Bonus CD-ROM
`Available!
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`for More Details
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1013, Page 1
`
`

`

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`material contained herein. This publication contains information relating to general principles of medical care which should not
`be construed as specific instructions for individual patients. Manufacturer's product information and package inserts should be
`reviewed for current information, including contraindications, dosages and precautions.
`
`Printed in the United States of America
`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington, in the Office of the Librarian of Congress, at
`Washington DC
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`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
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`Copyright 1926, 1936, by the Joseph P Remington Estate
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`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
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`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Philadelphia College of Pharmacy and Science
`
`Copyright 2000, 2006, by the University of the Sciences in Philadelphia
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`All Rights Reserved
`Library of Congress Catalog Card Information is available
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`
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`any, they will be pleased to make the necessary arrangements at the first opportunity.
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`The use of structural formulas from USAN and the USP Dictionary of Drug Names is by permission of The USP Convention. The
`Convention is not responsible for any inaccuracy contained herein.
`
`Notice-This text is not intended to represent, nor shall it be interpreted to be, the equivalent of or a substitute for the official
`United States Pharmacopeia (USP) and I or the National Formulary (NF). In the event of any difference or discrepancy between the
`current official USP or NF standards of strength, quality, purity, packaging and labeling for drugs and representations of them
`herein, the context and effect of the official compendia shall prevail.
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`1 2 3 4 5 6 7 8 9 10
`
`-
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1013, Page 2
`
`

`

`Contents
`
`Part 1
`
`Orientation
`
`2
`3
`4
`5
`6
`7
`8
`
`9
`10
`
`. .... .3
`. . . . .
`. . . . . . . . .
`. . . .
`Scope of Pharmacy
`Evolution of Pharmacy .. ........ .. ....... . ...... . . 7
`Ethics and Professionalism . . . . . .
`. . . . . . . . . .
`.20
`The Practice of Community Pharmacy . ............... 30
`Pharmacists in Industry . . . . . . . . . . . . . . . . . . . . .
`. ... 35
`Pharmacists in Government . . .
`. ........ . .40
`Pharmacists and Public Health . .
`. ..... . .. . . . . . ... .51
`Information Resources in Pharmacy and the
`Pharmaceutical Sciences
`Clinical Drug Literature
`Research .. . ... . .
`
`. .. 64
`.74
`. . . 87
`
`. '...
`
`Part 2
`
`Pharmaceutics
`
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`
`Metrology and Pharmaceutical Calculations .. . . . .. . . . . 99
`Statistics
`.... ... .. . ........ ........ . . ...... 127
`Molecular Structure, Properties, and States of Matter
`. 162
`Complex Formation
`. . . . . . . .
`. . . . . . . . . . . . . .
`. . 186
`. . . 201
`Thermodynamics . . . . . . . . . . . . . . . . . . . . . . . . . .
`.211
`Solutions and Phase Equilibria ..
`.231
`Ionic Solutions and Electrolytic Equil ibria
`. . 250
`Tonicity, Osmoticity, Osmolality, and Osmolarity
`.266
`Chemical Kinetics .... . . .... . . . . . ... .. .
`.2M
`lnterfacial Phenomena ....
`.293
`Colloidal Dispersions .
`.319
`Coarse Dispersions
`. ..... . ..... 338
`Rheology ....
`
`Part 3
`
`Pharmaceutical Chemist!}'_
`
`24
`25
`26
`27
`28
`29
`
`......... . ..... 361
`Inorganic Pharmaceutical Chemistry
`.3%
`Organic Pharmaceutical Chemistry
`. .410
`Natural Products .... . .
`Drug Nomenclature-United States Adopted Names ... .443
`Structure-Activity Relationship and Drug Design .. . . . . .468
`....... 479
`Fundamentals of Medical Radionuclides
`
`Part 4
`
`Pharmaceutical Testing, Analysis, and Control
`
`30
`31
`32
`33
`34
`35
`
`Analysis of Medicinals .
`Biological Testing
`. .. ..... . . . .
`Clinical Analysis
`. . . . . . . . . .
`Chromatography
`Instrumental Methods of Analysis
`Dissolution ...... . .
`
`.495
`.553
`.565
`.599
`... . ..... 633
`. .......... 672
`
`. . . ...
`
`Part S
`
`Pharmaceutical Manufacturing
`
`36
`37
`38
`39
`40
`41
`42
`43
`44
`45
`46
`47
`48
`
`Separation
`. ~1
`. .............. . . ... ... . ..... 7~
`Powders
`.720
`Property-Based Drug Design and Preformulation
`.MS
`Solutions, Emulsions, Suspensions, and Extracts . . ..
`Sterilization ..... . ..... . . .. . . .
`. 7~
`.M2
`Parenteral Preparations . . . . . . .
`. . ~7
`Intravenous Admixtures ........ . . .
`Ophthalmic Preparations . ....... . . . . . .
`. 8~
`Medicated Topicals . . . ... . .. . . .
`. ~1
`Oral Solid Dosage Forms
`.~9
`Coating of Pharmaceutical Dosage Forms
`.929
`. . ~9
`Extended-Release and Targeted Drug Delivery Systems
`The New Drug Approval Process and
`Clinical Trial Design .... . . . .. . . .. . .
`
`. ..... . .... 965
`
`. . . . ..
`
`49
`50
`51
`52
`53
`54
`55
`
`. .......... 976
`. . . . . . . . . .
`Biotechnology and Drugs
`Aerosols .... ... ............ . . . ... . .. . . . .. . .. 1000
`. .. 1018
`Quality Assurance and Control
`. . . . . . . . . . .
`Stability of Pharmaceutical Products
`. . . . . . . . .
`. ... 1025
`Bioavailability and Bioequivalency Testing .......... . 1037
`Plastic Packaging Materials
`................. . 1047
`Pharmaceutical Necessities
`.. 1058
`
`Part 6
`
`Pharmacokinetics and Pharmacodinamics
`
`56
`57
`58
`59
`60
`61
`62
`63
`
`Diseases: Manifestations and Pathophysiology .... . .. 1095
`Drug Absorption, Action, and Disposition ... ... . ... . 1142
`Basic Pharmacokinetics and Pharmacodynamics ...... 1 171
`Clinical Pharmacokinetics and Pharmacodynamics ... . . 1 191
`Priniciples of Immunology ..................... .. 1206
`... 1221
`Adverse Drug Reactions and Clinical Toxicology
`Pharmacogenomics .............. .
`. . . 1230
`Pharmacokinetics/Pharmacodynamics in
`Drug Development
`
`.. 1249
`
`Part 7
`
`Pharmaceutical and Medicinal Agents
`
`64
`65
`66
`67
`68
`69
`70
`71
`72
`
`73
`74
`75
`76
`77
`78
`79
`80
`81
`82
`83
`84
`85
`86
`87
`88
`89
`90
`91
`92
`93
`
`Diagnostic Drugs and Reagents ................. . . 1261
`.. 1277
`Topical Drugs
`Gastrointestinal and Liver Drugs ....... ... . . ...... 1294
`Blood, Fluids, Electrolytes, and Hematological Drugs .
`. 1318
`Cardiovascular Drugs ........ . . . ... . ........... 1350
`Respiratory Drugs
`............ . ... . ....... 1371
`Sympathomimetic Drugs . . . .
`. ............. . . 1379
`Chol inomimetic Drugs
`. . . . . . . .. 1389
`Adrenergic Antagonists and Adrenergic
`. .. . .... 1399
`Neuron Blocking Drugs .
`. . . . . . . . . . . . .
`Antimuscarinic and Antispasmodic Drugs ..... . ..... 1405
`Skeletal Muscle Relaxants ............... . . . ..... 141 1
`Diuretic Drugs . . . . . . .
`. ......... . ... . ..... . . 1422
`Uterine and Antimigraine Drugs ....... . . . ....... . 1432
`Hormones and Hormone Antagonists . . . . . . . . . .
`. 1437
`General Anesthetics
`. . . . . . .
`. . . . . . . . . . .
`. .. . . 1474
`.. 1479
`Local Anesthetics
`Antianxiety Agents and Hypnotic Drugs .. .. ....... . 1486
`Antiepileptic Drugs ........ . . . ................. 1501
`Psychopharmacologic Agents . . . . . . .
`. ...... 1 509
`Analgesic, Antipyretic, and Anti-Inflammatory Drugs ... 1 524
`...... 1543
`Histamine and Antihistaminic Drugs
`Central Nervous System Stimulants ... . . .... ... . ... 1551
`Antineoplastic Drugs .
`. . . . ........... . ....... . . 1 556
`lmmunoactive Drugs ......... . .. . . ... . . . . . . . ... 1588
`Parasiticides
`. . . . . . . . . . . . . . .
`. . . . . . .
`. . 1 595
`Immunizing Agents and Allergenic Extracts .......... 1600
`Anti-lnfectives . . . . . . . . . .
`. . 1626
`Enzymes . . . . . . . . . . . . . . . . . . .
`. .. . ......... . 1685
`Nutrients and Associated Substances
`.. . ... . ....... 1688
`. '' ' ........... 1719
`Pesticides
`
`Part 8
`
`Pharmac}'_ Practice
`
`A Fundamentals of Pharmacy Practice
`Application of Ethical Principles to Practice Dilemmas .. 1745
`Technology and Automation . . . . ..... . ....... . ... 1753
`The Patient: Behavioral Determinants . . . . . . . ... . ... 1762
`Patient Communication
`. . . .
`. ......... . 1770
`. .. 1782
`Patient Compliance . . . . . . . . . . . . . . . . . . . . .
`Drug Education . . . . . . . . . .
`. . . ... . ...... . ... 1 796
`
`94
`95
`96
`97
`98
`99
`
`xxi
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1013, Page 3
`
`

`

`xx ii
`
`CONTENTS
`
`100
`101
`102
`
`103
`104
`105
`106
`107
`108
`109
`110
`
`111
`112
`113
`114
`115
`116
`
`.......... 1808
`. ......... 1823
`
`Professional Communications
`The Prescription ........ .
`Providing a Framework for Ensuring
`................ . ..... 1840
`Medication Use Safety
`Poison Control
`.... . ....... . ....... 1881
`. ....... . ............ 1889
`. . . .
`Drug Interactions
`Extemporaneous Prescription Compounding
`.. 1903
`Nuclear Pharmacy Practice
`. . . . . . . .
`. .. 1913
`Nutrition in Pharmacy Practice . . . .
`.1925
`Pharmacoepidemiology .............. . ..... .. ... 1958
`Surgical Supplies . . . . . . . . . . . . . . . . . . . . . .
`. .1968
`Health Accessories
`. . . . . . . . . . . . . . . . . . .
`.1979
`
`B Social, Behavioral, Economic, and
`Administrative Sciences
`....... 2015
`Laws Governing Pharmacy
`. ....... 2055
`Re-engineering Pharmacy Practice .
`. ..... 2070
`Pharmacoeconomics . . . . . . . . . . . . . .
`Community Pharmacy Economics and Management ... 2082
`Product Recalls and Withdrawals .................. 2098
`Marketing Pharmaceutical Care Services
`.... . ... 2107
`
`117
`
`118
`119
`
`120
`121
`122
`
`123
`124
`125
`126
`127
`128
`129
`130
`131
`132
`133
`
`Documenting, Billing, and Reimbursement for
`Pharmaceutical Care Services
`. .... .
`Pharmaceutical Risk Management . .
`Integrated Health Care Delivery Systems
`
`. .2114
`.. 2124
`......... 2130
`
`..... 2155
`.2163
`
`C Patient Care
`Specialization in Pharmacy Practice
`Pharmacists and Disease State Management
`Development of a Pharmacy Care Plan and
`.2170
`Patient Problem-Solving
`. . . . . . . . . . . . .
`. .2179
`Ambulatory Patient Care . . . . . . . . . . . . . . . . .
`Self-Care . . . .
`. .......... . ....... 2197
`Diagnostic Self-Care . . . .
`. ... . . .. . .. ........ 2206
`Preventive Care . . .
`. . . . . . . . . . .
`.2223
`Hospital Pharmacy Practice
`..... . .......... 2247
`Emergency Medicine Pharmacy Practice
`..... 2265
`Long-Term Care . . . . . . . . .
`. .............. 2272
`Aseptic Processing for Home Infusion Pharmaceuticals
`.2290
`The Pharmacist's Role in Substance Use Disorders . . ... 2303
`Complementary and Alternative Medical Health Care .. 2318
`Chronic Wound Care
`. . . . . . . . .
`. .. 2342
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1013, Page 4
`
`

`

`I
`
`21 ST EDITION
`
`Remington
`
`The Science and Practice
`of Pharmacy
`
`\
`
`'~ LIPPINCOTT WILLIAMS & WILKINS
`
`A Wolters Kluwer Company
`Philadelphia• Baltimore· New York• London
`Buenos Aires • Hong Kong • Sydney • Tokyo
`
`•
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1013, Page 5
`
`

`

`Ophthalmic Preparations
`
`John C Lang, PhD
`Robert E Roehrs, PhD
`Rajni Jani, PhD
`
`Cl-\1\PT E R 43
`
`INTRODUCTION 1
`Ophthalmic preparations are specialized dosage forms de(cid:173)
`signed to be instilled onto the external surface of the eye (topi(cid:173)
`cal), administered inside (intraocular) or adjacent (periocular
`such asjuxtascleral or subtenon) to the eye, or used in conjunc(cid:173)
`tion with an ophthalmic device. The latter include preparations
`used in conjunction with surgical implantation (such as an in(cid:173)
`traocular lens), dry eye formulations compatible with a punctal
`appliance such as a punctal plug, and extends to a variety of so(cid:173)
`lutions utilized in maintenance of contact lenses. The prepara(cid:173)
`tions may have any of several purposes, therapeutic, prophy(cid:173)
`lactic or palliative for topically administered agents, but
`includes mechanical, chemical and biochemical actions of
`agents used in the care of ocular appliances, and tissue pro(cid:173)
`phylaxis during or following surgery. Because of the dangers
`associated with their administration, or repetitive administra(cid:173)
`tion, intraocular and periocular preparations are restricted to
`therapeutic applications or surgical adjuncts.
`The versatility of dosage forms enables them to be suitable
`for the function of the preparation. Therapeutically active for(cid:173)
`mulations may be designed to provide extended action for ei(cid:173)
`ther convenience or reduction in risk of repetitive administra(cid:173)
`tion, improved bioavailability of the agent, or improved delivery
`to a targeted tissue. The residence of an ocular preparation may
`range from a few seconds needed for tears to clear an irritating
`substance, to hours for a gel, a gel-forming solution or anoint(cid:173)
`ment, to months or years for an intraocular or periocular
`dosage form. The preparation may be strictly therapeutic, or
`may be administered for its prophylaxis. The latter include sur(cid:173)
`gical adjunctives to maintain the health of fragile cells, post(cid:173)
`surgical or post-trauma preparations designed to prevent or re(cid:173)
`duce the likelihood of infection. Another form of prophylaxis,
`that for a device, is the antisoiling function provided by some
`contact lens solutions.
`Ophthalmic preparations are similar to parenteral dosage
`forms in their requirement for sterility as well as considera(cid:173)
`tions for osmotic pressure (tonicity), preservation, tissue com(cid:173)
`patibility, the avoidance of pyrogens in intraocular dosage
`forms, particulate matter and suitable packaging.
`Topical therapeutic dosage forms have customarily been re(cid:173)
`stricted to solutions, suspensions and ointments. But with ad(cid:173)
`vances in material science, the range of ophthalmic dosage
`forms has expanded significantly to include gels, either pre(cid:173)
`formed or spontaneous gels responsive to the ocular environ(cid:173)
`ment, and ocular inserts, both forms reducing dosage fre(cid:173)
`quency. These are most often multi-dose products containing
`suitable preservative(s) to meet compendia! preservative effec(cid:173)
`tiveness test (eg, USP, 2 Pharm. Europa,3 or JP") requirements.
`Now, however, single-dose units, also referred to as unit-dose
`products, that are preservative-free preparations generally
`
`850
`
`packaged in form-fill-seal plastic containers with 0.25 m L to up
`to 0.8 mL, have become availablf!. These unit dose containers
`are designed to be discarded after a single use or after a single
`day's use ifthe container has a reclosable feature and the prod(cid:173)
`uct is so labeled.
`Injections and implants have been developed for intraocular
`drug delivery. Irrigating solutions and viscoelastic gels are
`available specifically for adjunctive use in ophthalmic surgery.
`Specialized formulations are now available for use in the care
`of contact lenses. The designs of these preparations meeting all
`of the requirements for safety, efficacy, component compatibil(cid:173)
`ity, tissue acceptability, storage, shipping, and shelflife are be(cid:173)
`yond the scope of this review. Nonetheless, a description of the
`requirements and the designs for somf! of these formulations
`should be illustrative and didactic.
`From a historical perspective, preparations intended for
`treatment of eye disorders can be traced to the writings of the
`Egyptians, Greeks, and Romans. In the Middle Ages, collyria
`were referred to as materials that weni dissolved in water, milk
`or egg white and used as eyedrops. One such collyrium con(cid:173)
`tained the mydriatic substance belladonna to dilate the pupils
`of miladys' eyes for cosmetic purpose.
`From the time of belladonna collyria, ophthalmic technol(cid:173)
`ogy progressed at a pharmaceutical snail's pace until after
`World War II. Prior to WWII and into the 1950s, ophthalmic
`preparations were mostly compounded by the pharmacist for
`immediate use. Not until 1953 was there a legal requirement
`by FDA that all manufactured ophthalmic solutions be sterile.
`The range of medicinal agents to treat eye disorders was lim(cid:173)
`ited as was the state of eye surgery and vision correction,
`which was limited to eyeglasses. In the past fifty years, a
`modern pharmaceutical industry specializing in ophthalmic
`preparations has developed to support the advances in diag(cid:173)
`nosis and treatment of eye diseases, eye surgery and contact
`lenses. Because of the variety of ophthalmic products readily
`available commercially, the pharmacist now is rarely required
`to compound a patient's ophthalmic prescription. More impor(cid:173)
`tant, however, is for the pharmacist to appreciate even subtle
`differences in formulations that may impact efficacy, comfort,
`compatibility or suitability of a preparation for particular
`patients.
`Currently and in the future, in addition to the advances in
`dosage-form technology, drug molecules will be designed and
`optimized specifically for ophthalmic application. New thera(cid:173)
`pies may become available for preventing blindness caused by
`degenerative disease - including age-related macular degener(cid:173)
`ation (AMD), macular edema, and diabetic retinopathy.
`Biotechnological products may also become available to treat
`causes of multifactorial eye disorders like glaucoma. Such spe(cid:173)
`cialized therapeutic agents also will require carefully designed
`compatible dosage forms.
`
`Bee
`quire
`for the
`functic
`their p
`
`· ANA
`THE
`Inmru
`admin
`UnlikE
`with0t
`investi
`tricate
`ulus it
`signal
`sensiti
`the fw
`man ti
`Thes~
`43-3.
`\den ti
`These
`the ey1
`struct
`phasiz
`troduo
`theey
`
`Eye I
`Eyelic
`and C'
`
`BO
`ME
`
`STF
`
`DES
`ME
`
`END
`
`Figur
`The d1
`eyebal
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1013, Page 6
`
`

`

`ER 43
`
`,
`
`125 mLto up
`e containers
`fter a single
`~d the prod-
`
`I
`intraocular
`tic gels are
`nic surgery.
`lin the care
`fleeting all
`com pa ti bi!-
`1 life are be-
`ption of the
`tmulations
`
`tended for
`ngs of the
`',s, collyria
`ater, milk
`iriurn con-
`he pupils
`
`c technol-
`ntil after
`hthalmic
`tiacist for
`uirement
`>e sterile.
`was lim-
`lrrection,
`years, a
`b.thalmic
`in diag-
`1 contact
`: readily
`required
`3 impor-
`n subtle
`:omfort,
`rticular
`
`mces in
`1ed and
`· thera-
`lSed by
`egener-
`1pathy.
`o treat
`ch spe-
`1signed ,
`
`Because dosage forms are fashioned to complement the re(cid:173)
`quirements of the therapeutic agent, and the latter are selected
`for their action upon particular tissues in order to modify their
`function, we will now turn to a description of ocular tissues and
`their physiology.
`
`ANATOMY AND PHYSIOLOGY OF
`THE EYE
`In many ways the human eye is an ideal organ for studying drug
`administration and disposition, organ physiology and function.
`Unlike many bodily organs, most of its structure can be inspected
`without surgical intervention. Its macroscopic responses can be
`investigated by direct observation. Its miraculous function so in(cid:173)
`tricate and complex - converting a physical electromagnetic stim(cid:173)
`ulus into a chemical signal that is coupled to distant neurons for
`signal processing by an electrochemical wave - can be detected by
`sensitive instruments attached to external tissues. The basis for
`the function and protection of this important organ that links
`man to his external environment are the tissues comprising it.
`ll'he structures to be described are illustrated in Figures 43-1 to
`~3-3. The first figure5 provides a horizontal section of the eyeball
`1dentifying the major structures and their interrelationships.
`The second figure6 shows in greater detail the anterior portion of
`the eye and eyelids, in vertical section, emphasizing some of the
`structures associated with tear apparatus. The third figure 6 em(cid:173)
`phasizes the flow of tears into the nasal structures. This brief in(cid:173)
`troduction will focus on the anatomical structures comprising
`the eye, and their function.
`
`Eyelids
`Eyelids serve two purposes: mechanical protection of the globe
`and creation of an optimum milieu for the cornea. The inner
`
`CHAPTER 43: OPHTHALMIC PREPARATIONS
`
`8 51
`
`surfaces of the eyelids and the outermost surfaces of the eye are
`lubricated by the tears, a composite of secretions from both
`lacrimal glands and specialized cells residing in both the bulbar
`(covering the sclera) and palpebral (covering the inner surface
`of the lids) conjunctiva. The antechamber has the shape of a
`narrow cleft directly over the front of the eyeball, with pocket(cid:173)
`like extensions upward and downward. The pockets are called
`the superior and inferior fornices (vaults), and the entire space,
`the cul-de-sac. The elliptical opening between the eyelids is
`called the palpebral fissure and the corner of the eyes where the
`eyelids meet are the canthi.
`
`Overview of Structure and Function of
`the Eyeball
`
`STRUCTURE
`The eyeball is housed in the bones of the skull, joined to form an
`approximately pyramid-shaped housing for the eyeball, called
`the orbit. The wall of the human eyeball (bulbus, globe) is com(cid:173)
`posed of three concentric layers that envelop the fluid and
`lenticular core. 7- 9
`Outer Fibrous Layer: The outer scleral layer is tough, pli(cid:173)
`able, but only slightly elastic. The anterior third is covered by
`the conjunctiva, a clear transparent mucous surface. The most
`anterior portion of the outer layer forms the cornea, a structure
`so regular and the water content so carefully adjusted that it
`acts as a clear, transparent window. It is devoid of blood ves(cid:173)
`sels. Over the remaining two-thirds of the globe the fibrous col(cid:173)
`lagen-rich coat is opaque (the white of the eye) and is called the
`sclera. It contains the microcirculation, which nourishes the tis(cid:173)
`sues of this anterior segment, and is usually white except when
`irritated vessels become dilated.
`The cornea, slightly thicker than the sclera and ranging in
`thickness from 500 microns to one millimeter, consists of five
`
`BOWMAN'S
`MEMBRANE
`
`ST ROMA
`L -
`DESCEMET'S
`MEMBRANE
`
`LATERAL RECTUS MUSCLE
`
`CENTRAL RETINAL
`VIEW
`
`TRABECULAR
`MESHWORK
`
`MEDIAL RECTUS MUSCLE
`
`Figure 43-1. A cutaway horizontal section of the eyeball illustrating the important anatomic structures and their interrelationships diagramatically.
`The different layers of the cornea are illustrated in the magnified view. Relative sizes are suggestive and not proportional. The diameter of a mature
`eyeball is generally slightly greater than one inch (courtesy, Alcon, Inc., Fort Worth, TX). See Color Plate 19.
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1013, Page 7
`
`

`

`852
`
`PART 5: PHARMACEUTICAL MANUFACTURING
`
`WOLFRING'S
`GLANDS-".,._----~~ll
`
`GLANDS OF
`#---;r.,-:-+---MANZ
`
`CRYPTS OF
`HENLE•---l'!--~-:ffio~
`
`MEIBOMIAN
`GLANDS--ll'---mt'H
`
`TARSALPLATE-¥.----f~IC.ID
`
`VITREOUS
`HUMOR
`
`Figure 43-2. The front half of the eye, in vertical section, identifying the
`important structures associated with cornea and the front of the eye, in(cid:173)
`cluding the eyelids and the glands associated with tears.
`
`identifiable layers. Proceeding from the most anterior layer,
`these are the hydrophobic stratified squamous epithelium, which
`is underlaid by Bowman's membrane, then the stroma and De(cid:173)
`scemet's membrane, and then the innermost layer, the endothe(cid:173)
`lium. The stroma is a hydrophilic elastic network of highly orga(cid:173)
`nized connective tissue and is the thickest layer of the cornea. The
`fibrous collagen-rich Descemet's membrane separates the
`stroma from the single-squamous-cell layer of endothelium, the
`location of the pump that keeps the cornea in its relatively dehy(cid:173)
`drated transparent state. Functionally, the cornea serves as a bi(cid:173)
`layer barrier, the hydrophobic epithelium being the primary bar(cid:173)
`rier to hydrophilic molecules, and the hydrophilic stroma, the
`primary barrier to hydrophobic molecules. A schematic drawing
`of the cornea is provided in Figure 43-1.
`Middle Vascular Layer: The middle vascular layer, or uvea,
`provides nourishment to the eye and consists, moving from the
`back of the eye forward, of the choroid, the ciliary body, and the
`iris. The choroid consists of a pigmented vascular layer, colored
`by melanocytes and traversed by medium-sized arteries and
`veins, with the choriocapillaris containing a network of small
`vessels that nourish the neural retina. The ciliary body con(cid:173)
`tains muscles that control the extension of the lens allowing vi(cid:173)
`sual accommodation, as well as the ciliary processes that se(cid:173)
`crete aqueous humor into the posterior chamber to maintain
`the intraocular pressure that in turn keeps the eyeball fully ex(cid:173)
`panded. The pigmented iris is a ring of muscular tissue around
`the pupil, a round centric hole that acts as a variable aperture
`to control pupil diameter, and thereby the level of light enter(cid:173)
`ing the eye. The canal of Schlemm, one of the important paths
`for outflow of the aqueous humor, resides in the angle of the
`iris. Bruch's membrane separates the choroid from the retina.
`
`Neural Retina: This innermost layer of the eyeball is a complex
`tissue that supports the harvesting oflight through the action of
`photoreceptors - nerve cells specialized for distinguishing white
`from black (rods), or discerning color (cones). In addition, the
`retina consists of cells that support metabolism (like the heavily
`pigmented retinal pigmented epithelium, the RPE, which purges
`photoreceptors of spent molecules and metabolites, and regener·
`ates the cis-retinal), provide structure (astrocytes and Muelle
`cells), or contribute to the primary function of photodetection I sig·
`nal processing (the ganglion cells that begin to process the rl ·
`trochemical information transmitted from the photoreceptorsJ.
`Ocular Core: Within the globe, the crystalline lens spans the
`interior fluid-filled center close to the iris and is anchored by
`zonule fibers to the ciliary body. The lens is composed of a sin(cid:173)
`gle layer ofreplicating epithelial cells that with age flatten into
`layers oflong thin crystalline-filled lamellar fibers. The le.ns i•
`the only tissue in the body that retains all cells ever produced,
`a fact that contributes to age-related alterations in size, clarity
`and extensibility. A tough thin transparent membrane called
`the capsule covers the outermost layer of the lens.
`The aqueous and vitreous humors are interposed between
`the solid structures of the eye. The clear, fluid aqueous humor
`fills the globe anterior to the lens and is primarily responsible
`for maintaining correct intraocular pressure. The gel-like vitre(cid:173)
`ous humor accounts for most of the weight of the eye and re(cid:173)
`sides posterior to the lens in direct contact with the retina.
`
`FUNCTION
`
`The eyeball houses the optical apparatus that causes inverted
`reduced images of the outside world to form on the neural retina.
`Dimensional Stability: The optical function of the eye calls
`for stability of its dimensions, which is provided partly by the fi(cid:173)
`brous outer coat, but more effectively by the intraocular pres(cid:173)
`sure (IOP), which exceeds the pressure prevailing in the sur(cid:173)
`rounding tissues. This intraocular pressure is the result of a
`steady production of specific fluid, the aqueous humor, which
`
`NASAL
`SEPTUM
`
`Figure 43-3. The structures associated with the tears and lacrimal flo
`and access to the nasolacrimal system.
`
`originates fo
`leaves the ey
`resistance en
`ous producti(
`the intraocul
`function, the
`strates, and 1
`Optical Pc
`of the precor;
`pupil, the cr1
`The chief re~
`face of the cc
`that of air (J
`traversing tr
`humor to the
`is regulated
`fractive elem
`allows object
`commodatior
`of the ciliary
`image on the
`cause of the t
`cause of its g
`the pathway
`magnetic lig'
`chemical sigr
`processed by
`ported throu1
`conversion ol
`processable i
`retina, and i
`rapidly metal
`neural retina
`lying cell lay
`such as detac
`can result in
`Tissues Re
`or transparer
`clear image; t
`may interfere
`of the eye. Tr
`its organized
`sence of blood
`sels except at
`therefore, mu
`certain perme
`from the fluici
`from the air. '
`vessels is an ~
`Cloudines!
`excess pressu
`coma), the prl
`ciency of oxyg
`the wearing o
`cornea may h
`impairment o
`cornea.
`The cornei
`the cornea, bt
`have a very lt
`most sensitivl
`that the corn1
`supplying the
`The cornea
`bacterial inva
`abrasion (a t:
`pathogenic ba
`therefore, pla1
`eases of the c<
`ing abrasions
`cornea with so
`to infection.
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1013, Page 8
`
`

`

`lll is a complex
`~ the action of
`luishing white
`addition, the
`ke the heavily
`which purges
`and regener(cid:173)
`and Mueller
`tletection I sig(cid:173)
`cess the elec(cid:173)
`breceptorsJ.
`ens spans tne
`anchored by
`osed of a sin(cid:173)
`fe flatten into
`~s. The lenl'> is
`ver produced,
`n size, clarity
`brane called
`
`osed between
`lueous humor
`y responsible
`gel-like vitre(cid:173)
`e eye and re-
`e retina.
`
`ses inverted
`eural retina.
`the eye calls
`~rtly by the fi(cid:173)
`aocular pres(cid:173)
`g in the sur(cid:173)
`le result of a
`umor, which
`
`NASAL
`SEPTUM
`
`~
`
`~
`
`lacrimal flow
`
`originates from the ciliary processes anterior to the lens and
`leaves the eye by an intricate system of outflow channels. The
`resistance encountered during this passage and the rate of aque(cid:173)
`ous production are the principal factors determining the level of
`the intraocular pressure. In addition to this hydromechanical
`function, the aqueous humor acts as a carrier of nutrients, sub(cid:173)
`strates, and metabolites for the avascular tissues of the eye. 10
`Optical Pathway: The optical pathway consists, in sequence,
`of the precorneal tear film, the cornea, the aqueous humor, the
`pupil, the crystalline lens, the vitreous humor, and the retina.
`The chief refraction of light for the eye occurs at the outer sur(cid:173)
`face of the cornea where the index of refraction changes from
`that of air (LOO) to that of precorneal substance (1.38). After
`traversing the cornea, light passes through the clear aqueous
`humor to the pupil, where the amount oflight entering the eye
`is regulated by the pupillary diameter, and to the second re(cid:173)
`fractive element of the eye, the lens, whose variable focal length
`allows objects both near and far to be brought into focus (ac(cid:173)
`commodation). The shape of the lens, controlled by the muscles
`of the ciliary body, refracts and focuses the reduced inverted
`image on the retina. That image is sharp and clear, in part, be(cid:173)
`cause of the high transparency of the vitreous humor, which be(cid:173)
`cause of its gel-like state keeps debris and cells from entering
`the pathway for the light. The image formed by the electro(cid:173)
`magnetic light signal on the neural retina is converted to a
`chemical signal, changing cis- to trans- retinal, which in turn is
`processed by neural cells into an electrochemical signal trans(cid:173)
`ported through axons to central nerve bodies. This continuous
`conversion of the excitation associated with a retinal image to
`processable information, is integral to the functioning of the
`retina, and is the reason retinal tissue is amongst the most
`rapidly metabolizing tissues in the body. The dependence of the
`neural retina on the metabolic support provided by the under(cid:173)
`lying cell layer, the RPE, explains why damage to the tissue -
`such as detachment of the retina or diminished blood supply -
`can result in nearly immediate and permanent loss ofvision. 11
`Tissues Responsible for Refraction: Any alteration in the shape
`or transparency of the cornea interferes with the formation of a
`clear-i