Pharmaceutical composition comprising a bi-cyclic compound and method for stabilizing the bi-cyclic compound
View Patent ↗Disclosed is a method for stabilizing a pharmaceutically active bi-cyclic compound of formula (I): comprising the step of: admixing the same with a polyol and/or a fatty acid ester other than glyceride and a composition obtained by the method. In addition a soft gelatin capsule formulation of the compound of formula (I) obtained by incorporating the compound in a soft gelatin capsule shell comprising gelatin and a polyol plasticizer.
1. A soft gelatin capsule formulation of a bi-cyclic compound of formula (I):
wherein, A is —CH 2 OH, —COCH 2 OH, —COOH or a functional derivative thereof;
X 1 and X 2 are hydrogen, lower alkyl or halogen;
V 1 and V 2 are carbon or oxygen;
W 1 and W 2 are
wherein R 4 and R 5 are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy (lower) alkyl with the proviso that R 4 and R 5 are not hydroxy or lower alkoxy at the same time;
Z is a carbon, oxygen, sulfur or nitrogen;
R 1 is a saturated or unsaturated bivalent lower-medium aliphatic hydrocarbon residue which is unsubstituted or substituted with halogen, lower alkyl, hydroxy, oxo, aryl or heterocyclic group;
R 2 is a saturated or unsaturated, lower or medium aliphatic hydrocarbon residue which is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkyloxy, aryl, aryloxy, heterocyclic group or heterocyclicoxy group; lower cycloalkyl; lower cycloalkyloxy; aryl, aryloxy, heterocyclic group or heterocyclicoxy group;
R 3 is hydrogen, a lower alkyl, lower cycloalkyl, aryl or heterocyclic group, which comprises:
a soft gelatin capsule shell comprising gelatin and a polyol selected from the group consisting of glycerin, propylene glycol and polyethylene glycol as a plasticizer, and
a mixture comprising said bi-cyclic compound and glyceride, which is filled in the shell.
2. The formulation of claim 1 , wherein
A is —COOH or functional derivative thereof;
X 1 and X 2 are halogen;
W 1 is ═O, or where one of R 4 and R 5 is hydrogen, another is hydroxy;
W 2 is where R 4 and R 5 are both hydrogen;
Z is oxygen;
R 1 is a saturated or unsaturated bivalent unsubstituted lower-medium aliphatic hydrocarbon residue;
R 2 is a saturated or unsaturated unsubstituted lower-medium aliphatic hydrocarbon residue;
R 3 is hydrogen.
3. The formulation of claim 1 , wherein the polyol is glycerin.
4. The formulation of claim 1 , wherein the glyceride is a medium chain fatty acid triglyceride.
5. A method for stabilizing a bi-cyclic compound of formula (I):
wherein, A is —CH 2 OH, —COCH 2 OH, —COOH or a functional derivative thereof;
X 1 and X 2 are hydrogen, lower alkyl or halogen;
V 1 and V 2 are carbon or oxygen;
W 1 and W 2 are
wherein R 4 and R 5 are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy (lower) alkyl with the proviso that R 4 and R 5 are not hydroxy or lower alkoxy at the same time;
Z is a carbon, oxygen, sulfur or nitrogen;
R 1 is a saturated or unsaturated bivalent lower-medium aliphatic hydrocarbon residue which is unsubstituted or substituted with halogen, lower alkyl, hydroxy, oxo, aryl or heterocyclic group;
R 2 is a saturated or unsaturated, lower or medium aliphatic hydrocarbon residue which is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkyloxy, aryl, aryloxy, heterocyclic group or heterocyclicoxy group; lower cycloalkyl; lower cycloalkyloxy; aryl, aryloxy, heterocyclic group or heterocyclicoxy group;
R 3 is hydrogen, lower alkyl, lower cycloalkyl, aryl or heterocyclic group, which comprises:
dispersing or mixing the bi-cyclic compound in a glyceride, and incorporating the liquid mixture in a soft-gelatin capsule whose shell comprises gelatin and a polyol selected from the group consisting of glycerin, propylene glycol and polyethylene glycol as a plasticizer.
6. The method of claim 5 , wherein
A is —COOH or functional derivative thereof;
X 1 and X 2 are halogen;
W 1 is ═O, or where one of R 4 and R 5 is hydrogen, another is hydroxy;
W 2 is where R 4 and R 5 are both hydrogen;
Z is oxygen;
R 1 is a saturated or unsaturated bivalent unsubstituted lower-medium aliphatic hydrocarbon residue;
R 2 is a saturated or unsaturated unsubstituted lower-medium aliphatic hydrocarbon residue;
R 3 is hydrogen.
7. The method of claim 5 , wherein the polyol is glycerin.
8. The method of claim 7 , wherein the glyceride is a medium chain fatty acid triglyceride.
9. The formulation of claim 1 , wherein the mixture does not include polyethylene glycol as a vehicle.
10. The method of claim 5 , wherein the mixture does not include polyethylene glycol as a vehicle.