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 Pharmaceutical Science and Technology
184
DRUGS AND THE PHARMACEUTICAL SCIENCES VOLUME 184

about the book…

This two volume Second Edition describes the anatomical, physiological, pharmaceutical, and
technological aspects of delivery routes, found in areas like:
• Oral • Ocular • Dermal and transdermal • Vaginal

Modified-Release Drug Delivery Technology

Modified-Release
• Colonic • Oral mucosal • Nasal • Pulmonary
Providing insight and critical assessment of the many available and emerging modified release drug
delivery systems for their current and future value, topics include:
• modified drug release landscape; academic, regulatory, and intellectual property viewpoints
• I-vation Sustained Release Intravitreal System

Drug Delivery Technology

• ViaNase Intranasal Device and controlled particle dispersion technology Platform
• Microneedles for drug delivery, PassPort system, Dot-Matrix technology, ultrasound,
iontophoretic and technologies
• DiretcHaler Nasal technology
• intravaginal ring systems, Supravail, Vagisite, C-Vad™ Vaginal Insert, and ‘Smart’ Vaginal

Second Edition
Delivery Systems

Second Edition, Volume 2

• the AERx® Pulmonary Drug Delivery System
• AAD-Adaptive aerosol delivery technology
• nebulizer technologies and dry powder inhaler systems
about the editors...
MICHAEL J. RATHBONE is Director, Research and Development, and General Manager of InterAg,
Volume 2

FILE NAME: XXXXX DATE CREATED: XXXXX DATE REVISED: XXXX NOTES:
a Division of DEC International NZ Limited, Hamilton, New Zealand. Dr. Rathbone received his
Ph.D. in Pharmaceutical Science from the University of Aston, Birmingham, England, and has
innovated many novel modified-release drug delivery systems, several of which have been commer-
cialized. Dr. Rathbone has written over 35 peer-reviewed articles, has licensed five US patents and
has edited or co-edited three books and numerous special issues of journals.
JONATHAN HADGRAFT is Professor of Biophysical Chemistry, University of London, United Kingdom.
Dr. Hadgraft received his D.Phil. in Chemistry and his D.Sc. in Medicine from the University of
Oxford, United Kingdom. His major research interests are in the application of physical chemistry to
drug delivery, with special reference to the skin. He has been elected to Fellowships of the Royal
Society of Chemistry and the American Association of Pharmaceutical Scientists, and has contributed
to over 500 publications. He has contributed numerous book chapters and has co-edited several
books. He serves on a number of editorial boards of pharmaceutical science journals.
MICHAEL S. ROBERTS is Professor, School of Medicine, University of Queensland, Brisbane, Australia;
Senior Principal Research Fellow, National Health and Research Council; Director Therapeutics
Research Unit, Princess Alexandra Hospital, Queensland Australia; Adjunct Professor, University of
Canberra, Australia; and Visiting Professor, University of Lyon, France. Dr. Roberts received his Ph.D.
and D.Sc. from the University of Sydney, Australia, and his M.B.A. from the University of Queensland.
Dr. Roberts has also written over 280 peer-reviewed articles, 36 chapters, and has edited or co-edited
five books. Rathbone
MAJELLA E. LANE is a lecturer in Pharmaceutics in the School of Pharmacy, University of London, •
United Kingdom. She received her Ph.D. from Trinity College, Dublin, Ireland, and spent a sabbatical Hadgraft
period at the University of Michigan, Ann Arbor, where she holds a Visiting Associate Scientist •
appointment. Her current research interests include development of vaccine dosage forms,
formulation of peptides, transdermal drug delivery and mucosal drug delivery, and modeling of
Roberts edited by
•
Michael J. Rathbone
absorption processes across epithelial barriers.
Printed in the United States of America
H5355 Lane
Jonathan Hadgraft
Michael S. Roberts

DESIGNER: XX
Majella E. Lane

Rathbone_978-1420053555.indd 1 4/28/08 12:59:14 PM

PANTONE 202 C
 Modified-Release
Drug Delivery Technology
 DRUGS AND THE PHARMACEUTICAL SCIENCES
A Series of Textbooks and Monographs

Executive Editor
James Swarbrick
PharmaceuTech, Inc.
Pinehurst, North Carolina

Advisory Board

Larry L. Augsburger Harry G. Brittain

University of Maryland Center for Pharmaceutical Physics
Baltimore, Maryland Milford, New Jersey

Jennifer B. Dressman Robert Gurny

Universite de Geneve
University of Frankfurt Institute of
Geneve, Switzerland
Pharmaceutical Technology
Frankfurt, Germany Jeffrey A. Hughes
University of Florida College
Anthony J. Hickey of Pharmacy
University of North Carolina Gainesville, Florida
School of Pharmacy
Chapel Hill, North Carolina Vincent H. L. Lee
US FDA Center for Drug
Ajaz Hussain Evaluation and Research
Sandoz Los Angeles, California
Princeton, New Jersey
Kinam Park
Joseph W. Polli Purdue University
West Lafayette, Indiana
GlaxoSmithKline Research Triangle
Park North Carolina Jerome P. Skelly
Alexandria, Virginia
Stephen G. Schulman
University of Florida Elizabeth M. Topp
Gainesville, Florida University of Kansas
Lawrence, Kansas
Yuichi Sugiyama
University of Tokyo, Tokyo, Japan Peter York
University of Bradford School of
Geoffrey T. Tucker Pharmacy
University of Sheffield Bradford, United Kingdom
Royal Hallamshire Hospital
Sheffield, United Kingdom
 1. Pharmacokinetics, Milo Gibaldi and Donald Perrier
2. Good Manufacturing Practices for Pharmaceuticals: A Plan for
Total Quality Control, Sidney H. Willig, Murray M. Tuckerman, and
William S. Hitchings IV
3. Microencapsulation, edited by J. R. Nixon
4. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa
and Peter Jenner
5. New Drugs: Discovery and Development, edited by Alan A. Rubin
6. Sustained and Controlled Release Drug Delivery Systems, edited by
Joseph R. Robinson
7. Modern Pharmaceutics, edited by Gilbert S. Banker and
Christopher T. Rhodes
8. Prescription Drugs in Short Supply: Case Histories, Michael A. Schwartz
9. Activated Charcoal: Antidotal and Other Medical Uses, David O. Cooney
10. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner and
Bernard Testa
11. Pharmaceutical Analysis: Modern Methods (in two parts), edited by
James W. Munson
12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky
13. Orphan Drugs, edited by Fred E. Karch
14. Novel Drug Delivery Systems: Fundamentals, Developmental Concepts,
Biomedical Assessments, Yie W. Chien
15. Pharmacokinetics: Second Edition, Revised and Expanded,
Milo Gibaldi and Donald Perrier
16. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality
Control, Second Edition, Revised and Expanded, Sidney H. Willig,
Murray M. Tuckerman, and William S. Hitchings IV
17. Formulation of Veterinary Dosage Forms, edited by Jack Blodinger
18. Dermatological Formulations: Percutaneous Absorption, Brian W. Barry
19. The Clinical Research Process in the Pharmaceutical Industry, edited by
Gary M. Matoren
20. Microencapsulation and Related Drug Processes, Patrick B. Deasy
21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roe
and T. Colin Campbell
22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme
23. Pharmaceutical Process Validation, edited by Bernard T. Loftus and
Robert A. Nash
24. Anticancer and Interferon Agents: Synthesis and Properties, edited by
Raphael M. Ottenbrite and George B. Butler
25. Pharmaceutical Statistics: Practical and Clinical Applications,
Sanford Bolton
26. Drug Dynamics for Analytical, Clinical, and Biological Chemists,
Benjamin J. Gudzinowicz, Burrows T. Younkin, Jr., and
Michael J. Gudzinowicz
27. Modern Analysis of Antibiotics, edited by Adjoran Aszalos
28. Solubility and Related Properties, Kenneth C. James
29. Controlled Drug Delivery: Fundamentals and Applications, Second Edition,
Revised and Expanded, edited by Joseph R. Robinson and
Vincent H. Lee
30. New Drug Approval Process: Clinical and Regulatory Management,
edited by Richard A. Guarino
31. Transdermal Controlled Systemic Medications, edited by Yie W. Chien
32. Drug Delivery Devices: Fundamentals and Applications, edited by
Praveen Tyle
33. Pharmacokinetics: Regulatory  Industrial  Academic Perspectives,
edited by Peter G. Welling and Francis L. S. Tse
34. Clinical Drug Trials and Tribulations, edited by Allen E. Cato
35. Transdermal Drug Delivery: Developmental Issues and Research Initiatives,
edited by Jonathan Hadgraft and Richard H. Guy
36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms,
edited by James W. McGinity
37. Pharmaceutical Pelletization Technology, edited by Isaac Ghebre-Sellassie
38. Good Laboratory Practice Regulations, edited by Allen F. Hirsch
39. Nasal Systemic Drug Delivery, Yie W. Chien, Kenneth S. E. Su,
and Shyi-Feu Chang
40. Modern Pharmaceutics: Second Edition, Revised and Expanded, edited by
Gilbert S. Banker and Christopher T. Rhodes
41. Specialized Drug Delivery Systems: Manufacturing and
Production Technology, edited by Praveen Tyle
42. Topical Drug Delivery Formulations, edited by David W. Osborne and
Anton H. Amann
43. Drug Stability: Principles and Practices, Jens T. Carstensen
44. Pharmaceutical Statistics: Practical and Clinical Applications,
Second Edition, Revised and Expanded, Sanford Bolton
45. Biodegradable Polymers as Drug Delivery Systems, edited by
Mark Chasin and Robert Langer
46. Preclinical Drug Disposition: A Laboratory Handbook,
Francis L. S. Tse and James J. Jaffe
47. HPLC in the Pharmaceutical Industry, edited by Godwin W. Fong
and Stanley K. Lam
48. Pharmaceutical Bioequivalence, edited by Peter G. Welling,
Francis L. S. Tse, and Shrikant V. Dinghe
49. Pharmaceutical Dissolution Testing, Umesh V. Banakar
50. Novel Drug Delivery Systems: Second Edition, Revised and Expanded,
Yie W. Chien
51. Managing the Clinical Drug Development Process, David M. Cocchetto and
Ronald V. Nardi
52. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality
Control, Third Edition, edited by Sidney H. Willig and James R. Stoker
53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth B. Sloan
54. Pharmaceutical Inhalation Aerosol Technology, edited by
Anthony J. Hickey
55. Radiopharmaceuticals: Chemistry and Pharmacology, edited by
Adrian D. Nunn
56. New Drug Approval Process: Second Edition, Revised and Expanded,
edited by Richard A. Guarino
57. Pharmaceutical Process Validation: Second Edition, Revised and Expanded,
edited by Ira R. Berry and Robert A. Nash
58. Ophthalmic Drug Delivery Systems, edited by Ashim K. Mitra
59. Pharmaceutical Skin Penetration Enhancement, edited by
Kenneth A. Walters and Jonathan Hadgraft
60. Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck
61. Pharmaceutical Particulate Carriers: Therapeutic Applications, edited by
Alain Rolland
62. Drug Permeation Enhancement: Theory and Applications, edited by
Dean S. Hsieh
63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan
64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel A. Halls
65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie
66. Colloidal Drug Delivery Systems, edited by Jörg Kreuter
67. Pharmacokinetics: Regulatory  Industrial  Academic Perspectives, Second
Edition, edited by Peter G. Welling and Francis L. S. Tse
68. Drug Stability: Principles and Practices, Second Edition, Revised and
Expanded, Jens T. Carstensen
69. Good Laboratory Practice Regulations: Second Edition, Revised
and Expanded, edited by Sandy Weinberg
70. Physical Characterization of Pharmaceutical Solids, edited by
Harry G. Brittain
71. Pharmaceutical Powder Compaction Technology, edited by Göran Alderborn
and Christer Nyström
72. Modern Pharmaceutics: Third Edition, Revised and Expanded, edited by
Gilbert S. Banker and Christopher T. Rhodes
73. Microencapsulation: Methods and Industrial Applications, edited by
Simon Benita
74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone
75. Clinical Research in Pharmaceutical Development, edited by
Barry Bleidt and Michael Montagne
76. The Drug Development Process: Increasing Efficiency and
Cost Effectiveness, edited by Peter G. Welling, Louis Lasagna,
and Umesh V. Banakar
77. Microparticulate Systems for the Delivery of Proteins and Vaccines, edited
by Smadar Cohen and Howard Bernstein
78. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality
Control, Fourth Edition, Revised and Expanded, Sidney H. Willig and
James R. Stoker
79. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms:
Second Edition, Revised and Expanded, edited by James W. McGinity
80. Pharmaceutical Statistics: Practical and Clinical Applications, Third Edition,
Sanford Bolton
81. Handbook of Pharmaceutical Granulation Technology, edited by
Dilip M. Parikh
82. Biotechnology of Antibiotics: Second Edition, Revised and Expanded,
edited by William R. Strohl
83. Mechanisms of Transdermal Drug Delivery, edited by Russell O. Potts and
Richard H. Guy
84. Pharmaceutical Enzymes, edited by Albert Lauwers and Simon Scharpé
85. Development of Biopharmaceutical Parenteral Dosage Forms, edited by
John A. Bontempo
86. Pharmaceutical Project Management, edited by Tony Kennedy
87. Drug Products for Clinical Trials: An International Guide to Formulation 
Production  Quality Control, edited by Donald C. Monkhouse and
Christopher T. Rhodes
88. Development and Formulation of Veterinary Dosage Forms: Second Edition,
Revised and Expanded, edited by Gregory E. Hardee and J. Desmond
Baggot
89. Receptor-Based Drug Design, edited by Paul Leff
90. Automation and Validation of Information in Pharmaceutical Processing,
edited by Joseph F. deSpautz
91. Dermal Absorption and Toxicity Assessment, edited by Michael S. Roberts
and Kenneth A. Walters
92. Pharmaceutical Experimental Design, Gareth A. Lewis, Didier Mathieu, and
Roger Phan-Tan-Luu
93. Preparing for FDA Pre-Approval Inspections, edited by Martin D. Hynes III
 94. Pharmaceutical Excipients: Characterization by IR, Raman, and
NMR Spectroscopy, David E. Bugay and W. Paul Findlay
95. Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain
96. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products,
edited by Louis Rey and Joan C.May
97. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology,
Third Edition, Revised and Expanded, edited by Robert L. Bronaugh and
Howard I. Maibach
98. Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches, and
Development, edited by Edith Mathiowitz, Donald E. Chickering III, and
Claus-Michael Lehr
99. Protein Formulation and Delivery, edited by Eugene J. McNally
100. New Drug Approval Process: Third Edition, The Global Challenge,
edited by Richard A. Guarino
101. Peptide and Protein Drug Analysis, edited by Ronald E. Reid
102. Transport Processes in Pharmaceutical Systems, edited by
Gordon L. Amidon, Ping I. Lee, and Elizabeth M. Topp
103. Excipient Toxicity and Safety, edited by Myra L. Weiner and
Lois A. Kotkoskie
104. The Clinical Audit in Pharmaceutical Development, edited by
Michael R. Hamrell
105. Pharmaceutical Emulsions and Suspensions, edited by Francoise Nielloud
and Gilberte Marti-Mestres
106. Oral Drug Absorption: Prediction and Assessment, edited by
Jennifer B. Dressman and Hans Lennernäs
107. Drug Stability: Principles and Practices, Third Edition, Revised
and Expanded, edited by Jens T. Carstensen and C. T. Rhodes
108. Containment in the Pharmaceutical Industry, edited by James P. Wood
109. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality
Control from Manufacturer to Consumer, Fifth Edition, Revised and
Expanded, Sidney H. Willig
110. Advanced Pharmaceutical Solids, Jens T. Carstensen
111. Endotoxins: Pyrogens, LAL Testing, and Depyrogenation,
Second Edition, Revised and Expanded, Kevin L. Williams
112. Pharmaceutical Process Engineering, Anthony J. Hickey and
David Ganderton
113. Pharmacogenomics, edited by Werner Kalow, Urs A. Meyer and
Rachel F. Tyndale
114. Handbook of Drug Screening, edited by Ramakrishna Seethala
and Prabhavathi B. Fernandes
115. Drug Targeting Technology: Physical  Chemical  Biological Methods,
edited by Hans Schreier
116. Drug–Drug Interactions, edited by A. David Rodrigues
117. Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian
and Anthony J. Streeter
118. Pharmaceutical Process Scale-Up, edited by Michael Levin
119. Dermatological and Transdermal Formulations, edited by
Kenneth A. Walters
120. Clinical Drug Trials and Tribulations: Second Edition, Revised and
Expanded, edited by Allen Cato, Lynda Sutton, and Allen Cato III
121. Modern Pharmaceutics: Fourth Edition, Revised and Expanded,
edited by Gilbert S. Banker and Christopher T. Rhodes
122. Surfactants and Polymers in Drug Delivery, Martin Malmsten
123. Transdermal Drug Delivery: Second Edition, Revised and Expanded, edited
by Richard H. Guy and Jonathan Hadgraft
124. Good Laboratory Practice Regulations: Second Edition, Revised
and Expanded, edited by Sandy Weinberg
125. Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Package
Integrity Testing: Third Edition, Revised and Expanded, Michael J. Akers,
Daniel S. Larrimore, and Dana Morton Guazzo
126. Modified-Release Drug Delivery Technology, edited by Michael J. Rathbone,
Jonathan Hadgraft, and Michael S. Roberts
127. Simulation for Designing Clinical Trials:
A Pharmacokinetic-Pharmacodynamic Modeling Perspective,
edited by Hui C. Kimko and Stephen B. Duffull
128. Affinity Capillary Electrophoresis in Pharmaceutics and Biopharmaceutics,
€
edited by Reinhard H. H. Neubert and Hans-Hermann Ruttinger
129. Pharmaceutical Process Validation: An International Third Edition, Revised
and Expanded, edited by Robert A. Nash and Alfred H. Wachter
130. Ophthalmic Drug Delivery Systems: Second Edition, Revised and
Expanded, edited by Ashim K. Mitra
131. Pharmaceutical Gene Delivery Systems, edited by Alain Rolland and
Sean M. Sullivan
132. Biomarkers in Clinical Drug Development, edited by John C. Bloom
and Robert A. Dean
133. Pharmaceutical Extrusion Technology, edited by Isaac Ghebre-Sellassie and
Charles Martin
134. Pharmaceutical Inhalation Aerosol Technology: Second Edition,
Revised and Expanded, edited by Anthony J. Hickey
135. Pharmaceutical Statistics: Practical and Clinical Applications, Fourth Edition,
Sanford Bolton and Charles Bon
136. Compliance Handbook for Pharmaceuticals, Medical Devices, and Biologics,
edited by Carmen Medina
137. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products:
Second Edition, Revised and Expanded, edited by Louis Rey and
Joan C. May
138. Supercritical Fluid Technology for Drug Product Development, edited by
Peter York, Uday B. Kompella, and Boris Y. Shekunov
139. New Drug Approval Process: Fourth Edition, Accelerating
Global Registrations, edited by Richard A. Guarino
140. Microbial Contamination Control in Parenteral Manufacturing,
edited by Kevin L. Williams
141. New Drug Development: Regulatory Paradigms for Clinical Pharmacology
and Biopharmaceutics, edited by Chandrahas G. Sahajwalla
142. Microbial Contamination Control in the Pharmaceutical Industry,
edited by Luis Jimenez
143. Generic Drug Product Development: Solid Oral Dosage Forms,
edited by Leon Shargel and Isadore Kanfer
144. Introduction to the Pharmaceutical Regulatory Process, edited
by Ira R. Berry
145. Drug Delivery to the Oral Cavity: Molecules to Market, edited by
Tapash K. Ghosh and William R. Pfister
146. Good Design Practices for GMP Pharmaceutical Facilities, edited by
Andrew Signore and Terry Jacobs
147. Drug Products for Clinical Trials, Second Edition, edited by
Donald Monkhouse, Charles Carney, and Jim Clark
148. Polymeric Drug Delivery Systems, edited by Glen S. Kwon
149. Injectable Dispersed Systems: Formulation, Processing, and
Performance, edited by Diane J. Burgess
150. Laboratory Auditing for Quality and Regulatory Compliance, Donald Singer,
Raluca-Ioana Stefan, and Jacobus van Staden
151. Active Pharmaceutical Ingredients: Development, Manufacturing,
and Regulation, edited by Stanley Nusim
152. Preclinical Drug Development, edited by Mark C. Rogge and David R. Taft
153. Pharmaceutical Stress Testing: Predicting Drug Degradation,
edited by Steven W. Baertschi
154. Handbook of Pharmaceutical Granulation Technology:
Second Edition, edited by Dilip M. Parikh
155. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology,
Fourth Edition, edited by Robert L. Bronaugh and Howard I. Maibach
156. Pharmacogenomics: Second Edition, edited by Werner Kalow,
Urs A. Meyer and Rachel F. Tyndale
157. Pharmaceutical Process Scale-Up, Second Edition, edited by Michael Levin
158. Microencapsulation: Methods and Industrial Applications, Second Edition,
edited by Simon Benita
159. Nanoparticle Technology for Drug Delivery, edited by
Ram B. Gupta and Uday B. Kompella
160. Spectroscopy of Pharmaceutical Solids, edited by Harry G. Brittain
161. Dose Optimization in Drug Development, edited by Rajesh Krishna
162. Herbal Supplements-Drug Interactions: Scientific and
Regulatory Perspectives, edited by Y. W. Francis Lam, Shiew-Mei Huang,
and Stephen D. Hall
163. Pharmaceutical Photostability and Stabilization Technology,
edited by Joseph T.Piechocki and Karl Thoma
164. Environmental Monitoring for Cleanrooms and Controlled Environments,
edited by Anne Marie Dixon
165. Pharmaceutical Product Development: In Vitro-In Vivo Correlation, edited by
Dakshina Murthy Chilukuri, Gangadhar Sunkara, and David Young
166. Nanoparticulate Drug Delivery Systems, edited by Deepak Thassu,
Michel Deleers, and Yashwant Pathak
167. Endotoxins: Pyrogens, LAL Testing and Depyrogenation,
Third Edition, edited by Kevin L. Williams
168. Good Laboratory Practice Regulations, Fourth Edition,
edited by Anne Sandy Weinberg
169. Good Manufacturing Practices for Pharmaceuticals, Sixth Edition, edited by
Joseph D. Nally
170. Oral-Lipid Based Formulations: Enhancing the Bioavailability
of Poorly Water-soluble Drugs, edited by David J. Hauss
171. Handbook of Bioequivalence Testing, edited by Sarfaraz K. Niazi
172. Advanced Drug Formulation Design to Optimize Therapeutic Outcomes,
edited by Robert O. Williams III, David R. Taft, and Jason T. McConville
173. Clean-in-Place for Biopharmaceutical Processes, edited by
Dale A. Seiberling
174. Filtration and Purification in the Biopharmaceutical Industry, Second Edition,
edited by Maik W. Jornitz and Theodore H. Meltzer
175. Protein Formulation and Delivery, Second Edition, edited by
Eugene J. McNally and Jayne E. Hastedt
176. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Third
Edition, edited by James McGinity and Linda A. Felton
177. Dermal Absorption and Toxicity Assessment, Second Edition, edited by
Michael S. Roberts and Kenneth A. Walters
178. Preformulation Solid Dosage Form Development, edited by Moji C. Adeyeye
and Harry G. Brittain
179. Drug-Drug Interactions, Second Edition, edited by A. David Rodrigues
180. Generic Drug Product Development: Bioequivalence Issues, edited by
Isadore Kanfer and Leon Shargel
181. Pharmaceutical Pre-Approval Inspections: A Guide to Regulatory Success,
Second Edition, edited by Martin D. Hynes III
182. Pharmaceutical Project Management, Second Edition, edited by
Anthony Kennedy
183. Modified Release Drug Delivery Technology, Second Edition, Volume 1,
edited by Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts,
and Majella E. Lane
184. Modified-Release Drug Delivery Technology, Second Edition, Volume 2,
edited by Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts,
and Majella E. Lane
 Modified-Release
Drug Delivery Technology
Second Edition
Volume 2

edited by
Michael J. Rathbone
InterAg
Hamilton, New Zealand
Jonathan Hadgraft
University of London
London, UK
Michael S. Roberts
University of Queensland
Brisbane, Australia
Majella E. Lane
University of London
London, UK
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742

© 2013 by Taylor & Francis Group, LLC

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International Standard Book Number-13: 978-1-4200-4526-0 (eBook - PDF)

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To my son Benjamin
—Michael J. Rathbone
 Preface

Over the last few decades, rapid developments have occurred in the area of
modified-release drug delivery technology, and significant research and
development has occurred in all routes of drug delivery. This is an ever-
expanding area of pharmaceutical research, and so we decided to update
and expand Modified-Release Drug Delivery Technology to achieve a more
comprehensive compilation of information.
To this end, the Second Edition is divided into two volumes. Volume 1
addresses modified-release drug delivery technologies developed for the oral
mucosal and gastrointestinal routes. Volume 2 addresses modified-release
drug delivery technologies for the parenteral, dermal, pulmonary, nasal,
vaginal, and ocular routes. Both volumes assume that the reader is already
familiar with fundamental controlled-release theories. The volumes are
divided into discrete parts, each of which is defined by the route for drug
delivery. Individual parts begin with an overview, written by the leaders in the
respective fields. They cover the anatomical, physiological, and pharmaceut-
ical challenges inherent in formulating a modified-release drug delivery
technology for a particular route of drug delivery. Each overview is followed
by chapters that provide specific examples of the different approaches that
have been taken to design and develop an innovative modified-release drug
delivery system for those routes (written by experts in that specific technology).
Modified-Release Drug Delivery Technology, Second Edition, aims to
describe as many examples of modified-release drug delivery technologies as
possible. Ultimately, however, inclusion of a given technology in this book
was based on author availability, rather than the desire to include a particular
technology or to select or reject a particular technology based on its relative
merits. We hope that the selection is representative of each field.
The first part of Volume 2, edited by Stephen Perrett and Michael J.
Rathbone, contains chapters that provide an overview of the modified drug
release landscape as observed from the commercial (Perrett) and academic
(Siepmann) viewpoints. An evaluation of the role of modified-release
formulations to address patient and doctors’ needs (Anelli), and a viewpoint
on investors’ requirements (Walton) are also discussed in this part. These
chapters provide an interesting insight into how these different disciples view
this area of research. In Part II, Robert Gurny and colleagues provide an
overview of currently available and emerging modified-release ophthalmic drug
v
vi Preface

delivery systems. Most of these systems are in the developmental stage, but
several technologies that have reached commercialization are described in depth.
Part III addresses implant and injection technologies. In their introduction
section leaders Majella Lane, Franklin Okumu, and Palani Balausubramanian
offer a comprehensive overview of this evolving and challenging area of drug
delivery. They complement their overview with chapters that cover a diverse
range of implant and injection technologies. Section leaders for Part IV,
Jonathan Hadgraft, Majella Lane, and Adam Watkinson, have written a
thorough overview of the dermal and transdermal area and have organized a
series of chapters that cover a wide range of diverse technologies, from wound
dressings, through nail delivery, to propulsion of solid drug particles into the skin
by means of a high-speed gas flow. Patches that deliver drugs via diffusion,
iontophoresis, sonophoresis, or microprojections are also covered.
The nasal route is covered in Part V. Section leader Ashim Mitra offers an
instructive overview into this interesting route of drug delivery that highlights
how difficult drug delivery can be for this route of administration. David
Woolfson (Part VI leader, vaginal route) presents a comprehensive account of
the biological and pharmaceutical challenges to the vaginal route of drug
delivery, which is restricted to 50 percent of the population and is limited by
cultural and societal constraints. The chapters associated with this section
provide an insight into the different approaches that can be employed to deliver
drugs via the vaginal mucosa. In the final section of this book (Part VII) section
leader Paul Myrdal provides an informative overview of the unique challenges
associated with delivering drugs via the pulmonary tract. The chapters in Part
VII describe the various systems, devices, formulations, and methods of drug
delivery to the lung. The focus of pulmonary drug delivery systems tends not to be on
the control of medicament release from the formulations in which they are presented,
but rather on inhalation systems that deliver drugs practically instantaneously to the
target organ (which is the “release” part for therapeutic activity for many of the
currently approved products for inhalation). Numerous different technological
approaches are described in the chapters associated with this section, each of which
provides descriptive comments on the complexity of this route of drug delivery.
We would like to express our thanks to each of the section leaders,
who spent a great deal of time identifying technologies, writing informative
overviews, and editing the chapters associated with the routes of drug
delivery in which they are expert. We would also like to thank all of the
authors who contributed chapters to this book, whose individual innovative
research activities have contributed so much to the current modified-release
drug delivery technology portfolio that exists today. We thank them for
taking the time to share their experiences and work.

Michael J. Rathbone
Jonathan Hadgraft
Michael S. Roberts
Majella E. Lane
 Contents

Preface v
Contributors xi

PART I: USING MODIFIED-RELEASE FORMULATIONS TO

MAINTAIN AND DEVELOP MARKETS

1. The Modified-Release Drug Delivery Landscape: The Commercial

Perspective 1
Stephen Perrett
2. The Modified-Release Drug Delivery Landscape: Academic
Viewpoint 17
Juergen Siepmann and Florence Siepmann
3. The Modified-Release Drug Delivery Landscape: Advantages and
Issues for Physicians and Patients 35
Marco M. Anelli
4. The Modified-Release Drug Delivery Landscape: Drug Delivery
Commercialization Strategies 49
Fintan Walton

PART II: OCULAR TECHNOLOGIES

5. Ophthalmic Drug Delivery 59

Pascal Furrer, Florence Delie, and Bernard Plazonnet
6. Intraocular Implants for Controlled Drug Delivery 85
Leila Bossy, Signe Erickson, Robert Gurny, and Florence Delie
7. Bioadhesive Ophthalmic Drug Inserts (BODI) for
Veterinary Use 101
Pascal Furrer, Olivia Felt, and Robert Gurny
8. Ion Exchange Resin Technology for Ophthalmic Applications 109
Rajni Jani and Erin Rhone

vii
viii Contents

PART III: INJECTION AND IMPLANT TECHNOLOGIES

9. Injections and Implants 123

Majella E. Lane, Franklin W. Okumu, and Palani Balausubramanian
10. Long-Acting Protein Formulation—PLAD Technology 133
Franklin W. Okumu
11. Long-Term Controlled Delivery of Therapeutic Agents by the
Osmotically Driven DUROSÒ Implant 143
Jeremy C. Wright and John Culwell
12. The SABERTM Delivery System for Parenteral Administration 151
Jeremy C. Wright, A. Neil Verity, and Franklin W. Okumu
13. Improving the Delivery of Complex Formulations Using the
DepotOneÒ Needle 159
Kevin Maynard and Peter Crocker
14. ReGel Depot Technology 171
Ramesh C. Rathi and Kirk D. Fowers
15. The AtrigelÒ Drug Delivery System 183
Eric J. Dadey
16. Enhancing Drug Delivery by Chemical Modification 191
Mimoun Ayoub, Christina Wedemeyer, and Torsten Wöhr
17. DepoFoamÒ Multivesicular Liposomes for the Sustained Release
of Macromolecules 207
William J. Lambert and Kathy Los
18. ALZAMERÒ DepotTM Bioerodible Polymer Technology 215
Guohua Chen and Gunjan Junnarkar
19. Pegylated Liposome Delivery of Chemotherapeutic Agents:
Rationale and Clinical Benefit 227
Francis J. Martin

PART IV: DERMAL AND TRANSDERMAL TECHNOLOGIES

20. Dermal and Transdermal Drug Delivery 263

Jonathan Hadgraft, Majella E. Lane, and Adam C. Watkinson
21. ALZA Transdermal Drug Delivery Technologies 273
Rama Padmanabhan, J. Bradley Phipps, Michel Cormier, Janet Tamada,
Jay Audett, J. Richard Gyory, and Peter E. Daddona
Contents ix

22. Microneedles for Drug Delivery 295

Mark R. Prausnitz, Harvinder S. Gill, and Jung-Hwan Park
23. TransfersomeÒ: Self-Optimizing and Self-Driven Drug-Carrier,
for Localized and Transdermal Drug Delivery 311
Gregor Cevc
24. Advances in Wound Healing 325
Michael Walker and Steven Percival
25. Ultrasound-Mediated Transdermal Drug Delivery 339
Samir Mitragotri and Joseph Kost
26. Lipid Nanoparticles with Solid Matrix for Dermal Delivery: Solid Lipid
Nanoparticles and Nanostructured Lipid Carriers 349
Eliana B. Souto, Rolf D. Petersen, and Rainer H. Mu€ller
27. LidoSiteÒ—Vyteris Iontophoretic Technology 373
Lakshmi Raghavan and Ashutosh Sharma
28. Nail Delivery 383
Darren M. Green, Keith R. Brain, and Kenneth A. Walters
29. Immediate Topical Drug Delivery Using Natural Nano-Injectors 395
Tamar Lotan
30. DOT MatrixÒ Technology 405
Juan A. Mantelle
31. The PassPortTM System: A New Transdermal Patch for Water-Soluble
Drugs, Proteins, and Carbohydrates 417
Alan Smith and Eric Tomlinson

PART V: NASAL TECHNOLOGIES

32. Nasal Drug Delivery 427

Pradeep K. Karla, Deep Kwatra, Ripal Gaudana, and Ashim K. Mitra
33. Controlled Particle DispersionÒ: A Twenty-First-Century Nasal Drug
Delivery Platform 451
Marc Giroux, Peter Hwang, and Ajay Prasad
34. DirectHalerTM Nasal: Innovative Device and Delivery Method 469
Troels Keldmann
PART VI: VAGINAL TECHNOLOGIES

35. Intravaginal Drug Delivery Technologies 481

A. David Woolfson
x Contents

36. Vaginal Rings for Controlled-Release Drug Delivery 499

R. Karl Malcolm
37. Phospholipids as Carriers for Vaginal Drug Delivery 511
Mathew Leigh
38. SITE RELEASEÒ, Vaginal Bioadhesive System 521
Jennifer Gudeman, Daniel J. Thompson, and R. Saul Levinson
39. Clindamycin Vaginal Insert 531
Janet A. Halliday and Steve Robertson
40. Bioresponsive Vaginal Delivery Systems 539
Patrick F. Kiser

PART VII: PULMONARY TECHNOLOGIES

41. Pulmonary Delivery of Drugs by Inhalation 553

Paul B. Myrdal and B. Steven Angersbach
42. AERxÒ Pulmonary Drug Delivery Systems 563
David C. Cipolla and Eric Johansson
43. Formulation Challenges of Powders for the Delivery of Small
Molecular Weight Molecules as Aerosols 573
Anthony J. Hickey and Heidi M. Mansour
44. Adaptive Aerosol Delivery (AADÒ) Technology 603
Kurt Nikander and John Denyer
45. Nebulizer Technologies 613
Martin Knoch and Warren Finlay
46. Formulation Challenges: Protein Powders for Inhalation 623
Hak-Kim Chan
47. The RespimatÒ, a New Soft MistTM Inhaler for Delivering Drugs
to the Lungs 637
Herbert Wachtel and Achim Moser
48. Pressurized Metered Dose Inhalation Technology 647
Ian C. Ashurst
49. Dry Powder Inhalation Systems from Nektar Therapeutics 659
Andrew R. Clark and Jeffry G. Weers
50. TechnosphereÒ/Insulin: Mimicking Endogenous Insulin Release 673
Andrea Leone-Bay and Marshall Grant
 Contributors

Marco M. Anelli Research and Development, Keypharma, Milan, Italy

B. Steven Angersbach College of Pharmacy, University of Arizona,
Tucson, Arizona, U.S.A.
Ian C. Ashurst GlaxoSmithKline Research and Development, Ware,
Hertfordshire, U.K.
Jay Audett ALZA Corporation, Mountain View, California, U.S.A.
Mimoun Ayoub Genzyme Pharmaceuticals, Liestal, Switzerland
Palani Balausubramanian DURECT Corporation, Cupertino,
California, U.S.A.
Leila Bossy Department of Pharmaceutics and Biopharmaceutics, School
of Pharmaceutical Sciences, University of Geneva, University of Lausanne,
Geneva, Switzerland
Keith R. Brain An-eX Analytical Services Ltd., Cardiff, U.K.
Gregor Cevc IDEA AG, Munich, Germany
Hak-Kim Chan Faculty of Pharmacy, University of Sydney, Australia
Guohua Chen ALZA Corporation, Mountain View, California, U.S.A.
David C. Cipolla Aradigm Corporation, Hayward, California, U.S.A.
Andrew R. Clark Nektar Therapeutics, San Carlos, California, U.S.A.
Michel Cormier ALZA Corporation, Mountain View, California, U.S.A.
Peter Crocker Imprint Pharmaceuticals Ltd., OCFI, Oxford, U.K.
John Culwell DURECT Corporation, Cupertino, California, U.S.A.
Peter E. Daddona Zosano Pharma, Fremont, California, U.S.A.
Eric J. Dadey QLT USA, Inc., Fort Collins, Colorado, U.S.A.
Florence Delie Department of Pharmaceutics and Biopharmaceutics,
School of Pharmaceutical Sciences, University of Geneva, University of
Lausanne, Geneva, Switzerland

xi
xii Contributors

John Denyer Respironics Respiratory Drug Delivery (UK) Ltd.,

Chichester, U.K.
Signe Erickson SurModics, Inc., Irvine, California, U.S.A.
Olivia Felt Department of Pharmaceutics and Biopharmaceutics, School
of Pharmaceutical Sciences, University of Geneva, University of Lausanne,
Geneva, Switzerland
Warren Finlay Department of Mechanical Engineering, University of
Alberta, Edmonton, Alberta, Canada
Kirk D. Fowers Protherics Plc, West Valley City, Utah, U.S.A.
Pascal Furrer Department of Pharmaceutics and Biopharmaceutics,
School of Pharmaceutical Sciences, University of Geneva, University of
Lausanne, Geneva, Switzerland
Ripal Gaudana University of Missouri-Kansas City, Kansas City,
Missouri, U.S.A.
Harvinder S. Gill The Wallace H. Coulter Department of Biomedical
Engineering at Georgia Tech and Emory University, Georgia Institute of
Technology, Atlanta, Georgia, U.S.A.
Marc Giroux Kurve Technology, Inc., Bothell, Washington, D.C., U.S.A.
Marshall Grant Formulation Development, MannKind Corporation,
Danbury, Connecticut, U.S.A.
Darren M. Green An-eX Analytical Services Ltd., Cardiff, U.K.
Jennifer Gudeman KV Pharmaceutical Company, St. Louis, Missouri,
U.S.A.
Robert Gurny Department of Pharmaceutics and Biopharmaceutics,
School of Pharmaceutical Sciences, University of Geneva, University of
Lausanne, Geneva, Switzerland
J. Richard Gyory Transform Pharmaceuticals, Lexington, Massachusetts,
U.S.A.
Jonathan Hadgraft School of Pharmacy, University of London, London,
U.K.
Janet A. Halliday Controlled Therapeutics (Scotland) Limited, East
Kilbride, Lanarkshire, U.K.
Anthony J. Hickey School of Pharmacy, Division of Molecular
Pharmaceutics, University of North Carolina-Chapel Hill, Kerr
Hall-Dispersed Systems Laboratory, Chapel Hill, North Carolina, U.S.A.
Contributors xiii

Peter Hwang Stanford Sinus Center, Stanford University School of

Medicine, Stanford, California, U.S.A.
Rajni Jani Pharmaceutical Research and Development, Alcon Research
Ltd., Fort Worth, Texas, U.S.A.
Eric Johansson Aradigm Corporation, Hayward, California, U.S.A.
Gunjan Junnarkar ALZA Corporation, Mountain View, California, U.S.A.
Pradeep K. Karla University of Missouri-Kansas City, Kansas City,
Missouri, U.S.A.
Troels Keldmann DirectHaler A/S, Copenhagen, Denmark
Patrick F. Kiser Department of Bioengineering, University of Utah,
Salt Lake City, Utah, U.S.A.
Martin Knoch PARI Pharma GmbH, Starnberg, Germany
Joseph Kost Department of Chemical Engineering, Ben Gurion
University of the Negev, Beer-Sheva, Israel
Deep Kwatra University of Missouri-Kansas City, Kansas City, Missouri,
U.S.A.
William J. Lambert Pacira Pharmaceuticals, Inc., San Diego, California,
U.S.A.
Majella E. Lane School of Pharmacy, University of London, London,
U.K.
Mathew Leigh PHARES Drug Delivery AG, Muttenz, Switzerland
Andrea Leone-Bay Pharmaceutical Development, MannKind
Corporation, Danbury, Connecticut, U.S.A.
R. Saul Levinson KV Pharmaceutical Company, St. Louis, Missouri,
U.S.A.
Kathy Los Pacira Pharmaceuticals, Inc., San Diego, California, U.S.A.
Tamar Lotan NanoCyte Inc., Jordan Valley, Israel
R. Karl Malcolm School of Pharmacy, Queen’s University Belfast,
Medical Biology Centre, Belfast, Northern Ireland, U.K.
Heidi M. Mansour School of Pharmacy, Division of Molecular
Pharmaceutics, University of North Carolina-Chapel Hill, Kerr
Hall-Dispersed Systems Laboratory, Chapel Hill, North Carolina, U.S.A.
Juan A. Mantelle Noven Pharmaceuticals, Inc., Miami, Florida, U.S.A.
xiv Contributors

Francis J. Martin Eclipse Nanomedical, Inc., San Francisco, California,

U.S.A.
Kevin Maynard Imprint Pharmaceuticals Ltd., OCFI, Oxford, U.K.
Ashim K. Mitra University of Missouri-Kansas City, Kansas City,
Missouri, U.S.A.
Samir Mitragotri Department of Chemical Engineering, University of
California, Santa Barbara, California, U.S.A.
Achim Moser Boehringer Ingelheim MicroParts GmbH, Dortmund,
Germany
Rainer H. Müller Department of Pharmacy, Free University of Berlin,
Berlin, Germany
Paul B. Myrdal College of Pharmacy, University of Arizona, Tucson,
Arizona, U.S.A.
Kurt Nikander Respironics, Inc., Respiratory Drug Delivery, Parsippany,
New Jersey, U.S.A.
Franklin W. Okumu DURECT Corporation, Cupertino, California,
U.S.A.
Rama Padmanabhan ALZA Corporation, Mountain View, California,
U.S.A.
Jung-Hwan Park Kyungwon University, Seoul, Korea
Steven Percival ConvaTec Wound TherapeuticsTM , Global Development
Centre, Deeside, Flintshire, U.K.
Stephen Perrett Eurand, Vandalia, Ohio, U.S.A.
Rolf D. Petersen Department of Pharmacy, Free University of Berlin,
Berlin, Germany
J. Bradley Phipps ALZA Corporation, Mountain View, California,
U.S.A.
Bernard Plazonnet Chamalières, France
Ajay Prasad University of Delaware, Newark, Delaware, U.S.A.
Mark R. Prausnitz School of Chemical and Biomolecular Engineering,
Georgia Institute of Technology, Atlanta, Georgia, U.S.A.
Lakshmi Raghavan Vyteris, Inc., Fair Lawn, New Jersey, U.S.A.
Ramesh C. Rathi Protherics Plc, West Valley City, Utah, U.S.A.
Contributors xv

Erin Rhone Pharmaceutical Research and Development, Alcon Research

Ltd., Fort Worth, Texas, U.S.A.
Steve Robertson Controlled Therapeutics (Scotland) Limited, East
Kilbride, Lanarkshire, U.K.
Ashutosh Sharma Vyteris, Inc., Fair Lawn, New Jersey, U.S.A.
Florence Siepmann College of Pharmacy, University of Lille, Lille,
France
Juergen Siepmann College of Pharmacy, University of Lille, Lille, France
Alan Smith Altea Therapeutics Corporation, Atlanta, Georgia, U.S.A.
Eliana B. Souto Health Sciences Department, Fernando Pessoa
University, Porto, Portugal
Janet Tamada ALZA Corporation, Mountain View, California, U.S.A.
Daniel J. Thompson KV Pharmaceutical Company, St. Louis, Missouri,
U.S.A.
Eric Tomlinson Altea Therapeutics Corporation, Atlanta, Georgia,
U.S.A.
A. Neil Verity DURECT Corporation, Cupertino, California, U.S.A.
Herbert Wachtel Boehringer Ingelheim Pharma GmbH & Co. KG,
Ingelheim, Germany
Michael Walker ConvaTec Wound TherapeuticsTM , Global Development
Centre, Deeside, Flintshire, U.K.
Kenneth A. Walters An-eX Analytical Services Ltd., Cardiff, U.K.
Fintan Walton Pharma Ventures Ltd., Oxford, U.K.
Adam C. Watkinson Acrux Ltd., Melbourne, Australia
Christina Wedemeyer Genzyme Pharmaceuticals, Liestal, Switzerland
Jeffry G. Weers Nektar Therapeutics, San Carlos, California, U.S.A.
Torsten Wöhr Genzyme Pharmaceuticals, Liestal, Switzerland
A. David Woolfson School of Pharmacy, Queen’s University Belfast,
Medical Biology Centre, Belfast, Northern Ireland, U.K.
Jeremy C. Wright DURECT Corporation, Cupertino, California, U.S.A.
Part I: Using Modified-Release Formulations
to Maintain and Develop Markets

__________________________________________________ 1 __________________________________________________

The Modified-Release Drug

Delivery Landscape
The Commercial Perspective

Stephen Perrett
Eurand, Vandalia, Ohio, U.S.A.

The life cycle management of pharmaceutical products through reformula-

tion is an established practice in the industry and, historically, many
commentators have recognized the opportunity that reformulation can
represent for specialist companies and technology-focused innovators. The
1990s saw an increasing number of companies being created that based
business models on the development of established therapeutic compounds
as this offered pharmaceutical product development which was faster,
cost less, and had a large part of the therapeutic risk removed. The
estimated size of market represented by reformulation varies between com-
mentators and relies upon the definition of drug delivery, but figures from
Datamonitor estimate it to be currently worth in the region of $114 billion.
If one also considers that on average between 2002 and 2005, 39% of all new
product launches by the top 50 manufacturers were reformulations of exist-
ing drugs (MIDAS prescribing insights: IMS Health March 2006) and that
IMS placed the global Pharmaceutical Market in 2006 at $643 billion, then
the monetary value of reformulation is clearly significant.

COMMERCIAL DRIVERS OF REFORMULATION

The goal and driver for product reformulation is the generation of a positive
return on the investment made to develop and launch a reformulated product
and both innovators and companies specializing in reformulation must

1
2 Perrett

carefully consider the financial implications in deciding whether or not to

adopt this strategy for a given compound as although reformulating a product
may improve it, it may not ultimately be worth it. Reformulation strategies
generally seek to expand the market for a compound, to defend the market of a
compound or to create a new market for a compound. There is inevitably some
crossover in the strategies used and the approach taken is also a function of the
competitiveness of the compound as it is and the actions of competitors.
In seeking to expand a market innovators are looking to take a
compound into new areas through label expansion, this generally involves
new clinical studies, it may also involve the concurrent production of dosage
forms that are more friendly to a particular patient group—such as orally
disintegrating tablets (ODTs) or suspension formulations.
In defending their markets, innovators are seeking to make their
products more competitive by, e.g., launching once a day formulations into
a therapeutic area where competing products are dosed multiple times per
day. The most common form of market defense, however, is defense against
generic launch and innovators seek to extend the life cycle of the brand by
making it non-substitutable by a generic product, this means that for-
mulation changes need not necessarily improve product performance,
although this would be a desired outcome.
The final reformulation approach is to seek to create a new market for
an already generic compound and, when they are not partnered with
innovators, this is where specialist reformulation companies operate. This is
not just the preserve of specialist companies and innovators will also play in
this space if they see an opportunity. The strategic driver of reformulation
depends on the position of a compound in the life cycle of a brand. The
weights that are given to differentiation, in the sense of just being different,
and true therapeutic differentiation vary greatly at different points in the life
cycle. As discussed below, differentiation for generic defense need only mean
that the product is different from the product used in an abbreviated new
drug application (ANDA) filing, whereas a reformulation launched into an
already generic market must represent a significant therapeutic improve-
ment over the now commoditized product.

GENERIC DEFENSE
Differentiation from Generic Products
The goal of reformulation as a means of generic defense is clear: to prevent the
substitution of the branded product by generics on patent expiry. To do this it
is sufficient to alter the branded product only to the extent that it is no longer
the same as the product that the generic companies are using as the reference
for their registrations. This prevents pharmacies substituting generic product
for the reformulated branded product which will not have been used as a
Modified-Release Drug Delivery: Commercial Perspective 3

reference formulation. It is essential that the brand holder switch their patients
to the new formulation prior to generic launch and the timing of the launch of
the new formulation is crucial. If it is launched too soon then the generics will
simply use the new formulation as the reference, if it is launched too late then
the market for the brand will have already been lost to the generics.
One of the clearest and most successful instances of this has been
the successive reformulations of fenofibrate by Fournier (now Solvay), who
have succeeded in defending Tricor (Abbott) through changing the
dosage strength or the form of the product. The first product iteration was a
300-mg capsule containing particulate drug; the second, a capsule contain-
ing 200 mg of finely milled drug; the third a 160-mg tablet containing finely
milled drug and surfactant; the fourth a 145-mg tablet containing nano-
particulate drug—all of these formulations are bioequivalent to one
another. Progressive size reduction resulted in more than a two-fold increase
in bioavailability, but all were bioequivalent to one another and essentially
directly substitutable formulations from a medical perspective: however,
they are not directly substitutable from a regulatory perspective. This means
that scrips written for Tricor cannot be substituted in the pharmacy and
this is true even if the dosage from is changed from a capsule to a tablet.
That said, the final nanoparticulate formulation did enable Abbot to
remove the food requirement for dosing from the label.
It is debatable whether any of these changes represented anything
other than a repackaging of the same ingredient; however, through the use
of successive periods of market exclusivity associated with the new dosages
the brand has been able to avoid substitution by generics, thus preserving its
value through three successive expirations of market exclusivity, as the
innovator was able to switch patients to the new formulation prior to this.
The great advantage to this approach was that it was a relatively inexpensive
series of progressions from the perspective of the clinical registration
requirement in that no efficacy studies were required for formulations that
aimed only at bioequivalence.
That it is the brand that drives value is further illustrated in the case of
this drug by Scieles nanoparticulate product of fenofibrate licensed from
Skyepharma, which is a low-dose small-particle formulation. The Sciele
product was largely similar to Tricor and had a similar label, including the
lack of a food requirement, yet it was reported by Sciele to have only 1.8%
of total prescriptions at the end of the first quarter 2007. That sales are a
tiny fraction of those of the Tricor brand may seem predictable, but it is
perhaps salutary to those who might think that the pharmaceutical market
differs substantially from any other.
While the market considerations driving Tricor seem to have been
paramount, there are other reformulation examples that more readily retain a
link between product improvement and market defense. Pfizer’s Procardia
XL, which used the Alza [now Johnson & Johnson; (J&J)] Oros sustained
4 Perrett

release tablet technology, changed the dosage form from a capsule to a tablet,
changed the divided dosage form to a once daily dosage form which also
provided for a zero-order drug release. Despite the fact that pharmacokinetic
profile of this formulation was eventually duplicated, the proprietary nature
of the formulation and its differentiated release characteristics were enough to
prevent direct generic substitution of the brand for over 10 years.

Timing of Reformulation
As mentioned above, timing is of crucial in optimizing the commercial
returns from a compound through its product life cycle and innovators must
launch at the right time, to launch too soon is to squander the 3 years of
market exclusivity offered by the FDA on the basis of new clinical studies,
to launch too late is not only to have missed this, but to launch into a
market in which reference pricing will have seriously eroded.
As an illustration, GlaxoSmithKline’s (GSK’s) Paxil CR, a refor-
mulation of GSK’s paroxetine obtained U.S. marketing approval for the
controlled-release form based on SkyePharma’s Geomatrix technology in
February 1999; however, the product was not launched until three years
later in 2002. This allowed Paxil to progress further in its life cycle as no
generic entry was anticipated prior to 2003, thereby allowing GSK to switch
patients to the new dosage form at an appropriate time and not pre-
maturely. Generic attack of the CR form will now only began in June 2007
when Mylan’s ANDA filing for a controlled release dosage form received
approval on the expiry of pediatric exclusivity related to a patent covering
the crystalline form of the active pharmaceutical ingredient (API). This also
illustrates an interesting point regarding reformulation; the new formulation
uses a proprietary technology with patent coverage until 2012, yet it is not
this that has prevented a generic from entering the market. This is worth
mentioning because, although formulation patents provide a significant
barrier, does not have the same defensive power as patents covering the
compound itself.
It is also worth recalling at this point that Paxil was a compound that
was dosed once-a-day; the CR form did not change that. In circumstances
where the brand was not available or where the market was already generic
reformulation in this way would not have been a viable option. The ther-
apeutic benefits of the reformulation are arguably minimal, as we saw
previously with Tricor, but the submission of new clinical studies qualifies
the product for 3 years regulatory exclusivity and renders it nonsubstitutable
by generic Paxil.
The D2/D3 agonists ropinirole (Requip) from GSK and pramipexole
(Mirapex) and their use in the treatment of Parkinson’s disease are also
illustrative of timing as a driver for the development launch of reformulated
products. GSK have again chosen to defend this brand against generic
Modified-Release Drug Delivery: Commercial Perspective 5

attack and to extend its life cycle with an extended-release formulation using
the Geomatrix technology—Requip CR. In this case, however, there is
the bonus of a less frequent dosing schedule, which is welcome for this
patient group. GSK originally filed for approval with the FDA in April 2006
in anticipation of patent term expiry in May 2008; however, administrative
problems with the submission meant that the FDA only finally accepted the
filing in April 2007. This means that GSK will struggle to switch their
Parkinson’s patients to the new formulation, before generic appearance in
the United States should they receive approval before May 2008, if they
receive approval after this date then they may be entering a reduced value
generic market. It is therefore fortunate that there is a clearly defined dif-
ference between the two products.
Mirapex (pramipexole) has an estimated patent constraint date of
2011, although Barr now has final approval for a generic version, Pfizer
hold patents to an extended-release dosage form, but as yet there are no
reports on the development of such a formulation, despite the fact that this
would be a better dosage form. To launch, at this stage in the product life
cycle would be to waste 3 years of regulatory exclusivity. That the devel-
opment of Requip CR has not caused Pfizer to move may be due to the
fact that the revenue that might be lost to during the 2 to 3 year period that
it will exist alongside Mirapex, would be as great as the 2 to 3 years’ of
revenue that would be lost to generics after 2011, if a CR formulation were
brought forward now. Mirapex easily outsold Requip in 2005, $254 as
opposed to $159 (IMS data) and one assumes that it is perception as a better
drug will to some extent counter the convenience of Requip CR. Certainly
of greater importance at this time is the registration of Mirapex for the
treatment of restless legs syndrome as this is a new market in which Requip
is currently unopposed. Since its approval in this indication in June 2005, U.
S. sales have increased from $159 in 2005 to $315 in 2006 (IMS data).
This speculated timing of the launch of a Mirapex CR can be con-
trasted with Pfizer’s reformulation of Detrol to Detrol LA. This refor-
mulation occurred early on in the product life cycle in response to the
appearance of Ditropan XL, as the market began its move to once-a-day
therapy. At this stage it was not possible to allow the competition to erode
the revenue expectation of Detrol over an extended period. In this case, the
potential loss over the remaining life span of the product would likely be
much greater than would have been recouped through the delay of generic
entry for a period of 2 to 3 years.

Defensibility and Value of Reformulation

Extended-release technology for oral drug delivery is a mature technology.
Approaches that are able to also build features that go beyond converting
multiple dose schedules to once-a-day are likely to fare best.
6 Perrett

An interesting modification of the extended release angle was used in

Pfizer’s Azithromycin Zmax azithromycin suspension. Azithromycin has a
long half-life and dosing of Zithromax was already once daily. By com-
bining a high dose (2 g) with a sustained release technology, Pfizer was able
to establish that a complete course of treatment was possible with a single
dose. It is unclear as to whether the high dose or the formulation technology
is the more important factor, but by using both, more defensibility can be
built into the formulation.
That the dose of the formulation may be the technology is very well
illustrated by Merck’s alendronate, where the 70-mg dose can now be dosed
once per week rather than being taken daily. This truly is a therapeutic
benefit to patients and, as a result, it created a very competitive product.
This has proven more difficult to defend from a patent viewpoint, but
not entirely due to the fact that the dosing schedule is harder to defend
per se.
The best technology patents look like new chemical entity (NCE)
patents and in some cases they are. The recent launch of GSK’s extended
release Coreg was based on Flamel’s Micropump technology: however,
this product owes much to the phosphate salt of carvedilol used in the
formulation. Carvedilol is poorly soluble at neutral and alkaline pH,
meaning that absorption of the immediate release formulation occurs pri-
marily in the upper part of the GI tract. A sustained release formulation
would need either to be based on upper GI retention and/or the use of a
bioavailability enhancement technology suited to insoluble drugs for the
delayed-release portion of the dose. Through consideration of Flamel and
GSK’s patent application (1) a key mechanistic part of the formulation is
linked to the increased solubility of the phosphate salt in combination with
acidic excipients in the delayed release fraction of the formulation. The
contribution of the Micropump technology is unclear, but should this patent
proceed to grant substitution of the formulation becomes much less
straightforward, being based more upon the chemistry of salt forms and
combinations of chemical species in a particular dosage construct it becomes
a more difficult task to duplicate without encroaching on the patents cov-
ering the product.
The move to use the phosphate salt and switch to a capsule from a
tablet also resets the competitive clock of technology-focused developers,
such as Biovail and Egalet, that were developing sustained elease carvedilol
formulations. The substitution of the sustained release formulation
that GSK had in development may not have been an express aim of their
program, but now it is no longer an option. Controlled release form-
ulations for substitution will need to be based on the phosphate form and on
a capsule.
If one pursues this theme, the very best of all defense strategies would
be new chemical entities, and one can reasonably say that Shire have taken
Modified-Release Drug Delivery: Commercial Perspective 7

such an approach to the life cycle management of Adderall XR. The recent
settlements between Shire and Barr and Shire and Impax will allow Barr to
market generic versions of Adderall XR in the United States on April 1,
2009 and Impax to market generic versions of Adderall XR in the United
States 181 days following Barr‘s launch. Through a $2.3 billion acquisition
of New River, Shire have obtained lisdexamphetamine, Vyvanse, a dex-
amphetamine pro-drug, something that can be looked upon as a molecular
sustained release technology. Vyvanse is also claimed to have less abuse
potential and to be safer that its active moiety, but its biggest commercial
advantage is the fact that it is a NCE and consequently entitled to 5 years
of NCE exclusivity as well as benefiting from patents covering the com-
pound itself.
We should not leave this area of life cycle management without
considering the relatively recent phenomenon of reformulations through
the separation of the active isomers from drugs that were previously
marketed as the raecemate. This approach has been largely pioneered
by the specialty pharmaceutical company Sepracor, who were among
the first to recognize this business opportunity. Through the purifica-
tion and selection of the most active isomer from a previously mixed
product, medications with equivalent efficacy can be made using a
lower dose of API, thus qualifying for market exclusivity in much the
same way as we saw above for Tricor fenofibrate: however, in this case
the protection is much more robust. The compound is also an NCE
and may be eligible for much longer term patent protection. The
weakness of this approach is that medical benefits, if present, are dif-
ficult to tease out. Despite this, Astra Zeneca’s rebranding of raecemic
omeprazole, Prilosec, to the single isomer esomeprazole Nexium has
been successful—the clinical benefits being generated largely through
what is effectively a dose increase.
A second example is Forest/Lundbeck’s citalopram (Celexa),
whose franchise has been protected through the registration and launch
of escitalopram with patent coverage now extending to March 2012
following a U.S. District Court ruling in July 2006 in Lundbeck/
Forest‘s favor (2).
This launch was not as successful as it might have been as Lexapro is
subject to more generic competition than anticipated due to Forest‘s failure
to switch patients quickly enough from Celexa to Lexapro before generic
Celexa entered the U.S. market; with 29% of Forest’s depression pre-
scriptions still being written for Celexa on that date.
While there is price pressure from payers where the raecemic generic is
available, and the very close similarities between the two products are self-
evident, the fact that this strategy works (and that it works to the extent
that it does) illustrates once again the power of marketing structures and
the brand.
8 Perrett

We have considered a series of formulation approaches with varying

degrees of complexity and have seen that a simple reformation does not
generally buy any more time from generic competition than is offered by
the three years of exclusivity for the new dosage form given by the
regulatory authorities. In many ways, the more challenging or suboptimal
the formulation is in the original product, the greater are the possibilities
for the innovator to retain control as improvements are sequentially
added.

MARKET EXPANSION
There is a disincentive to add new formulations, such as extended release
formulations, at points other than the late phases of the life cycle as this is to
forgo the extension of life cycle as a means of generic defense. There is also a
second disincentive: the cannibalization of the existing product. This will
inevitably occur, making this a questionable move in terms of return on
investment. Unless competitive products are gaining market share owing to
a better dosing regimen, innovators will not move in this direction until the
appropriate point in the life cycle.
At the approximate midpoint of a product life cycle, an appropriate
means to grow sales of the product, as it is within any market, is to enter
new markets. The expansion into new geographies is part of the normal
progression of the product. In addition, the product progresses into new
therapeutic areas through the performance of new clinical trials to add new
indications to the product label. These can be incremental or moves into
unrelated therapeutic areas or even the characterization of new disease
states, such as restless legs syndrome, which has become an important
market for Requip with sales almost doubling since approval.

Combination Products
The reformulation strategies used around the midpoint or a little beyond
are, therefore, designed to add value through expanding the market reach
of the compound, in these cases the original formulation will continue to
exist with the new. Examples of this type of approach are found in
combination products such as Novartis’s Exforge, a fixed dose combi-
nation of valsatran and amlodipine, and Lotrel, a fixed dose combination
of amlodipine and benazepril. Other examples include Pfizer’s Caduet, a
fixed dose combination of atorovastatin and amlodipine and Merck’s
Vytorin, a fixed dose combination of simvastatin and ezetimibe. The
Caduet and Vytorin products are interesting as they are arguably good
and bad examples of the combination formulation approach, from a
commercial perspective.
Modified-Release Drug Delivery: Commercial Perspective 9

Caduet was intended to be the first combination therapy to target both

dyslipidemia and hypertension. Although there is a strong correlation
between the disease states the cross-risk factors and the titration schemes
make the product difficult to use and the message of greater convenience is
lost in a cumbersome prescribing regimen that involves 11 different for-
mulations. Conversely, Vytorin, a combination of two cholesterol-lowering
drugs, is available in only 4 dosage combinations. The marketing message—
that it is superior to monotherapies in lowering cholesterol—is clear and its
prescribing is simple. This joint venture between Schering Plough and
Merck has been very effective in extending the life cycle of Zocor even
though generic simvastatin is now readily available.
These reformulation strategies may not make as much use of the
formulation scientists’ art as controlled release formulations, but there are
examples where technically innovative approaches are found in combination
product or in products that coexist with the original dosage forms. Abbott’s
Kaletra, a fixed dose combination of lopinavir and ritonavir, in which a
liquid product requiring refrigeration dosed as a liquid or six soft shells was
replaced by four tablets not requiring refrigeration. This was achieved using
Abbott’s Soliqs technology and was approved by the FDA in October 2005
and in the European Union (EU) in July 2006.
The now abandoned combination of atorvastatin and torcetrapib, a
product aimed to raise HDL levels while lowering LDL, which was under
development by Pfizer as part of the management of the life cycle of
Lipitor, also incorporated a solubility enhancement technology to increase
the absorption of torcetrapib (3). This added formulation complexity and,
of course, enhances defensibility.
One of the most successful combination products has occurred in
pulmonary medicine, and although there may be less opportunity for this
delivery route, some reformulated products have been strikingly successful.
Advair, in which the combination of two drugs, salmeterol and fluticasone,
which were previously separately available and remain so, has enabled GSK
to create product with over $6 billion in sales. This was the first fixed dose
combination of a bronchodilator and a steroid and accounted for 56% of
new scrips after its launch in 2004.
This field has also seen one truly innovative product reach the market
through the development of Exubera, inhaled insulin, which represents a
true breakthrough in the delivery of large molecules. Unfortunately, this has
not led to commercial success.
Other noteworthy examples in this space are the development of a dry
powder inhalation of the antimicrobial tombramycin for the treatment of
bacterial lung infections in patients with cystic fibrosis. The present for-
mulation is an air-jet nebulized delivery of a solution with an inhalation time
of at least 15 minutes, which is bulky and not portable. The new formulation
under development by Nektar and Novartis promises to be rapid and easily
10 Perrett

portable. In this patient group, who are the subjects of a high pharma-
ceutical burden, reduction in treatment times or treatment approaches that
contribute to an increase in their freedom is very welcome.

New Routes of Administration

The extended release formulations of J&J’s risperidone, Risperdal Consta
is an injectable formulation based on the Medisorb biodegradable micro-
sphere technology of Alkermes, with a single injection providing therapeutic
coverage for a two-week period. The oral form, Risperdal was launched in
the United States in 1994 and in the EU in 1997. Consta was launched in
the United States in 2003 and in the EU in 2002. It is the only injected
antipsychotic and it could reasonably be said that it has 100% of the market
represented by those patients who are unwilling to comply with oral ther-
apy; in 2006 worldwide sales of Risperdal Consta were $870 M (IMS data).
It should be noted that worldwide sales of the tablet form were $3.6 billion
(IMS data) and it has been suggested that there would have been more take
up of Risperdal Consta if pricing had not been at such variance to the
tablet—the difference being approximately five-fold in the United States.
J&J have chosen to manage the life cycle of Risperdal with an NCE
paliperidone, which is an active metabolite of risperidone. Invega (pal-
iperidone) was launched in the United States in January 2007 using J&J’s
Oros sustained release tablet technology. The fact that the product is an
NCE is currently providing the only means of U.S. defense for this product
as it qualifies for five years NCE exclusivity from the FDA, giving it
exclusivity until December 2011. The only Orange Book listed patent, which
is specific to the NCE, expires in October 2009. Despite this less than ideal
situation, which should be qualified by saying that this type of regulatory
exclusivity is watertight, the technology does offer advantages that will help
to drive the switching strategy, the Oros formulation of paliperidone is a
true once-a-day, which is not always the case with Risperdal. The for-
mulation also removes the need for titration at the onset of therapy; the
complement long-acting injectable formulation of paliperidone palmitate
has a longer period of action and can be injected less frequently, about six
weeks. The injectable form also uses Elan’s nanoparticle technology, cre-
ating a further entry barrier.
On the negative side, the product does face its stiffest competition
from generic risperidone. There may be enough to prevent the product from
being seen as purely created for the purposes of patent extension by
physicians and payers, but the pricing pressure exerted by a generic product
which is essentially therapeutically equivalent will be significant. Although
the medical advance offered by this reformulation is more incremental, there
is probably enough differentiation in the package for J&J to switch patients
to the new forms with appropriate pricing.
Modified-Release Drug Delivery: Commercial Perspective 11

The reformulation of products that were always injectables has also

provided a successful means to expand markets. They have added the most
in terms of the use of biodegradeable polymers to extend the efficacy of
LHRH agonists, which has been continued to the point where formulations
will provide coverage for several months and even as long as one year if the
Viadur titanium implant from Alza (now J&J) is used. One of the
advantages of this type of technology is that duplication is not a simple task.
The only real alternative is the Atrigel implant technology from QLT.
There are also approaches in the injectable arena that employ a
technology to sustain therapeutic effect through modifying the molecule
itself. Pegylated interferon has largely replaced the nonconjugated parent
molecule as a drug product. Frequent injections are both unpleasant and
time-consuming and products that alleviate this do well. Other reformula-
tions of injectable products have sought to decrease the toxicity of certain
products, most notably paclitaxel. Also, the removal of the surfactant
Cremophore from Taxol was seen to be desirable for the reduction in
premedication that this would bring, as the delivery vehicle itself was
pyrogenic and contributed to the dose-limiting toxicity of the medication.
This proved considerably more challenging than would-be formulators of
next generation Taxol imagined. But the eventual launch of Abraxane, in
which insoluble paclitaxel is absorbed to the surface of albumin particles,
promises to be both a safer and more efficacious therapy.
New Dosage Forms
Successful formulation-based approaches aimed at expanding markets need
not involve a switch to a different route of administration. The production
of more convenient dosage forms or dosage forms suited to a particular type
of patient are also used to expand the market reach of products and to
enhance the competitive profile of the brand. The production of more
convenient dosage forms, such as ODTs and suspension formulations, are
popular means of doing this. The development of such formulations may
also qualify for extension of patent terms of six months if directed toward
pediatrics.
The suspension formulation is particularly suited to pediatrics as it can
be easily titrated and is suited to all ages. The ODT is a relatively recent
development tablet and early formulations were brought to the market by
Cima (now Cephalon), Yamanouchi, Lafon (now Cephalon) and Ethypharm.
These early formulations were rather fragile, required special packaging, and
were not well-suited to high drug doses of active. Second-generation tech-
nologies such as Eurand’s Advatab and Cephalon’s Durasolv have char-
acteristics that are similar to conventional tablets, while still possessing the
ability to disintegrate very rapidly in the oral cavity.
The ODT dosage form has proven useful, not only for pediatric and
geriatric dosage forms, but also for particular types of patients and disease
12 Perrett

states. In cases where symptom onset is sudden and unpredictable, such as

migraine or acute pain, the ODT is useful as it can be taken immediately
by the patient, without the need for water, e.g., Zomig, and Fentora
(fentanyl). In cases such as psychiatric disease, where the patient may not
wish others to be aware that they are taking medication or where they may
avoid taking it by holding conventional pills in their cheek or under the
tongue, the ODT is useful. Examples of such products in include Risperdal
ODT, Remeron ODT, and Zyprexa ODT.
A particular problem that has been encountered in formulating tablets
that are designed to disintegrate in the oral cavity is that many drugs have
an unpleasant taste and an additional technology of taste-masking is
required to overcome this. This involves coating the drug particles so that a
polymer barrier exists between the drug particle and the tongue. This ideally
has to be achieved without delaying the release of the drug. This is partic-
ularly relevant to drugs that need to act rapidly, such as those for the relief
of acute pain such as migraine and the 3-hour Tmax of zolmitriptan in ODT
form as opposed to the 2-hour Tmax (Zomig prescribing information) of
the conventional tablet form is clearly a move in the wrong direction for a
drug designed to bring rapid pain relief.
Other applications where the ODT dosage form is used are those in
which the patient is extremely nauseas and would prefer not to contemplate
swallowing water. ODT dosage forms are found in Zofran (ondansetron),
which is used for the prevention of nausea and vomiting during chemo-
therapy. It is also found in other applications where GI symptoms may also
be a concern, such as the Prevacid ODT form.
It is thus necessary to have both a sophisticated ODT technology and
a sophisticated taste-masking technology to create successful products.
Companies, such as Eurand, that are able to combine a diversity and
experience in particle coating with advanced ODT technology are well
positioned to further expand the use of the ODTs as a means to extend the
market reach of products.

USING FORMULATION TO CREATE NEW PRODUCTS

The final area where reformulation can represent a commercial opportunity
is in the reformulation of drugs whose patent has already expired. In this
area, specialist companies need not partner with the innovator and brand
owner; brand owners may also be opportunistic and attack markets created
by others.
A well-publicized and illustrative example of this is the reformulation
of methylphenidate by J&J into a once-a-day formulation using the Oros
technology it acquired from Alza, to both revitalize a market with a superior
product and to take this market from the original franchise holder. J&J did
not have a methylphendidate franchise prior to their launch of Concerta, a
Modified-Release Drug Delivery: Commercial Perspective 13

once-a-day Oros formulation, in 2000. Methylphenidate (Ritalin), a

Novartis compound, had already endured four years of patent expiry and
sales had largely stagnated in the attention-deficit/hyperactivity disorder
(ADHD) market. The patient group is primarily school children and the
drug is a controlled substance. This had meant that the original twice-a-day
dosing schedule required that the drug be dispensed under the supervision of
a school nurse, making those on medication conspicuous with consequent
embarrassment.
The ability to dose methylphenidate once daily for ADHD offers
particular advantages, so despite a lack of a methyliphendiate franchise, J&J
were able to step in and not only transform the ADHD market, but to take
the ADHD market from the original franchisee through possession of a
formulation technology and foresight. There were also thought to be
additional advantages linked the Oros release kinetic, as ascending dose is
thought to be a more effective way for the drug to enter the body. Concerta
soon dominated the market for methylphenidate-based drugs. Following the
introduction of Concerta, between 2001 and 2003, the market exhibited a
compound annual growth rate of 28% reaching $852 million in 2003.
Concerta almost exclusively drove this growth, with 74% of all methyl-
phenidate sales in 2003 (IMS data). In 2006 J&J reported sales growth of
20.2% and sales of approximately $900 million. This product has not been
substituted in a now highly genericized market and still retains Orange Book
exclusivities until 2008.
J&J were not alone in exploiting the particular advantages offered by
once-a-day formulations in this market. Shire’s Adderall XR, a sustained
release formulation of mixed amphetamine salts, was approved by the
FDA on October 12, 2001. Although it was launched only six months
prior to the market entry of Barr’s generic, strong patient switching from
Adderall to Adderall XR was achieved. In its first quarter on the market,
Adderall XR accounted for 21% of total Adderall franchise sales. The
momentum of uptake of the new formulation was maintained following
the launch of further amphetamine generics from Eon and Ranbaxy in
2002. After three companies had launched generics, the XR reformulation
still represented 83% of franchise sales and 68% of total molecule sales.
That Shire has been able to regularly increase the price of Adderall XR, is
entirely due to the fact that it is such a highly differentiated product.
The effect of both Concerta and Adderall XR has been to transform a
generic market with products that have profiles similar to those of new
entrants rather than the follow-on profiles of reformulations associated with
generic defense that we considered earlier. These two products and their
market illustrate well the ability of reformulation to drive growth and alter
market structure. Further, the conception of these two approaches also
illustrates two distinct drivers for reformulation. In the case of Adderall XR,
14 Perrett

the defense against generic attack and in the case of Concerta the oppor-
tunistic conquest of an existing market with a superior product.
This is worth comparing with the reformulation of Xanax. After
patent expiry by Pfizer (Pharmacia and Upjohn), the extended-release
formulation was approved in the United States in January 2003, nine years
after patent expiry. This product offered a more convenient dosage
scheme, but that was all that it offered. It did not overcome a particular
problem in the way that Concerta did and could not claim any particular
advantages associated with the technology used or offer any patent pro-
tection, and after regulatory exclusivity expired it was rapidly substituted
by generics. In the three years before generic substitution occurred, rev-
enues increased by approximately $48 million (Datamonitor), but the
combination of clinical and launch costs probably make this a marginal
product in terms of return on investment. Xanax XR was never able to
gain the momentum of Concerta, and although this strategy would have
worked well for life cycle extension it did not work well as a means to
revitalize the market for this compound.
There are a limited number of examples where reformulation has
delivered a benefit to therapy to the extent that Concerta and Adderal
XR have and these were more associated to the particular problems
associated with the disease demographic than any unusual property of the
formulation itself.
The reformulation of fentanyl has provided examples where the
innovation associated with the formulation has also contributed in a large
part to the success of the product. Fentanyl was originally developed by J&J
in 1962. It is a highly potent opioid analgesic, with a potency approximately
100-fold that of morphine, and it is an important molecule in the manage-
ment of severe and chronic pain.
In collaboration with Alza, which J&J subsequently acquired, J&J
developed the Duragesic patch, which has a number of important
advantages over the injectable or oral means of delivery that had been used.
Patients were exposed to a smooth flow of drug, without the need for
infusion, over a long period (up to 72 hours). This was a better and more
convenient therapy than those offered by generics allowing Duragesic to
easily out-compete alternatives. At its peak, Duragesic represented a $1.6
billion market and worldwide sales have only just begun to decline 15 years
post-launch with the appearance of generics in 2005: Duragesic sales
reported by J&J for 2006 were $1.295 billion.
The approach that Anesta (now Cephalon) took with fentanyl was to
enter a new market with a formulation designed to meet the needs of
patients in that market. Actiq was specifically targeted to break through
cancer pain, which is a condition in which cancer sufferers experience acute,
unpredictable spikes of severe pain that overcome their pain therapy. Actiq
is a lollipop formulation of fentanyl, which patients place into their mouths
Modified-Release Drug Delivery: Commercial Perspective 15

when they experience an episode of breakthrough pain. The very high

potency of fentanyl together with its ability to cross the buccal mucosa
means that pain relief is achieved very rapidly without the need for injection,
furthermore patients can optimize dosing by removing the lollipop once
the pain has abated. From 200 to 2003 U.S. sales of Actiq grew from $14
to $245 million in 2003 giving Actiq a 16% of the fentanyl market
(Datamonitor). In that time the price of Actiq almost doubled. Sales of
Actiq reported by Cephalon for 2006 totaled $572.1 million, representing a
year-on-year growth of 39%. Cephalon has managed the life cycle of
this franchise through the launch in October 2006 of Fentora, an ODT
tablet for buccal absorption based on the Oravescent technology acquired
from Cima.
A very recent example of an innovative formulation of an old drug to
produce a differentiated product is provided by the launch in June 2006 of
Vivitrol, a sustained release injectable formulation of naltrexone licensed
from Alkermes. Following subcutaneous or intramuscular administration a
steady release rate of naltrexone release into the bloodstream is sustained for
up to 1 month.
Naltrexone is an opioid receptor antagonist and was approved for the
treatment of alcohol dependence in 1994 and for opioid dependence a
decade prior to that. Naltrexone acts at µ, δ, and κ opioid receptors, each of
which is implicated in at least one aspect of alcohol and opiate dependence.
The blockade of the µ opioid receptor in particular inhibits the reward
received from opioids or alcohol and is linked with diminished dependence.
The value of oral naltrexone in the long-term treatment of alcohol or opiate
dependence has been greatly undermined by the failure of the substance
abusers to adhere to the daily dosing schedule. There is an absence of
suitable alternative products in this arena, with only Disulfiram and
Acamaprosate available. Disulfuram relies on the severe aversive effect
produced by inhibition of acetaldehyde dehydrogenase during the metabo-
lism of ethanol, but the adverse side effects associated with this can be severe
and even fatal. Acamprosate is thought to act on γ-aminobutyric acid and
glutaminergic receptors, but it is administered orally requiring a total dose
of 2 g to be administered in three divided doses.
Market uptake to date has been slow, partly due to the fact that this
is a difficult market to define and manage. It will be interesting to see how
this product will progress. It has solved an important therapeutic draw-
back associated with naltrexone and entered an area of unmet therapeutic
need. The challenge for this product will be to convince doctors and
patients alike that pharmacotherapy is an effective treatment for alcohol
dependency. Unlike methylphenidate or fentanyl, naltrexone is not a gold
standard for the treatment of the condition which the improved for-
mulation addresses.
16 Perrett

CONCLUSION
The great majority of drug reformulations are driven by the life cycle of the
product and must occur in the right sequence and at the right time if the value
of the product is to be fully realized. With efficient planning, this would be
built into the life cycle management plans prior to product launch. Timing is
crucial, particularly toward the end of product life cycles, at which time it is
very difficult to recover from prior delays. The therapeutic advance offered by
a reformulation need not be great and may even be minimal if it is allied to the
brand. In this case, it is sufficient that it differentiates the new product from its
predecessor only to the extent that it can enjoy an extended period of regu-
latory exclusivity or patent protection. In addition, a reformulation that
improves the competitive profile of a compound only to the extent that it takes
sales from the previous formulation would be a pointless exercise.
Reformulations that occur beyond the product life cycle face a much
higher bar, the benefits offered by reformulation in this case must be akin to
those features possessed by new products: they must offer a clear therapeutic
advantage and they must be robustly defensible if their life cycle is to last
beyond the three years of exclusivity offered by Waxman Hatch. Only a
handful of these more independent products created by formulation have
emerged, and these have been successful as they have solved special
inconveniences present in their therapeutic area or have allowed the treat-
ment of a previously poorly or untreated condition.
In considering the target of reformulation, during the course of the
product life cycle this will be heavily biased to market need. It is only after
the completion of life cycle that priority can be given to therapeutic need.
This is not to give the impression that brands somehow do not respect
therapeutic need, it is the therapeutic compound that is leading the response
to this challenge in the earlier parts of the life cycle, priorities shift after this
goal has been met and the market is given up to generics.

REFERENCES
1. Castan, C, et al. Carvedilol FreeBase, salts, anhydrous forms or solvate thereof
corresponding pharmaceutical compositions, controlled release formulations
and treatment or delivery methods. Patent WO2005/051322 A2.
2. Press Release 2006, July 13: www.frx.com
3. Freisen DT, et al. Pharmaceutical compositions of cholesteryl ester transfer
protein inhibitors and HMG-Co—A reductase inhibitors. Patent WO
20061129167.
4. Garbutt JC, et al. Efficacy and tolerability of long-acting injectable Naltrexone
for alcohol dependence: A randomized controlled trial. JAMA 2005; 293(13):
1617–25.
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