WO1992000102A1 - Novel treatment - Google Patents

Novel treatment Download PDF

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Publication number
WO1992000102A1
WO1992000102A1 PCT/GB1991/000953 GB9100953W WO9200102A1 WO 1992000102 A1 WO1992000102 A1 WO 1992000102A1 GB 9100953 W GB9100953 W GB 9100953W WO 9200102 A1 WO9200102 A1 WO 9200102A1
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WIPO (PCT)
Prior art keywords
histamine
receptor antagonist
treatment
antacid
gastric
Prior art date
Application number
PCT/GB1991/000953
Other languages
French (fr)
Inventor
Adrian Francis Davis
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
Priority to KR1019920703296A priority Critical patent/KR930701196A/en
Priority to JP91510567A priority patent/JPH05507695A/en
Publication of WO1992000102A1 publication Critical patent/WO1992000102A1/en

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    • 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.

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Abstract

Co-administration of a histamine H2-receptor antagonist and antacid for the treatment of gastric disorders.

Description

NOVEL TREATMENT
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.
Although 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. In addition, 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.
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 H2-receptor antagonists in cirrhotics; Gut, .30., 1105-9, 1989; and Brack A. et εil. : Clinical failures with cimetidine; Surgery, .88.(3) , 417-24.
In addition, the known poor response to histamine ^-receptor antagonist treatment by hypersecreting patients, for example critically ill, multiple trauma patients (Martin L. et. a__ . : Failure of cimetidine prophylaxis in the critically ill; Arch. Surg., 114, 492-6, 1979) or those with Zollinger-Ellison syndrome (Stabile B.G. et. aJL. : Failure' of histamine ^-receptor antagonist therapy in 5 Zollinger-Ellison syndrome; Am. J. Surg., 145, 17-23, 1983) has led to the development of alternative treatments, notably the use of proton-pump inhibitors.
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.
15 Moveover, it will be appreciated that use of high dose levels in an attempt to achieve rapid relief of symptoms is not appropriate for non-prescription use. Indeed, a reduction from the standard therapeutic dose would be desirable for self-medication.
20
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.
However, it is well known (Bodemar G. et al... Lancet, __, 30444-445, 1979; Mihaly G.W. et al., B.M.J., 285, 998-9, 1982; Lin. J.H. et al., B.J. Clin. Pharmacol. 24./ 551-3, 1987) that 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.
Surprisingly, it has now been found that a combination of histamine ^-receptor antagonists with antacids, even those with high acid-neutralising capacity, leads to an increase in local stomach wall receptor site bioavailability of the histamine ^-receptor antagonist and thus further increases the acid-secretion reducing capacity of the histamine ^-receptor antagonist compared with that of the histamine ^-receptor antagonist alone. This synergistic effect is of benefit in the treatment of gastric disorders, particularly in the treatment of the so-called 'non responders' and in the self-medication of acute gastric disorders.
Accordingly, 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.
In a further aspect, 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 H2~receptor antagonists are readily available from pharmacological publications.
Similarly, the above-mentioned parameters for suitable antacids are readily available to those skilled in the art. 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.
Further suitable 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. With the introduction of further compartments to separately describe the stomach and the intestine, and with transport between the tissue compartment, representing the parietal cell tissue receptor compartment, and the stomach lumen, 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. Thus, 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. For example, where 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.
Excretion of histamine ^-receptor antagonist into the stomach lumen from the parietal cell tissue receptor causes a reduction in local bioavailability of the antagonist whilst gastric absorption of histamine ^-receptor antagonist into the parietal cell tissue receptor causes an increase in local bioavailability of the antagonist. 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.
It will be further appreciated that 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.
It is a feature of the antacid component that it 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 H2~receρtor 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.
It will be appreciated that certain pharmaceutical compositions for use in the present invention are novel and as such form a further aspect of the invention.
The following Examples illustrate the invention.
Powder Formulations
The ingredients are dry blended under conditions of controlled temperature and humidity using conventional equipment. Tablet Formulations
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.
Liquid Suspensions
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.
POWDER FORMULATIONS
EXAMPLE NO.
Figure imgf000011_0002
(all amounts in mg)
Figure imgf000011_0001
TABLET FORMULATIONS
EXAMPLE NO.
I
Figure imgf000012_0002
Figure imgf000012_0001
(all amounts in mg)
Figure imgf000013_0001
COMBINATION ANTACID TABLET FORMULATIONS
EXAMPLE NO.
I
Figure imgf000013_0003
(all amounts in mg)
Figure imgf000013_0002
LIQUID SUSPENSIONS
EXAMPLE NO .
I t
I
Figure imgf000014_0001
Figure imgf000014_0002
(all amounts in mg)

Claims

Clai s
1. The use of an orally administrable pharmaceutical • composition comprising a histamine H2_ eceptor antagonist
5 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 10 that of the pKa of the histamine ^-receptor antagonist.
2. Use as claimed in claim 1 characterised in that local levels of the histamine H2-receptor antagonist at the parietal cell receptor are increased, thereby increasing the
15 acid-secretion reducing capacity of the histamine H2- receptor antagonist.
3. Use as claimed in claim 1 or 2 for the treatment of gastric disorders in ulcer patients.
20
4. Use as claimed in claim 3 for the treatment of patients who do not respond to conventional histamine H^- receptor antagonist therapy.
255. Use as claimed in claim 3 for the treatment of acid hypersecreting patients.
6. Use as claimed in claim 1 or 2 for the single-dose treatment of acute gastric disorders.
30
7. Use as claimed in any preceding claim whereby the histamine ^-receptor antagonist is cimetidine, ranitidine, or famotidine.
8. Use as claimed in claim 7 whereby the histamine H2~ receptor antagonist is cimetidine.
9. Use as claimed in claim 8 whereby the dose level of 5 cimetidine is from 25 to 400mg per dosage form.
10. Use as claimed in claim 9 whereby the dose level of cimetidine is from 50 to 200mg per dosage form.
10 11. Use as claimed in any preceding claim whereby the antacid is aluminium hydroxide, magnesium hydroxide, aluminium hydroxide-magnesium carbonate co-dried gel, magnesium carbonate, magnesium oxide, magnesium trisilicate, sodium bicarbonate, calcium carbonate, bismuth carbonate,
15 magnesium aluminium silicate, alkali metal salts of citric, tartaric, benzoic, sorbic or phosphoric acid, or combinations of any of the aforementioned antacids.
12. A method of treatment of gastric disorders comprising 0 orally administering to a sufferer an effective amount of a pharmaceutical composition comprising a histamine H2~ 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 5 the pKa of the histamine H2~receptor antagonist.
13. A pharmaceutical composition for use in the treatment of gastric disorders comprising a histamine ^-receptor antagonist and an antacid wherein the equilibrium pH, the 0 acid neutralising capacity and the gastric residence time values confer a pH level substantially equal to that of the pKa of the histamine H2-receptor antagonist.
PCT/GB1991/000953 1990-06-22 1991-06-13 Novel treatment WO1992000102A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
KR1019920703296A KR930701196A (en) 1990-06-22 1991-06-13 New treatment
JP91510567A JPH05507695A (en) 1990-06-22 1991-06-13 new treatment

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9013910.6 1990-06-22
GB909013910A GB9013910D0 (en) 1990-06-22 1990-06-22 Novel treatment
GB9018676.8 1990-08-24
GB909018676A GB9018676D0 (en) 1990-08-24 1990-08-24 Novel treatment

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CA (1) CA2085873A1 (en)
IE (1) IE912133A1 (en)
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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0480691A2 (en) * 1990-10-11 1992-04-15 Merck & Co. Inc. Combination therapy for peptic ulcer treatment
WO1993012779A1 (en) * 1991-12-20 1993-07-08 Smithkline Beecham Plc Compositions containing histamine-h2-receptor antagonists at low dosage
EP0600725A1 (en) * 1992-12-01 1994-06-08 McNEIL-PPC, INC. Pharmaceutical compositions containing a guanidinothiazole and antacids
WO1995001792A1 (en) * 1993-07-06 1995-01-19 Merck & Co., Inc. H2 antagonist-antihistamine combinations
WO1995008997A1 (en) * 1993-09-30 1995-04-06 Glaxo Wellcome Inc. Ranitidine and calcium carbonate pharmaceutical combination product
US5424075A (en) * 1991-03-27 1995-06-13 Miles Inc. Delivery system for enhanced onset and increased potency
WO1995016446A1 (en) * 1993-12-16 1995-06-22 Nippon Glaxo Limited Ranitidine compositions
WO1996004888A1 (en) * 1994-08-12 1996-02-22 Applied Analytical Industries, Inc. Oral compositions of h2-antagonists
US5622980A (en) * 1993-08-17 1997-04-22 Applied Analytical Industries, Inc. Oral compositions of H2-antagonists
US5989588A (en) * 1996-10-04 1999-11-23 Merck & Co., Inc. Methods and compositions for preventing and treating heartburn
EP1019066A1 (en) * 1996-10-04 2000-07-19 Merck & Co., Inc. Methods and compositions for preventing and treating heartburn
WO2007090113A2 (en) 2006-02-01 2007-08-09 Weg Stuart L Use of antifungal compositions to treat upper gastrointestinal conditions
WO2016196205A1 (en) 2015-05-29 2016-12-08 Johnson & Johnson Consumer Inc. Use of organic citrus extract with high antimicrobial capacity as a preservative system in liquids, emulsions, suspensions, creams and antacids
WO2016196209A1 (en) 2015-05-29 2016-12-08 Johnson & Johnson Consumer Inc. Use of an organic citrus extract with high antimicrobial capacity and xylitol as a preservative system in liquids, emulsions, suspensions, creams and antacids
WO2017091166A1 (en) 2015-11-26 2017-06-01 Pharmacti̇ve İlaç San. Ve Ti̇c. A.Ş. Stable pharmaceutical compositions and process for their preparation

Citations (2)

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EP0480691A3 (en) * 1990-10-11 1993-03-10 Merck & Co. Inc. Combination therapy for peptic ulcer treatment
US5424075A (en) * 1991-03-27 1995-06-13 Miles Inc. Delivery system for enhanced onset and increased potency
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US5656652A (en) * 1991-12-20 1997-08-12 Smithkline Beecham Plc Compositions containing histamine-H2 -receptor antagonists at low dosage
AU674501B2 (en) * 1991-12-20 1997-01-02 Smithkline Beecham Plc Compositions containing histamine-H2-receptor antagonists at low dosage
EP0600725A1 (en) * 1992-12-01 1994-06-08 McNEIL-PPC, INC. Pharmaceutical compositions containing a guanidinothiazole and antacids
US5817340A (en) * 1992-12-01 1998-10-06 Mcneil-Ppc, Inc. Pharmaceutical compositions containing famotidine and aluminum hydroxide or magnesium hydroxide
WO1995001792A1 (en) * 1993-07-06 1995-01-19 Merck & Co., Inc. H2 antagonist-antihistamine combinations
US5622980A (en) * 1993-08-17 1997-04-22 Applied Analytical Industries, Inc. Oral compositions of H2-antagonists
AU677108B2 (en) * 1993-09-30 1997-04-10 Glaxo Wellcome Inc. Ranitidine and calcium carbonate pharmaceutical combination product
WO1995008997A1 (en) * 1993-09-30 1995-04-06 Glaxo Wellcome Inc. Ranitidine and calcium carbonate pharmaceutical combination product
WO1995016446A1 (en) * 1993-12-16 1995-06-22 Nippon Glaxo Limited Ranitidine compositions
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US5989588A (en) * 1996-10-04 1999-11-23 Merck & Co., Inc. Methods and compositions for preventing and treating heartburn
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WO2007090113A2 (en) 2006-02-01 2007-08-09 Weg Stuart L Use of antifungal compositions to treat upper gastrointestinal conditions
WO2016196205A1 (en) 2015-05-29 2016-12-08 Johnson & Johnson Consumer Inc. Use of organic citrus extract with high antimicrobial capacity as a preservative system in liquids, emulsions, suspensions, creams and antacids
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WO2017091166A1 (en) 2015-11-26 2017-06-01 Pharmacti̇ve İlaç San. Ve Ti̇c. A.Ş. Stable pharmaceutical compositions and process for their preparation

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EP0533770A1 (en) 1993-03-31
AU7981391A (en) 1992-01-23

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