Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Patent
1989-01-04
1992-12-08
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
424459, 424489, A61K 926
Patent
active
051696401
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a solid pharmaceutical dosage form comprising cimetidine and an antacid and to a method for the preparation of such a dosage form.
Cimetidine is a histamine H.sub.2 -antagonist which has been described in U.K. Patent Specification 1,397,436. Cimetidine has been shown to be useful in the treatment of duodenal, gastric, recurrent and stomal ulceration, and reflux oesophagitis and in the management of patients who are at high risk from haemorrhage of the upper gastrointestinal tract.
Cimetidine and antacids are frequently co-administered (see for example the article by H. Allgayer and G. Paumgartner, Arzneim Forsch. pp. 870-871, 34, No. 8 (1984)). The rationale for co-administration is that antacid brings about rapid relief from the symptoms of excess stomach acidity by neutralising the acid whereas the cimetidine brings about more sustained relief by inhibiting secretion of more acid.
However, it is well known (see Allgayer and Paumgartner, and Steinberg et al, New England J. Medicine, 1982; 307, 400-4) that when cimetidine is co-administered with antacids, particularly aluminium hydroxide and magnesium hydroxide, there is frequently a substantial reduction in the bioavailability of the cimetidine. The reason for the reduction in bioavailability is not clear, although a number of attempts to discover the mechanism responsible for the problem have been reported in the literature. Thus for example Allgayer and Paumgartner were unable to demonstrate why the decrease in bioavailability occurs although they indicated that it was not due to binding of the cimetidine by the antacid.
The benefits, particularly in terms of patient compliance with a treatment regimen, which would arise from an effective combination product containing cimetidine and an antacid, would be expected to be considerable. However, the problem of loss of bioavailability, and the lack of understanding of its cause have, up until now, precluded the development of such a product, as far as we are aware.
It has now been found, surprisingly, that the problem of the loss of bioavailability of the cimetidine can be solved by granulating at least part of the antacid separately, and in a particular manner, prior to mixing with the cimetidine.
In a first aspect, therefore, the invention provides a solid pharmaceutical dosage form comprising: granules comprising a freely water-soluble solid diluent, the antacid, and a rapidly swellable water-insoluble disintegrant.
It is preferred that at least 50% by weight of the total antacid in the dosage form is granulated in the particular manner described above in (ii). In general, as the ratio of antacid to cimetidine is increased, it is desirable to increase the proportion of antacid granulated in this way. In one preferred embodiment of the invention, substantially all of the antacid is thus granulated.
The term "freely soluble" is known in the art as referring to a particular level of solubility; thus, in the U.S. Pharmacopoeia, it is defined as meaning that a substance can form a 10% solution in a solvent. Preferably the substance can form at least a 50% solution in water.
Typically the freely water-soluble solid diluent is a sugar and/or sugar alcohol.
Examples of sugars and sugar alcohols are sucrose, lactose, sorbitol, xylitol and mannitol, preferred diluents being lactose, sorbitol and sorbitol/lactose mixtures.
It is preferred that the ratio (w/w) of solid diluent to antacid is in the range 1:1 to 8:1, particularly approximately 3:1.
Typically the rapidly swellable water-insoluble disintegrants are synthetic or semi-synthetic polymers of a type known in the art as superdisintegrants (see for example International Patent Application No. PCT/US 87/00302, published as WO 87/05804, and references cited therein). Examples of superdisintegrants include cross-linked polymeric disintegrants such as cross-linked carboxymethyl celluloses, particularly croscarmellose sodium and croscarmellose calcium, cross-linked polyvinyl pyrrolidone, and sodium starch glycolate.
Typically the disintegra
REFERENCES:
patent: 4676984 (1987-06-01), Wu et al.
patent: 4681756 (1987-07-01), Mergens et al.
patent: 4748023 (1988-05-01), Tamas
Steinberg et al., New England J. of Med., vol. 307, No. 7, pp. 400-404.
Chemical Abstracts, vol. 102, 1985, p. 375, abstract No. 137799m Columbus, Ohio, US.
France Gordon
Leonard Graham S.
Pearmain Kevin E.
Dinner Dara L.
Horne Leon R.
Lentz Edward T.
Page Thurman K.
Smith Kline & French Laboratories Ltd.
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