Pharmaceutical formulations for carrier-mediated transport statins and uses thereof

Abstract

The present invention relates to formulations comprising therapeutically effective amounts of at least one acid-stable, carrier-mediated transport statin, at least one poorly water-soluble, carrier-mediated transport statin, or at least one large molecular weight, carrier-mediated transport statin, such as atorvastatin and rosuvastatin, or a pharmaceutically acceptable salt thereof, and methods of their use. The present formulations and methods are designed to exhibit a controlled-release of a therapeutic amount of the statin in the small intestine, thereby limiting systemic exposure of the statin and maximizing liver-specific absorption of the drug. The formulations and methods of the present invention are particularly useful for treating and/or preventing conditions that are benefited by decreasing levels of lipids and/or cholesterol in the body.

1 . A method of increasing the hepatic bioavailability of at least one acid-stable, carrier-mediated transport statin, comprising administering to a subject a therapeutically effective amount of the at least one acid-stable, carrier-mediated transport statin, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, wherein the formulation releases the statin at a rate that avoids saturating the intestinal and hepatocytic absorption mechanisms. 
     
     
         2 . The method of  claim 1 , wherein the formulation does not delay the release of the statin in the stomach. 
     
     
         3 . The method of  claim 1 , wherein the formulation delays the release of substantial amounts of the statin until the formulation has passed out of the stomach. 
     
     
         4 . The method of  claim 1 , wherein the at least one acid-stable, carrier-mediated transport statin is atorvastatin. 
     
     
         5 . The method of  claim 1 , wherein the at least one acid-stable, carrier-mediated transport statin is rosuvastatin. 
     
     
         6 . The method of  claim 1 , wherein the formulation releases greater than about 80% of its statin content over a period of from about 1 hours to about 8 hours. 
     
     
         7 . The method of  claim 1 , wherein the administration achieves a relative systemic bioavailability of the at least one acid-stable, carrier-mediated transport statin, as compared to an equally effective dose of a conventional release formulation, of less than about 90%. 
     
     
         8 . The method according to  claim 7 , wherein the administration achieves a relative systemic bioavailability of the at least one acid-stable, carrier-mediated transport statin, as compared to an equally effective dose of a conventional release formulation, of less than about 80%. 
     
     
         9 . A method of treating hypercholesterolemia comprising administering to a subject in need of such treatment, a therapeutically effective amount of at least one acid-stable, carrier-mediated transport statin, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, wherein the formulation releases the at least one acid-stable, carrier-mediated transport statin over a period of greater than about 2 hours. 
     
     
         10 . The method of  claim 9 , wherein the at least one acid-stable, carrier-mediated transport statin is atorvastatin. 
     
     
         11 . The method of  claim 9 , wherein the at least one acid-stable, carrier-mediated transport statin is rosuvastatin. 
     
     
         12 . The method of  claim 9 , wherein the formulation exhibits an acid-stable, carrier-mediated transport statin release rate as follows:
 2 hours: less than or equal to about 40%;   4 hours: between about 20% and about 80%; and   6 hours: greater than about 70%.   
     
     
         13 . A modified-release formulation comprising a therapeutically effective amount of at least one acid-stable, carrier-mediated transport statin, or a pharmaceutically acceptable salt thereof, which formulation releases the at least one acid-stable, carrier-mediated transport statin at a rate that is about equal to or less than the rate of absorption in the intestine and in the liver. 
     
     
         14 . The formulation of  claim 13 , wherein the at least one acid-stable, carrier-mediated transport statin is atorvastatin. 
     
     
         15 . The formulation of  claim 13 , wherein the at least one acid-stable, carrier-mediated transport statin is rosuvastatin. 
     
     
         16 . The formulation according to  claim 13 , wherein the formulation exhibits an acid-stable, carrier-mediated transport statin release rate as follows:
 2 hours: less than or equal to about 40%;   4 hours: between about 20% and about 80%; and   6 hours: greater than about 70%.   
     
     
         17 - 44 . (canceled)