LUPIN EX 1058
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`Page 1 of 17
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`
`19m
`
`EDITION
`
` Remington:
`Practice of
`
`ALFONSO R GENNARO
`
`Chairman of the Editorial Board
`and Editor
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`Page 2 of 17
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`Page 2 of 17
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`:0naeCn...._...CSeh_.|
`yCam rahD..
`
`1995
`
`MACK PUBLISHING COMPANY
`
`Easton, Pennsylvania 18042
`
`Page 3 of 17
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`
`
` APTER 89
`eIive1y for C
`n
`O
`O
`“schemétn
`mhalmic Preparations
`Fathecalvl
`990.
`
`983.
`
`7 lniplamab
`
`ble Reservo
`
`:— ld Hecht, PhD
`a recrorr, Piisormoceuticol Sciences
`[0 on
`WOJTTX 75401
`
`
`
`phthalmic preparations are sterile products essentially
`e from foreign particles, suitably compounded and pack-
`d for instillation into the eye. Ophthalmic preparations
`ude solutions, suspensions, ointments and solid dosage
`mg, The solutions and suspensions are, for the most part,
`ueous. Ophthalmic ointments usually contain a white pet-
`atum-mineral oil base.
`ophthalmic preparations can be grouped broadly into two
`isions of major significance to the pharmacist. These in-
`de single or multidose prescription products and the cat-
`ory described as OTC or over-the-counter ophthalmic
`ducts. The latter group has been subjected to a searching
`‘ew and analysis by a body of experts as a part of the FDA’s
`C Drug Review process.
`.
`The single dominant factor characteristic of all ophthalmic
`ducts is the specification of sterility. Any product in-
`ded for use in thereye regardless of form, substance or
`ent must be sterile. This requirement increases the simi-
`parity between ophthalmic and parenteral products, however
`he physiology of the human eye in many respects imposes
`re rigid formulation requirements. This will be consid-
`ered in the following discussion.
`I
`Preparationsintended for the treatment of eye disorders
`‘anbe traced to antiquity. Egyptian papyri writings describe
`eye medications. The Greeks and Romans expanded such
`rises and gave us the term Collyria. Collyria refer collec-
`tively to materials which were dissolved in water, milk or egg
`
`tiful lady.” I
`‘ From the time of belladonna collyria, ophthalmic technol-
`ogy progressed at a pharmaceutical snail’s pacewell into
`.
`.
`It was not until after the second World War
`that the concept of sterility became mandatory for ophthalmic
`solutions. Prior to World War II and continuing into the
`
`ophthalmic ointment. This probably was due to the difficulty
`(at that time) of testing for sterility in such nonaqueous sys-
`tems and also for the anticipated difficulties in sterilizing and
`maintaining 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 adminis-
`tration of drugs. The basis of this can be found in the anatomi-
`cal 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 11 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. 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.
`_.
`Eyeba1l—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
`microcirculation which nourishes the tissues of this anterior
`segment and is usually white except when irritated and vessel
`dilatation occurs.
`The eyeball houses an optical apparatus that causes in-
`verted reduced images of the outside world to form on the
`retina, which is a thin translucent membrane. The optical
`apparatus consists, in sequence, of the precorneal film, the
`cornea, the aqueous humor, the pupil, the crystalline lens, the
`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
`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 fibrous outer coat;
`
`- Preparations to be ‘used in the eye, either solutions or oint-
`ments,
`invariably were compounded in the community or
`
`Such preparation and prompt use is reflected in
`the pharmaceutical literatureof thetimes. The stability of
`°Dhthalmic preparations is discussed in terms of days or a few
`months.
`.
`»
`l
`.
`I
`‘ One of the most important attributes of ophthalmic prod-
`“C138 is the requirement of sterility. Even that, however, is a
`Surprisingly recent event. The USP XV in 1955 was thefirst
`Official compendium to include a sterility requirement for
`Ophthalmic solutions. The FDA in 1958 adopted the posi-
`U011 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.
`.
`‘ The sterility requirements for ophthalmic ointments ap-
`~ D‘3_ared first in the USP XVIII, Third Supplement (1972).
`P1“10r to that date there was no legal requirement for a sterile
`
`Page 4 of 17
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`1563
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`Page 4 of 17
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`
`
`encountered during this passage and the rate of aque
`production are the principal factors determining the level .
`the intraocular pressure.
`In addition to this hydromech 0
`cal 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 pyra
`mid—shaped housing for the eyeball, called the orbit.
`Conjunctiva——The conjunctival membrane covers th
`outer surface of the white portion of the eye and the inne
`aspect of the eyelids.
`In most places it is attached loosei
`and thereby permits free movement of the eyeball.
`Th«
`makes possible subconjunctival injections. Except for th
`cornea the conjunctiva is the most exposed portion of the eye
`Lacrimal System—The conjunctival and corneal surface
`are covered and lubricated by a film of fluid secreted by th
`conjunctival and lacrimal glands. The secretion of the lacr-
`mal gland, the tears, is delivered through a number of fin
`ducts into the conjunctival fornix. The secretion is a clear
`watery fluid containing numerous salts, glucose, other organi
`compounds, approximately 0.7% protein and the enzyme
`lysozyme. Small accessory lacrimal glands are situated '
`the conjunctival fornices. Their secretion suffices for lubrica
`tion and cleansing under ordinary conditions and for maintain
`ing a thin fluid film covering the cornea and conjunctiva (th
`precorneal film). The mucin-protein layer of the film is espe
`cially important in maintaining the stability of the film. Th
`main lacrimal gland is called into play only on specia
`occasions. The sebaceous glands of the eyelids secrete a
`oily fluid which helps to prevent overflowing of tears at the li
`margin and reduces evaporation from the exposed surfaces 0
`the eye by spreading over the tear film.
`Spontaneous blinking replenishes the fluid film by pushing
`thin layer of fluid ahead of the lid margins as they com
`together. The excess fluid is directed into the lacrimal
`lake—a small triangular area lying in the angle bound by th
`innermost portions of the lids. The skin of the eyelids is th
`thinnest in the body and folds easily, thus permitting rapi
`opening and closing of the palpebral fissures. The move
`ment of the eyelids includes a narrowing of the palpebra
`,
`fissures in a zipper-like action from the lateral canthus towar
`the medial cant-hus (canthi:
`the corners where the eyelids 1
`meet). This aids the transport or movement of fluid toward i
`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 which 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. Lacrimation is induced
`reflexly by stimulation of nerve endings of the cornea 01”
`conjunctiva. The reflex is abolished by anesthetization of the
`surface of the eye and by disorders affecting its nerve compo-
`nents.
`
`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
`
`
`
`1564
`
`CHAPTER 89
`
`EXCRETORY DUCT
`
`CRYPTS OF
`HENLE
`
`MEIBOMIAN
`GLANDS
`
`TARSAL PLATE
`
`‘GLANDS OF
`ZEIS
`(SEBACEOUS)
`
`'
`
`
`
`
`
`\
`
`coNJuNcnvA—**"
`‘ CONJUNCTIVAL
`SAC
`
` GLAN DS 0 F
`MANZ
`
`VITREOUS
`HUMOR
`
`
`
`GLANDS OF MoLL/
`
`(SWEAT)
`
`Fig 1. The eye:
`
`vertical section.‘
`
`more effective as a stabilizing factor is the intraocular pres-
`sure, which is in 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 the ciliary processes and leaves the eye
`by an intricate system of outflow channels. The resistance
`
`
`
`LACRIMAL GLAND
`
`EXCRETOR’( DUCTS
`
`
`
`Fig 2. Nasolacrimal duct.‘
`
`Page 5 of 17
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`Page 5 of 17
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`

`
`OPHTHALMIC PREPARATIONS
`
`1565
`
`tonometer.
`Care must be used in applying the device to the
`Corneal abrasions
`cornea to avoid abrasion of the cornea.
`Every cor-
`sometimes result from wearing Contact lenses.
`neal abrasion is subject to infection.
`
`Bioavailability
`
`. ‘Physical Consideration—Under normal conditions the
`human tear volume averages about 7 p.L.2 The estimated
`maximum volume of the cul-de-sac is about 30 ML 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 ptL in volume, however, much in
`excess of 50 'p.L probably is unable to enter the cul-de-sac.
`Within the rabbit‘ cul-de-sac, the drainage rate has been
`shown to be proportional to the instilled drop volume.
`Multiple drops administered at intervals produced higher drug
`concentrations.
`Ideally, a high concentration of drug in a
`minimum drop volume is desirable. Patton3 has shown that
`approximately equal tear-film concentrations result from the
`instillation of 5 ptL of 1.61 X 10‘2 M pilocarpine nitrateor
`from 25 pL of 1.0 X l0“3M solution. The 5 ptL contains only
`38% as much pilocarpine, yet its bioavailability is greater due
`to decreased 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 which will deliver small
`volumes 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 5.0-7 .5-p.L
`dose’-volume range.
`‘
`The concept of dosage-volume drainage and cul-de-sac ca-
`pacity directly effects the prescribing and administering of
`separate ophthalmic preparations. The first drug adminis-
`tered may be diluted significantly by the administration of the
`second. On this basis combination drug products for use in
`ophthalmology have considerable merit.
`v
`Corneal Absorption
`Drugs administered by instilla-
`tion must penetrate the eye and do so primarily through the
`cornea. Corneal absorption is much more effective than
`scleral or conjunctival absorption where 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 which will depend on the pH
`and on the individual characteristics of the drug molecule.
`To aid in maintaining storage stability and solubility, the medi-
`cation may be acidic at the moment of instillation but, usually,
`the, neutralizing action of the lacrimal fluid will convert it
`rapidlyto the physiological pH range (approximately pH 7.4),
`at which there will be enough free base present to begin
`penetration of the corneal epithelium. Once inside the epi-
`thelium the undissociated free base dissociates immediately
`to a degree. The dissociated moiety then will tend to pen-
`etrate 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 epithelium must occur again.
`Finally, the dissociated drug leaves the 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 measur-
`able, degree. Under comparable conditions, the permeabili-
`ties are similar for all ions of small molecular weight, which
`suggests that thepassage is through extracellular spaces.
`The diameter of the largest particles which can ass across the
`cellular layers seems to be in the range 10-25 . 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.
`A 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
`
`
`
`> the upp_
`;of which
`
`acted in its
`; toward its ;
`:le relaxes. .
`
`:tion-force- ‘
`
`ll lake and-
`is induced‘
`cornea 0
`ation of th
`ve compo
`
`enic orgaI1-
`due partly
`ly destr0y5
`)athogenS- ‘
`ct that the
`he glands,
`~ nose.
`111
`ular struc-
`result that
`
`acrimal fluid becomes scanty. Furthermore, changes in
`m-unctival glands may lead to alteration in the character
`cretion so that quality as well as quantity of tearsmay
`This may lead to symptoms of dryness, burn-
`and general discomfort, and may. interfere with visual
`gcorneal Film—The cornea must be wet to be an opti-
`y adequate surface; when dry, it loses both its regular gloss
`its transparency. The precorneal film, part of the tear
`provides this important moist surface.
`Its character
`epénds on the condition of the corneal epithelium. The
`‘ Compatible with both aqueous and lipid ophthalmic prepa-
`ans, is composed of a thin outer lipid layer, a thicker
`queous layer and a thin inner mucoid layer.
`It is
`1
`flawed during each blink and when blinking isgsuppressed,
`may by drugs or by mechanical means, it dries in patches.
`ems to be unaffected by the addition of concentrations of
`r90
`2% sodium chloride to conjunctival fluid. A pH below 4
`p
`r{ above 9 causes derangement of the film. The film affects
`‘e movement of contact lenses and forms more easily on
`ass than on plastic prostheses.
`-
`Cornea—-The cornea, from 0.5 to 1 mm thick, consists
`ainly of the following structures (from the front backwards):
`:1, Corneal epithelium.
`2, Substantia propria (stroma).
`3. Corneal endothelium.
`
`,
`_,-
`periphery of the cornea.
`if The chief refraction of lightfor the eye occurs at the outer
`, urface of the cornea where the index of refraction changes
`i from that of air (1.00) to that of precorneal substance (1.38).
`j Any alteration in its shape or transparency interferes with the
`formation of a clear image; therefore, any pathological pro-
`;cess, however slight, may interfere seriously with the resolv-
`‘ing power or.visual acuity of the eye.
`.
`. The normal cornea possesses no blood vessels except at the
`corneoscleral junction. The cornea, therefore, must derive
`S nutrition by diffusion and must have certain permeability
`characteristics; it also receives nourishment from the fluid
`Circulating through the chambers of the eye and from the air.
`The fact that the normal cornea is devoid of blood ‘vessels is an
`important 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 avery low thresh-
`old, which makes the cornea one of the most sensitive areas on
`the surface of the body.
`It now is agreed generally that the
`Cornea possesses a true sense of touch; nerve endings supply-
`ing the sensation 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)
`Dathogenic bacteria, as a rule, cannot gain. a foothold.
`Trauma, therefore, plays an important part in mostof the
`Infectious diseases of the cornea which occur exogenously.
`Any foreign body that either scratches the cornea or lodges
`and becomes imbedded in the cornea is of serious moment
`because of the role it may play in permitting pathogenic
`bacteria to gain a foothold.
`.
`.
`,
`A means of detecting abrasions on the corneal surface is .
`afforded by staining the cornea with sodium fluorescein.
`If
`there is an abrasion on the epithelium, the underlying layer
`Stains a brilliant green, so that even pinpoint abrasions show
`llp quite clearly. Abrasion may occur during tonometry, that
`1S, during the measurement of ocular tension (pressure) with a
`
`Page 6 of 17
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`Page 6 of 17
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`

`
`
`
`How to Use Ophthalmic Ointments
`Wash hands.
`Remove cap from tube.
`With one hand, gently pull lower eyelid down.
`4. While looking up, squeeze a small amount of ointment (abou
`1/2 in) inside lower lid. Be careful not to touch tip of tube to eye, 'e'
`fingers, etc.
`5. Close eye gently and roll eyeball in all directions while eye is C
`Temporary blurring may occur.
`,
`6. The closed eyelid may be rubbed very gently by a finger to dist
`the drug throughout the fornix.
`7. Replace cap on tube.
`0 Take care to avoid contaminating cap when removed.
`0 When opening ointment tube for the first time, squeeze out’.
`first 1/4” of ointment and discard as it may be too dry.
`'
`_
`0 Never touch tip of tube to any surface.
`0
`If you have more than one tube of the same ointment, open 0
`one at a time.
`‘
`0
`If you are using more than one kind of ointment at the same ti
`wait about 10 minutes before use of another ointment.
`.
`0
`To improve flow of ointment, hold tube in hand several minut
`—
`warm before use.
`0
`It may be helpful in use of the ointment to practice use by posit
`ing yourself in front of a mirror.
`
`
`
`means of administering a drug to the eye.
`59 ophthalmic solutions. By definition, all ingredients
`completely in solution, uniformity is not a problem and th V
`is little physical interference with vision. The principal disa:
`vantage of solutions is the relatively brief contact time b
`tween the medication and absorbing surfaces. Contact tim
`may be increased to some extent by the inclusion of a viscosi
`increasing agent such as methylcellulose.
`Inclusions of th
`sort are permitted by the USP. A viscosity in the range of 1
`to 25 cps is considered optimum for drug retention and visu
`comfort.
`Ophthalmic Suspensions—Suspensions are dispersio
`of finely divided, relatively insoluble drug substances in a
`aqueous vehicle containing suitable suspending and disper
`ing agents. There are 29 listed in the USP. The vehicle i
`among other things, a saturated solution of the drug substanc
`Because of a tendency of particles to be retained in the cul-de-:
`sac, the contact time and duration of action of a suspension‘
`probably exceeds that 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, optimu
`activity should result from an optimum particle size.
`For aqueous suspensions the parameters of intrinsic solubil-
`ity and dissolution rate must be considered. The intrinsic
`solubility determines the amount of drug actually in solution
`and available for immediate absorption upon instillation 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 comparison of different drugs in suspension systemS 7
`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 and the initial
`saturated solution becomes depleted, the particles must dis-
`solve to provide a further supply of the drug. The require-
`ment here is that the particles must undergo significant disso-
`
`0 Never use eye drops that have changed color.
`
`_
`
`If you have more than one bottle of the same kind of drop
`0
`only one bottle at a time.
`0
`If you are using more than one kind of drop at the Samg ti
`several minutes before use of other drops.
`0
`It may be helpful in use of the medicine to practice
`positioning yourself in front of a mirror.
`0 After instillation of drops, do not close eyes tightly and try,
`blink more often than usual, as this removes the medicine from th
`on the eye where it will be effective.
`
`5’-°.Nf“
`
`1566
`
`CHAPTER 89
`
`example highly water soluble steroid phosphate esters pen-
`etrate the cornea poorly. Better penetration is achieved with
`the poorly soluble but more lipophilic steroid alcohol; still
`greater absorption 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
`disposition and pilocarpine bioavailability in the rabbit eye.
`Combining experimental work and computer simulation the
`investigators discussed the mechanisms competing with cor-
`neal absorption of pilocarpine.
`Includedwere solution drain-
`age, 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 > nonconjunctival loss > induced lacri-
`mation = conjunctival absorption > normal tear turnover.
`The authors discuss the implications of the mechanisms of
`precorneal drug loss in the design of ocular drug-delivery
`systems including the effect of instilled drug volume on aque-
`ous 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 con-
`centration the opposite is true; however, a smaller volume
`instilled remains more efficient, ie, the fraction of dose ab-
`sorbed is greater. Langfi discusses the transcorneal route of
`absorption of a drug into the eye as that 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 gradi-
`ent found in the cornea. As previously mentioned, the cor-
`nea is composed of three general layers:
`the lipid-rich epithe-
`lium, 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 contain approximately 100 times as much
`lipid as the corneal stroma. This, coupledwith the physiologi-
`cal pH of 7.2 : 0.2 and its effect on ionizable drug molecules
`plays the most significant 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 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
`poor vision who have difficulty 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 mind to aid in the instillation of eyedrops
`or ointments:
`
`How to Use Eyedrops
`
`1. Wash hands.
`2. With one hand, gently pull lower eyelid down.
`3.
`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 lowerlid. Try to keep eye open and not blink for at least 30
`seconds.
`6.
`If dropper is separate, replace on bottle and tighten cap.
`If dropper is separate, always hold it with tip down.
`0
`0 Never touch dropper to any surface.
`0 Never rinse dropper.
`0 When dropper is at top of bottle, avoid contaminating cap when
`removed.
`ie, when
`0 When dropper is a permanent fixture on the bottle,
`supplied by a pharmaceutical manufacturer to the pharmacist, the same
`rules apply to avoid contamination.
`*
`
`Page 7 of 17
`
`Page 7 of 17
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`

`
`‘ within the residence time of the dose in the eye if any
`(git is to be gained from their presence in the dosing
`ten; drug whose dissolution rate is rapid, the dissolution
`wfiement may present few problems, but for a slowly soluble
`fiance the dissolution rate becomes critical.
`If thedisso-
`S
`rate is not sufficiently rapid to supply significant addi-
`ai dissolved drug, there is the possibility that the slowly
`flble substance in suspension provides no more drug to the
`Gus humor than does a more dilute suspension or a
`. ated solution of the substance in a similar vehicle.
`the particle size of the suspended drug affects the
`Vlously’
`ace area available for dissolution. Particle size also plays
`portant part in the irritation potential of the dosing
`term This consideration is important, as irritation pro-
`ces
`excessive tearing and rapid drainage of the instilled
`It has been recommended that particles be less than
`m in size to minimize irritation to the eye.’ 1- Itshould be
`in mind, however, that in any suspension system the
`5 of prolonged storage and changes in storage tempera-
`emaycause the smallestparticles to dissolve and the
`'
`In summary, aqueous
`
`:3 95QC'-(D0
`us solutions.
`*
`The pharmacist should be aware of two potential difficulties
`“rerent in suspension dosage forms.
`In the first instance
`uniformity nearly always requires brisk shaking to
`tribute the suspended drug. Adequate shaking is a func-
`,
`,
`d most importantly, patient compliance.
`strated that a significant number of patients may not shake
`container at all, others may contribute a few trivial shakes.
`e pharmacist should stress the need of vigorous shaking
`enever an ophthalmic suspension is dispensed.
`A second and infrequent characteristic ofsuspensions is the
`enomenon of polymorphism or the ability of a substanceto
`in several different crystalline forms. A change in crys-
`‘structure may occur during storage resulting in an increase
`decrease) in crystal size and alteration in the suspension
`aracteristics causing solubility changes reflected in in-
`ased or decreased bioavailability.
`\
`The pharmacist should be aware of the procedures used by
`armaceutical manufacturers in the preparation of commer-
`lsterile ophthalmic suspensions and ointments, when called
`on to compound such preprations extemporaneously.7
`Ophthalmic 0intments—Despite disadvantages, ophthal-
`c ointments remain a popular and frequently prescribed
`, Osage form. There" are '58 ophthalmic ointments listed in
`e USP. Dosage variability probably is greater than with
`lutions (although probably not with suspensions). Oint-
`
`-
`instillation.
`, Ointments do offer the advantage of longer contact time and
`greater total drug bioavailability, albeit with slower onset and
`“me to peak absorption. The relationship describing the
`Wclilability of finely divided solids dispersed in an ointment
`13338 was given by Higuchis where the amount of solid (drug)
`_released in unit time is a function of concentration, solubility
`m the ointment base and diffusivity of the drug in the base.
`.0 Special precautions must be taken in the preparation of
`,pht_ha1mic_ ointments. They are manufactured from steril-
`reed Ingredients under rigidly aseptic conditions and meet the
`._ ‘lulrements of the official sterility tests. Terminal steriliza-
`Fllon ofthe finished ointment intubes is accomplished occasion-
`a 13’ llslng a validated dose of gamma radiation.
`If the spe-
`0 Ingredients used in the formulation do not lend themselves
`1‘0utine sterilization techniques, other ingredients that meet
`along with aseptic manufacture, may be employed
`m thalmic ointments must contain a suitable substance or
`lxture of substances to prevent growth of, or to destroy,
`;gu9r00rganisms introduced accidentally when the container
`H °Dened during use. The antimicrobial agents currently
`Sed are chlorobutanol, the parabens or one of the organic
`
`_
`
`OPHTHALMIC PREPARATIONS
`
`1567
`
`mercurials.
`The medicinal agent is added to the ointment
`base either as a solution or as a micronized powder. The
`finished ointment must be free from large particles. Most
`ophthalmic ointments are prepared with a base of white petro-
`latum and mineral oil, often with anhydrous lanolin. Some
`contain a polyethylene-mineral oil gel. Whichever base is
`selected, it must be nonirritating to the eye, permit diffusion of
`the drug throughout the secretions bathing the eye and retain
`the activity of the medicament for a reasonable period of time
`under proper storage conditions.
`It is obligatory that ophthalmic ointments not contain par-
`ticulate matter that may be harmful to eye tissues. Hence, in
`preparing such ointments special precautions must be taken
`to exclude or to minimize contamination with foreign particu-
`late matter, eg, metal particles fragmented from equipment
`used in preparing ointments and also to reduce the particle
`size of the active ingredient(s) to impalpability. The official
`compendium provides tests designed to limit to a level consid-
`ered to be unobjectionable the number and size of discrete
`particles that may occur in ophthalmic ointments.
`In these
`tests the extruded contents of 10 tubes of ointment, previ-
`ously melted in flat-bottom Petri dishes and then allowed to
`solidify, are scanned under a low-power microscope fitted
`with a micrometer eyepiece for metal particles 50 um or
`larg