Remington The
`ScMence and
`Practice
`of Pharmacy
`
`FAMY CARE - EXHIBIT 1016-0001
`
`

`
`E(.’2'f(,x:‘.' Daniel I,.imm€+r
`3!az23a§>‘z‘72f_f Eu’fz‘:>z'.' 3\1§"1tH1env J. Himber
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`227 East W':1:«:hingtrm B<112z::'e
`P}‘1.adel1:>}‘=i:z. PA 19l06
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`‘ved. This book is protected by :20}:-yzight. No part of\t}'zi:~; ';moi<. may
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`Cop”
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`fight 1889, ‘I894, 1905, 1907, 1917, by Jcaeph Y’ Remi:1gt.on
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`C‘.opyright. 1926f iS}f:§(5, by the Joseph E?’ Rez11i:1_g;ic>n Estat,<3
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`( 0pyr1'g'l::i1 1.,» ., 19:51, by the I-’hi1ad<3Ip§1i21 Cullcgr-, «3fP§1a1'n1;u:y a:‘1d S<:im1<:{~.
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`
`02 {>83 04
`23~15é37é‘~:91{)
`
`FAMY CARE - EXHIBIT 1016-0002
`
`

`
`Table of Contents
`
`Part
`
`Orientaflan
`
`Scope of Pharmacy
`
`Evolurion of Pharmacy
`Ethics and Professionahsm
`
`The Practice
`
`of Community Pharmacy
`
`Pharmacisrs in Industry
`Pharmacists in Government
`
`Pharmacists and Pubic Healrh
`
`Infotmorion Resources in Pharmacy and the
`Pharmaceutical
`Sciences
`
`Clinical Drug Literature
`10 Research
`
`Port
`
`Pharmaceufics
`
`11 Pharmaceutical Calculations
`
`12 Statistics
`13 Molecular Structure Properties and Srores of Mailer
`14 Complex Formation
`15 Thermodynamics
`16 Solutions and Phase Equilibria
`17
`Ionic Solurions and Elecrrolytic Equilibria
`18 Tonicity Osmorcity Osmolalty and Osmolariry
`19 Chemical Kinetics
`20 Interfociol Phenomena
`
`21 Colloidal Dispersions
`22 Coarse Dispersions
`23 Rheology
`
`Port
`
`28
`
`38
`
`47
`
`60
`
`70
`
`81
`
`91
`
`124
`
`159
`
`183
`
`198
`
`208
`
`227
`
`246
`
`263
`
`215
`
`288
`316
`335
`
`49 Biotechnology
`50 Aerosols
`
`and Drugs
`
`51 Quahty Assurance and Contro
`52 Stability of Pharmaceutical
`Products
`53 Bioavoilabrtry and Bioequivalency
`54 Plastic Packaging Materials
`55 Pharmaceutical
`Necessities
`
`Testing
`
`Part
`
`Pharmacodynamks
`
`56 Diseases Manifesrarions and Pathophysiology
`5/ Drug Absorption Action and Disposition
`58 Basic Phormocokinetics
`59 Clinical Pharmacokinetics
`60 Principles of Immunology
`61 Adverse Drug Reactions
`62 Pharmacogenetics
`63 Pharmacological
`
`Aspects of Substance Abuse
`
`Port
`
`Pharmaceutica and Medicina Agents
`
`Drugs
`
`944
`
`963
`
`980
`
`986
`
`995
`
`1005
`
`1015
`
`1053
`
`1098
`
`1121
`
`1145
`
`1156
`
`1165
`
`1169
`
`11/5
`
`1185
`
`1200
`
`1219
`
`1243
`
`1274
`
`1297
`
`1305
`
`1314
`
`1322
`
`1328
`
`Pharmoceutka Chemistry
`
`24 Inorganic Pharmaceutical Chemistry
`25 Organic Pharmaceutical Chemistry
`26 Narural Products
`27 Drug NomenclatureUnited
`Names
`28 Structure-Activity Relationship and Drug Design
`29 Fundamentals
`of Rodionuclides
`
`States Adopted
`
`Part
`
`Phormaceutica Testing Analysis and Control
`
`30 Analysis of Medicinals
`
`31 Biological Testing
`32 Clinical Analysis
`33 Chromatography
`34 Instrumental Methods of Analysis
`35 Dissolution
`
`Part
`
`Pharmaceutical Manufacturing
`
`36 Separation
`37 Powders
`38 Preformulation
`39 Solutions Emuisians Suspensions arid Extracts
`40 Sterilization
`
`41 Parenreral Preparar
`42 Intravenous Admixtures
`43 Ophrhalmic Preparariors
`44 Medicated
`Tapicols
`45 Oral solid 1osage
`arms
`46 Coating of Pharmaceutical Dosage Forms
`4/ Controlled Release Drug-Delivery Systems
`48 The Introduction of New Drugs
`
`385
`409
`
`441
`458
`469
`
`485
`
`540
`
`552
`
`587
`614
`654
`
`669
`
`681
`
`700
`
`721
`
`153
`
`180
`
`80/
`
`821
`
`836
`
`858
`
`894
`
`903
`930
`
`64 Diagnostic Drugs and Reagents
`65 Topical Drugs
`66 Gastrointestinal
`and Liver Drugs
`67 Blood Fluids Elecrtolyres
`and Hematological Drugs
`68 Cardiovascular Drugs
`69 Respiratory Drugs
`70 Symparhomimeric Drugs
`71 Cholinomimeric Drugs
`72 Adrenergic and Adrenergic Neuron Blocking Drugs
`/3 Antimuscarinic and Antispasmodic
`74 Skeletal Muscle Relaxants
`75 Diuretic Drugs
`76 Urerine and Anrimigraine Drugs
`77 Hormones and Hormone Antagonists
`78 General Anesthetics
`
`/9
`Local Anestherics
`80 Sedative and Hypnotic Drugs
`81 Antiepilepric Drugs
`82 Psychopharmacologic
`Agents
`83 Analgesic Anripyreric and Anti-Inflammatory
`Drugs
`84 Histamine and Anrihistaminic Drugs
`85 Cenrral Nervous System Stimulants
`86 Antineoplosric
`and Immunoactive
`87 Anti
`Infecrives
`
`Drugs
`
`88 Parositicides
`89 Immunizing Agents and Allergenic
`
`Extracts
`
`Port
`
`Pharmacy Practice
`
`Part BA Pharmacy Administration
`
`90 Laws Governing Pharmacy
`91 Pharmacoeconomics
`92 Marketing Pharmaceutical Care Services
`93 Documenting
`and Dill ng for Phatrnaceuticnl Care
`Services
`
`94 Community Pharmacy Economics and
`Management
`95 Pioouu Recoils
`
`or Wii
`
`ic rcrwals
`
`Part 8D
`
`Fundamentals
`
`of Pharmacy Practice
`
`96 Drug Educono
`
`xiv
`
`1333
`
`1344
`
`1354
`
`1358
`
`1395
`
`1400
`
`140/
`
`1421
`
`1429
`
`1444
`
`1464
`
`14/1
`
`14/7
`
`1507
`
`1562
`
`1567
`
`595
`
`1625
`
`1634
`
`1640
`
`1650
`
`66o
`
`1677
`
`FAMY CARE - EXHIBIT 1016-0003
`
`

`
`.
`.
`Q? The Pmgscrépaiorx .
`Q8 Exremfioronecus Presuipiiow Compounding .
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`101 Nudem Phorrhcrig Prccficp
`105 Enzymes
`“I06: Vircxmirxs one Other Nutrients ‘
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`Appendixes
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`Part M2 Pmient Care
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`Glassmry and index
`
`142 ‘Long-Term Come Fcrciiéties
`
`FAMY CARE - EXHIBIT 1016-0004
`
`

`
`Ophthalmic Preparations
`
`Gerad Hecht PhD
`Senior Director Pharrr aceutica Sciene
`Alien Laboratories
`Fort Worth IX 76101
`
`solutions
`
`are sterile products essentially free
`Ophthalmic preparations
`from foreign particles suitably compounded arid packaged
`for
`include so
`instillation into the eye Ophthalmic preparations
`lutions suspensions ointments and solid dosage forms The
`the most part aqueous
`and suspensions are for
`white petrolatum
`ointments usually contain
`Ophthalmic
`mineral oil base
`can be grouped broadly into two
`Ophthalmic preparations
`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
`searching review and
`latter group has been subjected to
`part of the Food and Drug
`body of experts as
`analysis by
`Administrations FDA OTC Drug Review process
`The single dominant
`factor characteristic of all ophthalmic
`intended
`products is the specification of sterility Any product
`for use in the eye regardless of form substance or intent must
`be sterile This requirement increases the similarity between
`the physiology
`however
`and parenteral products
`ophthalmic
`eye in many respects imposes more rigid
`the human
`of
`formulation requirements This is considered in the following
`discussion
`
`II
`
`the treatment of eye disorders
`intended for
`Preparations
`can be traced to antiquity Egyptian papyri writings describe
`eye medications The Greeks and Romans expanded such uses
`and gave us the term eollyria 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 miladys eyes for cosmetic
`lady
`purposes thus the term belladonna
`or beautiful
`From the time of belladonna collyria ophthalmic technology
`snails price well into modern
`pharmaceutical
`progressed at
`times It was not until after World War
`that the concept of
`for ophthalmic solutions Prior to
`became mandatory
`sterility
`World War
`II and continuing into the 1940s very few ophthal
`or were de
`mic preparations were available
`commercially
`The USP XIV official
`in 1950 included only
`scribed officially
`three were ointments
`three ophthalmic preparations and all
`Preparations to be used in the eye either solutions or oint
`inents 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
`literature of the times The stability of ophthalmic
`maceutical
`few months
`preparations is discussed in terms of days or
`One of the most important at tributes of ophthalmic products
`sur
`is the requirement of sterility Even that however
`The USI XV in 1955 was
`the first
`event
`prisingly recent
`official compendium to include
`requirement for oph
`sterility
`hiolni solutions The FDA in 1953 adopted the position that
`solution was adulterated Sterile oph
`nonsterile ophthalmic
`tlcalinic products were of course available prior to the mid
`date only
`1950s hosve or the legal
`requirement of sterility
`from 1955
`
`is
`
`li 43
`
`The sterility
`ointments
`for ophthalmic
`requirements
`ap
`in the USP XVIII Third Supplement 1972 Prior
`peared first
`to that date there was no legal requirement for
`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
`and filling of
`ing sterile conditions during the manufacture
`ointments on
`large scale
`
`ANATOMY AND PHYStOLOGY OF THE EYE
`
`The human eye is
`for topical administra
`challenging subject
`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
`in volume
`is suitably small
`into the eye unless the material
`and chemically
`and physiologically
`compatible with surface
`tissues Figures 4311 and 4321 include pertinent anatomy of
`the human eye
`EYELIDS--The
`two purposes mechanical
`eyelids serve
`protection of the globe and creation of an optimum milieu for
`the cornea The eyelids are lubricated and kept
`by
`fluid-filled
`secretions of the lacrimal glands and specialized cells residing
`The antechamber has the shape of
`in the bulbar conjunctiva
`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
`fissure
`called the palpebral
`EYEBALLThe wall of the human eyeball bulbus globe
`is composed of three concentric layers
`The outer
`
`fibrous layer
`the uvea or uveal tract consisting of the
`middle vascular
`layer
`choroid the ciliary body and the iris
`the retina
`nervous layer
`
`The outer layer is tough pliable but only slightly stretchable
`In its front portionthe portion facing the outside worldthe
`layer is so regular and the water
`fine structure of the outer
`content so carefully adjusted that it acts as
`clear transparent
`is devoid of blood vessels Over
`the
`window the cornea It
`the white of
`remaining two-thirds the fibrous coat
`is opaque
`the eye and is called the sclera It contains the snicrocircula
`tion which nourishes the tissues of this anterior segment and
`is usually white except when irritated and vessel dilatation
`occurs
`in
`The eyeball houses
`that causes
`an optical apparatus
`images of the outside world to form on time
`verted reduced
`The optical
`thin translucent
`nieinbrane
`retina which is
`film the
`in sequence of the prreointrrl
`consists
`apparatus
`cornea the aqueous humor the pupil the crystalline lens the
`
`821
`
`FAMY CARE - EXHIBIT 1016-0005
`
`

`
`822
`
`CHAPER43
`
`Figure 43-1 The eye vertical
`
`section.1
`
`vitreous humor and
`the retina The
`and vitreous
`aqueous
`humors are layers of clear fluid or gel-like material
`interposed
`between the solid structures The pupil
`round centric hole in
`contractile membranous partition called the iris acts as the
`variable aperture of the system The crystalline lens is
`re
`fractive element with variable power controlled and supported
`by muscle incorporated in the ciliary body The choroid is the
`for the retina
`metabolic support
`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
`is the intraocular pres
`stabilizing factor
`sure which exceeds the pressure prevailing in the surrounding
`tissues This intraocular pressure is the result of
`steady
`fluid the aqueous humor which origi
`production of specific
`and leaves
`nates from the ciliary processes
`the eye by an
`The resistance encoun
`intricate system of outflow channels
`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
`carrier of nutrients substrates and
`for the avascular
`tissues of the eye
`inetabolites
`The
`bones
`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 portien 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
`cuconjunctivd iiij
`tiu1 Except
`the oi nea the conjune
`tiva is the most exposed portion of the eye
`JACRIMAL SYSTEM The conjunctival
`and corneal sur
`faces are covered
`and lubricated by
`film of fluid secreted by
`the conjunctival and Iacriinal glands The secretion of the lac
`rimal gland the tears is delivered through
`number of fine
`lucts into the conjunctival
`fornix The secretion is
`clear
`watery fluid containing numerous salts glucose other organic
`
`of
`
`foi
`
`compounds approximately O.7i protein and the enzyme ly
`sozyrne Small accessory
`lacrimal glands are situated in the
`rglir
`fornices
`conjunctival
`secretion suffices for
`lubrication
`and cleansing under ordinary conditions and for maintaining
`thin fluid film covering the cornea and coujunctiva the precor
`neal film The mucin-protein
`layer of the film is especially
`in maintaining the stability of the film The main
`important
`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 replemshes the fluid film by pushing
`thin layer of fluid ahead of the lid margins as they come
`together The excess fluid is directed into the hacrimal
`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
`fissures The movement of the eyelids
`closing of the palpebral
`includes
`narrowing of the palpebral
`fissures in
`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 canaliculiwhich
`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 cnnaliculi 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
`suction force-pump action in removing tears from
`exerts
`lake and emptying them into the nasal cavity
`the lacrimal
`
`--u CoET
`
`LT Ti
`
`Figure 43
`
`Nasolacrirna duct.1
`
`FAMY CARE - EXHIBIT 1016-0006
`
`

`
`Lacrimation is induced reflexly by otimulatioii of nerve endings
`The reflex is abolished by anes
`of the cornea or conjunctiva
`thetization of the surface of the eye and by disordei
`affecting
`its nerve components
`organ
`The normal cul dc-sac usually is free of pathogenic
`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
`that the
`More effective in producing sterility may be the fact
`secretions which are normally sterile as they leave the glands
`constantly wash the bacteria dust etc down in the nose In
`the lacrimal gland like other glandular struc
`certain diseases
`tures in the body undergoes involution with the result that
`the lacrimal fluid becomes scanty Furthermore changes in the
`glands may lead to alteration in the character of
`conjunctival
`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 FILMThe cornea must be wet
`to be an
`surface when dry it
`loses both its regular
`optically adequate
`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
`and lipid ophthalmic prepara
`compatible with both aqueous
`thicker middle
`thin outer lipid layer
`tions is composed of
`thin inner mucoid layer It
`is renewed
`layer and
`aqueous
`during each blink and when blinking is suppressed either by
`drugs or by mechanical means it dries in patches It scenic
`to
`of up to 2%
`be unaffected by the addition of concentrations
`p11 below
`or above
`fluid
`sodium chloride to conjunctival
`the movement
`causes derangement of the film The film affects
`lenses and forms more easily on glass than on plastic
`of contact
`
`prostheses
`CORNEA The cornea from 0.5 to mm thick consists
`mainly of the following structures from the front backward
`
`Corneal epithelium
`Substantia propria stroma
`Corneal endotheliurn
`
`The
`to ordinary diffuse light
`is transparent
`cornea
`largely
`special laminar arrangement of the cells and fibers
`because of
`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
`wound of
`the cornea usually heals as an
`contact
`lenses
`permanent
`opaque patch that can be
`impairment of vision
`is located in the periphery of the cornea
`unless it
`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
`clear image therefore any pathological process
`formation of
`however slight mny interfere seriously with the resolving
`power or visual acuity of the eye
`sses no blood vessels except at the
`The normal cornea
`junction The cornea therefore must derive its
`corneoscleral
`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
`is an impor
`that the normal cornea is devoid of blood vessels
`tant feature in surgical grafting The corneal nerves do not
`ho orne P3j0 ind cold jre
`form of ccii
`fo
`iuppiy all
`very low threshold which
`well supplied The pain fibers have
`makes the cornea one of the most sensitive areas on the surface
`that the cornea pos
`It now is agieecl generally
`of the bcidy
`true sense of touch nerve endings supplying the sen
`sesses
`sation of heat are lacking
`The cornea epitheliurmi provides an efficient harrier against
`invasion Unless its continuity has been broken by an
`bacterial
`in the epithehum
`tiauniatic opening or defect
`
`abrasion
`
`OPHTHALMK
`
`PREPARAIIONS
`
`823
`
`foothold Trauma
`rule cannot gain
`pathogenic bacteria as
`in most of the infectious
`therefore plays an important part
`diseases of the cornea that occur exogenouly Any foreign body
`the cornea or lodge and becomes embed
`that either cratches
`ded in the cornea is of serious moment because of the role it
`foothold
`may play in permitting pathogemc bacteria to gain
`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
`brilliant green so that even pinpoint abrasions show
`stains
`lip quite clearly Abrasion may occur during tonometry ie
`tension pressure with
`during the measurement
`of ocular
`tonometer Care must be used in applying the device to the
`cornea to avoid abrasion ofthe cornea Corneal abrasions some-
`lenses Every corneal abra
`times result from wearing contact
`to infection
`sion is subject
`
`BOAVALABUTY
`
`of 1.0
`
`PHYSICAL CONSIDERATION -Under normal condi
`jiL.7 The esti
`tions the human tear volume averages about
`mated maximum volume of the cul dc-sac is about 30 jLL with
`lacrimation rate The outflow
`drainage capacity far exceeding
`capacity accommodates the sudden large volume resulting from
`the instillation of an eyedrop Most commercial eyedrops range
`from 50 to 75 rL in volume however much in excess of 50 tiL
`the cul-de-sac
`probably is unable to enter
`the drainage rate has been
`Within the rabbit cul-de-sac
`to the instilled drop volume Multiple
`shown to be proportional
`drops administered at intervals produced higher drug concen
`of drug in minimum
`high concentration
`trations Ideally
`drop volume is desirable Patton3 has shown that approxi
`niately equal tear-film concentrations result from the instilla
`pilocarpine nitrate or from 25 gL
`10
`rL of 1.61
`tion of
`solution The
`JLL contains only 384 as much
`10
`its bioavailability is greater because of de
`pilocarpine yet
`creased drainage loss
`limit or limits to the concept of mini
`There is
`practical
`in designing and
`mum dosage volume There is
`difficulty
`that will deliver small vol
`dropper configuration
`producing
`the
`umes reproducibly Also the patient often cannot detect
`small volume This sensation or lack
`administration of such
`of sensation is particularly apparent at the 5.0 to 7.5-fiL dose-
`volume range
`ca
`The concept of dosage-volume drainage and cul-de-sac
`and administering of
`the prescribing
`pacity directly affects
`separate ophthalmic preparations The first drug adminiatered
`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 ABSORPTIONDrugs 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
`occurs
`vessels into the general circulation
`Many ophthalmic drugs are weak bases and are applied to
`solutions of their salts The free base and
`the eye as aqueous
`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 solubihity time medication
`may be acidic at the moment of instillation hut usually the
`neutrahirine action of the lacminmal fluid will convert
`rapidly
`p11 7.4 at which there will be
`to the physiological pIT range
`of the corneal
`free base present
`to begin penetration
`enough
`epithehum Once inside the epithehum the unclissociated free
`degmee The dissociated moi
`base dissociates imnmmmecliately to
`tend to penetrate the stroma because it
`is water
`ety then will
`of the stroma and endotheliimm the
`soluble At
`the junction
`took place at the outer surface of the epitlie
`sallie process that
`hum must occur again Finally the dissociated drug leaves the
`
`it
`
`FAMY CARE - EXHIBIT 1016-0007
`
`

`
`824
`
`CHAPTER 43
`
`endotheliurn for the aqueous humor here it can readily diffuse
`to the iris and the ciliary body the site of its pharmacological
`action
`small but mea
`The cornea can be penetrated by ions to
`surable degree Under comparable conditions time permeabili
`ions of small molecular weight which
`ties are similar for all
`suggests that the passage is through extracellular spaces The
`diameter of the largest particles that can pass across the cel
`An instilled
`lular Layers seems to be in the range of 10 to 25
`fluid and meta
`to protein binding in the tear
`drug is subject
`bolic degradation by enzymes such as lysozymne in addition to
`the losses by simple overflow and lacrimal drainage
`Since the cornea is membrane including both hydropbilic
`and lipophilic layers most effective penetration
`is obtained
`with drugs having both lipid and hydrophilic properties Highly
`soluble drugs penetrate less readily As an example
`water
`highly water soluble steroid phosphate esters penetrate the
`cornea poorly Better penetration
`is achieved with the poorly
`soluble but more lipopisilic steroid alcohol still greater absorp
`tion is seen with the steroid acetate form
`In 1976 Lee and Robinson4 and in 1990 Lee5 presented
`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 lacrirnation and normal tear turnover Subject
`to exper
`imental conditions
`the relative
`the factors
`effectiveness of
`involved in precorneal drug removal are drainage
`nonconjunctival
`induced lacrimation
`tion
`loss
`normal tear turnover
`tival absorption
`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
`smaller volume
`allows more drug to be absorbed For
`given instilled concen
`tration the opposite is true however
`smaller volume instilled
`remains more efficient
`ie the fraction of dose absorbed is
`the transcorneal
`greater Lang6 discusses
`route of absorption of
`drug into the eye as the route most effective in bringing
`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 72
`0.2
`and its effect on ionizable drug molecules plays the most sig
`nificant role in corneal penetration
`ointments generally produce greater bioavail
`Ophthalmic
`ability than the equivalent
`solution Because of the
`aqueous
`time drug levels are prolonged and total drug
`greater contact
`absorption is increased
`
`vasodila
`
`conjunc
`
`Types of Ophthamk Products
`
`ADMINISTRATION_T1JC instillation
`re
`of eyedrops
`mains one of the less precise yet one of
`is more ncepted
`means of topical drug delivery The method of administration is
`cumbersome at best particularly for the elderly patients with
`poor vision wbo have difficulty
`seeing without eyeglasses and
`patients with other physical handicaps Perhaps surprisingly
`most patients become quite adept at routine instillation
`TIme pharmacist hould advise
`each patient
`the
`to keep
`following points in mimi to aid in the instillation of eyedrops or
`ointments
`
`HOW TO USE EYEDROPS
`Wash hands
`With one hand gently pull lower eyelid down
`If dropper
`is separate squeeze rubber bulb once while dropper
`bottle to bring liquid into dropper
`Holding dropper above eye diop medicine inside lower
`looking up do not touch dropper
`to eye or fingers
`lower lid Tiy to keep eye open and not blink for at least 30
`Release
`seconds
`
`lid while
`
`is in
`
`If dropper
`
`is separate replace on bottle and tighten cap
`
`cap when
`
`top of bottle avoid contaminating
`
`is separate always hold it with tip down
`If dropper
`Never
`touch dropper
`to any surface
`Never
`rinse thopper
`When dropper
`is at
`removed
`When dropper
`fixture on the bottle ie when sup
`permanent
`is
`pharmaceutical manufacturer
`plied by
`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
`time
`one bottle at
`If you are using more than one kind of drop at the same time wait
`several minutes before use of other drops
`It may be helpful in use of the medicine to practice use by position
`ing yourself in front of mirror
`After instillation of drops do not close eyes tightly and try not
`to
`blink more oftea than usual as this removes the medicine from the
`place on the eye where it will be effective
`
`HOW TO USE OPHTHALMK ONTMEN1S
`Wash hands
`Remove
`cap from tube
`lower eyelid down
`With one hand gently pull
`While looking up squeeze
`small amount of ointment about 114 to
`1/2 inch inside lower
`lid Be careful not
`to touch tip of tube to eye
`eyelid fingers etc
`Close eye gently and roll eyeball
`Temporary blurring niay occur
`The closed