NOVEL TREATMENT

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 H 2 -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 H 2 ~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 H 2 ~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. (all amounts in mg) TABLET FORMULATIONS EXAMPLE NO. I (all amounts in mg) COMBINATION ANTACID TABLET FORMULATIONS EXAMPLE NO. I (all amounts in mg) LIQUID SUSPENSIONS EXAMPLE NO . I t I (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 H 2 -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 H 2 -receptor antagonist.

Inventors: DAVIS ADRIAN FRANCIS, DAVIS, ADRIAN, FRANCIS
Applicants: BEECHAM GROUP PLC
Application year: 1991
Main classification: A61K33
IPC codes: A61K31, A61K33, A61K45, A61P1