`
`LUPIN EX 1058
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`Page 1 of 17
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`

`

`EDITION
`
`Remington
`Practice of
`
`ALFONSO R GENNARO
`
`Chairman of the Editorial Board
`and Editor
`
`
`
`
`Page 2 of 17
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`
`dna91Cn.mCS.eh_.|
`yCa,m\raInD..
`
`1995
`
`MACK PUBLISHING COMPANY
`
`Easton, Pennsylvania 18042
`
`Page 3 of 17
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`
`
`elivery for C
`d C
`S hemoth
`ratheCal d
`990.
`
`983.
`
`APTER 89
`
`,,
`o
`0
`mhalmic Preparations
`
`
`
`’ Implantab
`‘
`:5S3132? for
`ble Reserve
`
`hid Hecht, PhD
`r
`ired°rv Pharmaceutical Sciences
`bor0r3ri‘seiso1
`
`
`phthalmic preparations are sterile products essentially
`
`e from foreign particles, suitably compounded and pack-
`
`d for instillation into the eye. Ophthalmic preparations
`
`hide Solutions, suspensions, ointments and solid dosage
`
`rmS- The solutions and suspensions are, for the most part,
`ueous. Ophthalmic ointments usually contain a white pet-
`
`mum-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—
`
`arity 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.
`,
`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 collym'a. Collyria refer collec-
`
`tively to materials which were dissolved in water, milk or egg
`
`
`
`tifullady.” ,
`‘ From the time of belladonna Collyria, ophthalmic technol-
`
`Ogy progressed at a pharmaceutical snail’s pace'well 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
`
`
`
`
`. Preparations to be used in the eye, either solutions or oint—
`
`ments,
`invariably were compounded in the community or
`
`h_08pital pharmacy and were intended for immediate (prescrip-
`
`tlon) use. Such preparation and prompt use is reflected in
`
`the pharmaceutical literaturerof the'times. The stability of
`
`0Dhthalmic preparations is discussed in terms of days or a few
`months.
`,
`»
`,
`,
`,
`
`‘ One of the most important attributes of ophthalmic prod-
`
`“Cts is the requirement of sterility. Even that, however, is a
`
`SuI‘prisingly recent event. The USP XV in 1955 was the'first
`Official compendium to include a sterility requirement for
`0_Dhthalmic solutions. The FDA in 1958 adopted the posi-
`t10n that a nonsterile ophthalmic solution was adulterated.
`Sterile ophthalmic products were, of course, available prior to
`the mid 19505, 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).
`Prlor to that date there was no legal requirement for a sterile
`
`
`
`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 21 include pertinent anatomy
`of the human eye.
`Eyelids—«The eyelids serve two purposes: mechanical
`protection of the globe and creation of an optimum milieu for
`the cornea. The eyelids are lubricated and kept fluid-filled by
`secretions of the lacrimal glands and specialized cells residing
`in the bul'bar conjunctiva. The antechamber has the shape of
`a narrow cleft directly over the front of the eyeball, with
`pocket-like extensions upward and downward. The pockets
`are called the superior and inferior fornices (vaults), and the
`entire space, the cul-de-sac. The elliptical opening between
`the eyelids is called the palpebral fisSure.
`.-
`Eyeball—The wall of the human eyeball (bulbus, globe) is
`composed of three concentric layers.
`1. The outer fibrous layer.
`2. A middle vascular layer—-the uvea or uveal tract, consisting of the
`choroid, the ciliary body and the iris.
`3. A nervous layer—the retina.
`
`The outer layer is tough, pliable but only slightly stretchable.
`In its front portion—«the portion facing the outside world——
`the fine structure of the outer layer is so regular and the water
`content so carefully adjusted that it acts as a clear transparent
`window (the cornea).
`It is devoid of blood vessels. Over
`the remaining two-thirds the fibrous coat is opaque (the
`“white” of the eye) and is called the sclera.
`It contains the
`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;
`
`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 19Ve1 ,
`the intraocular pressure.
`In addition to this hydromech 0
`cal function, the aqueous humor acts as a carrier of “Utrientg
`
`substrates and metabolites for the avascular tissues of the eye
`
`The bones of the skull join to form an approximately Wm
`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
`
`In most places it is attached 100se‘
`aspect of the eyelids.
`
`and thereby permits free movement of the eyeball.
`Thi
`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 lacrimali
`
`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.
`meet). This aids the transport or movement of fluid toward '
`the lacrimal lake.
`.
`Tears are drained from the lacrimal lake by two small
`tubes—the lacrimal canaliculi—which lead into the upper
`part of the nasolacrimal duct, the roomy beginning of which is
`called the lacrimal sac. The drainage of tears into the nose
`does not depend merely on gravity. Fluid enters and passes
`along the lacrimal canaliculi by capillary attraction aided by
`aspiration caused by contraction of muscle embedded in the
`eyelids. When the lids close, as in blinking, contraction of
`the muscle causes dilatation of the upper part of the lacrimal
`sac and compression of its lower portion. Tears are thus
`aspirated into the sac, and any 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
`
`
`
`
`CONJUNCTIVA——‘
`‘ CONJUNCTIVAL
`[31
`
` SAC——-——‘-— ,
`
`WOLFRING‘S
`(
`GLANDS-—‘—-—-—————-
`GLANDS OF
`
`
`
`
`E
`
`MANZ
`
` \
`
`CRYPTS OF
`HENLE
`
`MEIBOMIAN
`GLANDS
`
`TARSAL PLATE
`
`
`
`VITREOUS
`HUMOR
`
`
`TGLANDS OF
`ZEIS
`
`(SEBACEOUS)
`'
`
`
`
`
`
`GLANDS OF MOLL/
`
`(SWEAT)
`
`Fig 1.
`
`The eye:
`
`vertical section.1
`
`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’r DUCTS
`
`NASAL
`SEPTUM
`
`
`
`
`INFERIOR CONCHA
`
`‘
`
`.
`
`"VALVE" OF HASNER/VII
`(LACRIMAL PLICA)
`
`Fig 2. Nasolacrimal duct.1
`
`
`
`Page 5 of 17
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`

`

`
`
`
` 1acrimal fluid becomes scanty. Furthermore, changes in
`COnjunctival glands may lead to alteration in the character
`he secretion so that quality as well as quantity of tearsmay
`
`abnormal. This may lead to symptoms of dryness, burn-
`, and general discomfort, and may. interfere with visual
`
`I.Z'corneal Film—The cornea must be wet to be an opti-
`1y adequate surface; when dry, it loses both its regular gloss
`
`its transparency. The precorneal film, part of the tear
`Ched 100
`d provides this important moist surface.
`Its character
`
`yeball,
`ends on the condition of the corneal epithelium. The
`
`(cept f0
`COmpatible with both aqueous and lipid ophthalmic prepa-
`
`on of thee
`«Ens. is composed of a thin outer lipid layer, a thicker
`
`neal Sulfa
`ddle aqueous layer and a thin inner mucoid layer.
`It is
`
`ewed during each blink and when blinking issuppressed,
`
`her by drugs or by mechanical means, it dries, in patches.
`
`gems to be unaffected by the addition of concentrations of
`
`to 2% sodium chloride to conjunctival fluid. A pH below 4
`above 9 causes derangement of the film. The film affects
`
`he movement of contact lenses and forms more easily on
`
`" 2155 than on plastic prostheses.
`-
`Cornea—The cornea, from 0.5 to 1 mm thick, consists
`
`inly of the following structures (from the front backwards):
`
`, Corneal epithelium.
`
`_ .2. Substantia propria (stroma).
`
`, 3. Corneal endothelium.
`
`s secrete
`he cornea is transparent to ordinary diffuse light, largely
`
`ars at the
`ecause Of a special laminar arrangement of the cells and
`
`hers and because of the absence of blood vessels.
`:1 surfaces
`
`Gioudiness of the cornea may be due to any one of several
`
`actors including excess pressure in the eyeball as in glau-
`by pushin
`
`‘oma; scar tissue due to injury, infection or deficiency of
`‘xygen or excess hydration such as may Occur during the
`
`ound byt
`wearing of improperly fitted contact lenses. A wound of the
`
`yelids ist
`ornea usually. heals as an opaque patch which can be a
`
`utting rap
`ermanent impairment of vision unless it is located in the
`
`‘eriphery of the cornea.
`_,-
`,
`
`; The chief refraction of lightfor the eye occurs at the outer
`
`urface of the cornea where the index of refraction changes
`
`rom that of air (1.00) to that of precorneal substance (1.38).
`
`Any alteration in its shape or transparency interferes with the
`
`ormation of a clear image; therefore, any pathological pro-
`
`two sm ,
`ess, however slight, may interfere seriously with the resolv-
`
`t the upper.
`ng power or.visual acuity of the eye.
`.
`
`g of which _
`The normal cornea possesses no blood vessels except at the
`
`to the nose?
`orneoscleral junction. The cornea, therefore, must derive
`
`and passes
`ts nutrition by diffusion and must have certain permeability
`
`)n aided b .
`,_ characteristics; it also receives nourishmentfrom the fluid
`dded in the
`:_ Circulating through the chambers of the eye and from the air.
`
`The fact that the normal cornea is devoid of blood vessels is an
`itraction of:
`
`iInportant feature in surgical grafting. The corneal nerves do
`he lacrimal
`not supply all forms of sensation to the cornea. Pain and
`rs are thus
`acted in its ‘
`Cold are well supplied. The pain fibers have avery low thresh—
`
`; toward its
`01d, which makes the cornea one of the most sensitive areas on
`
`:le relaxes.
`the surface of the body.
`It now is agreed generally that the
`
`as fluid into
`- cornea possesses a true sense of touch; nerve endings supply-
`
`eased from
`111g the sensation of heat are lacking.
`,
`
`:tion-force-
`The corneal epithelium provides an efficient barrier against
`
`ll lake and
`* bacterial invasion. Unless its continuity has been .broken by
`is induced
`an abrasion (a traumatic opening or defect in the epithelium)
`
`cornea 01”
`pathogenic bacteria, as a rule, cannot gain. a foothold.
`
`ation of the
`Trauma, therefore, plays an important part in mostof the
`
`ve compo-
`1 Infectious diseases of the cornea which occur exogenously.
`
`Any foreign body that either scratches the cornea or lodges
`
`enic organ-
`and becomes imbedded in the cornea is of serious moment
`due partly
`because of the role it may play in permitting pathogenic
`ly destroyS
`bacteria to gain a foothold.
`.
`.
`,
`)athogenS-
`A means of detecting abrasions on the corneal surface is _
`ct that the
`afforded by staining the cornea with sodium fluorescein.
`If
`:he glands.
`there is an abrasion 0n the epithelium, the underlying layer
`. nose.
`In
`stains a brilliant green, so that even pinpoint abrasions show
`ular struC'
`up quite clearly. Abrasion may occur during tonometry, that
`result that
`is, during the measurement of ocular tension (pressure) with a
`
`
`
`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.
`
`Bioavailabiilvity
`
`. ‘Physical Consideration—Under normal conditions the
`human tear volume averages about 7 uL.2 The estimated
`maximum volume of the cul-de-sac is about 30 uL 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 uL 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 uL of 1:61 x 10‘2 M pilocarpine nitrateor
`from 25 p.L of 1.0 X 10‘2M solution. The 5 uL 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-uL
`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.
`.
`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.
`’ 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
`
`
`
`
`
`Page 6 of 17
`
`

`

`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. Lang6 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 t 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
`0r 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.
`~
`
`
`
`0 Never use eye drops that have changed color.
`
`
`
`_
`
`
`If you have more than one bottle of the same kind of dmp
`0
`
`only one bottle at a time.
`If you are using more than one kind of drop at the same ti
`0
`
`several minutes before use of other drops.
`
`It may be helpful in use of the medicine to practiCe
`0
`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 11
`on the eye where it will be effective.
`
`93.“?
`
`
`
`
`
`
`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.
`If you have more than one tube of the same ointment, open 0
`0
`one at a time.
`_,
`o
`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.
`
`It may be helpful in use of the ointment to practice use by posit
`0
`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 ,
`
`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 tlm
`
`may be increased to some extent by the inclusion of a viscosi
`
`Inclusions of th
`increasing agent such as methylcellulose.
`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 1
`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-
`
`
`
`
`
`
`
`Page 7 of 17
`
`

`

`its
`
`‘ within the residence time of the dose in the eye if any
`2%: is to be gained from their presence in the dosing
`
`3:: drug whose dissolution rate is rapid, the dissolution
`. irement may present few problems, but for a slowly soluble
`
`Ptaflce the dissolution rate becomes critical.
`If the disso-
`5
`rate is not sufficiently rapid to supply significant addi-
`
`a1 dissolved drug, there is the possibility that the slowly
`
`{able substance in suspension provides no more drug to the
`
`0118 humor than does a more dilute suspension or a
`, ated solution of the substance in a similar vehicle.
`
`«ously, the particle size of the suspended drug affects the
`
`‘ ace area available for dissolution. Particle size also plays
`
`ponant part in the irritation potential of the dosing
`
`tem- This consideration is important, as irritation pro-
`
`c’es 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: ‘- lt‘should be
`
`in mind, however, that in any suspension system the
`
`s of prolonged storage and changes in storage tempera-
`
`e_may'cause the smallest’particles to dissolve and the
`
`“ st particles to become larger.
`In summary, aqueous
`
`nSions should, in general, give a more extended effect
`
`n aqueous solutions.
`"
`
`The pharmacist should be aware of two potential difficulties
`
`‘erent in suspension dosage forms.
`In the first instance
`
`uniformity nearly always requires brisk shaking to
`
`tribute the suspended drug. Adequate shaking is a func-
`
`nt at the same
`.
`.
`‘
`
`d most Importantly, patient compliance.
`1 several minu
`strated that a significant number of patients may not shake
`
`container at all, others may contribute a few trivial shakes.
`,ice use by pos
`e pharmacist should stress the need of vigorous shaking
`
`'enever an ophthalmic suspension is dispensed.
`
`A second and infrequent characteristic of'suspensions is the
`3 most com
`
`enomenon of polymorphism or the ability of a substance‘to
`e USP descr
`
`in several different crystalline forms. A change in crys-
`ingredients
`structure may occur during storage resulting in an increase
`)blem and t
`
`decrease) in crystal size and alteration in the suspension
`principal di
`
`aracteristics causing solubility changes reflected in in-
`ontact time
`
`ased or decreased bioavailability.
`,
`Contact
`The pharmacist should be aware of the procedures used by
`on of a visco
`
`armaceutical manufacturers in the preparation of commer-
`iclusions of
`
`lsterile ophthalmic suspensions and ointments, when called
`
`on to compound such preprations extemporaneously.7
`
`Ophthalmic Ointments—Despite disadvantages, ophthal-
`
`c ointments remain a popular and frequently prescribed
`
`_ Osage form. There are '58 ophthalmic ointments listed in
`ibstances in
`
`e USP. Dosage variability probably is greater than with
`ng and disp
`
`gh probably not with suspensions). Oint—
`The vehicl
`
`-
`instillation.
`
`_ Ointments do offer the advantage of longer contact time and
`
`greater total drug bioavailability, albeit with slower onset and
`
`t1me to peak absorption. The relationship describing the
`
`availability of finely divided solids dispersed in an ointment
`as is a func
`
`base Was given by Higuchi8 where the amount of solid (drug)
`)red by sma
`
`Feleased in unit time is a function of concentration, solubility
`thus, optim
`
`m the ointment base and diffusivity of the drug in the base.
`.0 SDecial precautions must be taken in the preparation of
`(1:12:310 50111
`
`The intfin
`.phthalmic ointments. They are manufactured from steril-
`
`reed ingredients under rigidly aseptic conditions and meet the
`ally in 5011,:
`
`stillation of
`ti quflements ofthe officral sterility tests.‘ Terminal steriliza-
`
`increases, th
`afin ofthe finished ointment intubes is accomphshed occasion—
`
`ltion surrO
`y 93mg a validated dose of gamma radiation.
`If the spe-
`For this r
`C 1ngredients used in the formulation do not lend themselves
`
`13%I‘Outine sterilization techniques, other ingredients that meet
`
`.ties.
`
`es may be
`:0 t5: along with aseptic manufacture, may be employed
`
`1 this phyS
`mPhthalmic ointments must contain a suita