Remington: The
`Science and
`Practice
`of Pharmacy
`
`ALFONSO R GENNARO
`
`TEVA - EXHIBIT 1016
`
`

`

`
`
`Editor: Daniel Limmer
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
`
`Lippincott Williams & Wilkins
`
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`Baltimore, Maryland 21201-2436 USA
`
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`
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`be reproduced in any form or by any means,including photocopying,orutilized
`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 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
`
`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 Informationis available
`ISBN 0-683-306472
`
`The publishers have made everyeffort to trace the copyright holders for borrowed
`material. If they 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-
`stble for any inaccuracy contained herein.
`Notice-—This text ts not intended to represent, nor shall it be interpretedto 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 of them herein, the
`context and effect of the official compendia shall prevail.
`
`To purchase additional copies of this book call our customer service department
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`02 03 04
`2345678910
`
`

`

`Table of Contents
`
`Part 1Orientation
`
`Scope of Pharmacy... 2.0.0.0... 00000000000,
`Evolution of Pharmacy........0..0....0 00000.
`Ethics and Professionalism... .... bee ee
`The Practice of Community Pharmacy ...........
`Pharmacists in Industry... 2... 0000000 0000000.
`Pharmacists in Government ..........0...00..
`Pharmacists and Public Health... 0.2 ...00..00.00.
`Information Resources in Pharmacy and the
`Pharmaceutical Sciences... 0... eee
`Clinical Drug Literature... eee
`Research. 6... ee
`
`Part 2 Pharmaceutics
`
`Pharmaceutical Calculations... 6... ..0..00020040.
`Statistics.0 ee eee
`Molecular Structure, Properties, and States of Matter. .
`.
`Complex Formation... 0.0.0... ... 0.002.000,
`Thermodynamics... 20... eee
`Solutions and Phase Equilibria... 2.2.0.0. 0.00002.
`lonic Solutions and Electrolytic Equilibria... 2... 2.
`Tonicity, Osmoticity, Osmolality, and Osmolarity. .
`.
`.
`Chemical Kinetics 2.0... 2 eee
`Interfacial Phenomena... .. 0.22.0. .000 000000.
`Colloidal Dispersions... 2... ee
`Coarse Dispersions... ee
`Rheology... ee
`
`Part 3. Pharmaceutical Chemistry
`
`Inorganic Pharmaceutical Chemistry ............
`Organic Pharmaceutical Chemistry .......00....
`Natural Products... eee
`Drug Nomenclature—United States Adopted
`Names... eee
`Structure-Activity Relationship and Drug Design... .
`.
`Fundamentals of Radionuclides ........0.00...
`
`Part 4 Pharmaceutical Testing, Analysis and Control
`
`Analysis of Medicinals... 20...
`Biological Testing ...... 0.0.0... 0000000000,
`Clinical Analysis... 00 ee
`Chromatography...2...
`Instrumental Methods of Analysis... 2.000.000...
`Dissolution. 00. eee
`
`Part 5 Pharmaceutical Manufacturing
`
`Separation0 ee
`Powders... ee
`Preformulation. 00.0
`Solutions, Emulsions, Suspensions, and Extracts... .
`.
`Sterilization0 ee
`Parenteral Preparations 6.0...
`Intravenous Admixtures .6.
`Ophthalmic Preparations... 0... ee
`Medicated Topicals 0...0.
`Oral Solid Dosage Forms 2...
`Coating of Pharmaceutical Dosage Forms... 2... .
`Controlled-Release Drug-Delivery Systems .... 2...
`The Introduction of New Drugs... 0.0.
`
`OnanOn=
`
`3
`
`14
`12
`13
`14
`45
`16
`17
`18
`19
`20
`21
`22
`23
`
`24
`25
`26
`27
`
`28
`29
`
`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
`
`444
`458
`469
`
`485
`540
`552
`587
`614
`654
`
`669
`681
`700
`724
`153
`780
`807
`824
`836
`858
`894
`903
`930
`
`49 Biotechnology and Drugs... 2... ee ee
`SO Aerosols
`51 Quality Assurance and Control...
`52 Stability of Pharmaceutical Products... ....00000..
`53 Bioavailability and Bioequivalency Testing... ....
`54 Plastic Packaging Materials... 2... 0... 00000000,
`55 Pharmaceutical Necessities... 0...
`
`Part 6 Pharmacodynamics
`
`.
`56 Diseases: Manifestations and Pathophysiology ... .
`57 Drug Absorption, Action, and Disposition. ........
`58 Basic Pharmacokinetics... .....000200.00.0000.
`39 Clinical Pharmacokinetics 2.2.0... 000000000.
`60 Principles of lmmunology................00..
`61 Adverse Drug Reactions.................000.
`62 Pharmacogenetics... 0.0.0.0... 000 eee
`63 Pharmacological Aspects of Substance Abuse... ..
`
`Part 7 Pharmaceutical and Medicinal Agents
`
`64 Diagnostic Drugs and Reagents........0..00...
`65 Topical Drugs... ee
`66 Gastrointestinal and Liver Drugs.........0.0.0...
`67 Blood, Fluids, Electrolytes, and Hematological Drugs.
`.
`.
`.
`68 Cardiovascular Drugs... 2. ee
`69 Respiratory Drugs... 26.2.2... eee
`70 Sympathomimetic Drugs... 2... ee
`71 Cholinomimetic Drugs 6... ee
`72 Adrenergic and Adrenergic Neuron Blocking Drugs. .
`73 Antimuscarinic and Antispasmodic Drugs .........
`74 Skeletal Muscle Relaxants... ...0..0.00...000.
`75 Diuretic Drugs 2.0... eee
`76 Uterine and Antimigraine Drugs ..........0000.
`77 Hormones and Hormone Antagonists ...........
`78 General Anesthetics... 00.0.2
`79 Local Anesthetics... 6. ee
`80 Sedative and Hypnotic Drugs .. 2.2.6...
`81 Antiepileptic Drugs... 0.2... ee
`82 Psychopharmacologic Agents..............0..
`83 Analgesic, Antipyretic, and Anti-Inflammatory
`Drugsoe
`84 Histamine and Antihistaminic Drugs... 2.2...
`85 Central Nervous System Stimulants... ........0....
`86 Antineoplastic and Immunoactive Drugs .........
`87 Anti-Infectives 6.2... 0 ee
`88 Parasiticides. 2... ee
`89 Immunizing Agents and Allergenic Extracts ......
`
`Part 8 Pharmacy Practice
`
`Part 8A Pharmacy Administration
`
`90 Laws Governing Pharmacy ..................
`91 Pharmacoeconomics 2... ee
`92 Marketing Pharmaceutical Care Services... 0.2...
`93 Documenting and Billing for Pharmaceutical Care
`SEVICESoe
`94 Community Pharmacy Economics and
`Management 2.0.00 ee
`95 Produci Recails and Withdrawals
`
`Part 8B Fundamentals of Pharmacy Practice
`
`96 Drug Education .
`
`944
`963
`980
`986
`995
`4005
`1015
`
`1053
`1098
`1127
`1145
`1156
`1165
`1169
`1175
`
`1185
`1200
`1219
`1243
`1274
`1297
`4305
`1314
`1322
`1328
`1333
`1344
`1354
`1358
`1395
`1400
`1407
`1424
`1429
`
`1444
`1464
`1474
`1477
`4507
`1562
`1567
`
`1595
`1625
`1634
`
`1640
`
`1650
`1666
`
`1677
`
`

`

`p
`
`97 The Prescription... ee
`98 ExtemporaneousPrescription Compounding ......
`99 PoisonControl 2... ee
`400 Nutrition in Pharmacy Practice .............---
`101 Self-Care/Diagnostic Products... ..........0 0-5.
`{02 Drug Interactions... 1... ee
`103 Complementary and Alternative Medical Health
`Care... eee.bee
`404 Nuclear Pharmacy Practice
`.........-555 500 5-
`105 Enzymes
`. 2... es
`106 Vitamins and Other Nutrients ...........--.45.
`107 Pesticides 2. ees
`
`108 Surgical Supplies 2... eee
`409 Health Accessories... ee
`
`Part 6C Patient Care
`
`140 Ambulatory Patient Care 2... eee
`411 Institutional Patient Care... ee eee
`1412 Long-Term Care Facilities... 6.2.26... eee
`
`1687
`1706
`1716
`1725
`1738
`1746
`
`1762
`1781
`1792
`1796
`1825
`1846
`1857
`
`1893
`1911
`1932
`
`113
`114
`115
`116
`117
`1418
`119
`
`The Patient: Behavioral Determinants ...........
`Patient Communication... 0.0... es
`
`Patient Compliance .....0... 00020002 eee
`Pharmacoepidemiology ..............0005-
`Integrated Health-Care Delivery Systems.........
`Home Health Patient Care... eee eee
`
`Aseptic Technology for Home-Care
`Pharmaceuticals... 0.0.0... 0 0006. ;
`
`Appendixes
`
`Dose Equivalents. ............0.- vee
`Periodic Chart...6.
`
`Logarithms . 6.0.0... ee le
`
`Glossary and Index
`
`Glossary2 ee
`INDEX ee eee
`
`1948
`1957
`1966
`4980
`1990
`2012
`
`2020
`
`2033
`2034
`2036
`
`2037
`2039
`
`XV
`
`
`
`
`
`

`

`Ophthalmic Preparations
`
`CHAPTER &3
`
`Gerald Hecht, PhD
`Senior Director, Pharmaceutica! Sciences
`Alcon Laboratories
`Fort Worth, TX 76101
`
`
`
`
`
`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
`andalso the anticipated difficulties in sterilizing and maintain-
`ing sterile conditions during the manufacture andfilling of
`ointments on a large scale.
`
`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
`ANATOMY AND PHYSIOLOGY OF THE EYE
`latter group has been subjected to a searching review and
`0)Seeea
`analysis by a body of experts as a part of the Food and Drug
`The humaneyeis a challenging subject for topical administra-
`Administration’s (FDA) OTC Drug Review process.
`tion of drugs. The basis of this can be found in the anatomical
`The single dominant factor characteristic of all ophthalmic
`arrangementof the surface tissues and in the permeability of
`products is the specification of sterility. Any product intended
`the cornea. The protective operation ofthe eyelids and lacrimal
`for use in the eye regardless of form, substance, or intent must
`system is such that there is rapid removal of material instilled
`be sterile. This requirement increases the similarity between
`into the eye, unless the material is suitably small in volume
`ophthalmic and parenteral products; however the physiology
`and chemically and physiologically compatible with surface
`of the human eye in many respects imposes more rigid
`tissues. Figures 43-1! and 48-2" include pertinent anatomy of
`formulation requirements. This is considered in the following
`the humaneye.
`discussion.
`EYELIDS—The eyelids serve two purposes: mechanical
`Preparations intended for the treatment of eye disorders
`protection of the globe and creation of an optimum milieu for
`can be traced to antiquity. Egyptian papyri writings describe
`the cornea. The eyelids are lubricated and kept fluid-filled by
`eye medications. The Greeks and Romans expanded such uses
`secretions of the lacrimal glands and specialized cells residing
`and gave us the term collyria. Collyria refers collectively to
`in the bulbar conjunctiva. The antechamber has the shape of a
`materials that were dissolved in water, milk, or egg white for
`narrowcleft directly over the front of the eyeball, with pocket-
`use as eyedrops. In the Middle Agescollyria included mydriatic
`like extensions upward and downward. The pockets are called
`substances to dilate the pupils of milady’s eyes for cosmetic
`the superior and inferior fornices (vaults), and the entire space,
`purposes, thus the term belladonna, or beautiful lady.
`the cul-de-sac. The elliptical opening between the eyelids is
`From the time of belladonnacollyria, ophthalmic technology
`called the palpebralfissure.
`progressed at a pharmaceuticalsnail’s pace well into modern
`EYEBALL—tThewall of the humaneyeball (bulbus, globe}
`times. It was not until after World WarII that the concept of
`is composed of three concentric layers.
`sterility became mandatory for ophthalmic solutions. Prior to
`1. The outerfibrous layer.
`World WarII and continuing into the 1940s very few ophthal-
`2. A middle vascular layer—the uvea or uvealtract, consisting of the
`mic preparations were available commercially or were de-
`choroid, the ciliary body, and the iris.
`scribed officially. The USP XIV,official in 1950, included only
`3. A nervous layer—theretina.
`three ophthalmic preparations, and all three were ointments.
`The outer layer is tough, pliable, but only slightly stretchable.
`Preparations to be used in the eye, either solutions or oint-
`In its front portion—the portion facing the outside world—the
`ments, invariably were compounded in the community or hos-
`fine structure of the outer layer is so regular and the water
`pital pharmacy and were intended for immediate (prescription)
`content so carefully adjusted that it acts as a clear, transparent
`use. Such preparation and prompt useis reflected in the phar-
`window (the cornea). It is devoid of blood vessels. Over the
`maceutical literature of the times. The stability of ophthalmic
`remaining two-thirds the fibrous coat is opaque (the white of
`preparationsis discussed in terms of days or a few months.
`the eye) andis called the sclera. It contains the microcircula-
`Oneof the most important attributes of ophthalmic products
`tion, which nourishes the tissues of this anterior segment, and
`is the requirement of sterility. Even that, however, is a sur-
`is usually white except when irritated and vessel dilatation
`prisingly recent event. The USP XV in 1955 was the first
`occurs.
`official compendium to includeasterility requirement for oph-
`The eyeball houses an optical apparatus that causes in-
`thalmic solutions. The FDA in 1958 adopted the position that a
`verted reduced images of the outside world to form on the
`nonsterile ophthalmic solution was adulterated. Sterile oph-
`retina, which is a thin translucent membrane. The optical
`thalmic products were, of course, available prior to the mid-
`apparatus consists, in sequence, of the precorneal film, the
`1950s; however the legal requirement of sterility dates only
`cornea, the aqueous humor, the pupil, the crystalline lens, the
`from 1955.
`
`821
`
`

`

`822
`
`CHAPTER 43
`
`EXCRETORY DUCT
`
`LACRIMAL
`
`CRYPTS OF
`HENLE
`
`
`.. GLAND
`
`CONJUNCTIVA
`
`! CONJUNCTIVAL
`fi
`sac———@ ff
`
`
` WOLFRING'S
`GLANDS
`GLANDS OF
`MANZ
`
`
`
`MEIBOMIAN
`
`GLANDS——,
`
`VITREOUS
`HUMOR
`
`
` GLANDS OF
`
`ZEIS
`(SEBACEOUS)
`
`TARSAL PLATE
`
`GLANDS OF wou
`(SWEAT)
`
`
`
`Figure 43-1. The eye:vertical section."
`
`compounds, approximately 0.7% protein, and the enzymely-
`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-
`nealfilm). The mucin-protein layer of the film is especially
`important in maintaining the stability of the film. The main
`lacrimal glandis 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 excessfluid is directed into the lacrimal lake—a
`small, triangular area lying in the angle bound by the inner-
`mostportionsofthe lids. The skin ofthe eyelids is the thinnest
`in the body andfolds easily, thus permitting rapid opening and
`closing of the palpebral fissures. The movementof the eyelids
`includes a narrowingof the palpebralfissures 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 movementof fluid toward the lacrimal lake.
`Tears are drained from the lacrimal lake by two small
`tubes—the lacrimal canalieuli—whichlead into the upper part
`of the nasolacrimal duct, the roomy beginningofwhichis 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 embeddedinthe eyelids. When
`the lids close, as in blinking, contraction of the muscle causes
`dilatationof the upperpart 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 andforces 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.
`
`LACRIMAL GLAND
`
`vitreous humor, and the retina. The aqueous and vitreous
`humors are layersof clear fluid or gel-like material interposed
`between thesolid structures. The pupil, a roundcentrichole in
`a contractile membranouspartition (called theiris), 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, whichorigi-
`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 humoracts asacarrier of nutrients, substrates, and
`metabolites for the avasculartissues of the eye.
`The bones of the skull join to form an approximately
`pyramid-shaped housingfor 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 movementof 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 bya filmof fluid secreted by
`the conjunctival and lacrimal glands. The secretion of the lac-
`rimal gland, the tears, is delivered through a numberoffine
`ducts into the conjunctival fornix. The secretion is a clear,
`watery fluid containing numeroussalts, glucose, other organic
`
`
`
`
`
`
`
`EXCRETORY DUCTS
`
`"VALVE" OF HASNER
`{LACRIMAL PLICA)
`
`
`
`Figure 43-2. Nasolacrimal duct.!
`
`

`

`Lacrimationis induced reflexly 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.
`ee
`The normal cul-de-sac usually is free of pathogenic organ-
`isms and often foundsterile. The sterility may be due partly to
`the action of lysozyme in the tears, which normally destroys
`saprophytic organismsbut haslittle action against pathogens.
`Moreeffective 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 maylead to alteration in the character of
`the secretion so that quality as well as quantity of tears may be
`abnormal. This may lead to symptomsof dryness, burning, and
`general discomfort and mayinterfere with visual acuity.
`PRECORNEAL FILM—tThe cornea must be wet to be an
`optically adequate surface; whendry, it loses both its regular
`gloss and its transparency. The precornealfilm,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 composedof 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%
`sodiumchloride to conjunctival fluid. A pH below 4 or above 9
`causes derangementof thefilm. Thefilm affects the movement
`of contact lenses and forms moreeasily on glass than on plastic
`prostheses.
`CORNEA—Thecornea, from 0.5 to 1 mmthick, consists
`mainlyof 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 arrangementofthe cells and fibers
`-and because of the absence of blood vessels. Cloudiness of the
`cornea may be dueto any oneof severalfactors including excess
`pressure in the eyeball as in glaucoma, andscartissue 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).
`Anyalteration in its shape or transparencyinterferes with the
`formationof a clear image; therefore, any pathological process,
`however slight, may interfere seriously with the resolving
`poweror visual acuity of the eye.
`The normal cornea possesses no blood vessels except at the
`corneoscleral junction. The cornea, therefore, must deriveits
`nutrition by diffusion and must have certain permeability char-
`acteristics; it also receives nourishment fromthe fluid circulat-
`ing through the chambersof 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 te 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 anefficient barrier against
`bacterial invasion. Unless its continuity has been broken by an
`abrasion (a traumatic opening or defect in the epithelium),
`
`OPHTHALMIC 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
`
`PHYSICAL CONSIDERATION—Under normal condi-
`tions the human tear volume averages about 7 pL.” The esti-
`mated maximum volumeof the cul-de-sac is about 30 wL, with
`drainage capacity far exceeding lacrimation rate. The outflow
`capacity accommodates the suddenlarge volume resulting from
`the instillation of an eyedrop. Most commercial eyedrops range
`from 50 to 75 pL in volume; however, much in excess of 50 pL
`probably is unable to enter the cul-de-sac.
`Within the rabbit cul-de-sac, the drainage rate has been
`shownto 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. Patton? has shown that approxi-
`mately equal tear-film concentrations result from the instilla-
`tion of 5 pL of 1.61 x 10? M pilocarpinenitrate or from 25 pL
`of 1.0 X 10-2 M solution. The 5 »L contains only 38% as much
`pilocarpine, yet its bioavailability is greater because of de-
`creased drainageloss.
`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. Thefirst drug administered
`maybe 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.
`Manyophthalmic drugs are weak bases and are applied to
`the eye as aqueoussolutions 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 momentofinstillation 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
`
`

`

`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.
`oo /
`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 seemsto 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 bothlipid 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 morelipophilic steroid alcohol; still greater absorp-
`tion is seen with the steroid acetate form.
`In 1976 Lee and Robinson‘ and, in 1990, Lee® 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 = conjune-
`tival absorption > normal tear turnover.
`The authors discuss the implications of the mechanismsof
`precorneal drugloss 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 volumeinstilled
`remains more efficient;
`ie, the fraction of dose absorbed is
`greater. Lang® 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 + 0.2
`andits effect on ionizable drug molecules plays the mostsig-
`nificant role in corneal penetration.
`Ophthalmic ointments generally produce greater bioavail-
`ability than the equivalent aqueous solution. Because of the
`greater contact time, druglevels are prolonged and total drug
`absorption is increased.
`
`Types of Ophthalmic Products
`
`re-
`ADMINISTRATION—The instillation of eyedrops
`mains one of the less precise, yet one of the more accepted,
`meansoftopical drug delivery. The method of administrationis
`cumbersomeat best, particularly for the elderly, patients with
`poorvision who havedifficulty seeing without eyeglasses, and
`patients with other physical handicaps. Perhaps surprisingly,
`most patients become quite adept at routine instillation.
`The pharmacist should advise each patient to keep the
`following points in mindto aid in the instillation of eyedrops or
`ointments:
`
`HOW TO USE EYEDROPS
`1. Wash hands.
`2. With one hand, gently pull lower eyelid down.
`3,
`Ifdropper is separate, squeeze rubber bulb once while dropperis in
`bottle to bring liquid into dropper.
`4. Holding dropper above eye, drop medicine inside lower lid while
`looking up; do not touch dropper to eye orfingers.
`5. Release lowerlid. Try to keep eye open andnot blink for at least 30
`seconds,
`If dropper is separate, replace on bottle and tighten cap.
`
`6.
`
`Ifdropper is separate, always hold it with tip down.
`¢
`e Never touch dropper to any surface.
`e Never rinse dropper.
`e When dropper is at top of bottle, avoid contaminating cap when
`removed.
`¢ When dropper is a permanent fixture on the bottle, ie, when sup-
`plied by a pharmaceutical manufacturer to the pharmacist, the
`same rules apply