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Summary for Patent: 4,853,230
|Title:||Pharmaceutical formulations of acid labile substances for oral use|
|Abstract:||Pharmaceutical preparation containing an acid labile compound together with an alkaline reacting compound or an alkaline salt of an acid labile compound optionally together with an alkaline compound as the core material, one or more subcoating layers comprising inert reacting compounds which are soluble or rapidly disintegrating in water, or polymeric, water soluble filmforming compounds, optionally containing pH-buffering alkaline compounds and an enteric coating as well as a process for the preparation thereof and the use in the treatment of gastrointestinal diseases.|
|Inventor(s):||Lovgren; Kurt I. (Molnlycke, SE), Pilbrant; Ake G. (Kungsbacka, SE), Yasumura; Mitsuru (Hyogo, JP), Morigaki; Satoshi (Hyogo, JP), Oda; Minoru (Ohita, JP), Ohishi; Naohiro (Fukuoka, JP)|
|Assignee:||Aktiebolaget Hassle (Molndal, SE)|
1. A pharmaceutical preparation comprising:
(a) an alkaline reacting core comprising an acid-labile pharmaceutically active substance and an alkaline reacting compound different from said active substance, an alkaline salt of an acid labile pharmaceutically active substance, or an alkaline salt of an acid labile pharmaceutically active substance and an alkaline reacting compound different from said active substance;
(b) an inert subcoating which rapidly dissolves or disintegrates in water disposed on said core region, said subcoating comprising one or more layers comprising materials selected from the group consisting of tablet excipients, film-forming compounds and alkaline compounds; and
(c) an enteric coating layer surrounding said subcoating layer, wherein the subcoating layer isolates the alkaline reacting core from the enteric coating layer such that the stability of the preparation is enhanced.
2. A preparation according to claim 1, wherein the acid labile compound has the general formula I, ##STR17## wherein A is an optionally substituted heterocyclic group, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same or different and select from among hydrogen, lower alkyl, lower alkoxy, --CF.sub.3, ##STR18## alkyl or halogen and R.sup.5 is H or a lower alkyl group wherein "lower" denotes 1-6 carbon atoms except the compound omerprazole, 5-methoxy-2[[(4-methoxy-3,5 dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole; or the acid labile compound is 2-[(2-dimethylaminobenzyl)sulfinyl]-benzimidazole.
3. A preparation according to dlaim 1 wherein the subcoating layer comprises one or more of magnesium oxide, magnesium hydroxide or composite substance [Al.sub.2 O.sub.3.6MgO.CO.sub.2.12H.sub.2 O or MgO.Al.sub.2 O.sub.3.2SiO.sub.2.nH.sub.2 O], wherein n is not an integer and less than two.
4. A preparation according to claim 2 wherein the subcoating comprises two or more sub-layers.
5. A preparation according to claim 4 wherein the subcoafting comprises hyroxypropyl methylcellulose, hyroxypropyl cellulose or polyvinyl-pyrrolidone.
6. A preparation according to claim 1, wherein an alkaline core comprises the acid labile compound and a pH-buffering alkaline reacting compound which renders to the micro-environment of the acid labile compound a pH of 7-12.
7. A preparation according to claim 6 wherein the alkaline reacting compound comprises one or more of magnesium oxide, hydroxide or carbonate, aluminium hydroxide, aluminium, calcium, sodium or potassium carbonate, phosphate or citrate, the composite aluminium/magnesium compounds Al.sub.2 O.sub.3.6MgO.CO.sub.2.12H.sub.2 O or MgO.Al.sub.2 O.sub.3.2SiO.sub.2.nH.sub.2 O, wherein n is not an integer and less than two.
8. A preparation according to claim 1, wherein the alkaline core comprises an alkaline salt of the acid labile compound such as the sodium, potassium, magnesium calcium or ammonium salt.
9. A preparation according to claim 7 wherein the alkaline core comprises an alkaline salt of the acid labile compound mixed with an inert, alkaline compound.
10. A preparation according to claim 1, wherein the enteric coating comprises hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, co-polymerized methacrylic acid/methacrylic acid methyl ester or polyvinyl acetate phthalate, optionally containing a plasticizer.
11. A preparation according to claim 1, wherein the water content of the final dosage form containing the acid labile compound does not exceed 1.5% by weight.
12. Process for the preparation of an oral pharmaceutical formulation containing an acid labile compound in which cores containing the acid labile compound mixed with an alkaline reacting compound or compounds or an alkaline salt of the acid labile compound optionally mixed with an alkaline reacting compound or compounds are coated with one or more inert reacting subcoating layers whereafter the subcoated cores are further coated with an enteric coating layer.
13. A method for the treatment of gastrointestinal disease characterized in that a preparation according to claim 1 is administered to a host in the need of such treatment in a therapeutically effective amount.
14. A preparation according to claim 8, wherein the salt of the acid labile compound is selected from among the sodium, potassium, magnesium, calcium and ammonium salts.
15. A preparation according to claim 1, wherein the subcoating further comprises an alkaline buffering compound.
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