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Nonirritating Aqueous Ophthalmic Compositions Comfort Formulation for Ocular Therepeutic Agents

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Europaisches Patentamt 0105 4 European Patent Office Publication number: 635 B1 Office europeen des brevets EUROPEAN PATENT SPECIFICATION Date of publication of patent specification: 04.04.90 |j) intci.5: A 61 K 45/06, A 61 K 31/52 // (A61K31/52,31:19) Application number: 83305184.0 Date of filing: 06.09.83 Nonirritating aqueous ophthalmic compositions comfort formulation for ocular therepeutic agents. Priority: 07.09.82 US 415758 Proprietor: ALCON LABORATORIES INC 6201 South Freeway P.O. Box 1959 Fort Worth Texas 76101 (US) Date of publication of application: 18.04.84 Bulletin 84/16 Inventor: Han, Wesley Wehsin 1006 Birch wood Publication of the grant of the patent: Mansfield Texas 76063 (US) 04.04.90 Bulletin 90/14 Inventor: Roehrs, Robert Eugene 3729 Hulen Park Fort Worth Texas 76109 (US) Designated Contracting States: AT BE CH DE FR GB IT LI LU NL SE Representative: Allard, Susan Joyce et al BOULT, WADE & TENNANT, 27 Furnival Street References cited: London EC4A1PQ(GB) FR-A-2 530469 483 US-A-4420 References cited: 18, 3rd May CHEMICAL ABSTRACTS, vol. 93, 25, 22nd CHEMICAL ABSTRACTS, vol. 96, no. no. Columbus, Ohio, December 1980, 67, no.230937k, 1982, page 422 , no.149162u, page 416 (KAKEN CHEMICAL CO. Columbus, Ohio, US; T. KAMEYAMA et al.: US; & JP - A - 81 154 "Combined effect of ibuprofen and bucetin in LTD.) 30-11-1981 IT) analgesic activity", & OYO YAKUR1 1980, 19(5), CO 809-14 CO in o 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 of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been Q. paid. (Art. 99(1 ) European patent convention). LU Courier Press, Leamington Spa, England. EP 0 105 635 B1 Description This invention relates generally to aqueous ophthalmic compositions for treatment of the eye, and more particularly, it relates to nonirritating aqueous non-steroidal ophthalmic compositions containing 5 aryl- and heteroarylcarboxylic acids, aryl- and heteroarylalkanoic acids and therapeutic agents which compositions contain an effective amount of a xanthine derivative which eliminates or reduces discomfort with acid containing ophthalmic drugs. Steroidal anti-inflammatory agents are useful therapeutic agents, but are known for their undesirable side effects including, but not limited to, salt retention, edema, and potential danger to pregnant women. 10 To avoid these undesirable side effects non-steroidal, anti-inflammatory agents such as aryl- and hetero- arylcarboxylic acids and aryl- and heteroarylalkanoic acids and pharmaceutically acceptable salts of such acids may be used. However, it has not been possible to formulate these acidic anti-inflammatory agents in aqueous ophthalmic compositions because the acids disassociate in aqueous solution forming soap-like compounds which cause severe ocular discomfort including stinging and excessive tear generation. In 15 addition to the discomfort to the patient caused by the stinging sensation, the excess tears generated may also dilute and/or wash away the drug from the ocular surface. Attempts to decrease ocular stinging of non-steroidal acidic anti-inflammatory agents through conventional formulation approaches have not proved successful. Aqueous solutions of suprofen and ketoprofen, two recognized non-steroidal acidic anti-inflammatory agents, when formulated with different 20 ophthalmic preservatives such as benzalkonium chloride, chlorobutanol, and thimerosal provide little or no reduction in the stinging or discomfort caused when these drugs are instilled into the eye in aqueous solution. Likewise changing buffering agents, such as sodium phosphate, sodium borate, and sodium citrate, and their concentrations provides little or no reduction in stinging. Changing the cations in solution from sodium to potassium gives rise to some improvement in reduction of the stinging effect, but not to a 25 satisfactory level. Incorporating inert adjuvants such as polyvinyl alcohol, glycerin, glycine and ethyl alcohol provides little or no reduction of the stinging or discomfort of the acidic anti-inflammatory agent. Varying the pH of the ocular solutions provides little or no reduction of discomfort. A need exists, therefore, for a non-steroidal, anti-inflammatory composition which has the advantages of not being a steroid, and which may be used in the topical treatment of diseases of the eye without 30 producing stinging or ocular discomfort. More particularly, a need exists for a formulation of aryl- and heteroarylcarboxylic acids or aryl- and heteroarylalkanoic acids and pharmaceutically acceptable salts thereof which with topical ocular use will not produce discomfort. Chemical Abstracts, Vol. 93, 1980, Page 67, No. 230937K, discloses a composition having a synergistic analgesic action comprising a bucetin-ibuprofen. mixture in admixture with caffeine and thiamin 35 hydrochloride. Chemical Abstracts, Vol. 96, 1982, Page 422, No. 149162U, discloses a combined analgesic and anti-pyretic formulation containing ibuprofen, caffeine and thiamin in the form of tablets. Neither of these documents discloses compositions suitable for ophthalmic use. It has been found that methyl and ethyl derivatives of xanthine when formulated in an aqueous non- steroidal, anti-inflammatory composition containing aryl- and heteroarylcarboxylic acids or aryF- and 40 heteroarylalkanoic acids or mixtures thereof, results in a composition that may be applied topically to the eye with little or none of the discomfort previously known with the use of such agents. Accordingly, the present invention provides an aqueous, nonirritating, nonsteroidal, ophthalmic composition for topical application to the eye comprising: a therapeutically effective amount of an acidic anti-inflammatory agent for topical treatment of 45 inflammation of the eye, which anti-inflammatory agent is an arylcarboxylic acid, heteroarylcarboxylic acid, arylalkanoic acid, heteroarylalkanoic acid, or a pharmaceutically acceptable salt thereof or a mixture thereof; a xanthine derivative in an amount of from the amount by which the derivative is soluble in the water contained in the composition to 0.05% by weight/volume of the composition which is effective to reduce so the discomfort associated with the anti-inflammatory agent upon topical application of the composition, the xanthine derivative having the formula: II") CP^N 'N R2 60 wherein Ri, R2 and R3 are each independently hydrogen, methyl, or ethyl, and at least two of R1# R2 and R3 are methyl or ethyl, or a mixture thereof; an ophthalmic preservative; and 65 a buffer, to provide an isotonic, aqueous, nonirritating and nonsteroidal ophthalmic composition. EP 0 105 635 B1 The xanthine derivatives which have been found to be effective in reducing ocular discomfort in accordance with the present invention are those having the following structure: ?3 R11J1'%'^ 70. R2 Where R1f R2 and R3 are either hydrogen, methyl or ethyl, and at least two of R1# R2 and R3 are methyl or ethyl. Theophylline, which has methyl groups at the 1 and 3 positions, caffeine, which has methyl groups at the 1,3, and 7 positions, and theobromine, which has methyl groups at the 3 and 7 positions are examples 15 of xanthine derivatives contemplated by the present invention. These derivatives when added to a finished buffered isotonic aqueous composition of aryl- and heteroarylcarboxylic acids and/or aryl- and heteroarylalkanoic acids or pharmaceutically acceptable salts of such acids with the concentration of the derivative at an upper level of about the solubility of the xanthine derivative to a lower concentration limit of the xanthine derivative of 0.05% by weight/volume of the be with little 20 aqueous composition, provide an ocular anti-inflammatory agent which can topically applied or no discomfort or ocular stinging to the patient. Ingredients including but not limited to benzalkonium chloride, thimerosal and NaCI may be optionally added to the composition as is known in the art. It is readily apparent that the amount of xanthine derivatives will vary depending on the particular acid drug used and the amount of drug in the composition. 25 There are a large number of acidic anti-inflammatory agents which can be incorporated in compositions in accordance with the present invention. Examples of aryl- or heteroarylcarboxylic acids include mefenamic acid or 2-[(2,3-dimethylphenyl)amino]benzoic acid, fiufenamic acid or 2[[3-(trifluoro- methyl)phenyl]amino]benzoic acid, clonixin or 2-(3-chloro-o-toluidino)nicotinic acid and flufenisal or 4' fluoro-4-acetate-biphenyl-3 carboxylic acid. 30 Examples of aryl- or heteroarylalkanoic acids include 4-(t-butyl)benezeneacetic acid, ibufenac or 4-(2- methylpropyDbenzeneacetic acid, ibuprofen or a-methyl-4-(2-methylpropyl)benezeneacetic acid, alclofenac or 3-chloro-4-(2-propenyloxy)benezeneacetic acid, fenoprofen or a-methyl-3-phenoxybenzene- acetic acid,- naproxen or 2-(6-methoxy-2-naphthyl)propionic acid, indomethacin or 1-(p-chlorobenzoyl)-5- methoxy-2-methylindole-3-acetic acid, tolmetin or 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid, 35 flurbiprofen or 2-fluoro-a-methyl[1,1'-biphenyl]-4-acetic acid, ketoprofen or 2-(3-benzoylphenyl)propionic acid, namoxyrate or 2-(p-biphenylyl)butyrate dimethylaminoethanol salt and suprofen or para-2-thenoyl- hydratropic acid. The acidic anti-inflammatory agent may be incorporated in
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