Amphiphile prodrugs

Abstract

Amphiphilic prodrugs of general formula A-X are disclosed, wherein A is a biologically active agent or may be metabolized to a biologically active agent; and X is R, or up to three R moieties attached to a linker, Y 1 , Y 2 or Y 3 . Self-assembly of the amphiphilic prodrugs into reverse lyotropic phases, particularly hexagonal, cubic and sponge, is disclosed.

1 - 12 . (canceled) 
     
     
         13 . A prodrug of a general formula (I):
   A-X  I
   wherein
 A is a biologically active agent or an agent capable of being metabolised to a biologically active agent; and 
 X is selected from the group consisting of a substituent according to formula (a), a substituent according to formula (b), a substituent according to formula (c) and a substituent according to formula (d): 
   
       
         
           
           
               
               
           
         
         wherein 
         R is selected from a group consisting of alkyl, alkenyl, alkynyl, branched alkyl, branched alkenyl, branched alkynyl, substituted alkyl, substituted alkenyl and substituted alkynyl groups and their analogues; 
         Y 1  is a linker group that is covalently attached to the group R at one attachment site and to A at a second attachment site; 
         Y 2  is a linker group that is covalently attached to two R groups (which may be identical or different) at two independent attachment sites and is attached to A at a third attachment site; 
         Y 3  is a linker group that is covalently attached to three R groups (which may be identical or different) at three independent attachment sites and is attached to A at a fourth attachment site; and 
         wherein A is selected from the group consisting of a compound according to formula (II) 
       
       
         
           
           
               
               
           
         
         cyclosporine, paclitaxel, indomethacin, fenofibrate, progesterone, amphotericin B (AMB) and dopamine. 
       
     
     
         14 . A prodrug according to  claim 13  wherein A is a compound according to formula (II). 
     
     
         15 . A prodrug according to  claim 14 , wherein X is represented by formula (a) and R has a chain length equivalent to 10 to 30 carbon atoms. 
     
     
         16 . A prodrug according to  claim 13 , wherein A is selected from the group consisting of cyclosporine, paclitaxel, indomethacin, fenofibrate, progesterone and amphotericin B (AMB). 
     
     
         17 . A prodrug according to  claim 13 , wherein A is dopamine. 
     
     
         18 . A self assembled structure formed from the prodrug of  claim 16 , wherein the structure exhibits a phase under physiological conditions selected from the group consisting of lamellar, hexagonal phase, cubic phase, and sponge phase. 
     
     
         19 . The self assembled structure of  claim 18 , wherein the phase is an inverse phase. 
     
     
         20 . A self assembled structure formed from the prodrug of  claim 17 , wherein the structure exhibits a phase under physiological conditions selected from the group consisting of lamellar, hexagonal phase, cubic phase, and sponge phase. 
     
     
         21 . The self assembled structure of  claim 20 , wherein the phase is an inverse phase. 
     
     
         22 . A self assembled structure formed from the prodrug of  claim 16 , wherein the structure is a colloidal particle selected from the group consisting of colloidosome and solid lipid particle. 
     
     
         23 . A self assembled structure formed from the prodrug of  claim 17 , wherein the structure is a colloidal particle selected from the group consisting of colloidosome and solid lipid particle. 
     
     
         24 . A prodrug according to  claim 13 , wherein A itself is a prodrug that is converted by hydrolytic, oxidative, reductive or enzymatic cleavage to the biologically active agent. 
     
     
         25 . A prodrug according to  claim 24 , wherein the biologically active agent is dopamine. 
     
     
         26 . A method of modulating the bioavailability of a biologically active agent or an agent capable of being metabolised to a biologically active agent, A, the method including covalently linking A to at least one tail component, X, to form an amphiphile, wherein the link is cleavable in vivo to release the biologically active agent or an agent capable of being metabolised to a biologically active agent from the self-assembled structure; and administering the amphiphile to a patient such that the amphiphile self-assembles into a self-assembled structure;
 wherein
 X is selected from the group consisting of a substituent according to formula (a), a substituent according to formula (b), a substituent according to formula (c) and a substituent according to formula (d): 
   
       
         
           
           
               
               
           
         
         
           wherein 
           R is selected from a group consisting of alkyl, alkenyl, alkynyl, branched alkyl, branched alkenyl, branched alkynyl, substituted alkyl, substituted alkenyl and substituted alkynyl groups and their analogues; 
           Y 1  is a linker group that is covalently attached to the group R at one attachment site and to A at a second attachment site; 
           Y 2  is a linker group that is covalently attached to two R groups (which may be identical or different) at two independent attachment sites and is attached to A at a third attachment site; and 
           Y 3  is a linker group that is covalently attached to three R groups (which may be identical or different) at three independent attachment sites and is attached to A at a fourth attachment site. 
         
       
     
     
         27 . The method of  claim 26 , wherein the self-assembled structure exhibits a phase under physiological conditions selected from the group consisting of lamellar, hexagonal phase, cubic phase, and sponge phase. 
     
     
         28 . The method of  claim 26 , wherein the phase is an inverse phase. 
     
     
         29 . The method of  claim 26 , wherein the self-assembled structure is a colloidal particle selected from the group consisting of colloidosome and solid lipid particle. 
     
     
         30 . The method of  claim 26 , wherein the amphiphile is an enzymatic substrate for an enzyme that promotes formation of A from the amphiphile. 
     
     
         31 . The method of  claim 26 , wherein R has a chain length equivalent to 10 to 30 carbon atoms. 
     
     
         32 . The method of  claim 26 , wherein A is selected from the group consisting of cyclosporine, paclitaxel, indomethacin, fenofibrate, progesterone and amphotericin B (AMB). 
     
     
         33 . The method of  claim 26 , wherein A is dopamine.