_ _ Remington The
`Scnence and Practice
`. ~
`of Pharmacy
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`Volume II
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`Celltrion Exhibit 1016
`Page 1
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`

`

`1 9TH
`EDITION
`
`Remington
`PraCtiCe of
`
`ALFONSO R GENNARO
`Chairman of the Editorial Board
`and Editor
`
`Celltrion Exhibit 1016
`Page 2
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`

`

`The Science and
`Pharmacy
`
`1995
`
`MACK PUBLISHING COMPANY
`Easton, Pennsylvania 18042 .
`
`Celltrion Exhibit 1016
`Page 3
`
`

`

`Entered according to Act of Congress,‘ 1n the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, at Washington DC
`~
`
`Copyright 1889,1894,1905,19071917,by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Cop'ylight 1948, l 951, by The Philadelphia College of Pharmacy and Science
`
`Copyright 1956,1960,1965,1970,1975,1980,1985,1990,1995, by The Philadelphia Co11ege of
`Pharmacy and Science
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`
`ISBN 0-9 1 2734-04-3
`
`The use of stntctural formulas from USAN and the USPDictionary of Drug Names is by
`permission of The USP Convention. The Convention is not responsible for any inaccuracy
`contained herein.
`
`NOTICE—This text is not intended to represent, nor shall it be interpreted to be, the equivalent
`of or a substitute for the qfiicial United States Pharmacopeia (USP) and/ or the National
`Formulary (NF). In the event of any diferenee or discrepancy between the current oficiat
`USP or NF standards of strength, quality, purity, packaging and Labelingfor drugs and
`representations of them herein, the context and efiect of the oflicial compendia shall prevail.
`
`Printed in the United States of America by the Mack Printing Company, Easton, Pennsylvania
`
`Celltrion Exhibit 1016
`Page 4
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`

`

`l
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`e
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`r
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`CHAPTER 89
`Ophthalmic Preparations
`
`Gerald Hecht, PhD
`Senior Director, Pharmaceutical Sciences
`Alcoa Laboratories
`Fort Wonh, TX 76101
`
`Ophthalmic preparations are sterile products essentially
`free from foreign particles, suitably compounded and pack-
`aged for instillation into the eye. Ophthalmic preparations
`include solutions, suspensions,-"ointments and solid dosage
`forms. . The solutions and Suspensions are, for the most part,
`aqueous. Ophthalmic ointments usually contain awhite pet-
`rolatum-mineral oil base.
`Ophthalmic preparations can be grouped broadly into two
`divisions of major significance to the pharmacist These 111-
`clude single or multidose prescription products and the cat-
`egory described as. OTC o r over-the-counter ophthalmic
`products The latter group has been subjected to a searching
`review and analysis by a body of experts as a part of the FDA's
`OTC Drug Review process.
`The single dominant factor characteristic of all ophthalmic
`products is the specification of sterility. Any product in-
`tended for use in the eye regardless of form, substance or
`intent must be sterile. This requirement increases the simi-
`larity between ophthalmic and parenteral proddcts, however
`the physiology of the human eye in many respects imposes
`more rigid formulation requirements. This will be consid-
`ered 1n 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 tenn-colly’n'a. 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' 5
`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 concept of sterility became mandatory for ophthalmic
`solutions. Prior to World War II and continuing
`into the
`19405 very few ophthalmic preparations were available com-
`mercially or were described oflicially. The USP XIV, official
`in 1950, included only three ophthalmic preparations and all
`three were ointments.
`Preparations to be u s e d ” 1n the eye, either solutions or oint-
`ments, invariably were compounded
`in the community or
`hospital pharmacy and were intended for immediate (prescrip-
`tion) use. Such preparation and prompt use is reflected in
`the pharmaceutical literature of the times. The stability of
`ophthalmic preparations is discussed' 1n terms of days or a few
`months.
`-
`One of the most important attributes of ophthalmic prod-
`ucts is the requirement of sterilityu 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 19505, however the legal requirement of sterility
`dates only from 1955.
`The sterility requirements for ophthalmic ointments ap-
`peared first in the USP XVIII _ 777.d Supplement (1972).
`Prior 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' 1n 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.
`1.
`-
`
`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 111 the permeability
`of the cornea The protective operation of the eyelids and
`lacrimal system rs such that there is rapid removal of material
`instilled into the eye, unless the material IS suitably small 1n
`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 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 15 called the palpebral fissure
`'
`Eyeball—The wall of the human eyeball (bulbus, globe) 1s
`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—~theportion 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 outsideworld 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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`Celltrion Exhibit 1016
`Page 5
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`ME'H‘OHJF‘Z
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`1564
`
`CHAPTER 89
`
`EXCRETORY DUCT
`
`comuncnw
`CONJUNCTIVAL
`SAC
`(
`
`WOLFRING‘S
`GLANDS
`
`CRYPTS OF
`HENLE
`
`MEIBOMIAN
`GLANDS
`TARSAL PLATE
`
`‘GLANDS 0F
`ZEIS
`(SEBACEOUS)
`
`GLANDS 0F MOLL
`‘
`(SWEAT)
`
`VlTREOUS
`HUMQB
`
`Fig1. 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‘r DUCTS
`
`NASAL '
`SEPTUM
`
`(LACRIMAL Pucm‘
`
`INFERIOR CONCHA
`
`' Fig 2. Nasolacrimalduct;1
`
`encountered during this passage and the rate of aqueous
`production are the principal factors determining the level of
`In addition to this hydromechani-
`the intraocular pressure.
`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 conjunctiva] 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 or the eyeball. This
`makes possible subconjunctival injections. ExCept for the
`cornea the conjunctiva is the most exposed portion of the eye.
`Lacrimal System—The 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 number of fine
`ducts into the conjunctival fornix.‘ The secretion is a clear,
`watery fluid containing numerous salts, glucose, other organic
`compounds, approximately 0.7% protein and the enzyme,
`lysozyme. Small accessory lacrimal glands are situated in
`the conjunctival fornices. Their secretion suflices for lubrica-
`tion and cleansing under ordinary conditions and for maintain-
`ing a thin fluid film covering the cornea and conjunctiva (the
`precomeal film). The mucin—protein layer of the film is 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 over the tear film
`Spontaneous blinking replenishes the fluid film by pushing a
`thin layer of fluid ahead of the lid margins as they come
`together. The excess fluid is directed into the lacrimal
`lake—a small triangular area lying in the angle bound by the
`innermost portions of the lids. The skin of the eyelids is the
`thinnest in the body and folds easily, thus permitting rapid
`opening and closing of the palpebral fissures. The move-
`ment of the eyelids includes a narrowing of .the palpebral
`fissures in a zipper-like aetion from the lateral canthustoward
`the corners where the eyelids
`the medial canthus (canthi:
`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 whichhave collected in its
`lower part are forced down the nasolacrimalduct 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 or
`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 rs 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 eiTective 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
`
`Samsung Bioepis Exhibit 1016
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`Celltrion Exhibit 1016
`Page 6
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`

`

`OPHTHALMIC PREPARATIONS
`
`1565
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`3 '
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`tonometer. Care must be used in applying the device to the
`cornea to avoid abrasion of the cornea Corneal abrasions
`sometimes result from wearing contact lenses. Every cor-
`neal abrasion' is subject to infection._ .
`-
`.
`-
`Bioavailability
`-
`.
`.
`..
`.. ‘-
`- Physical Consideration—Under normal conditions the
`human tear volume averages about 7 11L} The'estimated
`maximum volume of the cul-de-sac is about‘BO 11L 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 11L in volume, however, much' in
`excess of 50 11L 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 1.1L of 1.61 ><v10'2 M pilocarpine nitrate or
`from 25 11L of 1.0 x 10 2Msolution. The 5 1.1L contains only
`38% as much pilocarpine, yet its bioavailability is greater due
`to decreased drainage less.
`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. 5-1111
`dose-volume range. , '
`.
`The concept of dosage-volume drainage and cul— de-sac ca-
`pacity directly efl°ects 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 coniunctival absorption where rembval 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
`andon 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
`rapidly to 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 adegree. The dissociated moiety then will tend to pen-
`etrate the stroma because it is water-soluble. At thejunction
`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 actidn.
`‘ ‘
`The' cornea can be penetrated by 10115 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 the passage 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
`
`.
`
`.
`
`the lacrimal fluid becomes scanty. Furthermore, changes in
`the conjunctival glands may- lead to alteration in the character
`of the secretion so that quality as well as quantity of tears may
`be abnormal. This may lead to symptoms of dryness, burn-
`ing and general discomfort, and may interfere with visual
`acuity.
`Precorneal Film—The cornea must be wet to be an opti-
`cally adequate surface ,when dry, it loses both its regular gloss
`and its transparency. The precomeai 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 aqueous and lipid ophthalmic prepa-
`rations, is composed of a thin outer lipid layer, a thicker
`middle aqueous layer and a thin inner mucoid layer.
`It is
`renewed during each blink and when blinking is suppressed,
`either by drugs or by mechanical means, it dries in patches.
`It seems to be unaffected by the addition of concentrations of
`up to 2% sodium chloride to conjunctival fluid. A pH below 4
`or above 9 causes derangement of the film. The film affects
`the movement of contact lenses and forms more easily on
`'
`glass than on plastic prostheSes.
`Cornea—The cornea, from 0. 5 to 1 mm thick, consists
`mainly of the following structures (from the front backwards):
`1. Corneal epithelium
`'
`2. Substantia propria (stroma).
`3. Corneal endothelium.
`'
`,
`The cornea is transparent to ordinary diffuse light, largely
`because of a special laminar arrangement of the cells and
`fibers and because of the absence of blood vessels.
`Cloudiness of the cornea may be due to any one of several
`factors including excess pressure in the eyeball as in glau-
`coma; scar tissue due to injury, infection or deficiency of
`oxygen or excess hydration such as may occur'during the
`wearing of improperly fitted contact lenses. A wound of the
`cornea usually heals as an opaque patch which can. be a
`permanent impairment of vision unless it is located in the
`periphery of the cornea.
`The chief refraction of light for. the eye occurs at the outer
`surface of the cornea where the index of refraction changes
`from that of air (1.00) to that of precorneal substance (1.38);
`Any alteration in its shape or transparency interferes with the
`formation of a clear image; therefore, any pathological 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
`comeoscleral junction. The cornea, therefore, must derive
`its nutrition by diffusion and must have certain permeability
`it also receives nourishmentfrom the fluid
`characteristics;
`circulating through the chambers of the eye and from the air.
`The fact that the normal cornea isdevoid 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 comea one of the most sensitive areas on
`It now is agreed generally that the
`the surface of the body.
`cornea possesses atrue 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)
`pathogenic bacteria, as a rule, cannot gain a foothold.
`Trauma, therefore, plays an important part in most of the
`infectious diseases of the cornea which occur exogenously.
`Any foreign body that either scratches the cornea or lodges
`and becomes irnbedded in the cornea is of serious moment
`because of the role it may play in permitting pathogenic
`bacteria to gain a foothold.
`A means of detecting abrasions on the corneal surface is
`If
`afforded by staining the cornea with sodium fluorescein.
`there is an abrasion on the epithelium, the underlying layer
`stains a brilliant green, so that even pinpoint abrasions show
`up quite clearly. Abrasion may occur during tonometry, that
`is, during the measurement of ocular tension (pressure) with a
`
`_
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`_
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`-,__. _-_._
`__-__
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`Celltrion Exhibit 1016
`Page 7
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`. 0 Never use eye drops that have changed color.
`'
`’ ‘
`. 0
`Ifyou have more than one bottle of the same kind of drops, open
`.
`only one bottle at a time
`If you are using more than one kind of drop at the same time, wait
`0
`several minutes before use of other drops.
`0
`It may be helpful in use of the medicine
`positioning yourself‘ in front of a mirror.
`0 After instillation of drops, do not close eyes tightly and try not to
`blink more often than usual, as this removes the medicine from the place
`-'
`on the eye where it will be effective.
`:
`
`to practice use by
`
`How to .Use Ophthalmic Ointments
`Wash hands.
`.
`Remove cap from tube.
`With one hand, gently pull lower eyelid down.
`'
`While looking up, squeeze a small amount of ointment (about ‘A to
`1,3 in) inside lower lid. Be careful not to touch tip of tube to eye, eyelid,
`fingers, etc.
`' 5 Close eye gently and roll eyeball' in all directions while eye is closed
`Temporary blurring may occur.
`6. The closed eyelid may be rubbed very gently by a finger to distribute
`the drug throughout the fomix.
`'
`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 the
`first 1/4” of ointment and discard as it may be too dry.
`0 Never touch tip of tube to any surface.
`'
`D
`If you have more than one tube of the same ointment, open only
`One at a time.
`o
`If you are using more than one kind of ointment at the same time,
`wait about 1 0 minutes before use of another ointment.
`0 To improve flow of ointment, hold tube in hand several minutes to
`warm before use.
`It may be helpful in use of the ointment to practice use by position-
`0
`, .
`ing yourselfin front of a mirror.
`Ophthalmic Solutions—This is by far the most common
`means of administering a drug to the eye. 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. The principal disad-
`vantage of-‘ solutions is the relatively brief contact time'be-
`tween the medication and absorbing surfaces. Contact time
`may be increased to some extent by the inclusion of aviscosity
`increasing agent such as methylcellulose. . Inclusions of this
`sort are permitted by the USP. Aviscosity' 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 in the USP. The vehicle is,
`among other things, a saturated solution of the drug substance.
`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, optimum
`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 ambunt 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 su'spension 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 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-‘
`
`1593.592“
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`1566
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`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 Robinson“ and in 1990, Lee5 presented‘a
`summary of the factors controlling precomeal‘ 'pildcarpin'e
`disposition and pilocarpine bioavailability in the rabbit eye.
`Combining experimental work and. computer simulation the
`investigators discussed the mechanisms competing with cor-
`Included were solution drain-
`neal absorption of pilocarpine.
`agé,‘ drug-induced vasodilation, nonconjunctival loss includ-
`ing uptake by the ~nictitating membrane, coniunctival
`absorption, induced lacrirnation and normal tear turnover.
`Subject to experimental conditions the relative effectiveness
`of the factors involved in precomeal 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
`precomeal 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 efiiéient, ie, the fraction of dose ab-
`sorbed is greater. Lang6 discusses the transcomeal 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 waterglipid gradi-
`ent found in the cornea. As previously mentioned, the cor-
`the lipid-rich epithe-
`nea is composed of three general layers:
`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
`endotheliumboth contain approximately 100 times as much
`lipid as the corneal stroma. This, coupledwith the physiologi-
`cal pH of 7.2 1.0.2 and its effect on ionizable drug molecules
`plays the most significantrole 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. “nth one hand, gently pull lower eyelid down.
`If dropper: is separate, squeeze rubber bulb once while dropper is in
`. 3.
`bottle to bring liquid into dropper.
`4. Holding dropper above eye. drop medicine inside lower lid while
`looking up; do net touch dropper to eye or fingers.
`5. Release lower lid Try to keep eye open and not blink for at least 30
`seconds.
`If dropper' is separate, replace on bottle and tighten cap.
`6.
`if dropper' is separate, always hold it with tip down. -
`0
`0 Never touch dropper to any surface.
`0 Never rinse dropper.
`I When dropper' is at top of bottle, avoid contaminating cap when
`removed.
`'
`I When dropper is a permanent fixture on the bottle, ie, when
`supplied by a. pharmaceutical manufacuirer to the pharmacist, the. same
`rules apply to avoid contamination.
`'
`
`Celltrion Exhibit 1016
`Page 8
`
`

`

`Iution 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, but for a slowly soluble
`substance the dissolution rate becomes critical.
`If the disso-
`lution rate is not suficiently rapid to supply significant addi-
`tional dissolved drug, there is the possibility that the slowly
`soluble substance in suspension provides no more drug to 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 drug affects 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 recommended that particles be less than
`10 pm 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 the Smallest particles to dissolve and the
`largest particles to become larger.
`In summary, aquedus
`suspensions should, in general, give a more extended effect
`than aqueous solutions.
`The pharmacist should be aware of two potential difficulties
`inherent in suspension dosage forms.
`In the first 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 but also,
`and most importantly, patient compliance. Studies have dem-
`onstrated that a significant number of patients may not shake
`the container at all, others may contribute a few trivial shakes.
`The pharmacist should stress the need of vigorous shaking
`whenever an ophthalmic suspension is dispensed:
`A second and infrequent characteristic of suspensions is the
`phenomenon of polymorphism or the ability of a substance to
`exist in seVeral different crystalline forms.