EP0533770A1 - Nouveau traitement - Google Patents

Nouveau traitement

Info

Publication number
EP0533770A1
EP0533770A1 EP91911107A EP91911107A EP0533770A1 EP 0533770 A1 EP0533770 A1 EP 0533770A1 EP 91911107 A EP91911107 A EP 91911107A EP 91911107 A EP91911107 A EP 91911107A EP 0533770 A1 EP0533770 A1 EP 0533770A1
Authority
EP
European Patent Office
Prior art keywords
histamine
receptor antagonist
treatment
antacid
gastric
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Withdrawn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
EP91911107A
Other languages
German (de)
English (en)
Inventor
Adrian Francis Davis
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.)
Beecham Group PLC
Original Assignee
Beecham Group PLC
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
Priority claimed from GB909013910A external-priority patent/GB9013910D0/en
Priority claimed from GB909018676A external-priority patent/GB9018676D0/en
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0533770A1 publication Critical patent/EP0533770A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/12—Magnesium silicate
    • 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
    • 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
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • 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
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • 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
    • 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
    • A61K33/42—Phosphorus; Compounds thereof
    • 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

Definitions

  • This invention relates to the treatment of gastric disorders and pharmaceutical compositions for use therein. More particularly the invention relates to the treatment of gastric disorders, including acute disorders such as acid indigestion, heartburn and gastritis, and gastric and peptic ulcer using an orally administrable pharmaceutical composition comprising an H -receptor antagonist and an antacid.
  • Histamine I ⁇ -receptor antagonists for example cimetidine, ranitidine, nizatidine and famotidine, reduce acid secretion by acting directly on the acid-secreting parietal cell located within the gastric gland of the stomach wall.
  • histamine ⁇ -receptor antagonists are remarkably effective in the treatment of many gastric disorders, in particular peptic and gastric ulcers, there exist certain patient groups which do not respond to treatment.
  • the time lapse between dosing and onset of action limits the potential benefit of histamine f ⁇ -receptor antagonists in the treatment of acute, self-limiting gastric disorders.
  • non-responders A significant proportion of gastric and peptic ulcer patients, referred to as non-responders, do not respond to conventional histamine ⁇ -receptor antagonist therapy.
  • Walker et aJL. Frequent non-response to histamine H 2 -receptor antagonists in cirrhotics; Gut, .30., 1105-9, 1989; and Brack A. et ⁇ il. : Clinical failures with cimetidine; Surgery, .88.(3) , 417-24.
  • Histamine ⁇ -receptor antagonists are of potential benefit 10 in the self-medication of acute, self-limiting gastric disorders such as hyperacidity. However, their slow onset of action is unlikely to meet the consumer requirement for rapid relief of symptoms.
  • histamine ⁇ -receptor antagonists Co-administration of histamine ⁇ -receptor antagonists and antacids has been investigated.
  • the rationale for co-administration is that the antacid brings about rapid relief from the symptoms of excess stomach acidity by 25 neutralisation, whereas the histamine ⁇ -receptor antagonist independently acts by inhibiting secretion of acid from the parietal cell.
  • histamine ⁇ -receptor antagonists when histamine ⁇ -receptor antagonists are co-administered with antacids, especially antacids with high acid-neutralising capacity, there is frequently a 35 substantial reduction in the plasma bioavailability of the histamine ⁇ -receptor antagonist. Histamine ⁇ -receptor antagonist-antacid combinations are therefore generally contraindicated. This contraindication for histamine ⁇ -receptor antagonist-antacid therapy is supported by pharmacokinetic modelling using a standard two-compartment model which indicates a reduction in the systemic absorption of the histamine ⁇ -receptor antagonist.
  • the present invention provides the use of an orally administrable pharmaceutical composition comprising a histamine ⁇ -receptor antagonist and an antacid for the manufacture of a medicament for the treatment of gastric disorders, characterised in that the antacid has equilibrium pH, acid neutralising capacity and gastric residence time values which provide a pH profile with time conferring a local pH level substantially equal to that of the pKa of the histamine ⁇ -receptor antagonist.
  • Local levels of the histamine ⁇ -receptor antagonist at the parietal cell receptor are thereby increased, conferring an increase in the acid-secretion reducing capacity of the histamine ⁇ -receptor antagonist.
  • An increase in acid-secretion reducing capacity is advantageous in the treatment of ulcer patients, in particular hypersecreting patients, in the treatment of those patients diagnosed as non-responders, and also to reduce the onset-phase of single-dose, self-medication for acute gastric disorders, for example gastric disorders due to hyperacidity.
  • the invention also provides a method of treatment of gastric disorders comprising orally administering to a sufferer an effective amount of a pharmaceutical composition comprising a histamine ⁇ -receptor antagonist and an antacid wherein the equilibrium pH, the acid neutralising capacity and the gastric residence time values confer a pH level substantially equal to that of the pKa of the histamine ⁇ -receptor antagonist.
  • the invention provides a pharmaceutical composition for use in the treatment of gastric disorders which comprises a histamine ⁇ -receptor antagonist and an antacid wherein the equilibrium pH, the acid neutralising capacity and the gastric residence time values confer a " pH level substantially equal to that of the pKa of the histamine ⁇ -receptor antagonist.
  • Histamine ⁇ -receptor antagonists for use in compositions of the invention include cimetidine, ranitidine and famotidine, preferably cimetidine and ranitidine, and especially cimeditine.
  • pKa values for known histamine H 2 ⁇ receptor antagonists are readily available from pharmacological publications.
  • Suitable antacids for use in compositions of the invention include aluminium hydroxide, magnesium hydroxide, aluminium hydroxide-magnesium carbonate co-dried gel, magnesium carbonate, magnesium oxide, magnesium aluminium silicate, magnesium trisilicate, sodium bicarbonate, calcium carbonate, bismuth carbonate, alkali metal salts of citric, tartaric, benzoic, sorbic and phosphoric acid, and combinations thereof.
  • antacids may be selected by pharmacokinetic analysis of the acid-secretion reducing capacity of a selected histamine ⁇ -receptor antagonist using a pharmacokinetic model based upon a modified, standard two-compartment model.
  • the model may be used to describe pharmacokinetics for a selected histamine H2 ⁇ receptor antagonist.
  • the model demonstrates the reduction in local bioavailability of the histamine ⁇ -receptor antagonist at the parietal cell tissue receptor compartment as a function of gastric excretion and the increase in local bioavailability in the parietal cell tissue receptor compartment as a function of local, gastric absorption, and their dependence on gastric pH.
  • Gastric pH levels are influenced by antacid.
  • antacid By inserting known values for equilibrium pH, acid neutralising capacity and gastric residence time, the suitability of any given antacid may be determined.
  • the dose level o histamine ⁇ -receptor antagonist may be selected according to the potency of the chosen antagonist on a weight basis and the severity of the condition.
  • the antagonist is cimetidine
  • it will generally be present in an amount from about 25 to 400 mg per dosage form, typically from about 50 to 200 mg of cimetidine per dosage form.
  • An advantageous feature of the invention is the potential for using reduced dose levels of histamine ⁇ -receptor antagonist brought about by the synergistic effect of antacid and histamine ⁇ -receptor antagonist, effectively reducing antagonist excretion into the stomach lumen and increasing absorption from the stomach lumen.
  • treatment with the present compositions provides a more rapid onset of action which renders them particularly suitable for the treatment of acute gastritis.
  • a further aspect of the invention is that the amount of antacid present in any given composition is independent of the dose of histamine ⁇ -receptor antagonist.
  • the antacid component serves a dual role. In one aspect, in the accepted mode of action of antacids, it brings about relief from the symptoms of excess stomach acidity by neutralisation. In a second aspect, and more importantly, it serves to act as an appropriate buffered vehicle to histamine H 2 ⁇ rece ⁇ tor antagonist bioavailability in the parietal cell tissue receptor compartment.
  • the dose of antacid may be selected to achieve both the desired acid neutralising effect and to fulfil the role of the antacid component as a buffered vehicle to confer a pH level substantially equal to that of the pKa of the histamine ⁇ -receptor antagonist.
  • a suitable dose range for magnesium hydroxide is from about 150 mg to 3,000 mg, for example from about 300 mg to 1,500 mg, such as from about 300 mg to 600 mg.
  • a suitable dose range for aluminium hydroxide is from about 180 mg to 3,600 mg, for example from about 360 mg to 1,800 mg, such as from about 360 mg to 720 mg.
  • a suitable dose range for sodium bicarbonate is from about 400 mg to 8,000 mg, for example from about 800 mg to 4,000 mg, such as from about 800 mg to 1,600 mg.
  • compositions for use in the present invention may also contain pharmaceutically acceptable carriers.
  • Compositions may be formulated for oral administration in solid or liquid form, for example as tablets, capsules, powders, suspensions or dispersions.
  • Compositions may thus be formulated by admixture with pharmaceutically acceptable vehicles additionally containing, as desired, pharmaceutically acceptable adjuvants including inter alia thickeners, preservatives, and colouring and flavouring agents.
  • compositions for use in the present invention are novel and as such form a further aspect of the invention.
  • the active antacid ingredients are granulated or spray dried in a conventional manner.
  • the granule and the histamine ⁇ -receptor antagonist are blended along with conventional tabletting aids, fillers and palatability aids and the blend is tabletted on a conventional machine.
  • Aluminium hydroxide and magnesium hydroxide are received as commercially available suspensions. These active suspensions are added to a premix of thickeners. The resulting mixture is then blended with the histamine ⁇ -receptor antagonist, and preservatives and flavours as appropriate.

Abstract

Administration en combinaison d'un antagoniste de récepteur-H2 d'histamine et d'un antiacide destinés au traitement de troubles gastriques.
EP91911107A 1990-06-22 1991-06-13 Nouveau traitement Withdrawn EP0533770A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9013910 1990-06-22
GB909013910A GB9013910D0 (en) 1990-06-22 1990-06-22 Novel treatment
GB909018676A GB9018676D0 (en) 1990-08-24 1990-08-24 Novel treatment
GB9018676 1990-08-24

Publications (1)

Publication Number Publication Date
EP0533770A1 true EP0533770A1 (fr) 1993-03-31

Family

ID=26297238

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91911107A Withdrawn EP0533770A1 (fr) 1990-06-22 1991-06-13 Nouveau traitement

Country Status (7)

Country Link
EP (1) EP0533770A1 (fr)
JP (1) JPH05507695A (fr)
KR (1) KR930701196A (fr)
AU (1) AU7981391A (fr)
CA (1) CA2085873A1 (fr)
IE (1) IE912133A1 (fr)
WO (1) WO1992000102A1 (fr)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2052698A1 (fr) * 1990-10-11 1992-04-12 Roger G. Berlin Traitement des ulceres peptiques
CA2061520C (fr) * 1991-03-27 2003-04-22 Lawrence J. Daher Systeme de delivrance accelerant l'effet et accroissant la puissance
GB9127150D0 (en) * 1991-12-20 1992-02-19 Smithkline Beecham Plc Novel treatment
CA2110313C (fr) * 1992-12-01 2004-10-26 Edward John Roche Compositions pharmaceutiques contenant un compose de guanidothiazole et antiacides
WO1995001792A1 (fr) * 1993-07-06 1995-01-19 Merck & Co., Inc. Composes anti-h2-antihistaminiques
US5622980A (en) * 1993-08-17 1997-04-22 Applied Analytical Industries, Inc. Oral compositions of H2-antagonists
ZA947553B (en) * 1993-09-30 1995-05-26 Glaxo Inc Ranitidine and calcium carbonate pharmaceutical combination product
JP3587869B2 (ja) * 1993-12-16 2004-11-10 グラクソ・スミスクライン株式会社 医薬組成物
WO1996004888A1 (fr) * 1994-08-12 1996-02-22 Applied Analytical Industries, Inc. Compositions d'antagonistes h2 s'administrant par voie orale
AU728423B2 (en) * 1996-10-04 2001-01-11 Mcneil-Ppc, Inc. Methods and compositions for preventing and treating heartburn
US5989588A (en) * 1996-10-04 1999-11-23 Merck & Co., Inc. Methods and compositions for preventing and treating heartburn
WO2007090113A2 (fr) 2006-02-01 2007-08-09 Weg Stuart L Utilisation de compositions antifongiques pour traiter des conditions gastro-intestinales superieures
RU2715906C2 (ru) 2015-05-29 2020-03-04 Джонсон энд Джонсон Консьюмер Инк. Применение органического экстракта цитрусовых с высокой противомикробной активностью и ксилита в качестве системы консервантов в жидкостях, эмульсиях, суспензиях, кремах и антацидах
RU2714879C2 (ru) 2015-05-29 2020-02-20 Джонсон энд Джонсон Консьюмер Инк. Применение органического экстракта цитрусовых с высокой противомикробной активностью в качестве системы консервантов в жидкостях, эмульсиях, суспензиях, кремах и антацидах
WO2017091166A1 (fr) 2015-11-26 2017-06-01 Pharmacti̇ve İlaç San. Ve Ti̇c. A.Ş. Compositions pharmaceutiques stables et leur procédé de préparation

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3710462A1 (de) 1987-03-30 1988-10-13 Heumann Pharma Gmbh & Co Pharmazeutische zubereitung zur behandlung von erkrankungen des magen-darm-traktes
ATE73328T1 (de) 1987-05-08 1992-03-15 Smith Kline French Lab Pharmazeutische zusammensetzungen.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9200102A1 *

Also Published As

Publication number Publication date
WO1992000102A1 (fr) 1992-01-09
IE912133A1 (en) 1992-01-01
KR930701196A (ko) 1993-06-11
AU7981391A (en) 1992-01-23
JPH05507695A (ja) 1993-11-04
CA2085873A1 (fr) 1991-12-23

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