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Claims for Patent: 5,534,534

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Claims for Patent: 5,534,534

Title: Pharmaceutical compositions for oral use and method of preparing them
Abstract:A pharmaceutical composition for oral use comprising an effective amount of a compound of the formula (I) having antagonistic action to angiotensin II ##STR1## (wherein the ring W is an optionally substituted N-containing heterocyclic residue; R.sup.3 is a group capable of forming an anion or a group convertible thereinto; X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; and n is an integer of 1 or 2) and an oily substance having a lower melting point, and a method for preparing a pharmaceutical composition for oral use comprising an effective amount of a compound of the formula (I) and an oily substance having a lower melting point, which comprises admixing the compound of the formula (I) with an oily substance having a lower melting point and then subjecting the mixture to molding.
Inventor(s): Makino; Tadashi (Osaka, JP), Mizukami; Yashio (Osaka, JP), Kikuta; Jun-ichi (Osaka, JP)
Assignee: Takeda Chemical Industries, Ltd. (Osaka, JP)
Application Number:07/978,290
Patent Claims: 1. A solid pharmaceutical composition for oral use, which comprises an effective amount of a compound of the formula (I), in a crystalline form, having antagonistic action to angiotensin II ##STR15## wherein the ring W is an optionally substituted N-containing heterocyclic residue; R.sup.3 is a group capable of forming an anion or a group convertible thereinto; X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; and n is an integer of 1 or 2', and a polymer of alkylene oxide dispersed throughout the composition and is present in an amount from 0.005 to 0.15 weight per 1 weight of the composition.

2. A composition according to claim 1, wherein the compound of the formula (I) is a crystalline substance having a melting point of 100.degree. to 200.degree. C.

3. A composition according to claim 1, wherein the ring W in the compound of the formula (I) is a benzimidazole ring.

4. A composition according to claim 3, wherein the compound of the formula (I) is a benzimidazole-7-carboxylic acid compound or a derivative thereof.

5. A composition according to claim 3, wherein the ring W in the compound of the formula (I) is a benzimidazole ring of the formula (III) ##STR16## , wherein the ring A is a benzene ring; R.sup.1 is hydrogen or an optionally substituted hydrocarbon residue; R.sup.2 is an optionally esterified carboxyl group; Y is a bond, --O--, --S(O)m--, wherein m denotes 0, 1 or 2, or --N(R.sup.4)--, where R.sup.4 is hydrogen or an optionally substituted alkyl group.

6. A composition according to claim 5, wherein R.sup.2 in the benzimidazole ring of the formula (III) is a group represented by the formula --CO--D, wherein D is hydroxyl group or a lower (C.sub.1-4) alkoxy whose alkyl portion is optionally substituted with hydroxyl, amino, halogen, a lower (C.sub.2-6) alkanoyloxy, 1-lower (C.sub.1-6) alkoxycarbonyloxy or a lower (C.sub.1.sub.4) alkoxy.

7. A composition according to claim 1, wherein R.sup.3 in the compound of the formula (I) is an optionally substituted monocyclic heterocyclic residue.

8. A composition according to claim 7, wherein the heterocyclic residue is tetrazolyl.

9. A composition according to claim 1, the compound of the formula (I) is (.+-.)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl )biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate.

10. A composition according to claim 1, the compound of the formula (I) is 2-butyl-1[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carbo xylic acid.

11. A composition according to claim 1, wherein the melting point of the polymer of alkylene oxide ranges from about 20.degree. to 90.degree. C.

12. A composition according to claim 1, wherein the amount of the polymer of alkylene oxide is less than 0.1 part by weight per 1 part of the composition by weight.

13. A composition according to claim 1, wherein the compound of the formula (I) is (.+-.)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7 -carboxylate.

14. A composition according to claim 1, wherein the alkylene oxide is ethylene oxide.

15. A composition according to claim 1, wherein the alkylene oxide has a molecular weight of greater than 1000.

16. A composition according to claim 1, wherein the composition is in a tablet form.

17. A solid pharmaceutical composition for oral use, comprising an effective amount of the compound (.+-.)-1-(cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1[[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimid-azole- 7-carboxylate and polyethylene glycol (PEG) dispersed throughout the composition.

18. A composition according to claim 17, wherein the polyethylene glycol has a molecular weight of greater than 1000.

19. A composition according to claim 17, wherein the composition is in a tablet form.

20. A method for minimizing crystalline disorder of an active ingredient in a solid pharmaceutical composition for oral use, comprising:

(a) combining: (1) an active ingredient which is an effective amount of a compound of the formula (I), in a crystalline form, having antagonistic action to angiotensin II, ##STR17## wherein the ring W is an optionally substituted N-containing heterocyclic residue; R.sup.3 is a group capable of forming an anion or a group convertible thereinto; X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; and n is an integer of 1 or 2, and (2) a polymer of alkylene oxide present in an amount of from 0.005 to 0.15 weight per 1 weight of the composition; and

(b) molding the combination of the active ingredient and the alkylene oxide into the solid pharmaceutical composition, whereby the crystalline disorder of the active ingredient (I) is minimized.

21. A method according to claim 20, wherein the molding step is tableting under elevated pressure to form a tablet of the composition.

22. A method according to claim 20, wherein the alkylene oxide is polyethylene glycol.

23. A method according to claim 20, wherein the active ingredient is ##STR18##

24. A composition according to claim 5, wherein the ring A contains, besides the group represented by R.sup.2, further substituents selected from the group consisting of a halogen, a nitro, a cyano, a (C.sub.1-4) alkyl, a (C.sub.1-4) alkoxy, an amino, an N--(C.sub.1-4) alkylamino, an N,N-di-(C.sub.1-4) alkylamino, an N-arylamino, an alicyclic amino, tetrazolyl, trifluoromethanesulfonic acid amide, phosphoric acid, sulfonic acid, and a group represented by the formula --CO--D'--, wherein D' is selected from the group consisting of a hydroxyl and a (C.sub.1-4) alkoxy.

25. A composition according to claim 24, wherein said tetrazolyl, trifluoromethanesulfonic acid amide, phosphoric acid, and sulfonic acid are protected with a group selected from (C.sub.1-4) alkyl, C.sub.2-5 alkanoyl, and optionally substituted benzoyl.

26. A composition according to claim 24, wherein one or two of said further substituents are substituted simultaneously on optional positions of ring A.

27. A composition according to claim 24, wherein D' is a (C.sub.1-4) alkoxy whose alkyl portion is substituted with a group selected from a hydroxyl, a (C.sub.1-4) alkoxy, a (C.sub.2-6) alkanoyloxy, and a (C.sub.1-6) alkoxycarbonyloxy.
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