Novel Drug Delivery Systems

DRUGS AND THE PHARMACEUTICAL SCIENCES

A Series of Textbooks and Monographs

edited by

James Swarbrick School of Pharmacy

University of North Carolina Chapel Hill, North Carolina

Volume 1. PHARMACOKINETICS, Milo Gibaldi and Donald Perrier

Volume 2. GOOD MANUFACTURING PRACTICES FOR PHARMA-CEUTICALS: A PLAN FOR TOTAL QUALITY CONTROL, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV

Volume 3. MICROENCAPSULATION, edited by J. R. Nixon

Volume 4. DRUG METABOLISM: CHEMICAL AND BIOCHEMICAL AS-PECTS, Bernard Testa and Peter Jenner

Volume 5. NEW DRUGS: DISCOVERY AND DEVELOPMENT, edited by Alan A. Rubin

Volume 6. SUSTAINED AND CONTROLLED RELEASE DRUG DELIVERY SYSTEMS, edited by Joseph R. Robinson

Volume 7. MODERN PHARMACEUTICS, edited by Gilbert S. Banker and Christopher T. Rhodes

Volume 8. PRESCRIPTION DRUGS IN SHORT SUPPLY: CASE HISTORIES, Michael A. Schwartz

Volume 9. ACTIVATED CHARCOAL: ANTIDOTAL AND OTHER MEDICAL USES, David 0. Cooney

Volume 10. CONCEPTS IN DRUG METABOLISM (in two parts), edited by Peter Jenner and Bernard Testa

Volume 11 . PHARMACEUTICAL ANALYSIS: MODERN METHODS (in two parts), edited by James W. Munson

Volume 12. TECHNIQUES OF SOLUBILIZATION OF DRUGS, edited by Samuel H. Yalkowsky

Volume 13. ORPHAN DRUGS, edited by Fred E. Kerch

Volume 14. NOVEL DRUG DELIVERY SYSTEMS: FUNDAMENTALS, DE-VELOPMENTAL CONCEPTS, BIOMEDICAL ASSESSMENTS, Vie W. Chien

Volume 15. PHARMACOKINETICS, SECOND EDITION, REVISED AND EX-PANDED, Milo Gibaldi and Donald Perrier

Volume16. G O O D M A N U F A C T U R I N G P R A C T I C E S FOR PHARMACEUTICALS: A PLAN FOR TOTAL QUALITY CON-TROL, SECOND EDITION, REVISED AND EXPANDED, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV

Volume 17. FORMULATION OF VETERINARY DOSAGE FORMS, edited by Jack Blodinger

Volume 18. DERMATOLOGICAL FORMULATIONS: PERCUTANEOUS AB-SORPTION, Brian W. Barry

Volume 19. THE CLINICAL RESEARCH PROCESS IN THE PHAR-MACEUTICAL INDUSTRY, edited by Gary M. Matoren

Volume 20. MICROENCAPSULATION AND RELATED DRUG PROCESSES, Patrick B. Deasy

Volume 21 . DRUGS AND NUTRIENTS: THE INTERACTIVE EFFECTS, edited by Daphne A. Roe and T. Colin Campbell

Volume 22. BIOTECHNOLOGY OF INDUSTRIAL ANTIBIOTICS, Erick J. Vandamme

Volume 23. PHARMACEUTICAL PROCESS VALIDATION, edited by Bernard T. Loftus and Robert A. Nash

Volume 24. ANTICANCER AND INTERFERON AGENTS: SYNTHESIS AND PROPERTIES, edited by Raphael M. Ottenbrite and George B. Butler

Volume 25. PHARMACEUTICAL STATISTICS: PRACTICAL AND CLINICAL APPLICATIONS, Sanford Bolton

Volume 26. DRUG DYNAMICS FOR ANALYTICAL, CLINICAL, AND BIO-LOGICAL CHEMISTS, Benjamin J. Gudzinowicz, Burrows T. Younkin, Jr., and Michael J. Gudzinowicz

Volume 27. MODERN ANALYSIS OF ANTIBIOTICS, edited by Adjoran Aszalos

Volume 28. SOLUBILITY AND RELATED PROPERTIES, Kenneth C. James

Volume 29. CONTROLLED DRUG DELIVERY: FUNDAMENTALS AND AP-PLICATIONS, SECOND EDITION, REVISED AND EXPANDED, edited by Joseph R. Robinson and Vincent H. Lee

Volume 30. NEW DRUG APPROVAL PROCESS: CLINICAL AND REGULA-TORY MANAGEMENT, edited by Richard A. Guarino

Volume 3 1 . TRANSDERMAL CONTROLLED SYSTEMIC MEDICATIONS, edited by Yie W. Chien

Volume 32. DRUG DELIVERY DEVICES: FUNDAMENTALS AND APPLI-CATIONS, edited by Praveen Tyle

Volume 33. PHARMACOKINETICS: REGULATORY - INDUSTRIAL - ACA-DEMIC PERSPECTIVES, edited by Peter G. Welling and Francis L S. Tse

Volume 34. CLINICAL DRUG TRIALS AND TRIBULATIONS, edited by Allen E. Cato

Volume 35. TRANSDERMAL DRUG DELIVERY: DEVELOPMENTAL ISSUES AND RESEARCH INITIATIVES, edited by Jonathan Hadgraftand Richard H. Guy

Volume 36. AQUEOUS POLYMERIC COATINGS FOR PHARMACEUTICAL DOSAGE FORMS, edited by James W. McGinity

Volume 37. PHARMACEUTICAL PELLETIZATION TECHNOLOGY, edited by Isaac Ghebre-Sellassie

Volume 38. GOOD LABORATORY PRACTICE REGULATIONS, edited by Allen F. Hirsch

Volume 39. NASAL SYSTEMIC DRUG DELIVERY, Yie W. Chien, Kenneth S. E. Su, and Shyi-Feu Chang

Volume 40. MODERN PHARMACEUTICS, SECOND EDITION, REVISED AND EXPANDED, edited by Gilbert S. Banker and Christopher T. Rhodes

Volume 4 1 . SPECIALIZED DRUG DELIVERY SYSTEMS: MANUFACTURING AND PRODUCTION TECHNOLOGY, edited by Praveen Tyle

Volume 42. TOPICAL DRUG DELIVERY FORMULATIONS, edited by David W. Osborne and Anton H. Amann

Volume 43. DRUG STABILITY: PRINCIPLES AND PRACTICES, Jens T. Carstensen

Volume 44. PHARMACEUTICAL STATISTICS: PRACTICAL AND CLINICAL APPLICATIONS, SECOND EDITION, REVISED AND EXPANDED, Sanford Bolton

Volume 45. BIODEGRADABLE POLYMERS AS DRUG DELIVERY SYSTEMS, edited by Mark Chasin and Robert Langer

Volume 46. PRECLINICAL DRUG DISPOSITION: A LABORATORY HAND-BOOK, Francis L. S. Tse and James J. Jaffe

Volume 47. HPLC IN THE PHARMACEUTICAL INDUSTRY, edited by God-win W. Fong and Stanley K. Lam

Volume 48. PHARMACEUTICAL BIOEQUIVALENCE, edited by Peter G. Welling, Francis L. S. Tse, and Shrikant V. Dighe

Volume 49. PHARMACEUTICAL DISSOLUTION TESTING, Umesh V. Banakar

Volume 50. NOVEL DRUG DELIVERY SYSTEMS, SECOND EDITION, REVISED AND EXPANDED, Vie W. Chien

Volume 5 1 . MANAGING THE CLINICAL DRUG DEVELOPMENT PROCESS, David M. Cocchetto and Ronald V. Nardi

Volume 52. GOOD MANUFACTURING PRACTICES FOR PHARMACEU-TICALS: A PLAN FOR TOTAL QUALITY CONTROL, THIRD EDITION, edited by Sidney H. Willig and James Stoker

Additional Volumes in Preparation

PRODRUGS: TOPICAL AND OCULAR DRUG DELIVERY, edited by Kenneth B. Sloan

Second Edition, mused aid Expanded

Y i e W . C h i e n Controlled Drug-Delivery Research Center

College of Pharmacy Rutgers University

Piscataway, New Jersey

informa healthcare

New York London

CRC PressTaylor & Francis Group6000 Broken Sound Parkway NW, Suite 300Boca Raton, FL 33487-2742

1991 by Taylor & Francis Group, LLCCRC Press is an imprint of Taylor & Francis Group, an Informa business

No claim to original U.S. Government worksVersion Date: 20130322

International Standard Book Number-13: 978-1-84184-967-6 (eBook - PDF)

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To Margaret, my wife, for her understanding and encouragement

To Linda, my daughter, for her efforts and support

Preface

This second edition of Novel Drug Delivery Systems has maintained the same ob-jective as that of the first edition: to present a comprehensive, coherent treatment of the science, technology, and regulation of rate-controlled administration of thera-peutic agents, with comprehensive coverage of the basic concepts, fundamental prin-ciples, biomedical rationales, and potential applications.

Since the successful introduction of the first edition in 1982, much progress has been made in the science and technology of rate-controlled drug administration. It was my intention to rewrite this well-received book with incorporation of all the important scientific discoveries in recent years into the second edition. All the chap-ters have been extensively rewritten and updated, and new chapters have been added on the rate-controlled delivery of drugs across various mucosae and digestive tract membranes. A special chapter has been added on the issues associated with the sys-temic delivery of peptide/protein drugs, a new generation of therapeutic agents, via parenteral and nonparenteral routes of administration.

Over the years, the responses we have received from the readers have been very encouraging and have demonstrated to us that the book has been successful in pro-viding a useful source of scientific information for biomedical researchers and phar-maceutical R&D scientists/managers with diverse backgrounds who need to acquire the core knowledge critical to the conceptualization, development, and optimization of rate-controlled drug delivery. In addition, I also received several constructive comments and suggestions that I have implemented in writing this new edition to further enhance the quality of the book. One example of such changes is that the chapter on the fundamental aspects of rate-controlled drug delivery has been moved to the beginning of the book, preceding the chapters on rate-controlled drug delivery through various routes of administration. Also, the chapter on regulatory consider-ations in controlled drug delivery has been expanded to incorporate new guidelines used in the regulatory approval process.

Overall, the objective set for writing this new edition has been the same as for the first edition, that is, to provide the readers with a broad spectrum of scientific information in a concise, systematic manner, but with new vision and wider scope.

Yie W. Chien

v

Contents

Preface v

1. Concepts and System Design for the Rate-Controlled Drug Delivery 1

2. Fundamentals of Rate-Controlled Drug Delivery 43

3. Oral Drug Delivery and Delivery Systems 139

4. Mucosal Drug Delivery: Potential Routes for Noninvasive

Systemic Adminstration 197

5. Nasal Drug Delivery and Delivery Systems 229

6. Ocular Drug Delivery and Delivery Systems 269

7. Transdermal Drug Delivery and Delivery Systems 301

8. Parenteral Drug Delivery and Delivery Systems 381

9. Vaginal Drug Delivery and Delivery Systems 529

10. Intrauterine Drug Delivery and Delivery Systems 585

11. Systemic Delivery of Peptide-Based Pharmaceuticals 631

12. Regulatory Considerations in Controlled Drug Delivery 747

Index 777

vii

Novel Drug Delivery Systems