Stabilized statin formulations

Abstract

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

1 - 27 . (canceled) 
     
     
         28 . A stable liquid pharmaceutical formulation comprising sodium bisulfate, polyvinylpyrrolidone, and an effective amount of mevastatin complexed with a sufficient amount of sulfobutyl-ether-β-cyclodextrin in an aqueous solution having a pH of from about 7 to about 9 to provide a solubilized mevastatin concentration of at least about 3.32 mg/ml to about 25 mg/ml. 
     
     
         29 . The stable liquid pharmaceutical formulation of  claim 28 , wherein the sulfobutyl-ether-β-cyclodextrin comprises at least 13.5% of the formulation. 
     
     
         30 . The stable liquid pharmaceutical formulation of  claim 28 , wherein the solubilized mevastatin concentration is from about 5 to about 15 mg/ml. 
     
     
         31 . The stable liquid pharmaceutical formulation of  claim 28 , wherein the solubilized mevastatin concentration is about 10 mg/ml. 
     
     
         32 . The stable liquid pharmaceutical formulation of  claim 28 , which includes a dose of mevastatin from about 10 mg to about 80 mg. 
     
     
         33 . The stable liquid pharmaceutical formulation of  claim 28 , wherein the aqueous solution contains a pharmaceutically acceptable buffer or alkalizing agent selected from the group consisting of trimethylamine and meglumine L-Arginine. 
     
     
         34 . Lyophilized particles consisting essentially of sodium bisulfate, polyvinylpyrrolidone, and an effective amount of mevastatin complexed with a sufficient amount of sulfobutyl-ether-β-cyclodextrin to render the mevastatin water-soluble when the lyophilized particles are reconstituted in a pharmaceutically acceptable solution for injection. 
     
     
         35 . The lyophilized particles of  claim 34 , which are reconstituted to a mevastatin concentration from about 1 mg/ml to about 25 mg/ml. 
     
     
         36 . The lyophilized particles of  claim 34 , which when reconstituted in solution provide a pH from about 7 to about 9. 
     
     
         37 . The lyophilized particles of  claim 36 , which do not substantially degrade after storage for 1 month at 40° C. 
     
     
         38 . The lyophilized particles of  claim 36 , which degrade less than about 0.1% after storage for 1 month at 40° C. 
     
     
         39 . A method of treating a human patient at risk of MI or stroke, comprising intravenously administering to the human patient the stable liquid pharmaceutical formulation of claim  1 . 
     
     
         40 . The method of  claim 39 , wherein the mevastatin is administered in an effective amount to lower the human patient's lipid level. 
     
     
         41 . The method of  claim 39 , further comprising reconstituting the mevastatin complexed with the sulfobutyl-ether-β-cyclodextrin from lyophilized particles prior to said administration. 
     
     
         42 . The method of  claim 39 , wherein the solubilized mevastatin concentration is from about 1 mg/ml to about 25 mg/ml. 
     
     
         43 . A method of preparing lyophilized particles according to  claim 34  comprising:
 (a) adding mevastatin to a mixture of the sulfobutyl-ether-β-cyclodextrin 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. 
 (c) lyophilizing the mixture to obtain lyophilized particles. 
 
     
     
         44 . The method of  claim 43 , wherein the lyophilized particles are reconstituted in an effective amount of a pharmaceutically acceptable solution for injection into a human patient. 
     
     
         45 . The method of  claim 43 , wherein the sulfobutyl-ether-β-cyclodextrin comprises at least 13.5% of the formulation. 
     
     
         46 . The method of  claim 43 , wherein a solubilized mevastatin concentration of at least about 3.32 mg/ml is obtained.