Claims for Patent: 5,356,896

Summary for Patent: 5,356,896

Title:	Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound
Abstract:	A pharmaceutical dosage form comprising an HMG-CoA reductase inhibitor compound, e.g., fluvastatin sodium, is disclosed which is stabilized against pH-related degradation by an alkaline stabilizing medium capable of imparting a pH of at least 8 to an aqueous solution or dispersion of the composition.
Inventor(s):	Kabadi; Mohan B. (Marlboro, NJ), Vivilecchia; Richard V. (Rockaway, NJ)
Assignee:	Sandoz Ltd. (Basel, CH)
Application Number:	07/995,252
Patent Claims:	1. A pharmaceutical composition comprising an HMG-CoA reductase inhibitor compound of the formula: ##STR4## wherein R is an organic radical, X is --CH.dbd.CH--, and M is a physiologically acceptable cation, and an alkaline stabilizing medium capable of imparting a pH of at least 8 to an aqueous solution or dispersion of the composition wherein the alkaline stabilizing medium comprises at least one pharmaceutically acceptable carbonate salt. 2. A pharmaceutical composition according to claim 1 wherein R is selected from the group consisting of indolyl, pyrimidinyl, indenyl, pyridinyl and quinolinyl radicals and derivatives thereof, and X is (E)--CH.dbd.CH--. 3. A pharmaceutical composition according to claims 2 wherein the pharmaceutically acceptable carbonate salt is selected from the group consisting of sodium carbonate, sodium bicarbonate, calcium carbonate and mixtures thereof. 4. A pharmaceutical composition according to claim 1 wherein the alkaline stabilizing medium comprises a mixture of a water soluble carbonate and a water insoluble or sparingly soluble carbonate. 5. A pharmaceutical composition according to claim 4 wherein the ratio of water soluble carbonate to water insoluble or sparingly soluble carbonate is from 1:40 to 2:1. 6. A pharmaceutical composition comprising the HMG-CoA reductase inhibitor fluvastatin sodium and a pharmaceutically acceptable alkaline stabilizing medium capable of imparting a pH of at least 8 to an aqueous solution or dispersion of the composition. 7. A pharmaceutical composition according to claim 6 wherein the alkaline stabilizing medium comprises at least one pharmaceutically acceptable carbonate salt. 8. A pharmaceutical composition according to claim 7 wherein the pharmaceutically acceptable carbonate salt is selected from the group consisting of sodium carbonate, sodium bicarbonate, calcium carbonate and mixtures thereof. 9. A pharmaceutical composition according to claim 8 comprising fluvastatin sodium, (i) calcium carbonate and (ii) sodium carbonate or sodium bicarbonate. 10. A pharmaceutical composition according to claims 1, 3, or 8 which comprises 0.5 to 60 wt. % HMG-CoA reductase inhibitor compound, 0.5 to 40 wt. % calcium carbonate, 0.5 to 20 wt. % sodium bicarbonate, and 10 to 65 wt. % microcrystalline cellulose. 11. A pharmaceutical composition according to claims 2 or 6 in solid unit dosage form. 12. An oral pharmaceutical composition suitable for excapsulation for delivering fluvastatin sodium which comprises 0.5 to 60 wt. % of fluvastatin sodium, 25 to 40 wt. % of calcium carbonate, 0.5 to 10 wt. % of sodium bicarbonate, and 20 to 35 wt. % of microcrystalline cellulose. 13. An oral pharmaceutical composition suitable for tableting for delivering fluvastatin sodium which comprises 0.5 to 60 wt. % of fluvastatin sodium, 5 to 20 wt. % of calcium carbonate, 5 to 20 wt. % of sodium bicarbonate, and 50 to 65 wt. % of microcrystalline cellulose. 14. A composition according to claim 12 wherein the capsule is coated with an enteric and/or film coating. 15. A composition according to claim 13 wherein the tablet is coated with an enteric and/or film coating. 16. A composition according to claim 12 wherein fluvastatin sodium is present in a dosage amount selected from the group consisting of 5, 10, 15, 20 and 40 mg. amounts. 17. A composition according to claim 13 wherein fluvastatin sodium is present in a dosage amount selected from the group consisting of 5, 10, 15, 20 and 40 mg. amounts. 18. A composition according to claims 2 or 8 wherein the HMG-CoA reductase inhibitor compound and the pharmaceutically acceptable carbonate salt are in intimate contacting association. 19. A method of preparing the composition of claims 2 or 8 which comprises bringing the HMG-CoA reductase inhibitor compound and the alkaline stabilizing medium into intimate contacting association by co-lyophilizing the HMG-CoA reductase inhibitor compound and the alkaline stabilizing medium. 20. A pharmaceutical composition according to claim 2 wherein the HMG-CoA reductase inhibitor compound is a pharmaceutically acceptable salt of erythro-3R,5S-(E)-7-[4-fluorophenyl-6-(1-methylethyl)-2-(dimethylamino-pyr imidin-5-yl)-3,5-dihydroxy-6-heptenoic acid, or its racemate. 21. A pharmaceutical composition according to claim 2 wherein the HMG-CoA reductase inhibitor compound is a pharmaceutically acceptable salt of erythro-3R,5S-(E)-dimethoxy-7-[3'-(4"-fluorophenyl)-spiro[cyclopentane-1,1 '(1H)-inden]-2'-yl]-3-hydroxyhept-6-enoic acid, or racemate. 22. A pharmaceutical composition according to claim 2 wherein the HMG-CoA reductase inhibitor compound is a pharmaceutically acceptable salt of erythro-3R,5S-(E)-7-[4-(4-fluorophenyl)-2,6-bis(1-methylethyl)-5-methoxyme thyl-pyridin-3-yl]-3,5-dihydroxy-6-heptenoic acid, or its racemate. 23. A pharmaceutical composition according to claim 2 wherein the HMG-CoA reductase inhibitor compound is a pharmaceutically acceptable salt of erythro-(.+-.)-(E)-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-pyridin- 3-yl]-3,5- dihydroxy-6-heptenoic acid, or its 3R,5S isomer. 24. A pharmaceutical composition according to claim 2 wherein the HMG-CoA reductase inhibitor compound is a pharmaceutically acceptable salt of erythro-(.+-.)-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-quinolin-3-yl]- 3,5-dihydroxy-6- heptenoic acid, or its 3R,5S isomer. 25. A pharmaceutical composition according to claim 2 wherein the HMG-CoA reductase inhibitor compound is a pharmaceutically acceptable salt of erythro-(.+-.)-(E)-7-[4-(4-fluorophenyl)-2-cyclopropyl-quinolin-3-yl]-3,5- dihydroxy-6-heptenoic acid, or its 3R, 5S isomer. 26. A pharmaceutical composition according to claim 2 which comprises erythro-(E)-3R,5S-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3 ,5-dihydroxy-6-heptenoic acid, sodium salt. 27. A pharmaceutical composition according to claims 2 or 7 which comprises 0.5 to 60 wt. % HMG-CoA reductase compound, 10 to 55 wt. % pharmaceutically acceptable carbonate salts, and 10 to 65 wt. % filler.