2 O
`
`0 N
`
`Remington: The
`Science and
`Practice
`of Pharmacy
`
`ALFONSO R GENNARO
`Chairman of the Editorial Board
`
`and Editor
`
` EXHIBIT 1016
`
`

`
`Editor: Daniel Limmer
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
`
`Lippincott. Williams & Wilkins
`
`351 West Camden Street
`Baltimore, Maryland 21201-2436 USA
`
`227 East Washington Square
`Philadelphia, PA 19106
`
`All rights reserved. This book is protected by copyright, No part of this book may
`be reproduced in any form or by any means, including photocopying, or utilized
`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 Information is available
`ISBN 0-683-306472
`
`The publishers have made every effort 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
`sible 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/or the National Formulary INF). 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
`at (800) 638-3030 or fax orders to (301) 824-7390. International customers
`should call (301) 714-2324.
`
`02 03 04
`2 3 4 5 6 7 8 9 10
`
`

`
`Table of Contents
`
`Port 1 Orlenfotion
`
`1 Scope of Pharmacy
`2 Evolution of Pharmacy
`3 Ethics and Professionalism
`4 The Practice of Community Pharmacy . . . .
`5 Pharmacists in Industry
`6 Pharmacists in Government
`7 Pharmacists and Public Health
`8 Infotmofion Resources in Pharmacy and the
`Pharmaceutical Sciences
`9 Clinical Drug Literature
`10 Research
`
`Port 2 Phormaceutics
`
`11 Pharmaceutical Calculotions
`12 Statistics
`13 Molecular Structure, Properties, and States of Matter. . .
`14 Complex Formation
`15 Thermodynamics
`16 Solutions and Phase Equilibria
`17 Ionic Solutions and Electrolytic Equilibria
`18 ronicity, Osmoticity, Osmolality, and Osmolarity. . . .
`19 Chemical Kinetics
`20 Interfacial Phenomena
`21 Colloidal Dispersions
`22 Coarse Dispersions.
`23 Rheology
`
`Part 0 Pharmaceutical Chemistry
`
`24 Inorganic Pharmaceutical Chemistry
`25 Organic Pharmoceutical Chemistry
`26 Natural Products
`27 Drug Nomenclature—United States Adopted
`Names
`28 Structure-Activity Relationship ond Drug Design
`29 Fundamentals of Radionuclides
`
`Part 4 Pharmaceutical Testing, Analysis ond Control
`30 Analysis of Medicinals
`31 Biological Testing
`32 Clinical Analysis
`33 Chromatography
`34 Instrumental Methods of Analysis
`35 Dissolution
`
`Port 5 Pharmaceutical Manufacturing
`
`36 Separation
`37 Powders
`38 Preformulotion
`39 Solutions, Emulsions, Suspensions, and Extracts
`40 Sterilization
`41 Parenteral Preparations
`42 Intravenous Admixtures
`43 Ophthalmic Preparations
`44 Medicated Topicols
`45 Oral Solid Dosage Forms
`46 Coating of Pharmaceutical Dosage Forms . . .
`47 Controlled-Releose Drug-Delivery Systems . . .
`48 The Introduction of New Drugs
`
`49 Biofechnology and Drugs
`50 Aerosols
`51 Quality Assurance and Control
`52 Stability of Pharmaceutical Products
`50 Dioavailability and Dioequivolency Testing
`54 Plastic Packaging Materials
`55 Pharmaceutical Necessities
`
`Port 6 Phormocodynomics
`56 Diseases: Manifestations and Pathophysiology
`57 Drug Absorption, Action, and Disposition
`58 Basic Pharmacokinetics
`59 Clinical Pharmacokinetics
`60 Principles of Immunology
`61 Adverse Drug Reactions
`62 Pharmacogenetics
`63 Pharmacological Aspects of Substance Abuse
`
`. .
`
`. .
`
`Part 7 Pharmaceutical and Medicinal Agents
`64 Diagnostic Drugs and Reagents
`65 Topical Drugs
`66 Gastrointestinal and Liver Drugs
`67 Blood, Fluids, Electrolytes, and Hematological Drugs. . . .
`68 Cardiovascular Drugs
`69 Respiratory Drugs
`70 Sympathomimetic Drugs
`71 Cholinomimetic Drugs
`72 Adrenergic and Adrenergic Neuron Blocking Drugs. .
`/3 Antimuscorinic and Antispasmodic Drugs
`74 Skeletal Muscle Relaxants
`75 Diuretic Drugs
`76 Uterine and Antimigraine Drugs
`77 Hormones and Hormone Antagonists
`78 General Anesthetics
`79 Local Anesthetics
`80 Sedative and Hypnotic Drugs
`81 Antiepileptic Drugs
`82 Psychopharmacologic Agents
`83 Analgesic, Antipyretic, and Anti-Inflammatory
`Drugs
`84 Histamine and Antihistominic Drugs
`65 Central Nervous System Stimulants
`86 Antineoplastic and Immunoactive Drugs
`87 Anti-lnfectives
`88 Parasiticides
`89 Immunizing Agents and Allergenic Extracts
`
`Part 8 Pharmacy Practice
`
`Part 6A Pharmacy Administration
`90 Lows Governing Pharmacy
`91 Pharmacoecanomics
`92 Marketing Pharmaceutical Care Services
`93 Documenting and Billing for Pharmaceutical Core
`Services
`94 Community Pharmacy Economics and
`Management
`.
`95 Produci Recoils ond 'Vithdrawals
`
`Part 6D Fundamentals of Pharmacy Practice
`
`96 Drug Education . . .
`
`.
`
`3
`/
`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
`
`xlv
`
`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
`
`

`
`97 The Prescription
`98 Extemporoneous Prescription Compounding . . .
`99 Poison-Control
`100 Nutrition in Pharmacy Practice
`101 Self-Care/Diagnosric Products
`102 Drug Inrerocrions
`103 Complementary and Alternative Medical Health
`Core
`:
`104 Nuclear Pharmacy Practice
`105 Enzymes
`106 Vitamins and Other Nutrients
`107 Pesticides
`108 Surgical Supplies
`109 Health Accessories
`
`Part 6C Potient Core
`
`110 Ambulatory Potient Care
`111 Institutional Patient Care
`112 Long-Term Care Facilities
`
`1687
`1706
`1716
`1725
`1738
`1746
`
`1762
`1781
`1792
`1796
`1825
`1846
`1857
`
`1893
`1911
`1902
`
`113 The Parienr; Behavioral Defemninanfs . .
`114 Patient Communicotion
`115 Parienr Compliance
`116 Pharmacoepidemiology
`117 Inregrored Healrh-Care Delivery Systems
`118 Home Healrh Parienr Core
`119 Aseptic Technology for Home-Core
`Pharmoceuricols
`
`Appendixes
`
`Dose Equivalents
`Periodic Chart . .
`Logarithms ....
`
`Glossary
`Index . .
`
`Glossary and Index
`
`1948
`1957
`1966
`1980
`1990
`2012
`
`2020
`
`2033
`2034
`2036
`
`2037
`2039
`
`xv
`
`

`
`Ophthalmic Preparations
`
`C H A P T E R 43
`
`Gerald Hecht, PhD
`Senior Director, Pharmaceutical Sciences
`Aicon 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 (prescription)
`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
`the
`apparatus consists, in.sequence, of the precorneal film,
`cornea, the aqueous humor, the pupil, the crystalline lens, the
`
`821
`
`

`
`822
`
`CHAPTEK 43
`
`\
`
`GLANDS OF
`KRAUSE
`
`EXCRETORY DUCT / f l
`
`LACRIMAL
`. GLAND
`
`•
`,
`
`CONJUNCTIVA ///
`V /,
`#
`
`GLANDS OF
`MANZ
`
`V
`
`CONJUNCTIVAL
`SAC
`
`WOLFRiNG'S ](
`GLANDS —
`
`• 'Mill
`
`M
`HENLE- i IR'S-R
`U 1
`Ull
`
`CRYPTS OF
`
`MEIBOMIAN
`GLANDS'
`
`TARSAL PLATE
`
`GLANDS OF
`ZEIS
`(SEBACEOUS)
`
`cv
`
`— CORNEA
`
`LENS
`
`VITREOUS
`HUMOR
`
`•
`
`GLANDS OF MOLL
`(SWEAT)
`
`»:
`X
`
`v
`
`m
`
`V;
`
`Figure 43-1. The eye: vertical section.'
`
`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
`
`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.
`
`LACRIMAL GLAND
`
`V
`
`EXCrETORV DUCTS
`
`MASAI
`SEPTUM
`
`FORNIX
`
`i
`
`Ni
`
`i'M
`
`LACRIMAL SAC
`?r.
`
`WK
`
`/ • ' /
`11 e /
`
`' S;
`
`v VN
`
`,
`INFERIOR LACRIMAL PUNCTUM
`
`INFERIOR LACRIMAL CANALICULUS
`
`"VALVE" OF HASNER-
`(LACRIMAL PLICA)
`
`INFERIOR CONCHA-
`
`Figure 43-2. Nasolacrimal duct.
`
`NASAL V:vl ^ •
`CAVITY V: \ • >•/.:
`
`V--\
`
`/. i
`
`

`
`Lacrimation is 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.
`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 1%
`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).
`
`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
`If
`afforded by staining the cornea with sodium fluorescein.
`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 abi'asion 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 ixh.2 The esti­
`mated maximum volume of the cul-de-sac is about 30 /J.L, 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 /xL in volume; however, much in excess of 50 fxL
`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
`concen-
`drops administered at intervals produced higher drug
`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 fiL of 1.61 X 10-2 M pilocarpine nitrate or from 25 juL
`of 1.0 X ID-2 M solution. The 5 jiL 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-/JL 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
`
`

`
`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.
`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
`absoi-ption 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. Langs 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. Tliis, coupled with the physiological pH of 7.2 ± 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 total drug
`absorption is increased.
`
`Types of Ophthalmic Products
`
`ADMINISTRATION—The instillation of eyedrops re­
`mains one of the less precise, yet one of the more accepted,
`means of topical drug delivery. The method of administration is
`cumbersome at best, particularly for the elderly, patients with
`poor vision who have difficulty 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 mind to aid in the instillation of eyedrops or
`ointments:
`
`6.
`
`HOW TO USE EYEDROPS
`1. Wash hands.
`2. With one hand, gently pull lower eyelid down.
`3.
`If dropper is separate, squeeze rubber bulb once while dropper is 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 or fingers.
`5. Release lower lid. Try to keep eye open and not blink for at least 30
`seconds.
`If dropper is separate, replace on bottle and tighten cap.
`•
`If dropper is separate, always hold it with tip down.
`• Never touch dropper to any surface.
`• Never rinse dropper.
`• 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 to avoid contamination.
`• Never use eye drops that have changed color.
`•
`If you have more than one bottle of the same kind of drops, open only
`one bottle at a time.
`If you are using more tha