Stable pharmaceutical compositions containing 7-substituted-3,5-dihydroxyheptanoic acids or 7-substituted-3,5-dihydroxyheptenoic acids

Abstract

Pharmaceutical compositions that have excellent storage stability even though they include a active component that is susceptible to degradation in an acidic environment are disclosed. The stabilized pharmaceutical composition of the invention includes a ring-opened 7-substituted-3,5-dihydroxyheptanoic or a ring-opened 7-substituted-3,5-dihydroxyheptenoic acid, or a pharmaceutically acceptable salt thereof, as an active component and a stabilizing effective amount of at least one amido-group containing polymeric compound or at least one amino-group containing polymeric compound, or combination thereof; wherein the stabilized pharmaceutical composition does not contain a stabilizing effective amount of another stabilizer or a combination of other stabilizers. The pharmaceutical composition may optionally include one or more pharmaceutically acceptable excipients such as a filler, a disintegrating agent and one or more lubricants such as magnesium stearate to aid compression where a tablet dosage form is desired.

What is claimed is:  
     
       1. A stabilized pharmaceutical composition for the treatment of dyslipidemia,
 comprising 
 an active component consisting essentially of one or more compounds selected from the group consisting of (i) an HMG- CoA reductase inhibiting  ring-opened 7-substituted-3,5-dihydroxyheptafloic acid or a pharmaceutically acceptable acid salt thereof, and (ii) an HMG- CoA reductase inhibiting  ring-opened 7-substituted-3,5-dihydroxyheptenoic acid or a pharmaceutically acceptable acid salt thereof, and  
 a stabilizing effective amount of at least one amido-group containing polymeric compound or at least one amino-group containing polymeric compound, or combination thereof, wherein said stabilized pharmaceutical composition does not contain a stabilizing effective amount of another stabilizer or a combination of other stabilizers.  
 
 
     
     
       2. The composition of  claim 1  wherein the at least one amido-group containing polymeric compound or at least one amino-group containing polymeric compound, or combination thereof, comprises between about 10 and about 99 percent by weight of the composition. 
     
     
       3. The composition of  claim 2  wherein the at least one amido-group containing polymeric compound or at least one amino-group containing polymeric compound, or combination thereof, comprises between about 30 and about 80 percent by weight of the composition. 
     
     
       4. The composition of  claim 1  wherein the active component comprises between about 0.05 and about 70 percent by weight of the composition. 
     
     
       5. The composition of  claim 4  wherein the active component comprises between about 1 and about 60 percent by weight of the composition. 
     
     
       6. The composition of  claim 1  wherein the active component is a pharmaceutically acceptable acid salt of pravastatin. 
     
     
       7. The composition of  claim 6  wherein the pharmaceutically acceptable acid salt is pravastatin sodium. 
     
     
       8. The composition of  claim 1  wherein the active component is a pharmaceutically acceptable acid salt of atorvastatin. 
     
     
       9. The composition of  claim 8  wherein the pharmaceutically acceptable acid salt is atorvastatin calcium. 
     
     
       10. The composition of  claim 1  wherein the composition is in the form of a solid. 
     
     
       11. The composition of  claim 10  wherein the composition is in the form of a tablet. 
     
     
       12. The composition of  claim 11  wherein the tablet contains a lubricant. 
     
     
       13. The composition of  claim 12  wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, polyethylene glycol, stearic acid, hydrogenated vegetable oil and talc. 
     
     
       14. The composition of  claim 10  wherein the composition is in the form of granules. 
     
     
       15. The composition of  claim 14  wherein the granules are constituents of a dispersion. 
     
     
       16. The composition of  claim 10  wherein the composition is in the form of a suspension. 
     
     
       17. The composition of  claim 10  wherein the composition is in the form of a capsule. 
     
     
       18. The composition of  claim 10  wherein the composition is in the form of a cachet. 
     
     
       19. The composition of  claim 1  wherein the amido group in the amido-group containing polymeric compound or the amino group in the amino-group containing polymeric compound is present either in a pendant group attached to the backbone of the polymeric compound or as a component of the backbone of the polymeric compound. 
     
     
       20. The composition of  claim 19  wherein the amido-group containing polymeric compound is selected from the group consisting of polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl acetate, and polynoxylin. 
     
     
       21. The composition of  claim 1 , wherein the amido-group containing polymeric compound or amino-group containing polymeric compound, or combination thereof, imparts a pH of not more than about 10 to an aqueous dispersion of said composition. 
     
     
       22. The composition of  claim 21 , wherein the amido-group containing polymeric compound or amino-group containing polymeric compound, or combination thereof, imparts a pH of not more than about 8 to an aqueous dispersion of said composition. 
     
     
       23. The composition of  claim 19 , wherein the amino-group containing polymeric compound is a quaternary ammonium group-containing polymeric compound. 
     
     
       24. The composition of  claim 23 , wherein the quaternary ammonium group-containing polymeric compound is cholestyramine. 
     
     
       25. The composition of  claim 21  wherein the ring-opened 7-substituted-3,5-dihydroxyheptanoic acid or ring-opened 7-substituted-3,5-dihydroxyheptenoic acid, or pharmaceutically acceptable acid salt thereof, is a HMG-CoA reductase inhibitor medicament that is sensitive to a low pH environment. 
     
     
       26. A stabilized pharmaceutical composition for the treatment of dyslipidemia comprising, in admixture,
 (a) an active component consisting essentially of about 0.05% to about 70% by weight of one or more compounds selected from the group consisting of (i) an HMG- CoA reductase inhibiting  ring-opened 7-substituted-3,5-dihydroxyheptafloic acid or a pharmaceutically acceptable acid salt thereof or (ii) an HMG- CoA reductase inhibiting  ring-opened 7-substituted-3,5-dihydroxyheptenoic acid or a pharmaceutically acceptable acid salt thereof, and  
 (b) about 30% to about 99% by weight of a stabilizing effective amount of an amido-group containing polymeric compound or a stabilizing effective amount of an amino-group containing polymeric compound, or combination thereof; wherein said stabilized pharmaceutical composition does not contain a stabilizing effective amount of another stabilizer or a combination of other stabilizers.  
 
     
     
       27. The composition of  claim 26 , wherein the ring-opened 7-substituted 3,5-dihydroxy heptanoic acid salt is pravastatin sodium. 
     
     
       28. The composition of  claim 26 , wherein the ring-opened 7-substituted 3,5-dihydroxy heptanoic acid salt is pravastatin sodium and the amido-group containing polymeric compound is cross-linked polyvinylpyrrolidone. 
     
     
       29. The composition of  claim 26 , wherein the ring-opened 7-substituted 3,5-dihydroxy heptanoic acid salt is pravastatin sodium and the amido-group containing polymeric compound is polyvinylpyrrolidone. 
     
     
       30. The composition of  claim 26 , wherein the ring-opened 7-substituted 3,5-dihydroxy heptanoic acid salt is pravastatin sodium and the amino-group containing polymeric compound is cholestyramine. 
     
     
       31. The composition of  claim 26 , wherein the ring-opened 7-substituted 3,5-dihydroxy heptanoic acid is atorvastatin calcium. 
     
     
       32. The composition of  claim 26 , wherein the ring-opened 7-substituted 3,5-dihydroxy heptanoic acid salt is atorvastatin calcium and the amido-group containing polymeric compound is cross-linked polyvinylpyrrolidone. 
     
     
       33. The composition of  claim 26 , wherein the ring-opened 7-substituted 3,5-dihydroxy heptanoic acid salt is atorvastatin calcium and the amido-group containing polymeric compound is polyvinylpyrrolidone. 
     
     
       34. The composition of  claim 26 , in a solid tablet dosage form which further comprises a lubricant. 
     
     
       35. The composition of  claim 34 , wherein the lubricant is magnesium stearate. 
     
     
       36. A stabilized pharmaceutical composition comprising an active component consisting essentially of pravastatin sodium and about 40% or greater by weight of the composition of an amido-group or amino-group containing polymeric stabilizer. 
     
     
       37. A stabilized pharmaceutical composition comprising an active component consisting essentially of atorvastatin calcium and about 40% or greater by weight of the composition of an amido-group or amino-group containing polymeric stabilizer. 
     
     
       38. A method for the treatment of dyslipidemia, comprising the step of orally administering to a patient in need of such treatment a therapeutically effective unit dosage of the pharmaceutical composition of  claim 1 . 
     
     
       39. A method for the treatment of dyslipidemia, comprising the step of orally administering to a patient in need of such treatment a therapeutically effective unit dosage of the pharmaceutical composition of  claim 26 . 
     
     
       40. The stabilized pharmaceutical composition of  claim 36 , wherein the amount of pravastatin sodium ranges from about 7 to about 11 percent by weight of the composition. 
     
     
       41. The stabilized pharmaceutical composition of  claim 37 , wherein the amount of atorvastatin calcium ranges from about 7 to about 11 percent by weight of the composition. 
     
     
       42. A stable solid pharmaceutical composition for the treatment of dyslipidemia comprising:
   an active component consisting essentially of one or more compounds selected from the group consisting of  ( a )  an HMG - CoA reductase inhibiting ring - opened  7   - substituted-     3 , 5   - dihydroxyheptanoic acid or a pharmaceutically acceptable acid salt thereof and  ( b )  an HMG - CoA reductase inhibiting ring - opened  7   - substituted -   3 , 5   - dihydroxyheptenoic acid or a pharmaceutically acceptable acid salt thereof, and        at least one pharmaceutically acceptable excipient selected from the group consisting of a lubricant, a glidant, a binder, a filler, a disintegrant, a diluent, a carrier, a colorant, a coating material, and a preservative;        wherein the pH of the stable composition in water, if dispersed in a concentration of  1  mg active component per  1  ml water, would be about  5 . 4  to about  8 , and        wherein the composition does not contain a stabilizing effective amount of one or more buffering agents and does not contain a stabilizing effective amount of one or more basifying agents.     
     
     
       43. The stable solid pharmaceutical composition of  claim 42 , wherein the pH would be about  6 . 5  to about  8 . 
     
     
       44. The stable solid pharmaceutical composition of  claim 42 , wherein the pH would be about  6 . 5  to about  7 . 4 . 
     
     
       45. The stable solid pharmaceutical composition of  claim 42 , wherein the basifying agents are selected from the group consisting of inorganic alkaline salts, inorganic alkaline oxides, inorganic alkaline hydroxides, alkaline metal salts, alkaline metal oxides, and alkaline metal hydroxides. 
     
     
       46. The stable solid pharmaceutical composition of  claim 42 , wherein the composition does not contain a buffering agent. 
     
     
       47. A stable pharmaceutical composition for the treatment of dyslipidemia comprising an active component consisting essentially of one or more compounds selected from the group consisting of atorvastatin, pravastatin, and pharmaceutically acceptable acid salts thereof, and
   at least one pharmaceutically acceptable excipient selected from the group consisting of a lubricant, a glidant, a binder, a filler, a disintegrant, a diluent, a carrier, a colorant, a coating material, and a preservative;        wherein the pH of the stable composition in water, if dispersed in a concentration of  1  mg active component per  1  ml water, would be about  5 . 4  to about  8 , and        wherein the composition does not contain a stabilizing effective amount of one or more buffering agents and does not contain a stabilizing effective amount of one or more basifying agents.     
     
     
       48. The stable solid pharmaceutical composition of  claim 42  or  claim 47 , wherein no more than about  10 %  of the active component initially present in the composition would degrade into the corresponding lactone if  ( i )  tabletted,  ( ii )  packaged in a PVDC/PVC blister package and  ( iii )  stored for six months at  40 ° C. and  75   %  relative humidity.   
     
     
       49. The stable solid pharmaceutical composition of  claim 48 , wherein no more than about  5 %  of the active component initially present in the composition would degrade into the corresponding lactone.   
     
     
       50. The stable solid pharmaceutical composition of  claim 48 , wherein no more than  1 %  of the active component initially present in the composition would degrade into the corresponding lactone.   
     
     
       51. The stable solid pharmaceutical composition of  claim 48 , wherein no more than about  1 %  of the active component initially present in the composition would degrade into the corresponding lactone if  ( i )  tabletted,  ( ii )  packaged in packing equivalent to or better than a PVDC/PVC blister package and  ( iii )  stored for six months at  40 ° C. and  75   %  relative humidity.   
     
     
       52. A stable solid pharmaceutical composition for the treatment of dyslipidemia comprising:
   an active component consisting essentially of one or more compounds selected from the group consisting of  ( i )  an HMG - CoA reductase inhibiting ring - opened  7   - substituted-     3 , 5   - dihydroxyheptanoic acid or a pharmaceutically acceptable acid salt thereof and  ( ii )  an HMG - CoA reductase inhibiting ring - opened  7   - substituted -   3 , 5   - dihydroxyheptenoic acid or a pharmaceutically acceptable acid salt thereof, and        a stabilizing effective amount of a stabilizing compound, with the proviso that the composition does not contain a stabilizing effective amount of one or more buffering agents and does not contain a stabilizing effective amount of one or more basifying agents.     
     
     
       53. The stable solid pharmaceutical composition of  claim 52 , wherein the pH of the stable composition in water, if dispersed in a concentration of  1  mg active component per  1  ml in water, would be about  5 . 4  to about  8 . 
     
     
       54. The composition of  claim 52 , wherein the active component consists essentially of one or more compounds selected from the group consisting of atorvastatin, pravastatin, fluvastatin, cerivastatin and pharmaceutically acceptable acid salts thereof. 
     
     
       55. A stable solid pharmaceutical composition for the treatment of dyslipidemia comprising:
   an active component consisting essentially of one or more compounds selected from the group consisting of atorvastatin, pravastatin, fluvastatin, cerivastatin and pharmaceutically acceptable acid salts thereof, and        means for preventing degradation of the active component into the corresponding lactone,        wherein the pH of the stable composition in water, if dispersed in a concentration of  1  mg active component per  1  ml water, would be about  5 . 4  to about  8 , and        wherein the composition does not contain a stabilizing effective amount of one or more buffering agents and does not contain a stabilizing effective amount of one or more basifying agents.