Respiratory Drug Delivery PDF
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Respiratory Drug Delivery Editor Peter R. Byron, Ph.D. Associate Professor Department of Pharmacy and Pharmaceutics Medical College of Virginia/Virginia Commonwealth University Richmond, Virginia First published 1990 by CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 Reissued 2018 by CRC Press © 1990 by Taylor & Francis CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. 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PREFACE While bronchodilators, steroids, and antiallergic compounds have been administered as aerosols for some years, recent advances in respiratory physiology, immunology, and biotech nology have substantially increased the number of new drug candidates for delivery to the lung. Compounds requiring aerosol administration may be intended for local or systemic activity and to enable the nonparenteral administration of new generation peptides and protein requies that alternative routes are explored for all compounds with substantial first-pass metabolism and/or breakdown in other sites of administration. While some routes of drug delivery have been explored in detail, this cannot be said of the respiratory tract. Drug delivery to the lung can be difficult to accomplish and expertise in the area is spread across several academic disciplines. The present text, which is focused on subjects embracing the topic of drug delivery to the lung itself, has been created by a group of scientists who assembled at The University of Kentucky to present the subject material at a symposium on respiratory drug delivery held in May 1988. This text, and the symposium from which it was created, was designed to span the relevant subject areas from aerosol deposition through pharmaceutical chemistry and formulation, to the final clinical evaluation of pharmaceutical products. The authors, who are recognized authori ties in their subject areas, were asked to present and apply their topics through the current state of the art as it affects drug delivery to the lung. Thus, toxicology is considered from the point of view of drugs and the pharmaceutical excipients used in aerosols. Metabolism of drugs in the respiratory tract is addressed prior to considerations of pharmaceutical chemistry, where pro drug approaches are introduced as a means of improving molecular targeting to the lung. The simultaneous kinetic processes of particulate clearance, dissolution, and absorption are consid ered with specific regard to answering questions concerning drug longevity in the lung. Later chapters consider the formulation of drugs as metered and nonmetered aerosol dosage forms. An appendix to the chapter on formulation of MDIs reviews the importance of trace quantities of water to the stability of suspension formulations. Chapter 8 in the text reviews the current practices employed in the clinical testing of aerosol products alongside a number of issues which are currently undergoing debate between clinical scientists and regulatory authorities in the U.S. and other countries. As editor, I extend my thanks to all those who have contributed material for this book, to Michael Shannon who made the symposium at Kentucky possible, to numerous colleagues in the pharmaceutical industry, and to my graduate students who continued to provide data up to the last minute. Peter R. Byron THE EDITOR Peter R. Byron, Ph.D. is Associate Professor of Physical Pharmacy, Department of Pharmacy and Pharmaceutics, Medical College of Virginia/Virginia Commonwealth Univer sity School of Pharmacy, Richmond, VA. He graduated in 1970 from the University of Manchester, England, with a B.Sc. in Pharmacy (Honors in Pharmaceutics) and obtained his Ph.D. from the same institution in 1973. He performed postdoctoral research in the U.K. (University of Aston) and the U.S. (Ohio State University) between 1974 and 1977. Between 1975 and 1984 he held the position of Lecturer in Pharmaceutics at Aston University, Birmingham, England. He joined the faculty at the University of Kentucky College of Pharmacy in July 1984. He moved to Richmond to his present position in June 1988. Dr. Byron is a registered pharmacist in the U.K. and Charter Member of the American Association of Pharmaceutical Scientists in the U.S. He has received several awards and recognition for research and has made numerous invited presentations within the pharmaceu tical industry and academic institutions in Europe and the U.S. He has published over 40 research articles, received research funding from local, federal, and industrial institutions and acted as advisor and major professor for a number of graduate students and postdoctoral. His current research is focused on inhalation aerosol science where he is attempting optimized drug delivery to the respiratory tract and investigating physicochemical and formulation factors controlling aerosol generation, deposition, release, and absorption via the lung. ACKNOWLEDGMENTS The Continuing Education Office at the University of Kentucky is most pleased to have participated in the organization and delivery of the symposium on respiratory drug delivery which resulted in the publication of this text. We are grateful to two companies for support of our endeavors in this respect. These are 3M Company, St. Paul, MN and ATI Pharmaceuticals, New Canaan, CT. We thank Catherine Kriske and H. R. Shepherd in particular and also colleagues at the University of Kentucky and staff of the Continuing Education Office for their assistance in bringing events to such a successful conclusion. This marked a beginning for us in the area of scientific program development. It is our belief that symposia, such as this one, provide a much needed and extremely useful forum for the dissemination of scientific knowledge, the teasing out of innovative ideas among colleagues, and the cross-fertilization of the scientific enterprise. From such interactions come new and creative approaches to solving the problems faced by any science, collaborative research efforts, and the opportunity to develop a growing collegiality among like-minded scientists. Michael C. Shannon, Ph.D. Director, Continuing Pharmacy Education College of Pharmacy University of Kentucky Lexington, Kentucky Peter R. Byron, Ph.D. Associate Professor School of Pharmacy Virginia Commonwealth University Richmond, Virginia CONTRIBUTORS Tahir Ahmed, M.D. Harry B. Kostenbauder, Ph.D. Associate Professor of Medicine Professor, Associate Dean for Research Pulmonary Division/Department of College of Pharmacy Medicine University of Kentucky Mount Sinai Medical Center Lexington, Kentucky Miami Beach, Florida Nicholas C. Miller Peter R. Byron, Ph.D. Pharmaceuticals Division Associate Professor 3M Company Department of Pharmacy St. Paul, Minnesota Medical College of Virginia/Virginia Commonwealth University Elaine M. Phillips Richmond, Virginia Research Assistant Department of Pharmacy and Peter A. Crooks, Ph.D. Pharmaceutics The Southern Research Institute Medical College of Virgninia/Virginia Birmingham, Alabama Commonwealth University Richmond, Virginia L. A. Damani, Ph.D. Professor and Head Steven Slonecker Chelsea Department of Pharmacy Department of Pharmacy Kings College London University of Kentucky London, England Lexington, Kentucky Timothy R. Gerrity, Ph.D. David J. Velasquez, Ph.D. Chief, Aerobiology Section Research Specialist Clinical Research Branch Biosciences Laboratory EPA 3M Company Research Triangle Park, North Carolina St. Paul, Minnesota TABLE OF CONTENTS Chapter 1 Pathophysiological and Disease Constraints on Aerosol Delivery............................................1 Timothy R. Gerrity Chapter 2 Toxicological Responses to Inhaled Aerosols and Their Ingredients.....................................39 David J. Velasquez Chapter 3 Drug Application to the Respiratory Tract: Metabolic and Pharmacokinetic Considerations................................................................................................61 L. A. Damani and Peter A. Crooks Chapter 4 Pro-Drugs for Pulmonary Drug Targeting.................................................................................91 H. B. Kostenbauder and S. Sloneker Chapter 5 Absorption, Clearance, and Dissolution in the Lung..............................................................107 Peter R. Byron and Elaine M. Phillips Chapter 6 Aerosol Formulation, Generation, and Delivery Using Nonmetered Systems....................143 Peter R. Byron Chapter 7 Aerosol Formulation, Generation, and Delivery Using Metered Systems...........................167 Peter R. Byron Chapter 8 Clinical Testing of Aerosol Drugs............................................................................................207 Tahir Ahmed Appendix The Effects of Water in Inhalation Suspension Aerosol Formulations................................249 Nicholas C. Miller Index 259 1 Chapter 1 PATHOPHYSIOLOGICAL AND DISEASE CONSTRAINTS ON AEROSOL DELIVERY* Timothy R. Gerrity TABLE OF CONTENTS I. Introduction...........................................................................................................................2 II. Aerosols..................................................................................................................................3 III. Aerosol Dynamics.................................................................................................................4 A. Sedimentation..............................................................................................................5 B. Particle Stopping Distance.........................................................................................5 C. Stokes-Cunningham Slip Correction Factor............................................................5 D. Aerodynamic Equivalent Diameter..........................................................................6 E. Diffusion......................................................................................................................6 IV. Structure and Function of the Human Respiratory Tract..................................................6 A. Upper Respiratory Tract............................................................................................7 B. Conducting Airways...................................................................................................7 C. Alveolar Airspaces.....................................................................................................8 V. Morphometric Descriptions of the Respiratory Tract.......................................................8 VI. Aerosol Deposition Within the Lower Respiratory Tract...............................................10 A. Inertial Impaction......................................................................................................10 B. Sedimentation............................................................................................................11 C. Diffusion....................................................................................................................12 D. Other Mechanisms of Deposition............................................................................12 E. Joint Deposition Probability....................................................................................12 F. Calculation of Lower Respiratory Tract Deposition.............................................12 G. Predictions of Lower Respiratory Tract Deposition..............................................13 VII. Upper Respiratory Tract Deposition.................................................................................15 A. Deposition in the Mouth and Nose..........................................................................17 B. Deposition in the Larynx..........................................................................................18 VIII. Deposition Within the Entire Respiratory Tract and Comparisons with Data.......................................................................................................19 IX. Hygroscopic Aerosol Behavior.........................................................................................22 * This chapter has been reviewed by the Health Effects Research Laboratory, U.S. Environmental Protection Agency, and was approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.
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