Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Patent
1995-06-22
1998-05-19
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
424475, 424476, 424477, 424479, 424480, 424481, 424482, A61K 928, A61K 930, A61K 934
Patent
active
057532656
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention is related to new pharmaceutical preparations in the form of a multiple unit tableted dosage form comprising an active substance in the form of an acid labile H.sup.+ K.sup.+ -ATPase inhibitor. The novel tableted dosage form is intended for oral use. Furthermore, the present invention refers to a method for the manufacture of such preparations and, to the use of such preparations in medicine.
BACKGROUND OF THE INVENTION
Acid labile H.sup.+ K.sup.+ -ATPase inhibitors also named as gastric proton pump inhibitors are for instance compounds known under the generic names omeprazole, lansoprazole, pantoprazole, pariprazole and leminoprazole.
Compounds of interest for the novel tableted dosage form according to the present invention are compounds of the general formula I or an alkaline salt thereof or one of its single enantiomers or an alkaline salt thereof. ##STR1## wherein Het.sub.1 is ##STR2## Het.sub.2 is ##STR3## wherein substituted by R.sub.6 --R.sub.9 optionally may be exchanged for a nitrogen atom without any substituents; hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy; alkyl and aralkyl; alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolinyl, trifluoroalkyl, or adjacent groups R.sub.6 --R.sub.9 form ring structures which may be further substituted; halogen or alkyl except the compounds midazole, azole and -benzimidazole. ##STR4## The active compound used in the tableted dosage form according to the invention may be used in neutral form or in the form of an alkaline salt, such as for instance the Mg.sup.2+, Ca.sup.2+, Na.sup.+ or K.sup.+ salts, preferably the Mg.sup.2+ salts. The compounds may also be used in the form of one of its single enantiomers or alkaline salts thereof.
Some of the above compounds are for instance disclosed in EP-A1-0005129, EP-A1-174726, EP-A1-166287 and GB 2163747.
These active substances are useful for inhibiting gastric acid secretion in mammals and man. In a more general sense, they may be used for prevention and treatment of gastric acid related diseases in mammals and man, including e.g. reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. Furthermore, they may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia, in patients with symptomatic gastro-esophageal reflux disease, and in patients with gastrinomas. They may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre-and postoperatively to prevent acid aspiration of gastric add and to prevent and treat stress ulceration. Further, they may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections and diseases related to these.
The active compounds are, however, susceptible to degradation/transformation in acidic and neutral media. The degradation is catalyzed by acidic compounds and is stabilized in mixtures with alkaline compounds. The stability of the active substances is also affected by moisture, heat, organic solvents and to some degree by light.
In respect to the stability properties of the active substances, it is obvious that an oral solid dosage form must be protected from contact with the acidic gastric juice and the active substance must be transferred in intact form to that part of the gastrointestinal tract where pH is near neutral and where rapid absorption can occur.
A pharmaceutical oral dosage form of such acid H.sup.+ K.sup.+ -ATPase inhibitors is best protected from contact with acidic gastric juice by an enteric coating layer. In U.S. Pat. No. 4,853,230 such an enteric coated preparation is described. Said preparation contains an alkaline core comprising an acidic susceptible substance, a separating layer and an enteric coating layer. In order to further enhance the stability du
REFERENCES:
patent: 4853230 (1989-08-01), Lovgren et al.
patent: 4927640 (1990-05-01), Dahlinder et al.
Pharmaceutical Research, vol. 10 (1993), p. S-274.
Drugs Made in Germany, 37, No. 2 (1994), pp. 53-60.
Aulton M. E. (Churchill Livingston) Pharmaceutics: The Science of Dosage Form Design (1988), pp. 316-321.
Bergstrand Pontus John Arvid
Lovgren Kurt Ingmar
Astra Aktiebolag
Howard Sharon
Page Thurman K.
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