WO2005074898A2 - Nouvelle combinaison pour le traitement d'helicobacter pylori - Google Patents

Nouvelle combinaison pour le traitement d'helicobacter pylori Download PDF

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Publication number
WO2005074898A2
WO2005074898A2 PCT/EP2005/050337 EP2005050337W WO2005074898A2 WO 2005074898 A2 WO2005074898 A2 WO 2005074898A2 EP 2005050337 W EP2005050337 W EP 2005050337W WO 2005074898 A2 WO2005074898 A2 WO 2005074898A2
Authority
WO
WIPO (PCT)
Prior art keywords
pantoprazole
helicobacter
pharmaceutical composition
salt
composition according
Prior art date
Application number
PCT/EP2005/050337
Other languages
English (en)
Other versions
WO2005074898A3 (fr
Inventor
Reinhard Huber
Bernhard Kohl
Wolfgang Kromer
Wolfgang-Alexander Simon
Original Assignee
Altana Pharma Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Altana Pharma Ag filed Critical Altana Pharma Ag
Publication of WO2005074898A2 publication Critical patent/WO2005074898A2/fr
Publication of WO2005074898A3 publication Critical patent/WO2005074898A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to pharmaceutical compositions and their use in treating or preventing gastrointestinal disorders, in particular disorders caused or exacerbated by helicobacter infection and secreted gastric acid.
  • compositions comprising a helicobacter-inhibiting antimicrobial agent and pantoprazole and/or its salts are disclosed.
  • novel administration forms and preparations for acid- labile active compounds are described.
  • acid-labile active compounds pantoprazole and (-)- pantoprazole are mentioned inter alia.
  • the novel administration forms contain individual active compound units, the active compound being present in the active compound units in a matrix made of a mixture comprising at least one fatty alcohol and at least one solid paraffin, in a matrix made of a mixture of a triglyceride and at least one solid paraffin or in a matrix made of a mixture comprising at least one fatty acid ester and at least one solid paraffin.
  • the active compound units are microspheres which can be produced by prilling.
  • the novel administration forms can be combined, inter alia, with antimicrobial agents.
  • compositions of the invention which are outstandingly suited to achieve Helicobacter pylori eradication, thus favouring ulcer healing in patients with gastric ulcer, comprise a helicobacter-inhibiting anti-microbial agent and (S)-pantoprazole and/or its salts.
  • (S)-pantoprazole and/or its salts is understood to include:
  • Salts in the context of the invention means all pharmaceutically acceptable salts prepared by reacting (S)-pantoprazole [(-)-pantoprazole] with a suitable inorganic or organic base.
  • bases aluminium, sodium, potassium, lithium, magnesium, zinc or calcium salts. Particularly preferred is the magnesium salt.
  • (S) -pantoprazole and/or its salts are isolated in crystalline form, the crystals may contain variable amounts of solvent. Accordingly, according to the invention, the term "(S)-pantoprazole and/or its salts” also includes all solvates, in particular all hydrates, of (S)-pantoprazole and/or its salts.
  • a particularly preferred hydrate of (S)-pantoprazole and/or its salts is the (S)- pantoprazole-magnesium dihydrate.
  • substantially free in the context of the invention means that (S)-pantoprazole and/or its salts contains less than 10 % by weight of (R)-pantoprazole.
  • substantially free means that (S)- pantoprazole and/or its salts contains less than 5 % by weight of (R)-pantoprazole.
  • substantially free means that (S)-pantoprazole and/or its salts contains less than 1 % by weight of (R)-pantoprazole.
  • the present invention further relates to the use of a helicobacter-inhibiting anti-microbial agent and (S)-pantoprazole and/or its salts in treating or preventing gastrointestinal disorders in mammals, in particular humans.
  • This use may involve either concurrent or non-concurrent administration of the helicobacter-inhibiting antimicrobial agent and (S)-pantoprazole and/or its salts.
  • helicobacter-inhibiting anti-microbial agent means any natural, synthetic, or semi-synthetic compound or mixture thereof, which is effective in eradicating helicobacter pylori organisms.
  • Suitable anti-microbial agents include antibiotics, and bismuth salts such as bismuth subcitrate or bismuth subsalicylate.
  • Antibiotics are the preferred helicobacter-inhibiting anti-microbial agents useful herein.
  • Specific examples of such helicobacter-inhibiting anti-microbial agents include ⁇ -lactam antibiotics, for example penicillins (such as benzylpenicillin, phenoxymethylpenicillin, propicillin, azidocillin, dicloxacillin, flu- cloxacillin, oxacillin, amoxicillin, aspoxicillin, bacampicillin, ampicillin, mezlocillin, piperacillin or azlocillin), cephalosporins (such as cefadroxil, cefaclor, cefalexin, cefixim, cefuroxim, cefuroxime axetil, cefetamet, cefadroxil, ceftibuten, cefpodoxim, cefotetan, cefazolin, cefoperazon, ceftizoxim, cefotaxim, ceftazidim, cefozo
  • aztreonam lora- carbef, flomoxef, faropenem, carumonam, ertapenem, panipenem or meropenem
  • enzyme inhibitors for example sulbactam, tazobactam, tetracyclines, for example tetracycline, oxytetracycline, mino- cycline or doxycycline
  • aminoglycosides for example tobramycin, gentamicin, isepamicin, neomycin, streptomycin, amikacin, netilmicin, semduramycin, paromomycin or spectinomycin
  • amphenicols for example chloramphenicol orthiamphenicol
  • rifamycines for example rifamycine, rifampicin, rifapen- tine, rifaximin, rifabutin, lincomycins and macrolide antibiotics, for example clinda
  • helicobacter-inhibiting anti-microbial agents can be administered on their own or alternatively can be combined with one another. Accordingly, the expression "a helicobacter- inhibiting anti-microbial agent" is understood within the scope of the invention to include two, three or more different helicobacter-inhibiting substances, which are present together.
  • the preferred helicobacter-inhibiting anti-microbial agents are amoxicillin, clarithromycin, azithromy- cin, tetracycline, metronidazole, levofloxacin, rifabutin and tinidazole.
  • the more preferred helicobacter-inhibiting agent is a combination of two or three anti-microbial compounds, which are used - together with known proton pump inhibitors - in the so-called triple or quadruple therapy.
  • exemplary preferred compositions (combinations) according to the invention are those, which include:
  • composition of (S)-pantoprazole and/or its salts with amoxycillin and clarithromycin
  • composition of (S)-pantoprazole and/or its salts with amoxycillin and metronidazol is provided.
  • composition of (S)-pantoprazole and/or its salts with levofloxacin and rifabutin is provided.
  • composition of (S)-pantoprazole and/or its salts with amoxycillin, tetracyclin and a bismuth salt is provided.
  • composition of (S)-pantoprazole and/or its salts with tetracyclin, metronidazol and a bismuth salt is provided.
  • composition of (S)-pantoprazole and/or its salts with metronidazol and clarithromycin is provided.
  • the pharmaceutical composition of the present invention may be used in therapy to treat gastrointestinal diseases caused or exacerbated by helicobacter infection and secreted gastric acid.
  • they may be used to treat duodenal and gastric ulcer disease, in particular having a positive effect in lowering the relapse rate of such diseases compared to the relapse rate observed by treatment with (S)-pantoprazole and/or its salts alone.
  • the use of the present invention in therapy comprises administering the helicobacter-inhibiting antimicrobial agent and (S)-pantoprazole and/or its salts either concurrently or non-concurrently.
  • Concurrently means that the two agents are administered within 24 hours or less of each other, preferably within about 12 hours of each other, more preferably within about 1 hour of each other and most preferably within about 5 minutes of each other; and includes co-administration of the agents by administering a composition of the present invention.
  • non-concurrently means that the two agents are administered more than 24 hours apart.
  • the present invention provides a method of treatment of gastrointestinal diseases caused or exacerbated by Helicobacter pylori infection and elevated levels of gastric acid which comprises administering to a subject in need thereof, an effective amount of (S)-pantoprazole and/or its salts and a helicobacter-inhibiting anti-microbial agent.
  • an effective amount of (S)-pantoprazole and/or its salts and a helicobacter-inhibiting anti-microbial agent can be administered separately in a standard pharmaceutical composition, or together in a single composition. Standard compositions can be prepared by techniques well-known in the art of pharmacy.
  • the daily dose regimen for an adult patient involves administering the helicobacter-inhibiting antimicrobial agent in an amount from 1 mg to 10000 mg.
  • the specific quantity depends on the particular anti-microbial agent used.
  • penicillins such as amoxicillin are administered in an amount of from about 500 mg to about 3000 mg per day, preferably from about 750 mg to about 1500 mg per day;
  • bismuth salts such as bismuth subcitrate and bismuth subsalicylate are administered in an amount of from about 5mg to about 5000 mg per day, preferably from about 50 mg to about 250 mg per day.
  • the skilled person is familiar in the amount customary for the anti-microbial agent in standard triple or quadruple therapy.
  • the therapy is normally carried out for a period of from seven to fourteen days.
  • the anti-microbial agent and (S)-pantoprazole and/or its salts can be administered together in several unit doses, preferably 1-4 times per day. In the case of parenteral treatment lower doses can generally be used.
  • the compounds will be administered for a period of continuous therapy, for example a week or more.
  • the present invention provides the use of a helicobacter-inhibiting anti-microbial agent and (S)-pantoprazole and/or its salts in the manufacture of a medicament for treating or preventing gastrointestinal disorders, in particular ulcer relapse.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a helicobacter-inhibiting anti-microbial agent and (S)-pantoprazole and/or its salts for use in Helicobacter pylori eradication and ulcer healing in patients with gastric ulcer.
  • 'medicament' or 'pharmaceutical composition shall be taken to refer to a composition comprising both the helicobacter-inhibiting anti-microbial agent(s) and (S)-pantoprazole and/or its salts in a fixed combination (fixed unit dosage form), or a medicament pack comprising the two, three (in case of triple therapy) or four (in case of quadruple therapy) active ingredients as discrete separate dosage forms.
  • a medicament pack comprising the two, three or four active ingredients
  • the active ingredients are preferably packed into blister cards which are suited for improving compliance.
  • Each blister card preferably contains the medicaments to be taken on one day of treatment.
  • the medicaments can be disposed in different sections on the blister card according to the different ranges of times of day at which the medicaments are to be taken (for example morning and evening or morning, midday and evening).
  • the blister cavities for the medicaments to be taken together at a particular time of day are accommodated in the respective range of times of day.
  • the various times of day are, of course, also put on the blister in a clearly visible way. It is also possible, of course, for example to indicate a period in which the medicaments are to be taken, for example stating the times.
  • the daily sections may represent one line of the blister card, and the times of day are then identified in chronological sequence in this column.
  • Medicaments which must be taken together at a particular time of day are placed together at the appropriate time on the blister card, preferably a narrow distance apart, allowing them to be pushed out of the blister easily, and having the effect that removal of the dosage form from the blister is not forgotten.
  • a preferable medicament pack to be used in connection with the invention is that disclosed in International Patent Application WO 02000161.
  • the title compound can also be prepared from organic-aqueous solvent mixtures.
  • (-)-pantoprazole sodium, or (-)-pantoprazole together with one equivalent of aqueous, for example 2N, sodium hydroxide solution is dissolved in an organic solvent, for example warm acetone.
  • a magnesium salt for example magnesium chloride hexahydrate
  • water 0.5 to 0.55 equivalents of a magnesium salt (for example magnesium chloride hexahydrate), dissolved in water, are added drop by drop, and the mixture is cooled with stirring.
  • the precipitated solid is filtered off, washed with the solvent mixture in question and dried at 50°C under reduced pressure until the weight remains constant. This gives the title compound as a colourless to beige powder.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques ainsi que leur utilisation dans le traitement ou la prévention de troubles gastro-intestinaux, plus spécifiquement des troubles provoqués ou exacerbés par une infection d'helicobacter et l'acide gastrique sécrété.
PCT/EP2005/050337 2004-01-28 2005-01-27 Nouvelle combinaison pour le traitement d'helicobacter pylori WO2005074898A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP04001756 2004-01-28
EP04001756.8 2004-01-28

Publications (2)

Publication Number Publication Date
WO2005074898A2 true WO2005074898A2 (fr) 2005-08-18
WO2005074898A3 WO2005074898A3 (fr) 2006-07-27

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PCT/EP2005/050337 WO2005074898A2 (fr) 2004-01-28 2005-01-27 Nouvelle combinaison pour le traitement d'helicobacter pylori

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2343067A1 (fr) * 2009-12-31 2011-07-13 Synmosa Biopharma Corporation Composition pharmaceutique pour l'éradication de l'helicobacter pylori et son procédé de préparation
CN104814964A (zh) * 2015-04-16 2015-08-05 广州赛烽医药科技有限公司 一种抗胃幽门螺旋杆菌的药物组合物、制备方法及其应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992003135A1 (fr) * 1990-08-24 1992-03-05 Byk Gulden Lomberg Chemische Fabrik Gmbh Compositions pharmaceutiques contenant du 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyle) methylsulfinyle]benzimidazole et un agent anti-helicobacter pour le traitement des troubles gastro-intestinaux
US5888535A (en) * 1993-04-27 1999-03-30 Sepracor Inc. Methods and compositions for treating gastric disorders using optically pure (-) pantoprazole
WO2000010995A1 (fr) * 1998-08-18 2000-03-02 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouvelle forme de sel de pantoprazole
WO2000074654A1 (fr) * 1999-06-07 2000-12-14 Byk Gulden Lomberg Chemische Fabrik Gmbh Preparation et forme galenique comprenant un compose actif acido-labile
US20030136698A1 (en) * 2000-06-27 2003-07-24 Andreas Klatt Medicinal product package for eradication therapy

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992003135A1 (fr) * 1990-08-24 1992-03-05 Byk Gulden Lomberg Chemische Fabrik Gmbh Compositions pharmaceutiques contenant du 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyle) methylsulfinyle]benzimidazole et un agent anti-helicobacter pour le traitement des troubles gastro-intestinaux
US5888535A (en) * 1993-04-27 1999-03-30 Sepracor Inc. Methods and compositions for treating gastric disorders using optically pure (-) pantoprazole
WO2000010995A1 (fr) * 1998-08-18 2000-03-02 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouvelle forme de sel de pantoprazole
WO2000074654A1 (fr) * 1999-06-07 2000-12-14 Byk Gulden Lomberg Chemische Fabrik Gmbh Preparation et forme galenique comprenant un compose actif acido-labile
US20030136698A1 (en) * 2000-06-27 2003-07-24 Andreas Klatt Medicinal product package for eradication therapy

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KALE-PRADHAN PRAMODINI B ET AL: "Esomeprazole for acid peptic disorders" ANNALS OF PHARMACOTHERAPY, vol. 36, no. 4, April 2002 (2002-04), pages 655-663, XP009030827 ISSN: 1060-0280 *
TANAKA MAKOTO ET AL: "Stereoselective pharmacokinetics of pantoprazole, a proton pump inhibitor, in extensive and poor metabolizers of S-mephenytoin" CLINICAL PHARMACOLOGY AND THERAPEUTICS, vol. 69, no. 3, March 2001 (2001-03), pages 108-113, XP009030871 ISSN: 0009-9236 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2343067A1 (fr) * 2009-12-31 2011-07-13 Synmosa Biopharma Corporation Composition pharmaceutique pour l'éradication de l'helicobacter pylori et son procédé de préparation
CN104814964A (zh) * 2015-04-16 2015-08-05 广州赛烽医药科技有限公司 一种抗胃幽门螺旋杆菌的药物组合物、制备方法及其应用
CN104814964B (zh) * 2015-04-16 2018-07-31 广东赛烽医药科技有限公司 一种抗胃幽门螺旋杆菌的药物组合物、制备方法及其应用

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