Claims
- 1. A pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia characterized by improved stability comprising in a mixture, about 1% to about 50% by weight of the composition of 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)1
- R.sub.1 is 1-naphthyl; 2-naphthyl; cyclohexyl, norbornenyl; 2-,3-, or 4-pyridinyl; phenyl; 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 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 of 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; and
- about 5% to about 75% by weight of the composition of calcium carbonate to stabilize the composition.
- 2. The stable pharmaceutical composition of claim 1, wherein M is a pharmaceutically acceptable alkaline earth metal salt.
- 3. The stable pharmaceutical composition of claim 2, 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.
- 4. A pharmaceutical composition characterized by improved stability comprising in a mixture, about 1% to about 50% by weight of the composition of a pharmaceutically acceptable metal salt of [R--R*,R*)]-2-(4-fluorophenyl-.beta., .LAMBDA.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid; and about 5% to about 75% by weight of the composition of calcium carbonate to stabilize the composition.
- 5. The stable pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable metal salt is an alkaline earth metal salt.
- 6. The stable pharmaceutical composition of claim 5, 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.
- 7. A pharmaceutical composition characterized by improved stability comprising in a mixture, the Hemi-Calcium of Formula (IA): ##STR8## and an effective amount of calcium carbonate.
- 8. A method of improving the stability of a pharmaceutical composition comprising as an active ingredient a compound having the structural formula I ##STR9## 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 fluorine, 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 of 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;
- by adding an effective amount of an alkaline earth metal salt to the composition.
- 9. The method 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 method of claim 9, wherein the alkaline earth metal salt is calcium carbonate.
- 11. The method of claim 8, wherein M is a pharmaceutically acceptable alkaline earth metal salt.
- 12. The method of claim 11, 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.
- 13. A method of improving the stability of a pharmaceutical composition by adding an effective amount of calcium carbonate to a composition comprising 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.
- 14. The method of claim 13, wherein the pharmaceutically acceptable metal salt is an alkaline earth metal salt.
- 15. The method of claim 14, 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.
- 16. A method of improving the stability of a pharmaceutical composition by adding an effective amount of calcium carbonate to a composition comprising the Hemi-Calcium of Formula (IA): ##STR10##
- 17. A pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia characterized by improved stability comprising in a mixture, about 1% to about 50% by weight of the composition of a compound as active ingredient of structural formula I 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)1
- R.sub.1 is 1-naphthyl; 2-naphthyl; cyclohexyl, norbornenyl; 2-,3-, or 4-pyridinyl; phenyl; 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 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 of 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; and
- about 5% to about 75% by weight of the composition of at least one stabilizing pharmaceutically acceptable calcium or lithium salt additive.
- 18. The stable pharmaceutical composition of claim 17 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.
- 19. The stable pharmaceutical composition of claim 17 wherein the stabilizing pharmaceutically acceptable additive is a calcium salt.
Parent Case Info
This application is a continuation of Ser. No. 08/246,919 filed May 20, 1994 now U.S. Pat. No. 5,686,104, which is a continuation of Ser. No. 08/005,708 filed Jan. 19, 1993 now abandoned.
US Referenced Citations (3)
Number |
Name |
Date |
Kind |
4681893 |
Roth et al. |
Jul 1987 |
|
5030447 |
Joshi et al. |
Jul 1991 |
|
5686104 |
Mills et al. |
Nov 1997 |
|
Foreign Referenced Citations (1)
Number |
Date |
Country |
0 409 281 A1 |
Jan 1991 |
EPX |
Continuations (2)
|
Number |
Date |
Country |
Parent |
246919 |
May 1994 |
|
Parent |
005708 |
Jan 1993 |
|