EP0941101A1 - Compositions de traitement de troubles gastro-intestinaux contenant du bismuth, des anti-inflammatoires non steroidiens ainsi qu'un ou plusieurs agents anti-microbiens et methodes correspondantes - Google Patents

Compositions de traitement de troubles gastro-intestinaux contenant du bismuth, des anti-inflammatoires non steroidiens ainsi qu'un ou plusieurs agents anti-microbiens et methodes correspondantes

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Publication number
EP0941101A1
EP0941101A1 EP97948489A EP97948489A EP0941101A1 EP 0941101 A1 EP0941101 A1 EP 0941101A1 EP 97948489 A EP97948489 A EP 97948489A EP 97948489 A EP97948489 A EP 97948489A EP 0941101 A1 EP0941101 A1 EP 0941101A1
Authority
EP
European Patent Office
Prior art keywords
bismuth
days
milligrams
composition
administered
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97948489A
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German (de)
English (en)
Inventor
Jonathan Davidson Kaunitz
Owen Rickford Carryl
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Procter and Gamble Co
Original Assignee
Procter and Gamble Co
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Filing date
Publication date
Application filed by Procter and Gamble Co filed Critical Procter and Gamble Co
Publication of EP0941101A1 publication Critical patent/EP0941101A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/245—Bismuth; Compounds thereof

Definitions

  • H. pylori Helicobacter pylori
  • compositions and methods have been discovered by the present invention for the treatment of gastrointestinal disorders caused or mediated by H. pylori comprising the administration of bismuth salts, (other than salts formed between an H2 receptor antagonist and a complex of bismuth with a carboxylic acid), a non-steroidal anti- inflammatory drug, and one or more antimicrobials.
  • the present invention also comprises the optional administration of one or more antisecretory agents. It is believed that the administration of bismuth with a non-steroidal anti-inflammatory drug enhances gastric mucus bismuth concentrations.
  • an object of the present invention is to provide safe and effective compositions and methods of treating gastrointestinal disorders caused or mediated by H. pylori.
  • the present invention relates to a composition for treating a gastrointestinal disorder caused or mediated by Helicobacter pylori comprising from about 50 milligrams to about 5000 milligrams, per day, of bismuth; a gastropathic amount of a non-steroidal anti-inflammatory drug; a therapeutically effective amount of each of one or more antimicrobials; and pharmaceutically acceptable carriers.
  • the present invention also relates to a method for treatment of a human or lower animal subject having a gastrointestinal disorder caused or mediated by Helicobacter pylori comprising administering to the subject from about 50 milligrams to about 5000 milligrams of bismuth, per day, for from about 1 to about 42 days, a gastropathic amount of a non-steroidal anti-inflammatory drug for up to 14 days, and a therapeutically effective amount of each of one or more antimicrobials for from about 1 to about 21 days.
  • the present invention relates to methods and compositions for treating a gastrointestinal disorder caused or mediated by Helicobacter pylori comprising bismuth, a non-steroidal anti-inflammatory drug and one or more antimicrobials.
  • the inventions may optionally comprise therapeutically effective amounts of one or more antisecretory agents.
  • the compositions also comprise pharmaceutically acceptable carreiers.
  • the present invention and the essential and optional components therein are described fully below.
  • H. pylori are spiral bacteria which reside in the stomach. When first identified in the early 1980s, H. pylori was referred to by the name Campylobacter pyloridis. In recent years, these bacteria have been implicated as a causative factor for gastritis, non- ulcerative dyspepsia, and various ulcers of the gastrointestinal tract. These organisms are described in detail in the following publications, all of which are incorporated herein by reference in their entireties: Korman, M.G., Tygat, G.N., "Helicobacter pylori and Peptic Ulcer", Scandinavian Journal of Gastroenterology. Suppl., 210:92-96 (1995); Marshall, B.
  • gastrointestinal disorder encompasses any infection, disease or other disorder of the body, typically of the upper and/or lower gastrointestinal tract, caused or mediated by H. pylori.
  • An individual having such a gastrointestinal disorder may be symptomatic or asymptomatic.
  • Such disorders include, for example, H. pylori disorders not manifested by the presence of ulcerations in the gastric mucosa, including chronic active or atrophic gastritis, non-ulcer dyspepsia, esophageal reflux disease and gastric motility disorders; and peptic ulcer disease, i.e., H. /?v/ ⁇ r/-mediated pre-pyloric, marginal, gastric, duodenal and/or jejunal ulcers.
  • the presence of a gastrointestinal disorder caused or mediated by H pylori is preferably determined by any of the diagnostic methods recognized and utilized by the medical community. Details concerning such methods are described more fully in the following publications, all of which are incorporated herein by reference in their entireties: Megraud, F., "Diagnosis of Helicobacter pylori Infection", Scandinavian Journal of Gastroenterology, Supplement, 214: 44-46, 57-60 (1996); Cutler, A.
  • the present invention involves administration of bismuth.
  • the quantity of bismuth is by weight of elemental bismuth.
  • bismuth may be in the form of a pharmaceutically- acceptable salt, or may be in the form of an organic complex which contains bismuth as an active ingredient.
  • organic complexes include 2,2'-spirobi [ 1,3,2- benzodoxabismole]. Salts formed between an H2 receptor antagonist and a complex of bismuth with a carboxylic acid are not included for use in the present inventions.
  • bismuth is administered in the present methods as a pharmaceutically- acceptable salt.
  • Such bismuth salts include bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgallate, bismuth subnitrate, bismuth tartrate, bismuth subsahcylate, and mixtures thereof.
  • Bismuth citrate, bismuth subcitrate, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth subsahcylate, and mixtures thereof are preferred bismuth salts for use in this invention.
  • the bismuth useful herein may be administered alone, or in combination with other pharmaceutically-acceptable components in a bismuth-containing composition.
  • compositions containing bismuth salts are commercially available.
  • Such compositions include DeNol, containing tripotassium dicitrato bismuthate (by Brocades); Bislumina, containing bismuth aluminate (by Mazuelos); Roter, containing bismuth subnitrate (by Roterpharma); Devrom®, containing bismuth subgallate (by The Parthenon Co., Inc.); and Pepto-Bismol®, containing bismuth subsahcylate (by The Procter & Gamble Company).
  • bismuth may be administered in an amount of from about 50 milligrams to about 5000 milligrams per day, and preferably from about 50 milligrams to about 2500 milligrams, per day, for from about 1 to about 42 days, preferably for up to about 28 days, and most preferably for up to about 14 days.
  • NSAID refers to any agent which has anti- inflammatory, antipyretic and analgesic properties. Examples of NSAIDs are fully described in U.S. Patent 4,985,459 to Sunshine et al., issued January 15, 1991, incorporated by reference herein in its entirety. For detailed disclosure of the chemical structure, synthesis, side effects, etc. of non-steroidal anti-inflammatory agents, references may be had to standard texts, including Anti-Inflammatory and Anti- Rheumatic Drugs. K. D. Rainsford, Vol. I-III, CRC Press, Boca Raton (1985), and Anti- Inflammatory Agents. Chemistry and Pharmacology, 1 R. A. Scherrer, et al., Academic Press, New York (1974), both of which are incorporated by reference herein.
  • NSAIDs useful in the present invention include, but are not limited to: the oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304; the salicylates, such as acetylsalicylic acid, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, and felbinac; the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfena
  • NSAIDs useful in the present invention include, but are not limited to: acetylsalicylic acid, ibuprofen, fenbuprofen, fenoprofen, flurbiprofen, indomethacin, ketoprofen, naproxen, their pharmaceutically-acceptable salts, enantiomers thereof, and mixtures thereof. Ibuprofen, indomethacin, acetylsalicylic acid, and naproxen are especially preferred for use in the present invention.
  • NSAIDs are administered in a gastropathic amount.
  • the term "gastropathic amount", as used herein, refers to a level and frequency of administration of NSAID which is sufficient to produce gastropathy, e.g.
  • mucosal damage as judged by fiberoptic endoscopy, in normal subjects after a one week course of therapy.
  • Such an amount will vary depending on the particular NSAID being administered, the size and/or condition of the subject receiving treatment and/or other medical factors determined by the administering physician.
  • the gastropathic amounts for specific NSAIDs are known in the art. For example, acetylsalicylic acid administered at a levels of about 2.4 to 3.9 grams per day for one week will consistently produce mucosal injury without causing complications.
  • Gastropathic amounts for other NSAIDs are levels which produce comparable gastropathy to the gastropathy produced by the acetylsalicylic acid levels disclosed herein.
  • the duration of NSAID administration is for up to about 14 days, and preferably for from 1 about to about 10 days.
  • the duration of administration should be less than that associated with the development of complications. Therefore, the most preferred duration of administration of the NSAID is from about 1 to about 7 days.
  • the present inventions also include administration of a theraputically effective amount of each of one or more antimicrobials, per day.
  • antimicrobial refers to one or more antimicrobial agents, other than and in addition to bismuth, which are effective against H. pylori.
  • therapeutically effective amount refers to a level which is commonly known in the art and recognized and utilized by the medical community.
  • each of the one or more antimicrobials is administered at a level of from about 100 milligrams to about 10,000 milligrams, per day, for from about 1 to about 28 days.
  • each of the one or more antimicrobials is administered at a level of from about 100 milligrams to about 8000 milligrams per day, and more preferably at from about 100 milligrams to about 5000 milligrams per day. It is also preferred that each of the antimicrobials is administered for from about 1 to about 21 days, more preferably for from about 1 to about 14 days, and most preferably for from about 7 to about 10 days.
  • the specific dosage of antimicrobial(s) to be administered, as well as the duration of antimicrobial(s) treatment, are mutually dependent, and will also depend upon such factors as the specific antimicrobial used, the number of antimicrobials used in the treatment, the resistance pattern of the infecting organism to the antimicrobial used, the ability of the antimicrobial to reach minimum inhibitory concentrations at the site of the infection, the nature and extent of other infections (if any), the personal attributes of the subject, compliance with the treatment regimen, and the presence and severity of any side effects of the treatment. Therefore, in the case of prevention or treatment with more than one antimicrobial, the duration of administration should depend on the type of antimicrobial rather than the administration of the antimicrobials for the same number of days.
  • antimicrobial refers to any naturally-occurring, synthetic or semi-synthetic compound or composition or mixture thereof, which is safe for human use as used in the methods of this invention, and is effective in killing or substantially inhibiting H. pylori when used according to the present inventions. Antibiotics are preferred for use herein.
  • Antibiotics can be generally classified by chemical composition, into the following principal groups: the aminoglycosides, such as gentamicin, neomycin, kanamycin, and streptomycin; the macrolides, such as erythromycin, clindamycin, and rifampin; the penicillins, such as penicillin G, penicillin V, ampicillin and amoxycillin; the polypeptides such as bacitracin and polymyxin; the tetracyclines such as tetracycline, chlortetracycline, oxytetracycline and doxycycline; the cephalosporins such as cephalexin and cephalothin; quinolones such as ciprofloxacin, norfloxacin and ofloxacin; and such miscellaneous antibiotics as chloramphenicol and clindamycin. These antibiotics can generally be said to function in one of four ways: inhibition of cell wall synthesis, alteration of cell wall permeability, inhibition of protein
  • antimicrobials useful herein include the sulfonamides; nitrofurans, such nitrofurazon, nitrofurantoin, and furozolidone; metronidazole, tinidazole, and nimorazole. Antimicrobials among those useful herein are described in Remington's Pharmaceutical Sciences, 18th Edition, pp. 1173-1232 (1990), which is incorporated herein by reference.
  • antimicrobials penicillin, erythromycin, metronidazole, doxycycline, tinidazole, amoxycillin, ampicillin, tetracycline, nitrofurantoin, and mixtures thereof are among the preferred antimicrobials for use in the present invention.
  • the specific preferred quantity of antimicrobial and duration of treatment used in the methods of this invention will, in addition to other factors, depend upon the particular antimicrobial used and its pharmacology.
  • the tetracyclines are preferably administered at a level of from about 100 milligrams to about 2,000 milligrams per day.
  • Macrolides such as erythromycin
  • Penicillins are preferably administered at a level of from about 500 milligrams to about 3,000 milligrams per day.
  • aminoglycosides such as neomycin
  • Nitrofurans such as nitrofurantoin
  • metronidazole is administered at a level of from about 500 to about 2,000 milligrams per day.
  • the specific method of administering the antimicrobial may depend upon such factors as the particular antimicrobial(s) used, the site of infection, the amount of antimicrobial(s) to be administered per day, the presence of any adverse side effects, and the interactions (if any) between the antimicrobial(s) and the bismuth.
  • the antimicrobial(s) may be administered under the process of this invention by single daily doses, or by administration in two, three, four, or more doses per day.
  • the present invention can optionally include one or more antisecretory agents.
  • antisecretory agent refers to agents selected from the group consisting of H2 receptor antagonists, proton pump inhibitors, and mixtures thereof. These agents are administered in a therapeutically effective amount.
  • therapeutically effective amount refers to a level which is commonly known in the art and recognized and utilized by the medical community. Such an amount will vary depending on the particular agent(s) administered, the size and/or condition of the individual receiving treatment or other medical factors determined by the administering physician.
  • H2 receptor antagonists are disclosed fully in U.S. Patent No. 5,294,433 to
  • H2 receptor antagonists include cimetidine, etintidine, ranitidine, ICIA-5165, tiotidine, ORF- 17578, luptidine, donetidine, famotidine, rozatidine, pifatidine, lamtidine, BL-6548, BMY-25271, zaltidine, nizatidine, mifentidine, BMY-52368,SKF- 94482, BL-6341A, ICI-162846, ramixotidine, Wy-45727, SR-58042, BMY-25405, loxidine, DA-4634, bisfentidine, sufotidine, ebrotidine, HE-30-256,D-16637, FRG- 8813, FRG-8701, impromidine, L-643728, HB-4-08, and mixtures thereof.
  • Preferred for use in the present invention are cimetidine, ranitidine, famotidine, roxatidine, nizatidine, mifentidine, and mixtures thereof. Most preferred are cimetidine and ranitidine.
  • Proton pump inhibitors are described in greater detail in the following publications, which are incorporated by reference herein in their entireties: U.S. Patent No. 4,786,505 to Lovgren, issued November 22, 1988; U. S. Patent No. 4,255,431 to Junggren, issued March 10, 1981 ; and U.S. Patent No. 4,853,230 to Lovgren, issued August 1, 1989.
  • Preferred for use in the present invention are omeprazole, lansoprazole, pantoprazole, and mixtures thereof. Most preferred is omeprazole.
  • Antisecretory agents may be administered for from about 1 to about 42 days, preferably for up to about 28 days, and most preferably for up to about 14 days.
  • Pharmaceutically Acceptable Carriers may be administered for from about 1 to about 42 days, preferably for up to about 28 days, and most preferably for up to about 14 days.
  • compositions of the present invention may contain optional components which affect the physical and therapeutic characteristics of the present compositions.
  • a variety of pharmaceutically-acceptable carriers and excipients may be included, depending upon the particular dosage form to be used.
  • Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions, and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring, and flavoring agents.
  • compositions of this invention may be used according to the methods of this invention by administering the composition from 1 to 4 times per day, and preferably from 1 to 2 times per day; for from 1 to 28 days, preferably for from about 1 to about 21 days, and most preferably for from about 1 to about 14 days.
  • the specific frequency of administration will depend upon such factors as the specific NSAID, bismuth compound or composition and antimicrobial(s) used, the levels at which the components are incorporated in the composition, the nature and severity of the condition to be treated, and the nature of any concurrent therapy, if any.
  • the methods of the present invention comprise the treatment of a human or lower animal subject having a gastrointestinal disorder caused or mediated by Helicobacter pylori comprising administering to the subject bismuth, a non-steroidal anti-inflammatory drug, and one or more antimicrobials.
  • the present method may further comprise the administration of one or more antisecretory agents.
  • administering refers to any method which, in sound medical practice delivers the compounds or compositions used in this invention to the subject to be treated in such a manner so as to be effective in the treatment of the gastrointestinal disorder.
  • the bismuth, NSAID, antimicrobial(s) and antisecretory agent(s), if present, are administered orally.
  • the present invention encompasses methods wherein the administering of bismuth, the NSAID, the antimicrobial(s) and optionally the antisecretory agent(s) are performed simultaneously (beginning and ending on the same day), concurrently
  • the bismuth, NSAID and antimicrobial are administered concurrently and administration for bismuth, the NSAID and the antimicrobial is commenced on the same day. Additionally, if one or more antisecretory agents are also present, it is preferred that the bismuth and the antisecretory agent(s) are administered simultaneously.
  • EXAMPLE I An asymptomatic young volunteer identified as having H pylori infection through the results of a mass screening, is treated by a method of the present invention.
  • the subject is orally administered approximately 2500 milligrams of bismuth in the form of bismuth subcitrate ("DeNol", sold by Brocades) in four equal doses, for 28 days; approximately 100-200 milligrams of indomethacin daily, in four equal doses, for about 14 days; and approximately 1 gram of erythromycin daily, in two equal doses, for about 14 days.
  • a diagnostic test performed on the volunteer shows no evidence of H. pylori.
  • tripotassium dicitrato bismuthate, bismuth tartrate, bismuth citrate, and bismuth subnitrate are substituted, respectively, for bismuth subsahcylate, with substantially similar results.
  • a human subject is suffering from chronic active gastritis.
  • a diagnostic test reveals the presence of H pylori.
  • the individual is treated by orally administering approximately 2100 milligrams of bismuth daily, in the form of bismuth subsahcylate, ("Pepto-Bismol®", sold by The Procter & Gamble Company), in four equal doses, for about 14 days; approximately 3.9 grams of acetylsalicylic acid daily, in three equal doses, for about 14 days; approximately 20 milligrams of omeprazole daily, for 14 days; approximately 1000 milligrams of metronidazole daily, in four equal doses, for 14 days; and approximately 2000 milligrams of tetracycline daily in four equal doses, for 14 days.
  • Administration of all agents are commenced on the same day. One to two months later, the diagnostic test is repeated. The results show no evidence of H. pylori.
  • EXAMPLE III EXAMPLE III
  • a human subject is suffering from non-ulcer dyspepsia.
  • a biopsy of the gastric mucosa is taken from the stomach of the subject. Analysis of the biopsy sample indicates the presence of urease in the sample and the presence of H pylori in the stomach of the subject.
  • the subject is given approximately 1200 milligrams of bismuth daily, (administered as bismuth subsahcylate in the composition Pepto-Bismol®, sold by The Procter & Gamble Company), in four equal doses, for about 21 days; 1200-3200 milligrams of ibuprofen daily, in three to four equal doses, for about 7 days; 150 milligrams of ranitidine daily, in two equal doses, for about 21 days; and 500 milligrams of metronidazole daily, in four equal doses, for about 14 days. Administration of all agents are commenced on the same day. A biopsy sample taken and analyzed one to two months later shows no evidence of//, pylori.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des méthodes et des compositions pour traiter les troubles gastro-intestinaux provoqués par Helicobacter pylori, contenant du bismuth, une quantité gastropathique d'un médicament anti-inflammatoire non stéroïdien et une quantité suffisante pour avoir un effet thérapeutique d'un ou de plusieurs anti-microbiens. La composition peut également contenir une quantité suffisante pour avoir un effet thérapeutique, d'un ou de plusieurs médicaments anti-sécrétoires.
EP97948489A 1996-11-22 1997-11-21 Compositions de traitement de troubles gastro-intestinaux contenant du bismuth, des anti-inflammatoires non steroidiens ainsi qu'un ou plusieurs agents anti-microbiens et methodes correspondantes Withdrawn EP0941101A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US75551896A 1996-11-22 1996-11-22
US755518 1996-11-22
PCT/US1997/021461 WO1998022117A1 (fr) 1996-11-22 1997-11-21 Compositions de traitement de troubles gastro-intestinaux contenant du bismuth, des anti-inflammatoires non steroidiens ainsi qu'un ou plusieurs agents anti-microbiens et methodes correspondantes

Publications (1)

Publication Number Publication Date
EP0941101A1 true EP0941101A1 (fr) 1999-09-15

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EP97948489A Withdrawn EP0941101A1 (fr) 1996-11-22 1997-11-21 Compositions de traitement de troubles gastro-intestinaux contenant du bismuth, des anti-inflammatoires non steroidiens ainsi qu'un ou plusieurs agents anti-microbiens et methodes correspondantes

Country Status (4)

Country Link
EP (1) EP0941101A1 (fr)
CA (1) CA2271799A1 (fr)
NO (1) NO992469L (fr)
WO (1) WO1998022117A1 (fr)

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SE9600070D0 (sv) 1996-01-08 1996-01-08 Astra Ab New oral pharmaceutical dosage forms
AU8354498A (en) * 1997-08-25 1999-03-16 Procter & Gamble Company, The Combined preparations for treating upper gastrointestinal tract distress
IL145220A0 (en) * 1999-05-20 2002-06-30 Par Pharmaceutical Inc Stabilized composition based on pyridinyl-sulfinyl-benzimidazoles and process
TWI243672B (en) * 1999-06-01 2005-11-21 Astrazeneca Ab New use of compounds as antibacterial agents
SE0000774D0 (sv) 2000-03-08 2000-03-08 Astrazeneca Ab New formulation
IL142037A0 (en) * 2001-03-15 2002-03-10 Agis Ind 1983 Ltd Pharmaceutical compositions containing a non-steroidal anti-inflammatory drug
ATE474559T1 (de) 2001-06-01 2010-08-15 Pozen Inc Pharmazeutische zusammensetzungen für die koordinierte abgabe von nsaid
US8206741B2 (en) 2001-06-01 2012-06-26 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
SE0102993D0 (sv) 2001-09-07 2001-09-07 Astrazeneca Ab New self emulsifying drug delivery system
JP5035865B2 (ja) * 2005-09-26 2012-09-26 国立大学法人高知大学 Ｈｅｌｉｃｏｂａｃｔｅｒｐｙｌｏｒｉ菌株の増殖・運動抑制方法
BRPI0918492A2 (pt) 2008-09-09 2015-12-01 Astrazeneca Ab uso de naproxen, ou sal farmaceuticamente aceitável do mesmo, e esomeprazol, ou sal farmaceuticamente aceitável do mesmo
KR20120030106A (ko) 2009-06-25 2012-03-27 아스트라제네카 아베 Ｎｓａｉｄ-연관된 궤양의 발생 위험이 있는 환자의 치료 방법
WO2013101897A2 (fr) 2011-12-28 2013-07-04 Pozen Inc. Compositions et procédés d'administration d'oméprazole plus acide acétylsalicylique améliorés
ES2744406T3 (es) 2013-02-13 2020-02-25 Redhill Biopharma Ltd Composiciones farmacéuticas para el tratamiento de helicobacter pylori
US11096948B2 (en) * 2016-01-21 2021-08-24 Dexcel Pharma Technologies Ltd. Methods for treating helicobacter infection
US11878011B2 (en) 2020-05-07 2024-01-23 Redhill Biopharma Ltd. Method for eradicating Helicobacter pylori infection in patients regardless of body mass index

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FI910088A (fi) * 1990-01-09 1991-07-10 Gist Brocades Nv Oral farmaceutisk komposition.
DE69228738D1 (de) * 1991-12-06 1999-04-29 Glaxo Group Ltd Zusammensetzungen zur Behandlung von entzündlichen Zuständen oder Analgesie, die Ranitidin Wismuth Citrat und einen NSAID enthalten

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NO992469D0 (no) 1999-05-21
WO1998022117A1 (fr) 1998-05-28
CA2271799A1 (fr) 1998-05-28
NO992469L (no) 1999-07-22

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