Methods of increasing the bioavailability and/or cellular update of drugs

Abstract

This invention pertains to methods of increasing the bioavailability and/or cellular uptake of an amphiphilic drug when administered parenterally, which method comprises the step of parenterally co-administering the drug with a short-chain sphingolipid as described herein.

1 . A method of increasing the bioavailability and/or cellular uptake of an amphiphilic drug when administered parenterally, which method comprises the step of parenterally co-administering the drug with a short-chain sphingolipid of the following formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is independently an O-linked saccharide group, an O-linked polyhydric alcohol group, an O-linked (amino)-C 1-6 alkyl-phosphate group, an O-linked (N—(C 1-4 alkyl)-substituted amino)-C 1-6 alkyl-phosphate group, or an O-linked (polyhydric alcohol-substituted)-C 1-6 alkyl-phosphate group; 
 R 2  is linear or branched, saturated or partially unsaturated C 3-9 alkyl, and is optionally substituted with 1 to 3 substituents selected from —OH, C 1-4 alkoxy, —C(═O)OH, and —C(═O)O—C 1-4 alkyl; 
 R 3  is linear or branched, saturated or partially unsaturated C 7-19 alkyl, and is optionally substituted with 1 to 3 substituents selected from —OH, C 1-4 alkoxy, —C(═O)OH, and —C(═O)O—C 1-4 alkyl; 
 R 4  is independently —H, —OH, or —O—C 1-4 alkyl; 
 R N  is independently —H or C 1-4 alkyl; 
 the bond marked with an alpha (α) is independently a single bond or a double bond; 
 if the bond marked with an alpha (α) is a double bond, then R 5  is —H; 
 if the bond marked with an alpha (α) is a single bond, then R 5  is —H or —OH; 
 the carbon atom marked (*) is independently in an R-configuration or an S-configuration; 
 the carbon atom marked (**) is independently in an R-configuration or an S-configuration; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . A method according to  claim 1 , wherein R 1  is independently an O-linked mono-saccharide group, an O-linked di-saccharide group, or an O-linked tri-saccharide group. 
     
     
         3 . A method according to  claim 2 , wherein R 1  comprises one or more groups selected from: arabinose, lyxose, ribose, xylose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, sucrose, maltose, lactose, cellobiose, galabiose, globotriaose, isoglobotriaose, mucotriaose, lactotriaose, neolactotriaose, gangliotriaose, galatriaose, mollutriaose, and antrotriaose, and deoxy, di-deoxy, di-deoxy-di-dehydro, methoxy, acetoxy, carboxylic acid, sulfuric acid, amino-deoxy, N-acetyl-amino-deoxy, and N-sulfo-amino-deoxy derivatives thereof. 
     
     
         4 . A method according to  claim 1 , wherein R 1  is an O-linked polyhydric alcohol group. 
     
     
         5 . A method according to  claim 4 , wherein R 1  comprises one or more groups selected from: ethanediol, propanediol, butanediol, glycerol, and erythritol. 
     
     
         6 . A method according to  claim 1 , wherein R 1  is: 
       
         
           
           
               
               
           
         
       
       wherein:
 q is independently an integer from 0 to 5; 
 Q is independently —NH 2 , —NHR a , —NR a   2 , or —NR a   3   + ; and 
 each R a  is independently linear or branched saturated C 1-4 alkyl. 
 
     
     
         7 . A method according to  claim 1 , wherein R 1  is: 
       
         
           
           
               
               
           
         
       
       wherein:
 q is independently an integer from 0 to 5; 
 Q is a polyhydric alcohol group, linked via an oxygen atom; 
 each R a  is independently linear or branched saturated C 1-4 alkyl. 
 
     
     
         8 . A method according to  claim 7 , wherein Q comprises one or more groups selected from: ethanediol, propanediol, butanediol, glycerol, and erythritol. 
     
     
         9 . A method according to  claim 1 , wherein R 2  is —(CH 2 ) n CH 3 , wherein n is an integer from 2 to 8. 
     
     
         10 . A method according to  claim 1 , wherein R 3  is —(CH 2 ) n CH 3 , wherein n is an integer from 8 to 16. 
     
     
         11 . A method according to  claim 1 , wherein R 4  is independently —H, —OH, or —OMe. 
     
     
         12 . A method according to  claim 1 , wherein the bond marked alpha is a double bond and R 5  is —H. 
     
     
         13 . A method according to  claim 1 , wherein the bond marked alpha is a single bond and R 5  is independently —H or —OH. 
     
     
         14 . A method according to  claim 1 , wherein R N  is independently —H, -Me, or -Et. 
     
     
         15 . A method according to  claim 1 , wherein the carbon atoms marked (*) and (**) have a configuration as shown in the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A method according to  claim 1 , wherein the short-chain sphingolipid has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . A method according to  claim 1 , wherein the short-chain sphingolipid has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         18 . A method according to  claim 1 , wherein the short-chain sphingolipid has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         19 . A method according to  claim 1 , wherein the short-chain sphingolipid has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         20 . A method according to  claim 1 , wherein the drug is an anthracycline or an alkaloid. 
     
     
         21 . A method according to  claim 1 , wherein the drug is selected from: doxorubicin, idarubicin, epirubicin, aclarubicin, mitrozantrone, daunorubicin, topotecan, camptothecin, and salts thereof. 
     
     
         22 . A method according to  claim 1 , wherein the drug is doxorubicin or doxorubicin hydrochloride. 
     
     
         23 . A method according to  claim 1 , wherein the drug and the short-chain sphingolipid are co-administered as components of a liposomal pharmaceutical formulation.