INTRAOCULAR
`DRUG
`DELIVERY
`
`edited by
`Glenn J. Jaffe
` Duke University
`Durham, North Carolina, U.S.A.
`Paul Ashton
`Control Delivery Systems,
`Watertown, Massachusetts, U.S.A.
`P. Andrew Pearson
`University of Kentucky,
`Lexington, Kentucky, U.S.A.
`
`DK3489_FM.indd 2
`
`2/1/06 9:57:14 AM
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`DK3489_Discl.fm Page 1 Wednesday, January 11, 2006 1:14 PM
`
`Published in 2006 by
`Taylor & Francis Group
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`© 2006 by Taylor & Francis Group, LLC
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`No claim to original U.S. Government works
`Printed in the United States of America on acid-free paper
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`International Standard Book Number-10: 0-8247-2860-2 (Hardcover)
`International Standard Book Number-13: 978-0-8247-2860-1 (Hardcover)
`Library of Congress Card Number 2005046669
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`This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with
`permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish
`reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials
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`
`Library of Congress Cataloging-in-Publication Data
`
`Intraocular drug delivery / edited by Glenn J. Jaffe, Paul Ashton, Andrew Pearson.
`p. ; cm.
`Includes bibliographical references and index.
`ISBN-13: 978-0-8247-2860-1 (alk. paper)
`ISBN-10: 0-8247-2860-2 (alk. paper)
`1. Ocular pharmacology. 2. Drug delivery systems. 3. Therapeutics, Opthalmological. I. Jaffe, Glenn J.
`II. Ashton, Paul, 1960- III. Pearson, Andre, 1961-
`[DNLM: 1. Drug Delivery Systems. 2. Drug Administration Routes. 3. Eye Diseases--drug therapy. WB
`340 I61 2005]
`
`RE994.I62 2005
`617.7’061--dc22
`
`2005046669
`
`Taylor & Francis Group
`is the Academic Division of Informa plc.
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`Preface
`
`The development of drug treatments for diseases of the retina and back of the eye has
`been slow. Among the principal causes for this have been a failure of the pharma-
`ceutical industry to appreciate the potential size of the market these diseases repre-
`sent, a poor understanding of the disease processes themselves, and technical
`difficulty in delivering drugs to the back of the eye. There have been recent rapid
`advances in all three areas with many more changes likely to occur in the next decade.
`Until the 1990s, very few drugs had ever been developed specifically for
`ophthalmology. Virtually all drugs used in ophthalmology had initially been devel-
`oped for other applications and subsequently found to be useful in ophthalmology.
`One potential reason for this is economics. In 2001 it was estimated that it took over
`12 years and cost over $800 million to develop and commercialize a new drug (1).
`For a company to undertake such an investment there must be a reasonable expecta-
`tion that eventually sales of a new drug will, after allowing for development risk, at
`least recoupe its development costs. In 1996 the total world market for drugs for
`back-of-the-eye diseases was less than $500 million, providing little impetus to
`develop drugs for these conditions.
`A major contributor to both the cost and the time it takes to develop a drug is
`the regulatory approval process. Following animal experiments, drugs enter limited
`clinical trials that often involve very few patients. These early studies, often called
`Phase I or Phase I/II trials, are generally designed to get a preliminary indication
`of safety and possibly efficacy while exposing as few subjects to the drug as possible.
`Once these studies have been successfully completed, a product can proceed to
`larger, Phase II trials. The goal of these larger trials, often involving 50 to 100 people,
`is to generate sufficient efficacy data to adequately power the next, Phase III, studies.
`It is these studies, sometimes called pivotal trials, that are designed to provide suffi-
`cient data to satisfy the regulatory agencies that a product is both safe and effective.
`Data collected in Phase II is generally used to ensure pivotal studies are appropriately
`designed and have sufficient statistical power to meet these objectives. These larger
`trials involve hundreds to thousands of patients. In clinical trials of an agent to treat
`a previously untreated disease it can be difficult to decide on the primary clinical trial
`endpoint to demonstrate drug efficacy. This is particularly true for diseases that are
`slowly progressing, where a clinically significant progression of the disease can take
`years. Any drug therapy designed to slow down the progression of such a disease is
`likely to require very long term clinical trials, increasing the time, the cost and the risk
`of developing a drug. Diseases in this group include diabetic retinopathy, neovascular
`and non-neovascular age-related macular degeneration, retinitis pigmentosa and
`
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`iv
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`Preface
`
`others. For a company developing a drug to treat these conditions, while risks from
`competitors are always present, they become magnified in the face of very long-term
`and expensive clinical trials. As a trial progresses, science advances and a competitor
`may develop a better drug or a more creative way through the regulatory system.
`The difficulty of the Food and Drug Administration’s (FDA’s) task in approv-
`ing drugs, especially for previously untreated diseases, should not be underestimated.
`Considerable pressure is exerted on the FDA to both approve drugs quickly and to
`ensure drugs meet the appropriate standards of safety and efficacy. The FDA is in a
`difficult position. If after approval significant side effects are encountered, the FDA
`is likely deemed to be at fault. On the other hand, if a drug is not approved quickly,
`the FDA is likely deemed to be at fault. The voices decrying the ‘‘glacial’’ pace of
`drug approval are often the same ones decrying the ‘‘cavalier attitude’’ of the
`FDA should a drug be withdrawn. Despite these pressures, the FDA can move extre-
`mely quickly to approve new drug treatments. Although it takes an average of 12
`years for a drug to be developed, Vitrasert1, a sustained release delivery device
`to treat AIDS associated cytomegalovirus retinitis, progressed from in vitro tests
`to FDA approval in eight years. The total development time for Rertisert1, which
`recently became the first drug treatment approved for uveitis, was seven years. Both
`of these products were supported initially by grants from the National Eye Institute
`and without such support, the industry has rarely funded the development of such
`high-risk programs. For major pharmaceutical companies the risks of developing
`drugs for well understood diseases are high enough. Add to these risks an unknown
`market size, unfamiliar regulatory approval process, new drug delivery requirements
`and novel pharmacological drug targets, and the process becomes truly daunting.
`‘‘Big Pharma’’ has not perceived the opthalmic marketplace as large enough to sup-
`port a fully-fledged development effort. Pharmaceutical development has instead
`been largely limited to smaller, so-called ‘‘specialty’’ pharmaceutical companies.
`A turning point in ophthalmology came with the approval of Latanaprost, a
`prostaglandin analogue. This molecule was developed specifically for glaucoma and
`has been commercially extremely successful, generating over $1 billion per year in
`sales in 2003 (2). This appears to have triggered the realization that ophthalmology
`has the potential to support billion dollar products and has lead to an increased focus
`on the area by the pharmaceutical industry.
`In recent years there has been a dramatic increase in the understanding of the
`pathologies of ocular diseases and, perhaps not coincidentally, many new therapeu-
`tic candidates and pharmacological treatments. Unlike such mature fields as hyper-
`tension, there is as yet no clear consensus of the pharmacological targets best hit to
`generate an optimal therapeutic response. Not only are there now a large number of
`drugs under development but there are also a large number of different classes of
`drugs in development. Into the mix of increased commercial focus and rapidly
`advancing biology there is also the rapidly evolving field of drug delivery for the pos-
`terior segment of the eye. This state of high flux is exemplified by the three treat-
`ments for wet age-related macular degeneration that are either approved or
`awaiting approval. The first approved, Visudyne1,
`is an intravenous injection
`followed by an ocular laser to activate the drug in the eye. In 2005 it was followed
`by Macugen1, a vascular endothelial growth factor (VEGF) inhibitor, given by
`intravitreal injections every six weeks. RetaaneTM is pending approval and is an
`angiostatic steroid given as a peri-ocular injection every six months. All three of
`these treatments have completely different modes of action and completely different
`means of administration.
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`Preface
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`v
`
`This book is a snap shot in time. In it the contributors have attempted to
`describe some of the parameters influencing drug delivery and some of the attempts
`made, with varying degrees of success, to achieve therapeutic drug concentrations in
`the posterior of the eye. Also described are disease states of the back of the eye, some
`of which, like wet age-related macular degeneration, affect many people. Following
`the approval of Visudyne and Macugen, one could expect rapid changes in clinical
`management of these diseases. Other conditions, like retinitis pigmentosa, are very
`slowly progressing (making the design of clinical trials extremely difficult) or else
`affect only a small number of people, such as proliferative vitreoretinopathy (PVR).
`For these conditions there is as yet no precedent with the FDA for what constitutes
`an approvable drug. Progress in the management of such conditions is unfortunately
`likely to be much slower.
`
`Glenn J. Jaffe
`Paul Ashton
`P. Andrew Pearson
`
`REFERENCES
`
`1. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation. New estimates of drug
`development costs. J Health Econ 2003; 22:151–185.
`2. Form 10-K. SEC. Pfizer Annual Report Year End December 31, 2003.
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`Contents
`
`iii
`Preface . . . .
`Contributors . . . . xiii
`
`PART I: GENERAL
`1. Retinal Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
`Paul Ashton
`Basic Principles of Drug Delivery . . . . 1
`Drug Delivery to the Posterior Segment of the Eye . . . . 8
`Drug Elimination Mechanisms . . . . 12
`Posterior Delivery in Disease States . . . . 14
`Photodynamic Therapy . . . . 18
`Future Opportunities and Challenges . . . . 19
`References . . . . 19
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
`2. Blood–Retinal Barrier
`David A. Antonetti, Thomas W. Gardner, and Alistair J. Barber
`Introduction . . . . 27
`Function of the Blood–Retinal Barrier . . . . 27
`Formation of the Blood–Neural Barrier . . . . 28
`Ocular Disease and Loss of the Blood–Retinal Barrier . . . . 29
`Molecular Architecture of the Blood–Retinal Barrier . . . . 30
`Claudins . . . . 30
`Occludin . . . . 31
`Restoring Barrier Properties . . . . 33
`References . . . . 34
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
`3. Neuroprotection
`Dennis W. Rickman and Melissa J. Mahoney
`Introduction . . . . 41
`Excitotoxicity as a Stimulus for Neuronal Cell Death . . . . 41
`Intracellular Effectors of Cell Death . . . . 43
`Oxidative Stress and the Generation of Free Radicals . . . . 45
`Neurotrophins and Neurotrophin Deprivation as a Stimulus
`for Retinal Cell Death . . . . 46
`
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`viii
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`Neurotrophins Support the Development and Maintenance
`of Retinal Ganglion Cells . . . . 46
`Neurotrophins Support the Development of Inner Retinal
`Circuitry . . . . 47
`Models of Photoreceptor Degeneration and Strategies
`for Their Treatment . . . . 47
`Neurotrophin Delivery to CNS Tissue . . . . 48
`Summary . . . . 50
`References . . . . 51
`
`4. Regulatory Issues in Drug Delivery to the Eye
`Lewis J. Gryziewicz and Scott M. Whitcup
`Introduction . . . . 59
`Drug Development in the United States . . . . 60
`References . . . . 69
`
`. . . . . . . . . . . . . . . . 59
`
`PART II: SPECIFIC DELIVERY SYSTEMS
`5. Antiangiogenic Agents: Intravitreal Injection
`Sophie J. Bakri and Peter K. Kaiser
`Introduction . . . . 71
`Intravitreal Injection . . . . 72
`Technique for Intravitreal Injection . . . . 72
`VEGF . . . . 73
`References . . . . 81
`
`. . . . . . . . . . . . . . . . . 71
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
`
`6. Intravitreal Antimicrobials
`Travis A. Meredith
`Introduction . . . . 85
`Basic Pharmacokinetics . . . . 85
`Intravitreal Injections . . . . 87
`Therapeutic Concentration Range . . . . 89
`Toxicity . . . . 89
`Characteristics of Selected Antimicrobials . . . . 91
`References . . . . 93
`
`7. Pharmacologic Retinal Reattachment with INS37217 (Denufosol
`Tetrasodium), a Nucleotide P2Y2 Receptor Agonist . . . . . . . . . . . . . 97
`Ward M. Peterson
`Description of Drug Delivery System . . . . 97
`Spectrum of Diseases . . . . 97
`Mechanism of Action . . . . 99
`Animal Models of Disease Used . . . . 100
`Results of Animal Model Studies . . . . 101
`Drug Delivery and Distribution . . . . 105
`Clinical Study . . . . 107
`Future Horizons . . . . 108
`References . . . . 109
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`ix
`
`8. Cell-Based Delivery Systems: Development of Encapsulated Cell
`. . . . . . . . . . . . . . . . . . . 111
`Technology for Ophthalmic Applications
`Weng Tao, Rong Wen, Alan Laties, and Gustavo D. Aguirre
`Description of Encapsulated Cell Technology . . . . 111
`Spectrum of Diseases for Which This Delivery System
`Might Be Appropriate . . . . 116
`Animal Models Used to Investigate the Applicability
`of this Delivery System for the Diseases Mentioned . . . . 118
`Pharmacokinetic and Pharmacodynamic Studies
`Using the Delivery System . . . . 120
`Results of Animal Model Studies . . . . 120
`Techniques for Implanting or Placing the Implant in
`Humans . . . . 124
`Future Horizons . . . . 126
`References . . . . 126
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
`9. Photodynamic Therapy
`Ivana K. Kim and Joan W. Miller
`Introduction . . . . 129
`Preclinical Studies of Verteporfin for Experimental CNV . . . . 130
`Other Photosensitizers . . . . 136
`Future Directions . . . . 137
`References . . . . 139
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . 143
`10. Thermal-Sensitive Liposomes
`Sanjay Asrani, Morton F. Goldberg, and Ran Zeimer
`Introduction . . . . 143
`Methodology of Laser-Targeted Drug Delivery . . . . 144
`Potential Therapeutic Applications of LTD . . . . 147
`Diagnostic Applications . . . . 149
`Safety of Light-Targeted Drug Delivery . . . . 152
`Limitations . . . . 153
`Conclusion . . . . 153
`Disclosure of Financial Interest . . . . 154
`References . . . . 154
`
`11. Gene Therapy for Retinal Disease . . . . . . . . . . . . . . . . . . . . . . . 157
`Albert M. Maguire and Jean Bennett
`Description of Drug Delivery System . . . . 157
`Spectrum of Diseases for Which This Delivery System
`Might Be Appropriate . . . . 160
`Animal Models Used to Investigate the Applicability of This
`Delivery System for the Diseases Mentioned Above . . . . 162
`Pharmacokinetic Studies Using the Delivery System . . . . 163
`Results of Animal Model Studies . . . . 163
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`Contents
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`Techniques for Implanting or Placing the Implant
`in Humans (If Done) . . . . 167
`Future Horizons . . . . 168
`References . . . . 169
`
`12. Biodegradable Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
`Hideya Kimura and Yuichiro Ogura
`Fundamentals of Biodegradable Polymeric Devices . . . . 175
`Spectrum of Diseases for Which Biodegradable Systems
`May Be Useful
`. . . . 179
`Animal Models Used to Test Biodegradable Drug
`Delivery Systems . . . . 180
`Results of Efficacy Studies . . . . 181
`Pharmacokinetic and Pharmacodynamic Studies . . . . 183
`Summary and Future Horizons . . . . 189
`References . . . . 189
`
`13. Transscleral Drug Delivery to the Retina and Choroid . . . . . . . . . 193
`Jayakrishna Ambati
`Introduction . . . . 193
`Scleral Anatomy . . . . 193
`In Vitro Studies of Scleral Permeability . . . . 194
`In Vivo Studies of Scleral Permeability . . . . 196
`Future Directions . . . . 198
`References . . . . 199
`
`14. Nondegradable Intraocular Sustained-Release Drug
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
`Delivery Devices
`Mark T. Cahill and Glenn J. Jaffe
`Implanted Nondegradable Sustained-Release Devices . . . . 203
`Implanted Microdialysis Probes as Sustained-Release
`Drug Delivery Systems . . . . 216
`Microelectromechanical Systems Drug Delivery Devices . . . . 219
`References . . . . 222
`
`PART III: LOCAL DRUG DELIVERY APPROACH TO SPECIFIC
`CLINICAL DISEASES
`
`15. Photodynamic Therapy in Human Clinical Studies: Age-Related
`Macular Degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
`Ivana K. Kim and Joan W. Miller
`Introduction . . . . 227
`Phase I/II Design and Methodology . . . . 227
`Phase I/II Results . . . . 231
`Phase III Design/Methodology . . . . 234
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`Contents
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`xi
`
`Conclusions . . . . 244
`References . . . . 245
`
`. . . . . . . . . . . 249
`16. Age-Related Macular Degeneration Drug Delivery
`Kourous A. Rezaei, Sophie J. Bakri, and Peter K. Kaiser
`Treatment Modalities for Neovascular AMD . . . . 249
`Clinical Trials of Drug Delivery Devices for the Treatment of
`Neovascular AMD . . . . 250
`References . . . . 259
`
`17. Intraocular Sustained-Release Drug Delivery in Uveitis
`Mark T. Cahill and Glenn J. Jaffe
`Introduction . . . . 265
`Corticosteroid Devices . . . . 266
`Cyclosporine Devices . . . . 275
`Conclusions . . . . 276
`References . . . . 277
`
`. . . . . . . . 265
`
`18. Drug Delivery for Proliferative Vitreoretinopathy: Prevention
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
`and Treatment
`Stephen J. Phillips and Glenn J. Jaffe
`Retinal Detachment/Proliferative Vitreoretinopathy . . . . 279
`Systemic . . . . 282
`Local Delivery . . . . 283
`Direct Injection—Subconjunctival or Intravitreal
`Sustained Delivery and Co-Drugs . . . . 286
`References . . . . 287
`
`. . . . 283
`
`19. Pharmacologic Treatment in Diabetic Macular Edema . . . . . . . . . 291
`Zeshan A. Rana and P. Andrew Pearson
`Introduction . . . . 291
`Treatment . . . . 292
`Corticosteroids . . . . 292
`Intravitreal Triamcinolone Acetonide (Kenalog) Injection . . . . 293
`Intravitreal Fluocinolone Acetonide Implant (Retisert) . . . . 294
`Dexamethasone Implant (Posurdex1) . . . . 295
`Protein Kinase C Inhibition . . . . 296
`VEGF Inhibition . . . . 297
`New Agents on the Horizon . . . . 297
`References . . . . 298
`
`20. Retinal Vein Occlusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
`Michael M. Altaweel and Michael S. Ip
`Local Drug Delivery Approach: Retinal Vein Occlusion . . . . 301
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`xii
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`Contents
`
`Other Treatments . . . . 309
`Summary . . . . 319
`References . . . . 320
`
`21. Cytomegalovirus Retinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
`Caroline R. Baumal
`Introduction . . . . 325
`Virology and Epidemiology of CMV Infection . . . . 325
`CMV Retinitis in the Era of HAART . . . . 327
`Clinical Features of CMV Retinitis . . . . 328
`Diagnosis of CMV Retinitis . . . . 330
`Treatment of CMV Retinitis . . . . 330
`Systemic Anti-CMV Therapy . . . . 331
`Local Modes of Intraocular Drug Delivery . . . . 333
`Intravitreal Drug Injection . . . . 334
`The Ganciclovir Intraocular Implant . . . . 335
`Indications for the Ganciclovir Implant . . . . 339
`Replacement of the Ganciclovir Implant . . . . 340
`Complications of the Ganciclovir Implant . . . . 341
`Summary . . . . 342
`References . . . . 343
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
`22. Endophthalmitis
`Travis A. Meredith
`Overview . . . . 349
`Presentation . . . . 349
`Predisposing Factors . . . . 349
`Bacterial Spectrum . . . . 350
`Antimicrobial Therapy . . . . 350
`Injection of Intraocular Corticosteroids . . . . 352
`Prognosis . . . . 353
`Summary . . . . 353
`References . . . . 353
`
`Index . . . . 357
`
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`Contributors
`
`James A. Baker Institute for Animal Health, College of
`Gustavo D. Aguirre
`Veterinary Medicine, Cornell University, Ithaca, New York, U.S.A.
`
`Michael M. Altaweel Department of Ophthalmology and Visual Sciences,
`University of Wisconsin-Madison Medical School, Madison, Wisconsin, U.S.A.
`
`Jayakrishna Ambati Department of Ophthalmology and Visual Sciences and
`Physiology, University of Kentucky, Lexington, Kentucky, U.S.A.
`
`David A. Antonetti Departments of Cellular and Molecular Physiology and
`Ophthalmology, Penn State College of Medicine, Hershey, Pennsylvania, U.S.A.
`
`Paul Ashton Control Delivery Systems, Watertown, Massachusetts, U.S.A.
`
`Sanjay Asrani Duke University Eye Center, Durham, North Carolina, U.S.A.
`
`Sophie J. Bakri The Cole Eye Institute, Cleveland Clinic Foundation, Cleveland,
`Ohio, U.S.A.
`
`Alistair J. Barber Department of Ophthalmology, Penn State College of Medicine,
`Hershey, Pennsylvania, U.S.A.
`
`Caroline R. Baumal Department of Ophthalmology, Vitreoretinal Service,
`New England Eye Center, Tufts University School of Medicine, Boston,
`Massachusetts, U.S.A.
`
`Jean Bennett F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye
`Institute, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.
`
`Mark T. Cahill Duke University Eye Center, Durham, North Carolina, U.S.A.
`
`Thomas W. Gardner Departments of Cellular and Molecular Physiology and
`Ophthalmology, Penn State College of Medicine, Hershey, Pennsylvania, U.S.A.
`
`Morton F. Goldberg Wilmer Ophthalmological Institute, Johns Hopkins
`University, Baltimore, Maryland, U.S.A.
`
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`xiv
`
`Contributors
`
`Lewis J. Gryziewicz Regulatory Affairs, Allergan, Irvine, California, U.S.A.
`
`Michael S. Ip Department of Ophthalmology and Visual Sciences, University of
`Wisconsin-Madison Medical School, Madison, Wisconsin, U.S.A.
`
`Glenn J. Jaffe Duke University Eye Center, Durham, North Carolina, U.S.A.
`
`Peter K. Kaiser The Cole Eye Institute, Cleveland Clinic Foundation, Cleveland,
`Ohio, U.S.A.
`
`Ivana K. Kim Department of Ophthalmology, Harvard Medical School,
`Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, U.S.A.
`
`Hideya Kimura Nagata Eye Clinic, Nara, Japan
`
`Alan Laties Department of Ophthalmology, University of Pennsylvania School
`of Medicine, Philadelphia, Pennsylvania, U.S.A.
`
`Albert M. Maguire F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye
`Institute, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.
`
`Melissa J. Mahoney Departments of Ophthalmology and Neurobiology, Duke
`University Medical Center, Durham, North Carolina, U.S.A.
`
`Travis A. Meredith Department of Ophthalmology, University of North Carolina,
`Chapel Hill, North Carolina, U.S.A.
`
`Joan W. Miller Department of Ophthalmology, Harvard Medical School,
`Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, U.S.A.
`
`Yuichiro Ogura Ophthalmology and Visual Science, Nagoya City University
`Graduate School of Medical Science, Nagoya, Aichi, Japan
`
`P. Andrew Pearson Department of Ophthalmology and Visual Science,
`Kentucky Clinic, Lexington, Kentucky, U.S.A.
`
`Ward M. Peterson Department of Biology, Inspire Pharmaceuticals, Durham,
`North Carolina, U.S.A.
`
`Stephen J. Phillips Duke University Eye Center, Durham, North Carolina, U.S.A.
`
`Zeshan A. Rana Department of Ophthalmology and Visual Science,
`Kentucky Clinic, Lexington, Kentucky, U.S.A.
`
`Kourous A. Rezaei Department of Ophthalmology, Rush University Medical
`Center, University of Chicago, Chicago, Illinois, U.S.A.
`
`Dennis W. Rickman Departments of Ophthalmology and Neurobiology, Duke
`University Medical Center, Durham, North Carolina, U.S.A.
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`Contributors
`
`xv
`
`Weng Tao Neurotech USA, Lincoln, Rhode Island, U.S.A.
`
`Rong Wen Department of Ophthalmology, University of Pennsylvania School of
`Medicine, Philadelphia, Pennsylvania, U.S.A.
`
`Scott M. Whitcup Research and Development, Allergan, Irvine and Department of
`Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine at
`UCLA, Los Angeles, California, U.S.A.
`
`Ran Zeimer Wilmer Ophthalmological Institute, Johns Hopkins University,
`Baltimore, Maryland, U.S.A.
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`PART I: GENERAL
`
`1R
`
`etinal Drug Delivery
`
`Paul Ashton
`Control Delivery Systems, Watertown, Massachusetts, U.S.A.
`
`In any drug treatment, the overall goal of drug delivery is to achieve and maintain
`therapeutic concentrations of the drug at its site of action for sufficient time to pro-
`duce a beneficial effect. A secondary aim is to avoid exposing any other tissues to
`concentrations of the agent high enough to cause a deleterious effect. The efficacy
`of a compound is governed by its intrinsic effects on the target site (and any other
`sites with which it comes into contact), its distribution throughout and its elimina-
`tion from the body. Alterations to the and elimination of a compound can thus
`radically alter its efficacy. For regions of the body with a significant barrier to
`drug permeation, such as the eye and brain, great care should be taken to deliver
`drugs appropriately.
`In the design of a drug delivery system for the eye a balance must be struck
`between the limitations imposed by the physicochemical properties of the drugs,
`the limitations imposed by the anatomy and disease state of the eye, and the dosing
`requirements of the drug for that particular disease. This chapter gives an overview
`of some general concepts and tactics in drug delivery, barriers to getting drugs into
`the vitreous and retina, mechanisms by which drugs are cleared, and drug delivery
`for some specific ophthalmic problems.
`
`BASIC PRINCIPLES OF DRUG DELIVERY
`
`Delivery Rates
`
`As a means to predict the properties of drug delivery systems, it is useful to briefly
`review some basic thermodynamic functions. The rate or speed of a reaction is given by
`
`dc=dt
`
`where dc is the change in concentration and dt is the time interval over which that
`change occurs.
`In the simplest case, dc/dt is constant, i.e., the rate of change does not vary
`over time, this situation is termed zero order and can be expressed as
`dc=dt ¼ k
`where k is a constant, also known as the rate constant.
`
`ð1Þ
`
`1
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`Ashton
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`ð3Þ
`
`ð4Þ
`
`Integrating this with respect to time gives
`ð2Þ
`Ct C0 ¼ kt
`where C0 is the initial concentration and Ct is the concentration at time t. A graph of
`concentration (Ct) versus time would therefore have a constant gradient with k as the
`slope (Fig. 1).
`In drug delivery, a more common situation is one where the rate of change of
`concentration is directly proportional to the concentration of drug present. This situa-
`tion is termed first order and can be expressed as
`dc=dt ¼ kc
`Integrating this with respect to time gives
`ln Ct ln C0 ¼ kt
`Expressing (4) another way
`C ¼ C0ekt
`ð5Þ
`A graph of C versus time is shown in Figure 2A and a graph of ln C versus time is
`shown in Figure 2B.
`In the situation where Ct is half of C0 (i.e., the concentration has decreased by
`50%), and where t is the half-life, this equation becomes
`ln 2 ¼ kt1=2
`
`or
`
`ð6Þ
`
`ð7Þ
`
`ln 2=k ¼ t1=2
`i.e., larger the rate constant, shorter is the half-life.
`Zero-order reactions describe processes such as output from a pump or,
`in some cases, diffusion from a suspension. Radioactive decay is an example of a
`first-order process.
`Generally, a drug’s potential to diffuse from one region to another is directly
`proportional to its chemical potential, which can usually be approximated to its con-
`centration. The aforementioned equations can thus be readily applied to drug delivery.
`Considering the setup in Figure 3, drug diffusion from chamber A to chamber B
`is driven by the difference in concentration (or chemical potential) between the two
`chambers. Assuming that chamber B is a perfect sink and that chamber A is well stir-
`red, as the drug diffuses from A, the concentration in this chamber is decreased, and
`with it the driving force for diffusion. This results in a progressively slower release
`
`Figure 1 Zero-order or linear kinetics showing the decrease in drug concentration in a
`dosage form versus time.
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`Retinal Drug Delivery
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`3
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`Figure 2 First order kinetics showing, (A) the decrease in drug concentration in a dosage
`form versus time, (B) the natural log(ln) of the same concentration data plotted against time.
`
`rate. Drug diffusion from chamber A to chamber B in this system will follow first-
`order kinetics. Figure 3B describes a similar situation except that here chamber A
`contains a suspension of the drug. In this situation, drug delivery from A into B is
`again determined by the difference in chemical potential between A and B, but in this
`case as the drug diffuses from A, some of the solid drug in A dissolves so as to main-
`tain the concentration in A. As long as the dissolution of the drug in A is able to keep
`
`Figure 3 (A) Chamber A contains a diffusant that is fully dissolved in A and is at a higher
`concentration than in chamber B, which is a perfect sink. Diffusion from A to B is driven by
`the concentration difference between the two chambers. (B) Chamber A contains a suspension
`of a diffusant. As the diffusant moves to chamber B, the decrease in concentration can be off-set
`by the dissolution of the suspended particles, which acts to maintain the concentration gradient.
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`Ashton
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`pace with the diffusion across the membrane, the concentration of dissolved drug
`will be maintained and consequently the diffusion across the membrane will be con-
`stant provided B remains a perfect sink. Release rate from A will therefore follow
`zero-order kinetics.
`The aforesaid situations apply in special cases where diffusion through the mate-
`rial in chamber A is not important (A is well stirred) and where the dissolution rate of
`the drug particles in A is rapid. A more common situation arises when drug release is
`both a function of its concentration within a vehicle and its ability to diffusion through
`it. When placed into a release medium, the drug closest to the surface is released the
`fastest. Over a period of time, the drug must diffuse from further and further back
`within the bulk of the device, which progressively slows the release. Systems such as
`this can be described by solutions to Ficks’s second law of diffusion (1).
`
`dC=dt ¼ Dd2c=dx2
`where C is the concentration in a reservoir, t the time, x the distance and D the diffu-
`sion coefficient the diffusant through the media. Partial derivatives (d) are used
`because C is a function of both t and x.
`In the 1960s, Higuchi (2) proposed that if diffusion through a vehicle is rate
`limiting, then the amount of drug released from a vehicle (in which the drug is fully
`dissolved) can be described by
`
`ð8Þ
`
`Q ¼ 2 C0ðDt=pÞ1=2
`
`ð9Þ
`
`Figure 4 Square root time kinetics typical of release from a gel or ointment as described by
`Higuchi (2,3). (A) Decrease in concentration of drug versus time, (B) same data plotted against
`square root of time.
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`Retinal Drug Delivery
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`5
`
`where Q is the quantity of drug released per unit area, t the time of application, and
`C0 is the initial concentration of drug in the vehicle (2). It is assumed that the com-
`position of the vehicle is initially h