Ophthalmic Drug Delivery Systems - part 1 pptx

Ophthalmic Drug Delivery Systems Second Edition, Revised and Expandededited by Ashim K.. 23 Pharmaceutical Process Validation, edited by Bernard T Loftus andRobert A Nash 24 Anticancer a

Ophthalmic Drug Delivery Systems Second Edition, Revised and Expanded

edited by Ashim K Mitra

University of Missouri-Kansas City Kansas City, Missouri, U.S.A.

M A R C E l

MARCEL DEKKER, INC NEW YORK • BASEL

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DRUGS AND THE PHARMACEUTICAL SCIENCES

Trevor M Jones Jerome P SkellyThe Association of the Alexandria, VirginiaBritish Pharmaceutical Industry

London, United KingdomHans E Junginger Felix TheeuwesLeiden/Amsterdam Center Alza Corporationfor Drug Research Palo Alto, CaliforniaLeiden, The Netherlands

Vincent H L Lee Geoffrey T TuckerUniversity of Southern California University of Sheffield

Los Angeles, California Royal Hallamshire Hospital

Sheffield, United KingdomPeter G Welling

Institut de Recherche Jouveinal

Fresnes, France

DRUGS AND THE PHARMACEUTICAL SCIENCES

A Series of Textbooks and Monographs

1 Pharmacokmetics, Milo Gibaldi and Donald Perrier

2 Good Manufacturing Practices for Pharmaceuticals: A Plan for Total

Quality Control, Sidney H Willig, Murray M Tuckerman, and William

S Hitchings IV

3 Microencapsulation, edited by J R Nixon

4 Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa

and Peter Jenner

5 New Drugs: Discovery and Development, edited by Alan A Rubm

6 Sustained and Controlled Release Drug Delivery Systems, edited by

10 Concepts in Drug Metabolism (in two parts), edited by Peter Jenner

and Bernard Testa

11 Pharmaceutical Analysis: Modern Methods (in two parts), edited by

James W Munson

12 Techniques of Solubilization of Drugs, edited by Samuel H

Yalkow-sky

13 Orphan Drugs, edited by Fred E Karch

14 Novel Drug Delivery Systems: Fundamentals, Developmental

Con-cepts, Biomedical Assessments, Yie W Chien

15 Pharmacokinetics' Second Edition, Revised and Expanded, Milo

Gibaldi and Donald Perrier

16 Good Manufacturing Practices for Pharmaceuticals: A Plan for Total

Quality Control, Second Edition, Revised and Expanded, Sidney H.

Willig, Murray M Tuckerman, and William S Hitchings IV

17 Formulation of Veterinary Dosage Forms, edited by Jack Blodinger

18 Dermatological Formulations Percutaneous Absorption, Brian W.

Barry

19 The Clinical Research Process in the Pharmaceutical Industry, edited

by Gary M Matoren

20 Microencapsulation and Related Drug Processes, Patrick B Deasy

21 Drugs and Nutrients: The Interactive Effects, edited by Daphne A.

Roe and T Colin Campbell

22 Biotechnology of Industrial Antibiotics, Erick J Vandamme

23 Pharmaceutical Process Validation, edited by Bernard T Loftus and

Robert A Nash

24 Anticancer and Interferon Agents Synthesis and Properties, edited by

Raphael M Ottenbrite and George B Butler

25 Pharmaceutical Statistics Practical and Clinical Applications, Sanford

Bolton

26 Drug Dynamics for Analytical, Clinical, and Biological Chemists,

Benjamin J Gudzmowicz, Burrows T Younkin, Jr, and Michael J Gudzmowicz

27 Modern Analysis of Antibiotics, edited by Adjoran Aszalos

28 Solubility and Related Properties, Kenneth C James

29 Controlled Drug Delivery Fundamentals and Applications, Second

Edition, Revised and Expanded, edited by Joseph R Robinson and

Vincent H Lee

30 New Drug Approval Process Clinical and Regulatory Management,

edited by Richard A Guarmo

31 Transdermal Controlled Systemic Medications, edited by Yie W Chien

32 Drug Delivery Devices Fundamentals and Applications, edited by

Praveen Tyle

33 Pharmacokinetics Regulatory • Industrial • Academic Perspectives,

edited by Peter G Welling and Francis L S Tse

34 Clinical Drug Trials and Tribulations, edited by Alien E Cato

35 Transdermal Drug Delivery Developmental Issues and Research

Ini-tiatives, edited by Jonathan Hadgraft and Richard H Guy

36 Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms,

edited by James W McGmity

37 Pharmaceutical Pelletization Technology, edited by Isaac

Ghebre-Sellassie

38 Good Laboratory Practice Regulations, edited by Alien F Hirsch

39 Nasal Systemic Drug Delivery, Yie W Chien, Kenneth S E Su, and

Shyi-Feu Chang

40 Modern Pharmaceutics Second Edition, Revised and Expanded,

edited by Gilbert S Banker and Christopher T Rhodes

41 Specialized Drug Delivery Systems Manufacturing and Production

Technology, edited by Praveen Tyle

42 Topical Drug Delivery Formulations, edited by David W Osborne and

Anton H Amann

43 Drug Stability Principles and Practices, Jens T Carstensen

44 Pharmaceutical Statistics Practical and Clinical Applications, Second

Edition, Revised and Expanded, Sanford Bolton

45 Biodegradable Polymers as Drug Delivery Systems, edited by Mark

Chasm and Robert Langer

46 Preclmical Drug Disposition A Laboratory Handbook, Francis L S

Tse and James J Jaffe

47 HPLC in the Pharmaceutical Industry, edited by Godwin W Fong and

Stanley K Lam

48 Pharmaceutical Bioequivalence, edited by Peter G Welling, Francis L

S Tse, and Shnkant V Dinghe

49 Pharmaceutical Dissolution Testing, Umesh V Banakar

50 Novel Drug Delivery Systems Second Edition, Revised and

Expanded, Y/e W Chien

51 Managing the Clinical Drug Development Process, David M

Coc-chetto and Ronald V Nardi

52 Good Manufacturing Practices for Pharmaceuticals A Plan for Total

Quality Control, Third Edition edited by Sidney H Willig and James

56 New Drug Approval Process Second Edition, Revised and Expanded,

edited by Richard A Guarmo

57 Pharmaceutical Process Validation Second Edition, Revised and

Ex-panded, edited by Ira R Berry and Robert A Nash

58 Ophthalmic Drug Delivery Systems, edited byAshim K Mttra

59 Pharmaceutical Skin Penetration Enhancement, edited by Kenneth A

Walters and Jonathan Hadgraft

60 Colonic Drug Absorption and Metabolism, edited by Peter R Bieck

61 Pharmaceutical Particulate Carriers Therapeutic Applications, edited

by Alam Rolland

62 Drug Permeation Enhancement Theory and Applications, edited by

Dean S Hsieh

63 Glycopeptide Antibiotics, edited by Ramaknshnan Nagarajan

64 Achieving Sterility in Medical and Pharmaceutical Products, Nigel A

Halls

65 Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie

66 Colloidal Drug Delivery Systems, edited by Jorg Kreuter

67 Pharmacokmetics Regulatory • Industrial • Academic Perspectives,

Second Edition, edited by Peter G Welling and Francis L S Tse

68 Drug Stability Principles and Practices, Second Edition, Revised and

Expanded, Jens T Carstensen

69 Good Laboratory Practice Regulations Second Edition, Revised and

Expanded, edited by Sandy Wemberg

70 Physical Characterization of Pharmaceutical Solids, edited by Harry

G Bnttain

71 Pharmaceutical Powder Compaction Technology, edited by Goran

Al-derborn and Chnster Nystrom

72 Modern Pharmaceutics Third Edition, Revised and Expanded, edited

by Gilbert S Banker and Christopher T Rhodes

73 Microencapsulation Methods and Industrial Applications, edited by

Simon Benita

74 Oral Mucosal Drug Delivery, edited by Michael J Rathbone

75 Clinical Research in Pharmaceutical Development, edited by Barry

Bleidt and Michael Montagne

76 The Drug Development Process: Increasing Efficiency and Cost

Ef-fectiveness, edited by Peter G Welling, Louis Lasagna, and Umesh

V Banakar

77 Microparticulate Systems for the Delivery of Proteins and Vaccines,

edited by Smadar Cohen and Howard Bernstein

78 Good Manufacturing Practices for Pharmaceuticals: A Plan for Total

Quality Control, Fourth Edition, Revised and Expanded, Sidney H.

Willig and James R Stoker

79 Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms:

Second Edition, Revised and Expanded, edited by James W

McGimty

80 Pharmaceutical Statistics: Practical and Clinical Applications, Third

Edition, Sanford Bolton

81 Handbook of Pharmaceutical Granulation Technology, edited by Dilip

M Parikh

82 Biotechnology of Antibiotics' Second Edition, Revised and Expanded,

edited by William R Strohl

83 Mechanisms of Transdermal Drug Delivery, edited by Russell O Potts

and Richard H Guy

84 Pharmaceutical Enzymes, edited by Albert Lauwers and Simon

Scharpe

85 Development of Biopharmaceutical Parenteral Dosage Forms, edited

by John A Bontempo

86 Pharmaceutical Project Management, edited by Tony Kennedy

87 Drug Products for Clinical Trials An International Guide to

Formula-tion ProducFormula-tion • Quality Control, edited by Donald C Monkhouse

and Christopher T Rhodes

88 Development and Formulation of Veterinary Dosage Forms: Second

Edition, Revised and Expanded, edited by Gregory E Hardee and J.

Desmond Baggot

89 Receptor-Based Drug Design, edited by Paul Left

90 Automation and Validation of Information in Pharmaceutical

Pro-cessing, edited by Joseph F deSpautz

91 Dermal Absorption and Toxicity Assessment, edited by Michael S

Roberts and Kenneth A Walters

92 Pharmaceutical Experimental Design, Gareth A Lewis, Didier

Mathieu, and Roger Phan-Tan-Luu

93 Preparing for FDA Pre-Approval Inspections, edited by Martin D.

Hynes III

94 Pharmaceutical Excipients Characterization by IR, Raman, and NMR

Spectroscopy, David E Bugay and W Paul Findlay

95 Polymorphism in Pharmaceutical Solids, edited by Harry G Brittam

96 Freeze-Drymg/Lyophilization of Pharmaceutical and Biological

Prod-ucts, edited by Louis Rey and Joan C May

97 Percutaneous Absorption-

Drugs-Cosmetics-Mechanisms-Metho-dology, Third Edition, Revised and Expanded, edited by Robert L.

Bronaugh and Howard I Maibach

98 Bioadhesive Drug Delivery Systems: Fundamentals, Novel

Ap-proaches, and Development, edited by Edith Mathiowitz, Donald E.

Chickering III, and Claus-Michael Lehr

99 Protein Formulation and Delivery, edited by Eugene J McNally

100 New Drug Approval Process: Third Edition, The Global Challenge,

edited by Richard A Guanno

101 Peptide and Protein Drug Analysis, edited by Ronald E Reid

102 Transport Processes in Pharmaceutical Systems, edited by Gordon L.

Amidon, Ping I Lee, and Elizabeth M Topp

103 Excipient Toxicity and Safety, edited by Myra L Wemer and Lois A.

Kotkoskie

104 The Clinical Audit in Pharmaceutical Development, edited by Michael

R Hamrell

105 Pharmaceutical Emulsions and Suspensions, edited by Francoise

Nielloud and Gilberte Marti-Mestres

106 Oral Drug Absorption: Prediction and Assessment, edited by Jennifer B.

Dressman and Hans Lennernas

107 Drug Stability: Principles and Practices, Third Edition, Revised and

Expanded, edited by Jens T Carstensen and C T Rhodes

108 Containment in the Pharmaceutical Industry, edited by James P.

Wood

109 Good Manufacturing Practices for Pharmaceuticals A Plan for TotalQuality Control from Manufacturer to Consumer, Fifth Edition, Revised

and Expanded, Sidney H Willig

110 Advanced Pharmaceutical Solids, Jens T Carstensen

111 Endotoxms: Pyrogens, LAL Testing, and Depyrogenation, Second

Edition, Revised and Expanded, Kevin L Williams

112 Pharmaceutical Process Engineering, Anthony J Hickey and David

115 Drug Targeting Technology Physical • Chemical • Biological Methods,

edited by Hans Schreier

116 Drug-Drug Interactions, edited by A David Rodngues

117 Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian

and Anthony J Streeter

118 Pharmaceutical Process Scale-Up, edited by Michael Levin

119 Dermatological and Transdermal Formulations, edited by Kenneth A.

Walters

120 Clinical Drug Trials and Tribulations Second Edition, Revised and

Expanded, edited by Alien Cato, Lynda Sutton, and Alien Cato III

121 Modern Pharmaceutics: Fourth Edition, Revised and Expanded,

edi-ted by Gilbert S Banker and Christopher T Rhodes

122 Surfactants and Polymers in Drug Delivery, Martin Malmsten

123 Transdermal Drug Delivery: Second Edition, Revised and Expanded,

edited by Richard H Guy and Jonathan Hadgraft

124 Good Laboratory Practice Regulations Second Edition, Revised and

Expanded, edited by Sandy Wemberg

125 Parenteral Quality Control: Sterility, Pyrogen, Particulate, and

Pack-age Integrity Testing- Third Edition, Revised and Expanded, Michael

J Akers, Daniel S Larnmore, and Dana Morion Guazzo

126 Modified-Release Drug Delivery Technology, edited by Michael J

Rathbone, Jonathan Hadgraft, and Michael S Roberts

127 Simulation for Designing Clinical Trials A

Pharmacokmetic-Pharma-codynamic Modeling Perspective, edited by Hui C Kimko and

Ste-phen B Duffull

128 Affinity Capillary Electrophoresis in Pharmaceutics and

Biopharma-ceutics, edited by Remhard H H Neubert and Hans-Hermann

Rut-tinger

129 Pharmaceutical Process Validation: An International Third Edition,

Revised and Expanded, edited by Robert A Nash and Alfred H.

Wachter

130 Ophthalmic Drug Delivery Systems Second Edition, Revised and

Expanded, edited by Ashim K Mitra

131 Pharmaceutical Gene Delivery Systems, edited by Alain Rolland and

Sean M Sullivan

ADDITIONAL VOLUMES IN PREPARATION

Biomarkers in Clinical Drug Development, edited by John Bloom

Pharmaceutical Inhalation Aerosol Technology Second Edition,

Re-vised and Expanded, edited by Anthony J Mickey Pharmaceutical Extrusion Technology, edited by Isaac Ghebre-Sellas-

sie and Charles Martin

Pharmaceutical Compliance, edited by Carmen Medina

For new medications to be used effectively, and for those now available toprovide maximal benefit, improvements in ocular drug delivery are essential.Drug delivery is no less vital than drug discovery

Although many drugs can be safely delivered by eye drops, effectivetreatment depends on patient compliance Non-compliance is a majorproblem, especially in poorly educated patients and patients who are re-quired to apply drops frequently Lack of compliance frequently results insuboptimal therapeutics, which may lead to blindness People with chronicconditions or debilitating disease find complicated eye drop regimens to

be a serious handicap

Even when drugs can be delivered through the cornea and conjunctiva,concentrations may be suboptimal and the therapeutic effect minimal In thepast, a variety of approaches to topical drug delivery have been tested,including gelatin wafers or soft contact lenses soaked in drugs and placed

on the cornea or in the cul-de-sac, corneal collagen shields, and esis The diversity of these approaches is an indication of the need for asuperior method of topical drug delivery and a testament to the fact that nouniformly acceptable method has been developed to date Currently, vehi-cles and carriers such as liposomes and substances that gel, as well as nano-particles, are being evaluated Also, prodrugs, such as medicines thathydrolyze within the eye, are being developed to achieve higher concentra-tions, prolonged activity, and reduced toxicity of topically applied medica-tions These important techniques and others are considered in this book

iontophor-Perhaps even more important than surface delivery is the need toapply medications to the posterior segment of the eye Treatment of blindingposterior segment diseases, including uveitis, proliferative retinopathy, andmacular degeneration, requires drug delivery to the retina, the choroid, orthe ciliary body in a safe and convenient way Systemic delivery that canlocalize to the retina may be possible Improving scleral permeability may beimportant for periocular delivery, and devices inserted into the vitreous havecertainly been valuable Both nonbiodegradable controlled-release devicesand biodegradable implants inserted into both aqueous and vitreous showgreat promise.

Posterior segment drug delivery is also becoming important for genetherapy The need to deliver polypeptide medications and DNA inhibitorshas become clear The challenge of understanding the pharmacokinetics ofthe drug is matched by the challenge of providing a delivery system that canprovide optimal duration of drug delivery in therapeutically sufficient con-centrations and still be safe and convenient for the patient

Our approaches to these goals are imperfect at present, but this cally important book describes in vital detail and with great clarity theprogress that has been made so far and the course that needs to be pursued

criti-in the future In my pharmacological memory, it does not seem so long agothat we had no treatment for viral diseases, pilocarpine was the only treat-ment for glaucoma, and antibiotics were crude and relatively ineffective.Similarly, our present achievements in the field of ocular drug deliverymay seem equally primitive as we follow the paths to future progressdetailed in this book

Herbert E Kaufman, M.D.Boyd Professor of Ophthalmology, Pharmacology, and Microbiology

Louisiana State University Health Sciences Center

New Orleans, Louisiana, U.S.A

A major goal of pharmacotherapeutics is the attainment of an effective drugconcentration at the intended site of action for a desired length of time.Efficient delivery of a drug while minimizing its systemic and/or local sideeffects is the key to the treatment of ocular diseases The unique anatomyand physiology of the eye offer many challenges to developing effectiveophthalmic drug delivery systems, but the knowledge in this field is rapidlyexpanding Systems range from simple solutions to novel delivery systemssuch as biodegradable polymeric systems, corneal collagen shields, ionto-phoresis, and viral and nonviral gene delivery systems, to name a few Anincrease in our understanding of ocular drug absorption and dispositionmechanisms has led to the development of many of these new systems.The first edition of this book laid the foundation necessary for under-standing barriers to ophthalmic drug delivery and to review the conven-tional systems available and/or in various stages of research anddevelopment Since then, significant advances have been made in under-standing the molecular mechanisms involved in ocular drug transport.The book begins with a brief discussion on the anatomy and physiology

of the eye relevant to ocular drug delivery The latest techniques, such asmicrodialysis, and models developed to study ocular drug disposition arediscussed A review of both the conventional and novel delivery systemsfollows The book stresses the fact that simple instillation of drug solution

in the cul-de-sac is not always acceptable and emphasizes the need for thedevelopment of newer and more efficient systems The book concludes with

the basic information required for pharmaceutical scientists to protect theirinventions.

Part I investigates the fundamental considerations in ocular drugdelivery The three chapters in this part review the relevant ocular anatomyand physiology, the constraints imposed by the eye upon successful delivery,and the associated ion and solute transport processes in the eye They pro-vide information on the various transport processes as well as recentlyidentified drug efflux pumps, which regulate the transport of endogenousand exogenous substances

Part II opens with a discussion of pharmacokinetics relevant to oculardrug delivery The next chapter discusses the pharmacokinetic processesguiding the ocular disposition and expands on the pharmacokinetic/phar-macodynamic modeling processes to determine the appropriate dosage regi-men This chapter is followed by a detailed discussion of the variousmathematical models developed to describe the distribution and elimination

of drugs from the vitreous This part also includes chapters dealing with theapplication of microdialysis technique to study ocular drug delivery anddisposition, and the applicability of the microdialysis sampling approachfor the examination of ocular pharmacokinetics and dynamics of ophthal-mics

Part III is divided into conventional and advanced drug delivery stems The first section deals with such conventional systems as collagenshields, iontophoresis, microparticulates, and dendrimers These chaptershave been updated to include advances in ocular drug delivery achieved inthe past decade The second section examines the delivery of macromole-cules to treat various ocular pathologies The reader will find more informa-tion on the recent developments in animal models of retino-choroidaldiseases The viral and nonviral gene delivery systems introduced in thissection are still in their infancy but have the potential to provide enormoustherapeutic benefits This section also focuses on the advances in treatingretinal degenerative diseases The last chapter in this section discussesthe principles and delivery aspects of gene, oligonucleotide, and ribozymetherapy

sys-Part IV provides information on regulatory and patent considerations.Pharmaceutical scientists will gain knowledge of the regulations governinganimal and human testing and ultimately the release of the product com-mercially for public use The final chapter conveys the legal issues involved

in protecting inventions and the basic legal requirements for obtainingpatents

Ashim K Mitra

1 Overview of Ocular Drug Delivery 1

Sreeraj Macha, Patrick M Hughes, and Ashim K Mitra

2 Membrane Transport Processes in the Eye 13

Gangadhar Sunkara and Uday B Kompella

3 General Considerations in Ocular Drug Delivery 59

James E Chastain

II Transport Models in Ocular Drug Delivery

4 Ocular Drug Transfer Following Systemic Drug Administration 109

Nelson L Jumbe and Michael H Miller

5 Ocular Pharmacokinetics and Pharmacodynamics 135

Ronald D Schoenwald

6 Mathematical Modeling of Drug Distribution in the Vitreous

Stuart Friedrich, Bradley Saville, and Yu-Ling Cheng

7 Anterior Segment Microdialysis 223

Kay D Rittenhouse

8 Posterior Segment Microdialysis 251

Sreeraj Macha and Ashim K Mitra

III Drug Delivery Systems

A: Conventional Systems

9 Ocular Penetration Enhancers 281

Thomas Wai-Yip Lee and Joseph R Robinson

10 Corneal Collagen Shields for Ocular Drug Delivery 309

Shiro Higaki, Marvin E Myles, Jeannette M Loutsch,and James M Hill

11 The Noncorneal Route in Ocular Drug Delivery 335

Imran Ahmed

12 Ocular Iontophoresis 365

Marvin E Myles, Jeannette M Loutsch, Shiro Higaki,and James M Hill

13 Mucoadhesive Polymers in Ophthalmic Drug Delivery 409

Thomas P Johnston, Clapton S Dias, Hemant Alur,and Ashim K Mitra

14 Microparticles and Nanoparticles in Ocular Drug Delivery 437

Murali K Kothuri, Swathi Pinnamaneni, Nandita G Das,and Sudip K Das

15 Dendrimers: An Innovative and Enhanced Ocular Drug

Jeannette M Loutsch, Desiree Ong, and James M HillB: Delivery of Macromolecular Therapeutic Agents

16 Ocular Delivery and Therapeutics of Proteins and Peptides 493

Surajit Dey, Ramesh Krishnamoorthy, and Ashim K Mitra

17 Retinal Disease Models for Development of Drug and Gene

Leena Pitka¨nen, Lotta Salminen, and Arto Urtti

18 New Experimental Therapeutic Approaches for Degenerative

Diseases of the Retina 535

Joyce Tombran-Tink

19 Gene, Oligonucleotide, and Ribozyme Therapy in the Eye 609

Sudip K Das and Keith J Miller

IV Regulatory Aspects

Clapton S Dias Department of Pharmaceutical Sciences, University ofMissouri–Kansas City, Kansas City, Missouri, U.S.A

Stuart Friedrich, Ph.D Department of Chemical Engineering and AppliedChemistry, University of Toronto, Toronto, Canada

Shiro Higaki, M.D Department of Ophthalmology, LSU Eye and VisionCenter of Excellence, Louisiana State University Health Science Center,New Orleans, Louisiana, U.S.A

James M Hill, Ph.D Department of Ophthalmology, LSU Eye andVision Center of Excellence, Louisiana State University Health ScienceCenter, New Orleans, Louisiana, U.S.A

Patrick M Hughes, Ph.D Allergan Pharmaceuticals, Irvine, California,U.S.A

Thomas P Johnston, Ph.D Department of Pharmaceutical Sciences,University of Missouri–Kansas City, Kansas City, Missouri, U.S.ANelson L Jumbe Albany Medical College, Albany, New York, and AmgenInc., Thousands Oaks, California, U.S.A

Uday B Kompella, Ph.D Department of Pharmaceutical Sciences andOphthalmology, University of Nebraska Medical Center, Omaha,Nebraska, U.S.A

Murali K Kothuri Department of Pharmaceutical Sciences, Idaho StateUniversity, Pocatello, Idaho, U.S.A

Ramesh Krishnamoorthy, Ph.D Formulation Development, InspirePharmaceuticals, Durham, North Carolina, U.S.A

D Scott Krueger, Ph.D Regulatory Affairs, Alcon Research, Ltd., FortWorth, Texas, U.S.A

Thomas Wai-Yip Lee, B Pharm School of Pharmacy, University ofWisconsin–Madison, Madison, Wisconsin, U.S.A

Jeannette M Loutsch, Ph.D Department of Ophthalmology, LSU Eyeand Vision Center of Excellence, Louisiana State University HealthScience Center, New Orleans, Louisiana, U.S.A

Sreeraj Macha, Ph.D.
Department of Pharmaceutical Sciences,

University of Missouri–Kansas City, Kansas City, Missouri, U.S.A.Michael H Miller Albany Medical College, Albany, New York, U.S.A.Keith J Miller Bristol–Myers Squibb Company, Pennington, New Jersey,U.S.A

Ashim K Mitra, Ph.D Department of Pharmaceutical Sciences,University of Missouri–Kansas City, Kansas City, Missouri, U.S.A.Marvin E Myles, Ph.D Department of Ophthalmology, LSU Eye andVision Center of Excellence, Louisiana State University Health ScienceCenter, New Orleans, Louisiana, U.S.A

Desiree Ong Department of Ophthalmology, LSU Eye and Vision Center

of Excellence, Louisiana State University Health Science Center, NewOrleans, Louisiana, U.S.A

Swathi Pinnamaneniy Department of Pharmaceutical Sciences, IdahoState University, Pocatello, Idaho, U.S.A

Leena Pitka¨nen, Lic Med Department of Pharmaceutics, University ofKuopio, and Department of Ophthalmology, Kuopio University Hospital,Kuopio, Finland

Kay D Rittenhouse, Ph.D Nonclinical Drug Safety, Global Research andDevelopment, La Jolla Laboratories, Pfizer Inc., San Diego, California,U.S.A

Joseph R Robinson, Ph.D School of Pharmacy, University of Wisconsin–Madison, Madison, Wisconsin, U.S.A

Robert E Roehrs, Ph.D.z Alcon Research, Ltd., Fort Worth, Texas,U.S.A

* Current affiliation: Boehringer Ingelheim Inc., Ridgefield, Connecticut, U.S.A.

Company, New Brunswick, New Jersey, U.S.A.

z Retired.

Lotta Salminen, M.D Department of Ophthalmology, University ofTampere, and Department of Ophthalmology, Tampere UniversityHospital, Tampere, Finland

Bradley Saville, Ph.D Department of Chemical Engineering and AppliedChemistry, University of Toronto, Toronto, Canada

Ronald D Schoenwald, Ph.D College of Pharmacy, The University ofIowa, Iowa City, Iowa, U.S.A

Gangadhar Sunkara, Ph.D
Department of Pharmaceutical Sciences,

University of Nebraska Medical Center, Omaha, Nebraska, U.S.A.Joyce Tombran-Tink, Ph.D Department of Pharmaceutical Sciences,University of Missouri–Kansas City, Kansas City, Missouri, U.S.A.Arto Urtti, Ph.D Department of Pharmaceutics, University of Kuopio,Kuopio, Finland

Current affiliation: Clinical Pharmacology Division, Novartis Pharmaceuticals, East Hanover,

New Jersey, U.S.A.

Overview of Ocular Drug Delivery

Sreeraj Macha
and Ashim K Mitra

University of Missouri–Kansas City, Kansas City, Missouri, U.S.A

Current affiliation: Boehringer Ingelheim Inc., Ridgefield, Connecticut, U.S.A.

the appropriate duration Ocular disposition and elimination of a tic agent is dependent upon its physicochemical properties as well as therelevant ocular anatomy and physiology (1) A successful design of a drugdelivery system, therefore, requires an integrated knowledge of the drugmolecule and the constraints offered by the ocular route of administration.The active sites for the antibiotics, antivirals, and steroids are theinfected or inflamed areas within the anterior as well as the posterior seg-ments of the eye Receptors for the mydriatics and miotics are in the irisciliary body A host of different tissues are involved, each of which may poseits own challenge to the formulator of ophthalmic delivery systems Hence,the drug entities need to be targeted to many sites within the globe.Historically, the bulk of the research has been aimed at delivery to theanterior segment tissues Only recently has research been directed at delivery

therapeu-to the tissues of the posterior globe (the uveal tract, vitreous, choroid, andretina)

The aim of this chapter is merely to present the challenges of designingsuccessful ophthalmic delivery systems by way of introduction The reader isreferred to specific chapters within this book for a thorough discussion ofthe topic introduced in this section

II MECHANISMS OF OCULAR DRUG ABSORPTION

Topical delivery into the cul-de-sac is, by far, the most common route ofocular drug delivery Adsorption from this site may be corneal or noncor-neal A schematic diagram of the human eye is depicted inFigure 1 The so-called noncorneal route of absorption involves penetration across the scleraand conjunctiva into the intraocular tissues This mechanism of absorption

is usually nonproductive, as drug penetrating the surface of the eye beyondthe corneal-scleral limbus is taken up by the local capillary beds andremoved to the general circulation (2) This noncorneal absorption in gen-eral precludes entry into the aqueous humor

Recent studies, however, suggest that noncorneal route of absorptionmay be significant for drug molecules with poor corneal permeability.Studies with inulin (3), timolol maleate (3), gentamicin (4), and prostaglan-din PGF2
(5) suggest that these drugs gain intraocular access by diffusionacross the conjunctiva and sclera Ahmed and Patton (3) studied the non-corneal absorption of inulin and timolol maleate Penetration of theseagents into the intraocular tissues appears to occur via diffusion acrossthe conjunctiva and sclera and not through reentry from the systemic cir-culation or via absorption into the local vasculature Both compoundsgained access to the iris–ciliary body without entry into the anterior cham-

The outermost layer, the epithelium, represents the rate-limiting rier for transcorneal diffusion of most hydrophilic drugs The epithelium iscomposed of five to seven cell layers The basement cells are columnar innature, allowing for minimal paracellular transport The epithelial cells,however, narrow distal to Bowman’s membrane, forming flattened epithelialcells with zonulae occludentes interjunctional complexes This cellulararrangement precludes paracellular transport of most ophthalmic drugsand limits lateral movement within the anterior epithelium (9) Cornealsurface epithelial intracellular pore size has been estimated to be about

bar-60 A˚ (10) Small ionic and hydrophilic molecules appear to gain access tothe anterior chamber through these pores (11); however, for most drugs,paracellular transport is precluded by the interjectional complexes In arecent review, Lee (10) discusses an attempt to transiently alter the epithelialintegrity at these junctional complexes to improve ocular bioavailability.This approach has, however, only met with moderate success and has thepotential to severely compromise the corneal integrity

Sandwiched between the corneal epithelium and endothelium is thestroma (substantia propia) The stroma constitutes 85–90% of the totalcorneal mass and is composed of mainly of hydrated collagen (12) Thestroma exerts a diffusional barrier to highly lipophilic drugs owing to itshydrophilic nature There are no tight junction complexes in the stroma, andparacellular transport through this tissue is possible

Figure 2 Cross-sectional view of the corneal membrane depicting various barriers

to drug absorption (From Ref 12.)

The innermost layer of the cornea, separated from the stroma byDescermet’s membrane, is the endothelium The endothelium is lipoidal innature; however, it does not offer a significant barrier to the transcornealdiffusion of most drugs Endothelial permeability depends solely on mole-cular weight and not on the charge of hydrophilic nature of the compound(13,14).

Transcellular transport across the corneal epithelium and stroma is themajor mechanism of ocular absorption of topically applied ophthalmicpharmaceuticals This type of Fickian diffusion is dependent upon manyfactors, i.e., surface area, diffusivity, the concentration gradient established,and the period over which concentration gradient can be maintained Aparabolic relationship between octanol/water partition coefficient and cor-neal permeability has been described for many drugs (15–19) The optimallog partition coefficient appears to be in the range of 1–3 The permeabilitycoefficients of 11 steroids were determined by Schoenwald and Ward (15).The permeability versus log partition coefficient fit the typical parabolicrelationship, with the optimum log partition coefficient being 2.9.Narurkar and Mitra studied a homologous series of 50 aliphatic esters of5-iodo-20-deoxyuridine (IDU) (16,17) In vitro corneal permeabilities wereoptimized at a log partition coefficient of 0.88, as can be seen graphically inFigure 3 and in Table 1, where CMP represents the corneal permeabilityvalues as measured by in vitro perfusion experiments on rabbit corneas (I =IDU, II = IDU-propionate, III = IDU-butyrate, IV = IDU-isobutyrate,

Figure 3 A plot depicting the parabolic relationship between in vitro CMP andester chain length (From Ref 16.)

transport system actively clearing the retina of agents potentially able todisturb the visual process However, the same protective mechanisms maycause subtherapeutic drug levels at the intended site The difficulties can becompounded by the structure of the globe itself, where many of its internalstructures are isolated from the blood and the outside surface of the eye.

A major goal in ocular therapeutics is to circumvent these structuralobstacles and protective mechanisms to elicit desired pharmacologicalresponse

Physiological barriers to the diffusion and productive absorption oftopically applied ophthalmic drugs exist in the precorneal and cornealspaces Anterior chamber factor also greatly influence the disposition oftopically applied drugs Precorneal constraints include solution drainage,lacrimation and tear dilution, tear turnover, and conjunctival absorption.For acceptable bioavailability, a proper duration of contact with the corneamust be maintained Instilled solution drainage away from the precornealarea has been shown to be the most significant factor reducing this contact

Figure 4 Miosis-time profiles: Plots of the average observed changes in pupillarydiameter (
PD) as a function of time following the instillation of 25.0 mL of theisotonic 1% pilocarpine nitrate solutions, which contained the different concentra-tions of citrate buffer The vertical lines through the data points are SD (datapoints with standard deviation lines omitted is for clarity of the figure) (FromRef 20.)

time and ocular bioavailability of topical solution dosage forms (21,22).Instilled dose leaves the precorneal area within 5 minutes of instillation inhumans (21,23) The natural tendency of the cul-de-sac is to reduce its fluidvolume to 7–10 mL (24–26) A typical ophthalmic dropper delivers 30 mL,most of which is rapidly lost through nasolacrimal drainage immediatelyfollowing dosage This drainage mechanism may then cause the drug to besystemically absorbed across the nasal mucosa or the gastrointestinal tract(27) Systemic loss from topically applied drugs also occurs from conjuncti-val absorption into the local circulation The conjunctiva possesses a rela-tively large surface area, making this loss significant.

Simple dilution of instilled drug solution in the tears acts to reduce thetranscorneal flux of drug remaining in the cul-de-sac Lacrimation can beinduced by many factors, including the drug entity, the pH, and the tonicity

of the dosage from (28–30) Formulation adjuvants can also stimulate tearproduction (20)

Tear turnover acts to remove drug solution from the conjunctival de-sac Normal human tear turnover is approximately 16% per minute,which can also be stimulated by various factors, as described elsewhere(21,25) These factors render topical application of ophthalmic solutions

cul-to the cul-de-sac extremely inefficient Typically, less than 1% of the instilleddose reaches the aqueous humor (27,31) The low fraction of applied dose(1%) of drug solution reaching the anterior chamber further undergoesrapid elimination from the intraocular tissues and fluids Absorbed drugmay exit the eye through the canal of Schlemm or via absorption throughthe ciliary body of suprachoroid into the episcleral space (27) Enzymaticmetabolism may account for further loss, which can occur in the precornealspace and/or in the cornea (32,33) Age and genetics have been determined

to be two important factors in ocular metabolism (34,35)

Clearly, the physiological barriers to topical corneal absorption areformidable The result is that the clinician is forced to recommend frequenthigh doses of drugs to achieve therapeutic effect This pulsatile dosing notonly results in extreme fluctuations in ocular drug concentrations but maycause many local and/or systemic side effects Approaches taken to circum-vent this pulsatile dosing and their ramifications on ocular therapies are thesubject matter of this text

For the effective treatment of diseases involving the retina, drugs mustcross the blood-ocular barrier in significant amounts to demonstrate ther-apeutic effect The blood-ocular barrier is a combination of microscopicstructures within the eye, which physiologically separate it from the rest

of the body It is comprised of two systems: (a) blood-aqueous barrier,which regulates solute exchange between blood and the intraocular fluid,and (b) blood-retinal barrier, which separates the blood from the neural

retina Both barriers contain epithelial and endothelial components whosetight junctions limit transport.

A transient increase in the blood-retinal barrier permeability can beachieved by modification of the barrier properties For instance, opening ofthe blood-retinal barrier can be achieved by intracarotid infusion of a hyper-osmotic solution, such as mannitol or arabinose Perfusion with such asolution for about 30 seconds is shown to open the blood-retinal barrierreversibly Osmotically induced shrinkage of the retinal and brain capillaryendothelial cells causes opening of the tight junctions Other methodsinclude perfusion with oleic acid or protamine These methods, however,produce a nonspecific opening of the blood-retinal barrier, possibly withassociated retinal and central nervous system toxicity

Chemical modification is more commonly employed to enhance drugtransport across biological barriers Lipophilic analogs of the parent drugincrease lipid solubility and thereby their blood-retinal barrier perme-ability Another approach to enhance transport across the blood-retinalbarrier could involve utilizing specific carrier systems on the epithelialmembrane Drugs may be modified in such a way that their structuresresemble endogenous ligands for a specific carrier system on the blood-retinal barrier

Drug delivery through nutrient transport systems has been reportedpreviously with intestinal absorption (36–38) -Lactam antibiotics andother compounds that share the structural features of the endogenous pep-tides are recognized by the peptide transporters Recently valacyclovir (valylester of acyclovir) (39,40) and valganciclovir (valyl ester of ganciclovir) (41)were shown to be the substrates for peptide transporters These prodrugsincreased the oral bioavailability of acylclovir and ganciclovir significantly(42,43), thus reducing the daily oral dose requirement

Various transporters/receptors are reported to be present on the retinaand/or the blood-ocular barriers The reader is referred to specific chapters

in this volume for detailed description However, very few studies have beencarried out to explore the transporters present on the retina or the blood-ocular barrier The transporters/receptors present on the retina or theblood-ocular barrier may be exploited to increase ocular bioavailability ofdrugs with poor intrinsic permeability

ACKNOWLEDGMENTS

Supported by NIH grants R01 EY09171 and R01 EY10659

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38 I Tamai, T Nakanishi, H Nakahara, et al Improvement of L-dopa tion by dipeptidyl derivation, utilizing peptide transporter PepT1 J Pharm.Sci 87:1542–1546, 1998

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Membrane Transport Processes in

the Eye

Gangadhar Sunkara
and Uday B Kompella

University of Nebraska Medical Center, Omaha, Nebraska, U.S.A

I INTRODUCTION

Epithelial and/or endothelial cells sealed by tight junctions serve as themajor membrane barriers for the transport of nutrients, ions, and drugsinto intraocular tissues The principal membrane barriers of the eye arelocated in the cornea, conjunctiva, iris-ciliary body, lens epithelium, andretina (Fig 1) Various specialized transport processes in these barrierscontrol the movement of solutes into and out of intraocular chambers.These processes maintain the visual function, control intraocular pressure,provide nutrients to avascular cornea and lens, and protect ocular tissuesfrom xenobiotics An alteration in the function of these transporters is oftenthe underlying cause of various ocular diseases In addition, these transportprocesses can play a role in drug transport

Drug therapy is useful in the treatment of corneal epitheliopathy,keratitis, conjunctivitis, extracellular infections, glaucoma, iritis, and catar-act—diseases that afflict the anterior segment of the eye—and vitreoproli-ferative disorders, endophthalmitis of bacterial and fungal origins, uveitis,viral retinitis, diabetic retinopathy, and macular degeneration—diseases thatafflict the posterior segment of the eye Ocular drug therapy often involvestopical or systemic administration of drugs Therefore, for effective delivery

to intraocular tissues, drugs must penetrate across cornea, conjunctiva, and/

or sclera following topical administration or across endothelial barriers

Current affiliation: Novartis Pharmaceuticals, East Hanover, New Jersey, U.S.A.

or passive diffusion is a process that does not require cellular energy, butrequires a chemical gradient for the solute to be transported Facilitateddiffusion is similar to simple diffusion in not requiring energy and followingchemical gradient, but it requires a membrane transporter or carrier to facil-itate the transport Two primary modes of facilitated transport have beenrecognized in the biological systems: channel type and carrier type Inchannel-type facilitated diffusion, the solute passes in a diffusion-limitingprocess from one side of the membrane to the other via a channel or porethat is lined by appropriately hydrophilic, hydrophobic, or amphipathicamino acyl residues of the constituent proteins In carrier-type facilitateddiffusion, some part of the transporter is classically presumed to pass throughthe membrane together with the substrate Carriers usually exhibit rates oftransport, stereospecificity, and saturation kinetics in higher magnitude com-pared to channels Solute transport processes where energy is required totransport the solutes against a concentration gradient are referred to as activetransport processes In primary active transport, energy is directly expended

by the transporter in the form of ATP hydrolysis or electron flow Insecondary active transport, the transporter does not directly expend cellularenergy but relies on a primary active transport process for its driving force.Some macromolecules cross the cell bafflers through endocytosis (receptor-mediated, adsorptive, or fluid-phase) followed by exocytosis, a processknown as transcytosis Finally, with group translocation, the transportedsubstance is chemically modified by the membrane transporter during thetransport event, which may require energy either directly or indirectly

B Routes of Transport

Across any continuous epithelium, a solute can be transported either throughthe cells or between the cells The cellular pathway is known as the transcel-lular route, and the intercellular pathway is known as the paracellular route(Fig 2) The transport of most of the solutes is contributed by bothpathways Lipophilic molecules and molecules with specialized transportprocesses prefer the transcellular route, whereas hydrophilic molecules lack-ing membrane transport processes prefer the paracellular route However,dissecting the fraction contributed by each pathway is difficult (Ho et al.,1999) One measure of the overall barrier permeability is its electricalresistance, a measure of the resistance of the tissue to ion transport Theelectrical resistance of various ocular barriers is summarized inTable 1.The mechanisms of transcellular transport include simple diffusion,facilitated diffusion, active transport, and endocytosis The plasma mem-brane of a cell consists of a lipid bilayer with an array of peripherally andintegrally associated proteins, some of which serve as specific transporters or