0}
`
`Européisches Patentamt
`
`European Patent Office
`Office européen des brevets
`
`® Publication number:
`
`0 306 984
`A1
`
`@
`
`EUROPEAN PATENT APPLICATION
`
`@ Application number: 88114804.3
`
`@ int.CI.4:A61K 9/06 , A61K 47/00
`
`® Applicant: SYNTEX (U.S.A.) lNC.
`3401 Hillview Avenue
`
`Palo Alto, California 94304(US)
`
`69 Inventor: Roger Fu, Cherng-Chyi
`14050 Shadow Oaks Way
`Saratoga California 95070(US)
`Inventor: Lidgate, Deborah M.
`325 Arboleda Drive
`Los Altos California 94022(US)
`
`
`
`@ Date of filing: 09.09.88
`
`@ Priority: 11.09.87 us 96173
`
`Date of publication of application:
`15.03.89 Bulletin 89/11
`
`Designated Contracting States:
`AT BE CH DE FR GB IT LI LU NL SE
`
`Representative: Barz, Peter, Dr. el: al
`Patentanwalte Dr. V. Schmied-Kowarzik
`
`Dipl.-lng. G. Dannenberg Dr. P. Weinhold Dr.
`D. Gudel Dipl.-lng. S. Schubert Dr. P. Barz
`Eiegfriedstrasse 8
`0-8000 Miinchen 40(DE)
`
`@ Preservative system forophthalmic formulations.
`
`@ Stable. clear, antimicrobialiy effective, ophthalmic formulations include an ophthalmologically effective
`amount of a drug, especially a -COOH group-containing drug or a NSAlD, and a preservative system formed of a
`quaternary ammonium preservative and a nonionic surfactant, all
`in an aqueous vehicle. These formulations are
`useful
`for
`treating diseases that are either caused by, associated with or accompanied by inflammatory
`processes,
`including, among others, glaucoma, cystoid macular edema, uveitis, diabetic retinopathy, and
`conjunctivitis, or any trauma caused by eye surgery or eye injury.
`'
`
`EP0306984A1
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`EP 0 306 984 A1
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`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`
`The present invention relates to improved ophthalmic formulations, particularly to ophthalmic formula-
`tions for anti-inflammatory drugs, and specifically to an improved preservative system for ophthalmic
`formulations of carboxyl
`("-COOH") group-containing drugs, especially non-steroidal anti-inflammatory
`drugs ("NSAle").
`The invention also relates to methods of using these formulations for treating diseases that are either
`caused by, associated with or accompanied by inflammatory processes,
`including, among others, glau-
`coma, cystoid macular edema, uveitis, diabetic retinopathy, and conjunctivitis, or any trauma caused by eye
`surgery or eye injury.
`in the treatment of ophthalmic diseases was
`The topical use of NSAIDs, particularly pyrrolo pyrroles.
`first taught in U.S. Patent No. 4,454,151, where NSAID compounds (such as those described in U.S. Patents
`4,089,969; 4,232,038; 4,087,539 and 4,097,579) were exemplified in formulation with NaHzPOquo,
`NazHPOquO, NaCl, benzalkonium chloride ("BAC") and sterilized water. While the formulations described
`in the '151 patent were efficacious. an insoluble complex was found to form between the NSAID and the
`BAC. The formulations became cloudy or turbid and did not, therefore, have the stability desired for shelf
`life in commercial applications. A reasonable minimum shelf life (that is, the time during which a solution
`remains clear and retains its pharmaceutical activity) is at least about one year, representing sufficient time
`to package, ship, and store a formulation without having to replace expired stock too frequently. The
`solutions of the present invention have shown a shelf life of at least one year. Thus, the present invention
`entails an improvement over the formulations described in the ‘151 patent.
`In general, an opthalmic formulation contains an active compound and various ophthalmologically
`acceptable excipients,
`in the form of a solution, an ointment, a suspension, etc. An excipient is ophthal-
`mologically acceptable if
`it
`is non-irritating to the eye and if its active ingredient penetrates the blood-
`aqueous barrier and/or diffuses through the various ocular substructures to the site where it is pharmaco-
`logically active. The excipients can include a tonicifier, a preservative. a surfactant, a buffering system. a
`chelating agent, a viscosity agent as well as other stabilizing agents. Ophthalmic formulations must be
`sterile, and if intended for multiple dosing regimens. must be preserved with an effective anti-microbial
`agent.
`thimerosal, phenylmercuric acetate and phenylmercuric nitrate) have been
`Organo-mercurials (e.g.,
`used extensively as the preservative in ophthalmic solutions. These compounds. however, pose difficulties
`due to potential mercury toxicity as well as poor chemical stability. Benzalkonium chloride, a quaternary
`ammonium compound, has been widely used in ophthalmic solutions, and is considered to be the
`preservative of choice. However, BAC has typically been considered to be incompatible with anionic drugs
`(e.g., salicylates or nitrates, etc.), forming insoluble complexes which cause the solution to become cloudy
`or turbid. Such a complex between the anionic drug and benzalkonium chloride can cause a decrease in
`the pharmaceutical activity of the anionic drug.
`Many NSAIDs (such as ketorolac, indomethacin, flurbiprofen and diclofenac) are being developed for
`ocular use because of their activity as anti-inflammatory agents including their ability to prevent cystoid
`macular edema.
`
`In the past, as in the case with other ophthalmic drugs that contain a -COOH group, antiinflammatory
`solutions of NSAIDs for occular use have proven to be incompatible with quaternary ammonium compounds
`such as BAC. This incompatibility is due to the fact that the -COOH group can form a complex with the
`quaternary ammonium compounds. rendering the preservative less available to serve its function. and
`reducing the activity of the active ingredient. Indomethacin ophthalmic formulations have been prepared.
`however,
`these are suspensions, not solutions. Ocufen Ophthalmic solution. an NSAID (flurbiprofen)
`approved by the FDA for ophthalmic use, incorporates thimerosal (with EDTA) as its preservative system. In
`U.S. patent 4,454,151 there is a disclosure of an ophthalmic formulation using ketorolac, benzalkonium
`chloride (as the preservative) and polysorbate 80, however the solution became cloudy or turbid after a
`short period of time.
`It has remained desired to provide a stable, clear, antimicrobially effective ophthalmic formulation with a
`prolonged shelf life for -COOH group containing ophthalmic drugs, especially NSAle, using BAC as the
`preservative.
`It has now been discovered that stable, clear and antimicrobially effective, NSAID-containing ophthalmic
`formulations can be prepared which include a quaternary ammonium preservative. These solutions have an
`improved shelf life, exhibiting no cloudiness or turbidity over extended periods.
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`EF 0 306 984 A1
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`In one aspect of the invention, these compositions include an ophthalmologically effective amount of a
`NSAID, a quaternary ammonium preservative and a stabilizing amount of an ethoxylated octylphenol as a
`nonionic surfactant, all in an aqueous vehicle.
`Another aspect is an ophthalmic composition including an ophthalmologically effective amount of a
`NSAID, a quaternary ammonium preservative and a stabilizing amount of an ethoxylated octylphenol as a
`nonionic surfactant.
`
`Another aspect is an ophthalmic composition including an ophthalmologically effective amount of a
`NSAlD, benzalkonium chloride as a preservative and a stabilizing amount of an ethoxylated octylphenol as a
`nonionic surfactant.
`
`Another aspect is an ophthalmic composition including an ophthalmologically effective amount of a
`NSAID, benzalkonium chloride as a preservative and a stabilizing amount of Octoxynol 40 as a nonionic
`surfactant.
`
`Another aspect is an ophthalmic composition including an ophthalmologically effective amount of
`ketorolac or an isomer, an ester, or a pharmaceutically acceptable salt thereof, benzalkonium chloride as a
`preservative and a stabilizing amount of Octoxynol 40 as a nonionic surfactant.
`In another aspect of the invention, methods for treating ophthalmic diseases in mammals using the
`ophthalmic pharmaceutical formulations of the invention are also disclosed. These diseases are those that
`are either caused by, associated with or accompanied by inflammatory processes, including, among others,
`glaucoma, cystoid macular edema. uveitis, diabetic retinopathy and conjunctivitis, or any trauma caused by
`eye surgery or eye injury.
`
`Definitions
`
`As used herein, the term "NSAlD" means an ophthalmologically acceptable non-steroidal anti-inflam-
`matory drug. The NSAlD's include, for example, flurbiprofen, ketorolac, diclofenac, indomethacin, and the
`isomers, esters, and pharmaceutically acceptable salts thereof.
`As used herein, the term "q.s." means adding a quantity sufficient to achieve a state function, e.g., to
`bring a solution to the desired volume (i.e., 100%).
`As used'herein, the term "treatment" or "treating" means any treatment of a disease in a mammal,
`including:
`(i) preventing the disease, that is. causing the clinical symptoms of the disease not to develop;
`(ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or
`(iii) relieving the disease, that is. causing the regression of clinical symptoms.
`
`'
`As used herein, the term "effective amount" means a dosage sufficient to provide treatment for the
`disease state being treated. This will vary depending on the patient, the disease and the treatment being
`effected.
`
`As used herein. the term "antimicrobially effective" means ability to withstand the U.S. Pharmacopia
`antimicrobial challenge.
`As used herein, the term "surfactant" means a nonionic surfactant, preferably ethoxylated octylphenol
`compounds as described below.
`As used herein,
`the term "quaternary ammonium preservative" means a quaternary ammonium
`compound such as described below.
`As used herein, the term "stabilizing" means keeping a formulation clear and antimicrobially effective
`for its minimum reasonable shelf life, e.g., at least one year.
`
`Formulations
`
`The formulations of the present invention include an NSAID active agent in an effective amount for
`ophthalmic treatment. a quaternary ammonium preservative, a stabilizing amount of an ethoxylated octyl-
`phenol as a nonionic surfactant, optionally including other excipients such as a chelating agent. a tonicifier,
`a buffering system, a viscosity agent as well as other stabilizing agents. Ophthalmic solutions and
`suspensions typically contain an aqueous vehicle rather than an oily vehicle. Ophthalmic formulations must
`be sterile, and if intended for multiple dosing regimens, must be antimicrobially effective for their minimum
`reasonable shelf life. e.g., at least one year, and preferably two to three years or more. The ingredients
`used in the formulations of the present invention are typically commerically available or can be made by
`
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`so
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`50
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`Ingredient
`
`NSAID
`
`
`
`
`
`BAC (50% aq. soln.)
`Octoxynol 40 (70% aq. soln.)
`EDTA Naz
`NaCl
`1N NaOH or 1N HCI
`Purified Water
`
`
`
`
`
`
`
`
`
`0.002% to 5.0% thvoI.;
`
`
`
`
`
`
`0.002% to 1.0% wt/vol.;
`0.001% to 1.0% wt/vol.;
`0.01% to 1.0% wt/vol.;
`q.s. for isotonicity with Iacrimal fluid;
`q.s. to adjust pH to 7.4104; and
`q.s. to 100%.
`
`
`
`
`
`EP0306984A1
`
`methods readily known to those skilled in the art:
`Pharmaceutical ophthalmic formulations typically contain an effective amount, e.g.. 0.001% to 10%
`wt/vol. most preferably 0.005% to 1% wt/vol of an active ingredient (e.g.,
`wt/vol., preferably 0.002% to 5%
`the NSAID of the present invention). The amount of active ingredient will vary with the particular formulation
`and the disease state for which it is intended. The total concentration of solutes should be such that.
`if
`possible, the resulting solution is isotonic with the Iacrimal fluid (though this is not absolutely necessary)
`and has a pH in the range of 6 to 8.
`The formulations of the present invention are prepared as solutions incorporating the above-described
`ingredients within the following approximate ranges:
`
`Ingredient
`
`Active Agent
`Preservative
`
`
`
`
`
`0.001 % to 10.0% wt/vol.;
`0.001% to 1.0% wt/vol.;
`
`
`
`
`0.001% to 1.0% wt/vol.:
`Surfactant
`
`Other Excipients
`0% to 10.0% wt/voI.; and
`
`
`Purified Water
`q.s. to 100%.
`
`
`
`
`
`20 Optional other excipients, such as a chelating agent and a tonicifier, are used in the following approximate
`proportions:
`
`Ingredient
`
`
`
`Chelating agent
`Tonicifier
`1N NaOH or 1N HCI
`
`0.01 % to 1.0%wt/VOI.;
`q.s. to achieve isotonicity with Iacrimal fluid; and
`q.s. to adjust pH to 6.0 to 8.0.
`
`In a preferred ophthalmic NSAID solution, the ingredients are combined in the following proportions:
`
`In another preferred ophthalmic NSAID solution, the ingredients are combined in the following propor-
`tions:
`
`Ingredient
`
`NSAID
`
`
`
`
`
`
`
`
`
`0.005% to 1.0% wavoI.;
`BAC (50% aq. soln.)
`0.002% to 1.0% wt/vol.;
`
`
`
`Octoxynol 40 (70% aq. soln.)
`0.001% to 1.0% wt/vol.;
`
`
`EDTA Me;
`0.01% to 1.0% wt/vol.;
`
`NaCl
`q.s. for isotonicity with Iacrimal fluid:
`
`
`1N NaOH or 1N HCI
`q.s. to adjust pH to 7.4:0.4: and
`
`
`
`q.s. to 100%.
`Purified Water
`
`
`
`
`55
`
`In a more preferred ophthalmic NSAID solution.
`proportions:
`
`the ingredients are combined in the following
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`EP 0 306 984 A1
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`
`
`
`
`
`
`
`
`0.50% wflvol.;
`NSAID
`0.02% thvol.;
`SAC (50% aq. soln.)
`
`0.01% wt/vol.;
`Octoxynol 40 (70% aq. soln.)
`
`0.10% wt/vol.;
`EDTA N32
`
`
`q.s. for isotonicity with lacrimal fluid;
`NaCl
`
`
`
`q.s. to adjust pH to 7.4:0.4; and
`1N NaOH or 1N HCl
`
`
`q.s. to 100%.
`Purified Water
`
`
`
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`15
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`The invention relates primarily to formulations having as the active agent ophthalmologically acceptable
`drugs (including the isomers, esters and pharmaceutically acceptable salts thereof) that can form a complex
`with a quaternary ammonium compound, particularly NSAle and drugs with a carboxyl group.
`NSAle useful
`in the practice of this invention include, for example, ketorolac (and the other com-
`pounds described as being ophthalmologically effective in US. Patent No. 4,454,151 to Waterbury, issued
`June 12, 1984,
`the pertinent portions of which are incorporated herein by reference),
`indomethacin,
`flurbiprofen sodium, and diclofenac,
`including the isomers, esters and pharmaceutically acceptable salts
`thereof.
`
`Preservatives useful in the formulations of the present invention include quaternary ammonium com-
`pounds, such as cetyitrimethylammonium bromide, cetylpyridinium chloride and benzalkonium chloride,
`preferably, benzalkonium chloride.
`in the formulations of the present invention are preferably ethoxylated
`The nonionic surfactants useful
`octylphenol compounds, such as octylphenoxypoly-(ethyleneoxy)ethanols, more preferably, a homologous
`series of surfactants sold under the trade name lgepal CA with a numerical suffix indicating the mole ratio of
`ethylene oxide to octylphenol, the ratio being 3 to 40. Examples include Octoxynol 9, Octoxynol 12,
`Octoxynol 13, and Octoxynol 40, and most preferably Octoxynol 40, manufactured and sold by GAF under
`the trade name lgepal CA897 (a 70% aqueous solution of Octoxynol 40).
`Among the optional excipients, the chelating agents useful in the formulations of the present invention
`include 8-hydroxyquinoline sulfate, citric acid, and preferably disodium edetate. Under certain conditions,
`the chelating agent may also enhance the anti-microbial effect due to its ability to render essential metal
`ions unavailable to the microbes.
`
`in the formulations of the present
`
`Buffering systems optionally useful
`example, citrate, borate, or phosphate.
`Tonicifiers optionally useful
`in the formulations of the present invention include dextrose, potassium
`chloride and/or sodium chloride, preferably sodium chloride.
`Viscosity agents optionally useful
`in the formulations of the present invention include the cellulose
`derivatives such as hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and hydroxyethylcel-
`lulose.
`
`invention are based on, for
`
`Other optional ,excipients useful in the formulations of the present invention include stabilizing agents
`such as antioxidants, e.g., sodium metabisulfate and ascorbic acid, depending on the NSAlD used.
`the
`These formulations are prepared by dissolving the solutes (e.g.,
`the NSAlD,
`the preservative,
`surfactant, the chelating agent, and the buffering agent) in a Suitable quantity of water, adjusting the pH to
`about 6 to 8, preferably 6.8 to 8.0 and most preferably 7.4, making a final volume adjustment to 100% with
`additional water, and sterilizing the preparation using any suitable method known to those in the art.
`It has been discovered that ophthalmic formulations incorporating the preservative system of the
`invention are physically stable (i.e.,
`remain clear) and functionally stable (i.e.,
`remain antimicrobially
`effective) for at least the minimum reasonable shelf life of such products.
`
`Preferred Formulations
`
`The preferred preservative system of the invention includes a quaternary ammonium preservative and a
`stabilizing amount of a nonionic surfactant.
`The preferred ophthalmic formulation of the invention includes a NSAID active agent in an effective
`amount for ophthalmic treatment and an antimicrobially effective amount of the above-described preferred
`preservative system.
`The preferred preservative of the invention is benzalkonium chloride.
`The preferred surfactant of the invention is Octoxynol 40, especially when combined with benzalkonium
`
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`EP 0 306 984 A1
`
`chloride as the preservative.
`The preferred chelating agent of the invention is disodium edetate. especially when combined with
`benzalkonium chloride as the preservative and Octoxynol 40 as the nonionic surfactant.
`The preferred ophthalmic solutions of the invention include a NSAlD. benzalkonium chloride, Octoxynol
`40 and disodium edetate.
`
`A preferred ophthalmic NSAlD solution. the ingredients are combined in the following proportions:
`
`
`
`
`
`
`NSAlD
`BAC (50% aq. soln.)
`Octoxynol 40 (70% aq. soln.)
`EDTA N82
`
`NaCl
`
`1N NaOH or 1N HCl
`
`Purified Water
`
`
`
`
`
`
`
`
`
`
`
`0.002% to 5.0% wt/vol.:
`0.002% to 1.0% wt/vol.;
`0.001% to 1.0% wt/vol.;
`0.01 % to 1.0% wt/vol.;
`q.s. for isotonicity with lacrimal fluid:
`q.s. to adjust pH to 7.4:0.4: and
`q.s. to 100%.
`
`
`
`
`
`
`
`
`
`
`Another preferred ophthalmic NSAlD solution, the ingredients are combined in the following proportions:
`
`ingredient
`
`NSAlD
`
`
`
`
`0.005% to 1.0% wt/vol.:
`
`
`
`
`0.002% to 1.0% wt/vol.;
`BAC (50% aq. soln.)
`
`
`0.001% to 1.0% wt/vol.;
`Octoxynol 40 (70% aq. soln.)
`
`
`0.01% to 1.0% wt/vol.;
`EDTA Nag
`
`
`q.s. for isotonicity with lacrimal fluid:
`NaCl
`
`
`q.s. to adjust pH to 7.4104; and
`1N NaOH or 1N HCI
`
`
`
`Purified Water
`q.s. to 100%.
`
`
`
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`A preferred ophthalmic NSAlD solution has the following formulation:
`
`Master“
`
`
`
`
`
`0.50% wt/vol.
`NSAlD
`
`0.02% wt/vol.
`BAG (50% aq. soln.)
`
`
`0.01% wt/vol.
`Octoxynol 40 (70% aq. soln.)
`
`
`0.10% wt/vol.
`EDTA N32
`
`
`
`q.s. for isotonicity with lacrimal fluid
`NaCl
`
`
`
`q.s. to adjust pH to 7.4:0.4
`1N NaOH or 1N HCI
`
`
`
`Purified Water
`q.s. to 100%
`
`
`
`
`Most preferred is the ophthalmic solution according to the above formulation wherein the NSAlD is
`45 Ketorolac Tromethamine or an isomer thereof.
`
`Utility and Administration
`
`50
`
`This invention is directed to NSAlD ophthalmic formulations and a method useful for treating ophthalmic
`diseases in mammals. These diseases are either caused by. associated with or accompanied by inflam-
`matory processes. including, among others. glaucoma, cystoid macular edema. uveitis. diabetic retinopathy
`and conjunctivitis. or any trauma caused by eye surgery or eye injury.
`for example. pre-
`The method of this invention is both curative and preventative. Where applied.
`surgically or immediately post-traumatically, ie. before inflammation develops.
`it prevents develpment of
`inflammation. When applied directly to the eye suffering from any of the named ophthalmic diseases.
`it
`supresses already developed inflammatory processes.
`Ophthalmic formulations are typically administered by topical application to the eyelids or for instillation
`into the space (cul-de-sac) between the eyeball and the eyelids, of topically applied ophthalmic solutions.
`
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`EP 0 306 984 A1
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`suspensions or ointments, or by subconjunctival injection.
`The dosage level will, of course, depend on the concentration of the drops, the condition of the subject
`and the individual magnitude of responses to treatment. However, typical dosage ranges might be about 2
`to 10 drops of 0.5% solution of active ingredient per day.
`their preparation and administration, see
`For a more detailed discussion of ophthalmic formulations,
`Remington's Pharmaceutical Sciences, 15th Ed., pages 1489-1504, (1975).
`
`Testing
`
`Ophthalmic formulations such as the solutions of the present invention are typically tested for physical
`stability, chemical stability, and preservative efficacy, both when they are first manufactured and after a
`fixed period of
`time (9.9., after two years). They are generally considered to be safe and clinically
`acceptable if proven to be well tolerated in the eye.
`Physical stability is determined by observation of a solution after expiration of a fixed period of time. A
`solution is considered to be physically stable if its appearance (e.g., color and clarity) does not change and
`if the pH remain constant, within acceptable limits. Chemical stability involves a routine chemical analysis of
`the solution, to be sure that its active ingredient and the excipients have not changed after a fixed period of
`time.
`'
`
`Preservative efficacy is tested by the procedure described in the US. Pharmacopia Compendiary,
`whereby a solution is challenged with a microbe and a determination is made as to whether the microbe
`survives in it.
`
`The following examples are given to enable those skilled in the art to more clearly understand and to
`practice the present invention. They should not be considered as a limitation on the scope of the invention,
`but merely as being illustrative and representative thereof.
`
`EXAMPLE 1
`
`This example illustrates the preparation of a representative pharmaceutical formulation for ophthalmic
`administration containing the NSAlD Ketorolac Tromethamine.
`
`Ketorolac Tromethamine
`
`0.50% wt/vol.
`
`
`
`
`
`
`
`BAC (50% aq. soln.)
`0.02% wt/vol.
`
`
`
`
`Octoxynol 40 (70% aq. soln.)
`0.01% wt/vol.
`
`
`0.10% wt/vol.
`EDTA Nae
`
`
`0.79% wt/vol.
`NaCl
`
`
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`The above ingredients are mixed, adding purified water until they are dissolved, the pH is adjusted to
`7.4.20.4 and the balance of the formulation is made up with purified water, adding a quantity sufficient to
`make 100% volume. The solution is then sterilized.
`Other NSAle or their isomers, salts or esters. such as those described above, can be used as the
`active compound in the preparation of the formulation of this example.
`
`EXAMPLE 2
`
`This example illustrates the preparation of a representative pharmaceutical formulation for ophthalmic
`administration containing the NSAlD Ketorolac Tromethamine.
`
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`EP 0 306 984 A1
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`Ketorolac Tromethamine
`
`0.50% wt/vol.
`
`
`
`
`
`0.02% wt/vol.
`BAC (50% aq. soln.)
`
`
`0.02% wt/vol.
`Octoxynol 4O (70% aq. soln.)
`
`
`EDTA N32
`0.20% wt/vol.
`
`
`
`NaCl
`0.79% va01.
`
`
`
`
`
`
`The above ingredients are mixed. adding purified water until they are dissolved, the pH is adjusted to
`7.4204 and the balance of the formulation is made up with purified water, adding a quantity sufficient to
`make 100% volume. The solution is then sterilized.
`Other NSAle or their isomers, salts or esters, such as those described above, can be used as the
`active compound in the preparation of the formulation of this example.
`
`EXAMPLE 3
`
`5
`
`10
`
`15
`
`20
`
`This example illustrates the preparation of a representative pharmaceutical formulation for ophthalmic
`administration containing the NSAlD Ketorolac Tromethamine.
`
`25
`
`so
`
`ingredient
`
`
`
`
`
`0.10% wt/voi.
`Ketorolac Tromethamine
`0.004% wt/vol.
`BAC (50% aq. soln.)
`
`
`
`
`0.004% wt/vol.
`Octoxynol 40 (70% aq. soln.)
`
`
`EDTA N82
`0.05% wt/voi.
`
`
`
`NaCl
`0.88% wt/vol.
`
`
`
`
`
`The .above ingredients are mixed, adding purified water until they are dissolved, the pH is adjusted to
`7.4204 and the balance of the formulation is made up with purified water, adding a quantity sufficient to
`make 100% volume. The solution is then sterilized.
`Other NSAle their isomers, salts or esters, such as those described above. can be used as the active
`
`35
`
`compound in the preparation of the formulation of this example.
`
`EXAMPLE 4
`
`This example illustrates the preparation of a representative pharmaceutical formulation for ophthalmic
`administration containing the NSAID flurbiprcfen sodium.
`
`
`
`
`
`0.03% thvol.
`Flurbiprofen Sodium
`
`
`0.02% wt/vol.
`BAC (50% aq. soln.)
`
`
`
`0.01% wt/voi.
`Octoxynol 40 (70% aq. soln.)
`
`
`
`EDTA N32
`0.10% wt/vol.
`
`
`
`
`NaCi
`0.90% wt/vol.
`
`
`
`
`40
`
`45
`
`50
`
`The above ingredients are mixed, adding purified water until they are dissolved. the pH is adjusted to,
`7420.4 and the balance of the formulation is made up with purified water. adding a quantity sufficient to
`55 make 100% volume. The solution is then sterilized.
`Other ophthalmic drugs and NSAle, such as those described above, can be used as the active
`compound in the preparation of the formulation of this example.
`
`Page 8 of 13
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`Page 8 of 13
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`

`

`EP 0 306 984 A1
`
`EXAMPLE 5
`
`Physical stability of the formulations of the present invention is measured by preparing clear formula-
`tions,
`in the concentrations shown in the table below, sealing them in sterilized containers, and observing
`the clarity of the solution after a period of one month and again after five months. Solutions that remain
`clear are considered stable in this procedure.
`The formulations of the present invention have proven to be stable when tested in accordance with the
`above procedure. Formulations using surfactants other than the nonionic surfactants of the invention did not
`remain clear and were not stable.
`Three surfactants were evaluated for their ability to dissolve the ketorolac - benzalkonium chloride
`complex and maintain a physically clear solution over an extended period of time. The three surfactants
`tested were: Octoxynol 40; Polysorbate 80 (Tween 80); and Myrj 52. Two concentrations of each surfactant
`were incorporated into the ophthalmic formulation, and these were placed at various temperatures for future
`visual observations.
`
`
`
`- 0.004%
`
`0.02%
`
`0.0035%
`
`0.01%
`
`0.0015%
`
`0.01%
`
`
`
`
`very turbid
`very turbid
`
`turbid
`turbid
`
`
`turbid
`turbid
`
`
`
`clear
`
`turbid
`
`turbid
`
`
`clear
`
`clear
`
`60°C
`40°C
`RT
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`At the 5 month time period it was apparent that the Octoxynol 40 surfactant was superior to the other
`two surfactants. At 5 months. Tween 80 and Myrj 52 displayed turbidity when stored at RT. The presence
`of turbidity suggested the inability to solubilize a precipitate formation between the Ketorolac moiety and
`benzalkonium chloride.
`A further study has shown a 2 year shelf life for the ophthalmic formulation. Precipitate formation and
`turbidity are not a problem with this formulation. Preservative efficacy is maintained throughout the 2 year
`shelf life.
`
`EXAMPLE 0
`
`Preservative efficacy of the formulations of the present invention is measured by preparing formulations.
`e.g.. according to the foregoing Examples, and subjecting them to the U.S. Pharmacopia antimicrobial
`challenge.
`The formulations of the present invention demonstrate preservative efficacy when tested in accordance
`with the above procedure.
`
`EXAMPLE 7
`
`The objective of this clinical efficacy study was to compare the effectiveness and safety of ketorolac
`with a control solution in reducing inflammation following cataract removal and intraocular lens implantation.
`All patients underwent an extracapsular cataract extraction with intraocular lens implantation 1 day following
`initiation of treatment.
`Ophthalmic examinations were performed preoperatively (within 3 weeks of surgery) and during the first
`
`9
`
`Page 9 of 13
`
`Page 9 of 13
`
`

`

`EP 0 306 984 A1
`
`to 3), second week (postoperative days 4 through 12), and third week
`week (postoperative days 1
`(postoperative days 15 through 27) or treatment. Particular attention was given to signs and symptoms
`consistent with inflammation. Among the ocular characteristics assessed on a scale of none. mild,
`moderate, or severe were: lid edema, corneal edema, conjunctival injections, ciliary flush, and the presence
`of cells and flare in the anterior chamber.
`
`is by definition a
`iridocyclitis)
`iritis, cyclitis,
`Fluorophotometry: Anterior segment inflammation (i.e.,
`disruption of the blood-aqueous barrier. When inflammation is present, a careful slit lamp examination will
`reveal cells and flare within the anterior chamber of the eye. The clinical grading of cells and flare is a
`measure of degree of anterior segment inflammation; but consistent grading of these observations is
`difficult, even by experts.
`Ocular fluorophotometry is based on the fact that the blood-aqueous barrier becomes permeable to
`intravascular cells and proteinaceous fluid (explaining the observed cells and flare) and also to intravascular
`fluorescein. Furthermore, the appearance of fluorescein within the anterior chamber is a more sensitive
`indication of the breakdown of the blood-aqueous barrier than the gross observation of cells and flare, and
`is consistently quantifiable. For these reasons, a Flurortron® Master (Coherent, Sunnyvale, California),
`complete with software modifications designed for this study was used. Following oral administration of
`fluorescein. the fluorophotometer was used to determine the integrity of the aqueous barrier by measuring
`the concentration of fluorescein in the anterior chamber.
`
`The fluorophotometry data were analyzed using the Wilcoxon Ftank Sum Test or analysis of variance
`(ANOVA) of rank-transformed data by calculating the percentage difference in fluorescein concentration
`between the patient's two eyes, according to the formula:
`Percent difference = [(fluorescein concentration of operated eye - fluorescein concentration of unoperated
`eye)/fluorescein concentration of unoperated eye] x 100.
`This calculation allowed and corrected for any interpatient variation in the timing and concentration of
`fluorescein administered.
`
`In this study, the ketorolac
`129 patients began treatment for 21 days with either ketorolac or vehicle.
`formulation used was that illustrated in Example 1 above. During the first week 118 patients and during the
`second week 110 patients were evaluated for postoperative inflammation with ophthalmic examinations and
`fluorophotometry. During the third week, 83 patients were evaluated with ophthalmic examinations alone. At
`2 weeks ketorolac provide significantly greater anti-inflammatory activity than the vehicle as measured by
`fluorophotometry (p = 0.019). When patients were excluded who had greater than 40% difierence in
`fluorescein concentration between eyes at baseline, the p-value during week 2 rose to 0.06. in addition, the
`vehicle-treated patients had more ocular inflammation seen on slit lamp examination. e.g., eyelid edema (p
`= 0.001), conjunctival injection (p = 0.001), and Descemet folds (p = 0.002) than did the ketorolac-treated
`patients. Finally, there were significantly more complaints (p = 0.01) and more sever complaints consistent
`with ocular inflammation (photophobia, iritis, conjunctival injection) in the vehicle-treated group than in the
`ketorolac-treated group.
`In summary, ketorolac solutions proved significantly superior to vehicle in treating postoperative
`inflammation as quantitated by fluorophotometry, by routine slit lamp examination, by patients having fewer
`and milder adverse events, and by infrequent need of additional corticosteroidtherapy to control inflamma-
`tion.
`
`EXAMPLE E
`
`This was a double-blind, parallel comparison with vehicle to evaluate the efficacy of ketorolac 0.5%
`ophthalmic solution in reducing signs and symptoms of allergic conjunctivitis. Ketorolac 0.5% solution or a
`vehicle solution of the same pH and tonicity were instilled four times daily into the eyes of patients with
`allergic conjunctivitis (ocular itching with and without eosinophils seen in conjunctival scrapings) for 7 days.
`Thirty patients with allergic conjunctivitis participated in the study. Following admission to the study.
`patients reported to the investigator for baseline, mid-week, and final one-week examinations. At each of
`these visits, patients received ophthalmic examinations