Stabilized statin formulations

Abstract

The present invention is directed to statin formulations having improved solubility and/or stability and methods for the same.

1 . A liquid pharmaceutical formulation comprising an effective amount of a pharmaceutically acceptable water insoluble statin complexed with a sufficient amount of a pharmaceutically acceptable complexing agent in an aqueous solution having a pH of from about 7 to about 9 to provide a solubilized statin concentration of at least about 3.32 mg/ml, wherein the pharmaceutically acceptable water insoluble statin is atorvastatin. 
     
     
         2 . The formulation of  claim 1 , wherein the complexed statin is lyophilized. 
     
     
         3 . (canceled) 
     
     
         4 . The formulation of  claim 1 , wherein the complexing agent is a cyclodextrin. 
     
     
         5 . The formulation of  claim 4 , wherein the cyclodextrin is hydroxy-propyl-β-cyclodextrin. 
     
     
         6 . The formulation of  claim 1 , wherein the solubilized statin concentration is from about 1 mg/ml to about 25 mg/ml. 
     
     
         7 . The formulation  claim 1 , wherein the complexing agent comprises at least 13.5% of the formulation. 
     
     
         8 . The formulation of  claim 6 , wherein the solubilized statin concentration is from about 5 to about 15 mg/ml. 
     
     
         9 . The formulation of  claim 6 , wherein the solubilized statin concentration is about 10 mg/ml. 
     
     
         10 . (canceled) 
     
     
         11 . Lyophilized particles comprising a pharmaceutically acceptable water insoluble statin and a sufficient amount of a pharmaceutically acceptable complexing agent to render the statin water-soluble when the lyophilized particles are reconstituted in a pharmaceutically acceptable solution for injection, wherein the pharmaceutically acceptable water insoluble statin is atorvastatin. 
     
     
         12 . The lyophilized particles of  claim 11 , which do not substantially degrade after storage for 1 month at 40° C. 
     
     
         13 . The lyophilized particles of  claim 12 , which degrade less than about 0.1% after storage for 1 month at 40° C. 
     
     
         14 . (canceled) 
     
     
         15 . The lyophilized particles of  claim 12 , wherein the complexing agent is a cyclodextrin. 
     
     
         16 . The lyophilized particles of  claim 11 , wherein the cyclodextrin is Hydroxy-propyl-β-cyclodextrin. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . A method of preparing lyophilized particles comprising a pharmaceutically acceptable statin and a pharmaceutically acceptable complexing agent comprising:
 (a) adding a water insoluble statin to a mixture of the complexing agent and a suitable solvent; (b) mixing;   (c) adjusting the pH using a pharmaceutically acceptable buffer to a pH range of between about 7 and about 9.   (d) lyophilizing the mixture to obtain lyophilized particles, wherein the pharmaceutically acceptable statin is atorvastatin.   
     
     
         21 . The method of  claim 20 , wherein the lyophilized particles are reconstituted in an effective amount of a pharmaceutically acceptable solution for injection into a human patient. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 20 , wherein the complexing agent is a cyclodextrin. 
     
     
         24 . The method of  claim 20 , wherein the complexing agent comprises at least 13.5% of the formulation. 
     
     
         25 . The method of  claim 20 , wherein a solubilized statin concentration of at least about 3.32 mg/ml is obtained. 
     
     
         26 . A method of treatment comprising:
 (a) reconstituting the lyophilized particles according to  claim 11  in a pharmaceutically acceptable solution for injection; and   (b) administering a suitable quantity of the solution to provide an effective amount of statin to a human patient in need of treatment.   
     
     
         27 . The method of treatment of  claim 26 , wherein the statin is administered in an effective amount to lower the patient's lipid level, have an appropriate anti-inflammatory or other therapeutic effect.