`
`THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Ina, meeting at Washington, DC,
`March 8-10, I 990. Prepared by the Committee of
`Revision and published by the Board of Trustees
`
`Official from January I , 1995
`
`1mm.-SINCE 1820
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC."
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`Argentum Pharm. LLC V. Alcon Research, Ltd.
`Case IPR2017-01053
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`ALCON 203 3
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`The United States Pharmacopeia} Convention, Inc.
`@ 1994
`12601 Twinbrook Parkway, Rockville, MD 20852.
`All rights reserved
`ISSN 0195-7996
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`

`

`USP23
`
`General Information I Pharmaceutical Dosage Forms
`
`(1151)
`
`1945
`
`Solutions of drug substances in sterile water for inhalation or
`in sodium chloride inhalation solution may be nebulized by use
`of inert gases. Nebulizers are suitable for the administration of
`inhalation solutions only if they give droplets sufficiently fine and
`uniform in size so that the mist reaches the bronchioles. Neb(cid:173)
`ulized solutions may be breathed directly from the nebulizer or
`the nebulizer may be attached to a plastic face mask, tent, or
`intermittent positive pressure breathing (IPPB) machine.
`Another group of products, also known as metered-dose in(cid:173)
`hal~:rs (MD Is) are propellant driven drug suspensions or solutions
`in liquified gas pro{'Cllant with or without a cosolvent and are
`intended for delivenng metered doses of the drug to the respir(cid:173)
`atory tract. An· MDI contains multiple doses, often exceeding
`several hundred. The most common single-dose volumes deliv(cid:173)
`ered are from 25 to 100 ~tL (also expressed as mg) per actuation.
`Examples of MDis containing diug solutions and suspensions
`in this pharmacopeia are Epinephrine Inhalation Aerosol and
`Isoproterenol Hydrochloride and Phenylephrine Bitartrate In(cid:173)
`halation Aerosol, respectively.
`Powders may also be administered by mechanical devices that
`require manually produced pressure or a deep inhalation by the
`patient (e.g., Cromolyn Sodium for Inhalation).
`A special class of inhalations termed inhalants consists of drugs
`or combination of drugs, that by virtue of their high vapor pres(cid:173)
`sure, can be carried by an air current into the nasal passage where
`they exert their effect. The container from· which the inhalant
`generally is administered is known as an inhaler.
`
`INJECfiONS
`See Injections (1).
`
`IRRIGATIONS
`Irrigations are sterile solutions intended to bathe or flush open
`wounds or body cavities. They are used topically, never paren(cid:173)
`terally. They are labeled to indicate that they are not intended
`for injection.
`
`LOTIONS
`See Solutions or Suspensions.
`
`LOZENGES
`Lozenges are solid preparations, which are intended to dissolve
`or disintegrate slowly in the mouth. They contain one or more
`medicaments, usually in a flavored, sweetened base. They can be
`prepared by molding (gelatin and/or fused sucrose or sorbitol
`base) or by compression of sugar based tablets. Molded lozenges
`are sometimes referred to as pastilles while compressed lozenges
`are often referred to as troches. They are usually intended for
`treatment of local irritation or infections of the mouth or throat
`but may contain active ingredients intended for systemic absorp(cid:173)
`tion after swallowing.
`
`OINTMENTS
`Ointments are semisolid preparations intended for external ap(cid:173)
`plication to the skin or mucous membranes.
`Ointment bases recognized for use as vehicles fall into four
`general classes: the hydrocarbon bases, the absorption bases, the
`water-removable bases, and the water-soluble bases. Each ther(cid:173)
`apeutic ointment possesses as its base a representative of one of
`these four general classes.
`.
`
`Hydrocar~n Bases
`These bases, which are known also as .. oleaginous ointment
`bases," are represented by White Petrolatum and White Oi'!t(cid:173)
`ment. Only small amounts of an aqueous comp~>nent can. be In(cid:173)
`corporated into them. They. serve to keep medtca.ments m.pro(cid:173)
`longed contact with the skin and act as occlustve dressmgs.
`Hydrocarbon bases are used chiefly for their emollient effects,
`and are difficult to wash off. They do not .. dry out" or change
`noticeably on aging.
`
`Absorption Bases
`This class of bases may be divided into two groups: the first.
`group consisting of bases that permit the incorporation of aqueous
`solutions with the formation of a water-in-oil emulsion (Hydro(cid:173)
`philic Petrolatum and Lanolin), and the second group consisting
`of water-in-oil emulsions that permit the incorporatiOn of addi(cid:173)
`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(cid:173)
`ment, and are more correctly called "creams." (See Creams.r
`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(cid:173)
`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(cid:173)
`prised· of water-soluble constituents. Polyethylene Glycol Oint(cid:173)
`ment is the only Pharmacopeia} 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(cid:173)
`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(cid:173)
`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, aTe more stable in hydrocarbon bases than in bases
`contaming 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 ointme.nts for application to the eye.
`Special precautions must be taken in the /reparation of oph(cid:173)
`thalmic ointments. They are manufacture from sterilized in(cid:173)
`gredients under rigidly aseptic conditions and meet the require(cid:173)
`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(cid:173)
`scribed under Sterility Tests (71 ), along with aseptic manufac(cid:173)
`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(cid:173)
`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 under Ophthalmic Oint(cid:173)
`ments (771). The immediate containers for ophthalmic oint(cid:173)
`ments shall be sterile at the time of filling and closing. It is
`mandatory that the immediate containers for ophthalmic oint(cid:173)
`ments be sealed and tamper-proof so that sterility is assured at
`time of first use.
`The ointment base that is selected must be nonirritating to the
`eye, permit diffusion of the drug throughout the secretions ba(cid:173)
`thing the eye, and retain the activity of the medicament for a
`reasonable period under proper storage conditions.
`Petrolatum is mainly used as a base for ophthalmic drugs.
`Some absorption bases, water-removable bases, and water-soluble
`
`

`

`1946
`
`(1151) Pharmaceutical Dosage Forms I General Information
`
`USP23
`
`bases may be desirable for water-soluble drugs. Such bases allow
`for better dispersion of water-soluble medicaments, but they must
`be nonirritating to the eye.
`
`Solutions
`Ophthalmic solutions are sterile solutions, essentially free from
`foreign particles, suitably compounded and packaged for instil(cid:173)
`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(cid:173)
`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
`corresponding to that of a 0.9% sodium chloride solution. Ideally,
`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 that of a 2.0% sodium chloride
`solution without marked discomfort.
`Some ophthalmic solutions are necessarily hypertonic in order
`to enhance absorption and provide a concentration of the active
`ingredient(s) strong enough to exert a prompt and effective ac(cid:173)
`tion. Where the amount of such solutions used is small, dilution
`with lacrimal fluid takes place rapidly so that discomfort from
`the hypertonicity is only temporary. However, any adjustment
`toward isotonicity by dilution with tears is negligible where large
`volumes of hypertonic solutions are used as collyria to wash the
`eyes; it is therefore important that solutions used for this purpose
`be approximately isotonic.
`
`BUFFERING
`Many drugs, notably alkaloidal salts, are most effective at pH
`levels that favor the undissociated free bases. At such pH levels,
`however, the drug may be unstable so that compromise levels
`must be found and held by means of buffers. One purpose of
`buffering some ophthalmic solutions is to prevent an mcrease 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 capaco:ity
`of the tears. Many ophthalmic drugs, such as alkaloidal salts,
`are weakly acidic and have only weak buffer capacity. Where
`only I 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 pH may
`vary between 3.5 and 8.5. Some drugs, notably pilocarpine hy(cid:173)
`drochloride and epinephrine bitartrate, are more acid and overtax
`the buffer capacity of the lacrimal fluid. Ideally, an ophtha~~ic
`solution should have the same pH, as well as the same 1sotomc1ty
`value, as lacrimal fluid. This is not usually possible since, at pH
`7.4, many drugs are not appreciably soluble in water. Most a!(cid:173)
`kaloidal salts precipitate as the free alkaloid at this pH. Addi(cid:173)
`tionally, many drugs are chemically unstable at pH levels ap(cid:173)
`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(cid:173)
`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 be obtained by mixing a sterile solution
`of the drug with a sterile buffer solution using aseptic technique.
`Even so, the possibility of a shorter shelf-life 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
`pH, would not be stable in solution for long periods of time. These
`products are lyophilized and are intended for reconstitution im(cid:173)
`mediately before use (e.g., Acetylcholine Chloride for Ophthal(cid:173)
`mic Solution).
`
`STERILIZATION
`The sterility of solutions applied to an injured eye is of the
`greatest importance. Sterile preparations in special containers
`for individual use on one patient should be available in every
`hospital, office, or other installation where accidentally or sur(cid:173)
`gically traumatized eyes are treated. The method of attaining
`sterility is determined primarily by the character of the particular
`product (see Sterilization and Sterility Assurance of Compendia/
`Articles (1211) ).
`Whenever possible, sterile membrane filtration under aseptic
`conditions is the preferred method. If it can be shown that prod(cid:173)
`uct stability is not adversely affected, sterilization by autoclaving
`in the final container is also a preferred method.
`Buffering certain drugs near the physiological pH range makes
`them quite unstable at high tempera~ure.
`Avoiding the use of heat by employing a bacteria-retaining
`filter is a valuable technique, provided caution is exercised in the
`selection, assembly, and use of the equipment. Single-filtration,
`presterilized disposable units are available and should be utilized
`wherever possible.
`
`PRESERVATION
`Ophthalmic solutions may be packaged in multiple-dose con(cid:173)
`tainers when intended for the individual use of one patient and
`where the ocular surfaces are intact. It is mandatory that the
`immediate containers for ophthalmic solutions be sealed and
`tamper-proof so that sterility is assured at time of first use. Each
`solution must contain a suitable substance or mixture of sub(cid:173)
`stances to prevent the growth of, or to destroy, microorganisms
`accidentally introduced when the container is opened during use.
`Where intended for use in surgical procedures, ophthalmic so(cid:173)
`lutions, although they must be sterile, should not contain anti(cid:173)
`bacterial agents, since they may be irritating to the ocular tissues.
`
`THICKENING AGENT
`·A pharmaceutical grade of methylcellulose (e.g., I% if the
`viscosity is 25 centipoises, or 0.25% if 4000 centipoises) or other
`suitable thickening agents such as hydroxypropyl methylcellulose
`or polyvinyl alcohol occasionally are added to ophthalmic solu(cid:173)
`tions to increase the viscosity and prolong contact of the drug
`with the tissue. The thickened ophthalmic solution must be free
`from visible particles.
`
`Suspensions
`Ophthalmic suspensions are sterile liquid preparations con(cid:173)
`taining solid particles dispersed in a liquid vehicle intended for
`application to the eye (see Suspensions). It is imperative that
`such suspensions contain the drug in a micronized form to prevent
`irritation and/or scratching of the cornea. Ophthalmic suspen(cid:173)
`sions should never be dispensed if there is evidence of caking or
`aggregation.
`
`Strips
`Fluorescein sodium solution should be dispensed in a sterile,
`single-use container or in the form of a sterile, impregnated pap~r
`strip. The strip releases a sufficient amount of the drug for di(cid:173)
`agnostic purposes when touched to the eye being examined for
`a foreign body or a corneal abrasion. Contact of the paper with
`the eye may be avoided by leaching the drug from the strip onto
`the eye with the aid of sterile water or sterile sodium chloride
`solution.
`
`PASTES
`Pastes are semisolid dosage forms that contain one or more
`drug substances intended for topical application. One class is
`made from a single phase aqueous gel (e.g., Carboxymethylt:el(cid:173)
`/ulose Sodium Paste). The other class, the fatty pastes (e.g.,
`Zinc Oxide Paste), consists of thick, stiff ointments that do not
`ordinarily flow at body temperature, and therefore serve as pro(cid:173)
`tective coatings over the areas to which they are applied.
`The fatty pastes appear less greasy and more absorptive than
`ointments by reason of a high proportion of drug substance(s)
`having an affinity for water. These pastes tend to absorb serous
`
`