ANTIBACTERIAL SYNERGISTIC COMPOSITION COMPRISING RIFABUTIN

Abstract: Pharmaceutical anti-bacterial synergistic compositions against Helicobacter pylori, containing rifabutin and a proton pump inhibitor or a bismuth preparation.

Description: ANTIBACTERIAL SYNERGISTIC COMPOSITION COMPRISING RIFABUTIN The present invention relates to anti-bacterial pharmaceutical compositions against Helicobacter pylori and to their preparation. Helicobacter pylori plays a main role in the pathogenesis of gastritis and peptic ulcer. Known treatments include the use of amoxicilin or other antibacterial agents in dual or triple combination with other drugs, such as bismuth preparationε, metronidazole, tinidazole or with proton pump inhibitors, e.g. omeprazole. Such combinations have a relatively short duration of action and require high doses and repeated administrations (3-4 times per day) owing to the pharmacokinetics or the low antibacterial activity of the antibiotic and its limited stability in the stomach. We have discovered that a very effective treatment can be achieved by administration of a synergistic composition. The present invention provides a pharmaceutical composition suitable for use in the treatment of a Helicobacter pylori infection, which compoεition compriseε: (I) rifabutin; and (II) a proton pump inhibitor or a bismuth preparation in a quantity producing a synergistic activity against Helicobacter pylori . Rifabu in is the generic name of a chemical compound 4- deoxo-3,4- [2-spiro(N-isobutyl-4-piperidyl) -2,5-dihydro-lH- imidazo] -rifamycin S. Depending on the system used to name a chemical compound, it may also be identified as 6,9-dihydro- 5,17, 19,21-tetrahydroxy-8,9- [2-spiro- (N-isobutyl-4- piperidyl) -2,5 -dihydro-IH-imidazo] -23-methoxy - 2,4, 12, 16,18,20,22-heptamethyl-6-oxo-2, 7- (epoxypentadeca- [1,11,13] -trienimino) naphthol [2, 1] -b furan-1,11- (2H) -dione- 21-acetate; or (9S,12E, 14S,15R,16S, 17R, 18R, 19R,20S, 21S, 22E,24Z) -6, 16,18,20-tetrahydroxy-l' -isobutyl-14-methyloxy- 7,9,15,17,19,21,25-heptamethyl-spiro[9,4- (epoxypentadeca[1,11,13] trienimino-2H- furo[2' ,3' ,7,8]naphth[l,2-d] imidazole-2,4' -piperidine- 5,10,26, (3H,9H) -trione-16-acetate. Rifabutin has the structural formula Molecular formula : C 46 H S2 N 4 0 11 Molecular Weight : 847 . 12 The preparation of rifabutin is described in U.S. Patent 4,219,478 issued on August 26, 1980. Rifabutin is a red violet powder soluble in chloroform and methanol, and very slighly soluble in water; it has a melting point of 148°C-156° (with decomposition) . A proton pump inhibitor is typically omeprazole, lansoprazole, leminoprazole, pantoprazole or robeprazole; a bismuth preparation is typically bismuth subsalicyclate or bismuth subcitrate sol (dried) . The pharmaceutical composition of the invention may further comprise a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition according to the present invention shows an excellent antibacterial activity, good oral bioavailability and stability at low pH, and it is therefore suited for the treatment of Helicobater pylori infections. It was found that the activity of the composition of the invention is greater than the sum of the individual components. A noticeable antibacterial synergistic effect is evident. A pharmaceutical composition according to the invention possesses a good activity against Helicobacter pylori at small doses, which are insufficient when the components are used individually. Consequently, the combination of the two components according to the invention is more effective in the treatment of diseases caused by Helicobacter pylori , because it possesses a better therapeutic value than the individual antibiotic. In addition, antibacterials should not be used as monotheraphy to avoid the emergence of resistant strains. This is particularly important for long term therapy. The invention further provides a process for preparing the above mentioned composition, which process comprises mixing: (I) rifabutin; (II) a proton pump inhibitor or a bismuth preparation in a quantity producing a synergistic activity against Heli coba cter pyl ori • and (III) optionally, a pharmaceutically acceptable carrier or diluent . Suitable carriers or diluents are those conventionally used in pharmaceutical preparations . For example for tablets or capsules the carrier or diluent commonly comprises starches and binders and/or lubricants. The present invention also provides a pharmaceutical composition aε defined above for use in the treatment of a disease caused by Helicobacter pylori. The two components may be mixed immediately prior to administration. Then they be presented in a form suitable for combined administration in the treatment of disorders caused by Helicobacter pylori . The present invention therefore also provides products comprising: (I) rifabutin; and (II) a proton pump inhibitor or a bismuth preparation in a quantity producing a synergistic activity against Helicobacter pylori ; as a combined preparation for simultaneous, separate or sequential use in the treatment of a HelicoJbacter pylori infection. The daily doses of individual components in compositions according to the invention are lower as compared to the active doses of the individual components, when used without the other component. The weight ratio of rifabutin to proton pump inhibitor or bismuth preparation is generally from 1:100 to 100:1. Where the composition of the invention comprises rifabutin and a proton pump inhibitor, the weight ratio of rifabutin:proton pump inhibitor is typically from 25:1 to 5:1. Where the composition comprises rifabutin and a bismuth preparation, the weight ratio of rifabutin:bismuth preparation is typically from 1:10 to 10:1. Typically, for adults (70 kg) the daily doseε of rifabutin ranges from 100 to 1000 mg, preferably from 200 to 500 mg, more preferably 300 mg. The daily dose of the proton pump inhibitor is from 1 mg to 1000 mg, preferably from 10 to 100 mg and the daily dose for the bismuth preparation is from 50 mg to 5000 mg, preferably from about 50 mg to about 1000 mg. The combination of rifabutin and a proton pump inhibitor or bismuth preparation may be used in the treatment of gastrointenstinal disorders in a living being particularly a human. In vitro bactericidal activity Tests were carried out on several strains of Helicobacter pylori according to CZI N S. et al . Antimicrobial Agentε Chemoter 3J, 328-329, 1986 and Clinical Microbiology Procedure Handbook, Isenberg H.D. ed. ASM 1992 (modified) . In the following tables is reported the activity of rifabutin, omeprazole and bismuth subcitrate sol (BSM) as single drug and in combination, on selected H. pylori strains. The first example concerns the activity of rifabutin and BSM , the second one concerns the activity of rifabutin and omeprazole. As shown in the tables, the inhibiting drug concentrations are lower when drugs are combined together. Example 1 Combination of rifabutin and bismuth subcitrate sol. Helibacter pylori strain 46. rifabutin (μg/ml) BSM (μg/ml) effect 0.0037 _ MIC* — 4 MIC 0.0009 0.5 SYN* 0.00045 1 SYN Heli cobacter pylori strain 34 rifabutin (μg/ml) BSM (μg/ml) effect 0.0075 — MIC — 4 MIC 0.0018 0.5 SYN 0.0009 1 SYN Helicobacter pylori strain 13 rifabutin (μg/ml) BSM (μg/ml) effect 0.0075 — MIC 2 MIC " 0.0018 0.5 SYN * MIC: minimal inhibitory concentration ** SYN: inhibited at subMIC concentrations Example 2 Combination of rifabutin and omeprazole Helicobacter pylori strain 35 rifabutin (μg/ml) omeprazole (μg/ml) effect 0.0037 — MIC — 64 MIC 0.0009 4 SYN 0.00045 16 SYN 0.00022 16 SYN Helicobacter pylori strain 50 rifabutin (μg/ml) omeprazole (μg/ml) effect 0.0075 — MIC ~" 32 MIC 0.0018 4 SYN 0.0018 2 SYN rifabutin (μg/ml) omeprazole (μg/ml) effect 0.0009 8 SYN Helicobacter pylori strain 43 rifabutin (μg/ml) omeprazole (μg/ml) effect 0.0075 ~ MIC — 64 MIC 0.0018 2 SYN 0.0009 8 SYN 0.00045 16 SYN 0.00022 16 SYN

Claims: CLAIMS 1. A pharmaceutical composition suitable for use in the treatment of a Helicobacter pylori infection, which composition comprises: (I) rifabutin; and (II) a proton pump inhibitor or a bismuth preparation in a quantity producing a synergistic activity against Heli coba cter pyl ori . 2. A pharmaceutical composition according to claim 1 further comprising a pharmaceutically acceptable carrier or diluent . 3. A pharmaceutical compoεition according to claim 1 or 2 , wherein the proton pump inhibitor is selected from omeprazole, lansoprazole, leminoprazole, pantoprazole or robeprazole; or the bismuth preparation is selected from bismuth subsalicyclate or bismuth subcitrate sol (dried) . 4. A pharmaceutical composition according to claim 3 wherein the proton pump inhibitor iε omeprazole or the bismuth preparation is bismuth subcitrate sol (dried) . 5. A process for preparing a pharmaceutical compoεition according to any one of claimε 1 to 4, which proceεε compriεeε mixing: (I) rifabutin; (II) a proton pump inhibitor or a bismuth preparation in a quantity producing a synergiεtic activity against Helicobacter pylori ; and (III) optionally, a pharmaceutically acceptable carrier or diluent. 6. A pharmaceutical composition as defined in any one of claims 1 to 4 for use in the treatment of a Helicobacter pylori infection. 7. A pharmaceutical composition according to claim 6 for use in the treatment of gastritis or peptic ulcers. 8. Use, in the manufacture of a medicament for use in the treatment of a Helicobacter pylori infection, of: (I) rifabutin; and (II) a proton pump inhibitor or a bismuth preparation; component (II) being present in an amount producing a synergiεtic activity againεt Helicobacter pylori . 9. The uεe according to claim 8 wherein the medicament iε for use in the treatment of gastritis or peptic ulcers. 10. Products containing: (I) rifabutin; and (II) a proton pump inhibitor or a bismuth preparation in a quantity producing a synergistic activity against Heli coba cter pyl ori ; aε a combined preparation for simultaneouε, separate or sequential use in the treatment of a Helicobacter pylori infection.

Inventors: CASTELLANI PAOLA, JABES DANIELA, ROSSI ROSARIA, CASTELLANI, PAOLA, JABES, DANIELA, ROSSI, ROSARIA
Applicants: PHARMACIA & UPJOHN SPA, PHARMACIA & UPJOHN S.P.A.
Application year: 1996
Main classification: A61K33
IPC codes: A61K31, A61K33, A61K45, A61P1, A61P31, A61P43