ALCON 2049
`Apotex Corp. v. Alcon Research, Ltd.
`Case IPR2013-00428
`
`1
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`

`

`
`
` 23
`
`General Information / Pharmaceutical Dosage Forms
`
`(1151)
`
`1945
`
`
`utions of drug substances in sterile water for inhalation or
`
`him chloride inhalation solution may be nebulized by use
`
`tt gases. Nebulizers are suitable for the administration of
`
`tion solutions only if they give droplets sufficiently fine and
`
`{m in size so that the mist reaches the bronchioles. Neb-
`
`_
`‘olutions may be breathed directly from the nebulizer or
`
`hulizer may be attached to a plastic face mask, tent, or
`
`student positive pressure breathing (IPPB) machine.
`
`other group of products, also known as metered-dose in-
`
`; {MDIs) are propellant driven drug suspensions or solutions
`
`uified gas propellant with or without a cosolvent and are
`
`‘ d for delivering metered doses of the drug to the respir-
`
`tract. An MDI contains multiple doses, often exceeding
`
`hundred. The most common single-dose volumes deliv-
`
`itre from 25 to 100 pL (also expressed as mg) per actuation.
`
`' iples of MDls containing drug solutions and suspensions
`
`pharmacopeia are Epinephrine Inhalation Aerosol and
`
`,lerenol Hydrochloride and Phenylephrine Bitartrate In-
`
`It Aerosol, respectively.
`
`ders may also be administered by mechanical devices that
`
`its manually produced pressure or a deep inhalation by the
`
`all.
`
`in (e.g., Cromolyn Sodium for Inhalation).
`special class of inhalations termed inhalants consists of drugs
`
`hination of drugs, that by virtue of their high vapor pres-
`it: need
`
`.llllittg .
`ttsn be carried by an air current into the nasal passage where
`
`" xcrt their effect. The container from which the inhalant
`
`Eight
`hilly is administered is known as an inhaler.
`
`
`
`INJECTIONS
`
`See Injections (1).
`
`IRRIGATIONS
`
`
`
`irrigations are sterile solutions intended to bathe or flush open
`or body cavities. They are used topically, never paren-
`They are labeled to indicate that they are not intended
`. action.
`
`
`
`LOTIONS
`
`See Solutions or Suspensions,
`
`LOZENGES
`
`
`
`éswuges are solid preparations, which are intended to dissolve
`ntcgrate slowly in the mouth. They contain one or more
`,iIIIUYltS, usually in a flavored, sweetened base. They can be
`lincrzil
`
`ml by molding (gelatin and/or fused sucrose or sorbitol
`an illi‘
`
`4‘ by compression of sugar based tablets. Molded lozenges
`
`
`} wtimes referred to as pastilles while compressed lozenges
`,I or mt» as
`w referred to as troches. They are usually intended for
`
`‘l Jt‘fll‘l
`if of local irritation or infections of the mouth or throat
`
`--. contain active ingredients intended for systemic absorp-
`
`_- «an swallowing.
`
`:S (Hill’-
`
`ents) I
`OINTMENTS
`mm...
`
`wnts are semisolid preparations intended for external ap—
`5.6 N I
`
`«I to the skin or mucous membranes.
`iliiik‘
`
`IHJ‘JC‘“!
`egnt bases recognized for use as vehicles fall into four
`
`_
`'
`, kisses:
`1
`to 1W"
`the hydrocarbon bases, the absorption bases, the
`
`y aft ll *3
`.movable bases, and the water-soluble bases. Each ther-
`umtment possesses as its base a re resentative of one of
`,I an general classes.
`
`mg m
`I VfiiW“
`.teal L?"-
`
`HS 0f "I“
`oral r: I
`
`'
`
`‘1'
`
`Hydroearnen eases
`>
`loses, which are known also as “oleaginous ointment
`
`’ no represented by Whi‘
`*rolatizrn and White Oint—
`
`_, component can he in»
`. ml‘f small amounts of ar
`a. II into them. They serve to keep medicaments in pro“
`4 mutact with the skin and act as occlusive dressings.
`.1Il,ll)l’l bases are used chiefly for their emollient effects,
`difficult to wash off. They do not “dry out” or change
`“ Mil on aging.
`
`:
`
`.
`
`Absorption Bases
`
`the first
`This class of bases may be divided into two groups:
`group consisting of bases that permit the incorporation of aqueous
`solutions with the formation of a water-in-oil emulsion (Hydro—
`philic Petrolatum and Lanolin), and the second group consisting
`of water-in-oil emulsions that permit the incorporation of addi-
`tional quantities of aqueous solutions (Lanolin). Absorption bases
`are useful also as emollients.
`
`Water-removable Bases
`
`Such bases are oil-in-water emulsions, e.g., Hydrophilic Oint-
`ment, and are more correctly called “creams.” (See Creams.)
`They are also described as “water-washable,” since they may be
`readily washed from the skin or clothing with water, an attribute
`that makes them more acceptable for cosmetic reasons. Some
`medicaments may be more effective in these bases than in hy-
`drocarbon bases. Other advantages of the water—removable bases
`are that they may be diluted with water and that they favor the
`absorption of serous discharges in dermatological conditions.
`
`Water-soluble Bases
`
`This group of so-called “greaseless ointment bases” is com-
`prised of water-soluble constituents. Polyethylene Glycol Oint—
`ment is the only Pharmacopeial preparation in this group. Bases
`of this type offer many of the advantages of the water-removable
`bases and, in addition, contain no water-insoluble substances such
`as petrolatum, anhydrous lanolin, or waxes. They are more cor—
`rectly called “Gels.” (See Gels.)
`Choice of Base—The choice of an ointment base depends upon
`many factors, such as the action desired, the nature of the med-
`icament to be incorporated and its bioavailability and stability,
`and the requisite shelf—life of the finished product. In some cases,
`it is necessary to use a base that is less than ideal in order to
`achieve the stability required. Drugs that hydrolyze rapidly, for
`example, are more stable in hydrocarbon bases than in bases
`containing water, even though they may be more effective in the
`latter.
`
`OPHTHALMIC PREPARATIONS
`
`Drugs are administered to the eyes in a wide variety of dosage
`forms, some of which require special consideration. They are
`discussed in the following paragraphs.
`
`Ointments
`
`Ophthalmic ointments are ointments for application to the eye.
`Special precautions must be taken in the preparation of oph-
`thalmic ointments. They are manufactured from sterilized in-
`gredients under rigidly aseptic conditions and meet the require-
`ments under Sterility Tests (71 ). If the specific ingredients used
`in the formulation do not lend themselves to routine sterilization
`techniques, ingredients that meet the sterility requirements de—
`scribed under Sterility Tests (71), along with aseptic manufac—
`ture, may be employed. Ophthalmic ointments must contain a
`suitable substance or mixture of substances to prevent growth of,
`or to destroy, microorganisms accidentally introduced when the
`container is opened during use, unless otherwise directed in the
`individual monograph, or unless the formula itself is bacterio—
`static (see Added Substances under Ophthalmic Ointments
`(771)). 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 and must meet the requirements
`
`for Leakage and for Metal Particles and r
`;,>lzzhalmic Oint-
`ments (771). The immediate cont.“
`t
`rmhthalmic oint-
`
`ments shall be sterile at the time of
`.nr- and closing.
`It is
`mandatory that the immediate
`“ '
`'
`l
`%‘ ophthalmic oint-
`we
`Mtge
`O u
`ments be sealed and tamper—pr.
`time of first use.
`
`
`~
`.
`:5. he nonirritating to the
`that i“
`The ointment ba
`
`tonghout the secretions ba-
`eye, permit diffusion of t
`
`
`thing the eye, and retain it
`th‘llVily of the medicament for a
`reasonable period under proper storage conditions.
`
`Petrolatum is n “ly used as a base for ophthalmic drugs.
`
`Some absorption b
`. water~re1novable bases, and water-soluble
`
` ,;
`
`5
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`2
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`

`

`1946
`
`
`
`
`STERILIZATION
`The sterility of solutions applied to an thin
`L‘
`
`greatest importance. Sterile preparations in ‘
`
`for individual use on one patient should be at:
`
`hospital, office, or other installation where at.
`gically traumatized eyes are treated. The mat
`
`sterility is determined primarily by the charm
`
`
`product (see Sterilization and Sterility Assure
`Articles (121 1 y).
`
`Whenever possible, sterile membrane film;
`conditions is the preferred method.
`if it can
`
`uct stability is not adversely affected, sterilize
`
`in the final container is also a preferred met
`
`Buffering certain drugs near the physiiilog In!
`
`them quite unstable at high temperature.
`
`'
`Avoiding the use of heat by employing ii
`
`filter is a valuable technique, provided cautinfit
`
`selection, assembly, and use of the equipment
`-
`-
`presterilized disposable units are available an; .
`
`wherever possible
`
`
`PRESERVATION
`
`Ophthalmic solutions may be packaged tn r
`tainers when intended for the individual use it?
`
`where the ocular surfaces are intact.
`It
`is the:
`
`a
`immediate containers for ophthalmic sclut
`'
`
`tamper—proof so that sterility is assured at isms as ,
`
`i
`solution must contain a suitable substitute: a
`stances to prevent the growth of, or to drama
`
`accidentally introduced when the container t
`Where intended for use in surgical pmuriism
`
`lutions, although they must be sterile, alumna
`bacterial agents, since they may be irritating ti
`
`THICKENING AtBEN}
`
`A pharmaceutical grade of methyleullstnto ;
`
`viscosity is 25 centipoises, or 0.25% if 4th
`suitable thickening agents such as hydro;
`
`or polyvinyl alcohol occasionally are misled .
`tions to increase the viscosity and prolong
`
`with the tissue. The thickened ophtlialim:
`
`from visible particles.
`
`
`Suspensroiis
`_
`Ophthalmic suspensions are sterile l:
`
`taining solid particles dispersed in a l‘v-t
`
`application to the eye (see Suspensinm,»
`
`
`such suspensions contain the drug in n im- ;
`irritation and/or scratching of the Corn
`
`sions should never be dispensed if the,“ i
`.
`,
`
`aggregation.
`
`Si ,rips
`
`Fluorescein sodium solution should i,
`
`
`“their
`.
`single—use container or in the form of i.)
`strip. The strip releases a sufficicn‘
`
`agnostic purposes when touched to in. .
`
`a foreign body or a corneal abrasion ;
`
`the eye may be avoided by leaching tin f.
`_,
`
`the eye with the aid of sterile water
`solution.
`
`(1151) Pharmaceutical Dosage Forms / General Information
`ater-soluble drugs. Such bases allow
`soluble medicaments, but they must
`bases may be desirable for w
`_
`for better'dispersion of water-
`be nonirritating to the eye.
`Solutions
`olutions, essentially freefroiri
`,
`.
`,
`Ophthalmic solutions are sterile s
`foreign particles, su1tably compounded and packaged for instil-
`lation into the eye. Preparation of an ophthalmic solution requires
`careful consideration of such factors as the inherent toxicity of
`the drug itself, isotonicity value, the need for buffering agents,
`the need for a preservative (and, if needed, its selection), steril—
`ization, and proper packaging. Similar considerations are also
`made for nasal and otic products.
`ISOTONICITY VALUE
`.
`’
`.
`.
`Lacrimal fluid is isotonic with blood having an isotonicity value
`fa 09% sodium chloride solution. Ideally,
`corresponding to that 0
`an ophthalmic solution should have this isotonicity value; but the
`eye can tolerate isotonicity values as low as that;of a 0.6% sodium
`chloride solution and as high as t at of a 2 O 0 sodium ch on e
`.
`.
`.
`h
`.
`.
`1
`‘d
`Some ophthalmic solutions are necessarily hypertonic in order
`solution without marked discomfort.
`to enhance absorption and provide a concentration of the active
`ingredient(s) strong enough to exert a prompt and effective ac-
`tion. Where the amount of such solutions used is small, dilution
`with lacrimal fluid takes place rapidly so that discomfort from
`ary. HOWCVCL any adjustment
`toward isotonicity by dilution with tears is negligible where large
`the hypertonicity is only tempor
`volumes of hypertonic solutions are used as collyria to wash the
`eyes; it is therefore important that solutions used for this purpose
`be approx1mately 150t0mc~
`BUFFERING
`Many drugs, notably alkaloidal salts, are most effective at pH
`ated free bases. At SUCh PH levels,
`ble 30 that compromise 16/615
`levels that favor the undissoc1
`must be found and held by means of buffers. One purpose of
`however, the drug may be unsta
`buffering some ophthalmic solutions is to prevent an increase in
`pH caused by the slow release of hydroxyl ions by glass. Such
`a rise in pH can affect both the solubility and the stability of the
`drug. The decision whether or not buffering agents should be
`added in preparing an ophthalmic solution must be based on
`several considerations. Normal tears have a pH of about 7.4 and
`possess some buffer capacity. The application of a solution to
`the eye stimulates the flow of tears and the rapid neutralization
`of any excess hydrogen or hydroxyl ions within the buffer capacity
`of the tears. Many ophthalmic drugs, such as alkaloidal salts,
`are weakly acidic and have only weak buffer capacity. Where
`only 1 or 2 drops of a solution containing them are added to the
`eye, the buffering action of the tears is usually adequate to raise
`the pH and prevent marked discomfort.
`in some cases pl—l may
`vary between 3.5 and 8.5. Some drugs, notably pilocarpine hy—
`drochloride and epinephrine hitartrate, are more acid and overtax
`the buffer capacity of the lacrimal fluid.
`ideally, an ophthalmic
`solution should have the same pH, as well as the same isotonicity
`value, as lacrimal fluid. This is not usually possible since, at pH
`.
`_
`,
`50111101? m W333“ MOSt al-
`7.4, many drugs are not appreCiably
`kalmdal salts prempitate as the free alkalotd at this pH. Addi-
`tionally, many drugs are chemically unstable at pH levels ap-
`proaching 7.4. This instability is more marked at
`the high
`temperatures employed in heat sterilization. For this reason, the
`buffer system should be selected that is nearest to the physio—
`logical pH of 7.4 and does not cause precipitation of the drug or
`its rapid deterioration.
`An ophthalmic preparation with a buffer system approaching
`the physiological pH can he ol.
`ned by mixing a sterile solution
`
`of the drug with a s
`is buffer solution using aseptic technique.
`
`Even so, the possib.
`y of a sh‘
`ier sheiialife at the higher pH
`
`
`must be taken into consideration, and attention must be directed
`toward the attainment and maintenance of sterility throughout
`the manipulations.
`Many drugs, when buffered to a therapeutically acceptable
`pl—l, would not be stable in solution for long periods oftime. These
`products are lyophilized and are intended for reconstitution im—
`mediately before use (cg, Acetylchola’ne :Chloria'e for Ophthala
`mic Solution).
`
`F A git _ .
`n“ i“
`
`Pastas are semisolid dosage for:-
`
`drug substances intended for top-i: :;i
`made from a single phase aqneo
`
`
`lulose Sodium Paste). The 0th
`Zinc Oxide Paste), consists of th. ,.
`ordinarily flow at body temperat
`~
`tective coatings over the areas to
`The fatty pastes appear less g
`ointments by reason of a higl‘
`having an affinity for water. T
`
`‘
`
`.
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`3
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