Pharmaceutical Suspensions

Transcription

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2 Pharmaceutical Suspensions

3 Alok K. Kulshreshtha G. Michael Wall Editors Onkar N. Singh Pharmaceutical Suspensions From Formulation Development to Manufacturing

4 Editors Alok K. Kulshreshtha Alcon Research Ltd Forth Worth, TX USA Onkar N. Singh Alcon Research Ltd, Forth Worth, TX USA G. Michael Wall Alcon Research Ltd Forth Worth, TX USA ISBN e-isbn DOI / Springer New York Dordrecht Heidelberg London Library of Congress Control Number: AAPS 2010 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Printed on acid-free paper Springer is part of Springer Science+Business Media (

5 Preface The suspension dosage form has long been used for poorly soluble active ingredients for various therapeutic indications. Development of stable suspensions over the shelf life of the drug product continues to be a challenge on many fronts. A good understanding of the fundamentals of disperse systems is essential in the development of a suitable pharmaceutical suspension. The development of a suspension dosage form follows a very complicated path. The selection of the proper excipients (surfactants, viscosity imparting agents etc.) is important. The particle size distribution in the finished drug product dosage form is a critical parameter that significantly impacts the bioavailability and pharmacokinetics of the product. Appropriate analytical methodologies and instruments (chromatographs, viscometers, particle size analyzers, etc.) must be utilized to properly characterize the suspension formulation. The development process continues with a successful scale-up of the manufacturing process. Regulatory agencies around the world require clinical trials to establish the safety and efficacy of the drug product. All of this development work should culminate into a regulatory filing in accordance with the regulatory guidelines. Pharmaceutical Suspensions, From Formulation Development to Manufacturing, in its organization, follows the development approach used widely in the pharmaceutical industry. The primary focus of this book is on the classical disperse system poorly soluble active pharmaceutical ingredients suspended in a suitable vehicle. After discussing various disperse systems, the theory of disperse systems and commonly used excipients, the remaining chapters in this textbook systematically explain the development of pharmaceutical suspensions, from the pre-formulation stage to clinical development, regulatory submission and commercial manufacturing. Additionally, the emerging area of nano-suspensions as applied to the pharmaceutical field is also discussed. Each of the chapters in Pharmaceutical Suspensions was written independently by scientists who are skilled in their specific areas. Contributing authors represent a cross-sections of scholars from academic, industrial and governmental affiliations. Pharmaceutical Suspensions, From Formulation Development to Manufacturing is organized in a total of ten chapters: Chapter 1 introduces various pharmaceutical disperse systems in-depth. Chapter 2 presents the general principles of suspension dosage form and Chapter 3 discusses commonly used excipients in pharmaceutical v

6 vi Preface suspensions. Chapter 4 systematically highlights steps involved in pharmaceutical development of suspension dosage forms. Chapter 5 focuses on preclinical development of suspension formulations. Analytical tools needed to characterize pharmaceutical suspensions dosage forms are discussed in Chapter 6. The clinical development aspects of suspension drug products are discussed in Chapter 7. Chapter 8 highlights scale up and technology transfer of the development of pharmaceutical suspensions. Chapter 9 reviews the science and regulatory perspectives of pharmaceutical suspensions. Finally, Chapter 10 deals with the pharmaceutical applications of nano-suspensions as nanomedicine, an emerging technology area. Pharmaceutical Suspensions, From Formulation Development to Manufacturing should serve as a good resource for pharmaceutical scientists, process scientists and chemical engineers involved in the areas of research and development of pharmaceutical suspension dosage forms, and for new and sustaining scientists of the pharmaceutical and chemical fields. The fundamental aspects together with the practical case studies should also make this a useful source for undergraduate and graduate education. Forth Worth, TX Alok K. Kulshreshtha, Ph.D. Onkar N. Singh. Ph.D., M.B.A. G. Michael Wall, Ph.D.

7 Acknowledgements We wish to acknowledge our families for their support and encouragement. We also wish to express our sincere gratitude to all the contributors who made this textbook possible. Their patience and perseverance throughout this process is greatly appreciated. vii

8 Contents 1 Various Pharmaceutical Disperse Systems... 1 Chandrasekar Manoharan, Ashwin Basarkar and Jagdish Singh 2 General Principles of Suspensions Mohammad T. H. Nutan and Indra K. Reddy 3 Commonly Used Excipients in Pharmaceutical Suspensions R. Christian Moreton 4 Pharmaceutical Development of Suspension Dosage Form Yusuf Ali, Akio Kimura, Martin J. Coffey, and Praveen Tyle 5 Preclinical Development for Suspensions Sudhakar Garad, Jianling Wang, Yatindra Joshi, and Riccardo Panicucci 6 Analytical Tools for Suspension Characterization Alan F. Rawle 7 Clinical Trials of Suspension Drug Products G. Michael Wall and Terry K. Wiernas 8 Scale Up and Technology Transfer of Pharmaceutical Suspensions Yashwant Pathak and Deepak Thassu 9 The Science and Regulatory Perspectives of Pharmaceutical Suspensions Abhay Gupta, Vilayat A. Sayeed, and Mansoor A. Khan ix

9 x Contents 10 Solid Nanosuspensions: The Emerging Technology and Pharmaceutical Applications as Nanomedicine Sudhir Verma and Diane Burgess Index

10 Contributors Yusuf Ali, Ph.D. Vice President, Santen Incorporated, Napa, CA, USA Ashwin Basarkar, Ph.D. Pharmaceutical Sciences Department, North Dakota State University, Fargo, ND, USA Diane Burgess, Ph.D. Professor of Pharmaceutics, University of Connecticut, School of Pharmacy, Storrs, CT, USA Martin J. Coffey, Ph.D. Principal Scientist, Pharmaceutical Product Development, Bausch and Lomb, Inc., Rochester, NY, USA Sudhakar Garad, Ph.D. Group Head, Novartis Institute for Biomedical Research, Cambridge, MA, USA Abhay Gupta, Ph.D. Pharmacologist, Division of Product Quality Research, Office of Testing and Research, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA Yatindra Joshi, Ph.D. Vice President, Generic R&D, Teva Pharmaceuticals, North Wales, PA, USA (former Vice President, Novartis Pharmaceuticals, NJ, USA) Akio Kimura Head of Pharmaceutical Development, Santen Incorporated, Osaka, Japan Mansoor A. Khan, Ph.D. Director, Division of Product Quality Research (DPQR), Office of Testing and Research (OTR), Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD, USA xi

11 xii Contributors Alok K. Kulshreshtha, Ph.D. Associate Director, Pharmaceutical Technology, Alcon Research Ltd., Fort Worth, TX, USA Chandrasekar Manoharan, Ph.D. Pharmaceutical Sciences Department, North Dakota State University, Fargo, ND, USA R. Christian Moreton, Ph.D. FinnBrit Consulting, Waltham, MA, USA Mohammed T.H. Nutan, Ph.D. Irma Lerma Rangel College of Pharmacy, Texas A & M University, Kingsville, TX, USA Riccardo Panicucci, Ph.D. Global Head, Novartis Institute for Biomedical Research, Cambridge, MA, USA Yashwant Pathak, Ph.D. Assistant Dean of Academic Affairs, Professor and Chair, Pharmaceutical Sciences, College of Pharmacy, Sullivan University, Louisville, KY, USA Alan F. Rawle, Ph.D. Divisional Manager, Malvern Instruments, Inc., Westborough, MA, USA Indra K. Reddy, Ph.D. Professor and Dean, Irma Lerma Rangel College of Pharmacy, Texas A & M University, Kingsville, TX, USA Vilayat A. Sayeed, Ph.D. Division of Chemistry, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD, USA Jagdish Singh, Ph.D. Professor and Chairman, Pharmaceutical Sciences Department, North Dakota State University, Fargo, ND, USA Onkar N. Singh, Ph.D., MBA Assistant Director, Development, Alcon Research Ltd., Fort Worth, TX, USA Deepak Thassu, Ph.D., MBA Vice President of Pharmaceutical Development, PharmaNova Inc., Victor, NY, USA Praveen Tyle, Ph.D. Senior Vice President and Global Head, R&D and BD&L, OTC, Novartis Consumer Health Care, Parsippany, NJ, USA Sudhir Verma, Ph.D. University of Connecticut, School of Pharmacy, Storrs, CT, USA

12 Contributors xiii G. Michael Wall, Ph.D. Senior Director, Alcon Research Ltd., Fort Worth, TX, USA Jianling Wang, Ph.D. Senior Research Investigator, Novartis Institute for Biomedical Research, Cambridge, MA, USA Terry K. Wiernas, Ph.D., MBA Vice President, Alcon Inc., Fort Worth, TX, USA

13 About the Editors Alok K. Kulshreshtha, Ph.D., Associate Director, Pharmaceutical Technology at Alcon Research Ltd., Fort Worth, TX, has 20 years of experience in the development of sterile ophthalmic, contact lens care, and dry eye products. During this tenure in pharmaceutical industry, Dr. Kulshreshtha has worked on several suspension drug products in different stages of development. Dr. Kulshreshtha s interest in the suspension area started almost 30 years ago when he began his doctoral dissertation on suspension rheology. Over the years, Dr. Kulshreshtha has worked on many new technologies for producing sterile suspensions. Dr. Kulshreshtha is the inventor/co-inventor of several patents and has authored many peer-reviewed publications. Dr. Kulshreshtha is a member of the American Association of Pharmaceutical Scientists (AAPS) and has been reviewer for AAPS abstracts screening for posters and symposia. Dr. Kulshreshtha holds a Ph.D. and M.S. in Chemical Engineering from Purdue University, and a Bachelor s degree in Chemical Engineering from the Indian Institute of Technology, Kanpur, India. Onkar N. Singh, Ph.D., M.B.A., Assistant Director, Development at Alcon Research Ltd., Fort Worth, TX, has over 16 years of experience in pharmaceutical product research and development of nasal, sterile ophthalmic, sterile otic, and parentral products. Dr. Singh is inventor/co-inventor of many patents related to formulations, process and formulation technology and has authored several peerreviewed articles. Prior to joining Alcon Inc., Dr. Singh was Manager at Access Pharmaceuticals, Dallas, TX, leading efforts in the area of site-specific targeted drug delivery systems for diagnostic and therapeutic areas of cancer therapy. At Access Pharmaceuticals, Dr. Singh worked on nanoparticles, liposomes, emulsion formulations, protein pharmaceuticals and gene delivery technology. Dr. Singh served as Secretary/Treasurer of the Ocular Focus Group of AAPS from 2002 to 2005 and has been a reviewer for AAPS abstracts, posters and symposia. Dr. Singh is a member of the American Association of Pharmaceutical Scientists (AAPS) and currently serves as an editorial board member of American Pharmaceutical Review Journal. Dr. Singh holds a B.S. in Pharmacy, M.S. in xv

14 xvi About the Editors Pharmaceutics from Banaras Hindu University, India, Ph.D. in Pharmaceutics from University of Illinois at Chicago and M.B.A. from University of Texas at Arlington, TX. G. Michael Wall, Ph.D., Senior Director of Pharmaceutical Products Development at Alcon Research, Ltd., Fort Worth, TX, has over 21 years of pharmaceutical industrial experience in the development of intranasal, sterile ophthalmic and otic drug products. Dr. Wall is author or co-author of two patents and over 100 publications including peer-reviewed articles, abstracts, book chapters, book supplements and one book. Dr. Wall has led international, multidisciplinary teams in the development and approval of Ciprodex Sterile Otic Suspension and Patanase Nasal Spray, as well as other products in countries around the world. Dr. Wall is a Scientific Fellow of the American Academy of Otolaryngology Head and Neck Surgery. He has also served the American Chemical Society as a member for 30 years. Dr. Wall received a B.S. degree in chemistry from Auburn University, a M.S. degree in medicinal chemistry from Auburn University School of Pharmacy, a Ph.D. in medicinal chemistry from the University of Mississippi School of Pharmacy, and completed the Advanced Management Program (168th session) of the Harvard Business School.

15 Chapter 1 Various Pharmaceutical Disperse Systems Chandrasekar Manoharan, Ashwin Basarkar and Jagdish Singh Abstract This chapter discusses various types of dispersed systems, including applications of coarse and colloidal dispersions as pharmaceutical dosage and delivery systems. Applications of colloidal dispersions as controlled drug delivery systems are also discussed in this chapter. Introduction Dispersed systems consist of at least two phases: the substance that is dispersed known as the dispersed (or) internal phase, and a continuous (or) external phase. Based on the particle size of the dispersed phase, dispersions are generally classified as molecular dispersions, colloidal dispersions, and coarse dispersions. Molecular dispersions have dispersed particles lower than 1.0 nm in size. Colloidal dispersions have particle sizes between 1 nm and 1 mm. Microemulsions, nanoparticles, microspheres are some of the examples of colloidal dispersions. Coarse dispersions have particle size greater than 1 mm, which includes suspensions and emulsions. The scope of this chapter is to elaborate coarse and colloidal dispersions as pharmaceutical dosage and delivery systems. Applications of colloidal dispersions as controlled drug delivery systems have been discussed in the final section of this chapter. 1.2 Coarse Dispersions Suspensions Suspensions are a class of dispersed system in which a finely divided solid is dispersed uniformly in a liquid dispersion medium (Nash 1988). Suspensions can be C. Manoharan, A. Basarkar and J. Singh ( ) Department of Pharmaceutical Sciences, College of Pharmacy, Nursing, and Allied Sciences, North Dakota State University, Fargo, ND 58105, USA Jagdish.Singh@ndsu.edu A.K. Kulshreshtha et al. (eds.), Pharmaceutical Suspensions: From Formulation Development to Manufacturing, DOI / _1, AAPS