`Science and
`
`Practice
`of Pharmacy
`
`TEVA - EXHIBIT 1016
`
`
`
`
`
`Editor: Daniel Limmer
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
`
`Lippincott Williams & Wilkins
`
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`
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`by any information storage and retrieval system Without written permission
`from the copyright owner.
`
`The publisher is not responsible (as a matter of product liability, negligence or
`otherwise) for any injury resulting from any 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.
`Manufacturers’ product information and package inserts should be reviewed for
`current information, including contraindications, dosages and precautions.
`
`Printed in the United States ofAmerica
`
`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
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Phila-
`delphia College of Pharmacy and Science
`
`Copyright 2000, by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0—683—306472
`
`The publishers have made every effort to trace the copyright holders for borrowed
`material. Ifthey have inadvertently overlooked any, they will be pleased to make
`the necessary arrangements at the first opportunity.
`
`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 respon-
`sible for any inaccuracy contained herein.
`Notice—Th is 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/or the National Formulary (NF). In the event of any difference or discrep-
`ancy between the current official USP or NF standards of strength, quality,
`purity, packaging and labeling for drugs and representations ofthem herein, the
`context and effect of the official compendia shall prevail.
`
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`
`02 03 O4
`.2 3 4 5 6 7 8 9 10
`
`
`
`Table of Contents
`
`’ Par? 1__Orientation
`
`1
`
`03\lO\U\4>-(.Jl\)
`
`«O
`
`Scope of Pharmacy ........................
`Evolution of Pharmacy ......................
`Ethics and Professionalism ....... ..............
`The Practice of Community Pharmacy ...........
`Pharmacists in industry ......................
`Pharmacists in Government ..................
`Pharmacists and Public Health .................
`information Resources in Pharmacy and the
`Pharmaceutical Sciences .....................
`Clinical Drug Literature ......................
`Research ...............................
`
`Part 2 Pharmaceutics
`
`Pharmaceutical Calculations ..................
`Statistics .................................
`Molecular Structure, Properties, and States of Matter. .
`.
`Complex Formation ........................
`Thermodynamics ..........................
`Solutions and Phase Equilibria .................
`Ionic Solutions and Electrolytic Equilibria ..........
`Tonicity, Osmoticity, Osmoialiry, and Osmoiarity. .
`.
`.
`Chemical Kinetics .........................
`Interfaciai Phenomena ......................
`Colloidal Dispersions ........................
`Coarse Dispersions .........................
`Rheology ...............................
`
`Part 3 Pharmaceutical Chemistry
`
`Inorganic Pharmaceutical Chemistry ............
`Organic Pharmaceutical Chemistry .............
`Natural Products ...........................
`Drug Nomenclature—United States Adopted
`Names .................................
`Structure—Activity Relationship and Drug Design .....
`Fundamentals of Radionuclides ...............
`
`Part 4 Pharmaceutical Testing, Analysis and Control
`
`Analysis of Medicinais .......................
`Biological Testing .........................
`Clinical Analysis ...........................
`Chromatography ..........................
`instrumental Methods of Analysis ..............
`Dissolution ...............................
`
`Part 5 Pharmaceutical Manufacturing
`
`Separation ..............................
`Powders ................................
`Preformuiotion ............................
`Solutions, Emulsions, Suspensions, and Extracts .....
`Sterilization ..............................
`Parenteral Preparations .....................
`Intravenous Admixtures .....................
`Ophthalmic Preparations ....................
`Medicated Topicals ........................
`Oral Solid Dosage Forms ....................
`Coating of Pharmaceutical Dosage Forms ........
`Controlled-Release Drug-Delivery Systems ........
`The Introduction of New Drugs ...............
`
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`
`24
`25
`26
`27
`
`28
`29
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`30
`31
`32
`33
`34
`35
`
`36
`37
`38
`39
`40
`41
`42
`43
`44
`45
`46
`47
`48
`
`19
`28
`33
`38
`47
`
`60
`70
`81
`
`91
`124
`159
`183
`198
`208
`227
`246
`263
`275
`288
`316
`335
`
`359
`385
`409
`
`441
`458
`469
`
`485
`540
`552
`587
`614
`654
`
`669
`681
`700
`721
`753
`780
`807
`821
`836
`858
`894
`903
`930
`
`xiv
`
`49
`50
`51
`52
`53
`54
`55
`
`56
`57
`58
`59
`60
`61
`62
`63
`
`64
`65
`66
`67
`68
`69
`7O
`71
`72
`73
`74
`75
`76
`77
`78
`79
`80
`81
`82
`83
`
`84
`85
`86
`87
`88
`89
`
`Biotechnology and Drugs ....................
`Aerosols ................................
`Quality Assurance and Control ................
`Stability of Pharmaceutical Products .............
`Bioavaiiabiiity and Bioequivaiency Testing ........
`Plastic Packaging Materials ...................
`Pharmaceutical Necessities ...................
`
`Part 6 Pharmacodynamics
`
`Diseases: Manifestations and Pathophysioiogy .....
`Drug Absorption, Action, and Disposition .........
`Basic Pharmacokinetics ......................
`Clinical Pharmacokinetics ....................
`Principles of immunology ....................
`Adverse Drug Reactions .....................
`Pharmacogenetics .........................
`Pharmacological Aspects of Substance Abuse ......
`
`Part 7 Pharmaceutical and Medicinal Agents
`
`Diagnostic Drugs and Reagents ................
`Topical Drugs .............................
`Gastrointestinal and Liver Drugs ................
`Blood, Fluids, Electrolytes, and Hematological Drugs.
`.
`.
`.
`Cardiovascular Drugs .......................
`Respiratory Drugs ..........................
`Sympathomimetic Drugs ....................
`Cholinomimetic Drugs -. .....................
`Adrenergic and Adrenergic Neuron Blocking Drugs. .
`Antimuscarinic and Antispasmodic Drugs .........
`Skeletal Muscle Relaxants ....................
`Diuretic Drugs ............................
`Uterine and Antimigraine Drugs ...............
`Hormones and Hormone Antagonists ...........
`General Anesthetics ........................
`Local Anesthetics ..........................
`Sedative and Hypnotic Drugs .................
`Antiepiieptic Drugs .........................
`Psychopharmacoiogic Agents .................
`Analgesic, Antipyretic, and Anti—Inflammatory
`Drugs ..................................
`Histamine and Antihistaminic Drugs .............
`Central Nervous System Stimulants ..............
`Antineopiastic and Immunoactive Drugs .........
`Anti-infectives ............................
`Parasiticides ..............................
`Immunizing Agents and Allergenic Extracts ......
`
`Part 8 Pharmacy Practice
`
`Part 8A Pharmacy Administration
`90
`91
`92
`93
`
`Laws Governing Pharmacy ..................
`Pharmacoeconomics .......................
`Marketing Pharmaceutical Core Services .........
`Documenting and Billing for Pharmaceutical Care
`Services ................................
`Community Pharmacy Economics and
`Management ............................
`Product Recalls and Withdrawals ..............
`
`94
`
`95
`
`Part 813 Fundamentals of Pharmacy Practice
`96 Drug Education .
`
`......
`
`.
`
`944
`963
`980
`986
`995
`1005
`1015
`
`1053
`1098
`1127
`1145
`1156
`1165
`1169
`1175
`
`1185
`1200
`1219
`1243
`1274
`1297
`1305
`1314
`1322
`1328
`1333
`1344
`1354
`1358
`1395
`1400
`1407
`1421
`1429
`
`1444
`1464
`1471
`1477
`1507
`1562
`1567
`
`1595
`1625
`1634
`
`1640
`
`1650
`1666
`
`1677
`
`
`
`I
`
`97 The Prescription ...........................
`98 Extemporaneous Prescription Compounding ......
`99 Poison‘gControl ...........................
`100 Nutrition in Pharmacy Practice ................
`101 Selt—Care/Diagnostic Products ..................
`102 Drug Interactions ..........................
`103 Complementary and Alternative Medical Health
`Care .......... : ........................
`104 Nuclear Pharmacy Practice ..................
`105 Enzymes ...............................
`106 Vitamins and Other Nutrients .................
`107 Pesticides ...............................
`
`108 Surgical Supplies ..........................
`109 Health Accessories .........................
`
`Part 6C Patient Care
`
`1 10 Ambulatory Patient Care ....................
`1 11 Institutional Patient Care ....................
`
`1 12 Long-Term Care Facilities ....................
`
`1687
`1706
`1716
`1725
`1738
`1746
`
`1762
`1781
`1792
`1796
`1825
`1846
`1857
`
`1893
`1911
`1932
`
`113
`114
`115
`116
`117
`118
`119
`
`The Patient; Behavioral Determinants ...........
`Patient Communication .....................
`
`Patient Compliance .......................
`Phormacoepidemiology ...................
`Integrated Health-Care Delivery Systems .........
`Home Health Patient Care .................
`
`Aseptic Technology for Home-Care
`Pharmaceuticals ................. .
`
`Appendixes
`
`.
`.
`Dose Equivalents ................
`Periodic Chart ...........................
`
`Logarithms ......................... .
`
`.
`
`.
`
`.
`
`Glossary and Index
`
`Glossary ................................
`Index ..................................
`
`1948
`1957
`1966
`1980
`1990
`2012
`
`2020
`
`2033
`2034
`2036
`
`2037
`2039
`
`
`
`
`
`XV
`
`
`
`Ophthalmic Preparations
`
`CHAPTER 43
`
`Gerald Hecht, PhD
`Senior Director, Pharmaceutical Sciences
`Alcon Laboratories
`Fort Worth, TX 76101
`
`
`
`Ophthalmic preparations are sterile products essentially free
`from foreign particles, suitably compounded and packaged for
`instillation into the eye. Ophthalmic preparations include so-
`lutions, suspensions, ointments, and solid dosage forms. The
`solutions and suspensions are, for the most part, aqueous.
`Ophthalmic ointments usually contain a white petrolatum—
`mineral oil base.
`Ophthalmic preparations can be grouped broadly into two
`divisions of major significance to the pharmacist. These include
`single or multidose prescription products and the category de-
`scribed as OTC or over-the-counter ophthalmic products. The
`latter group has been subjected to a searching review and
`analysis by a body of experts as a part of the Food and Drug
`Administration’s (FDA) OTC Drug Review process.
`The single dominant factor characteristic of all ophthalmic
`products is the specification of sterility. Any product intended
`for use in the eye regardless of form, substance, or intent must
`be sterile. This requirement increases the similarity between
`ophthalmic and parenteral products; however the physiology
`of the human eye in many respects imposes more rigid
`formulation requirements. This is considered in the following
`discussion
`
`Preparations intended for the treatment of eye disorders
`can be traced to antiquity. Egyptian papyri writings describe
`eye medications. The Greeks and Romans expanded such uses
`and gave us the term collyria. Collyria refers collectively to
`materials that were dissolved in water, milk, or egg white for
`use as eyedrops. In the Middle Ages collyria included mydriatic
`substances to dilate the pupils of milady’s eyes for cosmetic
`purposes, thus the term belladonna, or beautiful lady.
`From the time of belladonna collyria, ophthalmic technology
`progressed at a pharmaceutical snail’s pace well into modern
`times. It was not until after World War II that the concept of
`sterility became mandatory for ophthalmic solutions. Prior to
`World War II and continuing into the 1940s very few ophthal-
`mic preparations were available commercially or were de-
`scribed officially. The USP XIV, official in 1950, included only
`three ophthalmic preparations, and all three were ointments.
`Preparations to be used in the eye, either solutions or oint-
`ments, invariably were compounded in the community or hos-
`pital pharmacy and were intended for immediate (preacription)
`use. Such preparation and prompt use is reflected in the phar—
`maceutical literature of the times. The stability of ophthalmic
`preparations is discussed in terms of days or a few months.
`One of the most important attributes of ophthalmic products
`is the requirement of sterility. Even that, however, is a sur-
`prisingly recent event. The USP XV in 1955 was the first
`official compendium to include a sterility requirement for oph-
`thalmic solutions. The FDA in 1953 adopted the position that a
`nonsterile ophthalmic solution was adulterated. Sterile oph-
`thalmic products were, of course, available prior to the mid--
`1950s; however the legal requirement of sterility dates only
`from 1955.
`
`The sterility requirements for ophthalmic ointments ap-
`peared first in the USP XVIII, Third Supplement (1972). Prior
`to that date there was no legal requirement for a sterile oph-
`thalmic ointment. This probably was due to the difficulty (at
`that time) of testing for sterility in such nonaqueous systems
`and also the anticipated difficulties in sterilizing and maintain—
`ing sterile conditions during the manufacture and filling of
`ointments on a large scale.
`
`
`
`ANATOMY AND PHYSIOLOGY OF THE EYE
`
`The human eye is a challenging subject for topical administra-
`tion of drugs. The basis of this can be found in the anatomical
`arrangement of the surface tissues and in the permeability of
`the cornea. The protective operation of the eyelids and lacrimal
`system is such that there is rapid removal of material instilled
`into the eye, unless the material is suitably small in volume
`and chemically and physiologically compatible with surface
`tissues. Figures 43-11 and 43-21 include pertinent anatomy of
`the human eye.
`EYELIDS—The eyelids serve two purposes: mechanical
`protection of the globe and creation of an Optimum milieu for
`the cornea. The eyelids are lubricated and kept fluid—filled by
`secretions of the lacrimal glands and specialized cells residing
`in the bulbar conjunctiva. The antechamber has the shape of a
`narrow cleft directly over the front of the eyeball, with pocket-
`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.
`EYEBALL—The wall of the human eyeball (bulbus, globe)
`is composed of three concentric layers.
`1. The outer fibrous layer.
`2. A middle vascular layer—the uvea or uveal tract, consisting of the
`choroid, the ciliary body, and the iris.
`3. A nervous layer—the retina.
`
`The outer layer is tough, pliable, but only slightly stretchable.
`In its front portion—the portion facing the outside world—the
`fine structure of the outer layer is so regular and the water
`content so carefully adjusted that it acts as a clear, transparent
`window (the cornea). It is devoid of blood vessels. Over the
`remaining two—thirds the fibrous coat is opaque (the white of
`the eye) and is called the sclera. It contains the microcircula—
`tion, which nourishes the tissues of this anterior segment, and
`is usually white except when irritated and vessel dilatation
`occurs.
`
`The eyeball houses an optical apparatus that causes in-
`verted reduced images of the outside world to form on the
`retina, which is a thin translucent membrane. The optical
`apparatus consists, in sequence, of the precorneal film, the
`cornea, the aqueous humor, the pupil, the crystalline lens, the
`
`821
`
`
`
`compounds, approximately 0.7% protein, and the enzyme ly-
`sozyme. Small accessory lacrimal glands are situated in the
`conjunctival fornices. Their secretion suffices for lubrication
`and cleansing under ordinary conditions and for maintaining a
`thin fluid film covering the cornea and conjunctiva (the precor—
`neal film). The mucin-protein layer of the film is especially
`important in maintaining the stability of the film. The main
`lacrimal gland is called into play only on special occasions. The
`sebaceous glands of the eyelids secrete an oily fluid that helps
`to prevent overflowing of tears at the lid margin and reduces
`evaporation from the exposed surfaces of the eye by spreading
`over the tear film.
`
`Spontaneous blinking replenishes the fluid film by pushing
`a thin layer of fluid ahead of the lid margins as they come
`together. The excess fluid is directed into the lacrimal lake——a
`small, triangular area lying in the angle bound by the inner-
`most portions of the lids. The skin of the eyelids is the thinnest
`in the body and folds easily, thus permitting rapid opening and
`closing of the palpebral fissures. The movement of the eyelids
`includes a narrowing of the palpebral fissures in a zipper-like
`action from the lateral canthus toward the medial canthus
`(canthi: the corners where the eyelids meet). This aids the
`transport or movement of fluid toward the lacrimal lake.
`Tears are drained from the lacrimal lake by two small
`tubes—the lacrimal canaliculi—which lead into the upper part
`of the nasolacrimal duct, the roomy beginning of which is called
`the lacrimal sac. The drainage of tears into the nose does not
`depend merely on gravity. Fluid enters and passes along the
`lacrimal canaliculi by capillary attraction aided by aspiration
`caused by contraction of muscle embedded in the eyelids. When
`the lids close, as in blinking, contraction of the muscle causes
`dilatation of the upper part of the lacrimal sac and compression
`of its lower portion. Tears are thus aspirated into the sac, and
`any that have collected in its lower part are forced down the
`nasolacrimal duct toward its opening into the nose. As the lids
`open,
`the muscle relaxes. The upper part of the sac then
`collapses and forces fluid into the lower part, which at the same
`time is released from compression. Thus, the act of blinking
`exerts a suction force-pump action in removing tears from
`the lacrimal lake and emptying them into the nasal cavity.
`
`
`
`LACRlMAL GLAND
`
`
`
`
`
`
`EXCRETORY DUCTS
`
`LACRIMAL SAC
`
`NASAL
`SEPTUM
`
`FORNIX—
`
`
`
`
`"VALVE" OF HASNER
`(LACRIMAL PLKCA)
`
`Figure 43-2. Nasolacrimal duct.1
`
`822
`
`CHAPTER 43
`
`EXCRETORY DUCT
`
`
` 'LACRIMAL _
`GLAND
`GLANDS OF
`KRAUSE—‘fi
`
`
`
`CONJUNCTIVA _ _r_
`' CONJUNCTIVAL
`SAC
` uA/W
`
`WOLFRING'S
`
`GLANDS
`
`GLANDS OF
`MANZ
`
`
`
`
`
`
`VITREOUS
`
` GLANDS OF
`ZEIS
`(SEBACEOUS)
`
`\ \
`
`\
`
`CRYPTS OF
`HENLE
`
`MEIBOMIAN
`GLANDS—
`
`TARSAL PLATE
`
`GLANDS OF MOLL/
`(SWEAT)
`
`
`
`Figure 43-1. The eye: vertical section.“1
`
`vitreous humor, and the retina. The aqueous and vitreous
`humors are layers of clear fluid or gel-like material interposed
`between the solid structures. The pupil, a round centric hole in
`a contractile membranous partition (called the iris), acts as the
`variable aperture of the system. The crystalline lens is a re-
`fractive element with variable power controlled and supported
`by a muscle incorporated in the ciliary body. The choroid is the
`metabolic support for the retina.
`The optical function of the eye calls for stability of its di-
`mensions, which is provided partly by the fibrous outer coat;
`more effective as a stabilizing factor is the intraocular pres-
`sure, Which exceeds the pressure prevailing in the surrounding
`tissues. This intraocular pressure is the result of a steady
`production of specific fluid, the aqueous humor, which origi-
`nates from the ciliary processes and leaves the eye by an
`intricate system of outflow channels. The resistance encoun-
`tered during this passage and the rate of aqueous production
`are the principal factors determining the level of the intraocu-
`lar pressure. In addition to this hydromechanical function, the
`aqueous humor acts as a carrier of nutrients, substrates, and
`metabolites for the avascular tissues of the eye.
`The bones of the skull join to form an approximately
`pyramid—shaped housing for the eyeball, called the orbit.
`CONJUNCTIVA—The conjunctival membrane covers the
`outer surface of the white portion of the eye and the inner
`aspect of the eyelids. In most places it is attached loosely and
`thus permits free movement of the eyeball. This makes possible
`subconjunctival injections. Except for the cornea the conjunc-
`tiva is the most exposed portion of the eye.
`LACRIMAL SYSTEM—The conjunctival and corneal sur-
`faces are covered and lubricated by a film of fluid secreted by
`the conjunctival and lacrimal glands. The secretion of the lac-
`rimal gland, the tears, is delivered through a number of fine
`ducts into the conjunctival fornix. The secretion is a clear,
`watery fluid containing numerous salts, glucose, other organic
`
`
`
`OPHTHALMlC PREPARATIONS
`
`823
`
`pathogenic bacteria, as a rule, cannot gain a foothold. Trauma,
`therefore, plays an important part in most of the infectious
`diseases of the cornea that occur exogenously. Any foreign body
`that either scratches the cornea or lodges and becomes embed-
`ded in the cornea is of serious moment because of the role it
`may play in permitting pathogenic bacteria to gain a foothold.
`A means of detecting abrasions on the corneal surface is
`afforded by staining the cornea with sodium fluorescein. If
`there is an abrasion on the epithelium, the underlying layer
`stains a brilliant green, so that even pinpoint abrasions show
`up quite clearly. Abrasion may occur during tonometry; ie,
`during the measurement of ocular tension (pressure) with a
`tonometer. Care must be used in applying the device to the
`cornea to avoid abrasion of the cornea. Corneal abrasions some-
`times result from wearing contact lenses. Every corneal abra-
`sion is subject to infection.
`
`BIOAVAILABILITY
`
`m P
`
`HYSICAL CONSIDERATION—Under normal condi-
`tions the human tear volume averages about 7 uL.2 The esti-
`mated maximum volume of the cul-de—sac is about 30 uL, with
`drainage capacity far exceeding lacrimation rate. The outflow
`capacity accommodates the sudden large volume resulting from
`the instillation of an eyedrop. Most commercial eyedrops range
`from 50 to 75 ML in volume; however, much in excess of 50 ML
`probably is unable to enter the cul-de—sac.
`Within the rabbit cul-de—sac, the drainage rate has been
`shown to be proportional to the instilled drop volume. Multiple
`drops administered at intervals produced higher drug concen-
`trations. Ideally, a high concentration of drug in a minimum
`drop volume is desirable. Patton3 has shown that approxi-
`mately equal tear-film concentrations result from the instilla-
`tion of 5 ML of 1.61 X 10—2 M pilocarpine nitrate or from 25 uL
`of 1.0 X 10—2 M solution. The 5 ML contains only 38% as much
`pilocarpine, yet its bioavailability is greater because of de—
`creased drainage loss.
`There is a practical limit or limits to the concept of mini-
`mum dosage volume. There is a difficulty in designing and
`producing a dropper configuration that will deliver small vol-
`umes reproducibly. Also, the patient often cannot detect the
`administration of such a small volume. This sensation or lack
`of sensation is particularly apparent at the 5.0 to 7.5-uL dose—
`volume range.
`The concept of dosage—volume drainage and cul-de—sac ca-
`pacity directly affects the prescribing and administering of
`separate ophthalmic preparations. The first drug administered
`may be diluted significantly by the administration of the sec-
`ond. On this basis combination drug products for use in oph-
`thalmology have considerable merit.
`CORNEAL ABSORPTION—Drugs administered by in-
`stillation must penetrate the eye and do so primarily through
`the cornea. Corneal absorption is much more effective than
`scleral or conjunctival absorption, in which removal by blood
`vessels into the general circulation occurs.
`Many ophthalmic drugs are weak bases and are applied to
`the eye as aqueous solutions of their salts. The free base and
`the salt will be in an equilibrium that will depend on the pH
`and the individual characteristics of the drug molecule. To aid
`in maintaining storage stability and solubility, the medication
`may be acidic at the moment of instillation but, usually, the
`neutralizing action of the lacrimal fluid will convert it rapidly
`to the physiological pH range (~ pH 7.4), at which there will be
`enough free base present to begin penetration of the corneal
`epithelium. Once inside the epithelium the undissociated free
`base dissociates immediately to a degree. The dissociated moi-
`ety then will tend to penetrate the stroma because it is water-
`soluble. At the junction of the stroma and endothelium the
`same process that took place at the outer surface of the epithe-
`lium must occur again. Finally, the dissociated drug leaves the
`
`Lacrimation is induced refiexly by stimulation of nerve endings
`of the cornea or conjunctiva. The reflex is abolished by anes—
`thetization of the surface of the eye and by disorders affecting
`its nerve components.
`”
`'
`'
`'
`'
`The normal cul-de—sac usually is free of pathogenic organ-
`isms and often found sterile. The sterility may be due partly to
`the action of lysozyme in the tears, which normally destroys
`saprophytic organisms but has little action against pathogens.
`More effective in producing sterility may be the fact that the
`secretions, which are normally sterile as they leave the glands,
`constantly wash the bacteria, dust, etc, down in the nose. In
`certain diseases the lacrimal gland, like other glandular struc-
`tures in the body, undergoes involution, with the result that
`the lacrimal fluid becomes scanty. Furthermore, changes in the
`conjunctival glands may lead to alteration in the character of
`the secretion so that quality as well as quantity of tears may be
`abnormal. This may lead to symptoms of dryness, burning, and
`general discomfort and may interfere with visual acuity.
`PRECORNEAL FILM—The cornea must be wet to be an
`optically adequate surface; when dry, it loses both its regular
`gloss and its transparency. The precorneal film, part of the tear
`fluid, provides this important moist surface. Its character de-
`pends on the condition of the corneal epithelium. The film,
`compatible with both aqueous and lipid ophthalmic prepara-
`tions, is composed of a thin outer lipid layer, a thicker middle
`aqueous layer, and a thin inner mucoid layer. It is renewed
`during each blink, and when blinking is suppressed, either by
`drugs or by mechanical means, it dries in patches. It seems to
`be unaffected by the addition of concentrations of up to 2%
`sodium chloride to conjunctival fluid. A pH below 4 or above 9
`causes derangement of the film. The film affects the movement
`of contact lenses and forms more easily on glass than on plastic
`prostheses.
`CORNEA—The cornea, from 0.5 to 1 mm thick, consists
`mainly of the following structures (from the front backward):
`1. Corneal epithelium.
`2. Substantia propria (stroma).
`3. Corneal endothelium.
`
`The cornea is transparent to ordinary diffuse light, largely
`because of a special laminar arrangement of the cells and fibers
`‘ and because of the absence of blood vessels. Cloudiness of the
`cornea may be due to any one of several factors including excess
`pressure in the eyeball as in glaucoma, and scar tissue due to
`injury, infection, or deficiency of oxygen or excess hydration
`such as may occur during the wearing of improperly fitted
`contact lenses. A wound of the cornea usually heals as an
`opaque patch that can be a permanent impairment of vision
`unless it is located in the periphery of the cornea.
`’The chief refraction of light for the eye occurs at the outer
`surface of the cornea where the index of refraction changes
`from that of air (1.00) to that of precorneal substance (1.38).
`Any alteration in its shape or transparency interferes with the
`formation of a clear image; therefore, any pathological process,
`however slight, may interfere seriously with the resolving
`power or Visual acuity of the eye.
`The normal cornea possesses no blood vessels except at the
`corneoscleral junction. The cornea, therefore, must derive its
`nutrition by diffusion and must have certain permeability char-
`acteristics; it also receives nourishment from the fluid circulat-
`ing thrOugh the chambers of the eye and from the air. The fact
`that the normal cornea is devoid of blood vessels is an impor-
`tant feature in surgical grafting. The corneal nerves do not
`supply all forms of sensation to the cornea. Pain and cold are
`well supplied. The pain fibers have a very low threshold, which
`makes the cornea one of the most sensitive areas on the surface
`of the body. It now is agreed generally that the cornea pos-
`sesses a true sense of touch; nerve endings supplying the sen-
`sation of heat are lacking.
`The corneal epithelium provides an efficient barrier against
`bacterial invasion. Unless its continuity has been broken by an
`abrasion (a traumatic opening or defect in the epithelium),
`
`
`
`-l__———_-—-
`
`824
`
`CHAPTER 43
`
`endothelium for the aqueous humor. Here it can readily diffuse
`to the iris and the ciliary body, the site of its pharmacological
`action.
`_
`‘
`,,
`_
`q
`7
`The cornea can be penetrated by ions to a small, but mea-
`surable, degree. Under comparable conditions, the permeabili-
`ties are similar for all ions of small molecular weight, which
`suggests that the passage is through extracellular spaces. The
`diameter of the largest particles that can pass across the cel—
`lular layers seems to be in the range of 10 to 25 A. An instilled
`drug is subject to protein binding in the tear fluid and meta—
`bolic degradation by enzymes such as lysozyme, in addition to
`the losses by simple overflow and lacrimal drainage.
`Since the cornea is a membrane including both hydrophilic
`and. lipophilic layers, most effective penetration is obtained
`with drugs having both lipid and hydrophilic properties. Highly
`water soluble drugs penetrate less readily. As an example
`highly water soluble steroid phosphate esters penetrate the
`cornea poorly. Better penetration is achieved with the poorly
`soluble but more lipophilic steroid alcohol; still greater absorp—
`tion is seen with the steroid acetate form.
`In 1976 Lee and Robinson4 and, in 1990, Lee5 presented a
`summary of the factors controlling precorneal pilocarpine dis-
`position and pilocarpine bioavailability in the rabbit eye. Com-
`bining experimental work and computer simulation the inves-
`tigators discussed the mechanisms competing with corneal
`absorption of pilocarpine. Included were solution drainage,
`drug—induced vasodilation, nonconjunctival loss including up-
`take by the nictitating membrane, conjunctival absorption, in-
`duced lacrimation, and normal tear turnover. Subject to exper-
`imental conditions the relative effectiveness of the factors
`involved in precorneal drug removal are drainage = vasodila-
`tion > nonconjunctival loss > induced lacrimation = conjunc-
`tival absorption > normal tear turnover.
`The authors discuss the implications of the mechanisms of
`precorneal drug loss in the design of ocular drug—delivery sys—
`tems including the effect of instilled drug volume on aqueous
`humor concentration and the amount of drug available for
`systemic absorption. On an absolute basis a smaller volume
`allows more drug to be absorbed. For a given instilled concen-
`tration the opposite is true; however, a smaller volume instilled
`remains more efficient;
`ie, the fraction of dose absorbed is
`greater. Lang6 discusses the transcorneal route of absorption of
`a drug into the eye as the route most effective in bringing a
`given drug to the anterior portion of the eye. This route of
`absorption is enhanced by the water-lipid gradient found in the
`cornea. As previously mentioned, the cornea is composed of
`three general layers: the lipid-rich epithelium, the lipid-poor
`stroma, and the lipid-rich endothelium. Differential studies on
`the relative lipid contents of these three layers have shown that
`the corneal epithelium and the corneal endothelium both con-
`tain approximately 100 times as much lipid as the corneal
`stroma. This, coupled with the physiological pH of 7.2 i 0.2
`and its effect on ionizable drug molecules plays the most sig-
`nificant role in corneal penetration.
`Ophthalmic ointments generally produce greater bioavail-
`ability than the equivalent aqueous solution. Because of the
`greater contact time, drug levels are prolonged and