Pharmaceutical formulations containing lipoic acid derivatives

Abstract

Pharmaceutical formulations containing lipoic acid derivatives are made.

1 . A pharmaceutical formulation comprising:
 (a) at least one lipoic acid derivative or salt thereof; and   (b) at least one ion pairing agent,   wherein the lipoic acid derivative and the ion pairing agent form an ion pair.   
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein the at least one lipoic acid derivative has the formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently selected from the group consisting of acyl defined as R 3 C(O)—, alkyl defined as C n H 2n+1 , alkenyl defined as C m H 2m−1 , alkynyl defined as C m H 2m−3 , aryl, heteroaryl, alkyl sulfide defined as CH 3 (CH 2 ) n —S—, imidoyl defined as R 3 C(═NH)—, hemiacetal defined as R 4 CH(OH)—S—, and hydrogen provided that at least one of R 1  and R 2  is not hydrogen; 
         wherein R 1  and R 2  as defined above can be unsubstituted or substituted; 
         wherein R 3  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or heterocyclyl, any of which can be substituted or unsubstituted; 
         wherein R 4  is CCl 3  or COOH; and 
         wherein x is 0-16, n is 0-10 and m is 2-10. 
       
     
     
         3 . The pharmaceutical formulation of  claim 2 , wherein R 1  and R 2  are acetyl groups. 
     
     
         4 . The pharmaceutical formulation of  claim 2 , wherein R 1  and R 2  are benzoyl groups. 
     
     
         5 . The pharmaceutical formulation of  claim 2 , wherein the alkenyl is selected from the group consisting of propenyl, 2,3-dimethyl-2-butenyl and heptenyl. 
     
     
         6 . The pharmaceutical formulation of  claim 2 , wherein the alkynyl is selected from the group consisting of acetylenyl, propynyl and octynyl. 
     
     
         7 . The pharmaceutical formulation of  claim 2 , wherein the aryl is a benzyl or a benzyl derivative. 
     
     
         8 . The pharmaceutical formulation of  claim 1 , wherein R 1  and R 2  are each a benzyl group. 
     
     
         9 . The pharmaceutical formulation of  claim 2 , wherein the alkyl is cyclopropyl. 
     
     
         10 . The pharmaceutical formulation of  claim 2 , wherein the alkenyl is cyclopentyl. 
     
     
         11 . The pharmaceutical formulation of  claim 1 , wherein the at least one lipoic acid derivative has the formula (II): 
       
         
           
           
               
               
           
         
         wherein M is a metal chelate, —[C(R 1 )(R 2 )] z — or other metal complex; 
         wherein R 1  and R 2  are independently selected from the group consisting of acyl defined as R 3 C(O)—, alkyl defined as C n H 2n+1 , alkenyl defined as C m H 2m−1 , alkynyl defined as C m H 2m−3 , aryl, heteroaryl, alkyl sulfide defined as CH 3 (CH 2 ) n —S—, imidoyl defined as R 3 C(═NH)—, hemiacetal defined as R 4 CH(OH)—S—, and hydrogen; 
         wherein R 1  and R 2  as defined above can be unsubstituted or substituted; 
         wherein R 3  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or heterocyclyl, any of which can be substituted or unsubstituted; 
         wherein R 4  is CCl 3  or COOH; and 
         wherein x is 0-16, z is 0-5, n is 0-10 and m is 2-10. 
       
     
     
         12 . The pharmaceutical formulation of  claim 1 , wherein the at least one lipoic acid derivative is present in a therapeutically effective amount. 
     
     
         13 . The pharmaceutical formulation of  claim 1 , wherein the at least one lipoic acid derivative is present in an amount to provide from about 0.001 mg/m 2  to about 10 g/m 2  of the at least one lipoic acid derivative. 
     
     
         14 . The pharmaceutical formulation of  claim 1 , wherein the at least one ion pairing agent is selected from the group consisting of triethanolamine, polyethyleneimine, diethanolamine, monoethanolamine, mefenamic acid, tromethamine and combinations thereof. 
     
     
         15 . The pharmaceutical formulation of  claim 14 , wherein the at least one ion pairing agent is triethanolamine. 
     
     
         16 . The pharmaceutical formulation of  claim 1 , wherein the at least one ion pairing agent is a polymer-conjugated ion pairing agent. 
     
     
         17 . The pharmaceutical formulation of  claim 1 , wherein the at least one ion pairing agent and the at least one lipoic acid derivative is present in a ratio ranging from about 1000:1 to about 1:1000. 
     
     
         18 . The pharmaceutical formulation of  claim 1  further comprising (c) a pharmaceutically acceptable diluent. 
     
     
         19 . The pharmaceutical formulation of  claim 18 , wherein the diluent is selected from the group consisting of saline, a sugar solution, an alcohol, dimethylformamide, dimethylsulfoxide, dimethylacetamide and combinations thereof. 
     
     
         20 . The pharmaceutical formulation of  claim 19 , wherein the diluent is a dextrose solution. 
     
     
         21 . The pharmaceutical formulation of  claim 20 , wherein the dextrose solution contains an amount of dextrose ranging from about 2.5% to about 10% by weight. 
     
     
         22 . The pharmaceutical formulation of  claim 1  further comprising at least one pharmaceutically acceptable additive selected from solvents, diluents, surfactants, solubilizers, preservatives, buffers, and combinations thereof. 
     
     
         23 . The pharmaceutical formulations of  claim 1 , wherein the ion pair is a salt. 
     
     
         24 . A pharmaceutical formulation comprising:
 bis-benzyl lipoate; and   triethanolamine.   
     
     
         25 . The pharmaceutical formulation of  claim 24  further comprising a dextrose solution containing about 5% dextrose by weight. 
     
     
         26 . A method of treating a disease characterized by disease cells that are sensitive to lipoic acid derivatives comprising administering to a patient in need thereof a pharmaceutical formulation of  claim 1 . 
     
     
         27 . A method of treating a disease characterized by disease cells that are sensitive to lipoic acid derivatives comprising administering to a patient in need thereof a pharmaceutical formulation of  claim 25 . 
     
     
         28 . The method of  claim 26  or  claim 27 , wherein the disease is selected from the group consisting of carcinoma, sarcoma, myeloma, lymphoma, leukemia and mixed types thereof. 
     
     
         29 . A method of preventing a disease characterized by disease cells that are sensitive to lipoic acid derivatives comprising administering to a patient in need thereof a pharmaceutical formulation of  claim 1 . 
     
     
         30 . A method of preventing a disease characterized by disease cells that are sensitive to lipoic acid derivatives comprising administering to a patient in need thereof a pharmaceutical formulation of  claim 25 . 
     
     
         31 . The method of  claim 29  or  claim 30 , wherein the disease is selected from the group consisting of carcinoma, sarcoma, myeloma, lymphoma, leukemia and mixed types thereof. 
     
     
         32 . An ion pair consisting of:
 (a) at least one lipoic acid derivative; and   (b) at least one ion pairing agent.   
     
     
         33 . The ion pair of  claim 32 , wherein the at least one lipoic acid derivative has the formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently selected from the group consisting of acyl defined as R 3 C(O)—, alkyl defined as C n H 2n+1 , alkenyl defined as C m H 2m−1 , alkynyl defined as C m H 2m−3 , aryl, heteroaryl, alkyl sulfide defined as CH 3 (CH 2 ) n —S—, imidoyl defined as R 3 C(═NH)—, hemiacetal defined as R 4 CH(OH)—S—, and hydrogen provided that at least one of R 1  and R 2  is not hydrogen; 
         wherein R 1  and R 2  as defined above can be unsubstituted or substituted; 
         wherein R 3  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or heterocyclyl, any of which can be substituted or unsubstituted; 
         wherein R 4  is CCl 3  or COOH; and 
         wherein x is 0-16, n is 0-10 and m is 2-10. 
       
     
     
         34 . The ion pair of  claim 32 , wherein the at least one lipoic acid derivative has the formula (II): 
       
         
           
           
               
               
           
         
         wherein M is a metal chelate, —[C(R 1 )(R 2 )] z — or other metal complex; 
         wherein R 1  and R 2  are independently selected from the group consisting of acyl defined as R 3 C(O)—, alkyl defined as C n H 2n+1 , alkenyl defined as C m H 2m−1 , alkynyl defined as C m H 2m−3 , aryl, heteroaryl, alkyl sulfide defined as CH 3 (CH 2 ) n —S—, imidoyl defined as R 3 C(═NH)—, hemiacetal defined as R 4 CH(OH)—S—, and hydrogen; 
         wherein R 1  and R 2  as defined above can be unsubstituted or substituted; 
         wherein R 3  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or heterocyclyl, any of which can be substituted or unsubstituted; 
         wherein R 4  is CCl 3  or COOH; and 
         wherein x is 0-16, z is 0-5, n is 0-10 and m is 2-10. 
       
     
     
         35 . The ion pair of  claim 32 , wherein the at least one ion pairing agent is selected from the group consisting of triethanolamine, polyethyleneimine, diethanolamine, monoethanolamine, mefenamic acid, tromethamine and combinations thereof. 
     
     
         36 . The ion pair of  claim 32 , wherein the at least one ion pairing agent is a polymer-conjugated ion pairing agent. 
     
     
         37 . The ion pair of  claim 32 , wherein the at least one ion pairing agent and the at least one lipoic acid derivative is present in a ratio ranging from about 1000:1 to about 1:1000. 
     
     
         38 . The ion pair of  claim 32 , wherein the ion pair is a salt. 
     
     
         39 . The ion pair of  claim 32 , wherein the at least one lipoic acid derivative is bis-benzyl lipoate and the at least one ion pairing agent is triethanolamine.