CA2085873A1 - Treatment - Google Patents
TreatmentInfo
- Publication number
- CA2085873A1 CA2085873A1 CA002085873A CA2085873A CA2085873A1 CA 2085873 A1 CA2085873 A1 CA 2085873A1 CA 002085873 A CA002085873 A CA 002085873A CA 2085873 A CA2085873 A CA 2085873A CA 2085873 A1 CA2085873 A1 CA 2085873A1
- Authority
- CA
- Canada
- 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.)
- Abandoned
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
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
Abstract
Co-administration of a histamine H2-receptor antagonist and antacid for the treatment of gastric disorders.
Description
WO92/001~2 PCT/GB91/0~953 -1- 2~ 3 NOVEL TREATMENT
This invention relates to the treatment of gastric ~isorders and pharmaceutical compositions for use therein. More s 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 H2-receptor antagonist and an 10 antacid.
Histamine H2-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 H2-receptor antagonists are remarkably effective in the treatment of many gastric disorders, in particular peptic and gastric ulcers, there exist certain 20 patient groups which do not respond to treatment. In addition, the time lapse between dosing and onset of action, limits the potential benefit of hlstamine H2-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 H2-receptor antagonist therapy.
(Walker et al.: Frequent non-response to histamine 30 H2-receptor antagonists in cirrhotics; Gut, 30, 1105-9, 1989; and Brack A. et al.: Clinical failures with cimetidine; Surgery, 88(3), 417-24.
In addition, the known poor response to histamine 35 H2-receptor antagonist treatment by hypersecreting patients, for example critically ill, multiple trauma patients (Martin , ,: : , ,: , ., . :. . . ..
This invention relates to the treatment of gastric ~isorders and pharmaceutical compositions for use therein. More s 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 H2-receptor antagonist and an 10 antacid.
Histamine H2-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 H2-receptor antagonists are remarkably effective in the treatment of many gastric disorders, in particular peptic and gastric ulcers, there exist certain 20 patient groups which do not respond to treatment. In addition, the time lapse between dosing and onset of action, limits the potential benefit of hlstamine H2-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 H2-receptor antagonist therapy.
(Walker et al.: Frequent non-response to histamine 30 H2-receptor antagonists in cirrhotics; Gut, 30, 1105-9, 1989; and Brack A. et al.: Clinical failures with cimetidine; Surgery, 88(3), 417-24.
In addition, the known poor response to histamine 35 H2-receptor antagonist treatment by hypersecreting patients, for example critically ill, multiple trauma patients (Martin , ,: : , ,: , ., . :. . . ..
L. et al.: Failure of cimetidine prophylaxis in the critically ill; Arch. Surg., 114, 492-6, 1979) or those with Zollinger-Ellison syndrome ~Stabile B.G. et al.: Failure of histamine H2-receptor antagonist therapy in s 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 H2-receptor antagonists are of potential benefit o 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.
Co-administration of histamine H2-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 2s neutralisation, whereas the histamine H2-receptor antagonist independently acts by inhibiting secretion of acid from the parietal cell.
However, it is well known (Bodemar G. et al., Lancet, 1, 30 444-445, 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 H2-receptor antagonists are co-administered with antacids, especially antacids with high acid-neutralising capacity, there is frequently a 3s substantial reduction in the plasma bioavailability of khe histamine H2-receptor antagonist.
'.
~3- ~ ~8~7~
Histamine H2-receptor antagonist-antacid combinations are therefore generally contraindicated. This contraindication for histamine H2-receptor antagonist-antacid therapy is 5 supported by pharmacokinetic modelling using a standard two-compartment model which indicates a reduction in the systemic absorption of the histamine H2-receptor antagonist.
Surprisingly, it has now been found that a combination of o histamine H2-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 H2-receptor antagonist and thus further increases the acid-secretion reducing capacity of the histamine H2-receptor antagonist compared with that of the histamine H2-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 H2-receptor antagonist and an antacid for the manufacture of a medicament for the treatment of gastric 25 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 H~-receptor antagonist. Local levels of the 30 histamine H2-receptor antagonist at the parietal cell receptor are thereby increased, conferring an increase in the acid-secretion reducing capacity of the histamine H2 receptor antagonist.
, ,: .
WO92/~0102 PCT/GB91/00~53 7 ~
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 5 reduce the onset-phase of single-dose, sel~-medication for acute gastric disorders, for example gastric disorders due to hyperacidity.
The invention also provides a method of treatment of gastric 10 disorders comprising 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 the pKa of the histamine H2-receptor antagonist.
In a further aspect, the invention provides a pharmaceutical composition for use in the treatment of gastric disorders 20 which comprises a histamine H2-receptor antagonist and an antacid wherein the equilibrium pH, the acid neutralising capacity and the gastric residence time values con~er a pH
level substantially equal to that of the pKa of the histamine H2-receptor antagonist.
2s Histamine H2-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 30 anta~onists are readily available from pharmacological publications.
Similarly, the above-mentioned parameters for suitable antacids are read:ily available to those skilled in the art.
35 Suitable antacids ~or use in compositions of the invention include aluminium hydroxide, magnesium hydroxida, aluminium hydroxide-magnesium carbonate co-dried gel, magnesium WO9~/00102 PCT/GB91/00953 _5_ 2~ 3 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 5 combinations thereof.
Further suitable antacids may be selected by pharmacokinetic analysis of the acid-secretion reducing capacity of a selected histamine H2-receptor antagonist using a lo 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 15 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 H2-receptor antagonist at the parietal cell tissue receptor 20 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 inserti~g known 25 ~alues for equilibrium pH, acid neutralising capacity and gastric residence time, the suitability of any given antacid may be determined.
The dose level of histamine H2-receptor antagonist may be 30 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 35 cimetidine per dosage form.
Excretion of histamine H2-receptor antagonist into the stomach lumen ~rom the parietal cell tissue receptor causes .
.. . . -. , ....... , . . , .... .,.,.. ., . . ~, . . .. ... . .
-. , . . .: ' -':, '~ . .: .;.. , ,. . , , , . ~. .. . . ,. . . . . . . .. : . , WO92/00102 PCr/GB91/00953 -6- ~8~87~
a reduction in local bioavailability of the anta~onist whilst gastric absorption of histarnine H2-receptor antagonist into the parietal cell tissue receptor causes an increase in local bioavailability of the antagonist. An S advantageous feature of the invention is the potential for using reduced dose levels of histamine H2-receptor antagonist brought about by the synergistic effect of antacid and histamine X2-receptor antagonist, effectively reducing antagonist excretion into the stomach lumen and lO 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 H2-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 2s more importantly, it serves to act as an appropriate buffered vehicle to histamine H2-receptor antagonist bioavailability in the parietal cell tissue receptor compartment.
30 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 con~er a pH
level subs~antially equal to that of the pKa of the histamine H2-receptor antagonist.
A suitable dose range for magnesium hydroxide is fro~ about 150 mg to 3,000 mg, for example from about 300 mg to l,500 W092/001~2 pcrJG~s1 /00~53 _7_ 2~8~7~
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 s mg, such as fro~ 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 8Q0 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 dispersi-ons. 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.
2s The following Examples illustrate the invention.
Powder Formulations The ingredients are dry blended under conditions of 30 controlled temperature and humidity using conventional equipment.
~-, ~,, ., . ' ~ . . '. j, , WO9~/00102 PCTIGB91/00953 , .
; -8- 2~ 73 Tablet Formulations The active antacid ingredients are granulated or spray dried in a conventional manner. The granule and the histamine 5 H2-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 15 H2-receptor antagonist, and preservatives and flavours as appropriate.
... .. .
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Histamine H2-receptor antagonists are of potential benefit o 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.
Co-administration of histamine H2-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 2s neutralisation, whereas the histamine H2-receptor antagonist independently acts by inhibiting secretion of acid from the parietal cell.
However, it is well known (Bodemar G. et al., Lancet, 1, 30 444-445, 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 H2-receptor antagonists are co-administered with antacids, especially antacids with high acid-neutralising capacity, there is frequently a 3s substantial reduction in the plasma bioavailability of khe histamine H2-receptor antagonist.
'.
~3- ~ ~8~7~
Histamine H2-receptor antagonist-antacid combinations are therefore generally contraindicated. This contraindication for histamine H2-receptor antagonist-antacid therapy is 5 supported by pharmacokinetic modelling using a standard two-compartment model which indicates a reduction in the systemic absorption of the histamine H2-receptor antagonist.
Surprisingly, it has now been found that a combination of o histamine H2-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 H2-receptor antagonist and thus further increases the acid-secretion reducing capacity of the histamine H2-receptor antagonist compared with that of the histamine H2-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 H2-receptor antagonist and an antacid for the manufacture of a medicament for the treatment of gastric 25 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 H~-receptor antagonist. Local levels of the 30 histamine H2-receptor antagonist at the parietal cell receptor are thereby increased, conferring an increase in the acid-secretion reducing capacity of the histamine H2 receptor antagonist.
, ,: .
WO92/~0102 PCT/GB91/00~53 7 ~
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 5 reduce the onset-phase of single-dose, sel~-medication for acute gastric disorders, for example gastric disorders due to hyperacidity.
The invention also provides a method of treatment of gastric 10 disorders comprising 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 the pKa of the histamine H2-receptor antagonist.
In a further aspect, the invention provides a pharmaceutical composition for use in the treatment of gastric disorders 20 which comprises a histamine H2-receptor antagonist and an antacid wherein the equilibrium pH, the acid neutralising capacity and the gastric residence time values con~er a pH
level substantially equal to that of the pKa of the histamine H2-receptor antagonist.
2s Histamine H2-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 30 anta~onists are readily available from pharmacological publications.
Similarly, the above-mentioned parameters for suitable antacids are read:ily available to those skilled in the art.
35 Suitable antacids ~or use in compositions of the invention include aluminium hydroxide, magnesium hydroxida, aluminium hydroxide-magnesium carbonate co-dried gel, magnesium WO9~/00102 PCT/GB91/00953 _5_ 2~ 3 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 5 combinations thereof.
Further suitable antacids may be selected by pharmacokinetic analysis of the acid-secretion reducing capacity of a selected histamine H2-receptor antagonist using a lo 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 15 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 H2-receptor antagonist at the parietal cell tissue receptor 20 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 inserti~g known 25 ~alues for equilibrium pH, acid neutralising capacity and gastric residence time, the suitability of any given antacid may be determined.
The dose level of histamine H2-receptor antagonist may be 30 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 35 cimetidine per dosage form.
Excretion of histamine H2-receptor antagonist into the stomach lumen ~rom the parietal cell tissue receptor causes .
.. . . -. , ....... , . . , .... .,.,.. ., . . ~, . . .. ... . .
-. , . . .: ' -':, '~ . .: .;.. , ,. . , , , . ~. .. . . ,. . . . . . . .. : . , WO92/00102 PCr/GB91/00953 -6- ~8~87~
a reduction in local bioavailability of the anta~onist whilst gastric absorption of histarnine H2-receptor antagonist into the parietal cell tissue receptor causes an increase in local bioavailability of the antagonist. An S advantageous feature of the invention is the potential for using reduced dose levels of histamine H2-receptor antagonist brought about by the synergistic effect of antacid and histamine X2-receptor antagonist, effectively reducing antagonist excretion into the stomach lumen and lO 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 H2-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 2s more importantly, it serves to act as an appropriate buffered vehicle to histamine H2-receptor antagonist bioavailability in the parietal cell tissue receptor compartment.
30 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 con~er a pH
level subs~antially equal to that of the pKa of the histamine H2-receptor antagonist.
A suitable dose range for magnesium hydroxide is fro~ about 150 mg to 3,000 mg, for example from about 300 mg to l,500 W092/001~2 pcrJG~s1 /00~53 _7_ 2~8~7~
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 s mg, such as fro~ 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 8Q0 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 dispersi-ons. 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.
2s The following Examples illustrate the invention.
Powder Formulations The ingredients are dry blended under conditions of 30 controlled temperature and humidity using conventional equipment.
~-, ~,, ., . ' ~ . . '. j, , WO9~/00102 PCTIGB91/00953 , .
; -8- 2~ 73 Tablet Formulations The active antacid ingredients are granulated or spray dried in a conventional manner. The granule and the histamine 5 H2-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 15 H2-receptor antagonist, and preservatives and flavours as appropriate.
... .. .
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Claims (13)
1. The use of an orally administrable pharmaceutical composition comprising a histamine H2-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 H2-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 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.
4. Use as claimed in claim 3 for the treatment of patients who do not respond to conventional histamine H2-receptor antagonist therapy.
5. 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.
7. Use as claimed in any preceding claim whereby the histamine H2-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 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.
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, 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 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 the pKa of the histamine H2-receptor antagonist.
13. A pharmaceutical composition for use in the treatment of gastric disorders 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 the pKa of the histamine H2-receptor antagonist.
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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2085873A1 true CA2085873A1 (en) | 1991-12-23 |
Family
ID=26297238
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002085873A Abandoned CA2085873A1 (en) | 1990-06-22 | 1991-06-13 | Treatment |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0533770A1 (en) |
| JP (1) | JPH05507695A (en) |
| KR (1) | KR930701196A (en) |
| AU (1) | AU7981391A (en) |
| CA (1) | CA2085873A1 (en) |
| IE (1) | IE912133A1 (en) |
| WO (1) | WO1992000102A1 (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2052698A1 (en) * | 1990-10-11 | 1992-04-12 | Roger G. Berlin | Treatment of peptic ulcer |
| CA2061520C (en) * | 1991-03-27 | 2003-04-22 | Lawrence J. Daher | Delivery system for enhanced onset and increased potency |
| GB9127150D0 (en) * | 1991-12-20 | 1992-02-19 | Smithkline Beecham Plc | Novel treatment |
| CA2110313C (en) * | 1992-12-01 | 2004-10-26 | Edward John Roche | Pharmaceutical compositions containing a guanidinothiazole compound and antacids |
| 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 |
| ZA947553B (en) * | 1993-09-30 | 1995-05-26 | Glaxo Inc | Ranitidine and calcium carbonate pharmaceutical combination product |
| JP3587869B2 (en) * | 1993-12-16 | 2004-11-10 | グラクソ・スミスクライン株式会社 | Pharmaceutical composition |
| AU2912695A (en) * | 1994-08-12 | 1996-03-07 | Henry C Caldwell | Oral compositions of h2-antagonists |
| EP1019066B1 (en) * | 1996-10-04 | 2006-11-15 | Merck & Co., 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 (en) | 2006-02-01 | 2007-08-09 | Weg Stuart L | Use of antifungal compositions to treat upper gastrointestinal conditions |
| BR112017025467A2 (en) | 2015-05-29 | 2018-08-07 | 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 |
| CA2984801A1 (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 |
| WO2017091166A1 (en) | 2015-11-26 | 2017-06-01 | Pharmacti̇ve İlaç San. Ve Ti̇c. A.Ş. | Stable pharmaceutical compositions and process for their preparation |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3710462A1 (en) | 1987-03-30 | 1988-10-13 | Heumann Pharma Gmbh & Co | PHARMACEUTICAL PREPARATION FOR THE TREATMENT OF DISEASES OF THE gastrointestinal tract |
| ATE73328T1 (en) | 1987-05-08 | 1992-03-15 | Smith Kline French Lab | PHARMACEUTICAL COMPOSITIONS. |
-
1991
- 1991-06-13 CA CA002085873A patent/CA2085873A1/en not_active Abandoned
- 1991-06-13 WO PCT/GB1991/000953 patent/WO1992000102A1/en not_active Application Discontinuation
- 1991-06-13 KR KR1019920703296A patent/KR930701196A/en not_active Application Discontinuation
- 1991-06-13 EP EP91911107A patent/EP0533770A1/en not_active Withdrawn
- 1991-06-13 JP JP91510567A patent/JPH05507695A/en active Pending
- 1991-06-13 AU AU79813/91A patent/AU7981391A/en not_active Abandoned
- 1991-06-20 IE IE213391A patent/IE912133A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE912133A1 (en) | 1992-01-01 |
| WO1992000102A1 (en) | 1992-01-09 |
| JPH05507695A (en) | 1993-11-04 |
| KR930701196A (en) | 1993-06-11 |
| EP0533770A1 (en) | 1993-03-31 |
| AU7981391A (en) | 1992-01-23 |
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