Europaiisches Patentamt
`Q European Patent office
`
`Office européen des brevets
`
`illlllllllllllllllllllllllllllllllllllllllllllllllllIlllllllllllllllll
`® Publication number:
`0
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`®
`
`EUROPEAN PATENT SPECIFICATION
`
`Date of pubtication of patent specification: 15.04.92 @ Int. C|.5: A51 K 9/03', A61 K 47/00
`
`@ Application number: 8B‘l‘l48€I4.3
`
`(29 Date of filing: 09.09.88
`
`@ Preservative system for ophtalmic formuiations.
`
`
` @) Priority: 11.09.87 us 95173
`
`@ Date of publication of application:
`15.93.89 Bulletin 89l11
`
`® Proprietor: svnrsx (U.S.A.) me.
`3401 Hillview Avenue
`
`
`
`Palo Alto California 94303(US)
`
`
`
`@ Publication of the grant of the patent:
`15.04.92 Bulletin 92/16
`
`Designated Contracting States:
`AT BE CH DE FR GB IT L3 LU NL SE
`
`@ inventor: Roger Fu, Cherng-Chyi
`14050 Shadow Oaks Way
`Saratoga, CA 95D70(US)
`inventor: Lidgate, Deborah M.
`325 Arbolecta Drive
`
`Los Altos, CA 94022(US)
`
`References cited:
`W0-A-85/04105
`DE-A- 3 025 402
`U3-A- 4 087 533
`
`CHEMICAL ABSTRACTS, Vol.88, £10.25, 19
`June 1978, Columbus, OH (US); M.T.NADlFl et
`al., p.166, no.183735c
`
`Representative: Barz, Peter, Dr. et al
`Patentanwéilte Dr. V. Schrnied-Kowarzik
`
`Dipi.-lng. G. Dannenberg Dr. P. Weinhold Dr.
`D. Gudel Dipi.-lng. S. Schubert Dr. P. Barz
`Siegfriedstrasse 8
`W-8000 Miinchen 40(DE}
`
`EP0306984B1
`
`Note: Within nine months from the publication of the mention of the grant of the European patent, any person
`may give notice to the European Patent Office oi opposition to the European patent granted. Notice of opposition
`shall be filed in a written reasoned statement. it shalt not be deemed to have been filed until the opposition fee
`has been paid (Art. 99(1) European patent convention).
`
`Flank xerox {UK} Business Services
`
`SENJU EXHIBIT 2330
`Lupin v Scnju,
`lPR2015-D1097, lPR20l5-01099,
`IPR2015-01100 & IPRZOIS-01105
`
`

`
`EP 0 306 984 B1
`
`Description
`
`The present invention relates to improved ophthaimic formulations, particularly to ophthalmic formula-
`tions for anti-inflammatory drugs, and specifically to an improved preservative system for ophthalmic
`formufations of carboxyl
`("-COOH") group-containing drugs, especially non-steroidal anti—infiammatory
`drugs ("t\|SAlDs").
`The invention also reiates 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 iniury.
`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 NaH2P0r‘H2O,
`Na;!~lPO4 ' H20, NaC|, benzalkonium chloride ("BAC") and sterilized water. White 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 commerciai appiicatlons. A reasonabie 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 repiace 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 't51 patent.
`In general, an opthalmic formulation contains an active compound and various ophthalrnologically
`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 andlor diffuses through the various ocular substructures to the site where it is pharmaco-
`logicaiiy 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 it intended for multiple closing regimens, must be preserved with an effective anti—microbial
`agent.
`
`thimerosal, phenylmercuric acetate and phenylmercuric nitrate) have been
`Organo—mercuriais (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 stabitlty. Benzalkonium chloride, a quaternary
`ammonium compound, has been widely used in ophthaimic solutions, and is considered to be the
`preservative of choice. However, BAC has typically been considered to be incompatible with anionic drugs
`(e.g., sallcylates or nitrates, etc.), forming insoluble complexes which cause the solution to become cloudy
`or turbid. Such a complex between the anionic drug and be-nzalkonium chloride can cause a decrease in
`the pharmaceutical activity of the anionic drug.
`Many NSA|Ds (such as ketorolac,
`indomethacin, tlurbiprofen and diclofenac) are being developed for
`ocular use because of their activity as anti-inflammatory agents including their abitity to prevent cystoid
`macular edema.
`
`in the past, as in the case with other ophthalmic drugs that contain a -COOH group, antiinflammatory
`solutions of NSAlDs for cccuiar use have proven to be incompatible with quaternary ammonium compounds
`such as BAG. 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 thimerosai (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 NSAlDs, 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 BAG. These solutions have an improved shelf Eife, exhibiting no
`cioudiness or turbidity over extended periods.
`In one aspect of the invention, these compositions include an ophthalmologically effective amount of a
`NSAID, BAC (preservative) and a stabilizing amount of Octoxynol 40 (nonionic surfactant), all in an aqueous
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`EP 0 306 984 B1
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`vehicle.
`
`is an ophthalmic Composition including an ophthalmologicaily effective amount of
`Another aspect
`ketorolac or an isomer, an ester, or a pharmaceutically acceptable satt thereof, benzalkonium chloride as a
`preservative and a stabilizing amount of Octoxynol 40 as a nonionic surfactant.
`The ophthalmic pharmaceutical
`formuiations of
`the invention can be used for treating ophthalmic
`diseases in mammals. 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 "NSAED" means an ophthalmologically acceptabie non-steroidal anti-inflam-
`matory drug. The NSA!D's include, ior example, flurbiproien, keiorolac, diclotenac, 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 stated 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 clinicat 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 chalienge.
`As used herein, the term "stabili2ing" means keeping a formulation clear and antimicrobiaily effective
`for its minimum reasonabie shelf life, e.g., at ieast one year.
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`Formulations
`
`The formulations of the present invention include an NSAID active agent in an efiective amount for
`ophthalmic treatment, beuzaikonium chioride, a stabilizing amount of Octoxynol 40, optionally inoiuding
`other excipients such as a chelating agent, a tonicilier, a buffering system, a viscosity agent as well as other
`stabilizing agents. Ophthaimic solutions and suspensions typically contain an aqueous vehicle rather than an
`oiiy vehicie. Ophthalmic formulations must be sterile, and it intended for muttiple dosing regimens, must be
`antimicrobiatly 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
`commercially availabie or can be made by methods readily known to those skilied in the art.
`Pharmaceutical ophthalmic formulations typicaliy contain an effective amount, e.g., 0.001% to 10%
`wtlvot, preferabiy 0.002% to 5% wt/vol, most preferably 0.005% to 1% wt/vol of an active ingredient (e.g.,
`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 tacrimal fluid (though this is not absoluteiy 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:
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`Ingredient
`
`Active Agent
`BAC
`
`Octoxynol 40
`Other Excipients
`
`Purified Water
`
`0.001% to 10.0% wb’voi.;
`0.001% to 1.0% wb’vo1.;
`0.001% to 1.0% wtlvo1.;
`0% to 10.0% wtfvo|.; and
`q.s. to 100%.
`
`Optional other excipients, such as a cheiating agent and a tonicifier, are used in the following approximate
`proportions:
`
`

`
`EP 0 308 984 B1
`
`
`
`'“9eie“t
`Chelating agent
`Tonicifier
`TN NaOH or 1N HCi
`
`
`
`0.01% to 1.0%wt/vol.;
`q.s. to achieve isotonicity with lacrimal fluid; and
`q.s. to adjust pH to 6.0 to 8.0.
`
`
`
`In a preferred ophthatmic NSAID solution. the ingredients are combined in the following proportions:
`
`
`
`0.002% to 5.0‘% wt/v0l.;
`0.002% to 1.0% wtlvo|.;
`0.001% to 1.0% wtlvo|.;
`0.01% to 1.0% wt/vol.;
`q.s. for isotonicity with lacrimai tiuid;
`q.s. to adjust pH to 7.4204; and
`q.s. to 100%.
`
`
`
`NSAiD
`BAG (50% aq. soln.)
`Octoxynoi 40 (70% aq. soln.)
`EDTA Na-2
`NaC|
`1N NaOH or 1N HCI
`Purified Water
`
`
`
`
`
`In another preferred ophthalmic NSAID solution, the ingredients as combined in the following propor-
`tions:
`
`
`
`
`
`0.005% to 1.0% wt/vol.;
`NSAID
`0.002% to 1.0% wt/vol.;
`BAC (50% aq. scln.)
`0.001% to 1.0% wt/vol.;
`Octoxynoi 40 (70% aq. soln.)
`0.01% to 1.0% w'tNol.;
`EDTA Nag
`q.s. for isotonicity with lacrimai fluid;
`NaC|
`
`1N NaOH or 1N HG]
`q.s. to adjust pH to 7,420.4; and
`Purified Water
`q.s. to 100%.
`
`In a more preferred ophthalmic NSAED solution,
`proportions:
`
`the ingredients are combined in the following
`
`NSAID
`
`BAG (50% aq. soln.)
`Octoxynol 40 (70% aq. soin.)
`EDTA Naz
`NaCl
`1N NaOH or 1N 3-tCl
`
`Purified Water
`
`0.50% wb’voi.;
`0.02% wt(vol.;
`0.01% wt(voi.;
`0.i0% wtfvol.;
`q.s. for isotonicity with lacrimal fluid;
`q.s. to adjust pH to 7420.4; and
`q.s. to 100%.
`
`The invention relates primarily to formulations having as the active agent ophthalmologically acceptable
`drugs (including the isomers. esters and pharmaceutically acceptabie salts thereof) that can form a complex
`with BAC, particularly NSAIDs and drugs with a carboxyl group.
`NSAIDS useful in the practice of this invention include, for example, ketoroiac (and the other compounds
`described as being ophihaimotogicaily effective in U.S. Patent No. 4,454,151 to Waterbury, issued June 12,
`1984,
`the pertinent portions of which are incorporated herein by reference).
`indomethacin,
`tlurbiprofen
`sodium, and diciofenac, including the isomers, esters and pharmaceutically acceptable salts thereof.
`The nonionic surfactant used in the formulations of the present invention, (i.e.. Octoxynol 40) is a
`octylphe-noxypoly(ethyleneoxyjetltanol, the mote ratio of ethytene oxide to ootyiphenol being 40. Octoxynol
`40 is manufactured and sold by GAF under the trade name igepal® CA897 (a 70% aqueous solution of
`Octoxynol 40).
`Among the optional excipients, the chelating agents useful in the formulations of the present invention
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`EP 0 306 984 131
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`include 8—hydroxyquino|ine sulfate, citric acid. and preferably disodium edetate. Under certain conditions,
`the chelating agent may also enhance the anti-microbiai effect due to its ability to render essential rnetai
`ions unavaiiable to the microbes.
`
`in the formulations of
`
`the present
`
`Buffering systems optionally useful
`example, citrate, borate, or phosphate.
`Toniciliers optionally useful
`in the formulations of the present invention include dextrose. potassium
`chloride and/or sodium chloride. preferably sodium chloride.
`Viscosity agents optionalty useful
`in the formuiations of the present invention include the cellulose
`derivatives such as hydroxypropylmethyl cellulose, sodium carboxymethylceltulose, and hydroxyethylcel-
`lulose.
`
`invention are based on, for
`
`in the formulations of the present invention include stabilizing agents
`Other optional excipients useful
`such as antioxidants, e.g., sodium metabisulfate and ascorbic acid, depending on the NSAID used.
`These formulations are prepared by dissoiving the solutes (e.g., the NSAED, BAC, the Octoxynol 40, 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.
`the
`It has been discovered that ophthalmic formulations incorporating the preservative system of
`invention are physically stable (Le...
`remain ctear) and functionally stable (i.e.,
`remain antimicrobially
`effective) for at least the minimum reasonable sheif life of such products.
`
`Preferred Formulations
`
`The preferred chelating agent of the invention is disodium edetate.
`The preferred ophthaimic sotutions of the invention include a NSAID, benzalkoniurn chioride, Octoxynel
`40 and disodium edetate.
`
`In a preferred ophthalmic NSAID solution, the ingredients are combined in the foltowing proportions:
`
`
`
`
`
`NSAID
`BAG (50% aq. soln.)
`Octoxynol 40 (70% aq. sotn.)
`EDTA Nag
`NaCl
`1N NaOl-i or 1N HCI
`Purified Water
`
`
`
`
`
`0.002% to 5.0% wtfvol.;
`0.002% to 1.0% wtr’vol.;
`0.001 % to 1.0% wtivolx,
`0.01 % to 1.0% wtfvoi.;
`q.s. tor isotonlcity with lacrimal fluid;
`q.s. to adjust pH to 71420.4; and
`q.s. to 100%.
`
`
`
`
`
`in another preferred ophthatmic NSAID solution, the ingredients are combined in the following propor-
`tions:
`
`NSAlD
`
`BAG (50% aq. soln.)
`Octoxynol 40 (70% aq. soln.)
`EDTA Nag
`NaGi
`1N Naoll or 1N HCI
`
`Purified Water
`
`0.005% to 1.0% wtlvol_;
`0.002% to 1.0% wt.’voi.;
`0.001% to 1.0% wt/vol.;
`0.01% to 1.0% wt/vol.;
`q.s. for isotonicity with lacrimal fluid:
`q.s. to adiust pH to 7.4304; and
`q.s. to 100%.
`
`A preferred ophthalmic NSAlD solution has the following formulation:
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`EP 0 306 984 B1
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`NSAED
`
`BAG (50% act. soln.)
`Octoxynol 40 (70% ad. soin.)
`EDTA N32
`NaCl
`1N NaOH or 1N HCI
`
`Purified Water
`
`0.50% wt/vol.
`0.02% wt/vol.
`0.01% wt/vol.
`0.10% wt/vol.
`
`q.s. for isotonicity with lacrimal fluid
`q.s. to adjust pH to 7.4104
`q.s. to t00%
`
`Most preferred is the ophthalmic sofution according to the above formulation wherein the NSAID is
`Ketorolac Tromethamine or an isomer thereof.
`
`Utility and Administration
`
`This invention is directed to NSAlD ophthalmic formulations useful for treating ophthalmic diseases in
`mammals. These diseases 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.
`The treatment is both curative and preventative. Where applied, for example, pre-surgically or imme-
`ciiatety post-traumaticaliy,
`i.e. before inflammation develops, it prevents develprnent of inflammation. When
`applied directly to the eye suffering from any of the named ophthalmic diseases.
`it suppresses already
`developed inflammatory processes.
`Ophthalmic formulations are typically administered by topical application to the eyelids or for instillation
`into the space (cul-do-sac) between the eyeball and the eyelids, of topically applied ophthalmic solutions,
`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
`lixed period of time (e.g., after two years). They are generaliy 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 stabie if its appearance (e.g., color and clarity) does not change and
`if the pH remain constant. within acceptable timits. 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
`tirne.
`
`Preservative efficacy is tested by the procedure described in the U.S. Pharmacopia Cornpendiary,
`whereby a sototion 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 NSAID Ketorolac Tromethamine.
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`EP 0 306 984 B1
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`Ketorolac Tromethamine
`BAC (50% aq. soln.)
`Octoxynol 40 (70% aq. soln.)
`EDTA Nae
`
`NaCl
`
`0.50% wtlvol.
`0.02% wtivoi.
`0.01% wt/voi.
`0.10% wtfvoi.
`0.79% wt/vot.
`
`The above ingredients are mixed, adding purified water until they are dissolved. the pH is adiustecl to
`72410.4 and the balance of the formulation is made up with purified water. adding a quantity sufficient to
`make 100% volume. The soiution is then sterilized.
`Other NSAIDS or their isomers. salts or esters, such as those described above, can be used as the
`active compound in the preparation of the iormuiation of this example.
`
`EXAMPLE 2
`
`This example illustrates the preparation of a representative pharmaceutical formulation for ophthalmic
`administration containing the NSND Ketorolac Tromethamine.
`
`
`
`'"9'e<ie"t
`Ketorolac Tromethamine
`BAC (50% aq. soln.)
`Octoxyno] 40 (70% aq. soln.)
`EDTA N32
`NaCl
`
`
`
`
`
`
`0.50% wtlvoi.
`0.02% wtlvoi.
`0.02% wt/voi.
`0.20% wt/vol.
`0.79% wt/voi.
`
`
`
`The above ingredients are mixed. adding purified water until they are dissolved, the pH is adjusted to
`71410.4 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 NSAIDS 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.
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`EXAMPLE 3
`
`This example iliustrates the preparation of a representative pharmaceutical formulation for ophthalmic
`administration containing the NSAID Ketoroiac Tromethamine.
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`.—'“9r9d*e"t
`Ketorolac Tromethamine
`
`BAC (50% aq. soin.)
`Octoxynol 40 (70% aq. soln.)
`EDTA N32
`
`NaC|
`
`0.10% wtivoi.
`
`0.004% wt/voi.
`0.004% wt./vol.
`0.05% wtlvoi.
`0.88% wt/voi.
`
`The above ingredients aie mixed, adding purified water unfit they are dissolved, the pH is adjusted to
`7.4x0.4 and the balance of the formulation is made up with purified water, adding a quantity sufficient to
`make 100% volume. The soiution is then sterilized.
`Other NSAIDs 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 4
`
`This exampie illustrates the preparation of a representative pharmaceutical formulation to: ophthalmic
`administration containing the NSAID fiurbipiofen sodium.
`
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`EP 0 306 984 B1
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`Fluzrbiprofen Sodium
`BAC (50% aq. sotn.)
`Gctoxynoi 40 (70% aq. soln.)
`EDTA Na;
`
`NaCl
`
`0.03% wt/vol.
`0.02% wt/vol.
`0.01% wt/vol.
`0.10% wt/vol.
`0.90% wt/vol.
`
`The above ingredients are mixed, adding purified water until they are dissolved, the pH is adjusted to
`7.4:0.4 and the balance of the formutation is made up with purified water, adding a quantity sufficient to
`make 100% volume. The solution is then sterilized.
`
`Other ophthalmic drugs and NSAlDs, such as those described above. can be used as the active
`compound in the preparation of the formulation of this example.
`
`EXAMPLE 5
`
`Physical stability of the formulations of the present invention is measured by preparing clear formula-
`tions,
`in the concentrations shown in the tabte below, sealing them in sterilized containers. and observing
`the ciarity 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 stabte when tested in accordance with the
`above procedure. Formulations using surfactants other than the nonionic surfactant of the invention dict not
`remain clear and were not stable.
`
`Three surfactants were evaluated for their ability to dissolve the ketorolac - benzalkonium chloride
`complex and maintain a physicaily 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%
`
`
`very turbid
`turbid
`turbid
`
`
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`clear
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`
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`0.001596
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`0.01%
`
`0.01“lo
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`clear
`
`very turbid
`turbid
`turbid
`
`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 Myri 52 displayed turbidity when stored at RT. The presence of
`turbidity suggested the inability to solubilize a precipitate formation between the Ketorolac moiety and
`benzatkoniurn 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 formutation. Preservative efficacy is maintained throughout the 2 year
`shelf life.
`
`EXAMPLE 6
`
`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.
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`EP 0 306 984 B1
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`The formulations of the present invention demonstrate preservative efficacy when tested in accordance
`with the above procedure.
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`EXAMPLE 7
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`T0
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`The objective of this clinical efficacy study was to compare the effectiveness and safety of ketorolac
`with a controt solution in reducing inflammation following cataract removal and intraocular lens implantation.
`All patients underwent an extracapsular cataract extraction with intraocular lens implantation 1 day foltowing
`initiation of treatment.
`
`Ophthalmic examinations were performed preoperativeiy (within 3 weeks of surgery) and during the first
`week (postoperative days 1
`to 8), second week (postoperative days 4 through 12), and third week
`(postoperative days 15 through 27) or treatment. Particular attention was given to signs and symptoms
`consistent with inttammation. Among the ocular characteristics assessed on a scaie of none, mild. moderate,
`or severe were:
`iid edema, corneal edema, conjunciival injections. ciliary flush, and the presence of cells
`and flare in the anterior chamber.
`
`is by definition a
`iridocyclitis)
`iritis, cyclitls,
`inflammation (i.e.,
`Fiuorophotometry: Anterior segment
`disruption of the blood-aqueous barrier. When inflammation is present, a careful slit lamp examination wiil
`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.
`Ocuiar fluorophotometry is based on the fact that the blood—aqueous barrier becomes permeabie to
`intravascular cells and proteinaceous fluid (explaining the observed celis and flare) and aiso to intravascular
`fiuorescein. Furthermore,
`the appearance of iiuorescein 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 ‘carrier by measuring
`the concentration of fiuorescein in the anterior chamber.
`
`The fluorophotometry data were analyzed using the Wllcoxon Flank Sum Test or anaiysis of variance
`(ANOVA) of rank-transformed data by calculating the percentage difference in tluorescein concentration
`between the patient's two eyes, according to the formula:
`
`Percent difference = [(fluorescein concentration of operated eye — lluorescein concentration of unoperated
`eye)l'f|uorescein 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 ophthatmic examinations and
`tiuorophotometry. 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% difference 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 quantltated by fiuorophotometry, by routine slit lamp examination, by patients having fewer
`and milder adverse events, and by infrequent need of additional corticosteroid therapy to control inflamma-
`tion.
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`EXAMPLE 8
`
`This was a double—blind, parallel comparison with vehicle to evaluate the efficacy of ketorolac 0.5%
`ophthaimic solution in reducing signs and symptoms of allergic conjunctivitis. Ketorolac 0.5% solution or a
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`vehicie solution of the same pH and tonicity were instilled four times daiiy into the eyes of patients with
`ailergic 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 ophthaimic examinations (visual acuity, external eye exam using slit iamp
`biornicroscopy, measurement of intraocular pressure, and undllated ophthaimoscopic examination). Labora-
`tory tests included a conjunctiva! scraping performed at baseiine and the final exam.
`All patients completed the study. There were no adverse events or toxicities in patients treated with
`vehicle while stinging on one occasion was reported from ketorclac 0.5% ophthalmic soiution. Ketorolac
`treatment was associated with a decrease in free eosinophilic granules as compared to vehicle (p = 0.025
`Fisher's Exact Test. two-tailed).
`The results of this study show that ketorolac 0.5% ophthalmic solution apptied four times daily for seven
`days produces a decrease in eosinophilic granules as compared to vehicle in the treatment of allergic
`conjunctivitis.
`
`EXAMPLE 9
`
`This study was a double-blind, paired comparison design travel to evatuate the tolerance of ketorolac
`0.5% ophthalmic solution and its vehicle in 26 healthy subjects. Solutions were instilled three times daiiy for
`21 days. Complete ophthalmic examinations were done pretreatment and on days 3, 10, 17, 24 (2 days
`after ending treatment). and 45 (23 days after ending treatment). No statistically significant difference in
`symptoms (burning, stinging,
`itchiness, scratchiness. photophobia) or signs (tearing, ocular discharge,
`conjunctival vasodilation, chernosis, keratitis, fluorescein staining, i‘-lose Bengal staining) was found between
`ketorolac and vehicle.
`
`EXAMPLE 10
`
`An ocular formulation containing 5 mg/ml ketorolac tromethamine was administered at a dose of 0.1
`ml/eye every one—half hour for a total of 12 doses to both eyes of 6 New Zealand albino rabbits. The
`iorrnulation contained benzalkonium chloride as the preservative system. Two additionai groups of animals
`served as saline and vehicle controls, respectively.
`Eyes were examined after the last dose was administered and on days 1, 2, 3, and 6 foliowing closing.
`Results indicated that no eye irritation or toxicity resulted from ketorclac tromethamine administration.
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`Claims
`
`1. A liquid ophthalmic NSAID formulation comprising a NSAID in an effective amount for ophthatmic
`treatment, benzalkonium chloride, a stabiiizing amount of Octoxynol 40, and an aqueous vehicle.
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`2. The ophthalmic NSAID formulation of Claim 1
`
`including disodium edetate.
`
`3. The ophthalmic NSAID formulation of any one of Claims 1 and 2 wherein said NSAiD is selected from
`ketorolac.
`indomeihacin. flurbiprofen, and dlclofenac, or their isomers, pharmaceutically acceptable
`salts, or esters.
`
`4. The ophthalmic NSAED formulation of any one of Claims 1
`Tromethamine.
`
`to 3 -wherein said NSAID is Ketorolac
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`5. The ophthalmic NSAID formuiation of