GB2259647A - Ranitidine salt compositions - Google Patents

Ranitidine salt compositions Download PDF

Info

Publication number
GB2259647A
GB2259647A GB9219749A GB9219749A GB2259647A GB 2259647 A GB2259647 A GB 2259647A GB 9219749 A GB9219749 A GB 9219749A GB 9219749 A GB9219749 A GB 9219749A GB 2259647 A GB2259647 A GB 2259647A
Authority
GB
United Kingdom
Prior art keywords
metronidazole
tetracyclin
bismuth citrate
treating
antibiotics
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.)
Granted
Application number
GB9219749A
Other versions
GB9219749D0 (en
GB2259647B (en
Inventor
Andrew Alexander Mccolm
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.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
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 Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of GB9219749D0 publication Critical patent/GB9219749D0/en
Publication of GB2259647A publication Critical patent/GB2259647A/en
Application granted granted Critical
Publication of GB2259647B publication Critical patent/GB2259647B/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis

Abstract

The use is described of both (i) ranitidine bismuth citrate and (ii) one or more Helicobacter pylori-inhibiting antibiotics in treating or preventing gastrointestinal disorders. Pharmaceutical compositions containing both (i) and (ii) and methods for the preparation of pharmaceutical compositions containing (i) and (ii) are also described.

Description

7 ^ r 111 4 L - 1 MEDICAMENTS FOR TREATING GASTROINTESTINAL DISORDERS The
present invention relates to improvements in the treatment of gastrointestinal disorders. More particularly it relates to the co-administration of a salt formed between ranitidine and a complex of bismuth with a carboxylic acid, with antibiotics.
In our published UK Patent Specification No. 2220937A we describe and claim salts formed between ranitidine and a complex of bismuth with a carboxylic acid, particularly tartaric acid and, more especially, citric acid. One such salt is N-[2-[[[5[(dimethylamino)methyll -2-furanyll methyl] thio] ethyl] -N'-methyl-2- nitro-l,l-ethenediamine 2-hydroxy-1,2,3-propanetricarboxylate bismuth (3') complex, also known as ranitidine bismuth citrate.
The salts disclosed in UK Patent Specification No. 2220937A. possess the
H2-antagonist antisecretory properties associated with ranitidine, together with antibacterial activity against Helicobacter pylori (formerly Campylobacter pylori). In addition, such salts possess cytoprotective properties, and display activity against the human gastric pepsins, with preferential inhibition of pepsin 1, a pepsin isozyme associated with peptic ulcer. The salts disclosed in UK Patent Specification No.
2220937A thus possess a particularly advantageous combination of properties for the treatment of gastrointestinal disorders, especially peptic ulcer disease and other gastroduodenal conditions, for example gastritis and non-ulcer dyspepsia.
We have now shown that the antibacterial activity of ranitidine bismuth citrate against Helicobacter organisms may be significantly enhanced by co- administering the compound with one or more antibiotics.
The present invention thus provides, in one aspect, the use of (i) ranitidine bismuth citrate and (ii) one or more Helicobacter pylori-inhibiting antibiotics in the manufacture of medicaments for simultaneous, separate or sequential use in treating or preventing gastrointestinal disorders.
The term "gastrointestinal disorder" as used herein encompasses a disease or other disorder of the gastrointestinal tract, including for example a disorder not manifested by the presence of ulcerations in the gastric mucosa (eg gastritis, non- ulcer dyspepsia, HA161C 2 esophagal reflux disease and gastric motility disorders), and peptic ulcer disease (eg gastric and duodenal ulcer disease). The ranitidine bismuth citrate is preferably co-administered with one or two antibiotics but, in particularly difficult cases, three antibiotics may be required. 5 A wide variety of antibiotics may be used according to the invention, including for example nitroimidazole antibiotics (e.g. tinidazole or metronidazole), tetracyclines (e.g. tetracyclin, doxycyclin and minocyclin), pencillins (e.g. amoxycillin, ampicillin and mezlocillin), cephalosporins (e.g. cefachlor, cefadroxil, cephradine, cefuroxime, cefuroxime. axetil, cephalexin, cefpodoxime proxetil, ceftazidime and ceftriaxone), carbopenems (e.g. imipenem and meropenem), amino-glycosides (e.g. paromonycin), macrolide antibiotics (e.g. erythromycin, clarithromycin and azithromycin), lincosamide antibiotics (e.g. clindamycin), 4-quinolones (e.g. ofloxacin, ciprofloxacin, pefloxacin and norfloxacin), rifamycins (e.g. rifampicin), nitrofurantoin and derivatives of 10-(lhydroxyethyl)11-oxo-l-azatricyclo[7.2.0.0.3.8]undec-2-ene-2-carboxylic acid described 15 in published European Patent Specification No. 0416953 and published International Patent Specification No. W092103437. Antibiotics which may be administered orally are generally preferred. Examples include metronidazole, tetracyclin (especially as tetracyclin hydrochloride), arnoxycillin, cefuroxime axetil and clarithromycin. 20 Preferred combinations include ranitidine bismuth citrate and metronidazole; ranitidine bismuth citrate and tetracyclin; ranitidine bismuth citrate and cefuroxime axetil; ranitidine bismuth citrate and arnoxycillin; ranitidine bismuth citrate and clarithromycin; ranitidine bismuth citrate, metronidazole and amoxycillin; ranitidine bismuth citrate, metronidazole and tetracyclin; and ranitidine bismuth citrate, tetracyclin and clarithromycin.
Combinations of ranitidine bismuth citrate and cefuroxime and rantidine bismuth citrate, cefuroxime and metronidazole may also be preferred.
Particularly preferred combinations comprise ranitidine bismuth - citrate co-administered with either metronidazole, tetracyclin, metronidazole and amoxycillin, or metronidazole and tetracyclin. Such combinations have shown a synergistic antibacterial effect against Helicobacter pylori in vitro and against Helicobactor mustelae in vivo in ferrets. Thus, for example, in combination studies in vivo, co-administration of 7 HAMC 3 ranitidine bismuth citrate with one or two antibiotics hereinabove has produced a level of antibacterial acitivity against Helicobacter mustelae which is better than that shown by the active ingredients individually or, in the case of co-administration with two antibiotics, that shown by the two antibiotics together.
The ranitidine bismuth citrate and the one or more antibiotics are preferably co-administered in the form of separate pharmaceutical compositions for simultaneous and/or sequential use. Alternatively the ranitidine bismuth citrate and the antibiotic(s) may be administered as a single pharmaceutical composition for oral use comprising effective amounts of the active ingredients.
Thus, according to a further aspect, the invention provides a product containing (i) ranitidine bismuth citrate and (ii) one or more Helicobacter pylori- inhibiting antibiotics as a combined preparation for simultaneous, separate or sequential use in treating or preventing gastrointestinal disorders.
When the ranitidine bismuth citrate and the one or more antibiotics are administered as separate preparations, each of the antibiotics may conveniently be provided in the manner known in the art and/or commercially for the compounds concerned.
Administration of both the ranitidine bismuth citrate and the antibiotic(s) by the oral route is preferred, although the antibiotic(s), where appropriate, may also be given by another route, for example parenterally (e.g. intravenously, intramuscularly or subcutaneously).
The ranitidine bismuth citrate may conveniently be formulated as tablets (including chewable tablets), capsules (of either the hard or soft type), or as a liquid preparation, as described for example in UK Patent Specification Nos. 2220937A and 2248185A.
Tablets are generally preferred.
As stated hereinabove, ranitidine bismuth citrate and the antibiotic(s) may be administered as a single pharmaceutical composition for oral use. Thus according to a further aspect the invention provides a pharmaceutical composition, for oral use in human or veterinary medicine, comprising ranitidine bismuth citrate and one or more Helicobacter pylori-inhibiting antibiotics. Such compositions may be formulated in a conventional manner using additional pharmaceutically acceptable carriers or excipients as appropriate. Thus, the composition may be prepared by conventional means with additional carriers or excipients such as binding agents (e.g. pregelatinised maize starch, HA161C 4 polyvinylpyrrolidone or hydroxypropyl methylcellu lose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e. g. magnesium stearate, tale or silica); disintegrates (e.g. starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). An alkaline salt of the type described in UK Patent Specification No. 2248185A may be added to improve the rate of disintegration andlor dissolution of the composition. Tablets may be coated by methods well known in the art.
The preparations may also contain flavouring, colouring and/or sweetening agents as appropriate.
The compositions may be prepared according to conventional techniques well known in the pharmaceutical industry. Thus, for example, the ranitidine bismuth citrate and the antibiotic(s) may be admixed together, if desired, with suitable excipients. Tablets may be prepared, for example, by direct compression of such a mixture. Capsules may be prepared by filling the blend along with suitable excipients into gelatin capsules, using a suitable filling machine.
When ranitidine bismuth citrate and the antibiotic(s) are administered as a single pharmaceutical composition for oral use the composition is preferably in the form of a capsule or, more particularly, a tablet.
Low packing density oral pharmaceutical compositions comprising a soluble bismuth-containing pharmaceutical agent, including ranitidine bismuth citrate, optionally also comprising a Helicobacter 12ylori inhibiting antibiotic were recently described in International Patent Specification No. W092[11849. Thus, according to a further aspect, the present invention provides a pharmaceutical composition for oral use comprising ranitidine bismuth citrate and one or more Helicobacter 12ylori- inhibiting antibiotics wherein the packing density of the composition is not less than lg/ml.
The compositions for use according to the invention may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients. The pack may for example comprise metal or plastic foil, such as a blister pack. Where the ranitidine bismuth citrate and the one or more antibiotics are intended for administration as separate compositions these may be presented in the form of, for example, a multiple (e-g. twin) pack.
Thus, according to a further aspect the present invention provides a multiple-container pack for use in treating or preventing gastrointestinal disorders, one of tl HA161C the containers containing ranitidine bismuth citrate and the other(s) containing a Helicobacter 12vlori-inhibiting antibiotic.
The doses at which the ranitidine bismuth citrate and the one or more antibiotics may be administered to man (of approximately 70kg body wight) will depend on the route of administration of the antibiotic and on the nature and severity of the condition being treated. It will also be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient.
A proposed dosage of ranitidine bismuth citrate for use according to the invention is 150rng to 1.5g, preferably 200 - 80Orng per unit dose. The unit dose may be administered, for example, 1 to 4 times per day.
The one or more antibiotics may conveniently be administered at doses within the normal dosage range at which the compound(s) are therapeutically effective, or at higher doses if required. The antibiotic(s) may be taken one or more times daily as appropriate.
In a further aspect, the present invention provides a method for treating or preventing gastrointestinal disorders in a human or animal subject, which comprises administering to said subject effective amounts of ranitidine bismuth citrate and one or more Helicobacter 12ylori-inhibiting antibiotics.
The methods of the present invention comprise administering the Helicobacter pyori-inhibiting antibiotic(s) and ranitidine bismuth citrate either concurrently or non-concurrently. As used herein, concurrent administration means that the agents are given within 24 hours of each other, whereas non-concurrent administration means that the agents are given more than 24 hours apart. When the agents are administered concurrently, it may be preferable to administer the agents within about 1 hour of each other or, more preferably, within about 5 minutes of each other.
For the methods of the present invention, the duration of administration of the agents during either concurrent or non-concurrent dosing will vary according to the specific gastrointestinal disorder being treated. However, a typical regime would be to administer ranitidine bismuth citrate for 4 to 8 weeks and during this period to administer one or more antibiotics for 1 to 2 weeks.
As stated hereinabove, certain combinations of ranitidine bismuth citrate with antibiotics have shown a synergistic effect in vitro against Helicobacter 12ylori and in vivo against Helicobacter mustelae.
HA161C In Vitro Synergy Methodology 6 Synergy was measured dependent on the rate of kill observed in minimal bactericidal concentrations (MBCs) using a 2-dimensional microtitre checkerboard method'. The checkerboard is produced by serially diluting agent A prior to addition to the plates. Agent B was then diluted in the wells containing A to a final volume of 50gl. Each well is then inoculated with 50gI of H.pylori cultured in broth and the plates incubated at 37T. Plates are then sampled at 24, 48 and 72 hours for H. pylori growth using a 0 - 6 quantitative scale. Mean fractional inhibitory concentrations (FICs) were 10 then determined from 2- dimensional isobolograms. A mean FIC index of less than 1 synergy'.
To confirm synergy, time kill studies using the apparently effective combinations were subsequently performed in 3 mI broth cultures.
FIC index = FICA+ FICB where FICA= MBC_ in presence of B MBCA and FICB = MBC_ in presence of A MBC13 In Vivo Synergy Methodology Ferrets naturally colonised with H.mustelae were treated with either ranitidine bismuth citrate (24rng/kg), amoxycillin and metronidazole (1Orng/kg and 20rng/kg respectively) or the combination of all three agents. Compounds were given orally three times daily for 28 days with the exception of metronidazole (day 0 - 9 only). The apparent colonisation frequency was assessed from gastric antral biopsies obtained by endoscopy before, during and after the therapy phase. A culture - positive biopsy means that the compound is still colonised.
Results In vitro, the combination of ranitidine bismuth citrate with tetracyclin, metronidazole, amoxycillin or cefuroxime demonstrated a synergistic effect. Indeed, the 3 h.
HA161C 7 combination of ranitidine bismuth citrate with tetracyclin or metronidazole gave a mean FIC index < 0.5.
In vivo, the combination of ranitidine bismuth citrate with metronidazole and amoxycillin proved superior to either ranitidine bismuth citrate alone or the antibiotics alone and lead to 2/6 infections being eradicated. The ranitidine bismuth citrate or antibiotic alone groups failed to eradicate but showed good suppression. The removal of metronidazole from the regime after ten days dosing resulted in a subsequent relapse of infections by day 28, particularly in the metronidazole/amoxycillin group.
References 1. Berenbaum, M.C., Applied Microbiology 16: 890-895, 1968.
2. McLaren, A and McDowell, S.R., Irish Journal of Medical Science, Sth Workshop on Gastroduodenal Pathology and Helicobacter pylori, p98 (1992).
HA161C

Claims (14)

  1. 8 1. The use of (i) ranitidine. bismuth citrate and (ii) one or more Helicobact RyLori-inhibiting antibiotics in the manufacture of medicaments for simultaneous, 5 separate or sequential use in treating or preventing gastrointestinal disorders.
  2. 2. The use according to Claim 1 in which the compounds (i) and (ii) are presented as separate compositions for said use.
  3. 3. A product containing compounds (i) and (ii) as defined in Claim 1 as a combined preparation for simultaneous, separate or sequential use in treating or preventing gastrointestinal disorders.
  4. 4. A pharmaceutical composition, for oral use, which comprises both a compound (i) and a compound (ii) as defined in Claim 1, together with a pharmaceutical carrier or excipient.
  5. 5. A use, product or composition according to any preceding claim in which (ii) is one or more antibiotics selected from metronidazole, tetracyclin, amoxycillin, cefuroxime axetil and clarithromycin.
  6. 6. A use, product or composition according to Claim 5 in which (ii) is selected from metronidazole, tetracyclin, cefuroxime- axetil, amoxycillin, clarithromycin, metronidazole and amoxycillin, metronidazole and tetracyclin, and tetracyclin and clarithromycin.
  7. 7. A use, product or composition according to Claim 6 in which (ii) is selected from metronidazole, tetracyclin, metronidazole and arnoxycillin, and metronidazole and tetracyclin.
  8. 8. A use or product according to any of Claims 1 - 3 in which (ii) is selected from cefuroxime, and cefuroxime and metronidazole.
    HA161C
  9. 9 9. A use or product according to any of Claims 1 - 7 in which compounds (i) and (ii) are in forms suitable for oral administration.
  10. 10. A use or product according to any preceding claim in which compound (i) is formulated as a tablet.
  11. 11. A multiple-container pack for use in treating or preventing gastrointestinal disorders, one of the containers containing (i) and the other(s) containing (ii) as defined in the preceding claims.
  12. 12. A composition according to any of Claims 4 - 7, or a pack according to Claim 11, in associated with instructions for the use of both (i) and (ii) in treating or preventing gastrointestinal disorders.
  13. 13. A method for the preparation of a composition according to any of Claims 4 - 7 which comprises admixing (i) and (ii) together, if desired, with suitable excipients.
  14. 14. A method for treating or preventing gastrointestinal disorders in a human or animal subject, which comprises administering to said subject effective amounts of compounds 20 (i) and (ii) as defined in the preceding claims.
GB9219749A 1991-09-20 1992-09-18 Medicaments for treating gastrointestinal disorders Expired - Fee Related GB2259647B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB919120131A GB9120131D0 (en) 1991-09-20 1991-09-20 Medicaments

Publications (3)

Publication Number Publication Date
GB9219749D0 GB9219749D0 (en) 1992-10-28
GB2259647A true GB2259647A (en) 1993-03-24
GB2259647B GB2259647B (en) 1995-11-29

Family

ID=10701750

Family Applications (2)

Application Number Title Priority Date Filing Date
GB919120131A Pending GB9120131D0 (en) 1991-09-20 1991-09-20 Medicaments
GB9219749A Expired - Fee Related GB2259647B (en) 1991-09-20 1992-09-18 Medicaments for treating gastrointestinal disorders

Family Applications Before (1)

Application Number Title Priority Date Filing Date
GB919120131A Pending GB9120131D0 (en) 1991-09-20 1991-09-20 Medicaments

Country Status (26)

Country Link
US (3) US5674858A (en)
EP (1) EP0533281B1 (en)
JP (1) JPH0692850A (en)
KR (1) KR100257367B1 (en)
AT (2) ATE228835T1 (en)
BE (1) BE1005808A5 (en)
CA (1) CA2078579A1 (en)
CH (1) CH685372A5 (en)
CY (1) CY2012A (en)
CZ (1) CZ282840B6 (en)
DE (1) DE69232864T2 (en)
ES (1) ES2188582T3 (en)
FR (1) FR2682040B1 (en)
GB (2) GB9120131D0 (en)
HK (1) HK78197A (en)
HU (1) HU211170A9 (en)
IE (1) IE922673A1 (en)
IL (1) IL103213A (en)
IT (1) IT1262993B (en)
MX (1) MX9205313A (en)
NO (1) NO301456B1 (en)
NZ (1) NZ244390A (en)
PT (1) PT533281E (en)
RU (1) RU2116071C1 (en)
SK (1) SK280283B6 (en)
ZA (1) ZA927157B (en)

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE68915272T2 (en) * 1988-10-31 1994-11-17 Sumitomo Cement Co ANTI-REFLECTION OBJECTS, PRODUCTION PROCESSES AND COATING COMPOSITIONS.
AU6436394A (en) * 1993-06-15 1995-01-03 Pfizer Inc. H2-antagonists as immune stimulants in bacterial infections of cattle or swine
DE69424487T2 (en) * 1993-09-09 2001-01-18 Takeda Chemical Industries Ltd Formulation containing an antibacterial and an antiulcus active ingredient
TW420610B (en) * 1994-04-07 2001-02-01 Pfizer A pharmaceutical composition for treating a H. pylori infection or gastric or duodenal ulcers
KR970702725A (en) * 1994-04-26 1997-06-10 노부히로 나리따 Medical Composition as a Remedy for Nonsmall Cell Lung Cancer
CN1177357A (en) * 1995-01-26 1998-03-25 耐克麦德英梅金公司 Bismuth compound
GB9501560D0 (en) * 1995-01-26 1995-03-15 Nycomed Imaging As Contrast agents
US5981522A (en) * 1995-09-01 1999-11-09 Kaneka Corporation Treatment of disease caused by infection of Helicobacter
KR970032861A (en) * 1995-12-29 1997-07-22 김준웅 Helicobacter pylori removal drug administration method
US5900410A (en) * 1996-08-27 1999-05-04 Hartmann; John F. Monotherapy of peptic ulcers and gastritis
DE19709897A1 (en) * 1997-03-11 1998-09-17 Hoechst Ag Bismuth salts of antibiotics of the moenomycin group, process for their preparation, their use and medicaments containing such salts
US6017950A (en) 1997-08-05 2000-01-25 Millennium Pharmaceuticals, Inc. Methods for controlling gram negative bacteria in mammals
IT1296980B1 (en) * 1997-12-17 1999-08-03 Istituto Pirri S R L DOUBLE CAPSULE AS A PHARMACEUTICAL FORM FOR THE ADMINISTRATION OF ACTIVE INGREDIENTS IN MULTIPLE THERAPIES
WO2000066174A2 (en) * 1999-04-29 2000-11-09 Russinsky Limited Compounds
IL151496A0 (en) * 2000-02-29 2003-04-10 Teva Pharma Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same
US7670612B2 (en) * 2002-04-10 2010-03-02 Innercap Technologies, Inc. Multi-phase, multi-compartment capsular delivery apparatus and methods for using same
BRPI0408442A (en) 2003-03-17 2006-04-04 Japan Tobacco Inc method for increasing the oral bioavailability of s- [2 - ([[1- (2-ethylbutyl) cyclohexyl] carbonyl] amino) phenyl] 2-methylpropanothioate
US20060194748A1 (en) * 2005-02-28 2006-08-31 National University Corporation Nagoya University Methods for treating disorders induced by H. pylori infections and pharmaceutical compositions for the same
RU2586289C1 (en) 2012-09-28 2016-06-10 Сантэн Фармасьютикал Ко., Лтд. Therapeutic or prophylactic agents to prevent meibomian gland dysfunction or blocking of meibomian gland
US10201518B2 (en) 2016-09-28 2019-02-12 The University Of Hong Kong Bismuth(III) compounds and methods thereof
US11890295B2 (en) 2018-08-31 2024-02-06 Korea Institute Of Geoscience And Mineral Resources Helicobacter pylori eradication method including step for orally administering composition including complex of non-absorbable antibiotic and clay mineral to subject

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2220937A (en) * 1988-07-18 1990-01-24 Glaxo Group Ltd Ranitidine derivatives
WO1992011849A1 (en) * 1991-01-14 1992-07-23 The Procter & Gamble Company Swallowable pharmaceutical compositions

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB772567A (en) * 1954-05-06 1957-04-17 Siegfried Fischl Preparation of stable, injectable bismuth-containing pharmaceutical compositions and the compositions formed thereby
JPS62502967A (en) * 1985-04-18 1987-11-26 ザ・プロクター・アンド・ギャンブル・カンパニー Treatment of non-ulcer dyspepsia
US5256684A (en) * 1985-06-13 1993-10-26 The Procter & Gamble Company Methods and compositions for the treatment of gastrointestinal disorders
EP0462631B1 (en) * 1985-06-13 1996-03-20 Barry James Dr. Marshall Methods and compositions for the treatment of gastrointestinal disorders
US4959384A (en) * 1985-10-24 1990-09-25 Norwich Eaton Pharmaceuticals, Inc. Use of nitrofurantoin for the treatment and prophylaxis of gastrointestinal disorders
DE3874917T2 (en) * 1987-03-09 1993-03-04 Procter & Gamble COMPOSITIONS AND THEIR USE FOR THE TREATMENT OF STOMACH.
IL85472A (en) * 1987-03-09 1991-06-30 Procter & Gamble Pharmaceutical compositions for treating gastrointestinal disorders
DE3887353T2 (en) * 1987-10-12 1994-05-05 Exomed Australia Pty Ltd TREATMENT PROCEDURE FOR STOMACH-DISEASES.
FI910088A (en) * 1990-01-09 1991-07-10 Gist Brocades Nv ORAL PHARMACEUTICAL COMPOSITION.
YU45590A (en) * 1990-03-07 1992-07-20 PLIVA FARMACEVTSKA, KEMIJSKA, PREHRAMBENA I KOZMETIČKA INDUSTRIJA s.p.o. NEW COMPLEXES OR CHELATES OF ANTIBIOTICS WITH TWO-VALENT AND / OR TROVALENT METALS AND PROCEDURES FOR THEIR OBTAINING
GB9019875D0 (en) * 1990-09-11 1990-10-24 Glaxo Group Ltd Pharmaceutical compositions
AU8941891A (en) * 1990-12-04 1992-07-08 Anton Jenni Sprinkler installation for the floors of riding halls, hothouses, etc.
US5176698A (en) * 1991-01-09 1993-01-05 Scimed Life Systems, Inc. Vented dilatation cathether and method for venting

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2220937A (en) * 1988-07-18 1990-01-24 Glaxo Group Ltd Ranitidine derivatives
WO1992011849A1 (en) * 1991-01-14 1992-07-23 The Procter & Gamble Company Swallowable pharmaceutical compositions

Also Published As

Publication number Publication date
IL103213A0 (en) 1993-02-21
CZ287892A3 (en) 1993-12-15
SK287892A3 (en) 1995-06-07
AU2458492A (en) 1993-03-25
EP0533281B1 (en) 2002-12-04
DE69232864T2 (en) 2003-11-20
ZA927157B (en) 1993-06-15
ITRM920681A0 (en) 1992-09-18
NO301456B1 (en) 1997-11-03
CA2078579A1 (en) 1993-03-21
KR100257367B1 (en) 2000-05-15
SK280283B6 (en) 1999-11-08
FR2682040A1 (en) 1993-04-09
NO923643D0 (en) 1992-09-18
US5629297A (en) 1997-05-13
IT1262993B (en) 1996-07-23
AT403656B (en) 1998-04-27
IE922673A1 (en) 1993-03-24
ITRM920681A1 (en) 1994-03-18
NZ244390A (en) 1997-06-24
RU2116071C1 (en) 1998-07-27
GB9219749D0 (en) 1992-10-28
CY2012A (en) 1998-02-20
ATA186692A (en) 1997-09-15
CH685372A5 (en) 1995-06-30
ATE228835T1 (en) 2002-12-15
HU211170A9 (en) 1995-11-28
DE69232864D1 (en) 2003-01-16
GB2259647B (en) 1995-11-29
MX9205313A (en) 1993-04-01
NO923643L (en) 1993-03-22
PT533281E (en) 2003-04-30
US5668130A (en) 1997-09-16
FR2682040B1 (en) 1994-10-28
ES2188582T3 (en) 2003-07-01
HK78197A (en) 1997-06-20
BE1005808A5 (en) 1994-02-01
US5674858A (en) 1997-10-07
KR930005619A (en) 1993-04-20
JPH0692850A (en) 1994-04-05
IL103213A (en) 2000-02-29
AU663520B2 (en) 1995-10-12
CZ282840B6 (en) 1997-10-15
GB9120131D0 (en) 1991-11-06
EP0533281A1 (en) 1993-03-24

Similar Documents

Publication Publication Date Title
US5629297A (en) Medicament for treating gastrointestinal disorders
AU590578B2 (en) Treatment of non-ulcer dyspepsia with bismuth salts
EP0550083B1 (en) Medicaments for treating inflammatory conditions or for analgesia containing a NSAID and ranitidine bismuth citrate
WO2011005355A1 (en) Combinations comprising a lpxc inhibitor and an antibiotic for use in the treatment of infections caused by gram-negative bacteria
EP0282131A2 (en) Compositions and methods for treating gastrointestinal disorders
EP0839530A1 (en) Use of ellagic acid in the manufacture of a medicament for stimulating gastrointestinal motility
EP0544760B1 (en) Pharmaceutical compositions containing 5-difluoromethoxy-2- (3,4-dimethoxy-2-pyridyl) methylsulfinyl] benzimidazole and an anti-helicobacter agent for the treatment of gastrointestinal disorders
KR100550839B1 (en) Antimicrobials
JPH08512321A (en) H-Lower 2 Antagonist-alginate-antacid combination
US20030109503A1 (en) Pharmaceutical formulations comprising clavulanic acid alone or in combination with other beta-lactam antibiotics
US20060235076A1 (en) Medicinal composition for treating infection with drug-resistant staphylococcus aureus
EP0384410B1 (en) Antimicrobial composition
JP2018502155A (en) Compositions and methods for treating gastrointestinal infections
JP2002029966A (en) Anti-helicobacter pylori agent
JP2000080031A (en) Antimicrobial agent
JPH03279329A (en) Antibiotic comprising cephamycin and cephalosporin
EP0839531A1 (en) Use of ellagic acid in the manufacture of a medicament for the treatment of duodenal or gastric ulcer
JPH11246401A (en) Therapeutic agent for helicobacter pylori infectious disease
JPS6143116A (en) Method and agent for remedy of bacteriosis

Legal Events

Date Code Title Description
PCNP Patent ceased through non-payment of renewal fee

Effective date: 20090918