modified release drug delivery technology

Marcel Dekker, Inc. New York Basel

Modified-ReleaseDrug Delivery

Technologyedited by

Michael J. RathboneInterAg

Hamilton, New Zealand

Jonathan HadgraftMedway Sciences, NRIUniversity of Greenwich

Chatham, England

Michael S. RobertsPrincess Alexandria Hospitaland University of Queensland

Brisbane, Queensland, Australia

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

Copyright 2003 Marcel Dekker, Inc.

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ISBN: 0-8247-0869-5

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PRINTED IN THE UNITED STATES OF AMERICA


To my daughter Jenna

M.J.R.


Preface

For over 50 years, interest has been expressed in optimizing drug therapy throughdelivery system design. For many years this revolved around incorporating drugsinto erodible or inert polymers, which then acted as platforms for controlled re-lease, an approach that has been well reviewed in the literature. In more recenttimes there has been a move away from simply formulating drugs into erodibleor inert polymers toward the design and development of more advanced drugdelivery systems that utilize sophisticated designs and manufacturing techniquesand rely on novel means for controlling the release of drug from the deliverysystem. Over the last few decades, rapid developments have occurred in this areaand we have witnessed the evolution of commercially successful companies thatspecialize in the design, development, and commercialization of specic (in-house) modied-release drug delivery systems.

This is an exciting and growing area of pharmaceutical research. However,to date no single volume provides detailed and specic information on even ahandful of individual modied-release drug delivery systems. Therefore, we de-cided to edit a book comprised of chapters that collectively address this voidand provide an insight into the various approaches currently adopted to achievemodied-release drug delivery.

The book is divided into parts, each of which addresses a particular routefor drug delivery. Although it is assumed that the reader is already familiar withfundamental controlled-release theories, each part opens with an overview ofthe anatomical, physiological, and pharmaceutical challenges in formulating amodied-release drug delivery technology for each route for drug delivery. The

v


vi Preface

chapters in each part provide examples of the different approaches that have beentaken to design and develop an innovative modied-release drug delivery system.Each chapter presents a detailed account of a specic modied-release drug deliv-ery technology, written by experts on that technology.

Our challenge in editing this book was that no single volume could beexpected to describe every modied-release drug delivery technology currentlymarketed or under development. This is because of the vast and evolving natureof the area, and the lack of availability of the innovators to write a monographon their particular technology, due to either time constraints or the proprietarynature of their work. Instead of using this as an excuse to reject the challenge,we set ourselves the aim to provide in the book as many examples of modied-release drug delivery technologies as possible.

Susan Charman and Bill Charman were the leaders of the rst part of thebook, which is devoted to the oral route. The Charmans provide an excellentoverview of the challenges of this popular route for modied-release durg deliv-ery. Their introduction is followed by 15 chapters that provide an insight intothe novel and innovative approaches that have been taken for this route for drugdelivery. These range from novel manipulations of tableting technologies (in-cluding geometric designs and osmotically driven technologies) through three-dimensional printing to the use of lipids. The second part, led by Professor CliveWilson, discusses several diverse approaches that may be used to deliver com-pounds to the colon. Chapters demonstrating the innovativeness of workers in thiseld complement an incisive introduction that highlights the unique challengesassociated with this site of absorption. The leader of Part III, Bernard Plazonnet,includes in his introduction a thorough review of currently available and emerg-ing modied-release ophthalmic drug delivery systems. Since most of these sys-tems are in the developmental stage and have not yet reached the commercialstage, this part contains only three chapters on specic technologies. Part IVfocuses on the oral cavity as a site of drug delivery. The part leader, ProfessorIan Kellaway, together with invited coauthors, provides an overview of the issuesrelating to the development of modied-release drug delivery systems for thisroute. The associated chapters highlight technologies developed for specic re-gions of the oral cavity, including sublingual, buccal cavity, gingiva, and peri-odontal pocket.

A diverse range of technology approaches are associated with the dermaland transdermal route. Part leader Professor Jonathan Hadgraft not only has writ-ten a thorough overview but has also organized a series of chapters that cover awide range of diverse technologies from wound dressings to sprays, to propulsionof solid drug particles into the skin by means of a high-speed gas ow, to patchesthat deliver drugs via diffusion, iontophoresis, sonophoresis, or microprojections.The sixth part of this book addresses implant and injection technologies. In theirintroduction, part leaders Franklin Okumu and Jeffrey Cleland offer a comprehen-


Preface vii

sive overview of this evolving and challenging area of drug delivery. They com-plement their efforts with chapters that cover a diverse range of technologies.Part VII, compiled by leaders Daniel Wermeling and Jodi Miller, offers a reveal-ing look into the nasal route of drug delivery. Professor David Woolfson, leaderof Part VIII, presents a comprehensive account of the biological and pharmaceuti-cal challenges to the vaginal route of drug delivery, which is restricted to 50%of the population and is limited by cultural and societal constraints. The chaptersdealing with this route provide an insight into the different approaches that canbe employed to deliver drugs via the vaginal passage.

In Part IX Igor Gonda provides an informative overivew of the uniquechallenges in delivering via the pulmonary tract. This part contains chapters de-scribing various systems, devices, formulations, and methods of delivery of drugsto the lung. It differs somewhat from other parts in the book in that the focus ofpulmonary drug delivery systems is not on the control of release of the medica-ments once they are deposited within the respiratory tract (although some chap-ters in this part do describe such approaches) but on the ability of inhalationsystems to deliver drugs practically instantaneously to the target organ that is therelease part of therapeutic activity for many of the currently approved productsfor inhalation. Numerous technological approaches are described in the chaptersin this part, each of which provides descriptive comments on the complexity ofthis route for drug delivery. In the nal part of this book the regulatory issuespertaining to these diverse and often complex drug delivery systems are addressedby Patrick Marroum of the United States Food and Drug Administration, whoprovides a regulatory overview for one of the most highly legalistic markets.

We would like to express our thanks to each of the part leaders, who spentso much time identifying technologies, communicating with contributors, writinginformative overviews, and editing the chapters. We also thank all the chapterauthors. Their individual innovative research activities have contributed greatlyto the current modied-release drug delivery technology portfolio that exists to-day within the pharmaceutical industry. We are grateful to them for taking thetime to share their experiences and work. Finally, we wish to express our sincerethanks to Dr. Colin Ogle. We are indebted to Colin for giving up so much of hisspare time to proofread nal drafts and offer many constructive suggestions forimprovement of this volume.

Michael J. RathboneJonathan HadgraftMichael S. Roberts


Contents

Preface vContributors xvii

Part I: Oral

1. Oral Modied-Release Delivery Systems 1Susan A. Charman and William N. Charman

2. TIMERx Oral Controlled-Release Drug Delivery System 11Troy W. McCall, Anand R. Baichwal, and John N. Staniforth

3. MASRx and COSRx Sustained-Release Technology 21Syed A. Altaf and David R. Friend

4. Procise: Drug Delivery Systems Based on GeometricConguration 35Sham K. Chopra

5. RingCap Technology 49David A. Dickason and George P. Grandol

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x Contents

6. Smartrix System: Design Characteristics and Release Propertiesof a Novel Erosion-Controlled Oral Delivery System 59Horst G. Zerbe and Markus Krumme

7. TheriForm Technology 77Charles W. Rowe, Chen-Chao Wang, and Donald C.Monkhouse

8. Accudep Technology for Oral Modied Drug Release 89S. S. Chrai, David R. Friend, G. Kupperblatt, R. Murari, JackieButler, T. Francis, Araz A. Raoof, and Brian McKenna

9. Osmotically Controlled Tablets 101Patrick S. L. Wong, Suneel K. Gupta, and Barbara E. Stewart

10. Three-Phase Pharmaceutical FormTHREEFORMwithControlled Release of Amorphous Active Ingredient for Once-Daily Administration 115Janez Kerc

11. Two Concepts, One Technology: Controlled-Release and SolidDispersions with Meltrex 125Jorg Breitenbach and Jon Lewis

12. DissoCubesA Novel Formulation for Poorly Soluble andPoorly Bioavailable Drugs 135Rainer H. Muller, Claudia Jacobs, and Oliver Kayser

13. IDD Technology: Oral Delivery of Water-Insoluble DrugsUsing Phospholipid Stabilized Microparticulate IDDFormulations 151Awadhesh K. Mishra, Michael G. Vachon, Pol-Henri Guivarch,Robert A. Snow, and Gary W. Pace

14. Liquid-Filled and -Sealed Hard Gelatin Capsule Technologies 177Ewart T. Cole

15. The Zydis Oral Fast-Dissolving Dosage Form 191Patrick Kearney

16. Orasolv and Durasolv: Efcient Technologies for the Productionof Orally Disintegrating Tablets 203S. Indiran Pather, Rajendra K. Khankari, and Derek V. Moe


Contents xi

Part II: Colonic

17. Colonic Drug Delivery 217Clive G. Wilson

18. Enteric Coating for Colonic Delivery 223Gour Mukherji and Clive G. Wilson

19. Biopolymers and Colonic Delivery 233Gour Mukherji and Clive G. Wilson

20. Time-Dependent Systems for Colonic Delivery 243Wang Wang Lee, Gour Mukherji, and Clive G. Wilson

21. New Approaches for Optimizing Oral Drug Delivery: Zero-Order Sustained Release to Pulsatile Immediate Release Usingthe Port System 249John R. Crison, Michael L. Vieira, and Gordon L. Amidon

22. Pulsincap and Hydrophilic Sandwich (HS) Capsules: InnovativeTime-Delayed Oral Drug Delivery Technologies 257Howard N. E. Stevens

23. Development of the Egalet Technology 263Daniel Bar-Shalom, Lillian Slot, Wang Wang Lee, andClive G. Wilson

24. The Enterion Capsule 273David V. Prior, Alyson L. Connor, and Ian R. Wilding

Part III: Ocular

25. Ophthalmic Drug Delivery 289Bernard Plazonnet

26. Ion Exchange Resin Technology for Ophthalmic Applications 315R. Jani and E. Rhone

27. New Ophthalmic Delivery System (NODS) 329L. Sesha Rao


xii Contents

28. Bioadhesive Ophthalmic Drug Inserts (BODI) 341Olivia Felt-Baeyens and R. Gurny

Part IV: Oral Mucosal

29. Oral Mucosal Drug Delivery 349Ian W. Kellaway, Gilles Ponchel, and D. Duchene

30. Slowly Disintegrating Buccal Mucoadhesive Plain-Tablet(S-DBMP-T) and Buccal Covered-Tablet System (BCTS) 365Katsumi Iga

31. The Oral PowderJect Device for Mucosal Drug Delivery 381George Costigan and Brian John Bellhouse

32. The Periochip 391Wilfred Aubrey Soskolne

33. Polysaccharide-Based Mucoadhesive Buccal Tablets 401Hemant H. Alur, Ashim K. Mitra, and Thomas P. Johnston

34. Medicated Chewing Gum 419Margrethe Rmer Rassing and Jette Jacobsen

35. Immediate-Immediate Release (I2R) Lingual or Buccal SprayFormulations for Transmucosal Delivery of Drug Substances 431Harry A. Dugger III, Kenneth E. Cleaver, and Donald P. Cox

36. Liquid Crystalline Phases of Glyceryl Mono-oleate as OralMucosal Drug Delivery Systems 447Jaehwi Lee and Ian W. Kellaway

37. Microparticles as Delivery Systems for Local Delivery to theOral Cavity 453Rita Cortesi, E. Menegatti, Claudio Nastruzzi, and ElisabettaEsposito

38. OraVescent: A Novel Technology for the TransmucosalDelivery of Drugs 463S. Indiran Pather, Rajendra K. Khankari, and John M. Siebert


Contents xiii

Part V: Dermal and Transdermal

39. Dermal and Transdermal Delivery 471Jonathan Hadgraft

40. D-TRANS Technology 481Rama Padmanabhan, Robert M. Gale, J. Bradley Phipps,William W. van Osdol, and Wendy Young

41. E-TRANS Technology 499J. Bradley Phipps, Rama Padmanabhan, Wendy Young, RodneyM. Panos and Anne E. Chester

42. Microfabricated Microneedles for Transdermal Drug Delivery 513Mark R. Prausnitz, Donald E. Ackley, and J. Richard Gyory

43. Metered-Dose Transdermal Spray (MDTS) 523Timothy M. Morgan, Barry L. Reed, and Barrie C. Finnin

44. Transfersomes: Innovative Transdermal Drug Carriers 533Gregor Cevc

45. Advances in Wound Healing 547Michael Walker

46. Ultrasound-Mediated Transdermal Drug Delivery 561Samir Mitragotri and Joseph Kost

47. SLN and Lipopearls for Topical Delivery of Active Compoundsand Controlled Release 571Rainer Helmut Muller and Sylvia Wissing

48. Macroux Technology for Transdermal Delivery of TherapeuticProteins and Vaccines 589Michel Cormier and Peter E. Daddona

49. Needle-Free Drug Delivery 599Franklin Pass and John Hayes

50. Dermal PowderJect Device 607Brian John Bellhouse and Mark A. F. Kendall


xiv Contents

51. Intraject: Prelled, Disposable, Needle-Free Injection of LiquidDrugs and Vaccines 619Adam Levy

Part VI: Injections and Implants

52. Implants and Injectables 633Franklin W. Okumu and Jeffrey L. Cleland

53. Alzamer Depot Bioerodible Polymer Technology 639Jeremy C. Wright, Roy Bannister, Guohua Chen, andCatherine Lucas

54. The Atrigel Drug Delivery System 647Richard Dunn

55. Long-Term Controlled Delivery of Therapeutic Agents via anImplantable Osmotically Driven System: The DUROS Implant 657James C. Wright, Anne E. Chester, R. Skowronski, andCatherine Lucas

56. Long-Acting Protein FormulationsProLease Technology 671OluFunmi L. Johnson and Paul Herbert

57. Sucrose Acetate Isobutyrate (SAIB) for Parenteral Delivery 679Arthur J. Tipton

58. Stealth Technology 689Frank Martin and Tony Huang

59. DepoFoam Technology 705Sankaram Mantripragada

60. Medipad Delivery System: Controlled Macromolecule Delivery 713Izrail Tsals and Diana Davidson

Part VII: Nasal

61. Intranasal Drug Delivery 727Daniel P. Wermeling and Jodi L. Miller


Contents xv

62. Poly(ethylene oxide)-b-Poly(propylene oxide)-b-Poly(ethyleneoxide)-g-Poly(acrylic acid) Copolymers as In Situ GellingVehicle for Nasal Delivery 749Lev Bromberg

Part VIII: Vaginal

63. Intravaginal Drug Delivery Technologies 759A. David Woolfson

64. The Intravaginal Ring 775R. Karl Malcolm

65. SupraVail Vaginal Gel 791Mathew Leigh

66. VagiSite Bioadhesive Technology 801R. Saul Levinson and Daniel J. Thompson

Part IX: Pulmonary

67. Pulmonary Delivery of Drugs by Inhalation 807Igor Gonda and Jeff Schuster

68. Aerogen Pulmonary Delivery Technology 817Paul S. Uster

69. The AERx Pulmonary Drug Delivery System 825Jeff Schuster and S. J. Farr

70. Formulation Challenges of Powders for the Delivery of SmallMolecular Weight Molecules as Aerosols 835Anthony J. Hickey

71. Nebulizer Technologies 849Martin Knoch and Warren Finlay

72. The Pressurized Metered-Dose Inhaler 857Akwete L. Adjei


xvi Contents

73. Passive Dry Powder Inhalation Technology 867Ian Ashurst and Ann Malton

74. Formulation Challenges: Protein Powders for Inhalation 879Hak-Kim Chan

75. The Development of Large Porous Particles for InhalationDrug Delivery 891Richard Batycky, Daniel Deaver, Sarvajna Dwivedi, JeffreyHrkach, Lloyd Johnston, Tracy Olson, James E. Wright, andDavid Edwards

76. Dry Powder Inhalation Systems from Inhale TherapeuticSystems 903Andy R. Clark

77. Spiros Inhaler Technology 913Clyde Witham and Elaine Phillips

78. The Respimat, a New Soft Mist Inhaler for Delivering Drugs tothe Lungs 925Bernd Zierenberg and Joachim Eicher

79. Regulatory Issues for Pulmonary Delivery Systems 935Darlene Rosario and Babatunde Otulana

Part X: Regulatory

80. Regulatory Issues Relating to Modied-Release DrugFormulations 943Patrick J. Marroum

Index 977


Contributors

Donald E. Ackley* Redeon, Inc., Burlington, Massachusetts, U.S.A.Akwete L. Adjei Kos Pharmaceuticals, Inc., Edison, New Jersey, U.S.A.Syed A. Altaf, Ph.D. Gilead Sciences, Foster City, California, U.S.A.Hemant H. Alur, Ph.D. Division of Pharmaceutical Sciences, School of Phar-macy, University of MissouriKansas City, Kansas City, Missouri, U.S.A.Gordon L. Amidon College of Pharmacy, The University of Michigan, AnnArbor, Michigan, U.S.A.Ian C. Ashurst, B.Sc., M.R.Pharm.S., M.Sc., Ph.D. GlaxoSmithKline, Ware,Hertfordshire, EnglandAnand R. Baichwal Penwest Pharm Company, Patterson, New York, U.S.A.Roy Bannister, Ph.D., D.A.B.T. ALZA Corporation, Mountain View, Califor-nia, U.S.A.Daniel Bar-Shalom Egalet A/S, Vaerlose, DenmarkRichard Batycky Alkermes, Inc., Cambridge, Massachusetts, U.S.A.Brian John Bellhouse, M.A., D.Phil. Department of Engineering Science,PowderJect Centre for Gene and Drug Delivery Research, University of Oxford,Oxford, EnglandJorg Breitenbach, Ph.D. Abbott GmbH & Co. KG, Soliqs drug delivery busi-ness, Ludwigshafen, Germany

* Current afliation: VSK Photonics, Irvine, California, U.S.A. Current afliation: Murty Pharmaceuticals, Inc., Lexington, Kentucky, U.S.A.

xvii


xviii Contributors

Lev Bromberg Department of Chemical Engineering, Massachusetts Instituteof Technology, Cambridge, Massachusetts, U.S.A.Jackie Butler Elan Drug Delivery, Athlone, IrelandGregor Cevc, Ph.D. IDEA AG, Munich, GermanyHak-Kim Chan, Ph.D. Faculty of Pharmacy, University of Sydney, Sydney,New South Wales, AustraliaSusan A. Charman, Ph.D. Department of Pharmaceutics, Victorian College ofPharmacy, Monash University (Parkville Campus), Parkville, Victoria, AustraliaWilliam N. Charman Department of Pharmaceutics, Victorian College ofPharmacy, Monash University (Parkville Campus), Parkville, Victoria, AustraliaGuohua Chen, Ph.D. ALZA Corporation, Mountain View, California, U.S.A.Anne E. Chester, Ph.D. ALZA Corporation, Mountain View, California,U.S.A.Sham K. Chopra Savit Consulting Inc., Brampton, Ontario, CanadaS. S. Chrai* Delsys Pharmaceutical, A Division of Elan Operations, Inc., Mon-mouth Junction, New Jersey, U.S.A.Andy R. Clark Inhale Therapeutic Systems, San Carlos, California, U.S.A.Kenneth E. Cleaver, Ph.D. Flemington Pharmaceutical Corporation, Flem-ington, New Jersey, U.S.A.Jeffrey L. Cleland, Ph.D. Genentech, Inc., South San Francisco, California,U.S.A.Ewart T. Cole, Ph.D. Department of Research and Development, CAPSU-GEL, A Division of Pzer Inc., Arlesheim, SwitzerlandAlyson L. Connor, Ph.D. Pharmaceutical Proles Ltd, Nottingham, EnglandMichel Cormier, Ph.D. Biological Sciences, ALZA Corporation, MountainView, California, U.S.A.Rita Cortesi, Ph.D. Department of Pharmaceutical Sciences, University of Fer-rara, Ferrara, ItalyGeorge Costigan, B.Sc., M.Phil., D.Phil. Department of Engineering Science,University of Oxford, Oxford, EnglandDonald P. Cox, Ph.D. Flemington Pharmaceutical Corporation, Flemington,New Jersey, U.S.A.John R. Crison Port Systems LLC, Ann Arbor, Michigan, U.S.A.Peter E. Daddona Biological Sciences, ALZA Corporation, Mountain View,California, U.S.A.Diana Davidson Elan Drug Delivery, King of Prussia, Pennsylvania, U.S.A.Daniel Deaver Alkermes, Inc., Cambridge, Massachusetts, U.S.A.David A. Dickason Alkermes, Inc., Cincinnati, Ohio, U.S.A.

* Current afliation: Chrai Associates, Cranbury, New Jersey, U.S.A. Current afliation: Research & Development, Targesome, Inc., Palo Alto, California, U.S.A.


Contributors xix

D. Duchene UMR, CNRS 8612 and University of Paris XI, Chatenay-Malabry,FranceHarry A. Dugger III, Ph.D. Flemington Pharmaceutical Corporation, Flem-ington, New Jersey, U.S.A.Richard L. Dunn, Ph.D. Atrix Laboratories, Fort Collins, Colorado, U.S.A.Sarvajna Dwivedi, Ph.D. Alkermes, Inc., Cambridge, Massachusetts, U.S.A.David Edwards Division of Engineering and Applied Sciences, Harvard Uni-versity, Cambridge, Massachusetts, U.S.A.Joachim Eicher, Ph.D. Steag Microparts, Dortmund, GermanyElisabetta Esposito Department of Pharmaceutical Sciences, University ofFerrara, Ferrara, ItalyS. J. Farr Aradigm Corporation, Hayward, California, U.S.A.Olivia Felt-Baeyens, Ph.D. School of Pharmacy, University of Geneva, Ge-neva, SwitzerlandWarren H. Finlay, Ph.D. Department of Mechanical Engineering, Universityof Alberta, Edmonton, Alberta, CanadaBarrie C. Finnin Department of Pharmaceutics, Victorian College of Phar-macy, Monash University (Parkville Campus), Parkville, Victoria, AustraliaT. Francis Elan Drug Delivery, Athlone, IrelandDavid R. Friend, Ph.D. Delsys Pharmaceutical, A Division of Elan Opera-tions, Inc., Monmouth Junction, New Jersey, U.S.A.Robert M. Gale ALZA Corporation, Mountain View, California, U.S.A.Igor Gonda Aradigm Corporation, Hayward, California, U.S.A.George P. Grandol, Ph.D. Alkermes, Inc., Cincinnati, Ohio, U.S.A.Pol-Henri Guivarch SkyePharma Canada Inc., Montreal, Quebec, CanadaSuneel K. Gupta, Ph.D. ALZA Corporation, Mountain View, California,U.S.A.R. Gurny, Ph.D. School of Pharmacy, University of Geneva, Geneva, Switzer-landJ. Richard Gyory* Redeon, Inc., Burlington, Massachusetts, U.S.A.Jonathan Hadgraft, D.Sc., F.R.S.C. Medway Sciences, NRI, University ofGreenwich, Chatham, EnglandJohn Hayes aForte, Chanhassen, Minnesota, U.S.A.Paul Herbert Alkermes Incorporated, Cambridge, Massachusetts, U.S.A.Anthony J. Hickey, Ph.D. University of North Carolina, Chapel Hill, NorthCarolina, U.S.A.Jeffrey Hrkach, Ph.D. Alkermes, Inc., Cambridge, Massachusetts, U.S.A.Tony Huang ALZA Corporation, Mountain View, California, U.S.A.Katsumi Iga, Ph.D. Takeda Chemical Industry Ltd., Osaka, Japan

* Current afliation: Transform Pharmaceuticals, Inc., Waltham, Massachusetts, U.S.A.


xx Contributors

Claudia Jacobs Department of Pharmaceutics, Biopharmaceutics and Biotech-nology, Free University of Berlin, Berlin, GermanyJette Jacobsen, M.Sc., Ph.D. Department of Pharmaceutics, The Royal DanishSchool of Pharmacy, Copenhagen, DenmarkRajni Jani, Ph.D. Department of Pharmaceutics, Alcon Research Ltd., FortWorth, Texas, U.S.A.OluFunmi L. Johnson, Ph.D. Alkermes Incorporated, Cambridge, Massachu-setts, U.S.A.Lloyd Johnston Alkermes Incorporated, Cambridge, Massachusetts, U.S.A.Thomas P. Johnston, Ph.D. Division of Pharmaceutical Sciences, School ofPharmacy, University of MissouriKansas City, Kansas City, Missouri, U.S.A.Oliver Kayser Department of Pharmaceutics, Biopharmaceutics and Biotech-nology, Free University of Berlin, Berlin, GermanyPatrick Kearney RP Scherer, Swindon, EnglandIan W. Kellaway, D.Sc., F.R.Pharm.S. School of Pharmacy, University ofLondon, London, EnglandMark A. F. Kendall, B.G., Ph.D. Department of Engineering Science,PowderJect Centre for Gene and Drug Delivery Research, University of Oxford,Oxford, EnglandJanez Kerc, Ph.D. Research and Development Division, Lek Pharmaceuticaland Chemical Company, Ljubljana, SloveniaRajendra K. Khankari, Ph.D. CIMA LABS INC, Brooklyn Park, Minnesota,U.S.A.Martin Knoch, Ph.D. PARI GmbH, Starnberg, GermanyJoseph Kost, Ph.D. Department of Chemical Engineering, Sontra Medical,Cambridge, Massachusetts, U.S.A.Markus Krumme, Ph.D. LTS Lohmann Therapie-Systeme AG, Andernach,GermanyGary B. Kupperblatt, Ph.D.* Delsys Pharmaceutical, A Division of Elan Op-erations, Inc., Monmouth Junction, New Jersey, U.S.A.Jaehwi Lee, Ph.D. School of Pharmacy, Purdue University, West Lafayette,Indiana, U.S.A.Wang Wang Lee Strathclyde Institute for Biomedical Sciences, Glasgow,ScotlandMathew Leigh, B.Pharm., M.R.Pharms., Ph.D. Phares Drug Delivery AG,Muttenz, SwitzerlandR. Saul Levinson, Ph.D. KV Pharmaceutical Company, St. Louis, Missouri,U.S.A.

* Current afliation: Department of Chemical Sciences, The Dow Chemical Company, Midland,Michigan, U.S.A.


Contributors xxi

Adam Levy, B.A., M.A., M.B.A. Weston Medical Group plc, Trumpington,EnglandJon Lewis, B.Sc., Ph.D. Abbott GmbH & Co. KG, Soliqs drug delivery busi-ness, Ludwigshafen, GermanyCatherine Lucas, Ph.D. ALZA Corporation, Mountain View, California, U.S.A.R. Karl Malcolm, Ph.D. Pharmaceutical Formulation Research Unit, Schoolof Pharmacy, Queens University Belfast, Belfast, Northern IrelandAnn Malton Inhalation Product Development, GlaxoSmithKline R&D, Ware,Hertfordshire, EnglandSankaram Mantripragada, Ph.D. SkyePharma Inc., San Diego, California,U.S.A.Patrick J. Marroum, Ph.D. Division of Pharmaceutical Evaluation I, Ofceof Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation andResearch, Food and Drug Administration, Rockville, Maryland, U.S.A.Frank Martin ALZA Corporation, Mountain View, California, U.S.A.Troy W. McCall Penwest Pharm Company, Patterson, New York, U.S.A.B. McKenna Elan Drug Delivery, Athlone, IrelandE. Menegatti Department of Pharmaceutical Sciences, University of Ferrara,Ferrara, ItalyJodi L. Miller, Pharm.D., M.S. College of Pharmacy, University of Kentucky,Lexington, Kentucky, U.S.A.Awadhesh K. Mishra, Ph.D. SkyePharma Canada Inc., Montreal, Quebec,CanadaAshim K. Mitra, B.S., M.S., Ph.D. Division of Pharmaceutical Sciences,School of Pharmacy, University of MissouriKansas City, Kansas City, Missouri,U.S.A.Samir Mitragotri, Ph.D. Department of Chemical Engineering, University ofCalifornia, Santa Barbara, California, U.S.A.Derek V. Moe, Ph.D. CIMA LABS Inc., Brooklyn Park, Minnesota, U.S.A.Donald C. Monkhouse, Ph.D. Therics, Inc., Princeton, New Jersey, U.S.A.Timothy M. Morgan, Ph.D., P.M.P. Acrux Limited, Melbourne, Victoria,AustraliaGour Mukherji, Ph.D. Ranbaxy Laboratories Ltd., Gurgaon, IndiaRainer Helmut Muller, Ph.D. Department of Pharmaceutics, Biopharmaceu-tics and Biotechnology, Free University of Berlin, Berlin, GermanyRamaswamy Murari, Ph.D. Delsys Pharmaceutical, A Division of Elan Oper-ations, Inc., Monmouth Junction, New Jersey, U.S.A.Claudio Nastruzzi, Ph.D. Department of Chemistry and Pharmaceutical Tech-nology, University of Perugia, Perugia, ItalyFranklin W. Okumu Genentech, Inc., South San Francisco, California,U.S.A.


xxii Contributors

Tracy Olson Alkermes, Inc., Cambridge, Massachusetts, U.S.A.Babatunde Otulana, M.D. Aradigm Corporation, Hayward, California, U.S.A.Gary W. Pace* SkyePharma Canada Inc., Montreal, Quebec, CanadaRama V. Padmanabhan, Ph.D. ALZA Corporation, Mountain View, Califor-nia. U.S.A.RodneyM.Panos, Ph.D. ALZACorporation,MountainView,California,U.S.A.Franklin Pass Antares Pharma, Inc., Minneapolis, Minnesota, U.S.A.S. Indiran Pather, D.Pharm. CIMA LABS INC., Brooklyn Park, Minnesota,U.S.A.Elaine Phillips Elan Pharmaceutical Technologies, San Diego, California,U.S.A.J. Bradley Phipps, Ph.D. ALZA Corporation, Mountain View, California,U.S.A.Bernard Plazonnet, Ph.D. Laboratory of Sensory Biophysics, University ofAuvergne, Clermont-Ferrand, FranceGilles Ponchel UMR, CNRS 8612 and University of Paris XI, Chatenay-Malabry, FranceMark R. Prausnitz, Ph.D. School of Chemical Engineering, Georgia Instituteof Technology, Atlanta, Georgia, U.S.A.David V. Prior, Ph.D., M.R.S.C., C.Chem. Pharmaceutical Proles Ltd, Not-tingham, EnglandL. Sesha Rao, Ph.D. Chauvin Pharmaceuticals Ltd., Romford, Essex, EnglandAraz A. Raoof, Ph.D. Elan Drug Delivery, Athlone, IrelandMargrethe Rmer Rassing, M.Sc., Ph.D. Department of Pharmaceutics, TheRoyal Danish School of Pharmacy, Copenhagen, DenmarkBarry L. Reed Department of Pharmaceutics, Victorian College of Pharmacy,Monash University (Parkville Campus), Parkville, Victoria, AustraliaErin Rhone Pharmaceutical Research and Development, Alcon Research Ltd.,Fort Worth, Texas, U.S.A.Darlene Rosario Aradigm Corporation, Hayward, California, U.S.A.Charles W. Rowe Therics, Inc., Princeton, New Jersey, U.S.A.Jeff Schuster, Ph.D. Aradigm Corporation, Hayward, California, U.S.A.John M. Siebert, Ph.D. CIMA LABS INC., Brooklyn Park, Minnesota, U.S.A.Roman J. Skowronski, M.D., Ph.D. ALZA Corporation, Mountain View,California, U.S.A.Lillian Slot Department of New Drug Development, Egalet A/S, Vaerlose,DenmarkRobert A. Snow, Ph.D., M.B.A. SkyePharma Canada Inc., Montreal, Quebec,Canada

* Current afliation: QRx Pharma Inc., Winchester, Massachusetts, U.S.A. Current afliation: Alexza Molecular Delivery Corporation, Palo Alto, California, U.S.A.


Contributors xxiii

Wilfred Aubrey Soskolne, B.D.S., Ph.D. The Department of Periodontology,Hebrew UniversityHadassah Faculty of Dentistry, Jerusalem, IsraelJohn N. Staniforth Vectura Ltd, University of Bath Campus, Bath, EnglandHoward N. E. Stevens Department of Pharmaceutical Sciences, University ofStrathclyde, Glasgow, ScotlandBarbara E. Stewart, Ph.D. Nonclinical Research and Development, ALZACorporation, Mountain View, California, U.S.A.Daniel J. Thompson, M.S., J.D. Department of Scientic Affairs, KV Pharma-ceutical, St. Louis, Missouri, U.S.A.Arthur J. Tipton Southern BioSystems, Birmingham, Alabama, U.S.A.Izrail Tsals Elan Drug Delivery, King of Prussia, Pennsylvania, U.S.A.Paul S. Uster Aerogen Inc., Mountain View, California, U.S.A.Michael G. Vachon, M.Sc.Phm., Ph.D. SkyePharma Canada Inc., Montreal,Quebec, CanadaWilliam W. van Osdol, Ph.D. ALZA Corporation, Mountain View, California,U.S.A.John L. Vieira Port Systems LLC, Ann Arbor, Michigan, U.S.A.Michael Walker ConvaTec Wound Care and Prevention Global DevelopmentCentre, Deeside, Flintshire, EnglandChen-Chao Wang, Ph.D. Department of Research and Development, Therics,Inc., Princeton, New Jersey, U.S.A.Daniel P. Wermeling, Pharm.D. College of Pharmacy, University of Ken-tucky, Lexington, Kentucky, U.S.A.Ian R. Wilding, Ph.D. Pharmaceutical Proles, Nottingham, EnglandClive G. Wilson, Ph.D. Strathclyde Institute for Biomedical Sciences, Glas-gow, ScotlandSylvia Andrea Wissing, Ph.D. Department of Pharmaceutics, Biopharmaceu-tics and Biotechnology, Free University of Berlin, Berlin, GermanyClydeWitham Elan Pharmaceutical Technologies, SanDiego, California, U.S.A.Patrick S. L. Wong, Ph.D. ALZA Corporation, Mountain View, California,U.S.A.A. David Woolfson, Ph.D. School of Pharmacy, Queens University Belfast,Belfast, Northern IrelandJames E. Wright Alkermes, Inc., Cambridge, Massachusetts, U.S.A.Jeremy C. Wright, Ph.D.* ALZA Corporation, Mountain View, California,U.S.A.Wendy Young ALZA Corporation, Mountain View, California, U.S.A.Horst G. Zerbe, Ph.D. Smartrix Technologies Inc, Kirkland, Quebec, CanadaBernd Zierenberg, Ph.D. Boehringer Ingelheim Pharma KG, Ingelheim, Ger-many

* Current afliation: DURECT Corporation, Cupertino, California, U.S.A.


1Oral Modied-Release DeliverySystems

Susan A. Charman and William N. CharmanVictorian College of Pharmacy, Monash University (Parkville Campus),Parkville, Victoria, Australia

I. INTRODUCTION

The oral route of drug delivery is typically considered the preferred and mostpatient-convenient means of drug administration. Consequently, much effort isdirected during drug discovery to identify orally active candidates that will pro-vide reproducible and effective plasma concentrations in vivo. The reality is thatmany compounds are either incompletely or ineffectively absorbed after oral ad-ministration (i.e., bioavailability is an issue), or that the required dosing frequencyis too short to enable once- or twice-daily administration (i.e., pharmacokinetichalf-life is an issue). Lead optimization typically addresses such shortcomingsduring a discovery program; however, in many cases it is not possible to iden-tify an appropriate clinical candidate with the requisite ideal physicochemicaland/or pharmacokinetic properties. For clinical research phase drug candidates,or drugs already marketed, the opportunity for enhancing their clinical pharma-cology prole after oral administration through attainment of more optimal blooddrug concentration-time proles should always be considered.

Modied-release formulation technologies offer an effective means to opti-mize the bioavailability and resulting blood concentration-time proles of drugsthat otherwise suffer from such limitations. Within the context of this chapter,the term modied release refers to both delayed- and extended-release systemsfor oral administration as well as oral delivery systems designed specically tomodify the release of poorly water-soluble drugs. Also included are the fast-dissolving dosage forms for which absorption occurs primarily (but not exclu-

1


2 Charman and Charman

sively) in the gastrointestinal (GI) tract. The chapters in this part describe a broadrange of pharmaceutical formulation technologies that address various limitingfeatures associated with oral drug bioavailability and dosing frequency. In plan-ning this part, we invited technology-focused chapters from expert contributorswho had direct experience with the individual systems. Our goal was to selectrelatively advanced technologies representative of the various contemporary ap-proaches being taken in the eldour success in this endeavor is a direct conse-quence of the willingness of the contributing authors who graciously acceptedour invitation. As with all written compilations of this nature, time, commercial,and intellectual property restrictions on the part of potential contributors unfortu-nately precluded the description of some highly relevant and successful technolo-gies.

II. PHYSIOLOGICAL AND PHYSICOCHEMICALCONSIDERATIONS IN THE DESIGN OF ORALMODIFIED-RELEASE FORMULATIONS

The human GI tract is a complex time-, position-, and patient-dependent absorp-tive, metabolizing, and excretive organ. Key physiological factors that controlthe absorption of drugs from the GI tract include gastric and intestinal transitproles, uid and food intake, bulk uid and luminal pH, gastric and intestinalsecretions, absorptive mechanisms, and enterocyte-based metabolism and se-cretion (efux). Coupled with these physiological factors, the physicochemicalproperties of a drug, such as its solubility, ionization, stability, and lipophilicity,strongly inuence the rate and extent of drug absorption from the GI lumen. Acritical assessment of fundamental physicochemical properties and a consider-ation of their interplay with the physiological constraints of the GI tract are para-mount to the successful design of modied-release oral drug delivery systems.Ideally, oral extended-release systems rely upon the dosage form to control therate of drug release with little or no effect from the intrinsic properties of thedrug or the conditions prevailing within the GI tract. Realistic candidates exhibithigh permeability across the GI epithelium (Class I and Class II drugs accordingto the Biopharmaceutic Classication System [1]) such that their absorption rateis controlled exclusively by the rate of release from the dosage form. It is onlyunder these conditions that in vitro dissolution rates can possibly be used to pre-dict in vivo absorption rates and guide formulation development.

Perhaps the greatest challenge in the design of oral modied-release formu-lations and the establishment of useful in vitroin vivo correlations is the chang-ing nature of the GI tract from the stomach to the colon [2]. While the vastmajority of drugs delivered in immediate-release preparations are absorbed fromthe upper regions of the small intestine, extended-release preparations rely upon


Oral Modied-Release Delivery Systems 3

absorption throughout the small intestine and sometimes into the colon. A recentreport of the regional absorption of late phase I new chemical entities indicatedthat for the majority of compounds tested, absorption decreased signicantly inthe distal intestine [3]. Site-dependent permeability greatly complicates the estab-lishment of useful in vitroin vivo correlations and potentially leads to variableabsorption due to transit time variations both within and between patients. Fur-thermore, the recent identication of efux-dependent drug permeability, withthe associated linkage to enterocyte-based metabolism mediated via cytochromeP450, further complicates the predictability of drug absorption and bioavailabilityfor modied-release dosage forms. This results from the dependence of efux/metabolism interactions on local drug concentrations, which are typically lowerfrom a modied-release product than an immediate-release product. Regionaldrug exposure (greater distal intestinal exposure with modied release comparedwith an immediate-release product) also contributes to variations in efux andmetabolism as expression and activity of both Pgp [4] and CYP3A4 [5] varyalong the length of the GI tract.

Transit time through the GI tract is a major factor that impacts the effective-ness of modied-release dosage forms as it directly inuences the site of drugrelease. Differing sites of drug release, as a function of transit proles, requireassessment of the changing pH and water content on subsequent drug absorption

Table 1 Approximate Fluid Flux, pH, and Residence Times Withinthe Gastrointestinal Tract

Input/day Output/day ResidenceSection Fluid (mL) (mL) pHa time (h)Mouth Water saliva 1200 1500Stomach Gastric uid 2000a 13.5 0.512a,b

Pancreatic juice 1500Duodenum 46.5

Bile 500 34cJejunum 57

Intestinal secretions 1500 8500Ileum 68

Colon Fluid transfer 500 350 68 10d

Source: Adapted from Refs. 6,7,25,27.a Varies depending on the postprandial state.b Highly dependent on dosage form size.c Relatively independent of dosage form size and postprandial state.d Not well dened.



(Table 1) [6,7]. While the rate of gastric emptying varies markedly depending onthe state (i.e., solid or liquid) and size of the dosage forms (i.e., multiparticulate ormonolithic) and on the presence and composition of food [8], intestinal transittimes for liquids or solids, in either the fed or fasted state, are relatively constantat approximately 34 h [9]. Hence, for a compound with limited permeabilityin the large intestine, this narrow window for intestinal release may limit thepotential utility of an extended-release dosage form. The interplay between GIphysiology (e.g., transit, environment) and formulation design (e.g., type of for-mulation, mechanism of release) is always a key determinant of the likely successof modied-release drug products.

III. RECENT ADVANCES AND FUTURE DIRECTIONSIN MODIFIED-RELEASE DELIVERY SYSTEMSFOR ORAL ADMINISTRATION

While signicant advances have been made in the development of elegant sys-tems to modify the oral delivery of drugs, the basic approaches have remainedlargely unchanged with the major systems being (a) insoluble, slowly eroding, orswelling matrices, (b) polymer-coated tablets, pellets, or granules, (c) osmoticallydriven systems, (d) systems controlled by ion exchange mechanisms, and (e)various combinations of these approaches. The scientic literature is full of otherintricate and complex examples of oral modied-release systems, but the com-mercial applicability and success of many of these systems/devices has yet to berealized.

Over the past 20 years, advances in oral modied-release technologies havebeen largely driven by signicant improvements in manufacturing equipment,most notably coating equipment, as well as the development of improved biocom-patible and biodegradable polymeric materials for controlling release rates [10].A further driving force has been the development of a greater appreciation by bothpharmaceutical scientists and regulatory authorities of the impact of physiologicalvariability on the performance of modied-release products leading to more strin-gent requirements to ensure their safety and efcacy. Establishing in vitroinvivo (Fig. 1) for modied-release systems has become almost mandatory for es-tablishing dosage form design criteria and for setting appropriate in vitro dissolu-tion limits and specications to ensure acceptable in vivo performance [2,11].

Monolithic matrices continue to be extensively utilized for the preparationof oral modied-release delivery systems owing to their simplicity and ease ofmanufacture using conventional processing equipment. Matrix systems generallyconsist of dissolved or dispersed drug within a swelling or slowly eroding poly-mer matrix. Drug release from these systems is governed by water penetrationinto the matrix followed by the diffusion of drug into the surrounding medium,



Figure 1 Development of an in vivo/in vitro correlation. (Adapted from Ref. 11.)

erosion of the matrix, or combination of the two. Hydrophilic gums, which forma viscous release-retarding gel layer upon hydration, continue to show popularityfor use in oral modied-release systems. The TIMERx technology (Chapter 2)incorporates a combination of xanthan gum and locust bean gum together witha saccharide component to form a rate-controlling matrix system. The MASRx/COSRx technologies (Chapter 3) utilize guar gum as the rate-controlling polymerand resulting tablets can be further lm-coated to obtain the desired release pro-le. Another such system, Contramid [12], incorporates a biodegradable, cross-linked high amylose starch as the rate-controlling tablet matrix.

A potential disadvantage of the simple monolithic matrix systems is thelack of zero-order release kinetics resulting from time-dependent changes in thediffusional path length and surface area. Several systems have been designed toovercome this limitation by modifying the matrix geometry such that the surfacearea available for diffusion increases with time to compensate for the increasein the diffusional distance. One such tablet system (Procise, Chapter 4) incorpo-



rates a coated geometric core in which diffusion occurs only from the cylindricalface of the disc. A banded capsule-shaped matrix tablet (RingCap, Chapter 5)has also been described and is based on similar geometric principles for control-ling the diffusion rate. Yet another variation to the geometric approach is thecomplex multilayered tablet, such as Smartrix (Chapter 6) in which a geometri-cally designed core is combined with slowly eroding cover layers to control therelease of active drug. The Geometrix technology represents a further systemthat operates on the same principle by combining a matrix core with modulatinglayers in a multilayer tablet conguration to provide linear, pulsatile, and delayedrelease of drugs [13].

In recent years, there has been an increase in the application of relatedtechnologies to the fabrication of modied-release dosage forms for drugs. Onesuch system, TheriForm (Chapter 7) is based on Three Dimensional Printingtechnology and uses a layer-by layer approach to accurately control the internalmicrostructure of the dosage form to provide complex release proles. Anotherexample, Accudep technology (Chapter 8) uses electrostatic deposition, similarto that used in copy machines for the precise deposition of ink particles, in combi-nation with erosional polymeric lm barriers to achieve sustained or pulsatilerelease proles of active materials. The LeQtracoat and LeQtradose technolo-gies also utilize dry powder electrostatic deposition to enable tablet coating and/or precise drug loading [14].

Osmotically controlled oral delivery systems (Oros, Chapter 9) were ini-tially described in the 1970s and have since been applied to a number of differentdrug products. The basic operation of these systems relies upon the osmoticallydriven inux of water through a semipermeable membrane followed by displace-ment of drug and release through an orice. The elementary osmotic pump, alongwith more specialized variations to the basic conguration, enable the controlleddelivery of actives with varying aqueous solubilities.

Multiparticulate dosage forms offer a number of potential advantages overmonolithic preparations in terms of their dispersion characteristics, transit timesthrough the GI tract, and reduced potential for gastric irritation. Classical extru-sion, spheronization, and pellitization processes typically result in pellets withirregular surfaces and out of varying sizes, which are inherently more difcultto lm-coat. A recent report described the preparation of almost perfectly spher-ical particles with a narrow size distribution for improved coating efciency(Ceform, [15]). A number of patented technologies for multiparticulate dosageforms have recently been described, such as the Micropump system [16], whichis an osmotically driven coated microparticle system designed to increase theabsorption time for rapidly absorbed drugs. Polymer coating materials and pro-cessing technologies have advanced signicantly in recent years and future devel-opment of new and improved polymers will be guided by regulatory and environ-mental pressure to reduce or eliminate organic solvents from coating processes[10].



The increased emergence of poorly water-soluble active compounds pre-sents specic obstacles for the development of both immediate-release and modi-ed-release dosage forms. Poorly water-soluble drugs will be inherently releasedat a slow rate owing to their limited solubility within the GI contents. The dissolu-tion and solubilization of these agents are typically more affected by the postpran-dial state, gastric, pancreatic, and biliary secretions, and pH [17]. The challengefor poorly soluble drugs is to control the rate of dissolution to minimize variationsand maintain a well-dispersed system that allows the drug to be absorbed. Chemi-cal approaches to facilitate this aim, such as incorporation of Cyclodextrin deriva-tives as solubilizing agents into modied-release systems [18], may also showincreased utility in future applications.

One approach to overcome the dissolution limitation of poorly water-soluble drugs is the formulation of active drug in an amorphouse form, whichovercomes many of the potential problems associated with changes in particlesize, crystallinity, and polymorphism. In the Threeform system (Chapter 10),amorphous drug is rst stabilized by a mixture of surfactant and polymers andis then incorporated into a polymeric matrix that is nally coated with a rate-controlling lm. In a different approach, the Meltrex technology (Chapter 11)uses a solvent-free, melt extrusion method to form a solid dispersion of amor-phous material that releases drug through diffusion and erosion.

A parallel strategy for the delivery of drugs with poor aqueous solubilityis a reduction in particle size through the preparation of nanoparticles or micro-particles. High-pressure homogenization is utilized to form a nanosuspension inthe DissoCube technology (Chapter 12), which facilitates drug dissolution andincreases the saturation solubility. The resulting nanosuspension can then be com-bined with traditional dosage forms to produce tablets or capsules with improveddissolution of active drug. The NanoCrystal technology incorporates a proprie-tary milling technique whereby agglomeration of the resulting particles is pre-vented by surface adsorption of GRAS stabilizers [19]. The IDD technology(Chapter 13) produces drug microparticles that are stabilized by surface-modifying agents, such as phospholipids, to provide a capsule domain that inhib-its particle growth due to aggregation, occulation, agglomeration, or Ostwaldripening. The resulting suspension can then be dried by lyophilization, spraydrying, or other suitable drying technique and incorporated into a convenientdosage form.

The introduction of liquid-lled and sealed hard gelatin capsules (Chapter14) has provided new opportunities for the development of liquid and semisoliddosage forms for poorly water-soluble drugs. This capsule technology can incor-porate liquid and semisolid lipophilic vehicles and various solubilizing agents toimprove the dissolution and dispersion properties in an attempt to obtain maximaland reproducible bioavailability.

It has been increasingly recognized that compliance issues with solid oraldosage forms can be signicant for those individuals who have difculty in swal-



lowing, particularly pediatric and geriatric patients. Fast-dissolving dosage formshave recently been developed as a convenient means of overcoming this problemwhile maintaining the processing and stability advantages of solid dosage forms.The Zydis technology (Chapter 15), one of the rst such technologies to beintroduced in the market, utilizes lyophilization to produce a fast-melting dos-age form that can be taken without water. Other variations include the OraSolvsystem (Chapter 16) which relies on the presence of water-soluble excipients anduse of low-compression forces to produce a highly porous tablet that disintegratesrapidly, and the related DuraSolv technology (Chapter 16), which incorporatessoluble, ne-particle llers to enhance dissolution while producing a more robustcompressed tablet preparation.

Future directions in oral modied-release technology will be largely guidedby the changing properties of active pharmaceutical compounds. As emergingmolecules trend toward increasing hydrophobicity and/or lipophilicity, the needand requirement for dosage forms to facilitate the release of these poorly solublecompounds is likely to increase. Dosage forms that enhance the solubility anddissolution rate, such as the amorphous, nanoparticulate, and microparticulatesystems, and those that incorporate solubilizing excipients such as modiedcyclodextrins [20], are likely to be increasingly employed. With the availabilityof new encapsulation technologies for liquid dosage forms, self-emulsifying lipid/surfactant systems [21] may also show greater utilization for poorly soluble drugs.Poorly permeable, high-molecular-weight compounds (e.g., peptides and pro-teins) present further, and signicant, challenges for oral delivery and numerousgroups are actively researching delivery strategies for this class of drugs. Currentand future approaches include various particulate systems [22], natural polymericpenetration enhancers such as chitosans [23], and prodrug approaches [24].

A further key driver for the development and commercialization of modi-ed-release technologies will be the realization that the pharmacodynamic proleof a drug might be enhanced by administering it in a modied-release oral doseform compared with a conventional immediate-release product. Although the his-tory of modied-release does form has been largely technology focused, the fu-ture may well build on this technology base to embrace and explore opportunitiesto enhance the pharmacodynamic prole of candidate drugs.

REFERENCES

1. GL Amidon, H Lennernas, VP Shah, JR Crison. A theoretical basis for a biopharma-ceutic drug classication: the correlation of in vitro drug product dissolution and invivo bioavailability. Pharm Res 12:413420, 1995.

2. E Lipka, GL Amidon. Setting bioequivalence requirements for drug developmentbased on preclinical data: optimizing oral drug delivery systems. J Control Rel 62:4149, 1999.



3. D Gardner, R Casper, F Leith, IR Wilding. The InteliSite capsule: a new easy touse approach for assessing regional drug absorption from the gastrointestinal tract.Pharm Technol Eur 9:4653, 1997.

4. G Fricker, J Drewe, J Huwyler, H Gutmann, C Beglinger. Relevance of p-glycopro-tein for the enteral absorption of cyclosporin A: in vitroin vivo correlation. Br JPharmacol 118:18411846, 1996.

5. MF Paine, M Khalighi, JM Fisher, DD Shen, KL Kunze, CL Marsh, JD Perkins, KEThummel. Characterization of interintestinal and intraintestinal variations in humanCYP3A-dependent metabolism. J Pharmacol Exp Ther 283:15521562, 1997.

6. JB Dressman, GL Amidon, C Reppas, VP Shah. Dissolution testing as a prognostictool for oral drug absorption: immediate release dosage forms. Pharm Res 15:1122, 1998.

7. R Lobenberg, GL Amidon. Modern bioavailability, bioequivalence and biopharma-ceutics classication system: new scientic approaches to international regulatorystandards. Eur J Pharm Biopharm 50:312, 2000.

8. IR Wilding, AJ Coupe, SS Davis. The role of -scintigraphy in oral drug delivery.Adv Drug Del Rev 46:103124, 2001.

9. SS Davis, FN Christensen, JG Hardy. The intestinal transit of pharmaceutical dosageforms. Gut 27:886892, 1986.

10. CT Rhodes, SC Porter. Coatings for controlled-release drug delivery systems. DrugDev Ind Pharm 24:11391154, 1998.

11. VRS Uppoor. Regulatory perspectives on in vitro (dissolution)/in vivo (bioavailabil-ity) correlations. J Control Rel 72:127132, 2001.

12. V Lenaerts, I Moussa, Y Dumoulin, F Mebsout, F Chouinard, P Szabo, MA Ma-teescu, L Cartilier, R Marchessault. Cross-linked high amylose starch for controlledrelease of drugs: recent advances, J Control Rel 53:225234, 1998.

13. U Conte, L Maggi. A exible technology for the linear, pulsatile and delayed releaseof drugs, allowing for easy accommodation of difcult in vitro targets. J ControlRel 64:263268, 2000.

14. HE Hogan, JN Staniforth, L Reeves, T Page. Electrostatic coating. US Patent6,117,479, 1997.

15. JC Richards, DV Prior, SE Frisbee, J Getz, IR Wilding. Pharmacoscintigraphic eval-uation of novel controlled release microsphere (Ceform) formulations. Proc IntSymp Control Rel Bioact Mater 25:920921, 1998.

16. C Castan, M Cicquel, R Meyrueix, P Autant, R Jorda, P Vivet, G Soula. Genvir:the rst sustained release dosage form of acyclovir. Proc Int Symp Control Rel Bi-oact Mater 27:11981199, 2000.

17. WN Charman, CJH Porter, S Mithani, JB Dressman. Physicochemical and physio-logical mechanisms for the effects of food on drug absorption: the role of lipids andpH. J Pharm Sci 86:269282, 1997.

18. MR Venkatramana, JL Haslam, VJ Stella. Controlled release matrices of poorlywater soluble drugs using (SBE)7M--CD as a solubilizing agent. Proc Int SympControl Rel Bioact Mater 26:929930, 1999.

19. GG Liversidge, KC Cundy, JF Bishop, DA Czekai. Surface modied drug nanopar-ticles. US Patent 5,145,684, 1992.

20. RA Rajewski, VJ Stella. Pharmaceutical applications of cyclodextrins. 2. In vivodrug delivery. J Pharm Sci 85:11421169, 1996.



21. CW Pouton. Formulation of self-emulsifying drug delivery systems. Adv Drug DelRev 25:4758, 1997.

22. R Langer, H Chen. Oral particulate delivery: status and future trends. Adv Drug DelRev 34:339350, 1998.

23. L Illum. Chitosan and its use as a pharmaceutical excipient. Pharm Res 15:13261331, 1998.

24. GM Pauletti, S Gangwar, TJ Siahaan, J Aube, RT Borchardt. Improvement of oralpeptide bioavailability: peptidomimetics and prodrug strategies. Adv Drug Del Rev27:235256, 1997.

25. KH Bauer, K Lehmann, HP Osterwald, G Rothgang. Coated Pharmaceutical DosageForms. Boca Raton, FL: CRC Press LLC, 1998, pp 126130.

26. IR Wilding. Evolution of the biopharmaceutics classication system (BCS) to oralmodied release (MR) formulations; what do we need to consider? Eur J Pharm Sci8:157159, 1999.


2TIMERx Oral Controlled-ReleaseDrug Delivery System

Troy W. McCall and Anand R. BaichwalPenwest, New York, New York

John N. StaniforthVectura Ltd., Bath, England

I. INTRODUCTION

The novel oral controlled-release drug delivery system TIMERx is a pregranu-lated blend composed of synergistic heterodisperse polysaccharides (usually xan-than gum and locust bean gum) together with a saccharide component (generallydextrose) [1]. The technology is capable of delivery a wide range of drugs andis customized to accommodate a variety of physicochemical and pharmacokineticproperties and release proles. The material has uniform packing characteristicsover a range of different particle size distributions and is capable of processinginto tablets using either direct compression, following addition of drug and lubri-cant, or conventional wet granulation. The synergism between the homo- andheteropolysaccharide components of the system enables formulation manipula-tion of different rate-controlling mechanisms. The ultimate rate of drug releaseis controlled by the rate of water penetration into the matrix. The technology iswell protected with over 90 patents issued worldwide [24].

Drug release from tablets containing the polysaccharide system is capableof control using a variety of different formulations and process methods to pro-vide a variety of release modalities that are capable of matrix-dimension indepen-dence. Control of drug release is achieved by manipulation of the synergisticinteractions of the heterodisperse polysaccharides to regulate the rate of water

11


12 McCall et al.

penetration into the tablet and subsequent diffusion of the drug across the gellayer.

II. HISTORICAL DEVELOPMENT

The TIMERx technology was conceived based on the premise that oral con-trolled-release systems do not have to be complicated to possess superior in vitroand in vivo performance characteristics. At the time the technology was invented,the predominant systems available were: (a) hydrophilic matrices, (b) oral os-motic pumps, and (c) multiparticulates (beads). Clearly, conventional matrix tab-lets represented the most simple, but possessed a number of weaknesses includingpolymer variablity, difculty in achieving zero-order release, little or no abilityto maintain a strong proprietary position, and problems in consistently releasingdrug for extended periods (i.e., 1224 h). On the other hand, oral osmotic andmultiparticulate systems overcame these problems but were difcult to developand manufacture on standard solid-dosage-form processing equipment. In theirsimplest forms, TIMERx tablet formulations consist of drug, bulk TIMERx, andlubricant, and are processed using conventional tableting equipment. This is incontrast to other matrix systems that require evaluation of numerous polymersto optimize drug release and typically need ow and compressibility aids to per-mit tablet production. Therefore, the TIMERx technology was developed to retainthe simplicity of conventional matrix systems while overcoming the problemsassociated with the more complicated technologies.

III. DESCRIPTION OF THE TECHNOLOGYA. Physical Characteristics of the Ungelled

(Unwetted) SystemParticle size distributions of some controlled release formulations developed fordifferent drugs show that the modal diameters vary from approximately 195 mto 215 m. In some cases, the size distributions are unimodal, while in others,some bimodality is evident. Other differences include the degree of kurtosis andskewness of the distributions. These factors may be important in optimizing themechanical properties, content uniformity, and release-sustaining characteristicsof a direct compression formulation for a given drug. Alternatively, in the caseof a wet granulation system, the particle size distribution, as well as the agglomer-ating properties, may be important. Notwithstanding the different particle sizedistributions available, it is interesting to note that the packing behavior resultsin loose and consolidated bulk densities (and Hausner ratios), which remain virtu-ally constant. This is a potentially valuable property in view of the dependency of


TIMERx Drug Delivery System 13

Figure 1 Scanning electron micrograph of a single heterodisperse polysaccharide ag-glomerate in the unwetted state.

powder ow and hence tablet weight and content uniformity on powder packingcharacteristics.

The surface morphology of the particles of the TIMERx system providesa generally regular, near-spherical particle shape, which helps to confer goodow properties (Fig. 1). The surface texture is relatively rough with clefts andlarge pores capable of conferring segregation resistance on the direct compressionformulation.

Tablets compacted using an instrumented rotary tablet machine possessstrength proles that are largely independent of the saccharide component. Scan-ning electron photomicrographs of ungelled tablet surfaces provide qualitativeevidence of extensive plastic deformation on compaction, both at the tablet sur-face and across the fracture surface. There is also evidence of surface poresthrough which initial solvent ingress and solution egress may occur.

B. Physical Characteristcs of the Gelled (Wetted) SystemThe properties and characteristics of the specic heterodisperse polysaccharidesystem are dependent on the individual characteristics of polysaccharide con-stituents, in terms of polymer solubility, glass transition temperatures, etc., as


14 McCall et al.

well as on the synergism both between different polysaccharides and betweenpolysaccharides and saccharides in modifying dissolutions uid-excipient inter-actions.

For example, the heteropolysaccharide xanthan gum has a molecular weightof approximately 300,0001,000,000, and is readily soluble, which as a homodis-perse system produces a highly ordered, helical or double-helical molecular con-formation that provides high viscosity without gel formation. In contrast, a homo-disperse system of the homopolysaccharide, locust bean gum, is only slowlysoluble and ungelled at low temperatures. Prolonged exposure to the dissolutionuid promotes solubilization, which allows molecules to associate and undergogelation as the result of intermacromolecular cross-linking in ribbon or helicalsmooth regions. The heterodisperse system contains both hetero- and homo-polysaccharides, which exhibit synergism. The heteropolysaccharide componentacts to produce a faster gelation of the homopolysaccharide component and thehomopolysaccharide acts to cross-link the normally free heteropolysaccharidehelices (Fig. 2). The resultant gel is faster forming and more rigid. The viscosityand solubilization speed are further potentiated by the saccharide component. Gelrigidity may also be further potentiated in the presence of some cations andanions. A diagram of the interactions occurring between the different materialsis provided in Figure 3.

Figure 2 Scanning electron micrograph of the gelled (wetted) heterodisperse polysac-charide tablet showing pore formation.



Figure 3 Molecular conformation of a heterodisperse polysaccharide system in the pres-ence of saccharide, drug, and cation. (See color insert.)

IV. RESEARCH AND DEVELOPMENTA. Formulation ConsiderationsA number of factors are important in the development of controlled-release dos-age forms using the TIMERx technology, including (a) dose of the active drug,(b) solubility of the active drug, (c) polymer ratios (xanthan gum:locust beangum) (d) active drug:polymer ratio, and (e) bulk excipient selection.

The rst two factors, dose and solubility, must be taken into considerationfor any drug delivery system. The differentiating factor for the TIMERx systemis the working range for eachdose: 4850 mg (representing approximately270% drug loading); and solubility: insoluble to freely soluble.

The next two factors are unique to the system. The ratio of the polymerscontrols both the rate and modality of drug release. In addition, the active drug:polymer ratio is important since, similar to other hydrophilic matrix systems, themore polymer that is added to the tablet formulation, the slower the rate of drugrelease. This effect reaches a maximum beyond which any further addition ofpolymer has little or no effect.

Finally, the addition of excipients can play an important role in the charac-teristics of the nished product. For example, materials can be added to promote


16 McCall et al.

Figure 4 In vitro and in vivo proles for a product developed using the TIMERx systemfor a low-dose, highly soluble drug to be delivered at a constant rate for twice-daily dosing.

stability or solubility of the drug and subsequently enhance release from the ma-trix.

B. System FlexibilityThe TIMERx technology is extremely exible in terms of the types of drugs itis capable of delivering. As mentioned previously, a large range of doses andsolubilities is possible. Moreover, a variety of release prole types can beachieved, including rst-order, zero-order, and pulsatile release. Figures 46 pro-vide three examples to demonstrate the capabilities of the system in which formu-lations were evaluated both in vitro and in vivo. These cases were examined inwhich drugs with different physicochemical and pharmacokinetic properties weredeveloped into controlled-release dosage forms. The formulations were evaluated

Figure 5 In vitro and in vivo proles for a product developed using the TIMERx systemfor a high-dose, highly soluble drug to be delivered at a pulsed rate for once-daily dosing.



Figure 6 In vitro and in vivo proles for a product developed using the TIMERx systemfor a medium-dose, poorly soluble drug to be delivered at a constant rate for once-dailydosing.

in vitro and in vivo and shown to have achieved the desired proles. The resultssupport the claim that the TIMERx technology is suitble for a variety of drugmolecules and release proles.

C. System ManufacturabilityThe TIMERx technology offers the additional benet of ease of manufacturecompared to more complicated drug delivery systems. For example, certain for-mulations have been developed that exhibit similar in vitro and in vivo prolescompared to alternative systems. In these cases, the TIMERx-based productswere manufactured using a simple, three-step process involving blending, com-pressing, and coating. By contrast, the alternate products were developed andmanufactured using a complex series of steps that required specialized equipmentand personnel. Formulations based on the TIMERx technology have been rou-tinely scaled-up from the laboratory to production.

D. In VitroIn Vivo RelationshipsIn vitroin vivo relationships (IVIVR) have been studied extensively and areused to establish a correlation between the physicochemical properties of a dos-age form and its biological performance. IVIVR can be used to (a) serve as asurrogate to bioequivalence testing for scale-up and postapproval changes (b)justify dissolution specications for quality control purposes, and (c) enhancepredictabiltiy of in vivo performance and thus improve product development ef-ciencies. Extensive work has been done to establish such relationships for prod-ucts developed using the TIMERx technology in both fasted and fed states. Al-though many researchers focus solely on the fasted condition, the postprandial


18 McCall et al.

state is equally important for controlled-release dosage forms since some systemscan exhibit dose dumping. While food effects are well documented, the mecha-nisms are not well understood. Two critical factors that can affect the absorption,distribution, metabolism, and excretion involve effects on the dosage form andgastrointestinal physiology. When prediction of in vivo behavior in the fed stateis attempted, the situation is confounded by the multiplicity of technologies thatexist. Therefore, when considering the effects on the dosage form, one must rstfully understand the mechanism by which drug is released in the body. Con-trolled-release systems deliver drugs by diverse mechanisms, and thus can beaffected by food in very different ways. Moreover, the effect of food on gastroin-testinal physiology is important in understanding such effects. Delayed gastricemptying, increased gastric pH and motility, and decreased polarity of the gastriccontents are all known to occur in the fed state. Therefore, signicant effortshave been made to develop predictive in vitro tests to provide an understandingof how the dosage form is expected to perform in the body.

In addition, a gamma scintigraphy study was performed using a placeboTIMERx tablet to determine the nature of the wetted core during gastrointestinaltransit. The results indicated that the tablet does not disintegrate, but rather slowlyerodes as it moves through the gastrointestinal tract. This is an important featuresince it suggests that there is no danger of gastrointestinal blockage.

V. SUMMARY

The TIMERx technology is among the leading oral drug delivery technologies. Itwas originally developed to provide a simple alternative to the more complicatedcontrolled-release systems while overcoming the deciencies associated withconventional hydrophilic matrices. The technology is one of the most exible interms of dealing with drugs with varying physicochemical and pharmacokineticproperties, doses, and desired release proles. The nished dosage forms canbe readily manufactured on standard processing equipment, resulting in ease oftechnology transfer and cost-effectiveness. In addition, the technology is wellprotected with more than 90 patents issued worldwide. Several products usingthe TIMERx system have been approved in the United States and Europe. Thesefeatures ultimately provide the end-user with the ability to rapidly develop andproduce superior oral controlled-release products.

REFERENCES

1. JN Staniforth, AR Baichwal. Synergistically interacting heterodisperse polysaccha-rides: function in achieving controllable drug delivery. In: MA El-Nokaly, DM Piatt,



BA Charpentier, eds. Polymeric Delivery Systems: Properties and Applications.American Chemical Society, 1993, pp. 327350.

2. AR Baichwal, JN Staniforth. Directly compressible sustained release excipient. USpatent 4,994,276, 1991.

3. AR Baichwal, JN Staniforth. Sustained release excipient and tablet formulation. USpatent 5,128,143, 1992.

4. AR Baichwal, JN Staniforth. Compressible sustained release solid dosage forms. USpatent 5,135,757, 1992.


3MASRx and COSRxSustained-Release Technology

Syed A. AltafGilead Sciences, Foster City, California, U.S.A.

David R. FriendDelsys Pharmaceutical, a division of Elan Operations, Inc.,Monmouth Junction, New Jersey, U.S.A.

I. INTRODUCTION

The advantages of administering a single dose of a drug that is released over anextended period of time, instead of numerous doses, have been obvious to thepharmaceutical industry for some time. The desire to maintain a near-constantor uniform blood level of a drug often translates into better patient compliance,as well as enhanced clinical efcacy of the drug for its intended use.

Various drug delivery techniques have been developed to sustain the releaseof drugs, including triple-layered tablets (Geomatrix technology) and osmoticpumps with laser-drilled holes (OROS technology). These technologies are intri-cate and relatively expensive to manufacture. Thus, there remains an interest indeveloping novel formulations that allow for sustained release of drugs usingreadily available, inexpensive excipients.

Hydrocolloids are often used in formulations to modify or sustain the re-lease of drug from matrix controlled drug delivery systems. A common problemassociated with high-viscosity water-soluble polymers is their ability to hydrate.Hydration is even more difcult when these polymers are compressed into soliddosage forms. Tablets containing elevated levels of high-viscosity polysaccha-rides begin to gel and hydrate, but the hydration oftens stops at a certain point.The core of the tablet remains dry and therefore not all the drug may be released.

21


22 Altaf and Friend

Depending on other excipients or the amount of the hydrocolloid, tablets com-posed of high-viscosity polysaccharides can disintegrate quickly, resulting indose dumping or the immediate release of the drug.

Guar gum, a naturally occurring, highly viscous, water-soluble polysaccha-ride, is used in the pharmaceutical industry primarily as a disintegrating and bind-ing agent in compressed tablets [13]. Guar gums potential in sustaining therelease of water-soluble drugs, such as diltiazem, has recently been published[4,5]. The advantages of guar gum as a sustained-release excipient are its highviscosity, low cost, and commercial availability [6,7]. Guar gum has also beenpuried and evaluated as an improved pharmaceutical excipient for sustained-release formulations [8].

II. EXPERIMENTAL

For guar-gum-based technologies, all the ingredients except magnesium stearatewere mixed together in a V-blender for 10 min. The powder mixture was dry-granulated using a Freund Mini Roller Compactor (pressure 90 kg/cm2, feedspeed 12 rpm, and roller speed 5 rpm). Resulting powder blend ribbonswere milled and sieved through screens, retaining granules between 250 mand 600 m. The collected granules were mixed with magnesium stearate in aV-blender for 10 min and then compressed into tablets. A wet granulation proce-dure was also evaluated and used for the optimized diltiazem formulations. Inthe case of nifedipine formulations, tablets were coated in a pan coater.

For dissolution studies, USP Apparatus II at 50, 100, and 200 rpm paddlespeed with simulated gastric uid (SGF) or simulated intestinal uid (SIF) wasused. Dissolution proles were reduced to a meaningful set of parameters bytting the dissolution curves to the Weibull function [9]. Analysis of covariancewas performed on the dissolution curves to examine whether differences weresignicant based on a predetermined level, which was set at 5%. Statisticswere performed using JMP (Version 3.2.2., SAS Institute, Cary, NC). In thecase of nifedipine, dissolution was performed at 100 rpm paddle speed with SIFunder yellow light; 0.25% sodium lauryl sulfate (SLS) was added to enhance thesolubility of nifedipine and maintain sink conditions. For drug product assay, avalidated high-performance liquid chromatography (HPLC) method was used forboth drugs.

The GMP manufacturing and stability of the clinical trial materials wereconducted at Penn Pharmaceuticals Ltd., Gwent, UK and Pharmaceutics Interna-tional, Inc., Hunt Valley, MD. Clinical studies were performed by Corning Bes-selaar Clinical Research Unit, Madison, WI. The plasma samples were analyzedby Hazelton Wisconsin, Madison, WI.


MASRx and COSRx Sustained-Release Technology 23

III. MASRx TECHNOLOGYA. Formulation DevelopmentThe objective was to assess factors affecting drug release from guar-gum-basedonce-daily matrix sustained-release formulations (MASRx). The tablets weredesigned to hydrate completely into the tablet core. In the process, the tablet coreexpanded and released the drug in a sustained-release manner.

Guar gum is a natural product that can vary in specications crop to crop,season to season. To evaluate the effect of varying lots of guar gum on dissolu-tion, formulation A (Table 1) was manufactured with three lots of guar gumobtained from the same manufacturer. The resulting dissolution release rate con-stants (Table 2) were insignicantly different (p 0.98). The variability amongthree commercial sources of guar gum was also evaluated by using formulationA. It was shown that guar gum source did not affect diltiazem release (Table 2).

The effect of nal powder blend particle size distribution on diltiazem re-lease showed a statistically signicant difference in the diltiazem release rateconstant as observed from tablets made with 150600-m granules comparedwith those made from 425600-m and 250600-m granules (Table 2). Thedifference in drug release is possibly due to the greater percentage of nes inthe 150600-m size granules, which causes the tablet to hydrate faster leadingto rapid gelling of the polymer, which in turn slows the drug release. The diltia-zem powder blend was also equilibrated to humidity levels of 11%, 56%, and

Table 1 Summary of the Clinical Trial Formulations Based on MASRx Technology

Formulations

Ingredients A B C D E

Diltiazem HCl, USP 31.00% 31.00% 31.00% 31.60% 31.60%Guar gum (Supercol G3-NF) 62.00 62.00 64.60 57.15Puried guar guma (Supercol

G3-NF) 67.00Methocel K100LV 5.00 2.50 10.00Polyethylene oxide (Polyox,

MW 8,000,000) 5.00Povidone 0.25 0.25Stearic acid 2.00 2.00 2.00Magnesium stearate, NF 2.00 2.00Total weight 785 mg 785 mg 785 mg 785 mg 785 mga See Ref. 8 concerning puried guar gum.


24 Altaf and Friend

Table 2 Summary of the Dissolution Parameters from Guar-Gum-Based DiltiazemFormulation A and the Commercial Dilacor XT Formulation

b(beta) d(Td) K 1/Td p valueLot Lot 1 0.8245 8.6181 0.1162

Lot 2 0.8718 7.7822 0.1167 0.98Lot 3 0.8471 8.6212 0.1160

Vendor Aqualon 0.8245 8.6181 0.1162Meer 0.9662 8.5856 0.1168 0.999TIC gums 0.9195 8.5954 0.1194

Particle size Less than 106 m 0.8360 6.0665 0.1648Greater than 150 m 0.8152 6.3235 0.1581 0.872Whole distribution 0.8230 8.1844 0.1222

Hardness 6 kp 0.8415 7.1947 0.13909 kp 0.8467 7.6799 0.1302 0.98112 kp 0.8230 8.1844 0.1222

Granule size 425600 m 0.8244 8.6181 0.1160250600 m 0.7668 8.5269 0.1173 0.621150600 m 0.6693 15.7700 0.0634

Relative humidity 11% 0.6811 6.0078 0.166556% 0.7681 7.8724 0.1270 0.86275% 0.7650 8.2545 0.1211

Paddle speed Formulation A, 50 rpm 0.9935 8.7374 0.1144Formulation A, 100 rpm 0.9865 7.3990 0.1352 0.831Formulation A, 200 rpm 0.9303 5.9415 0.1683Dilacor XR, 50 rpm 1.1648 8.0423 0.1243Dilacor XR, 100 rpm 1.2671 7.1083 0.1407 0.716Dilacor XR, 200 rpm 1.2119 4.7412 0.2109

Stability Initial 0.9865 7.3990 0.13521 month 0.9716 6.5471 0.1527 0.9793 month 0.9970 7.4006 0.1351

75% and compressed into tablets to evaluate the effect of relative humidity. Theresulting release rate constants show insignicant difference in diltiazem release(Table 2). Likewise, varying tablet hardness (6, 9, or 12 kp) did not signicantlyaffect dissolution of diltiazem (Table 2). The effect of paddle speeds, 50, 100,and 200 rpm (USP Apparatus II), was also evaluated on diltiazem release forboth the guar-gum-based and the commercial diltiazem product Dilacor XR. Aninsignicant difference in diltiazem release was observed at the 50- and 100-rpmpaddle speeds. At 200-rpm paddle speed, dissolution exhibits some differencesin diltiazem release at the later time points. Although both formulations showed



a qualitative increase in dissolution rate at 200 rpm, these differences were statis-tically insignicant.

Stability of guar-based tablets was assessed over 3 months at 40C and75% relative humidity. The release rate constants for the 1- and 3-month dissolu-tion data for the guar-gum-based diltiazem formulations are shown in Table 2.The results show that the dissolution proles over the 3 months do not changesignicantly (p 0.979).

B. Clinical EvaluationsThree guar-gum-based diltiazem formulations (formulation A, B, and C) wereselected for clinical trials along with the reference commercial product, DilacorXR 240 mg. In vitro release proles of diltiazem from the three guar-gum-basedformulations were very similar to those of the commercial product, Dilacor XR(Fig. 1). The three guar-gum-based diltiazem formulations differ slightly in theircomposition (Table 1). All three guar-gum-based formulations sustained the re-lease of diltiazem in vivo over 24 h nearly identical to Dilacor XR. Plasma diltia-zem concentration plots (Fig. 2) indicated that the absorption of diltiazem fromall four formulations was fairly constant over a period of 1624 h postdose.Among the guar-gum-based formulations, formulation A produced plasma con-

Figure 1 Diltiazem dissolution release proles of sustained release formulations A (),B (), C (), and the reference product, Dilacor XR 240 mg ().


26 Altaf and Friend

Figure 2 Mean plasma diltiazem concentrations from guar-gum-based formulations A(), B (), and C (), and the reference product, Dilacor XR 240 mg ().

centrations most similar to those of Dilacor XR. The physicochemical changeresulting from guar gum purication manifests itself with slightly lower variabil-ity in Cmax than the unpuried guar. Table 3 summarizes the pharmacokineticparameters for the clinical formulations. Based on these data, methods were ex-amined to bring the Cmax closer to the reference product in both fasted and fedconditions. First, increasing drug release rate over the rst 46 h followed by a

Table 3 Geometric Mean PharmacokineticParameters and 90% Condence Intervals (upper,lower) for Initial Diltiazem Formulations

AUC(0-36) CmaxFormulation (ng/h/mL) (ng/mL)Dilacor XR 1340 69.5A 1484 79.0

(0.91, 1.35) (0.91, 1.41)B 1588 83.6

(0.97, 1.44) (0.97, 1.49)C 1599 81.1

(0.98, 1.45) (0.94, 1.45)



period of slow release compared to the reference product (i.e., fast/slow formula-tion) was hypothesized. In this case, more drug should be available in the earlyhours following dosing bringing the Cmax down at a later time point. The secondapproach was to decrease the release rate for all time points, i.e., a slower releas-ing formulation. Based on these two approaches, two new diltiazem formulationswere developed (formulations D and E, see Table 1). The in vitro dissolutionproles for the two new formulations are shown in Figure 3. The two optimizedformulations were evaluated in a second fed and fasted trial.

All the enrolled subjects (nine and 12 in the fasted and fed studies, respec-tively) completed the three-period crossover studies. There were no serious ad-verse events. The mean plasma diltiazem concentrations following oral adminis-tration of Dilacor XR, formulations D and E to fasted and fed subjects are plottedto Figure 4. Absorption of diltiazem from formulations D and E was similar tothe reference product in both the fasted and fed state. The geometric means usedfor bioequivalence analysis of D and E with the fasted and fed data are given inTables 4 and 5, respectively. Based on the data collected under fed and fastedconditions, formulations D and E released diltiazem similar to the referencedproduct, Dilacor XR.

Figure 3 Diltiazem dissolution release proles of optimized sustained-release formula-tions D () and E () in reference to Dilacor XR 240 mg () (data are mean s.d.,n 12).


28 Altaf and Friend

Figure 4 Mean plasma diltiazem concentrations from formulations D (), E (), andDilacor XR 240 mg () in fasted (n 12) (panel A) and fed (n 9) subjects (panel B).

IV. COSRx TECHNOLOGYA. Formulation DevelopmentFormulations based on constant sustained-release matrix (COSRx) technologycan also be developed using guar gum as a major rate-controlling polymeric mate-rial. Depending on the solubility of the drug, low- or high-viscosity guar gum



Table 4 Geometric Means, Ratios, and 90% Condence Intervals of Diltiazem forFormulations D and E Under Fasted Conditions

90% condenceMean level

Ratio (%)Parameter Test Reference (T/R) Lower UpperTest (formulation D): Reference (Dilacor XR)AUC(0-36) (ng/h/mL) 1545 1553 99.5 0.87 1.13AUC(0-) (ng/h/mL) 1654 1702 97.2 0.85 1.11Cmax (ng/mL) 77.5 76.0 101.9 0.86 1.21

Test (formulation E): Reference (Dilacor XR)AUC(0-36) (ng/h/mL) 1342 1553 86.4 0.76 0.98AUC(0-) (ng/h/mL) 1470 1702 86.3 0.76 0.99Cmax (ng/mL) 73.3 76.0 96.4 0.81 1.14

can be used. The formulation involves a guar-gum-based tablet and a combinationof water-soluble and water-insoluble polymeric tablet coat. When the tablet isplaced in a dissolution medium, there is slow diffusion of water through thepolymeric wall leading to swelling and gelation of the guar gum/drug core. As thehydration progresses, the tablet continues to swell until the wall breaks, forming asandwich-like structure. The release of drug proceeds primarily out of the sidesof the tablet as it passes through the intestinal tract. The tablets provide a nearly

Table 5 Geometric Mean Diltiazem Ratios of Formulations D and E Under FedConditions

MeanRatio (%)

Parameter Test Reference (T/R)Test (formulation D): Reference (Dilacor XR)AUC(0-36) (ng/h/mL) 1992 1753 113.6AUC(0-) (ng/h/mL) 1984 1809 109.7Cmax (ng/mL) 122.7 108.1 113.5

Test (formulation E): Reference (Dilacor XR)AUC(0-36) (ng/h/mL) 1798 1753 102.6AUC(0-) (ng/h/mL) 1854 1809 102.5Cmax (ng/mL) 119.1 108.1 110.2


30 Altaf and Friend

zero-order drug release following a programmed period of delayed drug release.A variety of drug release proles can be obtained by adjusting the coating thick-ness and/or the matrix core composition.

To achieve a constant zero-order matrix sustained release formulation(COSRx) for a poorly water-soluble drug such as nifedipine (10 g mL1), alow-molecular-weight guar gum (Tico-LV) was used. Channeling agents such aswater-insoluble silicon dioxide or water-soluble lactose were used to enhance theporosity of the matrix aiding in the dissolution of drug. A combination of water-soluble (Eudragit RL PO) and water-insoluble polymers (Eudragit RS PO), in theratio of 1:9 (RL:RS), was used as coating material (2% w/w). The combinationproduced a lag time in drug release of 2 h, similar to that observed with thereference nifedipine product, Procardi

modified release drug delivery technology

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