Ionic Liquid-Based Nanoemulsion Formulation for the Efficient Delivery of Hydrophilic and Hydrophobic Therapeutic Agents

Abstract

The present invention discloses an ionic liquid composition comprising an at least partially hydrophobic ionic liquid, wherein the at least partially hydrophobic ionic liquid comprises a dication comprising two monocationic groups linked by a bridging group wherein the bridging group provides an at least partially hydrophobic character. The composition may also include a hydrophilic ionic liquid. The hydrophobic ionic liquid may include a quaternary ammonium group which may be substituted or unsubstituted, saturated or unsaturated, linear, branched, cyclic or aromatic and the bridging group is a unsubstituted or substituted C3-C10 alkylene or C3-C10 alkoxyalkyl. Also disclosed is a nanoemulsion formulation which includes the ionic liquid compositions, at least one polymer, a hydrophobic liquid, an aqueous liquid, and a hydrophobic or hydrophilic therapeutic agent. Methods to deliver a therapeutic agent by delivering a nanoemulsion and methods to make a nanoemulsion are also disclosed.

1 . An ionic liquid composition comprising:
 an at least partially hydrophobic ionic liquid, wherein the at least partially hydrophobic ionic liquid comprises at least one dication comprising two monocationic groups linked by a bridging group, wherein the bridging group provides an at least partially hydrophobic character.   
     
     
         2 . The ionic liquid composition of  claim 1 , further comprising a hydrophilic ionic liquid. 
     
     
         3 . (canceled) 
     
     
         4 . The ionic liquid composition of  claim 1 , wherein the ionic liquid composition comprises one or more dications characterized by Formula I: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , and R 3  are the same or different and are each independently substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted C 1 -C 5  hydroxyalkyl; or any two of R 1 , R 2  or R 3  may together form a substituted or unsubstituted C 5 -C 7  cyclic group or heterocyclic group; wherein each R 4  is independently unsubstituted or substituted C 3 -C 8  alkylene, C 3 -C 10  alkoxyalkylene or —R 5 OR 5 —, wherein each R 5  is independently unsubstituted or substituted C 1 -C 3  alkylene; and wherein n is 1, 2, 3, 4, 5, 6, 7 or 8. 
       
     
     
         5 - 6 . (canceled) 
     
     
         7 . The ionic liquid composition of  claim 4 , wherein the dication is characterized by Formula Ia or Formula Ib: 
       
         
           
           
               
               
           
         
         wherein q is 1, 2 3, or 4 and m is 0, 1, 2 or 3. 
       
     
     
         8 . The ionic liquid composition of  claim 7 , wherein each of R 1 -R 3  is independently H, C 1 -C 4  alkyl or —(CH 2 ) m OR 6 , wherein each R 6  is independently —CH 3 , C 2 H 5 , or H, and wherein m is 1, 2, 3 or 4. 
     
     
         9 - 15 . (canceled) 
     
     
         16 . The ionic liquid composition of  claim 4 , wherein each dication is characterized by formula 6, 7, 8, 9, 10, 1, 12, 13, 14 or 15: 
       
         
           
           
               
               
           
         
         wherein each R 6  independently is C 1 -C 4  alkylene or a bond, and each p and t independently is 1, 2, 3 or 4. 
       
     
     
         17 . The ionic liquid composition of  claim 4 , wherein each dication is characterized by formula 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25: 
       
         
           
           
               
               
           
         
         wherein Z has the formula: 
       
       
         
           
           
               
               
           
         
         wherein each p, m and t independently is 1, 2, 3 or 4. 
       
     
     
         18 . The ionic liquid composition of  claim 1 , wherein each dication is characterized by formula 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35: 
       
         
           
           
               
               
           
         
         wherein Z has the formula: 
       
       
         
           
           
               
               
           
         
         wherein each p, m and t independently is 1, 2, 3 or 4; wherein q is 0, 1, 2 or 3. 
       
     
     
         19 - 20 . (canceled) 
     
     
         21 . The ionic composition of  claim 1 , wherein said ionic liquid composition further comprises at least one anion. 
     
     
         22 . (canceled) 
     
     
         23 . The ionic composition of  claim 21 , wherein the anion is a substitutated or unsubstituted acetate, alkyl sulfate, or bis(trifluoromethylsulfonyl)imide. 
     
     
         24 . The ionic composition of  claim 21 , wherein the anion is characterized by a Formula II: 
       
         
           
           
               
               
           
         
         wherein each of R 7  and R 8  is independently a substituted or unsubstituted C 1 -C 10  alkyl, substituted or unsubstituted C 2 -C 10  hydroxyalkyl, or C 1 -C 10 haloalkyl. 
       
     
     
         25 . (canceled) 
     
     
         26 . The ionic composition of  claim 21 , wherein the anion is characterized by formula 36, 37, 38, 39, 40, 41, 42, 43 or 44: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The ionic liquid composition of  claim 1 , wherein the dication is characterized by formula 64, 65, 66, 67, 68, 69, 70, 71, 72 or 73: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The ionic liquid composition of  claim 1 , wherein the dication is characterized by a formula 74, 75, 76, 7, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87 or 88: 
       
         
           
           
               
               
           
         
       
     
     
         29 . The ionic liquid composition of  claim 1 , wherein the ionic liquid comprises dication and anions characterized by the formulas: 
       
         
           
           
               
               
           
         
       
     
     
         30 - 34 . (canceled) 
     
     
         35 . The ionic liquid composition of  claim 1 , further comprising a therapeutic agent. 
     
     
         36 - 38 . (canceled) 
     
     
         39 . A nanoemulsion for delivery of a therapeutic agent, said emulsion comprising an oil in water emulsion comprising:
 a hydrophobic liquid;   an aqueous solution;   said therapeutic agent;   an ionic liquid composition comprising an at least partially hydrophobic ionic liquid according to any one of  claims 1 - 38 ; and   a polymer;   wherein said ionic liquid composition is capable of at least partially solubilizing the therapeutic agent.   
     
     
         40 . A nanoemulsion for delivery of a therapeutic agent, said emulsion comprising an oil in water emulsion comprising:
 a hydrophobic liquid;   an aqueous solution;   said therapeutic agent;   an ionic liquid composition comprising a mixture of a hydrophilic ionic liquid and an at least partially hydrophobic ionic liquid according to any one of  claims 2  and  31 - 34 ; and   a polymer;   
       wherein said ionic liquid composition is capable of at least partially solubilizing the therapeutic agent. 
     
     
         41 . The nanoemulsion of  claim 39 , wherein said aqueous solution is a continuous phase of said nanoemulsion and said ionic liquid composition and hydrophobic liquid is a dispersed phase of said nanoemulsion. 
     
     
         42 - 48 . (canceled) 
     
     
         49 . The nanoemulsion of  claim 39 , wherein the polymer comprises an amphiphilic polymer having a hydrophilic region and a hydrophobic region. 
     
     
         50 - 96 . (canceled)