskeletal system Cardiovascular system Sensory motor system Immune system

Wound healing

Microgravity impact Decreased bone formation; increased bone resorption; decreased bone mass; decreased muscle mass; decreased functional capacity; increased muscle fatigue; postflight muscle necrosis Reduced heart rate; reduced diastolic pressure; cardiac dysrhythmias; Headword fluid redistribution; decreased plasma volume; postflight hypovolemia; postflight postural hypotension Deconditioning of posture and gait control; deconditioning of motion sensors; deconditioning of somatosensory system; altered perception of orientation; loss of balance Decreased number of T lymphocytes; decreased response of T lymphocytes to potent activator; reduced cytotoxic activity of natural killer cells; alterations in cytokine/chemokine activity Impaired matrix formation; impaired proliferation and migration of cells into wound; reduced wound collagen content; impaired revascularization; impaired keratinocyte migration

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tools, has enabled fabulous growth in such areas as rational drug design and delivery (Schroeder et al. 2012) and regenerative medicine (Orive et al. 2009). Nanostructures also have the aptitude to guard drugs encapsulated within them from physiologic degradation, target their delivery with sustained release, and moreover are appropriate for oral administration (Ochekpe et al. 2009). The use of polymeric nanoparticles presents a noninvasive strategy for penetrating the BBB for managing cerebrovascular and neurodegenerative disorders and inflammatory diseases (Sarabjeet et al. 2007). Research in space develops the altered gravitational tug found in LEO. There, the simulated and decoupled nano-effects can be at the microscale, as a result conquering the experimental restraints explicit to the nanoscale. In microgravity, micron-sized particles could make up a consistent and controllable substitute for molecules at nanoscale, permitting better considerate of the diffusive transport that manages drug delivery systems. Sustained microgravity will also make available an experimental setting with negligible hydrostatic pressure and mechanical stresses required for the study of bone resorption and progress of nanotechnologies headed for treatment of osteoporosis. Moreover, under these conditions, technologies can be urbanized for the early detection and treatment of kidney stone formation and pathologies associated with augmented levels of reactive oxygen species (ROS) (Grattoni et al. 2012). In the field of nanomedicine, a main focus has centered on the design and execution of drug delivery systems ranging from injectable therapeutics (Ashley et al. 2011; Tasciotti et al. 2008) to implantable, lab-on-a-chip devices (Santini et al. 1999). In this milieu, silicon-based drug delivery systems have been urbanized to present long-term steady (Desai et al. 1999) or else pulsatile (Farra et al. 2012; Prescott et al. 2006) release of therapeutics for the management of pathologies ranging from hepatitis to cancer. Despite these significant accomplishments, additional progress and modification of these and similar technologies necessitate (1) a healthier considerate of the nanofluidics and mass transport phenomenon in microand nanoconfinement within tissues, where attached molecule-surface interactions start to direct the molecular transport, and (2) a more inclusive analysis of cellsignaling mechanisms under unusual environments, for instance, the performance of osteoblasts and osteoprogenitors in nanotechnology-enhanced biological scaffolds under circumstances of microgravity. Finally, nanotechnology offers great potential for the development of safe and efficacious drug-delivery systems for preventive health care in space as well as on Earth.

Innovative Means for Drug Delivery A significant aspect of successful disease prevention and treatment modalities is an effectual and acquiescent drug-dosing regimen for the duration of space travel as here on Earth. At present, drugs are normally administered orally or intravenously through the delivery of a “bolus” that is often linked with a peak plasma drug levels, and drug levels above the therapeutic range may cause mild to severe side effects.

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This “temporary overdose” leads a trough in concentration that is below the effectual therapeutic level and inexorably needs a next “bolus” administration. Accordingly, in an efficient range, these peaks and valleys in drug bioavailability thus subject patients to considerable fluctuations. In this regard, the traditional practice signifies a basic approach to drug delivery, where agents are often ineffectually administered at maximum tolerated doses (Grattoni et al. 2012). These “trial and error” strategies force the need for innovative drug delivery mechanisms, which can either administer drugs at sustained, effectual doses over time or else at time-variable releases in response to the body ad hoc. Several implantable drug delivery devices have been urbanized to preserve precise control over the concentration, release rate, and dosing frequency of pharmaceutical agents (Bansal et al. 2011; Langer 1990). This automatic and conscious delivery presents the extra advantages of improved patient compliance as well as quality of life (Langer 1990). Further very talented progresses consist of microchips that port hundreds of mini-reservoirs, inside, a wide range of drug formulations are rooted within a silicon substrate capped with gold membranes which can be electrically ruptured to release their contents (Santini et al. 1999). These microchip device developed by Prescott et al. (2006) have been effectively demonstrated in vivo in a dog model for up to 6 months. Recently, implantable microchip-based drug delivery device was tested in clinical trials with the remotely controlled, pulsatile delivery of human parathyroid hormone fragments, the only FDA-approved treatment for anabolic osteoporosis (Farra et al. 2012). This technology has obvious potential for applications in extreme environments or emergency care, for example, in war zones as well as space. Restrictions of this otherwise practical design are limited reservoir volume and required augmented pulse frequency for zero-order release approximation. A next generation of implantable drug delivery vehicles was developed to address this downside that are capable to attain long-term, zero-order delivery using a range of actuation methods, counting osmotic pumping, electroosmotic pumping (Bhavaraju et al. 2010; Litster et al. 2010), and passive diffusion through nanofluidic membranes (Martin et al. 2005; Yang et al. 2010). Some of these designs have been established in animal models also (Walczak et al. 2005; Yang et al. 2010).

Constant Drug Delivery Nanotechnologies for Space Exploration Several groups have affianced in the expansion of nanofluidic systems to conquer the aforesaid restrictions, and this body of work has been broadly reviewed in the literature (Grattoni et al. 2010). Yang et al. (2010) developed a self-assembled block copolymer membrane wherein the size of cylindrical nanochannels was regulated by gold deposition. The system allowed for the formation of membranes with 6 nm channels from which a continuous, one-dimensional diffusion of human growth hormone (hGH) and bovine serum albumin was obtained over 3 weeks.

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Fig. 1 Scanning electron microscopy image of a nanochannel membrane surface. (Adapted from Fine et al. 2010)

Even though this design can gain controlled administration of drugs, the mechanical strength of such devices may be restricted and hard to shove toward clinical use. To defeat mechanical strength problems, study conducted over the past two decades focused on the progress of a new class of nanochannel membranes that permit the controlled and sustained release of therapeutic agents from implantable reservoirs (Fine et al. 2010; Martin et al. 2005; Sharma et al. 2006). Sacrificial layer techniques were used to produce silicon devices housing 105 nanochannels that are strongly controlled for size and surface properties (Fine et al. 2010) and geometrically prepared in extremely dense arrays (Fig. 1). Fluids confined in such nanochannels show different properties in contrast to their performance in macroscale (Plecis et al. 2005). Molecular interactions within these confines dominate molecular transport in a way where the classical laws of diffusion (Fick’s laws) no longer precisely envisage performance (Sparreboom et al. 2009). So, innovative theoretical formulations for molecular transport within nanochannels were formulated (Cosentino et al. 2005; Ziemys et al. 2011). Nanochannel membranes, presenting both one-dimensional and two-dimensional channels, make use of nanoscale molecule-to-wall interactions to attain concentrationindependent, continuous, and sustained release of drug molecules and nanoparticles over extended periods of time (weeks to months), and also membranes were shown to be suitable for medical applications (Fine et al. 2010) and flexible for a wide range of molecular sizes by effortless selection of the nanochannel size. The accuracy and specificity of this nanochannel delivery mechanism were established using varied, medically relevant agents: antibiotics, chemotherapeutics, hormones, the anticancer small peptide leuprolide (Grattoni et al. 2011a), and bevacizumab, a humanized monoclonal antibody. Through the constant delivery of interferon α-2b and lysozyme, this technology was established in vivo, in a rat model for over 6 months (Walczak et al. 2005). Especially, the exploit of nanochannel membranes for the controlled delivery of thioaptamers and nanoparticles was authenticated. This sustained release was accomplished by tweaking the ionic strength of solution to persuade electrostatic interactions among the particles and nanochannel wall (Grattoni et al. 2011b). Numerous studies have revealed that dendritic fullerene

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(DF-1) is an effective scavenger of ROS (Daroczi et al. 2006), therefore, one could conceivably use the controlled administration of DF-1 nanoparticles to efficiently compensate the raise in concentration of free radicals from overexposure to linear energy transfer radiation in long-duration interplanetary space exploration as well as for Earthbound radiation workers.

Applications of Nano-Gland for Space Medicine More consistent next-generation, nanoscale sensor technologies should allow the development of integrated biofeedback-based, molecular delivery plus health monitoring systems for use in intense environments. In fact, military special operations and long-duration space exploration missions signify conditions in which real-time identification and instant intervention are important, although admittance to decisive medical infrastructure and resources is inadequate. The extended exposure to microgravity characteristic of protracted spaceflight demands up to 2 h of daily resistance work out to preserve bone density. Nano-Glands capable of personalized regulation of hormone and drug release may ease the call for such an exhaustive exercise routine, in addition to give defense from radiation exposure with the timed release of a suitable radio protective pharmacological agent. It is to be renowned that the term “Nano-Gland” is not a trademark name and relates an implantable drug delivery system that imitates the functions of body glands (Grattoni et al. 2012).

Bionano Scaffolds (BNS) as a Space Nanomedicine BNS, a nanotechnology-enhanced biological scaffolds, have also been created from biodegradable and biocompatible materials proficient of enhancing tissue regeneration, despite of the implantation site within the body or the environmental circumstances (i.e., in the case of bone, with or without outwardly applied loads). Furthermore, nanoporous technologies have been utilized as diagnostic tools to recognize, directly from minute samples, the biological signature(s) of pathologies, for example, cancer at their early onset (Hu et al. 2010). Avoidance or reversal of tissue and bone loss due to age, illness, injury, or environment stays an alarming task for health clinicians and scientists. Such as, extended spaceflight missions in microgravity suppress osteoblast growth, ensuing in up to 19% of trabecular bone loss (Rambaut and Johnson 1979; Nabavi et al. 2011). This type of deregulated loss of bone density, very similar to that observed in patients with osteoporosis here on globe, can direct to a larger tendency for trauma-related fractures as well as intense surgical reconstruction. At present, reconstructive care for injuries that are also destructive for the body to fix unaided entails manifold taxing operations (Buijze et al. 2011; Chim et al. 2011). An idea recognized as facilitated endogenous repair has been established (Evans et al. 2007),

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and it relies on attaching the inherent regenerative prospective of endogenous tissues by applying molecular stimuli to start reparative processes in the body. Concurrently, the exploit of size-matched, biomolecule delivery systems to give out specific agents to the injury site will then carry on to endorse and preserve normal physiology. Enhancing growth factors or biomolecules delivery specifically to their active sites could possibly reverse or even avert the ailing effects of space travel and the devastate of disease or injury in patients on Earth. For any polymeric multicomponent systems, biocompatibility and in vivo osteoid formation are foremost distresses (Lanza et al. 2007); hence Tasciotti and co-workers reviewed these features by injecting the fracture putty into subcutaneous pockets in rats (Tasciotti et al. 2008, 2011). After 4 weeks, momentous vascularization was obvious to the unaided eye, whereas histology revealed vessel and osteoid formation around the porogens, succeeding in vivo testing demonstrated osteoid formation able to repair critically sized, long bone defects in rats. Papadimitropoulos et al. (2007) established the ingrowth of bone marrow stromal cells after 4 months of implantation using porous calcium phosphate. Altogether, these nanocomposite polymers comprise a vibrant system for cellular encapsulation, preservation, proliferation, and drug delivery with vast competence for extensive use in space nanomedicine.

Nanomedical Devices for Loss of Bone Density and Mass Under Microgravity Bone comprises of 60–65% calcium hydroxyapatite (Ca10(PO4)6(OH)2), chondroitin sulfate, collagen, and keratan sulfate lipids. Bisphosphonate drugs are used as therapeutics for osteoporosis and other bone problems owing to their affinity with bone matrices. More, fluoride is the only substances with the capability for the generation of new bone matrices along with mineral at inactive sites. The biggest problem with bisphosphonates, when administered orally is not efficiently taken up in the gastrointestinal tract, and fluoride in general given orally as sodium fluoride results in toxicity. To boost the bioavailability, safety, and efficiency of existing therapeutics for repairing bones of humans concerned in space, nanometric delivery reservoir might be engineered. Nanomedical devices may be used in the avoidance and alleviation of bone loss and, if required, for the episodic rebuilding of bone mass (Boehm 2013). The application of a voltage to the needle of a syringe, involves in electrospinning, dispensing a polymer melt onto a plate-like, or else rotating drum electrode in the manufacture of nanofibers, may be utilized to generate distinctive scaffolds. Shao et al. (2011) conducted studies into electrospun electrically conductive polymeric nanofibers infused with multi-walled carbon nanotubes and nanoscale topological features to explain their usefulness in assisting the growth and proliferation of osteoblasts. In comparison to randomly organized nanofibers, it was found that lined-up nanofibers improved the elongation and orientation of osteoblasts. It was observed by Badami et al. (2006), following to an study of MC3T3-E1 cells (mouse osteoblastic cell line) on electrospun poly(lactic acid) and poly(ethylene glycol)-poly

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(lactic acid) diblock copolymers that topographical factors planned into biomaterial scaffolds can control spreading, orientation, as well as proliferation of osteoblastic cells. More examinations have used nanoscale surface topologies encircling grooves, pits, ridges, and pillars, toward the added clarification of their impacts on performances of cells (Flemming et al. 1999; Curtis and Wilkinson 1997; Rutledge and Jabbarzadeh 2014; Klymov et al. 2016). Under microgravity together with exposure to ionizing radiation, the protection of bone mass, density, and strength will be crucial for astronauts because from the calcaneus, femur neck, tibia, trochanter, spine, and pelvis bone mass losses found to be 1%–1.6% per month and from the legs and overall body bone mass losses found to be 0.3%–0.4% per month (LeBlanc et al. 1998). In its early reiterations, the nanocarrier-based delivery of bone rebuilding elements may be needed for upholding and rebuilding of bone, for example, parathyroid hormone (PTH 1-84), human recombinant PTH peptide 1-34 (Teriparatide), oligodeoxynucleotides (ODNs), collagen type I fibers, and hydroxyapatite nanocrystals (~0.74 nm  11.0 nm  14.0 nm). Future medical personnel may advise a bone mass replenishment therapy that entails the exploitation of possibly millions of autonomous “osteolaminals” (Fig. 2). For the preservation and prospective improvement of bone mass, density, and strength, these intangible nanomedical devices might successfully “top-dress” the tapering bones of astronauts with multiple ultrathin laminated layers of bone rebuilding materials. An onboard balance of explicit molecules enclosed in each nanodevice that have vigorous binding affinities for bone-resident minerals, which can be superficially displayed for affinity-based targeting points. Their streamlined morphologies may permit them to navigate bone/tissue interfaces at a close immediacy to bone surfaces (theoretically) underneath the periosteum in an ordered way as semi-parallel arrays that might form travelling segmented “rings” to circumscribe bones that are in call for repair or reinforcement (Boehm 2013).

Piezo-actuated oscillating propulsive fin arrays Angled external docking key to assist multi-nanodevice circumscribing of bones

Communication beacons

Internal docking key for multi-nanodevice application to topdress degenerating bone

Multiple auxiliary reservoirs in addition to primary cargo hold are filled with bone matrix rebuilding elements

Dispenser array for direct application of bone matrix elements to existing bone surface

Fig. 2 Artistic illustration of conceptual autonomous “osteolaminal” nanomedical device. (Adapted from Boehm 2013)

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Carbon Nanotubes for Cardiac Function and Muscle Atrophy Carbon nanotubes (CNTs) are an allotropic form of carbon with cylindrical structure and deepening on number of sheets in concentric cylinders; they can be categorized as single-walled carbon nanotubes (SWCNTs) and multiwalled carbon nanotubes (MWCNTs) (Rastogi et al. 2014; Sanginario et al. 2017). Water-insoluble drugs can effortlessly be loaded in carbon nanotubes as they have very hydrophobic hollow interior. The large surface area allocates for outer surface functionalization and can be done specially for a particular cancer receptor as well as contrast agents (Dinesh et al. 2016). Ladeira et al. (2010) utilized carboxyl functionalized SWCNTs (50–500 nm long) as nanocarriers and established a prospective nanomedical approach for the delivery of siRNAs to cardiomyocytes with more than 95% effectiveness. The interior introduction of the nanotubes at doses of 0.05 mg/mL is not compromised by the defeat frequency of the cardiomyocytes, with their inbuilt integrity. This nanomedical approach may well allow the delivery of cardiac therapeutics to guarantee that heart muscle cells retain optimized physiological integrity beneath microgravity. Martinelli et al. (2012) was employed MWCNTs scaffold (162.75  11.4 nm thick) to show the promotion of growth, maturation, and initiation of impulsive electrical activity in cultured neonatal rat ventricular cardiac myocytes. It was assumed that this was the case owing to the scaffold’s resemblances to natural extracellular matrix. Such carbon nanotube-based scaffolds may be used to develop heart muscle cells as part of a sophisticated tissue engineering capacity involved in the future spacecraft for the possible replacement of degraded heart muscles of astronauts, as a result of extended exposure to microgravity (Boehm 2013).

Dendrimeric Nanodevice for Detection of Cellular Damage in Astronauts Dendrimers are highly branched macromolecules with a lot of functional groups existing for the attachment of drug, targeting, as well as imaging agents, and their absorption, distribution, metabolism, and elimination (ADME) profile is reliant upon a variety of structural feature (Somani and Dufes 2014; Kaminskas et al. 2011). For fruitful localization of folic acid, imaging (fluorescein), and delivery of methotrexate an anticancer drug in vitro, a polyfunctional dendrimer system has been reported by Quintana et al. (2002). The therapeutic index of cytotoxic drugs can be improved by nanoparticle therapeutics based on dendrimers through utilizing biocompatible components and the surface derivatization with acetylation, glycosylation, PEGylation, and various amino acids (Baker 2009; Cheng et al. 2011). Baker’s lab has been funded by NASA and the National Cancer Institute to create dendrimer-based nanodevices which can sense and report cellular damage because

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of radiation exposure in astronauts on long-term space missions (Betley et al. 2002). By mid-2002, the lab had fabricated a dendrimeric nanodevice to identify and report the intracellular presence of caspase-3, the first enzymes released at some stage in cellular suicide or apoptosis, one indication of a radiation-damaged cell. The device comprises one component that spots the dendrimer as a blood sugar, as a result the nanodevice is readily absorbed into a white blood cell, and a second component use fluorescence resonance energy transfer (FRET) that utilizes two closely bonded molecules. Before apoptosis, the FRET system keeps on bound mutually, and the white cell interior stays dark upon illumination. The bond is rapidly broken, and the white blood cell is soaked in fluorescent light, as soon as apoptosis starts and caspase-3 is released. Counteracting drugs can be taken if a retinal scanning device measuring the intensity of fluorescence in an astronaut’s body reads above a certain baseline (Freitas 2005).

Targeted Nanoparticles to Alleviate Microgravity-Induced Ocular Anomalies Mader et al. (2011) observed microgravity-induced ophthalmic anomalies in seven astronauts involved in long-duration (6 months) space missions to the International Space Station. The ophthalmic results for the seven astronauts under study showed that choroidal folds (in five), cotton wool spots (in three), decreased near-vision (in six), disk edema (in five), globe flattening (in five), and nerve fiber layer thickening (in six). Further, optic nerve sheath distension and tortuous optic nerves were observed. The Mader and co-workers concluded that the optic nerve and ocular alterations they explain may result from cephalad (toward the head) fluid shifts brought about by extended microgravity exposure. A NASA-designed rotating wall vessel (RWV) bioreactor was utilized by Roberts et al. (2006) to imitate microgravity to review its effects on human retinal pigment epithelial (hRPE) cells, contrary to controls in a nonrotating wall vessel under ambient gravity. It was experiential that in subsequent 24 h of simulated microgravity, the hRPE cells showed a noteworthy level of oligonucleotide (single-stranded DNA) breaks when compared with the controls, which were not set on 48 h postexposure. In opposition, when the cells were pretreated with 1 μM cysteine, followed by a 48 h recuperation period, the numbers of breaks were divided. Additionally, a momentous secretion of prostaglandin E2 was observed, which oblique an acute microgravity-induced inflammatory response. For the protection of neurons of the retina, cerium oxide nanoparticles can act as regenerative catalytic antioxidants on account of their redox capacities. It was revealed by Deshpande et al. (2005) that as the dimensions of ceria nanoparticles are reduced (~Ø3–5 nm), the population of available vacant sites for oxygen atoms within its crystalline structure is improved.

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Polymeric Nanofiber Scaffolds to Prevent or Counteract the Deleterious Effects of Microgravity on the Brain and DNA The functionality of degraded or destroyed populations of neurons and glial cells and neuronal circuitry might be nanomedically reinstated by using targeted nanocarriers, which may specifically carrying the apt biomaterials, molecules, and stem cells to any damaged sites of the nervous system to begin effectual repairs. Multilayered electrospun polymeric nanofiber scaffolds perhaps self-assembled from constituent components in vivo and employed to hold up the growth of stem cells. Alhosseini et al. (2012) established nanofiber scaffolds consist of electrospun polyvinyl alcohol (PVA)/chitosan nanofibers (~Ø 221 nm) to generate microscale pores at their interstices, which assisted cell tethering and migration, the proliferation of blood vessels, in addition to enable cellular nutrient as well as waste exchange. Pheochromocytoma (PC12) nerve cells from rat adrenal medulla were cultured on a PVA/chitosan nanofiber scaffold in vitro and observed to respond positively to the support. In a supplementary neural engineering investigation by Jang et al. (2010), the growth of E18 rat hippocampal neurites traced the micropatterns of a substrate that were recognized by octadecyltrichlorosilane (OTS) and pristine carbon nanotubes (Fig. 3), which biomimetically imitated extracellular matrices. A cell adhesion protein poly-l-lysine, which was coated onto the substrate, was an important factor for attachment, guidance, and elongation suggested by them. Santos et al. (2012) described that the nanomedical repair of the brain might entail the activation of renewable multipotent neural stem cells (NSCs), which can be located in two specific regions of the brain (germinal subventricular and hippocampal subgranular zones), to revitalize astrocytes, neurons, and oligodendrocytes. Through the delivery of targeted nanoparticles, the activation of NSCs might be started that stand payloads of neurogenesis-inducing biomolecules to these sites,

Fig. 3 Neuron networks (at seven divisions) shown on (a) carbon nanotube-only substrate and (b) patterned carbon nanotube/OTS substrate. (Adapted from Jang et al. 2010)

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whereas imparting negligible side effects (Reynolds and Weiss 1992; Gage et al. 1995; Quadrato and Giovanni 2013; Kazanis 2013; Gage 2002; Bible et al. 2009). A healthy means for the protection of the integrity and viability of DNA molecules and the proteins that they encode will be extremely important for long-haul human space travel and the ultimate human habitation of the moon, Mars, and beyond (Boehm 2013). Inside the nuclei of human cells, there innately subsist a dozen species of protein-based DNA repair mechanisms that are encoded by ~150 genes. All of these self-assembling biological “nanomachines” is dedicated to the repair of an explicit type of damage to the DNA duplex. In the space environment, microgravity in combination with ionizing radiation may harmfully impact a number of DNA repair mechanisms. After extensive studies of astronauts, Rowe (2012) revealed that human exposure to microgravity induces a significant decline in serum magnesium (Mg), an antioxidant and calcium blocker, which is vital for the binding of telomerase to DNA, and this telomerase eases telomere elongation, chromosome stability, and the promotion of transcription as well as replication. An inadequate concentration of magnesium is resulting into oxidative stress, unstable DNA, and reduced protein synthesis and mitochondrial performance. Under microgravity conditions to preserve sufficient levels of Mg, Mg loaded nanoparticles may have the ability for the prolonged release of Mg ions, to maintain healthy plasma levels and those within intracellular compartments, which reduce eventually and may not inevitably be related with concentrations in the plasma.

Quantum Dots for Diagnostic Testing The use of nanoparticle for diagnostic purposes is a region that at present engaged for clinical application but profoundly explored in academia (Kolluru et al. 2013). In view of the fact that existing technology for diagnostic testing is stuck by the inadequacies of fluorescent markers including fading of fluorescence after single use, color matching, and limited use of dyes attributable to a bleeding effect, fluorescent nanoparticles offer researchers with the answer to conquer these drawbacks (Wolfbeis 2015). One very important advance was the invention of quantum dots which can be custom-made in lots of piercingly defined colors. Their absorption spectrum ranges from UV to a wavelength within visible spectrum and give high quantum yield, tunable emission spectrum, as well as photostability. The size of the nanodot decides anywhere in the spectra that individual particle falls; larger particles have longer wavelengths and narrow emission (Emerich and Thanos 2006; Li and Zhu 2013; Michalet et al. 2005). Tagging of the quantum dots has numerous advantages; first, they are excitable using white light, and second, they can be connected to biomolecules that can spend considered amount of time in the living system to explore various biomechanisms. This technology further allows one to check numerous biological events concurrently by tagging a variety of biological molecules with nanodots of a specific color (Datta and Jaitawat 2006).

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Grapheme-Based Nanocomposites In recent years, graphene and its derivatives such as graphene oxide (GO) reduced graphene oxide (RGO), and GO nanocomposites have attracted remarkable attention in lots of different fields counting biomedicine because of their inimitable physical and chemical properties. Single-layered graphene demonstrates ultrahigh surface area available for resourceful molecular loading and bioconjugation through every atom exposed on its surface and has been extensively explored as novel nanocarriers for drug as well as gene delivery. Exploiting the inherent nearinfrared (NIR) optical absorbance, in vivo graphene-based photothermal therapy has been comprehended, attaining tremendous antitumor therapeutic efficiency in animal experiments. To obtain functional graphene-based nanocomposites with fascinating optical and magnetic properties, a range of inorganic nanoparticles can be grown on the surface of nano-graphene, which is useful for multimodal imaging and imaging-guided cancer therapy. In addition, momentous efforts have also been dedicated to learn the behaviors and toxicology of functionalized nano-graphene in animals. Yang et al. (2013) discussed future prospects and confronts of using graphene-based materials for theranostic applications. For stimulation-responsive drug delivery, magnetic metallic oxide nanoparticles may well linked with graphene. Wang et al. (2013) modified magnetic Fe3O4 nanoparticles onto the surface of GO nanosheets via an inverse coprecipitation method. A variety of inorganic nanoparticles have been anchored onto the surface of GO or RGO to present added optical and magnetic properties because GO presents many oxygencontaining groups, such as hydroxyl, carboxylic, and epoxide groups. Graphenebased nanocarriers can act as active materials for surface-enhanced Raman scattering (SERS) experiments, when hybridized with gold or silver nanoparticles, for observing the process of drug delivery (Ma et al. 2013; Wang et al. 2014). Moreover, graphene-based nanomaterials can be used as magnetic materials for MR imaging, when hybridized with magnetic nanoparticles (Swain et al. 2015; Fan et al. 2013; Wang et al. 2013).

Gold Nanoparticles for Biomedical Application Gold nanoparticles (Au NPs) have peaked interests for the biomedical use as they offer noticeable benefits. Firstly, we can effortlessly produce different shapes of Au NPs with sizes ranging from 1 nm to greater than 100 nm, for example, cage-like, rod-like, spherical, and so on. The optical and electrical properties of Au NPs significantly depend on their shape and size (Verissimo et al. 2016). Secondly, Au NPs can be simply functionalized by all kinds of biomolecules, for instance, drugs, genes, and targeting ligands owing to the presence of a negative charge on them (Fratoddi et al. 2015). Thirdly, Au NPs are biocompatible as well as harmless (Hainfeld et al. 2005). Fourthly, Au NPs have distinctive surface effect, macroscopic quantum tunneling effect, ultrasmall size, and the existence of surface plasmon resonance (SPR) bands (Kumar et al. 2013). All of these meticulous properties

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put together Au NPs, the most prospective material for a variety of biomedical applications, including biosensing, drug carriers, molecular imaging, and so on. In the therapy of endocellular diseases, conjugates of Au NPs with drug molecules play a significant role (Saha et al. 2007; Gu et al. 2003). Through ionic or covalent bonding or by physical absorption, antibiotics or other drug molecules are capable to directly conjugate with Au NPs, such as 13 nm colloidal Au, has been conjugated to methotrexate (Chen et al. 2007). Au NPs can as well be used as nanocarriers for protein delivery. For the applications of Au NPs in biology and biomedicine, the interfacial interaction between protein and Au NPs has profound implications, when Au NPs have been functionalized by chitosan, it can be used for delivering insulin (Bhumkar et al. 2007).

Conclusion As we expand the frontiers of space exploration, the requirement for effectual diagnostic and therapeutic tools favorable to long-distance travel becomes more and more important. More insight into the genesis of pathologies associated with space exploration such as osteoporosis, muscular atrophy, renal calculi formation, and radiation damage drives necessitate for sophisticated theranostic strategies. Per se, nanotechnology-based detection methods, targeted drug delivery, and tissue-engineering platforms have confirmed extremely productive and promising. Nevertheless, to tie together their full prospective for application in personalized and targeted disease treatment, further development and optimization of these nanomedical technologies are essential. A precious outcome to the investigations carried out in the space environment is the impact they will render on the medical technologies used for health management on Earth. Consequently, the power of space nanomedicine will hurl modern healthcare into the next era of personalized care. Nanotechnology is truthfully a multidisciplinary science where chemists, physicist, biologists, and pharmaceutical scientist all have played major roles to develop novel treatment and diagnosing modalities. It is obvious through this chapter that application of nanotechnology in drug delivery and medicine has cemented new pathways and opened many doors for providing customizable and safer treatment option.

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Basic Principles of Biopharmaceutics and Pharmacokinetics During Spaceflight Yichao Yu, Christoph N. Seubert, and Hartmut Derendorf

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basic Principles of Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Volume of Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Half-Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors Affecting Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Studies of Spaceflight Impact on Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors Affecting Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Studies of Spaceflight Impact on Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolism and Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors Affecting Metabolism and Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Studies of Spaceflight Impact on Metabolism and Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

136 138 138 139 139 140 140 141 144 147 148 152 155 156 159 162 162

Abstract

Despite more than 50 years of manned spaceflight, we still barely know if the medications that astronauts receive in space are as effective and safe as they are on Earth. The unique spaceflight environment may disrupt the physiological balance in astronauts, leading to alterations of pharmacokinetics and Y. Yu · H. Derendorf (*) Department of Pharmaceutics – College of Pharmacy, University of Florida, Gainesville, FL, USA e-mail: yyu2013@ufl.edu; hartmut@ufl.edu C. N. Seubert Department of Anesthesiology – College of Medicine, University of Florida, Gainesville, FL, USA e-mail: [email protected]fl.edu © Springer Nature Switzerland AG 2022 Y. V. Pathak et al. (eds.), Handbook of Space Pharmaceuticals, https://doi.org/10.1007/978-3-030-05526-4_19

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pharmacodynamics of therapeutic agents. To ensure that crewmembers receive efficacious and safe medications in space, it is critical to understand the unusual pharmacological responses of medications during missions. However, the field of space pharmacology has not been systematically evaluated yet. This chapter offers a review of basic principles of biopharmaceutics with special focus on pharmacokinetics and discusses how the potential physiological changes in space can influence the absorption, distribution, metabolism, and excretion of pharmacologic agents. These changes can be caused by spaceflight-associated alterations in gastric empty, intestinal transit, protein binding, fluid shifts, blood flow, and intrinsic clearance (metabolic enzymes and renal function). All these factors need to be considered to predict the influence of spaceflights on pharmacokinetics and subsequently the ultimate impact on drug efficacy and safety. Evidence from preliminary inflight studies is very limited due to technical and logistic difficulties; thus spaceflight analog models simulating physiological changes under microgravity provide an alternative way to investigate the spaceflight-associated pharmacological alterations on ground. However, discrepancies exist between real microgravity in space and space analog models simulating weightlessness. More well-controlled studies with more subjects and longer duration are warranted to better understand the pharmacokinetic changes in space and to provide optimum drug therapy for astronauts. Keywords

Spaceflight · Astronauts · Microgravity · Space medicine · Pharmacokinetics

Introduction Therapeutic treatment failure is one of the major concerns from NASA for space medicine practice in both short- and long-term missions. Astronauts use medications to treat or prevent spaceflight-associated medical conditions such as space motion sickness, sleep problems, pain, congestion, or allergy. In general, these medications were prescribed under the assumption that they have similar safety and efficacy profiles as they are on Earth based on previous knowledge and experience in terrestrial medicine. However, even after more than half a century of human spaceflight, this assumption has not been investigated actively and relies on very little supporting evidence. With both the mission duration and number of onboard human subjects increasing in the future, the risk of medical incidents will also rise during deep space missions. Therefore, it is crucial to ensure that the limited medications in medical kit onboard spacecraft are safe and efficacious to use on crewmembers when an immediate evacuation back to Earth is not feasible. Aspects of the spaceflight environment have been shown to alter human physiology; thus it is unlikely that space pharmacology would remain the same. If the space pharmacology is governed by the same principles on Earth, it can also be divided mainly into pharmacokinetics

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(PK, what the body does to the drug) and pharmacodynamics (PD, what the drug does to the body). PK describes how the body absorbs, distributes, metabolizes, and excretes administered medications, while PD studies the receptor or signaling systems that are the targets of medications and characterizes the resulting concentration-effect relationship. To achieve better clinical pharmacological effect of medications administered to crewmembers during missions, it is of high importance to understand the PK/PD alterations caused by this unique spaceflight environment. It is highly unlikely that medications have the same PK and PD as on Earth since human physiology is altered by spaceflight environment. The international space station (ISS) circles the Earth at an altitude of more than 300 km in a unique environment characterized by high vacuum, microgravity, extremes of temperature, and ultraviolet and ionizing radiation. With spacecraft orbits around the Earth once every 90 min, extreme temperatures occur outside the ISS when it passes through the Earth’s sunlit side and dark shadow. The irregular light pattern resulting from these 16 daily sunsets and sunrises may also disrupt the circadian rhythm of astronauts. Furthermore, the crewmembers are exposed to persistent ionizing radiation, which is about 60 times higher compared with the average dose received from natural landbased sources. The biologic consequences of this long-term and low-dose exposure to ionizing radiation in space are still unclear, but it may threaten astronauts’ health by killing cells, damaging genetic material, or even leading to cancer. Another major challenge associated with human spaceflight is microgravity (small gravity levels or low gravity). Therefore, crewmembers are exposed to potential spaceflightassociated risks due to the harsh environment in space. In order to treat or prevent some health risks caused by potential physiologic stressors, medications may be required during spaceflight missions. Medication usage during spaceflight missions is similar to that noted on the space shuttle and in adult ambulatory medicine. The standard medical kit includes drugs such as analgesics, antibiotics, antihistamines, antifungals, antipyretics, antivirals, cardiovascular, central nervous system stimulants, etc. (Putcha et al. 2016). It was reported that more than 94% of crewmembers take medications during spaceflight missions with the most frequently ones for the treatment of pain (31%), sleep problems (23%), congestion or allergy (13%), and space motion sickness (9%). Among these frequently used medications, the usage of sleep aids was about ten times higher during spaceflight missions compared to adult ambulatory medicine. Anecdotal data indicate about 8% of all treatments administered during spaceflight missions were reported as being ineffective (Putcha et al. 2016). The majority (88%) of the medications taken in space are tablets by mouth, although other routes of administration (such as intramuscular injections, rectal suppositories, ocular preparations, and topical agents) are also available in the onboard formulary. The diverse formulations available in space provide various routes of medication administration, therefore enhancing treatment capability during space missions. However, potential treatment failure still exists due to the possibility of drug interactions. This risk can be mitigated if better understanding of the effect of spaceflight on drug PK is provided.

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This chapter starts with a review of basic principles of PK including the most important PK parameters. The potential factors affecting drug absorption, distribution, metabolism, and elimination in space are discussed in each section. Up-to-date scientific literatures regarding PK alterations in space from preliminary inflight studies or studies using spaceflight analog models are also evaluated and compared in this chapter.

Basic Principles of Pharmacokinetics Pharmacokinetics describes what the body does to the drug. It provides a mathematical way to track the time course of drug and metabolite concentrations in the body. A fundamental understanding of pharmacokinetic characteristics can help in the identification of the optimum dose, dosage regimen, and dosage form to achieve the safety and efficacy target. The fate of a drug in the body can be further explained in the processes of absorption, distribution, metabolism, and excretion (ADME). These processes can be summarized in the key pharmacokinetic parameters: clearance (CL), volume of distribution (Vd), half-life (t1/2), and bioavailability (F).

Clearance Drug clearance can be defined as the volume of body fluid cleared per unit of time (L/h, mL/min) by the processes of metabolism and excretion. This PK parameter is constant if the drug elimination follows first-order kinetics (meaning elimination rate increases with drug concentration). Clearance can be expressed as the product of blood flow (Q) and extraction ratio (E) across an elimination organ: CL ¼ Q∙E If the well-stirred model is assumed, where the drug is evenly distributed in the elimination organ, clearance can also be calculated from intrinsic clearance (CLint), blood flow (Q), and fraction of drug unbound in the blood (fu): CL ¼

f u ∙CLint ∙Q f u ∙CLint þ Q

Based on the extraction ratio, drugs can be divided into high-extraction drugs (E > 0.8) and low-extraction drugs (E < 0.2). The clearance of high-extraction drugs is mainly depending on Q due to the high intrinsic clearance ( fu ∙ CLint  Q). However, for low-extraction drugs ( fu ∙ CLint  Q), the clearance depends on both fu and CLint. The liver and kidney are the two main organs responsible for drug elimination; other elimination pathways also include bile, the lung, sweat, saliva, tears, etc. The total body clearance is the sum of all individual organ clearance:

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CL ¼ CLren þ CLhep þ CLother

Volume of Distribution Volume of distribution is defined as the required volume into which the total amount of drug in the body (X) would be dissolved to attain the drug concentration (C): Vd ¼

X C

Even though this parameter is not “real” (usually referred to as the apparent volume of distribution) and has no exact physiologic significance, it can well indicate the amount of drug distributed into the tissues and help to determine optimal drug therapy. When equilibrium is achieved between blood and tissue, the volume of distribution depends on fraction of unbound drug in both blood (fu) and tissue (fuT) and corresponding volumes thereof (VB and VT): Vd ¼ V B þ

fu ∙V T f uT

Drug concentration in plasma may not be the same as that in the tissue; however, it is reasonable to assume that changes in drug concentration in plasma will result in proportional changes in tissues. For a normal adult man with body weight of 70 kg, the total body water (TBW) makes up approximately 60% (42 L) of the total body weight. This body water consists of 14 L (1/3 of TBW) extracellular fluid and 28 L (2/3 of TBW) intracellular fluid. Approximately 75% of the extracellular fluid is interstitial fluid (10.5 L), and plasma volume is only about 3.5 L. From pharmacokinetic perspective, the volume of distribution is not necessarily less than the actual physiologic volume. A large volume of distribution, which does not correspond to a real volume, suggests that the drug is extensively distributed into tissues. On the other hand, a value that is similar to physiological plasma volume implies that the drug stays mainly in the plasma and poorly distributes into tissues.

Half-Life One of the other essential pharmacokinetic parameters is half-life, which is defined as the time it takes to reduce the drug concentration to half of its previous value. It is an important parameter to evaluate effect duration and drug accumulation. In general, the therapeutic effects of a drug are negligible after four half-lives when there is only 6.25% of drug remaining. It is also important to notice that half-life is not a primary pharmacokinetic parameter but rather a secondary parameter depending on the clearance and volume of distribution of a drug:

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t 1=2 ¼

lnð2Þ∙Vd CL

Another secondary parameter related to half-life is the elimination rate (ke), which is ln(2)/t1/2 in the units of inverse time. In an infusion or repeated dosing, half-life can provide useful information of time to reach steady state and optimal dosing interval.

Bioavailability Bioavailability describes the rate and extent that the administered drug is absorbed and becomes available at the site of action. However, the drug concentrations at the target site may not be easy to measure due to inaccessibility. Instead, concentrations in the systemic circulation are generally measured to infer efficacy/safety assuming that the drug at the site of action is in equilibrium with the drug in the blood. Thus, bioavailability can provide insight into how much and how fast a drug appears in systemic circulation after administration. The extent of absorption is usually quantified as the fraction of the administered dose that reaches the systemic circulation: F¼

AUC AUC iv

where AUC is the area under the concentration-time curve. It is the parameter used to describe how much drug is in the body with units of the product of concentration and time (e.g., mg∙h/L). By definition, all intravenously administered drugs have a bioavailability of 100%. If the drug is administered by other routes, the bioavailability will be reduced due to first-pass metabolism, poor solubility, low permeability, or other reasons for incomplete absorption. When the presystemic metabolism is the only cause, the fraction of drug which reaches systemic circulation is related to hepatic blood flow (QH), fraction unbound in the blood (fu), and intrinsic clearance (CLint): F¼

QH QH þ f u ∙CLint

The rate of absorption can be quantified by the peak plasma concentration level (Cmax) and the time needed to reach this maximum plasma concentration (Tmax). A rapid onset is preferred if the drug is intended to treat acute conditions, while slow rate of absorption is desired to avoid adverse effects or to prolong effect duration.

Absorption Absorption is the movement of a drug from the site of administration to the blood circulation. It is one of the primary focuses in drug development since no systemic pharmacological effects can take place before drug is absorbed. In general, drug

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absorption process often depends on drug formulation and route of administration. A drug can be formulated in specific dosage form such as tablet, capsule, liquid, or aerosol, depending on its route of administration. Orally (PO) administered drugs are normally in forms of tablets or capsules. Injectable formulations are used with intravenous (IV), intramuscular (IM), or subcutaneous (SC) administration. Among these, oral administration is the most common route but may raise absorption complications as the drug passes through the gastrointestinal (GI) tract. Since intravenous administration does not involve the absorption process, it always results in fast therapeutic effect. This is ideal for acute treatment in emergency situations but requires well-trained personnel for drug administration, which may not be easily accessible during space missions. Data from Space Shuttle flights STS-1 through STS-80 indicated that most (88%) of the inflight medications were taken orally (Putcha et al. 2016). Absorption of oral medications is complicated, and the corresponding bioavailability is likely to be affected by various microgravityinduced reasons. This section will mainly focus on the absorption issue on orally administered medications. The first part of this section will be a discussion about the factors affecting drug absorption, followed by evidence from previous spaceflight and spaceflight analog studies in the second part.

Factors Affecting Absorption Microgravity-induced alterations in the absorption of orally administered drugs may affect the efficacy and safety of therapeutic agents. Drug bioavailability can be influenced by physiologic, pathophysiologic, and pharmacologic reasons including dissolution rate, intestinal microflora, intraluminal enzymes, epithelial enzymes, rate of passage across the gastrointestinal epithelium, gastric emptying rate, intestinal transit time, first-pass metabolism, and gastrointestinal and hepatic blood flow (Tietze and Putcha 1994). The overall impact of microgravity on drug absorption may consist of one or more of these factors.

Dissolution Rate Drug must be in solution prior to absorption, so the rate of dissolution from the solid dosage form is a key target for controlling the effectiveness of drug formulation. Dissolution rate is defined as the amount of drug substance solubilized in a given solvent per unit time, which can be described by the Noyes-Whitney equation: dW DAðC s  C Þ ¼ dt L where dW/dt is the dissolution rate of the drug, D is the diffusion coefficient, A is the surface area of the solid, Cs is the concentration of the drug in the diffusion layer surrounding the solid, C is the concentration in the bulk dissolution medium, and L is the diffusion layer thickness. From this equation, the rate of dissolution can be influenced by surface area of the drug, which highly depends on drug particle size. A reduction in the particle size will result in an increased surface area and therefore an

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enhanced dissolution rate. The physiochemical properties of medications and pH of fluids in the GI tract can also affect the rate of drug dissolution. Hydrophilic drugs dissolve more quickly and distribute into tissues easily, while hydrophobic oral drugs may require increased dosage due to incomplete absorption. Polymorphs may exist when a substance exists in more than one crystalline form, therefore affecting the solubility and dissolution of solid drugs. The amorphous form has higher aqueous solubility and dissolves faster than a stable crystalline polymorph. Reduced dissolution rate is usually noticed in drugs with coatings. Extendedrelease coatings reduce or delay drugs access to the systemic circulation and keep drug concentrations at a more consistent level. Enteric coatings prevent the drug from dissolving in the acidic environment of stomach before reaching targets in the intestine. Drug solubility also depends on pH, where acidic drugs will be well absorbed in the stomach (pH 1.4–2) and basic drugs will be absorbed better in the intestine (pH 7.5–8). Most drugs are available in forms of weak acids or weak bases. However, the mucosal lining of the GI tract is impermeable to the ionized drugs; only the non-ionized forms can be passed through due to their lipid solubility. The major absorption site of most drugs is the small intestine, with the stomach and colon contribute much less to this process. This is because, compared with the stomach, the larger surface area of the intestine can lead to relatively longer exposure time.

Gastric Emptying and Intestinal Transit Gastric emptying and intestinal transit are two important factors that govern GI function and hence influence oral drug absorption. Gastric emptying (the rate at which a substance leaves the stomach and enters the small intestine) and intestinal transit (the rate at which particles traverse the intestine) depend on factors relating to physical properties of the contents of the stomach and intestine, as well as factors regarding physiologic changes, gastrointestinal microflora, and pathologic conditions. Based on the physical mechanism of forces acting on a spherical particle on Earth, the ratio between gravitational forces and viscous forces can be expressed as the following equation (Amidon et al. 1991): d p 2 Δρg F G gravitational forces ¼ ¼ viscous forces 18η < v > FD This dimensionless ratio has been shown as a critical variable that can provide insight into better understanding of gravitational impact on gastric emptying and intestinal transit of oral medications. From the above equation, the gravitational forces depend on both particle density (Δρ: difference between the particle density and the fluid density) and particle diameter (dp), while the viscous forces highly correlate with fluid viscosity (η) and average velocity (). An increase in the size and density of a drug particle or a decrease in drug viscosity and/or mean fluid velocity will increase this ratio. In the absence of gravity, little dependence on density would be expected indicating microgravity would have a profound effect

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on gastric emptying. Moreover, rather than being restricted to the lower pyloric region of the stomach, the particles move through all areas of stomach without gravity limitation. Therefore, the influence of particle size on GI emptying appears to be less prominent than the kinetic energy of a particle. Furthermore, a faster intestinal transit may be reasonable to assume since the drag force (FD) is more pronounced than gravity and buoyancy forces during missions (Amidon et al. 1991). This increased transit rate may adversely affect complete absorption of a drug in the intestine. In addition, gastric emptying highly depends on the motility phase of the stomach. GI motility is a cyclical and periodic process that leads to a highly variable gastric emptying during each motility phase. Gastric emptying is slowest in phase I (quiescent phase), quicker in phase II (intermittent contractile phase), and fastest in phase III (strong contractile activity) (Amidon et al. 1991). This periodic contraction pattern reoccurs every 2 h in the GI tract. Thus, its influence on gastric emptying and intestinal transit may come from variations in the overall cycle length or the duration in each individual motility phase. It is also important to notice that both motion sickness and anti-motion sickness treatments (scopolamine and promethazine) might potentially inhibit gastric emptying in space. Food intake increases gastric emptying but decreases intestinal transit (Tietze and Putcha 1994). Significant differences have been found in gastric emptying patterns between fed and fasted states. The presence of food triggers release of gastric acid and digestive enzymes in the stomach, followed by increased local blood flow, therefore causing an alteration in drug absorption. Gastric emptying may also be affected by food types. If a high-caloric meal is consumed, the caloric content of the meal activates a negative feedback mechanism of the duodenum which allows only a fixed rate of calories to be delivered from the stomach (Brener et al. 1983). During the initial period of caloric delivery, gastric volume increases, resulting in a faster gastric emptying before the feedback inhibition starts. Previous evidence also indicated that spaceflight can change the predominant species of gut microflora. Significant reductions were found in the number of bacterial species cultured from the GI tract of crewmembers (Ilyin 2005). Their intestinal bacterial community may undergo major changes during spaceflight. However, it was also reported that a reduction in beneficial intestinal lactobacilli was even seen prior to launch, implying the preflight stress may be one of the driving factors in the changes in the composition of gastrointestinal microflora. With the prolonged GI residence time of drugs due to low solubility and/or permeability, there will be greater possibility that microbe-mediated biotransformation can occur and may ultimately influence the intestinal transit. Body position can influence the rate of gastric emptying as well. Enhanced gastric emptying was found for both acetaminophen and nifedipine when subjects were lying on the right side with stomach contents pooling over the pylorus (Renwick et al. 1992). A postural effect was also found in splanchnic-hepatic blood flow and plasma volume, which may substantially affect first-pass metabolism (Queckenberg and Fuhr 2009). Though evidence of a direct gravitational effect is lacking, it is reasonable to assume that gravity may play an important role in the effects of body position on gastric emptying.

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Gastric emptying and intestinal transit can also be altered by pathologic conditions. Hypercalcemia, uremia, and diabetes mellitus may decrease gastric emptying, while duodenal ulcers and chronic pancreatitis may increase gastric emptying (Tietze and Putcha 1994). It has also been reported that psychological stress can increase small bowel transit time and hence potentially alters drug absorption (Tietze and Putcha 1994).

Presystemic Metabolism After oral drugs get absorbed from the stomach and intestine, and before they reach the systemic circulation, therapeutic agents need to pass into the hepatic portal vein system and get exposed to the liver where metabolism is very likely to occur. A completely absorbed oral medication could be incompletely bioavailable due to firstpass effect/presystemic metabolism by the gut wall and/or liver. The liver is the main metabolic organ for most drugs; however, the gut wall is imperative in the first-pass metabolism of certain drugs such as benzylpenicillin and insulin. Cytochrome P450 3A4 (CYP3A4) is present in the intestinal mucosa, so its substrates may be metabolized in the gut. The first-pass metabolism through the liver may reduce concentrations of absorbed drug significantly if extensive presystemic metabolism occurs, resulting in very low bioavailability. Hence drugs with high first-pass effect usually have an oral dose that is much higher than the intravenous dose (e.g., propranolol, a wellabsorbed drug but with approximately 30% bioavailability). The first-pass effect can be avoided by alternative routes of administration via buccal mucosa or rectum, where the liver will be bypassed before drug enters the systemic circulation.

Studies of Spaceflight Impact on Absorption Up until today, the only inflight PK data that are available mainly focus on bioavailability. Considering the consistent saliva/plasma ratios over a wide range of plasma concentrations and the technical limitations in space, all these studies use saliva concentrations instead of plasma concentrations. Data from more thorough spaceflight analog studies are available; however, the validity of those conclusions needs to be further explored.

Inflight Studies of Drug Absorption Limited published studies (acetaminophen and scopolamine) exist regarding the effect of spaceflight on drug absorption. Oral acetaminophen has been well recognized as the standard measure of absorption. The first inflight pharmacokinetic study was conducted in 12 crewmembers (from 7 separate missions) to compare the bioavailability of 650 mg of acetaminophen preflight and inflight (Putcha and Cintron 1991). Pharmacokinetic profiles are significantly different during flight compared with preflight sessions, especially the absorption phase. The peak saliva concentration (Cmax) decreased during flight, while the time to reach maximum concentration (Tmax) increased inflight, indicating a prolonged acetaminophen

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absorption time in space. Although interindividual variability is tremendous in this inflight study with limited number of subjects, it seems like the between-subject variability in Cmax and Tmax is much greater during flight than that in ground control. One reasonable explanation would be that the physiological response to spaceflight varies among individuals and thus results in variations in drug absorption during flight. In addition, the information about the incidence of space motion sickness is lacking in this preliminary study, and the records on flight-specific activities such as exercise frequency, mission day, and co-medications are also incomplete. All these factors can extend the variation in drug absorption. This data imply that the bioavailability of acetaminophen may vary during the first few days of spaceflight. Future studies with well-controlled preflight and inflight sessions and with longer durations are warranted to draw more definitive conclusions. Similar reductions in the rate of absorption were shown in a more current study where 500 mg of acetaminophen was given orally in either tablets or capsules in ten subjects (five in each group) and the impact of long-term spaceflight on pharmacokinetics was compared with terrestrial conditions (Kovachevich et al. 2009). Spaceflight delayed absorption of tablet acetaminophen with about 60% longer Tmax. The peak concentration was also decreased during flight but with relative bioavailability (AUCflight/AUCground) slightly increased. Administration of the capsule acetaminophen during spaceflight resulted in approximately 30% shorter Tmax, whereas the relative bioavailability changed insignificantly. In the absence of gravity, different gastric motility would be expected with either of the formulations. Compared between these formulations under the same spaceflight environment, the interindividual variability after capsule drug intake was less than that found for tablets, indicating capsule acetaminophen may be preferred for space missions. Concurrent with the aforementioned acetaminophen study, Cintron et al. also conducted another inflight study to evaluate the effect of microgravity on the pharmacokinetics of scopolamine (Putcha and Cintron 1991). In their study, 0.4 mg of oral scopolamine was administered as a capsule combined with 5 mg of dextromethamphetamine. Both medications are poorly absorbed in the GI tract (not ideal to evaluate drug absorption), but it was still of clinical interest to assess the spaceflight impact on these drugs. Similarly, this study also indicated larger variations in concentration-time profiles during spaceflight compared with ground control. Lower Cmax but longer Tmax were observed in most crewmembers; however, completely opposite results were also obtained from other crewmembers. In this case, a definite conclusion can hardly be drawn with the limited sample size and information. The study suggested that the absorption of scopolamine may be influenced by the physical and physiological changes caused by microgravity during spaceflight. Taken together, these few studies provide very preliminary evidence that the rate of absorption of orally administered drugs may be decreased in space and the extent of absorption is likely to be changed. These preliminary results did not show drastic alterations in drug absorption during spaceflight; thus dose optimizations are probably not necessary.

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Simulated Microgravity Studies of Drug Absorption Due to the limited data from very few inflight studies and the limited access for conducting a pharmacokinetic study on astronauts in space, models simulating weightlessness have been used for more than half a century to study the impact of microgravity on pharmacokinetics. The head-down bed rest (HDBR) model, typically with a tilt degree of 6 , has been used extensively to study the short-term and long-term effect of weightlessness. This model mimics the spaceflight orthostatic intolerance by inducing similar fluid shifts from the bottom to the top of the body (Gandia et al. 2005). Although this model has not been thoroughly validated for pharmacokinetic studies, it can provide some useful information on the inflight PK alterations. The HDBR model was used to study the effect of simulated weightlessness on gastric emptying in 18 volunteers (Gandia et al. 2003). Gastric emptying was assessed by acetaminophen for both short-term and long-term weightlessness. Subjects were given 1 g of acetaminophen orally before bed rest and at days 1, 18, and 80. Both plasma and saliva samples were collected up to 12 hrs after each dosing. Results show the peak plasma concentration increased and occurred earlier as time in bed rest increased. A similar conclusion can also be drawn from saliva results, suggesting faster gastric emptying and more rapid absorption with prolonged bed rest. However, there was no significant difference in the extent of acetaminophen absorption since AUC was slightly changed during each evaluation time. The pharmacokinetics of oral scopolamine were also evaluated after 24 h of HDBR (Putcha et al. 2016). Plasma profiles indicated decreased absorption and bioavailability of oral scopolamine in simulated microgravity conditions. On the other hand, an increase in bioavailability of intranasal scopolamine gel formulation (0.4 mg) was found during antiorthostatic bed rest (Singh et al. 2011). Compared with the oral formulation, intranasal gel improved scopolamine bioavailability significantly. Even though the results regarding microgravity-induced changes in scopolamine bioavailability are inconsistent, these results suggested that the absorption of scopolamine, in either oral or intranasal dosage form, may be affected by microgravity. Gandia et al. also assessed the influence of simulated weightlessness on pharmacokinetics of promethazine in two dosage forms: intramuscular and oral (Gandia et al. 2006). This was a crossover study where 50 mg of promethazine was administered orally or intramuscularly to 12 volunteers before and after 48 hrs of HDBR. Similar time to peak concentration was found for both formulations under both bed rest and ambulatory conditions. When drug was given intramuscularly, simulated weightlessness did not affect the peak plasma concentration or relative bioavailability, whereas a significant increase (26%) in Cmax and relative bioavailability were seen compared with the ambulatory conditions after oral administration of promethazine. This increased bioavailability may result from the prolonged contact time between oral promethazine and gastrointestinal wall in simulated weightlessness.

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An increased rate of absorption for ibuprofen under simulated microgravity conditions was also shown in a study with six healthy volunteers (Idkaidek and Arafat 2011). Each subject was administered with a 600-mg oral dose of ibuprofen in both antiorthostatic bed rest and normal positions. It was shown that bioavailability of ibuprofen was unchanged in simulated microgravity. However, subjects in bed rest position reached peak plasma concentration much faster than those in normal position, but the interindividual variability under simulated microgravity conditions was high. To conclude, drug absorption can be altered by changes in influential factors including dissolution rate, gastric emptying rate, intestinal transit time, and presystemic metabolism. Increased absorption may result in overdose, and decreased absorption may diminish therapeutic effect. Anecdotal inflight and spaceflight analog studies suggest that drug absorption may be changed in spaceflight but not dramatically. So far, no records from crewmembers or flight surgeons reported any incidence that acetaminophen (gold standard to evaluate absorption) was ineffective or overdosed in space (Wotring 2012). Further inflight studies with larger sample size are needed to further assess the impact of spaceflight on drug absorption.

Distribution Distribution is the process where drug molecules leave the systemic circulation to another location within the body. It is usually rapid for the blood to circulate from arteries to tissues and then back to the heart via veins. During distribution process, drug molecules are carried by the blood to different body tissues including the target site for drug action, elimination organs (kidney and/or liver), and other tissues. However, most drugs do not distribute evenly throughout the body due to the differences in the physicochemical nature of therapeutic agents and tissues, as well as the differences in the degree of drug-protein binding in both blood and tissues. Hydrophilic drugs usually cross cell membranes slowly and tend to stay in the blood and interstitial space, while hydrophobic drugs generally penetrate tissues quickly and are prone to concentrate in fatty tissues. Moreover, drug tends to distribute in highly perfused organs such as the liver, heart, and kidney, but it is more difficult to distribute into less perfused tissues like the muscle, fat, and skin. In addition, protein binding is another critical factor for drug distribution because only the unbound drug is pharmacologically effective and can be distributed into tissues. Since most drugs bind to blood proteins, the rate of drug leaving the bloodstream highly depends on protein binding property. Drugs that bind tightly to blood proteins tend to leave slower than those less tightly bound. Furthermore, the rate of drug entering a tissue also depends on the rate of blood flow to that tissue, tissue mass, and partition characteristics between blood and tissue. For some tissues where drugs are retained for a longer period, the therapeutic effect will also be extended in them.

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Factors Affecting Distribution Volume of distribution (Vd) is the pharmacokinetic parameter to best quantify distribution characteristics. When equilibrium between blood and tissue is achieved, this parameter is proportional to the unbound fraction in the blood (fu) and inversely proportional to the unbound fraction in the tissue (fuT). Nevertheless, the change in fu may not reflect the change in fuT. Vd also depends on the volume of both blood (VB) and tissue (VT), which makes it difficult to accurately predict the overall change in distribution. Spaceflight can affect drug distribution by potential alterations in both binding and volume. Microgravity-induced fluid shift, changes in protein binding, and muscle loss may influence drug distribution inflight as well.

Fluid Shift Most drugs cross cell membranes by passive diffusion where drug moves from high concentration side to low concentration side. Besides that, hydrostatic pressure also plays a critical role in the process of drugs traversing capillary membranes into the tissue. Hydrostatic pressure is the pressure difference between the arterial end of the capillaries entering the tissue and the venous capillaries leaving the tissue. Blood flow-induced drug distribution occurs because of the high arterial pressure that allows drug molecules to be rapidly filtered into tissue. The filtrate will then return to venous capillary since venous pressure is lower than that of the tissue. When the body is in an upright position under terrestrial conditions, the gravitational forces cause a hydrostatic gradient of pressure along the body axis which result in a predominate accumulation of body fluids in the lower limbs. Under microgravity conditions, the absence of hydrostatic force leads to a decreased pressure on the capillary walls in lower limbs. This allows the vascular fluid to redistribute more evenly in the body, which would be perceived as a headward fluid shift. This headward fluid shift and venous congestion underlie the puffy face and sense of congestion in astronauts. However, since the volume of the blood accommodated cephalad of the heart remains small, this redistribution of body fluid triggers an increased central venous pressure and leads to an early adaptive response of the cardiovascular and renal/endocrine systems (Gandia et al. 2005). The fluid shift is initiated during the prelaunch period when the lower limbs of crewmembers are raised above the thoracoabdominal coronal plane in a supine position. Based on the Frank-Starling law, this physiologic mechanism of adaptation will induce the enlargement of heart volume and cardiac output. It has already been shown that an inflight blood volume loss of 2 L occurs from lower extremities on Space Shuttle missions compared with preflight (Moore and Thornton 1987). A higher increase (35–41%) of cardiac output and stroke volume was also reported for long-duration missions (Norsk et al. 2015). This initial phase of spaceflightassociated fluid shift occurs rapidly and is essentially complete in 6 to 10 hrs after exposure to microgravity (Fig. 1). During this period, the astronauts experience this fluid shift as the “puffy face-bird leg” syndrome with the unique puffy appearance of the head and reduced volume in the legs.

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Fig. 1 The body fluid distribution on Earth with normal gravity (1), at the initial stage in space (2), after adaptation to the weightlessness (3), and immediately after reentering the Earth (4) (Adapted from Charles and Lathers 1991)

The upward fluid shift also triggers the baroreceptors (i.e., pressure sensors) to signal the control centers to eliminate excess fluid. The body reacts to this situation by reducing the blood volume through urination and reduced thirst. Therefore, after couple days of spaceflight, the astronauts seem to adapt to this new weightlessness conditions. The overall blood volume decreases, due to decreased thirst and increased water output, resulting in a net effect of about 10% reduction in total blood volume (Williams et al. 2009). However, no direct inflight evidence can be used to substantiate this notion so far. No significant difference was found between pre-, in-, and postflight urine output (Norsk et al. 2015). Therefore, the mechanism of this overall blood loss in space is still unknown. Although the extracellular fluid volume decreased in microgravity conditions, the total body water was unchanged during missions (Leach et al. 1996). These results imply that the volume lost in extracellular fluid may be relocated to the intracellular space. Once the body adapts to microgravity environment, this new state of stabilization of body fluid remained until the end of the spaceflight mission. When returning to the Earth, the Earth’s gravity pulls the blood back to the lower body again but with reduced intravascular blood volume, leading to the occurrence of orthostatic hypotension. It was reported that more than 25% of astronauts were unable to complete a 10-min stand test on landing day after a short spaceflight mission due to postflight orthostatic intolerance (Williams et al. 2009). Both the heart rate and arterial pressure were found to be elevated during reentry and right after landing (Clément 2011). However, crewmembers seem to readapt to normal gravity after 1–2 days. Under terrestrial conditions, the regulation of blood pressure and related blood volume is primarily controlled by the kidney. It maintains the salt and water balance in body fluids via the help of hormones. One of the critical hormones is the antidiuretic hormone (ADH), a pituitary-secreted polypeptide hormone that is

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released once plasma osmolarity increases. This signal then directly induces the kidney to reabsorb water and produce less urine in order to retain water in the body. Alternatively, a reduction of ADH level will stimulate the kidney to eliminate more water from the body. In general, ADH secretion and thirst correlate well, with more thirst associated with higher ADH level. Surprisingly, a fourfold increase in ADH level but 41% less fluid intake was observed on day 1 during spaceflight (Leach et al. 1996). Therefore, other factors such as stress of launch and exposure of acceleration may also contribute to the ADH elevation. Also, the central volume expansion probably helps to reduce the thirst under microgravity. During early acclimation to weightlessness, the central nervous system may react to the combination effect of thirst and diuresis, where high ADH level primarily governs less renal water excretion and central blood volume expansion dominantly controls thirst level. The elevated ADH reduced to preflight level on the second day of spaceflight and remained at preflight level until the end of the mission, indicating other factors may also contribute to persistent inflight antidiuresis (Leach et al. 1996).

Protein Binding in the Blood Most drugs interact with proteins in the blood and/or tissues, so the binding of drug to proteins is a major determinant of drug distribution. The free drug theory has been widely accepted to explain the therapeutic effect and pharmacokinetic characteristics. In the absence of active transporter mechanisms, the free drug concentration in plasma (extracellular space) is equal to the free drug concentration in tissues (intracellular space) at steady-state equilibrium, and only the free drug can interact with pharmacologic target receptor(s). Although the total drug concentration in plasma may be significantly different than the total drug concentration at the target site in tissue, the unbound drug in plasma should be able to reflect the pharmacologically relevant concentration of unbound drug in tissue. Drug-protein binding can be categorized as reversible or irreversible. Irreversible binding usually involves a covalent bond that strongly attaches the substance with protein; reversible binding is formed by weaker chemical bonds (such as hydrogen bonds or Van der Waals forces) between drug and protein. In general, most drug-protein binding is reversible and thus of pharmacokinetic interest. The drug-protein complex is generally too large to traverse the capillary wall, and therefore only the unbound component can leave the blood stream, making it therapeutically active. Changes in protein binding in both blood and tissue have direct effects on the pharmacokinetic properties of drugs. Binding in blood can occur to plasma proteins, blood lipids, as well as red blood cells (RBCs). The plasma proteins that commonly involved in binding with drugs are albumin (human serum albumin-HSA), α-acid glycoprotein (AAG), lipoproteins, and immunoglobulins (IgG). Among these, HSA is the major component of plasma proteins, which tend to bind with acidic and neutral compounds since HSA is basic. Each HSA has eight binding sites which allows binding of endogenous compounds and xenobiotics with varying binding strength. A tail-suspended rat study showed a transient increase in serum albumin after initial suspension but followed by significantly reduced albumin concentrations after 3 days (Brunner et al. 1995).

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AAG is the primary binding protein for most basic substances, and globulins (α-, β-, γ-globulins) transport certain endogenous substances (e.g., corticosteroids). Discrepant results were also found for the impact of spaceflight on these proteins. An increase in the relative content of α-1 and α-2 globulins was found after landing from long-term space missions (Larina et al. 2017); however previous short- and long-term missions reported no increase in these proteins (Stein and Gaprindashvili 1994). Early inflight data indicated the concentration of IgG was increased in space (Guseva and Tashpulatov 1980), but no significant changes were observed in 53 cosmonauts after long expeditions (Rykova et al. 2001). Furthermore, a recent study from 18 Russian cosmonauts found a significant decrease of apolipoproteins after long-term spaceflight (Larina et al. 2017). The changes of these plasma protein levels in microgravity imply a significant alteration in drug-protein binding by weightlessness. The pharmacokinetic profiles may thus be altered, especially for drugs that are highly protein bound. Exogenous compounds can also bind to RBCs, which account for about 45% of the blood volume. Reduced red blood cell mass was commonly found in both US astronauts and Russian cosmonauts after short- and long-term spaceflights. This “spaceflight anemia” was well known as a consequence of adaptation to microgravity. However, a recent study of 31 crewmembers reported a significant elevation in RBCs after long-duration mission, suggesting astronauts do not develop persistent anemia during spaceflight (Kunz et al. 2017). Although the hematocrit may influence the total drug concentration in the blood, binding to RBCs may not significantly influence the volume of distribution as most drugs are reversibly bound to HSA. Similarly, the binding to blood lipids may not strongly impact drug distribution.

Protein Binding in Tissue Tissue has a significantly higher protein content than plasma; thus protein binding in tissue is also believed to have a critical impact on drug distribution. Spaceflight can affect tissue protein binding through various factors such as massive protein loss, muscle atrophy, and decreased body mass. Skeletal muscle is the largest deposit of proteins in the body and therefore also the major site of protein loss. The total muscle protein level reflects a dynamic turnover between protein synthesis and degradation. Spaceflight was known to alter the balance between the process of building and breaking down muscle proteins toward muscle atrophy under microgravity. A 15% decrease in the rate of protein synthesis was found in cosmonauts during long-term missions onboard Mir (Stein et al. 1999). Compared with previous HDBR experiments, this reduction was even more pronounced than expected, partially due to a reduced dietary intake during missions. Decreased protein synthesis and increased protein degradation were also observed in first 2 weeks of a hind-limb suspension experiment in rats (Thomason et al. 1989). The fact of a massive protein loss with inactivity indicates less drug will interact with proteins in tissue; therefore drug redistribution is likely to occur. Since more than 30% of the body mass is made up of skeletal muscle, the weight loss during and after spaceflight also implies muscle atrophy. Approximately 10–20% loss of muscle mass was observed in astronauts during short mission, and

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it might rise up to 50% on long missions without countermeasures (Clément 2011). Significant decreases in muscle volume were also found in some muscle groups after short- and long-term missions, but these changes were transient with muscle volume reversed to normal within 1–2 month after landing (LeBlanc et al. 2000). This decrement in volume not only implies muscle atrophy but may also be one of the consequences of fluid shift in microgravity. The reduced muscle volume, together with the potential increase in the fraction of unbound of drug in tissue, may eventually result in a decreased volume of distribution and potentially shortened half-life of drug in space.

Studies of Spaceflight Impact on Distribution So far, very few studies have been reported for the impact of microgravity on drug distribution in body fluids or tissue in spaceflight. Some pharmacokinetic data are available in bed rest studies rather than inflight studies. Although how closely these analog studies can mimic the spaceflight environment remains unknown, but these studies may provide some insight into drug distribution during spaceflight.

Simulated Microgravity Studies of Drug Distribution Two pharmacokinetic studies are available in the HDBR conditions (lidocaine and ciprofloxacin) with a few other studies conducted in supine position (acetaminophen, phenytoin, imipramine, and desipramine) to evaluate the influence of microgravity on drug distribution. However, all the drugs that have been studied so far are more of clinical interest rather than pharmacokinetic interest. Among all these, the lidocaine studies are the most pertinent ones to evaluate the changes in distribution. The impact of prolonged recumbency on lidocaine was first investigated by Kates et al. where 100 mg of lidocaine was administered intravenously in eight male subjects before and after 7 days of recumbency (Kates et al. 1980). They observed slightly lower mean plasma concentrations at most times after recumbency; however, the difference in drug disposition was not statistically significant before and after bed rest. Also, no significant changes in the binding of lidocaine were found after bed rest, although some subjects showed a substantial reduction in lidocaine binding. They concluded that lidocaine distribution and elimination were not altered by prolonged recumbency. Opposite results were found in a later study by Feely et al. where lidocaine (61  4 mg) was injected to idiopathic hypotensive patients (Feely et al. 1982). Compared with a sitting or upward tilt 30 position, a significant higher volume of distribution was measured in supine position with lower lidocaine plasma concentrations at all times. Nevertheless, the posture is unlikely to be the only explanation of the volume of distribution increase since posture does not influence lidocaine disposition in normal subjects. The most pertinent study for evaluating the impact of microgravity on drug distribution was conducted by Saivin et al. in a 4-day HDBR study with eight healthy subjects (Saivin et al. 1995). Intravenous lidocaine (1 mg/kg) was given

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daily 1 day before, during, and 2 days after the 4-day HDBR. Lidocaine distribution was significantly altered by simulated microgravity with a decrease in maximal concentration in HDBR. The volume of distribution was increased to about 36% on day 2 (3.73  2.52 L/kg) but decreased to 16% below the baseline (2.77  1.73 L/kg) on the other days (2.33  0.48 L/kg). It was also found that the cardiac output and diuresis were increased, while liquid intake was increased during HDBR; hence fluid shift is likely to occur. The modification of lidocaine distribution may be partially explained by the alterations in plasma volume, but other factors may also contribute, since the plasma volume only accounts for 3% of the lidocaine volume of distribution. The effects of simulated microgravity on disposition of ciprofloxacin and propofol in HDBR model were also investigated (Schuck et al. 2005; Liu et al. 2008). Six healthy volunteers participated in this crossover study, and the pharmacokinetics of ciprofloxacin were evaluated after a single 250 mg oral tablets dose in normal gravity and simulated microgravity (HDBR for 48 h). In each study session, plasma and urine samples were collected up to 12 h after dosing, the free interstitial concentrations of ciprofloxacin in tissue were measured by microdialysis technique, and the unbound plasma concentrations were assessed from ultrafiltrates for each collected plasma sample. It found that both total and free plasma concentrations were almost identical before and after 3-day HDBR (Fig. 2). Tissue penetration, determined by AUCtissue,free/AUCplasma,free, was slightly lower in microgravity (0.61  0.36) compared with that obtained in normal gravity (0.92  0.63), suggesting that tissue penetration may be impaired by microgravity. However, the

Fig. 2 Plasma ciprofloxacin concentration (round) and free interstitial concentration (triangle) versus time profile in the Earth’s gravity (1G, filled) and simulated microgravity (sμG, open) (Adapted from Schuck et al. 2005)

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Fig. 3 Plasma propofol concentration versus time profile in the Earth’s gravity (1G, filled) and simulated microgravity (sμG, open) (Adapted from Liu et al. 2008)

differences in tissue penetration were not statistically significant. Thus, the authors concluded that ciprofloxacin disposition was not affected by simulated microgravity. Similar results were also observed in a propofol study where eight volunteers received clinical equipotent general anesthesia over 60 min. Plasma concentrations of propofol were slightly higher in simulated microgravity than in the control, but a significant difference was only found at certain time points (Fig. 3). Similar volumes of distribution were observed in both conditions; therefore, we conclude that microgravity did not raise any novel pharmacokinetic concerns for propofol. In the same lidocaine study, Kate et al. also showed that the distribution and elimination of penicillin were not affected by prolonged bed rest (Kates et al. 1980). Similarly, Rumble et al. were unable to show a statistically significant difference in volume of distribution of penicillin between bed rest and ambulation (Rumble et al. 1986). Results from the same group on paracetamol (acetaminophen) also indicated that the proposed posture-related changes in volume of distribution do not exit. However, significantly lower plasma concentrations were observed in supine position for highly protein-bound drugs (such as phenytoin, imipramine, and desipramine), implying a potentially higher volume of distribution in bed rest compared to standing (Queckenberg and Fuhr 2009). To summarize, drug distribution variations predicted from models simulating weightlessness still cannot be validated due to lack of inflight data. The results obtained with the same drug from different study groups may not be the same (e.g., lidocaine), but overall it seems unlikely that prolonged bed rest or spaceflight will tremendously alter drug distribution. Apart from the physiochemical properties of the therapeutic agents, drug distribution is also determined by spaceflight-associated effects on fluid redistribution and protein binding. Inflight pharmacokinetic studies

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of drug distribution are warranted to rule out drug distribution as a potential pharmacokinetic issue for space medication or establish dose adjustment for any safety and efficacy concerns.

Metabolism and Excretion Drug metabolism and excretion are a set of biochemical reactions whereby xenobiotics are broken down or altered and then cleared from the body. The liver is well known as the major site of drug metabolism, and the kidney is mainly responsible for drug excretion. Except for prodrugs (inactive parent compounds but active metabolites), metabolism typically inactivates xenobiotics in a two-phase process where lipophilic compounds covert into hydrophilic products. In general, a functional group is usually introduced in phase I to make the drug less hydrophobic and then conjugated to endogenous substances with large polar moieties in phase II. The hydrophobic xenobiotics and metabolites are ultimately removed from cells by efflux transporters. Phase I nonsynthetic modification includes hydrolysis, reduction, and oxidation reactions principally dominated by cytochrome P450s (CYPs) enzymes, especially CYP1, CYP2, CYP3, and CYP4 families. Phase II synthetic conjugation occurs with charged molecules such as glutathione, glycine, sulfuric, acetic, or glucuronic acid. Phase I and/or phase II reactions make the drug more polar, thus more readily to be excreted by the kidney (in urine) and the liver (in bile). Some enzymes involved in drug metabolism are present in various tissues in the body but with majority being concentrated in liver. Other metabolism can occur in tissues associated with portals of drug entry into the body, such as the lung, skin, gastrointestinal mucosal cells, microbiological flora in the distal portion of the ileum, and large intestine. Some drugs may also undergo renal metabolism (e.g., insulin). The rate and extent of metabolism can affect the pharmacological effect of a drug. Rapid metabolism may potentially decrease drug efficacy, and slowed metabolism may possibly lead to toxic accumulation. The removal of metabolized compounds is dominated by renal excretion, a process where drug is passed through the kidney to the bladder and ultimately voided as urine. The process of renal excretion consists of glomerular filtration, active tubular secretion, and tubular reabsorption. Glomerular filtration is a passive diffusion process where the unbound drugs get filtered at the glomerulus by hydrostatic pressure within the glomerular capillaries. It is highly related to the glomerular filtration rate (GFR) and plasma protein binding. Tubular secretion is an active transport process where drugs are transported against concentration gradients. Both renal plasma flow and the capacity of carrier systems can have an impact on the rate of active tubular secretion. Tubular reabsorption occurs when glomerularly filtered drugs are transported back into the plasma. Urinary pH and pKa of the drug could influence drug reabsorption. Renal clearance may be comprised of all these mechanisms, but only one or two dominate renal excretion. Xenobiotics and metabolites can also be removed by other elimination pathways such as feces, bile, sweat, saliva, milk (via lactation), or other body fluids. Volatile

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drugs can also be cleared via the lung into the expired air. In microgravity, both drug metabolism and excretion can potentially be altered and therefore influence drug efficacy and toxicity in space.

Factors Affecting Metabolism and Excretion From a pharmacokinetic perspective, drug metabolism and excretion can be quantified by the sum of clearance from individual tissues or organs that are involved in the process. The rate and extent of metabolism are dependent on the intrinsic activity of the biotransformation enzymes, which may vary by genetic and environmental factors. Co-administrated medications, especially those involving in induction or inhibition of metabolic enzymes, may alter the intrinsic clearance (CLint) as well. Protein binding is another essential factor that has a direct effect on the clearance of low-extraction drugs, particularly for drugs being excreted mostly by glomerular filtration. For high-extraction drugs, the extent of elimination is primarily dependent on hepatic blood flow (Q). Renal, bile, and other elimination pathways may also contribute to the change of total clearance in microgravity. Therefore, drug metabolism and excretion in space can be affected in various ways.

Intrinsic Clearance The capacity of hepatocytes to metabolize the drug is commonly referred to as “intrinsic clearance.” It is the ability of the liver to clear drug without flow limitation or protein/cell binding in the blood. Drug metabolism is an enzymatic conversion, which is also a shifting process between first-order and zero-order kinetics. In general, only a small fraction of the enzyme’s metabolizing sites is occupied at therapeutic concentrations of most drugs, so metabolic rate increases with drug concentration (first-order kinetics). Saturation of the enzymes occurs when drug concentration is relatively high; therefore metabolism rate achieves maximum (zeroorder kinetics). The relationship between enzymatic reaction velocity and the drug concentrations can be described by Michaelis-Menten enzyme kinetics. CYP450 is the most important enzyme system for phase I metabolism. It has already been shown that the hepatic enzymatic activity can be altered by harsh environmental conditions like spaceflight. A 50% reduction of hepatic CYP450 content was observed in rats onboard Spacelab 3 compared with ground controls (Merrill Jr. et al. 1987). In a later study, significant changes were found in the hepatic content of CYP2C29, CYP2E1, and CYP1A2 in mice after 30 days of spaceflight (Moskaleva et al. 2015). After readaptation to Earth’s gravity, the content of CYP2C29 and CYP1A2 returned to similar level as the control, while the CYP2E1 level remained elevated. Significant changes in the abundance of various members of CYP450 were also detected postflight in mouse liver (Anselm et al. 2017). Upregulation was found in CYP2D subfamily members (CYP2D9, CYP2D10, and CYP2D26), but downregulation was observed in CYP3A subfamily (CYP3A11 and CYP3A13) inflight compared with postflight. However, CYP enzyme levels returned to normal within 7 days after landing.

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As for phase II enzymes, a dramatic decrease in liver glutathione, glutathione disulfide, and total glutathione content was seen in rats after an 8-day spaceflight (Hollander et al. 1998). A reduction of catalase, glutathione reductase, and sulfurtransferase activities was also seen in rat liver in the same study. Similarly, Blaber et al. also showed a decreased glutathione level in mice exposed to space for 13.5 days (Blaber et al. 2017). Although some of these findings of phase I and phase II enzymes are inconsistent, they suggest that spaceflight has the potential to alter hepatic metabolism by modification in metabolic enzymes. When drug concentrations are high and enzymes are saturated, the rate of metabolic reaction can potentially be changed due to altered enzyme content. The amount of metabolizing enzyme is likely to be altered in space; however, it remains unknown whether the enzyme content correlates well with activity. An induction of enzyme during spaceflight could lead to an accelerated biotransformation, and a reduction could also change the efficacy and toxicity of pharmacological agents. The genetic variability in enzymes should also be factored into the variation of drug response. Multiallelic genetic polymorphisms of CYPs 2D6, 2C19, 2C9, 2B6, 3A5, and 2A6 can lead to distinct pharmacogenetic phenotypes and thus play a major role in the interindividual variability of pharmacokinetic responses. Enzyme variants from genetic polymorphisms may change drug-metabolizing capacities on Earth, let alone the spaceflight environment where radiation could trigger further alterations of gene expression. Therefore, the potential for adverse effects and lack of efficacy impacted by genetic variability of metabolic enzymes need to be considered for astronauts in their unique environment. One good example related to genetic variation of medications commonly used in space is hydrocodone, which can be converted to hydromorphone via CYP2D6. Since the risk of hydromorphoneinduced respiratory depression is high, this drug should probably be avoided in astronauts of CYP2D6 ultrarapid metabolizers. For astronauts being CYP2D6 poor metabolizer, hydrocodone may lack efficacy because it is weaker than hydromorphone. Besides genetic variations, enzyme expression is also influenced by various factors including induction/inhibition of xenobiotics, regulation by cytokines, and hormones, as well as sex, age, and others. CYP450 enzymes can be induced or inhibited by other xenobiotics present in the body, leading to a clinically relevant drug-drug interaction where one drug effectively enhances the toxicity or unexpectedly reduces the efficacy. Therefore, it is essential to monitor co-administered medications and recognize whether the drugs involved act as enzyme substrates, inducers, or inhibitors. It is especially important for astronauts to avoid unanticipated adverse reactions or therapeutic failures during space missions. Other factors such as inhibited proliferation of hepatocytes, enhanced gluconeogenesis, and altered lipid metabolic hemostasis have been found in animals under spaceflight and simulated microgravity conditions (Anselm et al. 2017; Merrill Jr. et al. 1987; Jonscher et al. 2016). These findings can also contribute to the alteration of intrinsic clearance in microgravity. However, notice that the spaceflight environments for animals and humans may be different and the spaceflight analog models have not been validated

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so far, so the impact of spaceflight on enzymatic metabolism and liver composition in human remains unknown.

Protein Binding For low-extraction drugs, the clearance is proportional to the fraction of unbound drug (fu). As it has already been discussed in the distribution section, spaceflight can alter plasma proteins, blood lipids, and red blood cells, resulting in an overall change of drug binding in the blood. Protein binding in tissue may also vary in space because of massive protein loss in muscle and other tissues. Depending on the fraction of drug bound, changes in binding caused by the spaceflight environment have a more pronounced effect on low-extraction drugs with high protein binding (capacity limited and binding sensitive). A large increase in fraction unbound in these drugs will cause an increase in its rate of drug metabolism, leading to an elevated hepatic clearance. Similarly, protein binding also plays an important role in renal excretion for drugs removed mainly by glomerular filtration. This is because the protein-bound drugs are generally too big to be filtered at the glomerulus and thus are excluded from entering the urine. On the contrary, protein binding has little effect on elimination of the drugs excreted mostly by active secretion (e.g., penicillin) due to the rapid re-equilibration during secretion. Blood Flow Changes in hepatic blood flow are critical for drugs with high-extraction ratio because flow rate is directly proportional to clearance. Alterations in hepatic and renal blood flow by spaceflight could significantly affect the metabolism and excretion of flow-limited (high-extraction) drugs. Hepatic blood flow was indirectly estimated by clearance of indocyanine green in previous studies (Putcha et al. 1988; Daneshmend et al. 1981) where it was unchanged during HDBR in one study but increased in supine position in another. In another HDBR study where lidocaine was used as probe to evaluate hepatic blood flow, an enhanced blood flow velocity was measured in the hepatic artery on the first day of HDBR, but it was an exception of the correlation between blood flow and lidocaine clearance (Saivin et al. 1995). These ground spaceflight analog findings partially contradict each other due to different probes and measurements in the studies. There was no direct inflight evidence of the impact on hepatic blood flow, but slightly increased liver volume, size, and blood filling were observed in cosmonauts after 9 months of spaceflight (Grigoriev et al. 1991). However, Merrill et al. found no significant difference in rat liver weights in space (Merrill Jr. et al. 1987). Alterations in renal blood flow are particularly important for drugs excreted via glomerular filtration and tubular secretion. Renal clearance is a key pharmacokinetic parameter to indicate the main mechanism of renal excretion. Most drugs are prominently excreted via renal filtration. These drugs usually have a renal clearance approximate to the product of GFR and fu. A renal clearance less than this value implies reabsorption is involved in renal elimination; alternatively a renal clearance greater than this value suggests the presence of secretion. An early ground study showed no significant difference in GFR, estimated by [51Cr]EDTA plasma

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clearance, at different postures (Kamper et al. 1988). Few data are available on renal hemodynamic changes during spaceflight. Data from Spacelab Life Sciences (SLS) missions suggest that GFR, measured by creatinine clearance, was slightly increased in astronauts early in spaceflights (Kramer et al. 2001). However, this elevation was transient and independent of changes in renal plasma flow, leading to an increased filtration fraction. Compared with observations from short- term mission, the elevation in GFR was less prominent in long-term flights (Jones et al. 2008). Greater urinary flow rate was also found during bed rest studies on ground (Rumble et al. 1986). And as it has already been addressed in the previous section, microgravity results in a headward fluid shift and decreased blood volume; hence reduced hepatic and renal blood flow can also be expected in space. The effective circulating plasma volume could influence hepatic metabolism and renal function in spaceflight.

Other Routes of Elimination Besides the liver and kidneys, drug elimination can also occur in other organs. Drugs present in feces after oral administration often arise from biliary excretion or incomplete absorption. The portion that is excreted into the bile can be either eliminated unchanged in feces or reabsorbed into the bloodstream and excreted in the urine. Typically, drugs that are eliminated mostly in the biliary system have a relatively high molecular weight and with strong polar groups. Small amounts of drugs can also be excreted in saliva, sweat, and tears as they are the ultrafiltrates of plasma. Inhaled drugs can be eliminated in exhaled air. Very limited data are available for the effect of spaceflight on these elimination pathways. It was observed that spaceflight altered bile acid metabolism with an overall accumulation of deconjugated bile acids in mouse liver (Jonscher et al. 2016). Compared with results 7 days after landing, significantly higher levels of bile secretion-related proteins were seen in the flight in mouse liver (Anselm et al. 2017). Less bile secretion may result in a harmful accumulation of bile acids in hepatocytes. Since bile acid is a critical regulator of liver metabolism, the change in bile acid may ultimately modify drug metabolism in space.

Studies of Spaceflight Impact on Metabolism and Excretion Few data regarding the effects of spaceflight on drug metabolism and excretion are available with only one inflight study and a couple of ground spaceflight analog studies. Cell culture models and tail-suspended rat models have also been used to explore the impact of microgravity on pharmacokinetics. However, detailed and well-controlled studies are highly recommended to investigate how spaceflight can affect hepatic metabolism and renal hemodynamics, especially in the initial phase of spaceflight missions where the most controversial results occur.

Inflight Studies of Drug Metabolism and Excretion Antipyrine, a sensitive marker of liver function, was orally administered in two crewmembers during Mir-18 mission to indirectly assess hepatic metabolism

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alteration in space (Putcha et al. 2016). The clearance of antipyrine was measured from a series of saliva and urine samples collected pre-, in-, and postflight. However, results varied in two crewmembers where one had a more than 50% decrease in antipyrine clearance but the other a 30% increase in clearance during spaceflight compared with preflight values. Both crewmembers had approximately 20% reduction in antipyrine clearance postflight. Although the inflight results from each crewmember contradict each other, it is likely that spaceflight may alter hepatic metabolizing enzyme activity. The degree and magnitude of the spaceflight impact cannot be characterized by this inflight data.

Simulated Microgravity Studies of Drug Metabolism and Excretion: Bed Rest More data on drug metabolism and excretion are available in spaceflight analog models. Indocyanine green, a water-soluble dye nearly completely eliminated by liver, is recognized as a probe for the measurement of liver perfusion. In addition, the elimination of lidocaine is also largely limited by hepatic blood flow. In order to evaluate the effect of microgravity on liver metabolism, indocyanine green and lidocaine had been used in a few pharmacokinetic studies in simulated microgravity or the supine condition. The impact of weightlessness on renal excretion had also been studied for drugs that have primarily renal elimination pathways (e.g., lithium, penicillin). Hepatic blood flow was indirectly estimated by indocyanine green clearance in ten subjects during the normal ambulatory and HDBR conditions (Putcha et al. 1988). Each subject received 0.5 mg/kg indocyanine green intravenously after either being seated for 1 h or 24 h of HDBR. No evidence of altered hepatic blood flow was found compared to the control value. However in another study, significantly decreased hepatic blood flow, indicated by decreased indocyanine green clearance, was found when subjects changed posture from lying to standing (Daneshmend et al. 1981). In the studies where lidocaine was used as a pharmacokinetic probe to evaluate hepatic blood flow, similar controversial results were seen. No statistically significant differences were found in lidocaine clearance after 7 days of recumbency, suggesting similar hepatic blood flow in ambulatory and supine condition (Kates et al. 1980). Nevertheless, significant enhancement of liver blood flow in the supine position was observed in both healthy volunteers and hypertensive patients (Feely et al. 1982). Hepatic blood flow velocity increased during the first day of HDBR, and lidocaine clearance increased from 8.24  3.22 mL/kg∙min1 to 11.63  3.00 mL/ kg∙min1 after 4 days HDBR (Saivin et al. 1995). The initial increase in blood flow may result from the fluid shift from lower extremities toward upper body, and the nonsignificant changes later on may relate to adaptation to the new position. Results from different studies did not agree with each other, but an increase of hepatic blood flow seems likely to occur under microgravity, which may lead to elevated clearance for drugs with high-extraction ratio. The influence of prolonged recumbency had also been studied for penicillin, a drug predominantly cleared from body via kidney. No statistically significant

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difference was found in penicillin clearance, implying limited alteration in renal elimination after prolonged recumbency (Kates et al. 1980). Total and renal clearance of benzylpenicillin were found to be slightly elevated during bed rest compared with ambulation; however the difference was not significant either (Rumble et al. 1986). Increased total serum clearance and renal clearance of amoxicillin were also observed in supine subjects compared with ambulation (Roberts and Denton 1980). In another lithium study where GFR was estimated by [51Cr]EDTA plasma clearance and renal clearance, it was found that GFR was not influenced by posture changes (supine, sitting, and walking) (Kamper et al. 1988). Conversely, lithium clearance was significantly higher in the supine position compared with ambulation. This may indicate a potential inhibition of proximal tubular reabsorption during recumbency. These findings suggest an enhanced renal function is likely to occur in supine condition, but data from simulated microgravity settings or spaceflight missions are still lacking to further confirm the effect of weightlessness on renal elimination.

Simulated Microgravity Studies of Drug Metabolism and Excretion: Tail-Suspended Rat Model Several rat tail suspension antipyrine pharmacokinetic studies have been reported to evaluate the alterations in hepatic enzyme metabolism under simulated microgravity. The suspended rat model has been commonly used to simulated weightlessness. In one of the studies, pharmacokinetic characteristics of intravenously and orally administered antipyrine were evaluated at baseline (1) and 1, 3, and 7 days after initiation of tail suspension (Brunner et al. 1995). After 3 and 7 days of tail suspension, antipyrine clearance was significantly elevated in both dosing groups. Results from this study imply that rat liver metabolism can be dramatically altered by simulated microgravity. However, contradictory results were found in another rat tail suspension study where simulated microgravity significantly reduced the clearance of antipyrine by approximately 45% in male rats (Wei et al. 2012). No evidence showed simulated weightlessness would significantly affect antipyrine kinetics in female rats. The findings from this study indicated that a significant gender difference exists in microgravity-induced drug disposition, particularly hepatic enzyme metabolism. In conclusion, inflight pharmacokinetic data on metabolism and excretion are still lacking. Based on results from simulated microgravity studies (bed rest and tailsuspended rat model), liver and kidney functions are likely to be modified in space. These alterations may result from changes in intrinsic clearance, protein binding, and blood flow. So far, no drug-drug interaction data are available from inflight studies or spaceflight analog models, and only a few enzyme data exist from animals flown to space, thus making it difficult to predict the possible changes in liver metabolism during spaceflight missions. Enhanced metabolism and excretion in space may lead to treatment failure of the original medical complaint. Alternatively, reduced drug elimination may increase the incidence of severe side effects. Although new technologies in gene identification could probably help to efficiently understand the enzyme-metabolizing function, more detailed inflight studies are still necessary to evaluate drug disposition in space, especially drug metabolism and excretion.

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Conclusion Space pharmacology is a young and evolving discipline that has made great strides in understanding the changes in PK and PD during spaceflight missions. Alteration in absorption, distribution, metabolism, and elimination can occur in space. Drug absorption depends on both gastric emptying rate and intestinal transit time. Drastic increase in absorption for a drug with a narrow therapeutic index could potentially cause overdoses. Distribution is governed by physiologic factors such as protein binding in the blood and tissue, organ size, and modified fluid redistribution due to microgravity. Elimination is a function of blood flow, protein binding, and intrinsic metabolic and excreting activity. Inflight evidence of how spaceflight changes PK is very limited, and contradictory results were seen with certain medications. Headdown bed rest or tail suspension rat models provide information of the impact of spaceflight on PK. However, these models have not been validated with inflight data yet. More detailed inflight studies are needed to better assess the physiological and pharmacokinetic changes in humans during spaceflight, thus ensuring the optimum use of drug therapy in space.

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Putcha L, Cintron NM, Vanderploeg JM, Chen Y, Habis J, Adler J (1988) Effect of antiorthostatic bed rest on hepatic blood flow in man. Aviat Space Environ Med 59(4):306–308 Putcha L, Taylor PW, Daniels VR, Pool SL (2016) Clinical pharmacology and therapeutics. In: Nicogossian AE, Williams RS, Huntoon CL, Doarn CR, Polk JD, Schneider VS (eds) Space physiology and medicine: from evidence to practice. Springer, New York, pp 323–346. https:// doi.org/10.1007/978-1-4939-6652-3_12 Queckenberg C, Fuhr U (2009) Influence of posture on pharmacokinetics. Eur J Clin Pharmacol 65(2):109–119. https://doi.org/10.1007/s00228-008-0579-2 Renwick AG, Ahsan CH, Challenor VF, Daniels R, Macklin BS, Waller DG, George CF (1992) The influence of posture on the pharmacokinetics of orally administered nifedipine. Br J Clin Pharmacol 34(4):332–336 Roberts MS, Denton MJ (1980) Effect of posture and sleep on pharmacokinetics. I. Amoxycillin. Eur J Clin Pharmacol 18(2):175–183 Rumble RH, Roberts MS, Scott AR (1986) The effect of posture on the pharmacokinetics of intravenous benzylpenicillin. Eur J Clin Pharmacol 30(6):731–734 Rykova MP, Antropova EN, Meshkov DO (2001) Immunological examination. Post-flight clinical and physiological studies of orbital station “MIR”. Anika 1, Moscow Saivin S, Pavy-Le Traon A, Cornac A, Guell A, Houin G (1995) Impact of a four-day head-down tilt (6 degrees) on lidocaine pharmacokinetics used as probe to evaluate hepatic blood flow. J Clin Pharmacol 35(7):697–704 Schuck EL, Grant M, Derendorf H (2005) Effect of simulated microgravity on the disposition and tissue penetration of ciprofloxacin in healthy volunteers. J Clin Pharmacol 45(7):822–831. https://doi.org/10.1177/0091270005276620 Singh RP, Daniels VR, Crady CJ, Derendorf H, Putcha L (2011) Pharmacokinetics of intranasal scopolamine gel formulation during antiorthostatic bed rest, a microgravity analog. American College of Clinical Pharmacology, Chicago Stein TP, Gaprindashvili T (1994) Spaceflight and protein metabolism, with special reference to humans. Am J Clin Nutr 60(5):806S–819S Stein TP, Leskiw MJ, Schluter MD, Donaldson MR, Larina I (1999) Protein kinetics during and after long-duration spaceflight on MIR. Am J Phys 276(6 Pt 1):E1014–E1021 Thomason DB, Biggs RB, Booth FW (1989) Protein metabolism and beta-myosin heavy-chain mRNA in unweighted soleus muscle. Am J Phys 257(2 Pt 2):R300–R305 Tietze KJ, Putcha L (1994) Factors affecting drug bioavailability in space. J Clin Pharmacol 34(6):671–676 Wei B, Abobo CV, Ma J, Liang D (2012) Gender differences in pharmacokinetics of antipyrine in a simulated weightlessness rat model. Aviat Space Environ Med 83(1):8–13 Williams D, Kuipers A, Mukai C, Thirsk R (2009) Acclimation during space flight: effects on human physiology. CMAJ 180(13):1317–1323. https://doi.org/10.1503/cmaj.090628 Wotring VE (2012) Space pharmacology. SpringerBriefs in space development. Springer, New York

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Medications in Microgravity: History, Facts, and Future Trends Joan Vernikos

Contents Where Did We Begin? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evolution of the Medical Kit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Medical Kit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medical Incidents and Frequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dose Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Routes of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multiple Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ground Research Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

The use of drugs in space has been largely experimental as it has been over the years in supporting humans in various other extreme environments. However, space is different in that the progression of physiological changes has not adapted to-date and it entails being removed from the influence of gravity. It has become clear that systematic experimentation in space to develop an comprehensive understanding of pharmacokinetics and pharmacodynamics will be extremely limited. Alternate, creative approaches are needed to provide a reliable basis for therapeutic decisions in the remote environment of space. A data base in ground simulation models such as bed rest needs to be established. In addition, it may be useful to explore the value of the substantial gerontological pharmacological experience as a reliable and extensive resource.

J. Vernikos (*) Thirdage llc, Culpeper, VA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 Y. V. Pathak et al. (eds.), Handbook of Space Pharmaceuticals, https://doi.org/10.1007/978-3-030-05526-4_20

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Speculation among scientists and medical professionals about drug requirements and precautions began well before any human had ever been launched into space. Brainstorming at conferences, projection from military, and athletic and work environment experience preceded actual animal and human flight. As Schmidt and Lambertsen (1965) pointed out: “The purpose of using drugs in space is to maximize the capabilities and minimize the hazards to human subjects in sustained spaceflight.” To do that, the underlying premise of the purpose for which the drugs are used must be clear. Are drugs used to counteract or correct a response to living in microgravity? Or are you treating an injury, infection, allergy, or some other unique or unexpected, or unrelated to, microgravity medical event? Do you really want to change this response or merely slow it down? Is the purpose to maintain astronauts earth-healthy at all times? Or is the physiological response to living in space allowed to take its course completely or partially? Would pharmacological support be used just before or immediately after return to Earth’s gravity to minimize adverse reactions, such as to orthostatic hypotension (OH), and enable the course of recovery? Pharmacology, as practiced on Earth, is based on centuries of knowledge of human and animal physiology on Earth. We currently consider the physiological changes in space relative to Earth as disorders requiring treatment designed to return to that “normal” just as for any other disease. But as space missions become longer, should this approach hold? We have not seen adaptation to space within the time frame of current missions. No steady state has been achieved within a year in space as, for instance, when living at altitude for a few days or weeks. Space physiology and therefore pharmacology is a work in progress. The best we can do is to continue to document physiological changes and study pharmacological behavior incrementally with each successive mission duration. The ideal medication is one which will completely prevent or ameliorate functional abnormalities. The purpose is to keep them within the range of physiological compensations and allow successful accomplishment of what humans in space need to do, without causing undue harm. What is therefore required is to: (a) Based on past experience, anticipate functional abnormalities to be encountered. (b) As compared to some similarly reacting populations, choose drugs cautiously with the most relevant pharmacodynamic properties. (c) Test them in space or space analogs such as bed rest (BR) and head-down bed rest (HDBR). (d) Always assess the possibilities of doing harm. Yet there are numerous other factors that can interfere with normal physiology in space that are unrelated to microgravity. The fundamental problem is how to use known pharmacological interventions to counteract functional aberrations, which are produced in normal and fit men and women by a set of interacting environmental abnormalities of unprecedented type and scope. Included in these abnormalities must be nutritional and environmental considerations.

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These interferences may include: • Abnormal radiation or CO2 levels. • Sources of chemical sterilization of water, such as iodine, which was used for many years to sterilize the water in the US program that was found to have toxic actions. In contrast silver was used apparently safely in the Soviet/Russian spacecraft. • Spacecraft light intensity is inadequate to maintain biological rhythms. • Day-night cycles in Earth orbit last 90 min and are not coordinated with light/dark and work cycles either inside the spacecraft or with ground control communications. • Occasionally missions operate on a shift-work basis further complicating circadian rhythm issues. • Activities such as EVAs, daily exercise, workload, eating, social interaction, and participation of astronauts as test subjects in flight experiments or drugs administered as preventive or countermeasures. Any, or all, of these could interfere with the pharmacological action of a drug administered for a specific medical event as well as with the health of the astronaut or their physiological baseline. They may also interfere with human factors and performance, such as what might occur in communicating with the ground or in interactions among multinational, multilingual crews.

Where Did We Begin? As an integral part of space medicine, space pharmacology evolved out of the young field of aerospace medicine, of specialized courses mostly tailored around the physiology of extreme environments with ensuing navy and air force practice. Flight surgeons were and are at the forefront of space medical care. Step-by-step space medicine was used to build on lessons from each mission, experience from analog environments, and extrapolation from clinical advances on Earth. They served to identify optimal pharmacological tools for space as well as after return. Weight, volume and power restrictions of each spacecraft, and mission priorities dictated diagnostic monitoring as well as the makeup of the medical kit and packaging. Knowledge of alterations in basal physiology that might affect drug action in space often came after the fact. The evolution of medical kits was therefore based on both evidence-based medicine and research and clinical experience. Predictive tools, such as modeling with a Monte Carlo analysis, the development of a Patient Condition Database, sharing of inflight experience with international partners as that became available, and the space experience astronaut health longitudinal tracking database, have allowed choices of therapies to evolve as evidencebased, medical data, accumulated. Simultaneously reliance resorted on current clinical experience when evidence was lacking. As veteran US flight surgeon Craig Fischer emphasized, “The design

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and content of any medical suite is always an unfinished work in progress with continuous updating based on science, research, mission objectives, vehicle constraints, training of the caregivers and levels of desired care” (Fischer 2007; Putcha et al. 2007). In addition to prescribed medications, such as those in the medical kit, pharmacology and toxicology of substances found in the spacecraft environment and the life support system, including water, food, added preservatives, as well as air, outgassing from construction or shielding materials, waste management, and other environmental issues, must be taken into account. On the other hand, the stability and safety of medications is also a factor to be considered both during the preflight sterilization process and the storage conditions during the course of an extended mission. Appropriate packaging, temperature, pressure, and radiation are all factors that may affect stability and safety of medications. What is a best-before date in space is unknown.

Evolution of the Medical Kit When we started out, the development of a medical strategy depended on such factors as availability of voice and later video and wireless communication with the crew, physiologic monitoring including sampling, conditions to transport and store the medical kit, or the ease of self-administration of drugs. The medical kit evolved with successive flights as symptomatic crew reports, observations, and medical findings emerged. Two decision levels were involved: • What the kit should contain anticipating what might be needed for medical incidents, such as emergency use, and whether and when its contents were used. • Was a medic always part of the crew or would astronauts be trained in the handling and administration of drugs in the kit? Another factor was the cultural philosophy of each space program. For instance, NASA’s primary emphasis was on drugs to treat medical events and emergencies as they happened or were anticipated. The kit would be designed to include: • Perceived health risk of each mission • Past experience of events in space • Current medical standards on Earth with new medications as they became available • Medical technology: minimally invasive and feasible in space • Crew skills and training • Impact and constraints of each mission – volume, weight, time, and power limitations The Soviet program’s medical kit underlined preventive approaches based on previous flight experience with humans and animals as well as what had and was

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anticipated to happen based on extensive ground analog studies such as bed rest studies. With over 50 years’ experience with human spaceflight, what drugs were most commonly used is a good indicator of potential and most regular needs. These were drugs to treat sleep disturbances, allergies, space motion sickness, pain, and sinus congestion. Their choice and effectiveness varied depending on: • • • •

The assumption that they act in a similar way as on Earth The route of administration on Earth which is just as effective in space Their pharmacokinetics which is mostly unknown and is similar to that on Earth Drug stability and safety which has not been altered by storage in the spacecraft environment • Human physiology in space which is not changing as a function of duration All or none of these have been found to be true.

The Medical Kit From the first human spaceflight in the Mercury mission to present-day International Space Station (ISS) operations, the kit grew from 3 medications to >191. Early flights were designed to prove that man could survive and function in the space environment. Voice communication was a crucial connection to the crew. Basic physiologic monitoring was for heart rate, ECG, and respiration. Medical findings from the first six Mercury flights from 1961–1963 of up to 34 hours duration, noted dehydration which explained weight loss and the transient tendency to faint (orthostatic hypotension) on landing. The Russians reported the first experience of nausea by Titov on his 1-day mission on the Vostok in 1961. The Mercury kit included drugs to be used for emergency use only. Intramuscular autoinjectors made it possible for the astronaut to self-administer drugs through the pressure suit. The first four Mercury missions were designed to include an anti-motion sickness drug, a stimulant, and a vasoconstrictor for the treatment of shock. These were later identified as Tigan for space motion sickness, Demerol for pain, as well as the stimulant amphetamine to be taken by mouth. Project Gemini (1965–1966) was a giant leap to 14 days of in-space duration designed to be long enough for a lunar mission with EVAs and more extensive physiological monitoring and sample collection in flight. The Gemini VII medical kit contained 11 drugs, with enough for daily consumption as needed. Both oral and injectable Marezine replaced Tigan for space sickness. APC (aspirin, phenacetin, caffeine) for headache or mild pain and oral and injectable Meperidine replaced Demerol for more severe pain. The need for a decongestant for the stuffy head feeling was fulfilled by Actifed or Sudafed. Tetracycline was the antibiotic, and eye drops of methyl cellulose were also provided. Finally, the crew requested something to counter possible diarrhea though it was mainly thought the reason was to avoid having a bowel movement at all. Lomotil was provided for this purpose. The crew

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was tested preflight for the first time for possible drug reactions to the drugs in their kit. Research proposals were solicited, which resulted in the first systematic investigations of the effects of microgravity, albeit in only two astronauts. More advanced technical vital sign monitoring was collected throughout the flight as well as during EVA. The 14-day orbital exposure confirmed mild dehydration and lack of thirst with reduced plasma volume and cell mass and post-flight OH on landing. Twenty-four-hour urine samples were collected throughout, stored and returned to Earth for analysis together with the samples collected on the ground before and after flight. There were no means of refrigeration, so all samples had to be stable at room temperature. These samples were used to monitor changes in minerals and metabolite indicators of bone and muscle loss, fluid and electrolyte changes, and endocrine parameters such as stress-related 17-hydroxycorticosteroids. These were the first data to show dramatic daily loss of calcium, confirming measurable muscle loss and reduced post-flight exercise tolerance. The Moon landing Project Apollo, though shorter in duration, differed in complexity but followed similar precautions to Gemini. Medical data were transmitted by voice communication and physiological monitoring using a telemetry multiple sensor device called the bio-belt, and private medical conferences were available to the astronauts for the first time. The bio-belt measured O2 consumption, CO2 levels, temperature, and vital signs such as heart rate, blood pressure, and respiration. Metabolic expenditure was also monitored during EVA. The lunar orbit and particularly landing aspect of the Apollo missions involved a greater degree of stress and uncertainty than Gemini. Astronauts landing on the Moon were faced with the irritating lunar fiberglass-type composition of the surface. Furthermore, mobility in lower lunar G (0.16 G) was a totally unknown feature. Medical observations confirmed and complemented previous findings such as space motion sickness, dehydration, reduced red cell mass, bone mineral loss with post-flight OH, and reduced exercise tolerance. One significant added event included an unanticipated transient arrhythmia event on Apollo 15 for which there was no medication on board. A modified medical kit was supplemented with each Apollo mission. One new feature reported in all Apollo missions was nausea and vomiting in the first few days as well as consistent difficulty sleeping. Marezine tablets were taken and Seconal capsules added for sleep problems. Astronauts who landed on the Moon had skin, eye, and respiratory tract irritation and self-medicated with Lomotil either prophylactically or for intestinal gas secondary to H2 ingestion. Actifed helped with nasal congestion. Scopolamine/Dexedrine began to be used prophylactically before reentry in the latter Apollo missions. The Skylab (1973–1974) was the first NASA space station. It covered three missions of a large station-like spacecraft. Each crew team of three astronauts included a medical officer and spent 24, 54, or 84 days in space. A crew return vehicle served to transport crew back and forth for crew exchange and could provide evacuation capability if needed.

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Skylab was specifically designed for biomedical research to study the effect on human health of living and working longer in space. The same basic tests were done in all nine astronauts which enabled identical basic study and data to be obtained in a significant number of astronauts who were trained to conduct all experiments (9 for the first 24-day segment, 6 for the second 54-day segment, and 3 for the last 84-day segment). Additional tests were added later. Since it was research-oriented, it used tele-science and data downlinking for 12–24 h after each experiment. The Skylab medical kit also known as the inflight medical support system (IMSS) was expanded to include both a medical kit and diagnostic and laboratory equipment. These were needed for diagnostic and other medical monitoring activities and weighed about 113 lbs. For example, a dental kit was included, as well as an air sampler, incubator, microscope, slide and staining kit, splints and bandages, hematology and urinalysis supplies, and an intravenous fluid kit, a kit for minor surgery as well as for diagnostic and therapeutic purposes. Problems with sleep were evident since four different sleep medications, Seconal, Restoril, Dalmane, and even chloral hydrate, were provided. After-flight records showed that all four medications had been taken at one time or another on Skylab IV including chloral hydrate in the later stages. Inadequate sleep has been a common complaint among astronauts and cosmonauts. The number and type of medications in the medical kit have grown exponentially during shuttle (STS) and International Space Station (ISS) flights. Anticipated needs were identified as research using periodic monitoring of vital signs, the development of technologies enabling real-time tele-science, wireless monitoring, more crew members as well as storage space, and a trained physician and/or medic on board. As the duration exposure on shuttle and ISS grew longer, the variety of medical events that require treatment also increased. Classes of drugs on the shuttle orbiter medical system (SOMS) began to include injectable and oral drugs, suppositories, eye drops, ointments, and dental treatments. First aid and emergency drugs such as antiemetics for space sickness, adrenergic agonist agents in the form of an EpiPen or amphetamine, antiarrhythmic and cardiotropic drugs for cardiac incidents, antimicrobials, and local anesthetics are now included. Corticosteroids for internal or external use, female hormone therapy if requested, and antiviral ointment effective against herpesviruses are other examples. Drug classes on STS and ISS have come to include narcotics, analgesics and their antidotes, anti-diarrheals like Lomotil and Pepto-Bismol, and the laxative Dulcolax tablets. More than ten antimicrobials as well as antifungal and antibiotic dermatological topical medications make now part of the kit. Hypnotics, anxiolytics, and sedatives continue to be needed as Restoril, Valium, Versed, and Ambien have now replaced Seconal and chloral hydrate. Antihistamines, decongestants, and cough lozenges are there for a variety of allergic reactions. The Russian space medical kit on ISS is not very different with fewer drugs provided. Medications include anti-inflammatory, antiseptic, pain, burn, and wound kits. Cardiovascular, gastrointestinal, urological, psychotropic, preventive, and ointment kits round up their supplies.

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Medical Incidents and Frequency Both US and Russian choices have been guided by the occurrence of incidents and their frequency. • Space nausea and vomiting. • Headache and congestion. • Back pain from decompression in space and compression on return, especially after atrophy of the paraspinal muscle support system. • Urinary tract infection is not uncommon. • Urinary retention – relieved by bladder catheterization; one case is believed to be due to unexpected reaction to medications. • Cardiac dysrhythmias, cardiac ischemia, or other cardiac abnormalities. • Human factors – crew-crew and crew-ground interpersonal conflicts, crew concerned about other’s aggressive behavior, grief reaction seen in all programs, exercise-related discomfort or irritation, and variability in transitions of memory such as language skills and social attachments. • Misuse of on-orbit medications and possible excessive use before EVA. Though trained, crews have latitude in their assessment of “need to use” medications and when. • EVA-related injuries, discomfort, and occasional cardiac abnormality. • Variable environmental events such as chemical irritation or pneumonia due to leaks of preservatives, solvents, and gases like formaldehyde and CO2, combustion, contaminated air and water, odors, and ventilation, lunar dust in Apollo program, and light, noise, and dry eyes. • Nutrition – both timing, quantity and quality – interacts with physiological changes as well as with any drugs taken for whatever reasons. • Drugs and tests as part of research experimentation may cause expected or unexpected interactions as well as interfere with operational duties. • Drugs as testing or treatment of an ongoing spaceflight-related event such as bone loss. • Drugs as chronic treatment to supplement minerals and electrolytes and to measure for vitamin D3 deficiency occurring in the inadequate light intensity of the space habitat or from nutritional deficiency.

Dose Response Shelf life: The effectiveness of a medication depends on its shelf life as well as its route of administration, absorption, action, effectiveness, and metabolism. Some medication shelf life studies have been done but not enough. Each item in the kit must be systematically tested over periods of time in a consistent, ongoing, and well-controlled study. There is no doubt that more medication shelf life data is needed as are extensive pharmacokinetic studies.

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Pharmacokinetic studies during spaceflight were valiantly attempted by L Putcha et al. (1994) and her colleagues but are limited. Not only are they complicated to conduct in space, but the few that were done were attempted during STS missions of a few days when physiological responses to the space environment are dynamically changing. In my view, it is virtually impossible to conduct systematic and reliable pharmacokinetic studies in space since so much else is going on in the astronaut’s busy day. On the other hand, extensive studies can be done in the ground simulation HDBR model where similar shifts in fluids and electrolytes and protein and glucose metabolism are known to occur. Then only selected time points and medications can be reproduced in space. Thus, space data can be compared against a thorough database from HDBR studies. In this model evaluation of absorption, binding and metabolism may be similarly established. For example, little is known about general anesthesia in space except incidentally and in a limited way in some space animal experimentation. In these cases, anesthesia was used as a tool and not studied for the purpose of understanding the effect of microgravity on anesthesia. Though not in space, one of these occasions serendipitously provided valuable insight. Immediately post-flight in two nonhuman primates, animals were anesthetized to conduct bone scans. One primate died. The other experienced distress in the sitting position even before it was ever anesthetized. A thorough investigation of the events revealed that the death of the first animal was caused after anesthesia from a deficient orthostatic response to being tilted up. The second animal survived by maintaining it horizontal the entire time before as well as during the anesthesia. The incident was reviewed in depth. The conclusion of the review committee was that under the post-flight conditions, death was the result of enhanced orthostatic hypotension where orthostatic hypotension was likely aggravated by the anesthesia when picking the animal up to move it and therefore challenged by upright posture. Sad as the loss of this animal was, the results pointed to the need to be particularly cautious about accelerating the resumption of upright posture when and if general anesthesia may be needed in an astronaut immediately post-flight. Care of the astronaut does not end with the landing of the spacecraft. The Russians have always paid a great deal of attention to the post-recovery period. Fortunately, as US flights have grown in duration as well as landing in Russia, similar attention is being paid to the recovery period. No doubt systems other than BP reflexes must be affected post-flight in similar ways. It seems logical that emergency procedures in returning astronauts requiring anesthesia must take into account possible space-induced changes in sensitivity of all systems. Furthermore, as mission grows longer, recovery is slower.

Routes of Administration It has been known from the earliest days of humans in space that drugs taken orally were not as effective. Attempts to treat the nausea with or without vomiting with pills were not effective. This triggered the design of skin patches. These were

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being introduced by the drug company Alza for hormone administration. We asked them to develop and test scopolamine patches to treat space motion sickness. They provided relief and were particularly used for the nausea during reentry and return to Earth. From scopolamine, promethazine was adopted as the antiemetic of choice, but taken orally it was also not very effective. Astronaut Jim Bagian, anesthesiologist by training, used the preparation in the intramuscular syringe, and the effect was instant and miraculous. Research has also shown that gastrointestinal transit time is considerably slowed down in space (Amidon et al. 1991). This fact is now taken into account whenever drugs are administered in space. Sublingual and intranasal administration of drugs may offer solutions. Though suppositories are available for some medications, their popularity varies with cultural differences of international crews. Hypnotics may be one such class of drugs that have been found consistently to be less or ineffective in space. Their usefulness may be increased by changing the route of administration, possibly bypassing gastrointestinal absorption issues.

Multiple Causes In assessing the effectiveness of any medication in space, the importance of multiple factors has become overwhelmingly highlighted by the work of Pierce and his colleagues (Pierson et al. 1994). In fact, space is bringing increased awareness of how multiple factors should be considered in every therapeutic use of drugs. Not only could the choice and use of a drug be affected, but the condition of the host and their reaction to a drug must be considered. Challenge Infection

Host Man in Space "Bacterial proliferation "Viral reactivation

Drug Antibiotic Antibiotic Antiviral agent

Baseline physiology of Host #Sensitivity to drug "Resistance to drug "Resistance to drug

The table points out the multiple sites that can interfere with the effective action of a drug to infection (Pierson et al. 2008). For example, as in the case of the response of astronauts in space to infections, there are multiple targets that could change the outcome. Since the early days of the space program, it was observed that bacteria multiplied rapidly in vitro. Changes in the virulence of the microorganism by microgravity, its resistance to antibiotic or antiviral agent in vitro in space, as well as on the effect of microgravity on the host, and the sensitivity or resistance of the host to the antibiotic due to prior overuse or other treatment are all factors to be considered (Wilson et al. 2008). One of the most common complaints in microgravity is difficulty in getting restful sleep. All astronauts without exception have complained that even though they might sleep several hours, when they wake up, they do not feel rested. A variety of sleeping medications have been provided and used but still seem to fall short of helping them get satisfactory sleep. A pervasive complaint has been the discomfort

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of sleeping in the spacecraft. Noise is a factor. Cosmonaut and cardiologist Oleg Atkov who spent 6 months on the Russian Space Station Salyut explained that though he slept, he woke up feeling “unrested.” He attributed this to his inability to “sense, that you could put your head down as you do on Earth.” This logical explanation, as far as I know, has not been generally discussed. For instance, did the Apollo astronauts have similar sensations? On Skylab, sleeping medications ranged from Seconal to the old-time sleeping medication, chloral hydrate drops also known as “knockout drops,” because of their effectiveness on Earth. The fact that the crew of three, on Skylab IV, the longest of the Skylab missions, kept trying everything in the medical kit to help them sleep attests to the difficulty of finding something that worked. Records of sleep medications taken during Skylab IV, the 84-day mission, showed that all four sleeping medications were taken by the three astronauts presumably with little satisfaction. Records show how many sleeping medications were left at the end of the mission with no information on who took what and when. More accurate records would have been useful. We all know that we do not sleep quite as well sitting up as lying down. The importance of gravity on sleep has not been studied. EEGs have been monitored in space and seem normal (Dijk et al. 2001). However, reported effectiveness of that sleep does not match the quality of the EEGs.

Future Recommendations It must be recognized that systematic studies of pharmacokinetics and pharmacodynamics in space are not likely to be done in the near future. New drugs will be considered for the kit as missions grow longer. Anesthetics, for instance, or antiarrhythmics may need to be used with little specific prior knowledge. A program of systematic studies of carefully chosen representative drugs can be performed using prolonged HDBR or other microgravity simulation. But that assumes a longterm commitment of a well-planned pharmacokinetic and pharmacodynamic series of studies. However, pertinent information may be derived from another model of the considerable database in individuals that share physiological changes with those living in the microgravity of space. Where could such a database be found?

Ground Research Models Considerable work has now accumulated indicating not only that the ground simulation model of HDBR could serve as a test system for the study of pharmacodynamics in space but that space and aging result in similar physiological changes (Vernikos and Schneider 2010; Vernikos 2018). The latter is particularly relevant since a pharmacological and pharmacokinetic database in the over 65 population is now considerable and growing. Aging and deconditioning in space are similar in many if not all respects. For example, progressive hypovolemia and reduced aerobic

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capacity are also seen in aging. OH becomes evident. There is an age-related reduction in the sensitivity of the arterial baroreflex (Ferrari et al. 2003), and the endothelium lining is affected (Delp 2007). The calculated loss of cardiovascular functional capacity in 3 weeks of HDBR as measured by cardiac output is equivalent to that seen in the same subjects after 30–40 years of aging (McGavock et al. 2009). Where physiological changes in space and aging are similar, this database could provide an invaluable indicator of what might be expected in space. Such a database not only exists and is growing but includes comprehensive information across genders on factors pertinent to drug absorption, distribution, metabolism, and elimination. Absorption changes, for example, reduced absorptive surface, splanchnic blood flow, and gastric motility, have been observed in space travelers as well as older persons. Age-like changes in absorption would be expected in space, as a result of the reduced plasma volume and total body water, decreased lean body mass, increased body fat particularly with fatty infiltration of muscle and other organs, reduced protein synthesis, and altered protein binding. Distribution is the amount of drug that enters in various parts of the body. Drugs may be distributed more easily in the fatty tissue than in the lean muscular tissue, due to the physiological changes that are occurring with aging or living in microgravity. This might include a higher proportion of fat in lean body tissue, a decrease in total body water, and decreased plasma albumin, the main protein in the blood. If so, it may be necessary to adjust proportionately the dose of some highly fat-soluble, water-soluble, or protein-bound drugs to compensate in each case for the physiological changes in the body. For instance, fat-soluble drugs like hypnotics or analgesics, like valium or phenobarbital, will be more widely distributed and may result in less intense immediate effect than expected. They may also show a prolonged elimination half-life in older persons or in space lasting longer as a result in slow release of the drug stored in fatty tissue. For example, the volume of distribution of diazepam is increased almost twofold in older patients, and its elimination half-life is prolonged from 24 h in young patients to approximately 90 h in older patients. Does the same apply in astronauts or HDBR volunteers? On the other hand, the volume of distribution of water-soluble drugs is reduced in older persons and expected to be reduced in astronauts as well, implying that a reduced dose would be required. A lower dose of drugs such as cimetidine, gentamycin, and meperidine may be required in HDBR and in space. Metabolism drug oxidation, reduction, and hydrolysis decrease substantially with age. Does spaceflight result in a similar effect? A reduction in Phase 1 metabolism involving the P450 system would be expected to prolong the half-lives of drugs like barbiturates, amitriptyline, diazepam, diphenhydramine, flurazepam, lidocaine, or ibuprofen. Drugs that are metabolized by conjugation to organic substrates such as through sulfation, acetylation, methylation, or glucuronidation are less affected with age and would not have a prolonged half-life. Drugs such as triazolam may therefore be a safer choice. Elimination of drugs and their metabolites through the kidneys varies considerably with age and probably in astronauts. It would be affected by reduced renal

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plasma flow and glomerular filtration rate. Reduced excretion in the elderly is also seen with drugs that depend on glomerular function such as gentamycin or on tubular secretion like penicillin. It should be noted that though serum creatinine level remains unchanged at about 1.0 mm/Dl, creatinine clearance steadily decreases from age 25 to age 85. What can and should be started immediately is a systematic analysis of the drugs in the medical kit against the extensive pharmacokinetic and pharmacodynamic database now available in those 65 years and older. Such an analysis can provide a guide to possible pharmacological alterations and side effects in space. Age is not a static state. And though the existing pharmacokinetic database is based on persons 65 and older, it might prove more useful to break it down by age groups, perhaps in decades, to provide greater detail. Similarly, in space the rate of bone loss or some other more readily accessible biomarker that shows an age-like rate of decrease in space could be used for comparison purposes. Days in space could be checked against this database as a general guide of what might be expected. It may not be, at first, a definite information but would provide a useful guide where no information currently exists. Several physiological changes in space in fact are said to proceed at a faster rate than they do on Earth during aging. If this comparison holds true as mission duration gets ever longer, then the aging pharmacodynamic database, once validated, could provide a valuable tool in the decision-making process of medical operations.

References Amidon G, DeBrincaet GA, Najib N (1991) Effect of gastric emptying, intestinal transit, and drug absorption. J Clin Pharmacol 31(10):877–1040. https://doi.org/10.1002/j.1552-4604.1991. tb03658.x Delp MD (2007) Arterial adaptations in microgravity contribute to orthostatic tolerance. J Appl Physiol 102:836 Dijk DJ, Neri DF, Wyatt JK, Ronda JM, Riel E, Ritz-De Cecco A, Hughes RT, Elliott AR, Prisk GK, West JB (2001) Sleep, performance, circadian rhythms and light-dark cycles during two space shuttle flights. Am J Phys 281:1647–1664 Ferrari AU, Radaeli A, Cantola M (2003) Aging and the cardiovascular system. J Appl Physiol 95:2591–2597 Fischer CL (2007) The evolution and decision-making process for medical kits in space medical operations. Aviat Space Env Med Ann Mtg New Orleans 78:211–313 McGavock JM, Hastings JD, Snell PG, McGuire DK, Pacini E, Levine BD, Mitchell JH (2009) A forty-year follow-up of the Dallas bed rest and training study: the effect of age on the cardiovascular response to exercise in men. J Gerontol Biol Sci Med 64:293–299 Pierson DL (1994) Ch 8 Microbiology. In: Nicogossian AE, Huntoon CL, Pool SL (eds) Space physiology and medicine, 3rd edn, Lea & Febiger, Philadelphia, PA, pp 157–166 Pierson DL, Mehta SK, Stowe RP (2008) Chapter 40 Reactivation of latent herpes viruses in astronauts. In: Ader R (ed) Psychoneuroimmunology, vol 1. Elsevier, Amsterdam, pp 851–868 Putcha L, Vaksman Z, Boyd J (2007) Pharmacotherapeutic challenges of human space exploration. J Gravit Physiol 13:28 Putcha L, Pool SL, Cintron NM (1994) Ch 25 Pharmacology. In: Nicogossian AE, Huntoon CL, Pool SL (eds) Space physiology and medicine, 3rd edn, Lea & Febiger, Philadelphia, PA, pp 435–446

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Schmidt CF, Lambertsen CJ (1965) Pharmacology in space medicine. Annu Rev Pharmacol 10:383–404. https://doi.org/10.1146/annurev.pa.05.040165.002123 Vernikos J (2018) Aging. In: Young LF, Young JP (eds) Encyclopedia of bioastronautics. Springer International Publishing AG. https://doi.org/10.1007/978-3-319-10152-1_96-1 Vernikos J, Schneider VA (2010) Space, gravity and the physiology of aging: a mini-review. Gerontology 56:157–166 Wilson JW, Ott CM, Quick L, Davis R, Zu Bentrup KH, Crabbe A, Richter E, Sarker S, Barilla J, Porwollik S, Cheng P, McClelland M, Tsaprailis G, Pierson DL, Smith SM, Nickerson CA et al (2008) Media ion composition controls regulatory and virulence response of Salmonella in spaceflight. PLoS One 3:3923

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Tekilanand Persaud and Yashwant V. Pathak

Contents Causes of Physical and Chemical Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiation Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Magnetic and Electric Field Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects of Acceleration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects of Vibration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects of Freefall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Atmospheric Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Decomposition and Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Packaging and Coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Container Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Realized Changes from Experimentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Space Transportation System (Du et al. 2011) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . International Space Station (Wotring 2016) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Specific Drug Susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Manufacturing Pharmaceuticals for Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

The use of pharmaceuticals has been and remains commonplace in human spaceflight missions. In this chapter, the causes of physical and chemical changes of pharmaceuticals in the spaceflight environment are detailed from first T. Persaud Department of Aeronautics and Astronautics, Purdue University, West Lafayette, IN, USA e-mail: [email protected] Y. V. Pathak (*) USF Health Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA Faculty of Pharmacy, Airlangga University, Surabaya, East Java, Indonesia e-mail: [email protected] © Springer Nature Switzerland AG 2022 Y. V. Pathak et al. (eds.), Handbook of Space Pharmaceuticals, https://doi.org/10.1007/978-3-030-05526-4_30

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principles. Experimentally-realized changes of pharmaceuticals aboard spacecraft such as the space shuttle (STS) and ISS are compared against United States Pharmacopeia standards and provide a means of assessing the viability of pharmaceuticals in long-term human space missions; analysis of results and the widespread use of pharmaceuticals in human missions suggests variability in the quality of pharmaceuticals for space missions ought to be narrowed to provide consistency in the expected lifetime of pharmaceuticals and support expected future increases in mission duration. Pharmaceuticals remain an integral part of space missions. Medications have been used in 94% of 219 instances of human spaceflight from 79 space shuttle missions (Putcha et al. 1999), indicating that their proper use is paramount to the success of manned missions. This chapter details the physical and chemical changes experienced by pharmaceuticals in the spaceflight environment. The physical and chemical changes undergone by pharmaceuticals flown on space missions must be thoroughly evaluated to determine the feasibility of using pharmaceuticals with spaceflight. Loss of potency and transformation of chemical composition of medications may jeopardize the health and lives of astronauts on extended spaceflight missions; while medications are replaced 6 months before their expiry dates on the International Space Station (ISS) (NASA 2011), such resupply services are not available on extended missions significantly beyond Earth’s sphere of influence, such as on manned missions to Mars and the outer solar system, where transit times may range from 9 months to several years (Foster and Daniels 2010). It is therefore pertinent to measure the stability of medications along standard parameters, such as shelf life, which is the time it is expected for a medication to degrade below 90% of its claimed effectiveness (Carstensen 1974). The US Department of Human Health and Services and Food and Drug Administration (FDA) define a significant change to be a failure of a drug to meet acceptance criterion in degradation amount, measurable characteristics (color, phase separation, hardness, pH, etc.), or a 5% change in measured quantities from the initial value (ICH 2003). The FDA requires that drug manufacturers determine the lifespan of a produced drug within which the drug can be used with full potency, which is usually 1–2 years after the manufacture date (Du et al. 2011). The shelf life of pharmaceuticals may be determined under conditions like those seen in spaceflight to provide an accurate measure of pharmaceutical effectiveness and to determine whether more rigorous storage methods are required to extend the medication’s life. The modelling of spacecraft failure rates provides a useful reference that may be expected in pharmaceutical failure rates, considering their very similar environments. Spacecraft are designed to shield sensitive components from environmental hazards and prolong their individual useful life. Given that the integrity of the payload is contingent on seamless shielding, pharmaceuticals, which must be shielded from radiation, are expected to have overall failure rates governed by a typical bathtub curve with three Weibull failure rates (Pisacane 2008) for the probability density function, p(t), shown in (1):

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1 0.9

End of life wear-out Increasing failure rate

0.8

b>1

Failure rate

0.7

Infant mortality Decreasing failure rate

0.6

b