Multiparticulate Oral Drug Delivery

489 Pages·1994·20.756 MB·English

by  Isaac Ghebre-Selassie

II I
IMS IIAll!I
IQpiific ftJMD THE PHARMACEUTICAL SCIENCES
A Series of Textbooks and Monographs
edited by
James Swarbrlck
Applied Analytical Industries, Inc.
Wilmington, North Carolina
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 0. 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. Techni< s of Solubilization of Drugs, edited by Samuel H. Yalkowsky
13. Orphar ugs, edited by Fred E. Karch
14. Novel [ I Delivery Systems: Fundamentals, Developmental Concepts,
Biomec Assessments, Vie W. Chien
15. Pharm< nineties: Second Edition, Revised and Expanded, Milo Gibaldi
and Do 1 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. Dermatoiogical Formulations: Percutaneous Absorption, Brian W. Barry
19. The Clinical Research Process in the Pharmaceutical Industry, edited by
Gary M.
21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roe
and T. Colin Campbell
22. Biotechnology of Industrial Antibiotics, Erich 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, Benja
min J. Gudzinowicz, Burrows T. Younkin, Jr., and Michael J. Gudzino-
wicz
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 Edi
tion, 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 Vie 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 Ini
tiatives, edited by Jonathan Hadgraft and Richard H. Guy
36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, edited
by James W. McGinity
37. Pharmaceutical Peptization 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 Tech
nology, 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, Ding he
49. Pharmaceutical Dissolution Testing, Umesh V. Banakar
50. Novel Drug Delivery Systems: Second Edition, Revised and Expanded,
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.
Mickey
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 Ex
panded, 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.
Hails
65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie
66. Colloidal Drug Delivery Systems, edited by Jorg Kreuter
ADDITIONAL VOLUMES IN PREPARATION
HI III HI U|§ HHIIBWI *
edited by
Isaac Ghebre-Sellassie
Parke-Davis Pharmaceutical Research Division
Wamer-Lamhert Company
Morris Plains, Mew Jersey
informa
healthcare
CRC Press
Taylor & Francis Group
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Preface
Although multiparticulates, which comprise minitablets, pellets, and granules,
have been taken by patients in one dosage form or another for quite some time, it
is only in the last two decades that the full potential of multiparticulates as drug
delivery systems has been realized in terms of both flexibility during formulation
development and therapeutic benefits to patients. Not only can multiparticulates
be divided into desired doses without formulation and process changes, but they
can also be blended to deliver simultaneously incompatible bioactive agents, or
particles with different release profiles at the same site or at different sites within
the gastrointestinal tract. In addition, technological advances in dosage form
design, the advent of highly specialized pieces of equipment, and the popularity
of controlled-release dosage forms as a means of drug delivery have made
multiparticulates a viable and attractive alternative to single-unit dosage forms.
Multiparticulates also have numerous therapeutic advantages over single
units. When taken orally, multiparticulates generally disperse freely in the
gastrointestinal tract, maximize absorption, minimize side effects, and reduce
inter- and intrapatient variability. As a result, interest in multiparticulates as oral
drug delivery systems has been growing steadily over the last few years, and
there is a multimillion dollar market for Wurster coaters, rotary granulators, and
extruders/spheronizers.
Multiparticulates are diverse in size and shape, and are manufactured by
employing a variety of technologies, some of which have already been discussed
extensively elsewhere (e.g., Pharmaceutical Pelletization Technology and Mi
croencapsulation, Marcel Dekker, Inc.). The objective of the book is fourfold: to
review additional manufacturing technologies for multiparticulates, to describe
the various aspects of multiparticulate dosage form development, to assess the in
111
iv PREFACE
vivo behavior and performance of multiparticulates, and to compare the market
position of multiparticulates relative to other dosage forms.
Balling (spherical agglomeration), spray congealing, and cryopelletization
are discussed in Chapters 1 through 3, respectively. While all three processes
produce core pellets that may or may not require subsequent coating to generate a
target release profile, the formulation and processing requirements are drastically
different, and are discussed at length in the respective chapters. Coating of
multiparticulates using polymeric solutions, polymeric dispersions, and molten
materials is covered in Chapters 4 through 6. Both formulation factors and
processing variables that affect film formation, integrity, and performance are
critically discussed. In addition, conditions that minimize agglomeration of the
particles during the coating process are described. After multiparticulates are
manufactured, they may be filled into hard-shell gelatin capsules, compressed
into tablets, suspended in liquids or packaged in sachets, as described in Chap
ters 7 through 9. Chapter 10 addresses key formulation and process factors that
are critical to the development of controlled-release products. It highlights the
various conditions that can adversely affect the functional performance of the
rate-controlling membranes used in in vitro dissolution testing. Chapter 11
delineates the main chemical and physical forces that control the release of drugs
from coated multiparticulate dosage forms. Chapters 12 and 13 discuss at length
the biopharmaceutical aspects and in vivo performance of multiparticulates and
the therapeutic advantages they offer over single units such as tablets. Chapter 14
describes in detail the intricate and well-controlled manufacturing process of
hard-shell gelatin capsules. The composition of various packaging materials, a
description of packaging machinery, and the importance of packaging during and
beyond the development phase are articulated in Chapter 15. A thorough discus
sion on the assessment of the marketing potential of multiparticulate oral drug
delivery system vis-a-vis other oral dosage forms is given in Chapter 16.
This book is intended to complement other volumes that deal with multi
particulate oral dosage forms. As such, it will provide scientists engaged in
pharmaceutical research and development with the necessary information re
quired to develop multiparticulate drag delivery systems systematically.
I would like to express my sincere thanks to the outstanding contributors,
who devoted their time and effort to bring about the successful completion of the
project. Thanks also to Dr. Mahdi B. Fawzi, Vice President, and Dr. Russell U.
Nesbitt, Senior Director, Product Development, Parke-Davis Pharmaceutical
Research Division, Warner-Lambert Company, for their continuous support and
encouragement.
Isaac Ghebre-Sellassie
Preface Hi
Contributors vii
1. Manufacture of Core Pellets by Balling 1
Lucy S. C. Wan
2. Preparation of Micropellets by Spray Congealing 17
A. Atilld Hincal and H. Suheyla Ka§
3. Cryopelletization 35
Axel Knock
4. Coating of Multiparticulates Using Polymeric Solutions:
Formulation and Process Considerations 51
Klaus Lehmann
5. Coating of Multiparticulates Using Polymeric Dispersions:
Formulation and Process Considerations 79
Yoshinobu Fukumori
6. Coating of Multiparticulates Using Molten Materials:
Formulation and Process Considerations 113
David M. Jones and Phillip J. Percel
7. Suspensions and Dispersible Dosage Forms of Multiparticulates 143
Roland Bodmeier and Ornlaksana Paeratakul
¥