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Claims for Patent: 5,686,104

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Claims for Patent: 5,686,104

Title: Stable oral CI-981 formulation and process of preparing same
Abstract:An oral pharmaceutical composition is provided for treating hypercholestereolemia or hyperlipidemia containing an advantageous formulation for stabilizing the HMG-CoA coenzyme A inhibitor, CI-981 Hemi-Calcium, of formula (IA) ##STR1## with effective amounts of calcium carbonate. A method for preparing a CI-981 stabilizing composition is described.
Inventor(s): Mills; Nancy (Mt. Arlington, NJ), Muhammad; Nouman A. (Long Valley, NJ), Weiss; Jay (East Brunswick, NJ), Nesbitt; Russell U. (Somerville, NJ)
Assignee: Warner-Lambert Company (Morris Plains, NJ)
Application Number:08/246,919
Patent Claims: 1. A pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia characterized by improved stability comprising in a mixture, a compound as active ingredient of structural formula I ##STR7## wherein X is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH(CH.sub.3);

R.sub.1 is 1-naphthyl; 2-naphthyl; cyclohexyl, norbornenyl; 2-, 3-, or 4-pyridinyl; phenyl; phenyl substituted with flourine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;

either R.sub.2 or R.sub.3 is --CONR.sub.5 R.sub.6 where R.sub.5 and R.sub.6 are independently hydrogen; alkyl of from one to six carbon atoms; 2-, 3-, or 4-pyridinyl; phenyl; phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms; and the other R.sub.2 or R.sub.3 is hydrogen; alkyl of from one to six carbon atoms; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;

R.sub.4 is alkyl of from one to six carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or trifluoromethyl;

M is a pharmaceutically acceptable metal salt;

at least one stabilizing pharmaceutically acceptable alkaline metal salt additive and comprising by weight of the total solid composition at least one binder selected from the group consisting of methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, starch, and hydroxymethylcellulose comprising by weight between about 0.5% and about 6%;

at least one diluent selected from the group consisting of microcrystalline cellulose, hydrous lactose, cornstarch, sucrose, and silicic anhydride comprising by weight between about 1% and about 80%;

at least one disintegrant selected from the group consisting of carboxymethylcellulose, croscarmellose and starch comprising by weight between about 1% and about 15%;

at least one surfactant selected from the group consisting of polyoxyethylene sorbitan and polyoxyethylene-polyoxypropylene copolymer comprising by weight between about 0.1% and about 4%;

at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and talc comprising by weight between about 0.25% and about 2%;

and optionally at least one antioxidant selected from the group consisting of butylated hydroxanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, and ascorbic acid comprising by weight up to about 3%.

2. The stable pharmaceutical composition of claim 1 wherein the active ingredient is a pharmaceutically acceptable metal salt of [R-(R*,R*)]-2-(4-fluorophenyl-.beta.,.delta.-dihydroxy-5(1-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.

3. The stable pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable metal salt is an alkaline earth metal salt.

4. The stable pharmaceutical composition of claim 2, wherein the active ingredient is CI-981 Hemi-Calcium of Formula (IA): ##STR8## and wherein the stabilizing pharmaceutically acceptable metal salt additive is calcium carbonate.

5. The stable pharmaceutical composition of claim 1, 2 or claim 4, wherein the active ingredient dosage is between about 1% and about 50% by weight of the composition.

6. A method for preparing a stable pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia comprising a step of mixing thoroughly about 1% to about 50% by weight of the active ingredient of claim 1, claim 2 or claim 4 with about 5% to about 75% by weight of a stabilizing pharmaceutically acceptable additive.

7. The stable pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable metal salt is an alkaline earth metal salt.

8. The stable pharmaceutical composition of claim 1 wherein the stabilizing pharmaceutically acceptable metal salt additive is an alkaline earth metal salt.

9. The stable pharmaceutical composition of claim 8, wherein the alkaline earth metal salt is selected from the group consisting of calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate and aluminum magnesium hydroxide.

10. The stable pharmaceutical composition of claim 1, wherein the stabilizing pharmaceutically acceptable metal salt additive is calcium carbonate.

11. The stable pharmaceutical composition of claim 10 wherein the stabilizer calcium carbonate is in the range from about 5% to about 75% by weight of the composition.

12. The stable pharmaceutical composition of claim 1, further comprising an antioxidant.

13. The stable pharmaceutical composition of claim 12 wherein the composition comprises by weight between about 5% and about 75% microcrystalline cellulose; between about 1% and about 80% of hydrous lactose; between about 1% and about 15% of croscarmellose sodium; between about 0.5% and about 6% hydroxypropyl cellulose; between about 0.1% and about 4% of Tween 80; between about 0.25% and about 2% of magnesium stearate; and up to about 3% of sodium ascorbate or butylated hydroxyanisole of the total solid composition.

14. A stabilized solid pharmaceutical composition for peroral treatment of hypercholesterolemia or hyperlipidemia comprising in solid unit dosage form an active ingredient [R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemicalcium salt and a stabilizer selected from the group consisting of calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, and aluminum magnesium hydroxide and comprising by weight of the total solid composition at least one binder selected from the group consisting of methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, starch, and hydroxymethylcellulose comprising by weight between about 0.5% and about 6%;

at least one diluent selected from the group consisting of microcrystalline cellulose, hydrous lactose, cornstarch, sucrose, and silicic anhydride comprising by weight between about 1% and about 80%;

at least one disintegrant selected from the group consisting of carboxymethylcellulose, croscarmellose and starch comprising by weight between about 1% and about 15%;

at least one surfactant selected from the group consisting of polyoxyethylene sorbitan and polyoxyethylene-polyoxypropylene copolymer comprising by weight between about 0.1% and about 4%;

at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and talc comprising by weight between about 0.25% and about 2%;

and optionally at least one antioxidant selected from the group consisting of butylated hydroxanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, and ascorbic acid comprising by weight up to about 3%.

15. A method for preparing a stabilized pharmaceutical composition formulated for peroral therapy of hypercholesterolemia or hyperlipidemia comprising:

(a) milling an excess of the drug, CI-981 Hemi-Calcium of the formula IA: ##STR9## (b) dissolving at least one binder additive in aqueous surfactant solution;

(c) blending the milled drug with at least one drug-stabilizing alkaline earth metal salt additive and at least one diluent additive ingredient with the drug-stabilizing additive and one half of a disintegrant additive in a rotary mixing vessel equipped with a chopping device;

(d) granulating the blended drug mixture of step (c) with the surfactant/binder solution of step (b) in gradual increments in the chopper equipped mixing vessel;

(e) drying the granulated drug mixture overnight at about 50.degree. C.;

(f) sieving the dried granulated drug mixture;

(g) tumble blending the sieved drug mixture with the remaining amount of the disintegrant additive;

(h) mixing separately an aliquot of the step (g) drug mixture with magnesium stearate, sieving same, and returning same to the drug mixture of step (g) and tumble blending the entire drug mixture; and compressing aliquots of the step (h) drug mixture into tablets.

16. The method claimed in claim 15, wherein in step (c) the drug stabilizing additive comprises a basic inorganic salt of calcium or magnesium.

17. The method claimed in claim 15, wherein in step (b) the binder additive comprises methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol or starch; and the surfactant comprises Tween 80 or polyoxyethylene-polyoxypropylene copolymer.

18. The method of claim 15 wherein in step (c) the disintegrant additive comprises croscarmellose sodium, carboxymethyl cellulose calcium or starch.

19. The method claimed in claim 15 wherein in step (c) the diluent additive is selected from the group consisting of microcrystalline cellulose, hydrous lactose, corn starch, sucrose, silicic anhydride and mixtures thereof.

20. The method claimed in claim 15 wherein the diluent additive is at least one polysaccharide.

21. A peroral pharmaceutical composition for treating hypercholesterolemia comprising an effective, cholesterol synthesis inhibitory amount of the enantiomer [R-R*,R*)]-2(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, hemicalcium salt; stabilized by calcium carbonate, and comprising by weight of the total solid composition at least one binder selected from the group consisting of methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, starch, and hydroxymethylcellulose comprising by weight between about 0.5% and about 6%;

at least one diluent selected from the group consisting of microcrystalline cellulose, hydrous lactose, cornstarch, sucrose, and silicic anhydride comprising by weight between about 1% and about 80%;

at least one disintegrant selected from the group consisting of carboxymethylcellulose, croscarmellose and starch comprising by weight between about 1% and about 15%;

at least one surfactant selected from the group consisting of polyoxyethylene sorbitan and polyoxyethylene-polyoxypropylene copolymer comprising by weight between about 0.1% and about 4%;

at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and talc comprising by weight between about 0.25% and about 2%;

and optionally at least one antioxidant selected from the group consisting of butylated hydroxanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, and ascorbic acid comprising by weight up to about 3%, in a dosage of solid enantiomer ranging from about 0.1 to about 8.0 mg/kg body weight per day.

22. A method of treating hypercholesterolemia or hyperlipidemia comprising a therapeutically effective unit dosage of the peroral pharmaceutical composition of claim 21 in the form of tablets or capsules.
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