Nonirritating Aqueous Ophthalmic Compositions Comfort Formulation for Ocular Therepeutic Agents

Home , Alclofenac, Bucetin, Clonixin, Suprofen

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 heteroarylcarboxylic 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 nonsteroidal, 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 the ophthalmic composition in accordance with known practices in order to provide an effective rate of delivery of the therapeutic agent to the eye 40 when applied topically. For example, the ophthalmic composition may contain between about 0.5 percent and about 3.0 percent by weight/volume suprofen. The exact amount of anti-inflammatory agent will of the depend upon the particular anti-inflammatory agent selected and the strength ophthalmic composition. Further, additional therapeutic agents including steroids such as dexamethazone, antibiotics such as gentamicin, antiinfectives such as sulfonamides, and antiallergics such as antihistamines may be 45 added to and supplement the ophthalmic composition as is known. The composition contain ophthalmic preservatives such as thimerosal, chlorobutanol, benzalkonium chloride, or chlorhexidine. The composition contains a buffering agent such as a phosphate, borate, carbonate or citrate, and may contain thickening agents such as high molecular weight carboxy vinyl polymers such as the ones sold under the name of Carbopol® which is a trademark of the B. F. Goodrich with the art. so Chemical Company, hydroxymethylcellulose and polyvinyl alcohol, all in accordance prior The compositions are prepared by dissolving the various ingredients in the required amount of water with stirring to insure that all the ingredients are dissolved. The aqueous compositions of the invention the may be solutions, suspensions, or gels. After preparation of the solution, suspension, or gel compositions are then packaged in dispensers suitable for delivery of the ophthalmic composition. in which the invention be 55 The following examples of ophthalmic compositions typify the manner may practiced. The percentages are expressed on a weight/volume basis.

65 EP 0105 635 B1 Example I Suprofen 0.5% Solution with Benzalkonium Chloride

Suprofen 0.5% + 5% excess of the drug Caffeine 1.0%

Pluronic® F127* 0.5%

10 Benzalkonium Chloride 0.01% + 10% excess Disodium Edetate 0.1%

Dried Sodium Phosphate 0.1% 15 Sodium Biphosphate 0.03%

Sodium Chloride 0.6%

20 pH adjustment with NaOH or HCI q.s. pH 7.4

Purified Water q.s. 100%

* a high molecular weight non-ionic surfactant sold under the registered trademark of the 25 Wyandotte Chemicals Corp.

Example II Indomethacin 0.5% Suspension

30 Indomethacin 0.5% plus a 5% excess of the 0.5% drug Caffeine 1.0%

Thimerosal 0.005% plus a 10% excess of theThermerosal 35 Disodium Edetate 0.1%

Sodium Chloride 0.7%

40 Tyloxapol 0.1%

Dried Sodium Phosphate 0.1%

Sodium Biphosphate 0.03% 45 pH adjustment with NaOH or HCI to pH of 7.4 q.s. pH 7.4

Purified Water q.s. 100% 50

65 EP 0 105 635 B1 Example III Melofenamic Acid 0.1% Suspension

Melofenamic Acid 0.1% plus a 5% excess of the 0.1% drug 5 Caffeine 1.0%

Thimerosal 0.005% plus a 10% excess of the 0.005% Thimerosal

'0 Disodium Edetate 0.1%

Dried Sodium Phosphate 0.1%

Sodium Biphosphate 0.03% 15 Sodium Chloride 0.7%

pH adjustment with HCI or NaOH to a pH of 7.4 q.s. pH 7.4 20 i/ater q.s. 100%

Example IV Ketoprofen Solution 25 Ketoprofen 0.25%

Theophylline 0.5% Thimerosal 0.01 % 30 Sodium Biphosphate 0.03%

Dried Sodium Phosphate 0.1%

35 Sodium Chloride 0.65%

Diethanolamine 0.25%

Disodium Edetate • 0.01% 40 pH adjustment with NaOH or HCI to a pH of 7.4 q.s. pH 7.4

Purified Water q.s. 100%

45 Example V Flurbiprofen Flurbiprofen 0.5%

Caffeine 1% 50 Thimerosal, 0.005%

Disodium Edetate, 0.1%

55 Dried Sodium Phosphate, 0.1%

Sodium Chloride, 0.7%

pH adjustment with HCI or NaOH to pH 7.4 q.s. 7.4 60 Purified Water. q.s. 100%

65 EP 0105 635 B1

Claims

1. An aqueous, nonirritating, nonsteroidal, ophthalmic composition for topical application to the eye comprising: 5 a therapeutically effective amount of an acidic anti-inflammatory agent for topical treatment of 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 10 contained in the composition to 0.05% by weight/volume of the composition which is effective to reduce the discomfort associated with the anti-inflammatory agent upon topical application of the composition, the xanthine derivative having the formula:

0 R3 1B [I I LI>

R2 20 l wherein R1f R2 and R3 are each independently hydrogen, methyl, or ethyl, and at least two of R,, R2 and R3 are methyl or ethyl, or a mixture thereof; an opthalmic preservative; and 25 a buffer, to provide an isotonic, aqueous, nonirritating and nonsteroidal ophthalmic composition. 2. An aqueous, nonirritating, nonsteroidal, ophthalmic composition as claimed in claim 1 wherein the xanthine derivative is theophylline, caffeine, theobromine or a mixture thereof. 3. An aqueous, nonirritating, nonsteroidal, ophthalmic composition as claimed in claim 1 or claim 2 wherein the anti-inflammatory agent is mefenamic acid, flufenamic acid, clonixin, flufenisal, 4-(t- 30 butyDbenzeneacetic acid, ibufenac, ibuprofen, alclofenac, fenoprofen, naproxen, indomethacin, tolmetin, flurbiprofen, ketoprofen, namoxyrate, suprofen or a mixture thereof. 4. An aqueous nonsteroidal ophthalmic composition as claimed in any one of the preceding claims which is in the form of a solution, suspension or gel. 5. An aqueous, nonirritating, nonsteroidal, ophthalmic composition as claimed in claim 1 wherein the 35 xanthine derivative is caffeine and the anti-inflammatory is suprofen. 6. A method for the preparation of an ophthalmic composition as claimed in any one of the preceding claims in which the desired amounts of the active ingredients are dissolved in the required amount of water, with stirring, to ensure that all of the ingredients are dissolved. 7. The use of an anti-inflammatory agent which is an arylcarboxylic acid, heteroarylcarboxylic acid, 40 arylalkanoic acid, heteroarylalkanoic acid, or a pharmaceutically acceptable salt thereof, or a mixture thereof, and a xanthine derivative having the formula

8 i3

50 wherein R1( 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; for the manufacture of an ophthalmic composition for topical application to the eye. 8. The use as claimed in claim 7 wherein the xanthine derivative is theophylline, caffeine, theobromine or a mixture thereof. 55 9. The use as claimed in claim 8 wherein the anti-inflammatory agent is mefenamic acid, flufenamic acid, clonixin, flufenisal, 4-(t-butyl)benzeneacetic acid, ibufenac, ibuprofen, alclofenac, fenoprofen, naproxen, indomethacin, tolmetin, flurbiprofen, ketroprofen, namoxyrate, suprofen, or a mixture thereof. 10. The use as claimed in claim 7 wherein the xanthine derivative is caffeine and the anti-inflammatory is suprofen. 60 Patentanspriiche

1. WaKrige, nicht reizende, nicht steroidale, ophthalmische Zusammensetzung zur ortlichen Anwendung fur das Auge, enthaltend: 65 eine therapeutisch wirksame Menge eines sauren, entzundungshemmenden Mittels zur ortlichen EP 0105 635 B1

Behandlung einer Entziindung des Auges, wobei das entziindungshemmende Mittel eine Arylcarbonsaure, Heteroarylcarbonsaure, Arylalkansaure, Heteroarylalkansaure oder ein pharmazeutisch vertragliches Salz davon oder ein Gemisch davon ist, ein Xanthinderivat in einer Menge, von jener Menge, in der das Derivat im Wasser loslich ist, das in der Zusammensetzung enthalten ist, bis 0,05% (Gewicht/Volumen) der Zusammensetzung, die wirksam ist, um die Beschwerden zu verringern, die mit dem entzundungshemmenden Mittel bei der ortlichen Anwendung der Zusammensetzung verbunden sind, wobei das Xanthinderivat^die Formel besitzt: O R 10 U I

O^^NT "N R2 15 C worin R1f R2 und R3 jeweils unabhangig Wasserstoff, Methyl oder Ethyl sind, und mindestens zwei von Rv R2 und R3 Methyl oder Ethyl sind, oder ein Gemisch davon, ein ophthalmisches Schutzmittel und 20 einen Puffer, um fur eine isotonische, wafcrige, nicht reizende und nicht steroidale ophthalmische Zusammensetzung zu sorgen. 2. WalSrige, nicht reizende, nicht steroidale ophthalmische Zusammensetzung nach Anspruch 1, worin das Xanthinderivat Theophyllin, Coffein, Theobromin oder ein Gemisch davon ist. 3. WaBrige, nicht reizende, nicht steroidale ophthalmische Zusammensetzung nach Anspruch 1 oder 2, 25 worin das entzundungshemmende Mittel Mefenaminsaure, Flufenaminsaure, Clonixin, Flufenisal, 4-(t- ButylJ-benzoeessigsaure, Ibufenac, Ibuprofen, Alclofenac, Fenoprofen, Naproxen, Indomethacin, Tolmetin, Flurbiprofen, Ketoprofen, Namoxyrat, Suprofen oder ein Gemisch davon ist. 4. WafSrige, nicht steroidale ophthalmische Zusammensetzung nach einem der vorhergehenden Anspriiche, die in Form einer Losung, Suspension oder eines Gels ist. 30 5. WaBrige, nicht reizende, nicht steroidale ophthalmische Zusammensetzung nach Anspruch 1, worin das Xanthinderivat Coffein und das enzundungshemmende Mittel Suprofen ist. 6. Verfahren fur die Herstellung einer ophthalmischen Zusammensetzung nach einem der vorhergehenden Anspriiche, worin die gewiinschten Mengen der aktiven Bestandteile in der erforderlichen Menge Wasser aufgelost werden, unter Ruhren, um sicherzustellen, daft die gesamten Bestandteile 35 aufgelost sind. 7. Verwendung eines entzundungshemmenden Mittels, das eine Arylcarbonsaure, Heteroaryl- carbonsaure, Arylalkansaure, Heteroarylalkansaure oder ein pharmazeutisch vertragliches Salz davon oder ein Gemisch davon ist, und eines Xanthinderivats mit der Formel

o R3

-j!i> N 45 Cr^N R2

worin Rv R2 und R3 jeweils unabhangig Wasserstoff, Methyl oder Ethyl sind, und mindestens zwei von R,, R2 und R3 Methyl oder Ethyl sind, oder einem Gemisch davon, zur Herstellung einer ophthalmischen so Zusammensetzung zur ortlichen Beha'ndlung des Auges. 8. Verwendung nach Anspruch 7, worin das Xanthinderivat Theophyllin, Coffein, Theobromin oder ein Gemisch davon ist. 9. Verwendung nach Anspruch 8, worin das entzundungshemmende Mittel Mefenaminsaure, Flufenaminsaure, Clonixin, Flufenisal, 4-(t-Butyl)-benzoeessigsaure, Ibufenac, Ibuprofen, Alclofenac, 55 Fenoprofen, Naproxen, Indomethacin, Tolmetin, Flurbiprofen, Ketoprofen, Namoxyrat, Suprofen oder ein Gemisch davon ist. 10. Verwendung nach Anspruch 7, worin das Xanthinderivat Coffein und das entzundungshemmende Mittel Suprofen ist.

60 Revendications

1. Composition ophtalmique aqueuse, non-irritante, non-stero'fdienne, pour application locale sur I'oeil, comprenant: une quantite therapeutiquement efficace d'un agent anti-inflammatoire acide, pour traitement local de 65 I'inflammation de I'oeil, lequel agent anti-inflammatoire est un acide arylcarboxylique, un acide heteroaryl- EP 0 105 635 B1 carboxylique, un acide arylalcanoTque, un acide heteroarylalcanoi'que ou I'un de leurs sels pharmaceutiquement acceptable, ou I'un de leurs melanges; un derive de la xanthine, en une quantite comprise entre la quantite pour laquelle le derive est soluble dans I'eau contenue dans la composition de 0,05% en poids/en volume par rapport a la composition, 5 quantite efficace pour reduire I'inconvenient associe a I'agent anti-inflammatoire apres application locale de la composition, le derive de \f xanthine ayant la formule suivante:

o R3

IX Cr^N N R2 15 dans laquelle R1# R2 et R3 representent chacun, independamment I'un de I'autre, un hydrogene, le radical methyle ou ethyle, et au moins deux des radicaux R1( R2 et R3 sont des radicaux methyle ou ethyle, ou I'un de leurs melanges; 20 un antiseptique ophtalmique; et un tampon, destine a donner une composition ophtalmique isotonique, aqueuse, non-irritante et non- steroTdienne. 2. Composition ophtalmique aqueuse, non-irritante, non-steroTdienne, selon la revendication 1, dans laquelle le derive de la xanthine est la theophylline, la cafeine, la theobromine ou I'un de leurs melanges. 25 3. Composition ophtalmique aqueuse, non-irritante, non-steroTdienne, selon la revendication 1 ou la revendication 2, dans laquelle I'agent anti-inflammatoire est I'acide mefenamique, I'acide flufenamique, la clonixine, le flufenisal, I'acide 4-(tert-butyl)benzenacetique, I'ibufenac, I'ibuprofene, I'alclofenac, le fenoprofene, le naproxene, I'indomethacine,- la tolmetine, le fluorbiprofene, le ketoprofene, le namoxyrate, le suprofene ou I'un de leurs melanges. 30 4. Composition ophtalmique aqueuse non-steroTdienne selon Tune quelconque des revendications precedentes, qui se presente sous la forme d'une solution, d'une suspension-ou d'un gel. 5. Composition ophtalmique aqueuse non-irritante, non-steroTdienne, selon la revendication 1, dans laquelle le derive de la xanthine est la cafeine et I'anti-inflammatoire est le suprofene. 6. Procede pour la preparation d'une composition ophtalmique selon I'une quelconque des 35 revendications precedentes, dans lequel les quantites souhaitees des principes actifs sont dissoutes dans la quantite requise d'eau, sous agitation, pour assurer la dissolution de la totalite des ingredients. 7. Utilisation d'un agent anti-inflammatoire, qui est un acide arylcarboxylique, un acide heteroaryl- carboxylique, un acide arylalcanoTque, un acide heteroarylalcanofque ou I'un de leurs sels pharmaceutiquement acceptables, ou un de leurs melanges, et d'un derive de la xanthine, ayant la formule 40 suivante

n Rq

so dans laquelle R1( R2 et R3, independamment les uns des autres, representent chacun un hydrogene ou le radical methyle ou ethyle, et au moins deux des radicaux R1f R2 et R3 representent des radicaux methyle ou ethyle, ou I'un de leurs melanges; pour la fabrication d'une composition ophtalmique pour application locale a I'oeil. 8. Utilisation selon la revendication 7, dans laquelle le derive de la xanthine est la theophylline, la 55 cafeine, la theobromine ou I'un de leurs melanges. 9. Utilisation selon la revendication 8, dans laquelle I'agent anti-inflammatoire est I'acide mefenamique, I'acide flufenamique, la clonixine, le flufenisal, I'acide 4-(tert-butyl)benzenacetique, I'ibufenac, I'ibuprofene, I'alclofenac, le fenoprofene, le naproxene, I'indomethacine, la tolmetine, le fluorbiprofene, le ketoprofene, le namoxyrate, le suprofene ou I'un de leurs melanges. 60 10. Utilisation selon la revendication 7, dans laquelle le derive de la xanthine est la cafeine et I'anti- inflammatoire est le suprofene.