`
`
`Remington: The
`"Scienceand Practice
`of Pharmacy
`
`Volume Il
`
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`

`
`
`EDITION
`
`Remington:
`
`Practice of
`
`
`
`ALFONSO R GENNARO
`Chairman ofthe Editorial Board
`and Editor
`
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`

`

`The Science and
`Pharmacy
`
`1995
`
`MACK PUBLISHING COMPANY
`Easton, Pennsylvania 18042 _
`
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`

`

`kntered accordingto 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 Philadelphia College of
`Pharmacyand Science
`
`:
`
`: .
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`
`ISBN 0-912734-04-3
`
`The use ofstructuralformulasfrom USAN and the USP Dictionary ofDrug Namests by
`permission ofThe USP Convention. The Convention is not responsiblefor any inaccuracy
`contained herein.
`
`Notice—This teat ts not intended to represent, nor shall it be interpreted to be, the equivalent
`ofor a substitutefor the official United States Pharmacopeia (USP) and/orthe National
`Formulary (NF). Inthe event ofany difference or discrepancy between the current official
`USP or NF standards ofstrength, quality, purity, packaging and labelingfor drugs and
`representations ofthem herein, the context and effect ofthe official compendia shallprevail.
`
`Printedin the United States ofAmerica by the Mack Printing Company, Easton, Pennsylvania
`
`
`
`{
`
`|i
`
`i
`
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`

`

`Ophthalmic Preparations
`OT
`
`Gerald Hecht, PhD
`Senior Director, Pharmaceutical Sciences
`Alcon Laboratories
`Fort Worth, TX 76104
`
` CHAPTER 89
`
`Ophthalmic preparations are sterile products essentially
`ophthalmic ointment. This probably was due to the difficulty
`free from foreign particles, suitably compounded and pack-
`(at that time) of testing for sterility in such nonaqueous sys-
`aged for instillation into the eye. Ophthalmic preparations
`tems and also for the anticipated difficulties in sterilizing and
`include solutions, suspensions, ointments and solid dosage
`maintaining sterile conditions during the manufacture and
`forms..The solutions and suspensionsare, for the most part,
`%
`filling of ointments on a large scale.
`aqueous. Ophthalmic ointments usually contain a white pet-
`rolatum-mineral oil base.
`:
`Ophthalmic preparations can be grouped broadly into two
`divisions of major significance to the pharmacist,
`Thesein-
`cludesingle or multidose prescription productsand the cat-
`egory described 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 asa part of the FDA’s
`OTC Drug Review process.
`.
`:
`:
`The single dominant factor characteristic ofall ophthalmic
`products is the specification of sterility. «Any product in-
`tended for use in the eye regardless of form, substance or
`intent mustbe sterile. This requirement increases the simi-
`larity between ophthalmic and parenteral products, however
`the physiology of the human eye in many respects imposes
`more rigid formulation requirements. This will be consid-
`eredin 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 refer collec-
`tively to materials which were dissolved in water, milk or egg
`white for use as eyedrops.
`In the Middle Ages collyria in-
`cluded mydriatic substances to dilate the pupils of milady’s
`eyes for cosmetic purposes,thus the term belladonna or “beau-
`tiful lady.”
`:
`From the time of belladonna collyria, ophthalmic technol-
`ogy progressed at a pharmaceutical snail’s pace well into
`modern times.
`It was not until after the second World War
`that the conceptofsterility became mandatory for ophthalmic
`solutions... Prior to World War Il and continuing into the
`1940s very few ophthalmic preparations were available com-
`mercially or were described 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
`hospital pharmacy andwereintended for immediate (prescrip-
`tion) use. Such preparation and prompt useis reflected in
`the pharmaceuticalliterature of the times. The stability of
`ophthalmic preparationsis discussed in terms of days or afew
`months.
`:
`:
`:
`One of the most importantattributes of ophthalmic prod-
`ucts is the requirementofsterility... Even that, however,is a
`surprisingly recent event. The USP XV in 1955 was the first
`official compendium to include a sterility requirement for
`ophthalmic solutions. The FDA in 1953 adopted the posi-
`tion that a nonsterile ophthalmic solution was adulterated.
`Sterile ophthalmic products were, of course,available prior to
`the mid 1950s, however. the legal requirement of sterility
`dates only from 1955.
`toe
`The sterility requirements for ophthalmic ointments ap-
`peared first in the USP XVIIL,. Third Supplement (1972).
`Prior to that date there was no legal requirementfor a sterile
`
`Anatomy and Physiology ofthe Eye
`The humaneye is a challenging subject for topical adminis-
`tration of drugs. The basis ofthis can be foundinthe anatomi-
`cal arrangement ofthe surface tissues andin the permeability
`of the cornea. The protective operation of the eyelids and
`lacrimal system is such thatthere is rapid removal of material
`instilled into the eye, unless the material is suitably small in
`volume and chemically and physiologically corapatible with
`surface tissues. Figures 1! and 2! 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.
`Theeyelids are lubricated and keptfluid-filled by
`secretionsofthe lacrimal glands and specializedcelis residing
`inthe 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 palpebralfissure.
`my
`Eyeball—Thewail of the human eyebail (bulbus, globe)is
`composed of three concentriclayers.
`1. The outerfibrouslayer.
`2. A middle vascular layer—the uvea or uveal tract, consisting of the
`choroid, the ciliary body and theiris.
`3. Anervous layer—theretina.
`The outerlayer is tough, pliable but only slightly stretchable.
`In its front portion—the portion facing the outside world——
`the fine structure ofthe outer layeris so regular and the water
`content so carefully adjusted thatit 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) andis called the sclera.
`It contains the
`microcirculation which nourishes the tissues ofthis anterior
`segmentand is usually white except when irritated and vessel
`dilatation occurs.
`The eyeball houses an optical apparatus that causes in-
`verted reduced images of the outside. world to form on the
`retina, which is a thin translucent membrane. The optical
`apparatus consists, in sequence, of the precorneal film, the
`cornea, the aqueous humor,the pupil, the crystalline lens, ihe
`vitreous humor and the retina. The aqueous and vitreous
`humorsare layers of clear fluid or gel-like material interposed
`between the solid structures. The pupil, around centric hole
`in a contractile membranouspartition (called theiris), acts as
`the variable aperture of the system. The crystalline lens is a
`refractive element with variable power controlled and sup-
`ported 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
`dimensions, which is provided partly by the fibrousouter coat;
`1563
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`

`encountered during this passage and the rate of aqueous
`production are the principal factors determiningthe level of
`the intraocular pressure.
`In addition to this hydromechani-
`cal function, the aqueous humoracts as a carrier of nutrients,
`substrates and metabolites for the avasculartissues of the eye.
`The bonesof the skull join to form an approximately pyra-
`- mid-shaped housingfor the eyeball, called the orbit.
`Conjunctiva—tThe 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 thereby permits free movement of the eyéball. This
`makes possible subconjunctival injections. Except for the
`cornea the conjunctiva is the most exposed portion of the eye.
`Lacrimal System—tThe conjunctival and corneal surfaces
`are covered and lubricated by a film of fluid secreted by the
`conjunctival and lacrimal glands. The secretion of the lacri-
`mal gland, the tears, is delivered through a numberoffine
`ductsinto the conjunctival fornix:. The secretion is a clear,
`watery fluid containing numeroussalts, glucose, other organic
`compounds, approximately 0.7% protein and the enzyme,
`lysozyme. Small accessory lacrimal glands are situated in
`the conjunctivalfornices. Their secretion sufficesfor lubrica-
`tion and cleansing underordinary conditions and for maintain-
`ing a thin fluid film covering the cornea and conjunctiva (the
`precomeal film). The mucin-proteinlayerof the filmis espe-
`cially 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 which helps to prevent overflowing of tears at the lid
`margin and reduces evaporation from the exposed surfaces of
`the eye by spreading overthetearfilm.
`Spontaneousblinking replenishesthe fluid film by.pushinga
`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
`innermostportionsof 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 move-
`ment 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 ofwhich 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 embeddedin 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 which.have coliected in its
`lower part are forced down the nasolacrimal duct toward its
`opening intothe nose. As the lids open, the muscle relaxes.
`The upperpart of the sac then collapses and forcesfluid into
`the lower part, which at the same time is released from
`compression. Thus, the act of blinking exerts a suction-force-
`INFERIOR LACRIVIAL PUNCTUM
`eeaaeoeSoeereen)
`
`pump action in removing tears from the lacrimal lake and
`INFERIOR LACRIMAL CANALICULUS
`
`“VALVE"OFHASNat
`emptying them into the nasal cavity..Lacrimation is induced
`reflexly by stimulation of nerve endings of the cornea or
`
`conjunctiva. The reflex is abolished by anesthetization of the
`surface of the eye and by disorders affecting its nerve compo-
`
`nents.
`INFERIORween socNASAL
`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 lysozymein the tears, which normally destroys
`
`saprophytic organismsbut has little 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
`
`ametCemRRRhomMeerahs,
`
`eeONRRRr
`beROTRmARRRROD
`
`
`
`oeeterna as
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`1564
`
`CHAPTER 89
`
`EXCRETORY DUCT
`
`
`
`
`GLANDS OF
`MANZ
`
`GLANDS
`
`CRYPTS OF
`HENLE
`
`
`
` WOLFRING'S
` GLANDS OF
`LACRIMAL
`
`'
`KRAUSE 7%
`CONJUNCTIVA
`|ners 4 f
`
`
`
`
`GLANDS OFoe(SWEAT)
`
`
`MEIBOMIAN
`GLANDS
`TARSAL PLATE
`
`
`VITREOUS
`HUMOR
`
`
`“GLANDS,ef
`seBacrousyk=
`
`Figi. Theeye:
`
`vertical section.!
`
`more effective as a stabilizing factor is the intraocular pres-
`sure, which isin excess of the pressure prevailing in the
`surrounding tissues. This intraocular pressure is the result
`of a steady production of specific fluid, the aqueous humor,
`which originates from theciliary processes and leaves the eye
`by an intricate system of outflow channels. The resistance
`
`
`
`LACRIMAL GLAND
`
`-EXCRETORY DUCTS
`
`NASAL
`SEPTUM
`
`(LACRIMAL PLICA)
`
`\. CAVITY
`
`Fig 2. Nasolacrimal duct.
`
`

`

`OPHTHALMIC PREPARATIONS
`
`1565
`
`the lacrimal fluid becomes scanty..Furthermore, changesin
`tonometer. Care must be used in applying the deviceto the
`the conjunctival glands may leadto alteration in the character
`cornea to. avoid. abrasion of the cornea. .. Corneal abrasions
`of the secretion so that quality as well as quantity of tears may
`sometimes result from wearing contact lenses. Every cor-
`be abnormal. This may lead to symptomsof dryness, burn-
`neal abrasion is subject to infection...
`ae
`ing and general discomfort, and may interfere with visual
`Bioavailability
`acuity.
`SO
`oe
`Precorneal Film—tThe cornea must be wet to be an opti-
`cally adequate surface; when dry, it loses bothits regular gloss
`and its transparency. The precorneal film, part of the tear
`fluid, provides this important moist surface.
`Its character
`depends on the condition of the corneal epithelium. The
`film, compatible with both aqueousand lipid ophthalmic prepa-
`rations,
`is cormposed of a thin outerlipid 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 seemsto be unaffected by the addition of concentrations of
`up to 2% sodium chloride to conjunctivalfluid. ApH below 4
`or above 9 causes derangement ofthe film.
`Thefilmaffects
`the movement of contact lenses and forms more easily on
`glass than on plastic prostheses.
`:
`‘
`Cornea—The cornea, from 0.5 to 1 mmthick, consists
`mainly ofthe following structures (from the front backwards):
`1. Corneal epithelium.
`2. Substantia propria (stroma).
`3. Corneal endothelium.
`
`
`
`Physical Consideration—-Under normal conditions thé
`human tear volume averages about 7 pL.2 The estimated
`maximum volumeof the cul-de-sac is about'30 u.L with drain-
`age capacity far exceeding lacrimation rate. The outflow
`capacity accommodates the sudden large volume resulting
`from the instillation of an eyedrop: Most commercial eye-
`drops range from 50 to 75 ,L in volume, however, much in
`excess of 50 wL probably is unable to enter the cul-de-sac.
`Within the rabbit ‘cul-de-sac, the drainage rate has been
`shown to be proportional to the instilled drop volume:
`Multiple drops administeredat intervals produced higherdrug
`concentrations.
`Ideally, a high concentration of drug in a
`minimum drop volumeis desirable.
`Patton® has shown that
`approximately equal tear-film concentrations result from the
`instillation of 5 wL of 1.61 x-10-2 M pilocarpine nitrate or
`from 25 pL of 1.0 x 10-2. M solution. The 5 pL contains only
`38%as muchpilocarpine,yet its bioavailability is greater due
`to decreased drainageloss.
`:
`There is a practical limit or limits to the concept. of mini-
`mum dosage volume.
`Thereis a difficulty in designing and
`The cornea is transparent to ordinary diffuse light, largely
`producing a dropper configuration which will deliver small
`because of a special laminar arrangement ofthe cells and
`volumes reproducibly. Also, the patient often cannot detect
`fibers and because of the absence of blood vessels.
`the administration of such asmall volume. This sensation or
`Cloudiness of the cornea may be due to any one of several
`lack of sensation is particularly apparent at the 5.0-7.5-pL
`factors including excess pressure inthe eyeball as in glau-
`dose-volume range."
`,
`:
`coma; scar tissue due to injury, infection or deficiency of
`The concept of dosage-volume drainage and cul-de-sac ca-
`oxygen or excess hydration such as may occur during the
`pacity directly effects the prescribing and administering of
`wearing of improperly fitted contact lenses. A wound of the
`separate ophthalmic preparations. The first drug adminis-
`cornea usually heals as an opaque patch which can.be a
`tered may be diluted significantly by the administration of the
`permanent impairment of vision unless it is located in the
`second. On this basis combination drug products for use in
`periphery of the cornea.
`:
`a,
`
`ophthalmology have considerable merit.:
`a
`.
`The chiefrefractionof light for the eye occurs at the outer
`. Corneal Absorption
`Drugs administered by instilla-
`surface of the cornea where the index of refraction changes
`tion must penetrate the eye and do so primarily through the
`from that ofair (1.00) to that of precorneal substance (1.38):
`cornea. Corneal absorption is much more effective than
`Any alteration in its shape or transparencyinterferes with the
`scleral or conjunctival absorption where removal by blood
`formation of a clear image; therefore, any pathological pro-
`vessels into the general circulation occurs.
`cess; howeverslight, may interfere seriously with the resolv-
`Many ophthalmic drugs are weak bases and are applied to
`ing powerorvisual acuity of the eye.
`.
`2
`the eye as aqueous solutions oftheir salts.
`‘The free base and
`The normal cornea possesses no blood vessels except at the
`the salt will be in an equilibrium whichwill depend on the pH
`corneoscleral junction.. The cornea, therefore, must derive
`and-on the individual characteristics of the drug molecule.
`its nutrition by diffusion and must have certain permeability
`To aid in maintaining storage stability and solubility, the medi-
`characteristics; it also receives nourishment from the fluid
`cation may be acidic at the momentofinstillation but, usually;
`circulating through the chambersofthe eye and from theair.
`the neutralizing action ofthe lacrimal fluid will convert: it
`Thefact that the normal corneais devoid ofblood vessels is an
`rapidly to the physiological pH range (approximately pH. 7.4),
`important feature in surgical grafting. The corneal nerves do
`at which there will be enough free base present to: begin
`not supply all forms of sensation to the cornea. Pain and
`penetration of the corneal epithelium.
`Onceinside the epi-
`coldare wellsupplied. The pain fibers have avery low thresh-
`thelium the undissociated free base dissociates immediately
`old, which makes the cornea one of the most sensitive areas on
`to a.degree. The dissociated moiety then will tend to pen-
`the surface of the body.
`It now is agreed generally that the
`etrate the stroma because it is water-soluble. At the junction
`cornea possesses a true sense of touch; nerve endings supply-
`of the stroma and endothelium the same process that took
`ing the sensationof heatare lacking.
`place at the outer surface of the epithelium must occuragain.
`The corneal epithelium providesan efficient barrier against
`Finally, the dissociated drug leaves the endothelium for the
`bacterial invasion..Unless its continuity has been broken by
`aqueous humor. Here it can readily diffuse to the iris and the
`an abrasion (a traumatic opening or defect in the epithelium)
`ciliary body,the site of its pharmacological action.
`pathogenic bacteria, as a rule, cannot gain a foothold.
`The'cornéa can be penetrated by ions to a'small, but measur-
`Trauma, therefore, plays an important part in most of the
`able, degree. Under comparable conditioris, the permeabili-
`infectious diseases of the cornea which occur exogenously.
`ties are similar forall ions of small molecular weight, which
`Any foreign body that either scratches the cornea or lodges
`suggesis that the passage is through extracellular spaces.
`and becomes imbedded in the cornea is of serious moment
`The diameterofthe largest particles which canpass acrossthe
`because of the role it may play in permitting pathogenic
`cellular layers seems to be inthe range 1025 A. An instilled
`bacteria to gain a foothold.
`:
`drug is subject to protein binding in the tear fluid and meta-
`A means of detecting abrasions on the corneal surface is
`bolic degradation by enzymes such as lysozyme,in addition to
`afforded by staining the cornea with sodium fluorescein.
`If
`the losses by simple overflow and lacrimal drainage.
`,
`there is an abrasion on the epithelium, the underlying layer
`' Since'the cornea is a membraneincluding both hydrophilic
`stains a brilliant green, so that even pinpoint abrasions show
`and lipophilic layers, most effective penetration is obtained
`up quite clearly. Abrasion may occur during tonometry, that
`with drugs having both lipid and hydrophilic properties.
`is, during the measurementof ocular tension (pressure) witha
`Highly water soluble drugs penetrate less readily.. As an
`
`we
`
`nm1awe
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`

`1566
`
`CHAPTER 89
`
`popCoN
`
`How to Use Ophthalmic Ointments
`Wash hands.
` .
`Remove cap fromtube.
`With one hand,gently pull lower eyelid down.
`While looking up, squeeze a small amountof ointment (about 4 to
`¥, in) inside lower lid. Be careful not to touch tip of tube to eye, eyelid,
`fingers,etc.
`5. Close eye gently and roll eyeball invall directions while eye is closed.
`Temporary blurring may occur.
`6. The closed eyelid may be rubbed very gently bya fingerto distribute
`the drug throughout the fornix. -
`7. Replace cap on tube.
`@ Take care to avoid contaminating cap when removed.
`'
`@ When opening ointment tube for thefirst time, squeeze out the
`first 14” of ointment and discard as it may be too dry.
`® Nevertouchtip of tube to any surface.
`@
`Ifyou have more than one tube of the same ointment, open only
`one at atime.
`®
`Ifyou are using more than one kind of ointmentat the sametime,
`wait about 10 minutes before use of another ointment.
`® To improve flow of ointment, hold tube in hand several minutes to
`warm before use.
`®
`Itmay be helpful in use of the ointmentto practice use by position-
`ing yourself in front of a mirror.
`-
`
`
`
`@ Neveruse eye drops that have changedcolor.
`’
`example highly water soluble steroid phosphate esters pen-
`@
`Ifyou have more than one bottle of the same kind of drops, open
`etrate the cornea poorly..Better penetration is achieved with
`only one bottle at a time.
`the poorly soluble but more lipophilic steroid alcohol; still
`@
`Ifyou are using more thanone kind ofdropat the same time, wait
`greater absorption is seen with the steroid acetate form.
`several minutes beforc use of other drops.
`In 1976 Lee and Robinson‘ and in 1990, Lee® presented a
`©
`it may be helpful in use of the medicine to practice use by
`summary of the factors controlling precorneal ‘pilocarpine
`positioning yourselfin front of a mirror.
`@
`Afterinstillation of drops, do not close eyes tightly and try not to
`disposition and pilocarpine bioavailability in the rabbit eye.
`Combining experimental work and computer simulation the
`blink more often than usual, as this removes8
`the medicine from the place
`investigators discussed the mechanisms competing with cor-
`on the eye whereit will be effective,
`:
`neal absorption of pilocarpine.
`Included weresolution drain-
`agé, drug-induced vasodilation, nonconjunctival loss includ-
`ing uptake by the -nictitating membrane, conjunctival
`absorption, induced lacrimation and normal -tear turnover.
`Subject to experimental conditions the relative effectiveness
`of the factors involved in precorneal drug removal are drain-
`age = vasodilation > nonconjunctivalloss > inducedlacri-
`mation = conjunctival absorption > normal tear turnover.
`The authors discuss the implications of the mechanismsof
`precorneal drug loss in the design of ocular drug-delivery
`systems including the effect of instilled drug volume on aque-
`ous humorconcentration and the amountof drugavailable for
`systemic absorption. On an absolute basis a smaller volume
`allows more drug to’be absorbed.
`Fora given instilled con-
`centration the opposite is true; however, a smaller volume
`instilled remains more efficient, ie, the fraction of dose ab-
`sorbed is greater. Lang® discusses the transcorneal route of
`absorption of a drug into the eye as that route mosteffective in
`bringing a given drug to the anterior portion of-the eye.
`This route of absorption is enhanced by the water-lipid gradi-
`ent found in the cornea. As previously mentioned, the cor-
`nea is composed ofthree generallayers:
`the lipid-rich epithe-
`lium, the lipid-poor stroma and thelipid-rich endothelium.
`Differential studies onthe relative lipid contents of these three
`layers have shown that the corneal epithelium and the corneal
`endothelium both contain approximately 100 times as much
`lipidasthe cornealstroma. This, coupled with the physiologi-
`cal pH of 7.2 + 0.2 andits effect on ionizable drug molecules
`plays the mostsignificant.role in corneal penetration.
`- Ophthalmic ointments generally produce greater bioavail-
`ability than the equivalent aqueous solution. Because ofthe
`greater contact time drug levels areprolonged aandtotal drug
`absorptionis increased.
`
`Ophthalmic Solutions—Thisis by far the most common
`means of administering adrugtotheeye. The USP describes
`59 ophthalmic solutions. By definition, all ingredients are
`completely in solution, uniformity is not a problem and there
`is little physical interference with vision. Theprincipal disad-
`vantage ofsolutions is the relatively brief ‘contact time be-
`tween the medication and absorbing surfaces. Contact time
`may be increased to someextent by the inclusion of a viscosity
`increasing agent such as methylcellulose. Inclusionsofthis
`sort are permitted bythe USP. A-viscosity in the range of 15
`to 25 cps is considered optimum for drug retention and visual
`comfort.
`Ophthalmic Suspensions—Suspensions are dispersions
`of finely divided, relatively insoluble drug substances in an
`aqueous vehicle containing suitable suspending and dispers-
`ing agents. There are 29 listed inthe USP. The vehicle is,
`among other things, a saturated solution ofthe drug substance.
`Because of a tendencyofparticles to bé retained in‘the cul-de-
`sac, the contact time and duration of action of a suspension
`probably exceedsthat of a solution. The drug is absorbed
`from solution and the solution concentration is replenished
`from retained particles. Each of these actions is a function
`of particle size, with solubility rate being favored by smaller
`size and retention favored by a larger size; thus, optimum
`activity should result from an optimum particlesize.
`For aqueous suspensions the parametersofintrinsic solubil-
`ity and dissolution rate must be considered. The intrinsic
`solubility determines the amount of drug actuallyin solution
`and available for immediate absorption uponinstillation of the
`dose. As the intrinsic solubility of the drug increases, the
`concentration of the drug in the saturated solution surround-
`ing the suspended drug particle also increases. For this rea-
`son, any comparisonof different drugs in suspension systems
`should include their relative intrinsic solubilities. The ob-
`served differences in their biological activities may be as-
`cribed wholly or in part to the differences in this physical
`parameter. As the drug penetrates the cornea andtheinitial
`saturated solution becomes depleted, the particles must dis-
`solve to provide a further supply of the drug. The require-
`menthere is that the particles must undergosignificant disso-
`
`Types of Ophthalmic Products
`
`Administration——Theinstillation of eyedrops remains one
`of the less precise, yet one of the more accepted means of
`topical drug delivery. The method of administration is cum-
`bersome at best, particularly for the elderly, patients with
`poorvision who havedifficulty seeing without eyeglasses and
`patients with other physical handicaps. Perhaps, surpris-
`ingly, the majority of patients become quite adept at routine
`instillation.
`The pharmacist should advise each patient to keep the
`following points in mindto aid in theinstillation of eyedrops
`or ointments:
`
`How to Use Eyedrops /
`1. Wash hands.
`2. With one hand,gently pull lower eyelid down.
`3.
`If dropperis separate, squeeze rubber bulb oncewhile dropperis in
`bottle to bring liquid into dropper.
`4. Holding dropper above eye, drop medicine inside lower ‘lid while
`looking up; do not touch dropperto eyeorfingers.
`5. Release lowerlid.
`‘Try to keep eye operandnotblinkforat least 30
`seconds.
`6.
`-If dropperis separate, replace on bottle and tightencap.
`Ifdropperis separate, alwayshold it with tip down.
`®
`@ Never touch dropperto any surface.
`@ Neverrinse dropper.
`@ Whendropperis at top of bottle, avoidcontaminating cap when
`removed.
`- @ When dropper is a permanent fixture on the bottle, ie, when
`supplied by a pharmaceutical manufacturer to the pharmacist, thesame
`rules apply to avoid contamination.
`
`||
`
`Apotex Exhibit1025
`Apotex Exhibit 1025
`Page 8 of 18
`Page 8 of 18
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`lution within the residence time of the dose in the eye if any
`benefit is to be gained from their presence in the dosing
`system.
`For a drug whose dissolution rate is rapid, the dissolution
`requirement may present few problems,butfor aslowly soluble
`substancethe dissolution rate becomescritical.
`If the disso-
`lution rate is not sufficiently rapid to supply significant addi-
`tional dissolved drug, there is the possibility that the slowly
`soluble substance in suspension provides no more drugto the
`aqueous humor than does a more dilute suspension or a
`saturated solution of the substance in a similar vehicle.
`Obviously,the particle size of the suspended drugaffects the
`surface area available for dissolution. Particle size also plays
`an important part in the irritation potential of ‘the dosing
`system. This consideration is important, as irritation pro-
`duces excessive tearing and rapid drainage of the instilled
`dose.
`It has been recommendedthat particles be less than
`10 xm in size to minimize irritation to the eye.
`It should be
`kept in mind, however, that in any suspension system the
`effects of prolonged storage and changes in storage tempera-
`ture may cause thesmallest particles to dissolve and the
`largest particles to become larger.
`In summary, aqueous
`suspensions should, in general, give a more extended effect
`than aqueoussolutions.
`The pharmacist should be aware of two potential difficulties
`inherent in suspension dosage forms.
`In thefirst instance
`dosage uniformity nearly always requires brisk shaking to
`distribute the suspended drug. Adequate shaking is a func-
`tion of the suitability of the suspension formulation butalso,
`and mostimportantly, patient compliance. Studies have dem-
`onstrated that a significant number of patients may not shake
`the containerat all, others may contribute a few trivial shakes.
`The pharmacist should stress the need of vigorous shaking
`wheneveran ophthalmic suspensionis dispensed:
`Asecond and infrequent characteristic of suspensionsis the
`phenomenon of polymorphism orthe ability of a substance to
`exist in several different crystalline forms. A changein crys-
`tal structure may occur during storage resulting in an increase
`(or decrease) in crystal size and alteration in the suspension
`characteristics causing solubility changes reflected. in in-
`creased or decreased bioavailability.
`The pharmacist should be awareof the procedures used by
`pharmaceutical manufacturers in the preparation of commer-
`cial sterile ophthalmic suspensions and ointments, when called
`upon to compound such preprations extemporanecously.?
`Ophthalmic Ointments—Despite disadvantages, ophthal-
`mic ointments remain a popular and frequently