Medicaments for Treating Inflammatory Conditions Or for Analgesia

Europaisches Patentamt (19) J European Patent Office

Office europeen des brevets (11) EP 0 550 083 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) mt ci6: A61K 31/34, A61K31/54, of the grant of the patent: A61K 31/415, A61K 31/40, 24.03.1999 Bulletin 1999/12 A61K 31/405, A61K 31/62, (21) Application number: 92203674.4 A61K 31/645 //(A61K31/645, 31:34), (22) Dateof filing: 27.11.1992 (A61K31/54, 31:34), (A61K31/415, 31:34), (A61K31/405, 31:34), (A61K31/40, 31:34), (A61K31/34, 31:24), (A61K31/34, 31:195), (A61K31/34, 31:19)

(54) Medicaments for treating inflammatory conditions or for analgesia containing a NSAID and ranitidine bismuth citrate Zusammensetzungen zur Behandlung von entzundlichen Zustanden oder Analgesie, die Ranitidin Wismuth Citrat und einen NSAID enthalten Medicaments pour le traitement de conditions inflammatoires ou pour I'analgesie contenants un NSAID et du citrate de bismuth-ranitidine

(84) Designated Contracting States: (74) Representative: DE DK ES GR NL PT SE Reed, Michael Antony et al Intellectual Property Department (30) Priority: 06.12.1991 GB 9126027 Glaxo Wellcome pic 20.03.1992 GB 9206083 Glaxo Wellcome House Berkeley Avenue (43) Date of publication of application: Greenford, Middlesex UB6 0NN (GB) 07.07.1993 Bulletin 1993/27 (56) References cited: (73) Proprietor: GLAXO GROUP LIMITED EP-A- 0 426 479 GB-A-2105193 Greenford, Middlesex UB6 0NN (GB) GB-A- 2 220 937 (72) Inventor: Stables, Roger, Glaxo Group Research Ltd. Ware, Hertfordshire, SG12 0DP (GB)

CO CO CO o

LO Note: Within nine months from the publication of the mention of the grant of the European patent, give LO any person may notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in o a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. Q_ 99(1) European Patent Convention). LU Printed by Xerox (UK) Business Services 2.16.7/3.6 EP 0 550 083 B1

Description

[0001] The present invention relates to improvements in the treatment of inflammatory conditions and for analgesia. More particularly it relates to the co-administration of a non-steroidal anti-inflammatory drug with a salt formed between 5 ranitidine and a complex of bismuth with a carboxylic acid. [0002] Systemic non-steroidal anti-inflammatory drugs, such as aspirin, indomethacin, ibuprofen and piroxicam, are known to give rise to undesirable side effects. In particular, they are known to be ulcerogenic and can thus, for example, give rise to gastric and/or duodenal ulceration when administered orally. This side effect may be further enhanced in combination with other factors such as stress and smoking. Since in some treatments these compounds may have to 10 be used for an extended period, such side effects can prove a serious disadvantage. [0003] GB-A-2105193 relates to a pharmaceutical composition comprising a systemic non-steroidal anti-inflammatory drug together with the histamine H2-antagonist ranitidine or physiologically acceptable salts thereof. The histamine H2-antagonist reduces gastric mucosal lesions caused by the anti-inflammatory drug. [0004] In our UK Patent Specification No. 2220937B we describe and claim salts formed between ranitidine and a 15 complex of bismuth with a carboxylic acid, particularly tartaric acid and, more especially, citric acid. One such salt is N- [2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1 ,1 -ethenediamine 2-hydroxy-1 ,2,3-pro- panetricarboxylate bismuth (3+) complex, also known as ranitidine bismuth citrate. [0005] The salts disclosed in UK Patent Specification No. 222937B possess the H2-antagonist antisecretory properties associated with ranitidine, together with antibacterial activity against Helicobacter pylori (formerly Camphylobacter 20 pylori). In addition, such salts possess cytoprotective properties, and display activity against the human gastric pepsins with preferential inhibition of pepsin 1 , a pepsin enzyme associated with peptic ulcer. The salts disclosed in UK Patent Specification No. 2220937B thus possess a particularly advantageous combination of properties for the treatment of gastrointestinal disorders, especially peptic ulcer disease (e.g. gastric and duodenal ulceration) and other gastroduo- denal conditions, for example gastritis and non-ulcer dyspepsia. 25 [0006] Tests in animals and humans have now shown that mucosal lesions of the gastrointestinal tract caused by non- steroidal anti-inflammatory drugs are significantly reduced by administering ranitidine bismuth citrate. In particular, we have demonstrated in rats the ability of ranitidine bismuth citrate to prevent indomethacin induced gastric antral ulceration using a modification of the method of Satoh etal.. Gastroenterology (1981), 81, 719-725. In this test ranitidine bismuth citrate was markedly more potent than both ranitidine hydrochloride and tripotassium dicitrato bismuthate as 30 DeNol™. A recently published human clinical study (N. Hudson etal.. Gut 1992, 33 supplement, s47) also demonstrates that ranitidine bismuth citrate confers substantial protection from aspirin-induced injury to the gastric mucosa. [0007] The present invention thus provides, in one aspect, the use of (i) ranitidine bismuth citrate and (ii) a non-steroidal anti-inflammatory drug in the manufacture of medicaments for simultaneous, separate or sequential use in treating or preventing inflammatory conditions or for analgesia. 35 [0008] In a further, or alternative, aspect the present invention provides the use of ranitidine bismuth citrate in the manufacture of medicaments to prevent gastrointestinal damage caused by non-steroidal anti-inflammatory drugs. [0009] Combination therapy according to the present invention may be used in the treatment of inflammatory conditions, particularly acute and chronic musculoskeletal inflammatory conditions such as rheumatoid and osteo-arthritis and ankylosing spondylitis and for analgesia in conditions such as dysmenorrhoea, especially where the use of the anti- 40 inflammatory drug is limited by gastrointestinal side effects. As stated above, co-administration of ranitidine bismuth citrate with a systematic non-steroidal anti-inflammatory drug may also be used to prevent gastrointestinal damage caused by non-steroidal anti-inflammatory drugs. Such gastrointestinal damage includes duodenal and/or gastric ulceration, non-steroidal anti-inflammatory drug associated gastritis and gastric erosions, and non-steroidal anti-inflammatory drug associated mucosal damage to the small intestine. 45 [001 0] Suitable systemic non-steroidal anti-inflammatory drugs which may be employed in the invention generally also show analgesic activity and include, for example, aspirin, indomethacin, ibuprofen, piroxicam, fenoprofen, ketoprofen, naproxen, mefenamic acid, diflunisal, benorylate, azapropazone, diclofenac, fenbufen, feprazone, fenclofenac, flufenamic acid, flurbiprofen, oxyphenbutazone, phenylbutazone, sulindac and tolmetin. [001 1 ] The ranitidine bismuth citrate and the anti-inflammatory drug are preferably co-administered in the form of sep- 50 arate pharmaceutical compositions for simultaneous and/or sequential use. Alternatively the ranitidine bismuth citrate and the anti-inflammatory drug may be administered as a single pharmaceutical composition for oral use comprising effective amounts of the active ingredients. [001 2] Thus, according to a further aspect, the invention provides a product containing (i) ranitidine bismuth citrate and (ii) a non-steroidal antiinflammatory drug as a combined preparation for simultaneous, separate or sequential use 55 in treating or preventing inflammatory conditions or for analgesia. [001 3] When the ranitidine bismuth citrate and the non-steroidal anti-inflammatory are administered as separate preparations, the anti-inflammatory may be provided in any convenient formulation, such as in the manner known in the art and/or commercially for the compound concerned. Administration of both the ranitidine bismuth citrate and the non-

2 EP 0 550 083 B1

steroidal anti-inflammatory by the oral route is preferred, although the anti-inflammatory, where appropriate, may also be given by another route, for example parenterally (e.g. intravenously) or rectally (e.g. by suppository). [0014] The ranitidine bismuth citrate may conveniently be formulated as tablets (including chewable tablets), capsules (of either the hard or soft type), or as a liquid preparation, as described for example in UK Patent Specification Nos. 5 2220937B and 22481 85A. Tablets are generally preferred. [0015] As stated hereinabove, ranitidine bismuth citrate and the non-steroidal anti-inflammatory drug may be administered as a single pharmaceutical composition for oral use. Thus, according to a further aspect the invention provides a pharmaceutical composition, for oral use in human or veterinary medicine, comprising ranitidine bismuth citrate and a non-steroidal anti-inflammatory drug, together, where appropriate, with a pharmaceutical^ acceptable carrier or 10 excipient. [001 6] Suitable additional carriers or excipients include binding agents (e.g. pregelatinised maize starch, polyvinylpyr- rolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phos- phate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). An alkaline salt of the type described in UK Patent Specification No. 15 22481 85A may be added to improve the rate of disintegration and/or dissolution of the composition. [0017] The compositions may be prepared according to conventional techniques well known in the pharmaceutical industry. Thus, for example, the ranitidine bismuth citrate and the non-steroidal anti-inflammatory drug may be admixed together, if desired, with suitable carriers or excipients. Tablets may be prepared, for example, by direct compression or wet granulation of such a mixture. Capsules may be prepared by filling the blend along with suitable carriers or excipi- 20 ents into gelatin capsules, using a suitable filling machine. Tablets may be coated by methods well known in the art. The preparations may also contain flavouring, colouring and/or sweetening agents as appropriate. [0018] When ranitidine bismuth citrate and the non-steroidal anti-inflammatory drug are administered as a single pharmaceutical composition for oral use the composition is preferably in the form of a capsule or, more particularly, a tablet. 25 [001 9] The compositions for use according to the invention may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients. The pack may for example comprise metal or plastic foil, such as a blister pack. Where the ranitidine bismuth citrate and the non-steroidal anti-inflammatory drug are intended for administration as separate compositions these may be presented in the form of, for example, a twin pack. 30 [0020] Thus, according to a further aspect the present invention provides a twin-container pack for use in treating or preventing inflammatory conditions or for analgesia, one of the containers containing ranitidine bismuth citrate and the other containing a non-steroidal anti-inflammatory drug. [0021 ] The doses at which the ranitidine bismuth citrate and the non-steroidal anti-inflammatory may be administered to man (of approximately 70kg body weight) will depend on the route of administration of the anti-inflammatory and on 35 the nature and severity of the condition being treated. It will also be appreciated that it may be necessary to make rou- tine variations to the dosage depending on the age and weight of the patient. [0022] A proposed dosage of ranitidine bismuth citrate for use according to the invention is 1 50mg to 1 .5g, preferably 200 - 800mg per unit dose. The unit dose may be administered, for example, 1 to 4 times per day, preferably once or twice per day. 40 [0023] The non-steroidal anti-inflammatory may conveniently be administered at doses within the normal dosage range at which the compound is therapeutically effective, -for example 50mg-1g of aspirin, 10-100 mgof indomethacin, 5 - 50 mg of piroxicam, 100-500mg of ibuprofen and 200-800mg of mefenamic acid per dosage unit taken one or more times daily in accordance with the normal dosage regime for the drug in question. [0024] In a further aspect, the present invention provides a method of treating inflammatory conditions or for analgesia 45 in a human or animal subject, which comprises administering to said subject effective amounts of ranitidine bismuth citrate and a non-steroidal anti-inflammatory drug. [0025] In another, or alternative, aspect the present invention provides a method of treating gastrointestinal damage caused by non-steroidal anti-inflammatory drugs in a human or animal subject, which comprises administering to said subject an effective amount of ranitidine bismuth citrate. so [0026] References herein to treatment include prophylactic treatment as well as the alleviation of acute symptoms. [0027] The methods of the present invention comprise administering the non-steroidal anti-inflammatory drug and ranitidine bismuth citrate either concurrently or non-concurrently. As used herein, concurrent administration means that the agents are given within 24 hours of each other, whereas non-concurrent administration means that the agents are given more than 24 hours apart. When the agents are administered concurrently, it may be preferable to administer the 55 agents within about 1 hour of each other or, more preferably, within about 5 minutes of each other. [0028] For the methods of the present invention, the duration of administration of the agents during either concurrent or non-concurrent dosing will vary according to the specific condition being treated. [0029] The following examples illustrate pharmaceutical compositions for oral use containing both ranitidine bismuth

3 EP 0 550 083 B1 citrate and a suitable non-steroidal anti-inflammatory drug.

Example 1

TABLETS

[0030]

mg/tablet (a) Ranitidine bismuth citrate 400.00 Ibuprofen 400.00 Lactose 200.00 Hydroxypropyl methylcellulose 5.00 Sodium starch glycollate 30.00 Magnesium stearate 10.00 Compression weight 1045.00

[0031] The ranitidine bismuth citrate and ibuprofen are sieved through a 250 urn sieve and blended with the lactose. This mix is granulated with a solution of the hydroxypropyl methylcellulose. The granules are dried, screened and blended with the sodium starch glycollate and the magnesium stearate. The lubricated granules are compressed into tablets using 15.0mm punches.

mg/tablet (b) Ranitidine bismuth citrate 400.00 Indomethacin 50.00 Microcrystalline cellulose 1 1 4.00 Anhydrous sodium carbonate 30.00 Magnesium stearate 6.00 Compression weight 600.00

[0032] The ranitidine bismuth citrate and indomethacin are blended with the microcrystalline cellulose, sodium carbonate and magnesium stearate and compressed using 12.5mm punches. EP 0 550 083 B1

Example 2

CAPSULES

5 [0033]

Capsule (a) Ranitidine bismuth citrate 200.00 Ibuprofen 400.00 Starch 1500** 196.00 Magnesium stearate 4.00 Fill weight 800.00 ** A form of directly compressible starch sup- plied by Colorcon Ltd, Orpington, Kent. 20

[0034] The ranitidine bismuth citrate and ibuprofen are sieved through a 250 urn sieve and blended with the Starch 1500 and magnesium stearate. The resultant mix is filled into size 0 hard gelatin capsules using a suitable filling machine. 25

mg/capsule (b) Ranitidine bismuth citrate 200.00 Indomethacin 50.00 Starch 1500 48.50 Magnesium stearate 1 .50 Fill weight 300.00

[0035] The ranitidine bismuth citrate and indomethacin are sieved through a 250 urn sieve and blended with the Starch 1 500 and magnesium stearate. The resultant mix is filled into size 2 hard gelatin capsules using a suitable filling 40 machine.

Example 3

INHIBITION OF INDOMETHACIN-INDUCED GASTRIC LESIONS IN THE RAT 45 [0036] The ability of ranitidine bismuth citrate to prevent indomethacin-induced gastric antral ulceration was compared with that of ranitidine hydrochloride and De-Nol™. [0037] Female rats, which had been fasted for 24 hours and then re-fed, received ranitidine bismuth citrate (1 to 100mg/kg), ranitidine hydrochloride (10 to 100mg/kg) or De-Nol™ (3 to 100mg/kg) by oral gavage. Ranitidine bismuth so citrate was administered as a suspension and the other test compounds as solutions. Thirty minutes after dosing with the test compound, animals received indomethacin (60mg/kg sc) as an ulcerogenic stimulus and after a further 6 hours the animals were killed and the antral region assessed macroscopically for damage. [0038] Results are presented in the table below. Ranitidine bismuth citrate produced a dose-related inhibition of indomethacin-induced lesions and was relatively potent, an ED50 value of 4.5mg/kg po being calculated. Ranitidine 55 hydrochloride and De-Nol™ were markedly less potent.

5 EP 0 550 083 B1

ED50 Values for Inhibition of Indomethacin - Induced Antral Ulceration Compound Ranitidine Bismuth Citrate Ranitidine Hydrochloride De-Nol™ ED50 mg/kg p.o. 4.5 23.4 43.2 95% confidence limits 0.5- 10.7 16.0-33.0 23.6-93.0

Claims

1 . The use of (i) ranitidine bismuth citrate and (ii) a non-steroidal anti-inflammatory drug in the manufacture of medicaments for simultaneous, separate or sequential use in treating or preventing inflammatory conditions or for analgesia.

2. The use of ranitidine bismuth citrate in the manufacture of medicaments to prevent gastrointestinal damage caused by non-steroidal anti-inflammatory drugs.

3. The use according to Claim 1 in which the compounds (i) and (ii) are presented as separate compositions for said use.

4. A use according to any one of Claims 1 to 3 wherein the non-steroidal anti-inflammatory drug is selected from aspirin, indomethacin, ibuprofen, piroxicam, fenoprofen, ketoprofen, naproxen, mefenamic acid, diflunisal, benorylate, azapropazone, diclofenac, fenbufen, feprazone, fenclofenac, flufenamic acid, flurbiprofen, oxyphenbutazone, phenylbutazone, sulindac and tolmetin.

5. A use according to any preceding claim in which compounds (i) and (ii) are in forms suitable for oral administration.

6. A use according to any preceding claim in which compound (i) is formulated as a tablet.

7. A use according to claim 6 in which compound (i) is suitable for administration at a dosage of 200 - 800mg per unit dose.

8. A product containing compounds (i) and (ii) as defined in Claim 1 as a combined preparation for simultaneous, separate or sequential use in treating or preventing inflammatory conditions or for analgesia.

9. A pharmaceutical composition, for oral use, which comprises both a compound (i) and a compound (ii) as defined in Claim 1 , optionally together with suitable pharmaceutical carriers or excipients.

1 0. A product as claimed in Claim 8 or a composition as claimed in Claim 9 in which the non-steroidal anti-inflammatory drug is as defined in Claim 4.

11. A product as claimed in Claim 8 or Claim 10 in which compounds (i) and (ii) are formulated as defined in any one of Claims 5 to 7.

12. A composition according to Claim 9 or Claim 10, in association with instructions for the use of both compound (i) and compound (ii) in treating or preventing inflammatory conditions or for analgesia.

13. A twin-container pack for use in treating or preventing inflammatory conditions or for analgesia, one of the containers containing compound (i) and the other containng compound (ii) as defined in any one of claims 1 , 4, 5, 6 or 7.

14. A pack according to Claim 13, in association with instructions for the use of both compound (i) and compound (ii) in treating or preventing inflammatory conditions or for analgesia.

1 5. A method for the preparation of a composition according to Claim 9 or Claim 1 0 which comprises admixing compounds (i) and (ii) optionally together with suitable pharmaceutical carriers or excipients. EP 0 550 083 B1

Patentanspruche

1 . Verwendung von (i) Ranitidin-Bismutcitrat und (ii) einem nicht-steroidalen entzundungshemmenden Arzneistoff zur Herstellung von Medikamenten zur gleichzeitigen, separaten oder aufeinanderfolgenden Verwendung bei der Behandlung oder Vorbeugung entziindlicher Zustande oder zur Analgesie.

2. Verwendung von Ranitidin-Bismutcitrat zur Herstellung von Medikamenten zur Vorbeugung gastrointestinaler Schadigung, verursacht durch nicht-steroidale entziindungshemmende Arzneistoffe.

3. Verwendung gemaB Arispruch 1 , worin die Verbindungen (i) und (ii) als separate Zusammensetzungen fur die Ver- wendung angeboten werden.

4. Verwendung gemaB einem der Anspriiche 1 bis 3, worin der nicht-steroidale entziindungshemmende Arzneistoff ausgewahlt ist aus Aspirin, Indomethacin, Ibuprofen, Piroxicam, Fenopro£en, Ketoprofen, Naproxen, Mefenamin- saure, Diflunisal, Benorylat, Azapropazon, Diclofenac, Fenbufen, Feprazon, Fenclofenac, Flufenaminsaure, Flurbi- profen, Oxyphenbutazon, Phenylbutazon, Sulindac und Tolmetin.

5. Verwendung gemaB einem der vorhergehenden Anspriiche, worin die Verbindungen (i) und (ii) in zur oralen Ver- abreichung geeigneten Formen sind.

6. Verwendung gemaB einem der vorhergehenden Anspriiche, worin die Verbindung (i) als Tablette formuliert ist.

7. Verwendung gemaB Anspruch 6, worin die Verbindung (i) zur Verabreichung mit einer Dosierung von 200 bis 800 mg je Einheitsdosis geeignet ist.

8. Produkt, enthaltend die Verbindungen (i) und (ii), wie in Anspruch 1 definiert, als eine kombinierte Zubereitung zur gleichzeitigen, separaten oder aufeinanderfolgenden Verwendung zur Behandlung oder Vorbeugung entziindlicher Zustande oder zur Analgesie.

9. Pharmazeutische Zusammensetzung zur oralen Verwendung, die sowohl eine Verbindung (i) als auch eine Verbin- dung (ii) umfaBt, wie in Anspruch 1 definiert, gegebenenfalls zusammen mit geeigneten pharmazeutischen Tragern oder Arzneimittelzusatzstoffen.

10. Produkt gemaB Anspruch 8 oder Zusammensetzung gemaB Anspruch 9, worin der nicht-steroidale entziindungshemmende Arzneistoff wie in Anspruch 4 definiert ist.

11. Produkt gemaB Anspruch 8 oder Anspruch 10, worin die Verbindungen (i) und (ii) wie in einem der Anspriiche 5 bis 7 definiert formuliert sind.

12. Zusammensetzung gemaB Anspruch 9 oder 10 in Verbindung mit Anweisungen zur Verwendung sowohl der Ver- bindung (i) als auch der Verbindung (ii) zur Behandlung oder Vorbeugung entziindlicher Zustande oder zur Anal- gesie.

13. Paar-Behalterpackung zur Verwendung zur Behandlung oder Vorbeugung entziindlicher Zustande oder zur Anal- gesie, wobei einer der Behalter die Verbindung (i) enthalt und der andere Behalter die Verbindung (ii) enthalt, wie in einem der Anspriiche 1, 4, 5, 6 oder 7 definiert.

14. Packung gemaB Anspruch 13 in Verbindung mit Anweisungen zur Verwendung sowohl der Verbindung (i) als auch der Verbindung (ii) zur Behandlung oder Vorbeugung entziindlicher Zustande oder zur Analgesie.

15. Verfahren zur Herstellung einer Zusammensetzung gemaB Anspruch 9 oder 10, welches das Vermischen der Ver- bindungen (i) und (ii) umfaBt, gegebenenfalls zusammen mit geeigneten pharmazeutischen Tragern oder Arznei- mittelzusatzstoffen.

Revendications

1 . Utilisation de (i) citrate de ranitidine bismuth et (ii) d'un medicament anti-inf lammatoire non sterolde dans la fabrication de medicaments pour une utilisation simultanee, separee ou sequentielle dans le traitement ou la prevention EP 0 550 083 B1

des etats inflammatoires ou pour I'analgesie.

2. Utilisation de citrate de ranitidine bismuth dans la fabrication de medicaments pour empecher les alterations gas- trointestinales provoquees par les medicaments anti-inflammatoires non steroi'des. 5 3. Utilisation suivant la revendication 1 , dans laquelle les composes (i) et (ii) sont presentes sous la forme de compositions separees pour ladite utilisation.

4. Utilisation suivant I'une quelconque des revendications 1 a 3, dans laquelle le medicament anti-inflammatoire non 10 steroi'de est choisi parmi I'aspirine, I'indomethacine, I'ibuprofen, le piroxicam, le fenoprofen, le cetroprofen, le naproxene, I'acide mefenamique, le diflunisal, le benorylate, I'azapropazone, le diclofenac, le fenbufen, la feprazone, le fenclofenac, I'acide flufenamique, le flurbiprofen, I'oxyphenbutazone, la phenylbutazone, le sulindac et la tolmetine.

15 5. Utilisation suivant I'une quelconque des revendications precedentes, dans laquelle les composes (i) et (ii) sont sous des formes destinees a I'administration orale.

6. Utilisation suivant I'une quelconque des revendications precedentes, dans laquelle le compose (i) est formule sous la forme d'un comprime. 20 7. Utilisation suivant la revendication 6, dans laquelle le compose (i) est destine a I'administration a un dosage de 200-800 mg par dose unitaire.

8. Produit contenant des composes (i) et (ii) tels que definis a la revendication 1 sous la forme d'une preparation com- 25 binee pour une utilisation simultanee, separee ou sequentielle dans le traitement ou la prevention des etats inflammatoires ou pour I'analgesie.

9. Composition pharmaceutique, pour I'utilisation orale, qui comprend a la fois un compose (i) et un compose (ii) tels que definis a la revendication 1 , eventuellement en meme temps qu'avec des supports ou excipients pharmaceu- 30 tiques appropries.

10. Produit suivant la revendication 8 ou composition suivant la revendication 9, dans lequel le medicament anti-inflammatoire non steroi'de est tel que defini a la revendication 4.

35 11. Produit suivant I'une ou I'autre des revendications 8 et 1 0, dans lequel les composes (i) et (ii) sont formules tels que definis dans I'une quelconque des revendications 5 a 7.

12. Composition suivant I'une ou I'autre des revendications 9 et 10, en association a des instructions pour I'utilisation a la fois de compose (i) et de compose (ii) dans le traitement ou la prevention des etats inflammatoires ou pour 40 I'analgesie.

13. Emballage a deux recipients utilisable dans le traitement ou la prevention des etats inflammatoires ou pour I'analgesie, I'un des recipients contenant le compose (i) et I'autre contenant le compose (ii) tels que definis dans I'une quelconque des revendications 1 , 4, 5, 6 et 7. 45 14. Emballage suivant la revendication 13, en association a des instructions pour I'utilisation a la fois de compose (i) et de compose (ii) dans le traitement ou la prevention des etats inflammatoires ou pour I'analgesie.

15. Procede de preparation d'une composition suivant I'une ou I'autre des revendications 9 et 10, qui comprend le so melange des composes (i) et (ii) eventuellement en meme temps qu'avec des supports ou excipients pharmaceu- tiques appropries.