Modified-Release
`Drug Delivery
`Technology
`
`edited by
`Michael J. Rathbone
`InterAg
`Hamilton, New Zealand
`Jonathan Hadgraft
`Medway Sciences, NRI
`University of Greenwich
`Chatham, England
`Michael S. Roberts
`Princess Alexandria Hospital
`and University of Queensland
`Brisbane, Queensland, Australia
`
`Marcel Dekker, Inc.
`
`New York (cid:129) Basel
`
`Copyright © 2002 by Marcel Dekker, Inc. All Rights Reserved.
`
`Copyright © 2003 Marcel Dekker, Inc.
`
`Liquidia's Exhibit 1069
`Page 1
`
`

`

`Library of Congress Cataloging-in-Publication Data
`A catalog record for this book is available from the Library of Congress.
`
`ISBN: 0-8247-0869-5
`
`This book is printed on acid-free paper.
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`Copyright © 2003 by Marcel Dekker, Inc. All Rights Reserved.
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`Neither this book nor any part may be reproduced or transmitted in any form or by any
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`Current printing (last digit):
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`PRINTED IN THE UNITED STATES OF AMERICA
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`Copyright © 2003 Marcel Dekker, Inc.
`
`Liquidia's Exhibit 1069
`Page 2
`
`

`

`To my daughter Jenna
`
`—M.J.R.
`
`Copyright © 2003 Marcel Dekker, Inc.
`
`Liquidia's Exhibit 1069
`Page 3
`
`

`

`Preface
`
`For over 50 years, interest has been expressed in optimizing drug therapy through
`delivery system design. For many years this revolved around incorporating drugs
`into 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 recent
`times there has been a move away from simply formulating drugs into erodible
`or inert polymers toward the design and development of more advanced drug
`delivery systems that utilize sophisticated designs and manufacturing techniques
`and rely on novel means for controlling the release of drug from the delivery
`system. Over the last few decades, rapid developments have occurred in this area
`and we have witnessed the evolution of commercially successful companies that
`specialize in the design, development, and commercialization of specific (in-
`house) modified-release drug delivery systems.
`This is an exciting and growing area of pharmaceutical research. However,
`to date no single volume provides detailed and specific information on even a
`handful of individual modified-release drug delivery systems. Therefore, we de-
`cided to edit a book comprised of chapters that collectively address this void
`and provide an insight into the various approaches currently adopted to achieve
`modified-release drug delivery.
`The book is divided into parts, each of which addresses a particular route
`for drug delivery. Although it is assumed that the reader is already familiar with
`fundamental controlled-release theories, each part opens with an overview of
`the anatomical, physiological, and pharmaceutical challenges in formulating a
`modified-release drug delivery technology for each route for drug delivery. The
`
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`Page 4
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`vi
`
`Preface
`
`chapters in each part provide examples of the different approaches that have been
`taken to design and develop an innovative modified-release drug delivery system.
`Each chapter presents a detailed account of a specific modified-release drug deliv-
`ery technology, written by experts on that technology.
`Our challenge in editing this book was that no single volume could be
`expected to describe every modified-release drug delivery technology currently
`marketed or under development. This is because of the vast and evolving nature
`of the area, and the lack of availability of the innovators to write a monograph
`on their particular technology, due to either time constraints or the proprietary
`nature 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 modified-
`release drug delivery technologies as possible.
`Susan Charman and Bill Charman were the leaders of the first part of the
`book, which is devoted to the oral route. The Charmans provide an excellent
`overview of the challenges of this popular route for modified-release durg deliv-
`ery. Their introduction is followed by 15 chapters that provide an insight into
`the novel and innovative approaches that have been taken for this route for drug
`delivery. 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 Clive
`Wilson, discusses several diverse approaches that may be used to deliver com-
`pounds to the colon. Chapters demonstrating the innovativeness of workers in this
`field complement an incisive introduction that highlights the unique challenges
`associated 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 modified-release ophthalmic drug delivery systems. Since most of these sys-
`tems are in the developmental stage and have not yet reached the commercial
`stage, this part contains only three chapters on specific technologies. Part IV
`focuses on the oral cavity as a site of drug delivery. The part leader, Professor
`Ian Kellaway, together with invited coauthors, provides an overview of the issues
`relating to the development of modified-release drug delivery systems for this
`route. The associated chapters highlight technologies developed for specific 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 dermal
`and 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 a
`wide range of diverse technologies from wound dressings to sprays, to propulsion
`of solid drug particles into the skin by means of a high-speed gas flow, to patches
`that deliver drugs via diffusion, iontophoresis, sonophoresis, or microprojections.
`The sixth part of this book addresses implant and injection technologies. In their
`introduction, part leaders Franklin Okumu and Jeffrey Cleland offer a comprehen-
`
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`Preface
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`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, leader
`of 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 chapters
`dealing with this route provide an insight into the different approaches that can
`be employed to deliver drugs via the vaginal passage.
`In Part IX Igor Gonda provides an informative overivew of the unique
`challenges in delivering via the pulmonary tract. This part contains chapters de-
`scribing various systems, devices, formulations, and methods of delivery of drugs
`to the lung. It differs somewhat from other parts in the book in that the focus of
`pulmonary 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 inhalation
`systems to deliver drugs practically instantaneously to the target organ that is the
`“release” part of therapeutic activity for many of the currently approved products
`for inhalation. Numerous technological approaches are described in the chapters
`in this part, each of which provides descriptive comments on the complexity of
`this route for drug delivery. In the final part of this book the regulatory issues
`pertaining to these diverse and often complex drug delivery systems are addressed
`by Patrick Marroum of the United States Food and Drug Administration, who
`provides 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 spent
`so much time identifying technologies, communicating with contributors, writing
`informative overviews, and editing the chapters. We also thank all the chapter
`authors. Their individual innovative research activities have contributed greatly
`to the current modified-release drug delivery technology portfolio that exists to-
`day within the pharmaceutical industry. We are grateful to them for taking the
`time to share their experiences and work. Finally, we wish to express our sincere
`thanks to Dr. Colin Ogle. We are indebted to Colin for giving up so much of his
`spare time to proofread final drafts and offer many constructive suggestions for
`improvement of this volume.
`
`Michael J. Rathbone
`Jonathan Hadgraft
`Michael S. Roberts
`
`Copyright © 2003 Marcel Dekker, Inc.
`
`Liquidia's Exhibit 1069
`Page 6
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`Contents
`
`Preface
`Contributors
`
`Part I: Oral
`
`1. Oral Modified-Release Delivery Systems
`Susan A. Charman and William N. Charman
`
`2. TIMERx Oral Controlled-Release Drug Delivery System
`Troy W. McCall, Anand R. Baichwal, and John N. Staniforth
`
`3. MASRx and COSRx Sustained-Release Technology
`Syed A. Altaf and David R. Friend
`
`4. Procise: Drug Delivery Systems Based on Geometric
`Configuration
`Sham K. Chopra
`
`5. RingCap Technology
`David A. Dickason and George P. Grandolfi
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`xvii
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`x
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`Contents
`
`6. Smartrix System: Design Characteristics and Release Properties
`of a Novel Erosion-Controlled Oral Delivery System
`Horst G. Zerbe and Markus Krumme
`
`7. TheriForm Technology
`Charles W. Rowe, Chen-Chao Wang, and Donald C.
`Monkhouse
`
`8. Accudep Technology for Oral Modified Drug Release
`S. S. Chrai, David R. Friend, G. Kupperblatt, R. Murari, Jackie
`Butler, T. Francis, Araz A. Raoof, and Brian McKenna
`
`9. Osmotically Controlled Tablets
`Patrick S. L. Wong, Suneel K. Gupta, and Barbara E. Stewart
`
`10. Three-Phase Pharmaceutical Form—THREEFORM—with
`Controlled Release of Amorphous Active Ingredient for Once-
`Daily Administration
`Janez Kercˇ
`
`11. Two Concepts, One Technology: Controlled-Release and Solid
`Dispersions with Meltrex
`Jo¨rg Breitenbach and Jon Lewis
`
`12. DissoCubes—A Novel Formulation for Poorly Soluble and
`Poorly Bioavailable Drugs
`Rainer H. Mu¨ller, Claudia Jacobs, and Oliver Kayser
`
`13.
`
`IDD Technology: Oral Delivery of Water-Insoluble Drugs
`Using Phospholipid Stabilized Microparticulate IDD
`Formulations
`Awadhesh K. Mishra, Michael G. Vachon, Pol-Henri Guivarc’h,
`Robert A. Snow, and Gary W. Pace
`
`14. Liquid-Filled and -Sealed Hard Gelatin Capsule Technologies
`Ewart T. Cole
`
`15. The Zydis Oral Fast-Dissolving Dosage Form
`Patrick Kearney
`
`16. Orasolv and Durasolv: Efficient Technologies for the Production
`of Orally Disintegrating Tablets
`S. Indiran Pather, Rajendra K. Khankari, and Derek V. Moe
`
`59
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`77
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`89
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`101
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`115
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`125
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`135
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`151
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`177
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`Contents
`
`Part II: Colonic
`
`17. Colonic Drug Delivery
`Clive G. Wilson
`
`18. Enteric Coating for Colonic Delivery
`Gour Mukherji and Clive G. Wilson
`
`19. Biopolymers and Colonic Delivery
`Gour Mukherji and Clive G. Wilson
`
`20. Time-Dependent Systems for Colonic Delivery
`Wang Wang Lee, Gour Mukherji, and Clive G. Wilson
`
`21. New Approaches for Optimizing Oral Drug Delivery: Zero-
`Order Sustained Release to Pulsatile Immediate Release Using
`the Port System
`John R. Crison, Michael L. Vieira, and Gordon L. Amidon
`
`22. Pulsincap and Hydrophilic Sandwich (HS) Capsules: Innovative
`Time-Delayed Oral Drug Delivery Technologies
`Howard N. E. Stevens
`
`23. Development of the Egalet Technology
`Daniel Bar-Shalom, Lillian Slot, Wang Wang Lee, and
`Clive G. Wilson
`
`24. The Enterion Capsule
`David V. Prior, Alyson L. Connor, and Ian R. Wilding
`
`Part III: Ocular
`
`25. Ophthalmic Drug Delivery
`Bernard Plazonnet
`
`26.
`
`Ion Exchange Resin Technology for Ophthalmic Applications
`R. Jani and E. Rhone
`
`27. New Ophthalmic Delivery System (NODS)
`L. Sesha Rao
`
`xi
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`223
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`233
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`243
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`249
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`257
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`263
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`273
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`289
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`315
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`xii
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`28. Bioadhesive Ophthalmic Drug Inserts (BODI)
`Olivia Felt-Baeyens and R. Gurny
`
`Part IV: Oral Mucosal
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`Contents
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`341
`
`29. Oral Mucosal Drug Delivery
`Ian W. Kellaway, Gilles Ponchel, and D. Ducheˆne
`
`30. Slowly Disintegrating Buccal Mucoadhesive Plain-Tablet
`(S-DBMP-T) and Buccal Covered-Tablet System (BCTS)
`Katsumi Iga
`
`31. The Oral PowderJect Device for Mucosal Drug Delivery
`George Costigan and Brian John Bellhouse
`
`32. The Periochip
`Wilfred Aubrey Soskolne
`
`33. Polysaccharide-Based Mucoadhesive Buccal Tablets
`Hemant H. Alur, Ashim K. Mitra, and Thomas P. Johnston
`
`34. Medicated Chewing Gum
`Margrethe Rømer Rassing and Jette Jacobsen
`
`35.
`
`Immediate-Immediate Release (I2R) Lingual or Buccal Spray
`Formulations for Transmucosal Delivery of Drug Substances
`Harry A. Dugger III, Kenneth E. Cleaver, and Donald P. Cox
`
`36. Liquid Crystalline Phases of Glyceryl Mono-oleate as Oral
`Mucosal Drug Delivery Systems
`Jaehwi Lee and Ian W. Kellaway
`
`37. Microparticles as Delivery Systems for Local Delivery to the
`Oral Cavity
`Rita Cortesi, E. Menegatti, Claudio Nastruzzi, and Elisabetta
`Esposito
`
`38. OraVescent: A Novel Technology for the Transmucosal
`Delivery of Drugs
`S. Indiran Pather, Rajendra K. Khankari, and John M. Siebert
`
`349
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`365
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`381
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`391
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`401
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`419
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`431
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`447
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`453
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`Contents
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`Part V: Dermal and Transdermal
`
`39. Dermal and Transdermal Delivery
`Jonathan Hadgraft
`
`40. D-TRANS Technology
`Rama Padmanabhan, Robert M. Gale, J. Bradley Phipps,
`William W. van Osdol, and Wendy Young
`
`41. E-TRANS Technology
`J. Bradley Phipps, Rama Padmanabhan, Wendy Young, Rodney
`M. Panos and Anne E. Chester
`
`42. Microfabricated Microneedles for Transdermal Drug Delivery
`Mark R. Prausnitz, Donald E. Ackley, and J. Richard Gyory
`
`43. Metered-Dose Transdermal Spray (MDTS)
`Timothy M. Morgan, Barry L. Reed, and Barrie C. Finnin
`
`44. Transfersomes: Innovative Transdermal Drug Carriers
`Gregor Cevc
`
`45. Advances in Wound Healing
`Michael Walker
`
`46. Ultrasound-Mediated Transdermal Drug Delivery
`Samir Mitragotri and Joseph Kost
`
`47. SLN and Lipopearls for Topical Delivery of Active Compounds
`and Controlled Release
`Rainer Helmut Mu¨ller and Sylvia Wissing
`
`48. Macroflux Technology for Transdermal Delivery of Therapeutic
`Proteins and Vaccines
`Michel Cormier and Peter E. Daddona
`
`49. Needle-Free Drug Delivery
`Franklin Pass and John Hayes
`
`50. Dermal PowderJect Device
`Brian John Bellhouse and Mark A. F. Kendall
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`xiii
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`471
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`481
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`499
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`513
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`523
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`547
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`561
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`571
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`xiv
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`51.
`
`Intraject: Prefilled, Disposable, Needle-Free Injection of Liquid
`Drugs and Vaccines
`Adam Levy
`
`Part VI: Injections and Implants
`
`52.
`
`Implants and Injectables
`Franklin W. Okumu and Jeffrey L. Cleland
`
`53. Alzamer Depot Bioerodible Polymer Technology
`Jeremy C. Wright, Roy Bannister, Guohua Chen, and
`Catherine Lucas
`
`54. The Atrigel Drug Delivery System
`Richard Dunn
`
`55. Long-Term Controlled Delivery of Therapeutic Agents via an
`Implantable Osmotically Driven System: The DUROS Implant
`James C. Wright, Anne E. Chester, R. Skowronski, and
`Catherine Lucas
`
`56. Long-Acting Protein Formulations—ProLease Technology
`OluFunmi L. Johnson and Paul Herbert
`
`57. Sucrose Acetate Isobutyrate (SAIB) for Parenteral Delivery
`Arthur J. Tipton
`
`58. Stealth Technology
`Frank Martin and Tony Huang
`
`59. DepoFoam Technology
`Sankaram Mantripragada
`
`60. Medipad Delivery System: Controlled Macromolecule Delivery
`Izrail Tsals and Diana Davidson
`
`Part VII: Nasal
`
`61.
`
`Intranasal Drug Delivery
`Daniel P. Wermeling and Jodi L. Miller
`
`Contents
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`619
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`633
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`639
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`647
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`657
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`671
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`679
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`689
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`705
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`713
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`727
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`Contents
`
`62. Poly(ethylene oxide)-b-Poly(propylene oxide)-b-Poly(ethylene
`oxide)-g-Poly(acrylic acid) Copolymers as In Situ Gelling
`Vehicle for Nasal Delivery
`Lev Bromberg
`
`Part VIII: Vaginal
`
`63.
`
`Intravaginal Drug Delivery Technologies
`A. David Woolfson
`
`64. The Intravaginal Ring
`R. Karl Malcolm
`
`65. SupraVail Vaginal Gel
`Mathew Leigh
`
`66. VagiSite Bioadhesive Technology
`R. Saul Levinson and Daniel J. Thompson
`
`Part IX: Pulmonary
`
`67. Pulmonary Delivery of Drugs by Inhalation
`Igor Gonda and Jeff Schuster
`
`68. Aerogen Pulmonary Delivery Technology
`Paul S. Uster
`
`69. The AERx Pulmonary Drug Delivery System
`Jeff Schuster and S. J. Farr
`
`70. Formulation Challenges of Powders for the Delivery of Small
`Molecular Weight Molecules as Aerosols
`Anthony J. Hickey
`
`71. Nebulizer Technologies
`Martin Knoch and Warren Finlay
`
`72. The Pressurized Metered-Dose Inhaler
`Akwete L. Adjei
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`Copyright © 2003 Marcel Dekker, Inc.
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`749
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`759
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`775
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`791
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`801
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`807
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`817
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`825
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`xvi
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`Contents
`
`73. Passive Dry Powder Inhalation Technology
`Ian Ashurst and Ann Malton
`
`74. Formulation Challenges: Protein Powders for Inhalation
`Hak-Kim Chan
`
`75. The Development of Large Porous Particles for Inhalation
`Drug Delivery
`Richard Batycky, Daniel Deaver, Sarvajna Dwivedi, Jeffrey
`Hrkach, Lloyd Johnston, Tracy Olson, James E. Wright, and
`David Edwards
`
`76. Dry Powder Inhalation Systems from Inhale Therapeutic
`Systems
`Andy R. Clark
`
`77. Spiros Inhaler Technology
`Clyde Witham and Elaine Phillips
`
`78. The Respimat, a New Soft Mist Inhaler for Delivering Drugs to
`the Lungs
`Bernd Zierenberg and Joachim Eicher
`
`79. Regulatory Issues for Pulmonary Delivery Systems
`Darlene Rosario and Babatunde Otulana
`
`Part X: Regulatory
`
`80. Regulatory Issues Relating to Modified-Release Drug
`Formulations
`Patrick J. Marroum
`
`867
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`879
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`891
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`903
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`913
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`925
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`78
`The Respimat, a New Soft Mist
`Inhaler for Delivering Drugs
`to The Lungs
`
`Bernd Zierenberg
`Boehringer Ingelheim Pharma KG, Ingelheim, Germany
`
`Joachim Eicher
`Steag microParts, Dortmund, Germany
`
`I.
`
`INTRODUCTION
`
`The inhalation of drugs provides the most direct noninvasive route either for
`treating respiratory disorders topically or for administering drugs systematically.
`To ensure that the drug reaches the lungs, it must be administered as an aerosol.
`This means that the required amount of drug per application consists of drug
`particles, either solid or liquid droplets in a size range of 1–5 μm, which are
`inhaled by the patient. In the past, pressurized metered-dose inhalers (pMDIs)
`have been popular devices for generating inhalable aerosols. These devices de-
`pend on chemical propellants to generate an aerosol from a drug solution or
`suspension; however, their future is now uncertain.
`Early pMDIs containing chlorofluorocarbon (CFC) propellants are cur-
`rently being phased out, and there are also concerns over the global warming
`potential of alternative propellants such as hydrofluoroalkanes, developed to re-
`place CFCs. Efforts to develop alternative devices include various dry powder
`inhalers but these have their own shortcomings, as described by Ganderton [1].
`There is therefore an urgent need for a convenient propellant-free inhaler device
`to deliver aerosols from solutions.
`This chapter describes the setup, development, and performance data of
`Respimat® (Boehringer Ingelheim, Ingelheim am Rhein, Germany), a novel soft
`
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`926
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`Zierenberg and Eicher
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`mist inhaler, designed to substitute for pMDIs, to improve their existing perfor-
`mance, and to broaden the possibility of delivering drugs via the lungs.
`
`II. GENERAL TECHNICAL APPROACHES FOR SOFT MIST
`INHALERS AND RESPIMAT
`
`The generation of an inhalable aerosol from a drug solution requires that the bulk
`liquid be dosed and then converted into appropriately sized droplets. There are
`several technically feasible methods for achieving the aerosolization of a drug
`solution in a pocket-sized device. These methods (e.g., piezoelectric effect [2],
`extrusion through micron-sized holes [3], electrohydrodynamic effect [4]) require
`either electric energy from a battery or mechanical energy to produce the aerosol.
`In any case, the energy has to be focused in an intelligent way for the aerosoliza-
`tion process. This is necessary to ensure that the applied energy is transformed
`into droplet-generating energy in a sufficiently efficient manner. In the case of
`Respimat, the technical breakthrough is based on the approach of forcing drug
`solution through a two-channel nozzle [5]. During this process the solution is
`accelerated and split into two converging jets. By impaction of the jets, which
`converge at a carefully controlled angle, the drug solution disintegrates into inha-
`lable droplets. This new patented procedure of aerosolizing a liquid requires only
`a small amount of mechanical energy, which is easily generated by the hand of
`the patient. Additionally, this approach has no need for a battery, which would
`increase costs and the need for maintenance by the patient.
`
`III. DEVELOPMENT OF RESPIMAT
`
`The concept was demonstrated in a laboratory model, consisting of a metal body
`with a syringe as a solution reservoir (Fig. 1), and was shown to function cor-
`rectly. The device was operated by means of a lever arm, which simultaneously
`tightened the mainspring and withdrew a metered volume of drug solution of
`about 13.5 μL from the reservoir. Pressing a button released the spring, forcing
`the metered dose through the channels as liquid jets that impact 25 μm from the
`nozzle outlet to produce the aerosol. A feasibility study using an aqueous drug
`solution of a β2-agonist showed that the droplet size distribution in the aerosol
`was in the range suitable for inhalation; the majority of the particle mass was in
`the size range 1–5 μm.
`In this first model, the nozzle openings were tiny holes pierced into a stain-
`less steel disk; however, a nozzle design better suited for mass production was
`needed. This was achieved by developing a miniature “sandwich” concept, the
`
`Copyright © 2003 Marcel Dekker, Inc.
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`The Respimat
`
`927
`
`Figure 1 Laboratory model for demonstrating correct functioning of the concept. (See
`color insert.)
`
`uniblock, consisting of a rectangle (2 ⫻ 2.5 mm) cut from a glass plate bonded
`to a silicon wafer. By use of photolithographic techniques adapted from the mi-
`croelectronics industry, multiple copies of the uniblock, each comprising filter
`structures as well as inlet and outlet channels (Fig. 2), are etched into the silicon
`wafer with high precision and accuracy. Currently, the accuracy of the photolitho-
`graphic exposure process is better than 0.1 μm over a single uniblock bearing
`the etched nozzle microstructure.
`Further development of this first model included exchanging all metal parts
`for components made from polymers whenever possible and adapting all parts
`of the device for mass production. In addition, the torque required for loading
`the dose was minimized (approximately 40 cNm) so that the energy needed to
`generate the aerosol could be easily produced by hand. After initial stability and
`technical performance tests, the device was successfully used in the first lung
`deposition study, in comparison with a pMDI containing CFCs, carried out on
`healthy volunteers.
`
`Copyright © 2003 Marcel Dekker, Inc.
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`Liquidia's Exhibit 1069
`Page 17
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`Figure 2 Schematic drawing of the uniblock. (From Ref. [5].) (See color insert.)
`
`The experience accumulated with the various prototypes (I–IV) and the
`need to make a functional practical device with a smaller number of individual
`components were combined with the results of device-handling studies, in which
`patients evaluated the four different design concepts. The resultant device, Proto-
`type IV, incorporated a radical change in design. Compared to the prototype I
`design, which released the dose at an angle of 90° relative to the device exit (i.e.,
`the mouthpiece was at right angles to the drug cartridge), the final design released
`the dose in a direction parallel to the exit. This parallel version (Fig. 3) is currently
`being tested in clinical phase II and phase III studies.
`
`Figure 3 Prototype IV of Respimat used in clinical trials. (From Ref. [5].) (See color
`insert.)
`
`Copyright © 2003 Marcel Dekker, Inc.
`
`Liquidia's Exhibit 1069
`Page 18
`
`

`

`The Respimat
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`929
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`IV. MODE OF ACTION OF RESPIMAT
`
`The principal parts of Respimat are shown in a schematic diagram (Fig. 4). To
`use the device, the patient removes the bottom case, inserts the cartridge con-
`taining the drug solution, and replaces the case. The cartridge is now connected
`by a capillary tube (containing a nonreturn valve) to the uniblock. To load a dose,
`the patient simply turns the lower half of the device through 180°. The helical
`can transforms the rotation into a linear movement, which tightens the spring
`and moves the capillary with the nonreturn valve to a defined lower position.
`During this movement, the drug solution is drawn through the capillary into a
`pump chamber as shown in Figure 4. When the patient presses the release button
`to actuate the device, the mechanical power from the spring pushes the capillary
`with the now closed nonreturn valve to the upper position. This operation drives
`the metered volume of drug solution (about 13.5 μL) through the nozzle in the
`
`Figure 4 Schematic drawing of the key elements of Respimat. (From Ref. [5].) (See
`color insert.)
`
`Copyright © 2003 Marcel Dekker, Inc.
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`Liquidia's Exhibit 1069
`Page 19
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`Zierenberg and Eicher
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`uniblock. Here the two fine jets of liquid are produced at the outlet of the uni-
`block, which converge at a carefully controlled angle. The resulting impact of
`the two jets of liquid generates a slow-moving aerosol cloud, or soft mist. When
`a cartridge is inserted for the first time, the device has to be primed to expel air
`from its inner parts. The device is then ready for use.
`
`V. RESPIMAT PERFORMANCE DATA
`
`A. Technical Performance Data
`
`Respimat is an active system, which means that the aerosol is generated by a
`constantly available and consistent energy source and that its quality in terms of
`dose and particle size distribution is independent of both the patient’s inspiratory
`flow and ambient conditions. Water, ethanol, or a mixture of both can be used
`as a solvent for formulating the drug solution. Aqueous drug solutions also con-
`tain the two excipients benzalkonium chloride and EDTA as preservatives.
`
`Figure 5 Particle size distribution for aerosols generated by Respimat using (A) aqueous
`drug solution (β2-agonist) and (B) ethanolic solution (steroid). (From Ref. [5].) (See color
`insert.)
`
`Copyright © 2003 Marcel Dekker, Inc.
`
`Liquidia's Exhibit 1069
`Page 20
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`The Respimat
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`931
`
`The fine-particle fraction, defined as the mass percentage of the aerosol
`consisting of particles smaller than 5.8 μm, is higher for an ethanolic formulation
`than for an aqueous formulation generated by the Respimat. Figure 5 shows typ-
`ical examples of the particle size distribution of aqueous and ethanolic solu-
`tions measured in an Anderson Cascade Impactor (Anderson Instruments, Inc.,
`Smyrna, GA). The fine-particle fraction amounts to approximately 66% for the
`aqueous drug solution (β2-agonist) and 81% for the ethanolic drug solution (corti-
`costeroid). These values are 2.5 times higher than the corresponding values for
`aerosols produced by chlorofluorocarbon pMDIs. This particle size distribution
`can also be described in terms of a mass median aerodynamic diameter value.
`The mass median aerodynamic diameter values with Respimat were 2.0 ⫾ 0.4
`μm for the aqueous solution and 1.0 ⫾ 0.3 μm for the ethanolic solution, both
`of which were determined by measurements with an Anderson Cascade Impactor
`conducted at a temperature of 22°C ⫾ 2°C and a relative humidity of 50 ⫾ 10%.
`The velocity of the aerosol output generates a relatively long duration of
`dose release by Respimat (approximately 1.2 and 1.6 s for aqueous and ethanolic
`solutions, respectively), which should facilitate maximal inhalation of the dose,
`allowing the patient time to inhale after pressing the dose-release button, in con-
`trast to the critical need to coordinate actuation and inspiration that is required
`during the use of pMDIs. In addition, the soft mist produces a perceptible taste
`or sensation, providing appropriate feedback to indicate that the dose has been
`released in contrast to findings with some powder inhalers.
`
`B. Clinical Performance Data
`
`The in vitro performance data of the aerosol produced by Respimat led to the
`hypothesis that the delivery of drugs to the lungs is improved compared to the
`existing treatment with pMDIs. This hypothesis was tested in several scinti-
`graphic deposition studies carried out in volunteers and patients. In these studies
`the radionuclide 99mTc is added to the formulation so that it forms a physical
`association with the micronized drug particles in a suspension formulation (e.g.,
`of a pMDI) or is incorporated into the droplets of a solution formulation. The
`topographical deposition of the aerosol in the lungs is visualized using a gamma
`camera and quantified in terms of the percentage of lung or oropharyngeal deposi-
`tion with reference to the metered dose. A survey of the numerical results ob-
`tained for pMDIs, dry powder inhalers, and Respimat with this type of investiga-
`tion is reported by Newman [6]. In summary, the deposition data show that the
`soft mist generated by Respimat, both from an aqueous solution with the drug
`fenoterol and from an ethanolic solution with the drug flunisolide, results in a two-
`to threefold increase in lung deposition compared to the corresponding pMDI.
`In parallel, the oropharyngeal deposition is significantly reduced for the aerosol
`administered by Respimat.
`
`Copyright © 2003 Marcel Dekker, Inc.
`
`Liquidia's Exhibit 1069
`Page 21
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`Finally, the ratio of deposition in peripheral regions to deposition in the
`central lung zone is similar for Respimat and a pMDI. The increased drug delivery
`to the lungs from Respimat measured with the gamma scintigraphy technique
`suggests that clinically comparable therapeutic responses should be achievable
`with lower doses administered to patients from Respimat compared to a pMDI.
`In two clinical studies for aqueous drug solutions with fenoterol (Berotec®)
`and the combination of fenoterol/ipratropium bromide (Berodual®), this expected
`result was confirmed. For Berotec, 12.5 and 25 μg administered by Respimat
`were therapeutically equivalent to either 100 or 200 μg administered via pMDI
`[7]. For Berodual, the bronchodilatory effects of 25/10 or 50/20 μg (fenoterol/
`ipratropium bromide) doses administered via Respimat were equal or slightly
`superior to the recommended dose of 100/40 μg given via pMDI [8]. These
`results suggest that the improved lung deposition observed with Respimat allows
`lower absolute doses to be administered for a similar clinical effect in the local
`treatment of lung diseases. Additionally Respimat’s high performance may result
`in a more efficient systemic delivery of drugs via the lungs.
`
`VI. CONCLUSIONS
`
`Demonstrating a new approach to inhalation therapy, Respimat, a propellant-free
`inhaler with a novel patented mechanism of generating a soft mist from a dosed
`volume of a drug solution, shows distinct advantages over contemporary inhaler
`devices. Like many other inhalers Respimat delivers multiple doses of an aerosol;
`however, Respimat does this actively without the use of propellants. Respimat
`simply uses mechanical energy that is easily produced by the patient before each
`administration. The soft mist demonstrates improved particle characteristics com-
`pared to existing inhalers, especi