A Double Capsule for the Administration of Active Principles in Multiple Therapies

Europäisches Patentamt *EP001037614B1* (19) European Patent Office

Office européen des brevets (11) EP 1 037 614 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.7: A61K 9/48 of the grant of the patent: 26.11.2003 Bulletin 2003/48 (86) International application number: PCT/EP98/08167 (21) Application number: 98966618.5 (87) International publication number: (22) Date of filing: 14.12.1998 WO 99/030693 (24.06.1999 Gazette 1999/25)

(54) A DOUBLE CAPSULE FOR THE ADMINISTRATION OF ACTIVE PRINCIPLES IN MULTIPLE THERAPIES DOPPELKAPSEL ZUR VERABREICHUNG VON ARZNEIMITTELN FÜR VIELFACHE THERAPIEN DOUBLE CAPSULE POUR ADMINISTRER DES PRINCIPES ACTIFS SELON UNE POLYTHERAPIE

(84) Designated Contracting States: (74) Representative: Riccardi, Sergio et al AT BE CH DE DK ES FI FR GB GR IE IT LI NL PT Riccardi & Co. SE Via Macedonio Melloni, 32 20129 Milano (IT) (30) Priority: 17.12.1997 IT MI972788 (56) References cited: (43) Date of publication of application: WO-A-89/03219 DE-A- 2 729 068 27.09.2000 Bulletin 2000/39 FR-A- 1 454 013 FR-A- 2 524 311 GB-A- 2 103 564 US-A- 5 501 857 (73) Proprietor: Axcan Pharma Inc. Québec J3H 4XB (CA) • DATABASE WPI Week 8546 Derwent Publications Ltd., London, GB; AN 85-285478 (72) Inventor: SANSO’, Giovanni [46] XP002108270 & JP 60 193917 A (SHIIRA) 2 I-20125 Milano (IT) October 1985 (1985-10-02)

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 paid. (Art. 99(1) European Patent Convention). EP 1 037 614 B1

Printed by Jouve, 75001 PARIS (FR) EP 1 037 614 B1

Description

FIELD OF THE INVENTION

5 [0001] This invention concerns a pharmaceutical dosage form consisting of a double capsule for the administration of active principles in multiple therapies. The double capsule consists in a capsule placed inside another one.

BACKGROUND OF THE INVENTION

10 [0002] Therapies for the administration of more than one active principle at a time or at short intervals of time are already well known. The most common pharmaceutical dosage form consists of tablets for the various active principles with coatings allowing the differentiated release of the chemical compounds. [0003] Among said therapies, the most common ones are those concerning affections of the digestive system caused by the presence of the microorganisms Helicobacter Pylori, such as gastritis and gastroduodenal ulcers, which in due 15 time can lead to tumoral forms. As known, Helicobacter pylori is a modem appellation of Campilobacter pylori. [0004] Patent US-5 196 205 (corresponding to patent application WO 89/03219) describes a method for the treatment of those pathological agents, consisting of the administration of a compound of bismuth, an antibiotic belonging to the group of penicillins and tetracycline and a second antibiotic such as metronidazole. The relevant therapy consists of the administration of three tablets (one for each active principle) several times a day. 20 [0005] Consequently, this therapy results in being extremely complicated.The therapy described by patent US-5 196 205 has been further modified by the addition of a fourth active principle, omeprazole which reduces the gastric se- cretion by inhibiting irreversibly enzyme H +/K + ATP. Omeprazole must be administered at a different time from the above-mentioned active principles, which are determined by the physician according to the seriousness of the disease, the age of the patient and other factors which could affect its efficacy. 25 [0006] Therefore, it can certainly be stated that therapies requiring a complicated posology such as multiple therapies, are subject to mistakes that can compromise the outcome of the therapy itself. [0007] Other patents and patent applications describing single or multiple therapies for eradication of Helicobacter pylori are known such as US-5 472 695, US-5 560 912, US-5 582 837, WO 92/11848 and WO 96/02237. None of these previous patents and patent applications overcome the problem of the interaction between active principles by using 30 a way as simple and ingenious than the one proposed by the present invention. [0008] US-5 310 555 and US-5 501 857 teach to use double capsules for the delivery of nutritional supplements to animals. [0009] Patent JP 60-193917 teaches a soft capsule containing several smaller soft capsules. [0010] Patent DE 2,729,068 teaches a standard hard gelatine capsule having an additional hard gelatine capsule 35 inside, with the same or different dissolution characteristics. [0011] Patent FR 2,524,311 teaches a double capsule and a triple capsule. [0012] Patent FR 1,454,013 teaches a double capsule where the inner capsule has retarded released characteristics. [0013] Patent application GB 2,103,564 teaches a capsule assembly for oral administration of a prophylactic drug characterized by a frangible outer capsule and an inner edible capsule with an air-space therebetween allowing the 40 user to bite through the outer capsule and swallow the inner capsule intact. [0014] Among multiple therapies for eradication of Helicobacter pylon, the following combinations of active principles have been tested on humans, and published:

1. Amoxicilline, metronidazole and furazolidone; 45 2. Bi Subsalicylate, lansoprazole and clarithromycine; 3. Bi Subsalicylate, roxithromycine, metronidazole and ranitidine; 4. Clarithromycine, colloidal bismuth subcitrate and furazoline; 5. Colloidal bismuth subcitrate, amoxicilline and metronidazole; 6. Ebrotidine, amoxicilline and metronidazole; 50 7. Lansoprazole, amoxicilline and azithromycine; B. Lansoprazole, amoxicilline and clarithromycine; 9. Lansoprazole, amoxicilline and rebamipide; 10. Lansoprazole, clarithromycine and furazoline; 11. Lansoprazole, azithromycine and metronidazole; 55 12. Lansoprazole, miconazole and amoxicilline; 13. Lansoprazole and norfloxacine; 14. Metronidazole and dirithromycine; 15. Omeprazole, amoxicilline and azithromycine;

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16. Omeprazole, amoxicilline, clarithromycine and metronidazole; 17. Omeprazole, amoxicilline, metronidazole and bismuth; 18. Omeprazole, amoxicilline and rebamipide; 19. Omeprazole, amoxicilline and tinidazole; 5 20. Omeprazole and amoxicilline; 21. Omeprazole and azithromycine; 22. Omeprazole, bismuth and ciprofloxacine; 23. Omeprazole, bismuth and clarithromycine; 24. Omeprazole, clarithromycine and tinidazole; 10 25. Omeprazole and dirithromycine; 26. Omeprazole, lansoprazole and rebamipide; 27. Omeprazole, metronidazole and amoxicilline; 28. Omeprazole, metronidazole and azithromycine; 29. Omeprazole, metronidazole and clarithromycine; 15 30. Omeprazole and norfloxacine; 31. Omeprazole, sucralfate, metronidazole and tetracycline; 32. Omeprazole, clarithromycine and tinidazole; 33. Pantoprazole, clarithromycine and amoxicilline; 34. Pantoprazole and clarithromycine; 20 35. Ranitidine bismuth citrate, clarithromycine and tetracycline; 36. Ranitidine bismuth citrate and clarithromycine; 37. Ranitidine bismuth citrate, metronidazole and clarithromycine; 38. Ranitidine bismuth citrate and cefuroxime; 39. Rifaximin and erythromycine; 25 40. Omeprazole, bismuth, tretracycline and metronidazole; 41. Omeprazole, bismuth subcitrate, tretracycline and metronidazole; 42. Bismuth subcitrate, tretracycline and metronidazole.

SUMMARY OF THE INVENTION 30 [0015] An object of the present invention is the use of a pharmaceutical dosage form comprising two capsules one placed inside the other for the administration of active principles in multiple therapies, in the therapy against the microorganisms Helicobacter pylori. [0016] In accordance with the present invention, that object is achieved with the use of a soluble salt of bismuth, a 35 first antibiotic and a second antibiotic for the preparation of a pharmaceutical dosage form comprising two capsules one placed inside the other for a triple therapy against the microorganisms Helicobacter pylori, wherein the external capsule comprises the soluble salt of bismuth and the first antibiotic, and the internal capsule comprises the second antibiotic. [0017] The object of the present invention is also achieved with the use of a soluble salt of bismuth, a first antibiotic, 40 + + a second antibiotic, and a K /Na ATPase inhibitor or anti-H2, for the preparation of a pharmaceutical dosage form comprising two capsules one placed inside the other for a quadruple therapy against the microorganisms Helicobacter pylori, wherein the external capsule comprises the soluble salt of bismuth and the first antibiotic, and the internal + + capsule comprises the second antibiotic and the K /Na ATPase inhibitor or anti-H2. [0018] The object of the present invention is further achieved with the use of a soluble salt of bismuth, a first antibiotic, 45 + + a second antibiotic, and a K /Na ATPase inhibitor or anti-H2, for the preparation of a pharmaceutical dosage form comprising two capsules one placed inside the other for a quadruple therapy against the microorganisms Heticobacter pylori, wherein the external capsule comprises the soluble salt of bismuth, the first antibiotic, and the K+/Na+ATPase inhibitor or anti-H2; and the internal capsule comprises the second antibiotic. [0019] The object of the present invention is also further achieved with the use of a soluble salt of bismuth, a first 50 + + antibiotic, a second antibiotic, and a K /Na ATPase inhibitor or anti-H2, for the preparation of a first pharmaceutical dosage form and a second pharmaceutical dosage form, the first pharmaceutical dosage form comprising two capsules one placed inside the other for a quadruple therapy against the microorganisms Helicobacter pylori, wherein the external capsule comprises the soluble salt of bismuth and the first antibiotic, and the internal capsule comprises the + + second antibiotic; the second pharmaceutical dosage form comprising a K /Na ATPase inhibitor or anti-H2. 55 [0020] An advantage of the pharmaceutical dosage form of the invention is to be used in multiple therapies, which allows a simple and safe posology. [0021] One of the major advantages of the pharmaceutical dosage form of the present invention is that it overcomes problems related with the interaction of the active principles by means of a physical barrier.

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[0022] The characteristics and advantages of the invention will be better understood after reading the following non restrictive description.

DETAILED DESCRIPTION OF THE INVENTION 5 Double Capsule

[0023] The present invention provides a pharmaceutical dosage form for the administration of active principles in multiple therapies featured by the presence of two capsules one placed inside the other and including respectively one 10 or more active principles. This pharmaceutical dosage form is called double capsule and the two capsules are respectively called internal capsule and external capsule. [0024] Both internal and external capsules are preferably made of hard gelatin. If desired, the internal capsule may be made of gelatin treated so as to make it gastroresistant or slow release. [0025] The capsules already on the market are identified by numbers or letters according to their size (length, diam- 15 eter and thickness), as indicated in Table 1 (CAPSUGEL MULTISTATE FILE, 2° Ed.)

TABLE 1: SIZE OF THE JELLY CAPSULES

20 Type of capsule Format of Capsule Total length of the Diameter of the Thickness of the wall capsule (nm +/- 0,3 external body (nm) (nm) nm) CONI-SNAP SNAP-FIT 000 26,14 9,55 - 25 00 23,3 8,18 0,231 0+ 23,8 7,36 0,224 0 21,2 7,33 0,212 30 1 19,0 6,63 0,216 2 17, 5 6,07 0,211 3 15,6 5,57 0,203

35 4 13,9 5,05 0,198 5 11,0 4,64 0,173 CONI-SNAP SUPRO A 18,00 8,18 0,231 40 B 14,20 8,18 0,231 C 13,50 7,33 0,224 D 12,60 6,63 0,216

45 E 11, 60 6,07 0,211 LICAPS 0 21,70 7,33 0,224 1 19,70 6,63 0,216 50 2 17,90 6,07 0,211

[0026] Accordingly to the invention, the double capsule has an internal capsule smaller than the external one, since according to this principle all the combinations of the Table 1 are possible except for the combination of external capsule 55 of format 0+ with internal capsule of format A or 0 of any types of capsules. Such combinations are chosen to facilitate the use for the patient and according to the quantity of substance to be introduced into the two capsules. As a matter of fact, the volume between the two capsules and the volume of the internal capsule should be suitable to allow the insertion of the quantities foreseen by the therapeutic dosage. The internal capsule should preferably be a 2 or 3 format,

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while the external capsule should be respectively a 0 + or 1 format. In accordance with a preferred embodiment of the invention, an internal capsule of format 3 is inserted in an external capsule of format 0+. [0027] Said pharmaceutical form is realised by means of an intermittent or continuous motion capsule filling machine equipped with dosators to feed empty capsules with powders, tablets, pellets or filled capsules. Exemples of said 5 capsule filling machines are the Zanazi 40 of the company IMA in Bologna and the model MG Futura level 02 of the company MG2 in Bologna. As an alternative, the new double capsule can be realised by means of a manual machine type Zuma 150 or 300 and type Parke-Davis/Capsugel. [0028] Besides, it must be taken into consideration that even the movement of the capsules caused by the capsule filling machines, either automatic or manual, and the simple act of inserting the internal capsule are enough to form 10 between the two capsules a layer of powder which keeps them separated.

Triple Therapy

[0029] This pharmaceutical dosage form is particularly suitable to be used in a triple therapy for the eradication of 15 the pathologic agents Helicobacter pylori (also known as Campilobacter pylori), consisting of the administration of three active principles which are a soluble salt of bismuth, a first antibiotic and a second antibiotic. Each internal and external capsule contains one or more active principles. [0030] The bismuth salt is preferably selected from the group consisting of bismuth subcitrate, bismuth aluminate, bismuth carbonate, bismuth citrate, colloidal bismuth subnitrate, bismuth germanate, bismuth germanium oxide, bis- 20 muth nitrate, bismuth oxide, bismuth oxychloride, bismuth phosphate, bismuth salicylate, bismuth subcarbonate, bismuth subnitrate, bismuth subsalicylate, bismuth tribromophenate, bismuth trioxyde, bismuth vanadate, and bismuth vanadium tetraoxide. Bismuth salts may be used in a complex form. For example, bismuth biscalcitrate is a complex form of bismuth subcitrate. [0031] The first antibiotic is selected from the group consisting of the nitroimidazoles. The nitroimidazoles are pref- 25 erably selected from the group consisting of metronidazole, apronidazole, azomycine, benzonidazole, carnidazole, demetridazole, etanidazole, flunidazole, misonidazole, nimorazole, ornidazole, panidazole, ronidazole, and tinidazole. Preferably, the first antibiotic is metronidazole. [0032] The second antibiotic is selected from the group consisting of the macrolides and the compounds of the family of tetracyclines. The macrolides are preferably selected from the group consisting of azithromycine, clarithromycine 30 and erythromycine. The compounds of the family of tetracyclines are preferably selected from group consisting of tetracycline, chlortetracycline, doxycycline, glycocycline, guamecycline, lymecycline, methacycline and sancycline. As known in the field, tetracycline correspond to tetracycline hydrochloride. [0033] In accordance with a preferred embodiment of the invention, the external capsule contains bismuth subcitrate and metronidazole, and the internal capsule contains tetracycline. 35 [0034] When the external capsule, preferably containing bismuth subcitrate in a complex form and metronidazole, dissolves, it allows the complex bismuth to form a curative gel at the gastric level. After a certain period of time, according to the therapeutic indications, the internal capsule dissolves and releases tetracycline, which also acts at the gastric level. [0035] The triple therapy as described above, usually consists of the administration of, two identical double capsules 40 several times a day, with no particular care as to the sequence of consumption and of the manipulation of the said double capsules. Ingestion of capsules is preferably done before meals and before a snack at bedtime.

Quadruple Therapy

45 [0036] An further way of realisation of the invention consists of the administration of a fourth active principle such as + + aK/Na ATP-ase inhibitor or a anti-H2, together with the double capsule described above. In this case, the double capsule as foreseen by the invention will be destined to use in a quadruple therapy for the affections of the digestive + + system. K /Na ATP-ase inhibitor or anti-H2 is selected from group consisting of BY841; cimetidine; ebrotidine; etintidine; famotidine; flunarizine; ICI-162,846; lansoprazole; metiamide; mifentidine; niperotidine; nizatidine; omeprazole; 50 oxmetidine; pantoprazole; rabeprazole; ramixotidine; ranitidine; ritanserin; roxatidine acetate hydrochloride; ZKF- 93479; SKF-94482; sufotidine; tiotidine; TY-11345; Wy-45,727; and zaltidine. Preferably, omeprazole is used as K+/ Na+ATP-ase inhibitor. + + [0037] The K /Na ATP-ase inhibitor or anti-H2 may be introduced in the external capsule, in the internal capsule or + + in a separate pharmaceutical form. Since it is a requirement that K /Na ATP-ase inhibitor or anti-H2 reach the small 55 intestine, it may be delivered embedded in the gastroresistant coated pellets, multiple small tablets or single tablet. + + Considering that K /Na ATP-ase inhibitor or anti-H2 must be administered according to criteria other than those fore- + + seen for triple therapy, double capsules without K /Na ATP-ase inhibitor or anti-H2 may be alternatively administered + + to double capsules containing K /Na ATP-ase inhibitors or anti-H2, following a therapeutic scheme prescribed by the

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physician, depending on the seriousness of the disease and the condition of the patient. [0038] In accordance with another preferred embodiment of the invention, the external capsule contains bismuth subcitrate and metronidazole, and the internal capsule contains tetracycline and omeprazole.

5 Characteristics of the Invention

[0039] Preferably, both capsules contain excipients. These excipients are selected from the group consisting of magnesium stearate; talc; cellulose and its derivatives; silica and its derivatives; sugars; polyethylene-glycols; wax; mono-, di- and tri-glycerides of hydrogenated fat acids; alcohols and acids at high molecular weight; and relevant mixtures 10 thereof. [0040] Both internal and external capsule containing the active principles as described above are stable at a temperature comprised between 5 and 50°C and at a humidity comprised between 35 and 65%.

Stability Trials 15 [0041] Two products have been analysed, respectively a single capsule containing coated tetracycline hydrochloride, bismuth biscalcitrate, metronidazole and a double capsule as foreseen by the invention containing, in the internal capsule, non-coated tetracycline and, in the external capsule, bismuth biscalcitrate and metronidazole. [0042] A sample for each product to be analysed has been incubated at room temperature, 37°C and 44°C for a 20 period of 1 month. At the time zero and at the end of the incubation period (1 month), an analysis of the macroscopic characteristics of the products under analysis has been performed.

TIME ZERO Single capsule 25

External capsule white Content mixture of white powder (bismuth biscalcitrate) and yellow powder (tetracycline hydrochloride) 30 Double capsule

External capsule white Internal capsule brown 35 Content of the External capsule white powder (bismuth biscalcitrate, metronidazole) Content of the internal capsule yellow powder (tetracycline hydrochloride)

40 TABLE 2 AFTER 1 MONTH SINGLE CAPSULE ROOM TEMPERATURE 37°C 44°C External capsule Slightly yellowish White white 45 Content Mixture of white and Mixture of white and beige Mixture of white and beige yellow powder powder powder DOUBLE CAPSULE ROOM TEMPERATURE 37° C 44° C External capsule white white white 50 Internal capsule brown Brown brown Content of the External white powder white powder white powder capsule Content of the Internal yellow powder yellow powder yellow powder 55 capsule

[0043] As it can be observed in Table 2, at the temperatures 37°C and 44°C, the content of the single coated capsule

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forms a beige-coloured product while the double capsule as foreseen by the invention does not form any degradation product. This effect is encouraged by the physical barrier represented by the coating of the internal capsule which does not allow the overflow of tetracycline.

5 Dissolution Trials

[0044] Five double capsules have been taken from one of the batches under examination, all five of them featured by the same characteristics:

10 External capsule of format 0+ containing bismuth biscalcitrate 215 mg metronidazole 125 mg

15 Internal capsule of format 3 containing tetracycline hydrochloride 125 mg

20 [0045] The capsules have been analysed separately and under identical conditions according to the criteria of the Pharmacopoeia of the United States USP 23 Ed. for the dissolution trial. [0046] The purpose of the trial is to check if the exact quantity of tetracycline hydrochloride contained in the internal capsules dissolves (as indicated in the above Pharmacopoeia, which complies with all the other Pharmacopoeias). In this case, the presence of the external capsule and of its components should not affect the quantity of material under 25 dissolution nor the time taken to release the active principle tetracycline hydrochloride. [0047] The quantity of material to be dissolved within 60 minutes must not be inferior to 80% of the quantity present in the capsule according to said limit, foreseen by the Pharmacopoeia. [0048] As for the double capsules, the following percentage dissolution results have been obtained:

30 Minimum value of dissolution 81,4% Maximum value of dissolution 107,9% Average value 100,0% RSD = 9,7% (RSD = Relative Standard Deviation)

35 [0049] From the results obtained, it is clear that the double capsule as described by the invention is in compliance with the foreseen dissolution characteristics.

Example I

40 [0050] Capsules of format 3 have been prepared with the following content:

Tetracycline hydrochloride 125 mg Gastroprotected omeprazole 5 mg Magnesium stearate 5 mg 45 Talc 5 mg

Capsules of format O+ have been prepared with the following content:

50 Bismuth biscalcitrate 215 mg (corresponding to 53,7 mg of Bismuth) Metronidazole 125 mg Magnesium stearate 5 mg Talc 5 mg

55 The capsules 0 + have not been completely sealed, so that it will be possible to open them again with a manual machine (Zuma), and insert in the inside the capsule of format 3, previously prepared. [0051] The capsules have then been sealed and subjected to the controls concerning the disaggregation time, the

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average weight of the content, the sealing procedure, the assay of the single components and the microbiological purity, as foreseen in the Pharmacopoeia.

5 Claims

1. Use of a soluble salt of bismuth, a first antibiotic and a second antibiotic for the preparation of a pharmaceutical dosage form for a triple therapy against the microorganisms Helicobacter pylori, the pharmaceutical dosage form being characterized in that it comprises an internal capsule placed inside an external capsule, wherein the ex- 10 ternal capsule comprises the soluble salt of bismuth and the first antibiotic, and the internal capsule comprises the second antibiotic.

+ + 2. Use of a soluble salt of bismuth, a first antibiotic, a second antibiotic, and a K /Na ATPase inhibitor or anti-H2, for the preparation of a pharmaceutical dosage form for a quadruple therapy against the microorganisms Helicobacter 15 pylori, the pharmaceutical dosage form being characterized in that it comprises an internal capsule placed inside an external capsule, wherein the external capsule comprises the soluble salt of bismuth and the first antibiotic, + + and the internal capsule comprises the second antibiotic and the K /Na ATPase inhibitor or anti-H2.

+ + 3. Use of a soluble salt of bismuth, a first antibiotic, a second antibiotic, and a K /Na ATPase inhibitor or anti-H2, for 20 the preparation of a pharmaceutical dosage form for a quadruple therapy against the microorganisms Helicobacter pylori, the pharmaceutical dosage form being characterized in that it comprises an internal capsule placed inside an external capsule, wherein the external capsule comprises the soluble salt of bismuth, the first antibiotic, and + + the K /Na ATPase inhibitor or anti-H2; and the internal capsule comprises the second antibiotic.

25 + + 4. Use of a soluble salt of bismuth, a first antibiotic, a second antibiotic, and a K /Na ATPase inhibitor or anti-H2, for the preparation of a first pharmaceutical dosage form and a second pharmaceutical dosage form for a quadruple therapy against the microorganisms Helicobacter pylori, the first pharmaceutical dosage form being characterized in that it comprises an internal capsule placed inside an external capsule, wherein the external capsule comprises the soluble salt of bismuth and the first antibiotic, and the internal capsule comprises the second antibiotic; the 30 + + second pharmaceutical dosage form being characterized in that it comprises a K /Na ATPase inhibitor or anti-H2.

5. Use as claimed in any one of claims 1 to 4, characterized in that the salt of bismuth is selected from the group consisting of bismuth subcitrate, bismuth aluminate, bismuth carbonate, bismuth citrate, colloidal bismuth subnitrate, bismuth germanate, bismuth germanium oxide, bismuth nitrate, bismuth oxide, bismuth oxychloride, bismuth 35 phosphate, bismuth salicylate, bismuth subcarbonate, bismuth subnitrate, bismuth subsalicylate, bismuth tribromophenate, bismuth trioxyde, bismuth vanadate, and bismuth vanadium tetraoxide.

6. Use as claimed in claim 5, characterized in that the salt of bismuth is bismuth subcitrate.

40 7. Use as claimed in any one of claims 1 to 6, characterized in that the first antibiotic is selected from the group consisting of the nitroimidazoles.

8. Use as claimed in claim 7, characterized in that the nitroimidazoles are selected from the group consisting of metronidazole, apronidazole, azomycine, benzonidazole, carnidazole, demetridazole, etanidazole, flunidazole, mi- 45 sonidazole, nimorazole, ornidazole, panidazole, ronidazole, and tinidazole.

9. Use as claimed in claim 8, characterized in that the nitroimidazole is metronidazole.

10. Use as claimed in any one of claims 1 to 9, characterized in that the second antibiotic is selected from the group 50 consisting of the macrolides and the compounds of the family of tetracyclines.

11. Use as claimed in claim 10, characterized in that the macrolides are selected from the group consisting of azithromycine, clarithromycine and erythromycine.

55 12. Use as claimed in claim 10, characterized in that the compounds of the family of tetracyclines are selected from the group consisting of tetracycline, chlortetracycline, doxycycline, glycocycline, guamecycline, lymecycline, methacycline and sancycline.

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13. Use as claimed in claims 12, characterized in that the second antibiotic is tetracycline.

+ + 14. Use as claimed in any one of claims 2 to 4, characterized in that the K /Na ATPase inhibitor or anti-H2 is selected from the group consisting of BY841; cimetidine; ebrotidine; etintidine; famotidine; flunarizine; ICI-162,846; lanso- 5 prazole; metiamide; mifentidine; niperotidine; nizatidine; omeprazole; oxmetidine; pantoprazole; rabeprazole; ramixotidine; ranitidine; ritanserin; roxatidine acetate hydrochloride; ZKF-93479; SKF-94482; sufotidine; tiotidine; TY- 11345; Wy-45,727; and zaltidine.

+ + 15. Use as claimed in claim 14, characterized in that the K /Na ATPase inhibitor or anti-H2 is omeprazole. 10 16. Use as claimed in any one of claims 1 to 15, characterized in that both internal and external capsules are stable at a temperature comprised between 5 and 50°C and at a humidity comprised between 35 and 65%.

17. Use as claimed in any one of claims 1 to 16, characterized in that both internal and external capsules are made 15 of hard gelatin.

18. Use as claimed in any one of claims 1 to 17, characterized in that the internal capsule has a format between 2 or 3 and the external capsule has a format between 0 + or 1.

20 19. Use as claimed in claim 18, characterized in that the external capsule has a format of 0 + and the internal one has a format 3.

20. Pharmaceutical dosage form characterized in that it comprises an internal capsule placed inside an external capsule, wherein the external capsule comprises a soluble salt of bismuth and a first antibiotic, and the internal 25 capsule comprises a second antibiotic.

21. Pharmaceutical dosage form characterized in that it comprises an internal capsule placed inside an external capsule, wherein the external capsule comprises a soluble salt of bismuth and a first antibiotic, and the internal + + capsule comprises a second antibiotic, and a K /Na ATP-ase inhibitor or anti-H2. 30 22. Pharmaceutical dosage form characterized in that it comprises an internal capsule placed inside an external capsule, wherein the external capsule comprises a soluble salt of bismuth, a first antibiotic, and a K+/Na+ATP-ase inhibitor or anti-H2; and the internal capsule comprises a second antibiotic.

35 23. Pharmaceutical dosage form as claimed in any one of claims 20 to 22, characterized in that the bismuth salt is selected from the group consisting of bismuth subcitrate, bismuth aluminate, bismuth carbonate, bismuth citrate, colloidal bismuth subnitrate, bismuth germanate, bismuth germanium oxide, bismuth nitrate, bismuth oxide, bismuth oxychloride, bismuth phosphate, bismuth salicylate, bismuth subcarbonate, bismuth subnitrate, bismuth subsalicylate, bismuth tribromophenate, bismuth trioxyde, bismuth vanadate, and bismuth vanadium tetraoxide. 40 24. Pharmaceutical dosage form as claimed in claim 23, characterized in that the bismuth salt is bismuth subcitrate.

25. Pharmaceutical dosage form as claimed in any one of claims 20 to 24, characterized in that the first antibiotic is selected from the group consisting of the nitroimidazoles. 45 26. Pharmaceutical dosage form as claimed in claim 25, characterized in that the nitroimidazoles are selected from the group consisting of metronidazole, apronidazole, azomycine, benzonidazole, carnidazole, demetridazole, eta- nidazote, flunidazole, misonidazole, nimorazole, ornidazole, panidazole, ronidazole, and tinidazole.

50 27. Pharmaceutical dosage form as claimed in claim 26, characterized in that the nitroimidazole is metronidazole.

28. Pharmaceutical dosage form as claimed in any one of claims 20 to 27, characterized in that the second antibiotic is selected from the group consisting of the macrolides and the compounds of the family of tetracyclines.

55 29. Pharmaceutical dosage form as claimed in claim 28, characterized in that the macrolides are selected from the group consisting of azithromycine, clarithromycine and erythromycine.

30. Pharmaceutical dosage form as claimed in claim 28, characterized in that the compounds of the family of tetra-

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cyclines are selected from the group consisting of tetracycline, chlortetracycline, doxycycline, glycocycline, guamecycline, lymecycline, methacycline and sancycline.

31. Pharmaceutical dosage form as claimed in claims 28 or 30, characterized in that the second antibiotic is tetra- 5 cycline.

32. Pharmaceutical dosage form as claimed in claim 21 or 22, characterized in that the K+/Na+ATP-ase inhibitor or anti-H2 is selected from the group consisting of BY841; cimetidine; ebrotidine; etintidine; famotidine; flunarizine; ICI-162,846; lansoprazole; metiamide; mifentidine; niperotidine; nizatidine; omeprazole; oxmetidine; pantoprazole; 10 rabeprazole; ramixotidine; ranitidine; ritanserin; roxatidine acetate hydrochloride; ZKF-93479; SKF-94482; sufotidine; tiotidine; TY-11345; Wy-45,727; and zaltidine.

33. Pharmaceutical dosage form as claimed in claim 32, characterized in that omeprazole is selected.

15 34. Pharmaceutical dosage form as claimed in any one of claims 20 to 33, characterized in that the internal capsule has a format between 2 or 3 and the external capsule has a format between 0 + or 1.

35. Pharmaceutical dosage form as claimed in claim 34, characterized in that the external capsule has a format of 0 + and the internal one has a format 3. 20 36. Pharmaceutical dosage form as claimed in any one of claims 20 to 35, characterized in that the internal and external capsules are made of hard gelatin.

37. Pharmaceutical dosage form as claimed in any one of claims 20 to 36, characterized in that the internal and 25 external capsules contain respectively and independently one or more excipients.

38. Pharmaceutical dosage form as claimed in claim 37, characterized in that the excipients are selected from the group consisting of magnesium stearate; talc; cellulose and its derivates; silica and its derivates; sugars; polyeth- ylenglycols; wax, mono-, di-and tri-glycerids of hydrogenated fat acids; alcohols and acids at high molecular weight; 30 and relevant mixtures thereof.

Patentansprüche

35 1. Verwendung eines löslichen Wismutsalzes, eines ersten Antibiotikums und eines zweiten Antibiotikums zur Zu- bereitung einer pharmazeutischen Dosierungsform für eine Dreifachtherapie gegen die Mikroorganismen Helico- bacter pylori, wobei die pharmazeutische Dosierungsform dadurch gekennzeichnet ist, dass sie eine innere Kapsel umfasst, die sich im Innern einer äußeren Kapsel befindet, wobei die äußere Kapsel das lösliche Wismut- salz und das erste Antibiotikum enthält und die innere Kapsel das zweite Antibiotikum enthält. 40 2. Verwendung eines löslichen Wismutsalzes, eines ersten Antibiotikums, eines zweiten Antibiotikums und eines K+/ + Na ATPase-Hemmstoffs oder Anti-H2, zur Zubereitung einer pharmazeutischen Dosierungsform für eine Vierfach- therapie gegen die Mikroorganismen Helicobacter pylori, wobei die pharmazeutische Dosierungsform dadurch gekennzeichnet ist, dass sie eine innere Kapsel umfasst, die sich im Innern einer äußeren Kapsel befindet, wobei 45 die äußere Kapsel das lösliche Wismutsalz und das erste Antibiotikum enthält und die innere Kapsel das zweite + + Antibiotikum und den K /Na ATPase-Hemmstoff oder Anti-H2 enthält.

3. Verwendung eines löslichen Wismutsalzes, eines ersten Antibiotikums, eines zweiten Antibiotikums und eines K+/ + Na ATPase-Hemmstoffs oder Anti-H2, zur Zubereitung einer pharmazeutischen Dosierungsform für eine Vierfach- 50 therapie gegen die Mikroorganismen Helicobacter pylori, wobei die pharmazeutische Dosierungsform dadurch gekennzeichnet ist, dass sie eine innere Kapsel umfasst, die sich im Innern einer äußeren Kapsel befindet, wobei die äußere Kapsel das lösliche Wismutsalz, das erste Antibiotikum und den K+/Na+ATPase-Hemmstoff oder Anti- H2 enthält und die innere Kapsel das zweite Antibiotikum enthält.

55 4. Verwendung eines löslichen Wismutsalzes, eines ersten Antibiotikums, eines zweiten Antibiotikums und eines K+/ + Na ATPase-Hemmstoffs oder Anti-H2, zur Zubereitung einer ersten pharmazeutischen Dosierungsform und einer zweiten pharmazeutischen Dosierungsform für eine Vierfachtherapie gegen die Mikroorganismen Helicobacter pylori, wobei die erste pharmazeutische Dosierungsform dadurch gekennzeichnet ist, dass sie eine innere Kap-

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sel umfasst, die sich im Innern einer äußeren Kapsel befindet, wobei die äußere Kapsel das lösliche Wismutsalz und das erste Antibiotikum enthält und die innere Kapsel das zweite Antibiotikum enthält; und wobei die zweite pharmazeutischen Dosierungsform dadurch gekennzeichnet ist, dass sie einen K+/Na+ATPase-Hemmstoff oder Anti-H2 enthält. 5 5. Verwendung gemäß einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass das Wismutsalz aus folgender Gruppe ausgewählt wird: Wismutsubcitrat, Wismutaluminat, Wismutkarbonat, Wismutcitrat, kolloides Wismutsub- nitrat, Wismutgermanat, Wismutgermaniumoxid, Wismutnitrat, Wismutoxid, Wismutoxychlorid, Wismutphosphat, Wismutsalicylat, Wismutsubkarbonat, Wismutsubnitrat, Wismutsubsalicylat, Wismuttribromophenat, Wismuttri- 10 oxid, Wismutvanadat und Wismutvanadiumtetraoxid.

6. Verwendung gemäß Anspruch 5, dadurch gekennzeichnet, dass das Wismutsalz Wismutsubcitrat ist.

7. Verwendung gemäß einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass das erste Antibiotikum aus 15 der Gruppe der Nitroimidazolen ausgewählt wird.

8. Verwendung gemäß Anspruch 7, dadurch gekennzeichnet, dass die Nitroimidazole aus folgender Gruppe aus- gewählt werden: Metronidazol, Apronidazol, Azomycin, Benzonidazol, Carnidzol, Demetridazol, Etanidazol, Fluni- dazol, Misonidazol, Nimorazol, Ornidazol, Panidazol, Ronidazol und Tinidazol. 20 9. Verwendung gemäß Anspruch 8, dadurch gekennzeichnet, dass das Nitroimidazol Metronidazol ist.

10. Verwendung gemäß einem der Ansprüche 1 bis 9, dadurch gekennzeichnet, dass das zweite Antibiotikum aus der aus den Macroliden und den Verbindungen der Familie der Tetracycline bestehenden Gruppe ausgewählt wird. 25 11. Verwendung gemäß Anspruch 10, dadurch gekennzeichnet, dass die Macrolide aus folgender Gruppe ausge- wählt werden: Azithromycin, Clarithromycin und Erythromycin.

12. Verwendung gemäß Anspruch 10, dadurch gekennzeichnet; dass die Verbindungen der Familie der Tetracycline 30 aus folgender Gruppe ausgewählt werden: Tetracyclin, Chlortetracyclin, Doxycyclin, Glycocyclin, Guamecyclin, Lymecyclin, Methacyclin und Sancyclin.

13. Verwendung gemäß Anspruch 12, dadurch gekennzeichnet, dass das zweite Antibiotikum Tetracyclin ist.

35 14. Verwendung gemäß einem der Ansprüche 2 bis 4, dadurch gekennzeichnet, dass der K+/Na+ATPase-Hemmstoff oder Anti-H2 aus folgender Gruppe ausgewählt wird: BY841, Cimetidin, Ebrotidin, Etintidin, Famotidin, Flunarizin, ICI-162,846, Lansoprazol, Metiamid, Mifentidin, Niperotidin, Nizatidin, Omeprazol, Oxmetidin, Pantoprazol, Rabe- prazol, Ramixotidin, Ranitidin, Ritanserin, Roxatidin-Azetat-Hydrochlorid, ZKF-93479, SKF-94482, Sufotidin, Tio- tidin, TY-11345, Wy-45,727 und Zaltidin. 40 + + 15. Verwendung gemäß Anspruch 14, dadurch gekennzeichnet, dass der K /Na ATPase-Hemmstoff oder Anti-H2 Omeprazol ist.

16. Verwendung gemäß einem der Ansprüche 1 bis 15, dadurch gekennzeichnet, dass sowohl die innere als auch 45 die äußere Kapsel bei einer Temperatur zwischen 5°C und 50°C und einer Luftfeuchtigkeit zwischen 35 % und 65 % beständig ist.

17. Verwendung gemäß einem der Ansprüche 1 bis 16, dadurch gekennzeichnet, dass sowohl die innere als auch die äußere Kapsel aus Hartgelatine gefertigt ist. 50 18. Verwendung gemäß einem der Ansprüche 1 bis 17, dadurch gekennzeichnet, dass die innere Kapsel ein Format zwischen 2 und 3 hat und die äußere Kapsel ein Format zwischen 0+ und 1 hat.

19. Verwendung gemäß Anspruch 18, dadurch gekennzeichnet, dass die äußere Kapsel ein Format von 0+ hat und 55 die innere Kapsel ein Format 3 hat.

20. Pharmazeutische Dosierungsform, dadurch gekennzeichnet, dass sie eine innere Kapsel umfasst, die sich im Innern einer äußeren Kapsel befindet, wobei die äußere Kapsel ein lösliches Wismutsalz und ein erstes Antibio-

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tikum enthält und die innere Kapsel ein zweites Antibiotikum enthält.

21. Pharmazeutische Dosierungsform, dadurch gekennzeichnet, dass sie eine innere Kapsel umfasst, die sich im Innern einer äußeren Kapsel befindet, wobei die äußere Kapsel ein lösliches Wismutsalz und ein erstes Antibio- 5 + + tikum enthält und die innere Kapsel ein zweites Antibiotikum und einen K /Na ATPase-Hemmstoff oder Anti-H2 enthält.

22. Pharmazeutische Dosierungsform, dadurch gekennzeichnet, dass sie eine innere Kapsel umfasst, die sich im Innern einer äußeren Kapsel befindet, wobei die äußere Kapsel ein lösliches Wismutsalz, ein erstes Antibiotikum 10 + + und einen K /Na ATPase-Hemmstoff oder Anti-H2 enthält und die innere Kapsel ein zweites Antibiotikum enthält.

23. Pharmazeutische Dosierungsform gemäß einem der Ansprüche 20 bis 22, dadurch gekennzeichnet, dass das Wismutsalz aus folgender Gruppe ausgewählt wird: Wismutsubcitrat, Wismutaluminat, Wismutkarbonat, Wismut- citrat, kolloides Wismutsubnitrat, Wismutgermanat, Wismutgermaniumoxid, Wismutnitrat, Wismutoxid, Wismu- 15 toxychlorid, Wismutphosphat, Wismutsalicylat, Wismutsubkarbonat, Wismutsubnitrat, Wismutsubsalicylat, Wis- muttribromophenat, Wismuttrioxid, Wismutvanadat und Wismutvanadiumtetraoxid.

24. Pharmazeutische Dosierungsform gemäß Anspruch 23, dadurch gekennzeichnet, dass das Wismutsalz Wis- mutsubcitrat ist. 20 25. Pharmazeutische Dosierungsform gemäß einem der Ansprüche 20 bis 24, dadurch gekennzeichnet, dass das erste Antibiotikum aus der aus den Nitroimidazolen bestehenden Gruppe ausgewählt wird.

26. Pharmazeutische Dosierungsform gemäß Anspruch 25, dadurch gekennzeichnet, dass die Nitroimidazole aus 25 folgender Gruppe ausgewählt werden: Metronidazol, Apronidazol, Azomycin, Benzonidazol, Carnidazol, Demetri- dazol, Etanidazol, Flunidazol, Misonidazol, Nimorazol, Ornidazol, Panidazol, Ronidazol und Tinidazol.

27. Pharmazeutische Dosierungsform gemäß Anspruch 26, dadurch gekennzeichnet, dass das Nitroimidazol Me- tronidazol ist. 30 28. Pharmazeutische Dosierungsform gemäß einem der Ansprüche 20 bis 27, dadurch gekennzeichnet, dass das zweite Antibiotikum aus der aus den Macroliden und den Verbindungen der Familie der Tetracycline bestehenden Gruppe ausgewählt wird.

35 29. Pharmazeutische Dosierungsform gemäß Anspruch 28, dadurch gekennzeichnet, dass die Macrolide aus folgender Gruppe ausgewählt werden: Azithromycin, Clarithromycin und Erythromycin.

30. Pharmazeutische Dosierungsform gemäß Anspruch 28, dadurch gekennzeichnet, dass die Verbindungen der Familie der Tetracycline aus folgender Gruppe ausgewählt werden: Tetracyclin, Chlortetracyclin, Doxycyclin, Gly- 40 cocyclin, Guamecyclin, Lymecyclin, Methacyclin und Sancyclin.

31. Pharmazeutische Dosierungsform gemäß Anspruch 28 oder 30, dadurch gekennzeichnet, dass das zweite An- tibiotikum Tetracyclin ist.

45 32. Pharmazeutische Dosierungsform gemäß Anspruch 21 oder 22, dadurch gekennzeichnet, dass der K+/Na+AT- Pase-Hemmstoff oder Anti-H2 aus folgender Gruppe ausgewählt wird: BY841, Cimetidin, Ebrotidin, Etintidin, Fa- motidin, Flunarizin, ICI-162,846, Lansoprazol, Metiamid, Mifentidin, Niperotidin, Nizatidin, Omeprazol, Oxmetidin, Pantoprazol, Rabeprazol, Ramixotidin, Ranitidin, Ritanserin, Roxatidin-Azetat-Hydrochlorid, ZKF-93479, SKF- 94482, Sufotidin, Tiotidin, TY-11345, Wy-45,727 und Zaltidin. 50 33. Pharmazeutische Dosierungsform gemäß Anspruch 32, dadurch gekennzeichnet, dass Omeprazol ausgewählt wird.

34. Pharmazeutische Dosierungsform gemäß einem der Ansprüche 20 bis 33, dadurch gekennzeichnet, dass die 55 innere Kapsel ein Format zwischen 2 und 3 hat und die äußere Kapsel ein Format zwischen 0+ und 1 hat.

35. Pharmazeutische Dosierungsform gemäß Anspruch 34, dadurch gekennzeichnet, dass die äußere Kapsel ein Format von 0+ hat und die innere Kapsel ein Format 3 hat.

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36. Pharmazeutische Dosierungsform gemäß einem der Ansprüche 20 bis 33, dadurch gekennzeichnet, dass sowohl die innere als auch die äußere Kapsel aus Hartgelatine gefertigt ist.

37. Pharmazeutische Dosierungsform gemäß einem der Ansprüche 20 bis 36, dadurch gekennzeichnet, dass die 5 innere und die äußere Kapsel jeweils unabhängig voneinander einen oder mehrere Arzneistoffträger enthalten.

38. Pharmazeutische Dosierungsform gemäß Anspruch 37, dadurch gekennzeichnet, dass die Arzneistoffträger aus folgender Gruppe ausgewählt werden: Magnesiumstearat, Talk, Zellulose und ihre Derivate, Siliciumdioxid und seine Derivate, Zucker, Polyethylenglykole, Wachs, Mono-, Di- und Tri-Glyzeride hydrierter Fettsäuren, Alko- 10 hole und Säuren von hoher Molmasse sowie entsprechende Mischungen daraus.

Revendications

15 1. Utilisation d'un sel soluble de bismuth, un premier antibiotique et un deuxième antibiotique pour la préparation d'une composition pharmaceutiquement acceptable pour une trithérapie contre les micro-organismes Helicobacter pylori, la composition étant caractérisée en ce qu'elle comprend une capsule interne placée dans une capsule externe, où la capsule externe comprend le sel soluble de bismuth et le premier antibiotique, et la capsule interne comprend le deuxième antibiotique. 20 2. Utilisation d'un sel soluble de bismuth, un premier antibiotique, un deuxième antibiotique, et d'un inhibiteur de K+/ + Na ATPase ou anti-H2, pour la préparation d'une composition pharmaceutiquement acceptable pour une quadruple thérapie contre les micro-organismes Helicobacter pylori, la composition étant caractérisée en ce qu'elle comprend une capsule interne placée dans une capsule externe, où la capsule externe comprend le sel soluble 25 de bismuth et le premier antibiotique, et la capsule interne comprend le deuxième antibiotique et l'inhibiteur de K+/ + Na ATPase ou anti-H2.

3. Utilisation d'un sel soluble de bismuth, un premier antibiotique, un deuxième antibiotique, et d'un inhibiteur de K+/ + Na ATPase ou anti-H2, pour la préparation d'une composition pharmaceutiquement acceptable pour une quadru- 30 ple thérapie contre les micro-organismes Helicobacter pylori, la composition étant caractérisée en ce qu'elle comprend une capsule interne placée dans une capsule externe, où la capsule externe comprend le sel soluble + + de bismuth, le premier antibiotique, et l'inhibiteur de K /Na ATPase ou anti-H2; et la capsule interne comprend le deuxième antibiotique.

35 4. Utilisation d'un sel soluble de bismuth, un premier antibiotique, un deuxième antibiotique, et d'un inhibiteur de K+/ + Na ATPase ou anti-H2, pour la préparation d'une première composition pharmaceutiquement acceptable et une deuxième composition pharmaceutiquement acceptable pour une quadruple thérapie contre les micro-organismes Helicobacter pylori, la première composition étant caractérisée en ce qu'elle comprend une capsule interne placée dans une capsule externe, où la capsule externe comprend le sel soluble de bismuth et le premier antibiotique et 40 la capsule interne comprend le deuxième antibiotique; la deuxième composition étant caractérisée en ce qu'elle + + comprend un inhibiteur de K /Na ATPase ou anti-H2,

5. Utilisation selon l'une quelconque des revendications 1 à 4, caractérisée en ce que le sel de bismuth est choisi dans le groupe constitué par le subcitrate de bismuth, le subcalcitrate de bismuth, l'aluminate de bismuth, le car- 45 bonate de bismuth, le citrate de bismuth, le subnitrate colloïdal de bismuth, le germanate de bismuth, l'oxyde de germanium de bismuth, le nitrate de bismuth, l'oxyde de bismuth, l'oxychlorure de bismuth, le phosphate de bismuth, le salicylate de bismuth, le subcarbonate de bismuth, le subnitrate de bismuth, le subsalicylate de bismuth, le tribromophénate de bismuth, le trioxyde de bismuth, le vanadate de bismuth et le tétraoxyde de vanadium de bismuth. 50 6. Utilisation selon la revendication 5, caractérisée en ce que le sel de bismuth est le subcitrate de bismuth.

7. Utilisation selon l'une quelconque des revendications 1 à 6, caractérisée en ce que le premier antibiotique est un nitroimidazole. 55 8. Utilisation selon la revendication 7, caractérisée en ce que le nitroimidazole est choisi dans le groupe constitué par le métronidazole, l'apronidazole, l'azomycine, le benzonidazole, le carnidazole, le démétridazole, l'étanidazole, le flunidazole, le misonidazole, le nimorazole, l'ornidazole, le panidazole, le ronidazole et le tinidazole.

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9. Utilisation selon la revendication 8, caractérisée en ce que le nitroimidazole est le métronidazole.

10. Utilisation selon l'une quelconque des revendications 1 à 9, caractérisée en ce que le deuxième antibiotique est choisi dans le groupe constitué par les macrolides et les composés de la famille des tétracyclines. 5 11. Utilisation selon la revendication 10, caractérisée en ce que les macrolides sont choisis dans le groupe constitué par l'azithromycine, la clarithromycine et l'érythomycine.

12. Utilisation selon la revendication 10, caractérisée en ce que les composés de la famille des tétracyclines sont 10 choisis dans le groupe constitué par la tétracycline, la chlortétracycline, la doxycycline, la glycocycline, la guamé- cycline, la lymécycline, la méthacycline et la sancycline.

13. Utilisation selon la revendication 12, caractérisée en ce que le deuxième antibiotique est la tétracycline.

15 14. Utilisation selon l'une quelconque des revendications 2 à 4, caractérisée en ce que l'inhibiteur de K+/Na+ ATPase ou anti-H2 est choisi dans le groupe constitué du BY841; la cimetidine; l'ébrotidine; l'étintidine; la famotidine; la flunarizine; l'ICI-162,846; le lansoprazole; le métiamide; la mifentidine; la nipérotidine; la nizatidine; l'oméprazole; l'oxmétidine; le pantoprazole; le rabeprazole; la ramixotidine; la ranitidine; la ritansérine; le chlorhydrate d'acétate de roxatidine; le ZKF-93479; le SKF-94482; la sulfotidine; le tiotidine; le TY-11345; le Wy-45,727 et la zaltidine. 20 + + 15. Utilisation selon la revendication 14, caractérisée en ce que l'inhibiteur de K /Na ATPase ou anti-H2 est l'omeprazole.

16. Utilisation selon l'une quelconque des revendications 1 à 15, caractérisée en ce que les capsules internes et 25 externes sont stables à une température comprise entre 5 et 50°C et à une humidité comprise entre 35 et 65%.

17. Utilisation selon l'une quelconque des revendications 1 à 16, caractérisée en ce que les capsules internes et externes sont faites de gélatine dure.

30 18. Utilisation selon l'une quelconque des revendications 1 à 17, caractérisée en ce que la capsule interne a une taille entre 2 ou 3 et la capsule externe a une taille entre 0+ ou 1.

19. Utilisation selon la revendication 18, caractérisée en ce que la capsule externe a une taille de 0+ et la capsule interne a une taille 3. 35 20. Composition pharmaceutiquement acceptable caractérisée en ce qu'elle comprend une capsule interne placée à l'intérieur d'une capsule externe, où la capsule externe comprend un sel soluble de bismuth et un premier antibiotique, et la capsule interne comprend un deuxième antibiotique.

40 21. Composition pharmaceutiquement acceptable caractérisée en ce qu'elle comprend une capsule interne placée à l'intérieur d'une capsule externe, où la capsule externe comprend un sel soluble de bismuth et un premier anti- + + biotique, et la capsule interne comprend un deuxième antibiotique, et un inhibiteur de K /Na ATPase ou anti-H2.

22. Composition pharmaceutiquement acceptable caractérisée en ce qu'elle comprend une capsule interne placée 45 à l'intérieur d'une capsule externe, où la capsule externe comprend un sel soluble de bismuth, un premier antibio- + + tique, et un inhibiteur de K /Na ATPase ou anti-H2; et la capsule interne comprend un deuxième antibiotique.

23. Composition selon l'une quelconque des revendications 20 à 22, caractérisée en ce que le sel de bismuth est choisi dans le groupe constitué par le subcitrate de bismuth, l'aluminate de bismuth, le carbonate de bismuth, le 50 citrate de bismuth, le subnitrate colloïdal de bismuth, le germanate de bismuth, l'oxyde de germanium de bismuth, le nitrate de bismuth, l'oxyde de bismuth, l'oxychlorure de bismuth, le phosphate de bismuth, le salicylate de bismuth, le subcarbonate de bismuth, le subnitrate de bismuth, le subsalicylate de bismuth, le tribromophénate de bismuth, le trioxyde de bismuth, le vanadate de bismuth et le tétraoxyde de vanadium de bismuth.

55 24. Composition selon la revendication 23, caractérisée en ce que le sel de bismuth est le subcitrate de bismuth.

25. Composition selon l'une quelconque des revendications 20 à 24, caractérisée en ce que le premier antibiotique est un nitroimidazole.

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26. Composition selon la revendication 25, caractérisée en ce que le nitroimidazole est choisi dans le groupe constitué par le métronidazole, l'apronidazole, l'azomycine, le benzonidazole, le carnidazole, le démétridazole, l'étanidazole, le flunidazole, le misonidazole, le nimorazole, l'ornidazole, le panidazole, le ronidazole et le tinidazole.

5 27. Composition selon la revendication 26, caractérisée en ce que le nitroimidazole est le métronizadole.

28. Composition selon l'une quelconque des revendications 20 à 27, caractérisée en ce que le deuxième antibiotique est choisi dans le groupe constitué par les macrolides et les composés de la famille des tétracyclines.

10 29. Composition selon la revendication 28, caractérisée en ce que les macrolides sont choisis dans le groupe cons- titué par l'azithromycine, la clarithromycine et l'érythromycine.

30. Composition selon la revendication 28, caractérisée en ce que les composés de la famille des tétracyclines sont choisis dans le groupe constitué par la tétracycline, la chlortétracycline, la doxycycline, la glycocycline, la guamé- 15 cycline, la lymécycline, la méthacycline et la sancycline.

31. Composition selon la revendication 28 ou 30, caractérisée en ce que le deuxième antibiotique est la tétracycline.

+ + 32. Composition selon la revendication 21 ou 22, caractérisée en ce que l'inhibiteur de K /Na ATPase ou anti-H2 20 est choisi dans le groupe constitué par le BY841; 1a cimétidine; l'ébrotidine; l'étintidine; la famotidine; la flunarizine; l'ICI-162,846; le lansoprazole; le métiamide; la mifentidine; la nipérotidine; la nizatidine; l'oméprazole; l'oxmétidine; le pantoprazole; le rabeprazole; la ramixotidine; la ranitidine; la ritansérine; le chlorhydrate d'acétate de roxatidine; le ZKF-93479; le SKF-94482; la sufotidine; la tiotidine; le TY-11345; le Wy-45,727 et la zaltidine.

25 + + 33. Composition selon la revendication 32, caractérisée en ce que l'inhibiteur de K /Na ATPase ou anti-H2 est l'oméprazole.

34. Composition selon l'une quelconque des revendications 20 à 33, caractérisée en ce que la capsule interne a une taille entre 2 ou 3 et la capsule externe a une taille entre 0 + ou 1. 30 35. Composition selon la revendication 34, caractérisée en ce que la capsule externe a une taille 0+ et la capsule interne a une taille 3.

36. Composition selon l'une quelconque des revendications 20 à 35, caractérisée en ce que les capsules interne et 35 externe sont faites de gélatine dure.

37. Composition selon l'une quelconque des revendications 20 à 36, caractérisée en ce que les capsules interne et externe contiennent respectivement et indépendamment un ou plusieurs excipients.

40 38. Composition selon la revendication 37, caractérisée en ce que les excipients sont choisis dans le groupe constitué par le stéarate de magnésium; le talc; la cellulose et ses dérivés; la silice et ses dérivés; les sucres; les polyé- thyglycols; la cire, les mono-, di- et tri-glycérides d'acides gras hydrogénés; les alcools et les acides de poids moléculaire élevé; et leurs mélanges appropriés.