Synthesis of fatty alcohol esters of alpha-hydroxy carboxylic acids and their use as percutaneous absorption enhancers

Abstract

The present invention provides a novel approach for the preparation of fatty alcohol esters of α-hydroxy carboxylic acids. In one form of the invention, the target fatty alcohol ester of α-hydroxy carboxylic acid is produced by converting a lower alkyl ester of α-hydroxy carboxylic acid into a fatty alcohol ester of α-hydroxy carboxylic acid via alcoholysis (i.e., transesterification). The transesterification process is an equilibrium reaction, catalyzed chemically (i.e., with acids or bases) or enzymatically, that is shifted in the desired direction to produce the desired product. One preferred way of shifting the reaction in the direction of the desired product is by reducing the concentration of one of the products (e.g., distillation of a lower-boiling alcohol as soon as it is formed). Another preferred way of shifting the reaction in the direction of the desired product is by increasing the concentration of one of the reactants (e.g., adding more of the starting ester).

1 . A method for synthesizing a fatty alcohol ester of α-hydroxy carboxylic acid, comprising:
 converting a lower alkyl ester of α-hydroxy carboxylic acid into a fatty alcohol ester of α-hydroxy carboxylic acid via transesterification, wherein the transesterification process is an equilibrium reaction that is shifted in the desired direction to produce the desired product. 
 
     
     
         2 . A method according to  claim 1  wherein the transesterification process is catalyzed, chemically. 
     
     
         3 . A method according to  claim 2  wherein the transesterification process is catalyzed with an acid. 
     
     
         4 . A method according to  claim 2  wherein the transesterification process is catalyzed with a base. 
     
     
         5 . A method according to  claim 1  wherein the transesterification process is catalyzed with an enzyme. 
     
     
         6 . A method according to  claim 5  wherein the enzyme is a lipase. 
     
     
         7 . A method according to  claim 6  wherein the lipase is obtained from a microorganism selected from the group consisting of:  Aspergillus  species,  Rhizopus  species,  Penicillum  species,  Candida  species,  Pseudomonas  species,  Mucor  species, and  Humicola  species. 
     
     
         8 . A method according to  claim 6  wherein the lipase is immobilized by attachment to a suitable water-insoluble material. 
     
     
         9 . A method according to  claim 8  wherein the suitable water-insoluble material is selected from the group consisting of: silica, ion exchange resins, acrylate resins and porous polystyrene. 
     
     
         10 . A method according to  claim 1  wherein the equilibrium reaction is shifted in the direction of the desired product by reducing the concentration of one of the products of the transesterification process. 
     
     
         11 . A method according to  claim 10  wherein the concentration of one of the products of the transesterification process is removed by using at least one of the following: evaporation under ambient conditions, evaporation facilitated by heat, rotary evaporation, convection, inert gas flow, application of a vacuum, vacuum filtration, distillation;
 azeotropic distillation, vacuum distillation; chemical modification, enzymatic modification and adsorption. 
 
     
     
         12 . A method according to  claim 10  wherein one of the products of the transesterification process is an alcohol, and further wherein the concentration of that alcohol is reduced by distillation. 
     
     
         13 . A method according to  claim 1  wherein the equilibrium reaction is shifted in the direction of the desired product by increasing the concentration of one of the reactants of the transesterification process. 
     
     
         14 . A method according to  claim 13  wherein the equilibrium reaction is shifted in the direction of the desired product by adding more of the lower alkyl ester of α-hydroxy carboxylic acid. 
     
     
         15 . A method according to  claim 1  wherein the lower alkyl ester of α-hydroxy carboxylic acid is represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of: H, straight chained or branched alkyl; cycloalkyl, substituted alkyl, arylalkyl, aryl, substituted aryl and heteroaryl; 
         R 2  is selected from the group consisting of: H and alkyl; and 
         R 3  is selected from the group consisting of: methyl, ethyl, 2,2,2-trifluoroethyl, vinyl, propyl, isopropyl, isopropenyl, butyl, isobutyl, sec-butyl and tert-butyl. 
       
     
     
         16 . A method according to  claim 1  wherein the lower alkyl ester of α-hydroxy carboxylic acid is selected from the group consisting of: the ethyl esters of glycolic acid, lactic acid, mandelic acid, 2-hydroxyisobutyric acid, 2-hydroxycaproic acid, ethyl lactate and ethyl mandelate. 
     
     
         17 . A method according to  claim 1  wherein the transesterification process comprises combining the lower alkyl ester of α-hydroxy carboxylic acid with an alcohol. 
     
     
         18 . A method according to  claim 17  wherein the alcohol is a straight-chain alcohol represented by the following formula:
   R 4 OH 
 wherein R 4  is an alkyl group greater than or equal to an eight carbon chain. 
 
     
     
         19 . A method according to  claim 17  wherein the alcohol is selected from the group consisting of primary, secondary, branched, monounsaturated and polyunsaturated alcohols. 
     
     
         20 . A method according to  claim 17  wherein the alcohol contains a substituent other than hydroxyl. 
     
     
         21 . A method according to  claim 17  wherein the alcohol is selected from the group consisting of: 1-dodecanol, 2-dodecanol, 1-tetradecanol, 1-hexadecanol, 3,7-dimethyl-1-octanol and 1-octadecanol. 
     
     
         22 . A method according to  claim 1  wherein the fatty alcohol ester of α-hydroxy carboxylic acid is lauryl lactate. 
     
     
         23 . A method according to  claim 22  wherein the lauryl lactate has a purity >95%. 
     
     
         24 . A method for the synthesis of high-purity lauryl lactate comprising:
 providing:
 a lower-alkyl ester of an α-hydroxy carboxylic acid; 
 an alcohol; and 
 an enzyme; and 
   converting the lower-alkyl ester of an α-hydroxy carboxylic acid into lauryl lactate through transesterification, wherein the transesterification process is an equilibrium reaction that is shifted in the desired direction to produce the desired product.   
     
     
         25 . A method according to  claim 24  wherein the enzyme is a lipase. 
     
     
         26 . A method according to  claim 25  wherein the lipase is obtained from a microorganism selected from the group consisting of:  Aspergillus  species,  Rhizopus  species,  Penicillum  species,  Candida  species,  Pseudomonas  species,  Mucor  species, and  Humicola  species. 
     
     
         27 . A method according to  claim 25  wherein the lipase is immobilized by attachment to a suitable water-insoluble material. 
     
     
         28 . A method according to  claim 27  wherein the suitable water-insoluble material is selected from the group consisting of: silica, ion exchange resins, acrylate resins and porous polystyrene. 
     
     
         29 . A method according to  claim 24  wherein the equilibrium reaction is shifted in the direction of the desired product by reducing the concentration of one of the products of the transesterification process. 
     
     
         30 . A method according to  claim 29  wherein the concentration of one of the products of the transesterification process is removed by using at least one of the following: evaporation under ambient conditions, evaporation facilitated by heat, rotary evaporation, convection, inert gas flow, application of a vacuum, vacuum filtration, distillation;
 azeotropic distillation, vacuum distillation; chemical modification, enzymatic modification and adsorption. 
 
     
     
         31 . A method according to  claim 29  wherein one of the products of the transesterification process is an alcohol, and further wherein the concentration of that alcohol is reduced by distillation. 
     
     
         32 . A method according to  claim 24  wherein the equilibrium reaction is shifted in the direction of the desired product by increasing the concentration of one of the reactants of the transesterification process. 
     
     
         33 . A method according to  claim 32  wherein the equilibrium reaction is shifted in the direction of the desired product by adding more of the lower alkyl ester of α-hydroxy carboxylic acid. 
     
     
         34 . A method according to  claim 24  wherein the lower alkyl ester of α-hydroxy carboxylic acid is represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of: H, straight chained or branched alkyl, cycloalkyl, substituted alkyl, arylalkyl, aryl, substituted aryl and heteroaryl; 
         R 2  is selected from the group consisting of: H and alkyl; and 
         R 3  is selected from the group consisting of: methyl, ethyl, 2,2,2-trifluoroethyl, vinyl, propyl, isopropyl, isopropenyl, butyl, isobutyl, sec-butyl and tert-butyl. 
       
     
     
         35 . A method according to  claim 24  wherein the lower alkyl ester of α-hydroxy carboxylic acid is selected from the group consisting of: the ethyl esters of glycolic acid, lactic acid, mandelic acid, 2-hydroxyisobutyric acid, 2-hydroxycaproic acid, ethyl lactate and ethyl mandelate. 
     
     
         36 . A method according to  claim 24  wherein the alcohol is a straight-chain alcohol represented by the following formula:
   R 4 OH 
 wherein R 4  is an alkyl group greater than or equal to an eight carbon chain. 
 
     
     
         37 . A method according to  claim 24  wherein the alcohol is selected from the group consisting of primary, secondary, branched, monounsaturated and polyunsaturated alcohols. 
     
     
         38 . A method according to  claim 24  wherein the alcohol contains a substituent other than hydroxyl. 
     
     
         39 . A method according to  claim 24  wherein the alcohol is selected from the group consisting of: 1-dodecanol, 2-dodecanol, 1-tetradecanol, 1-hexadecanol, 3,7-dimethyl-1-octanol and 1-octadecanol. 
     
     
         40 . A method according to  claim 24  wherein the lauryl lactate has a purity >95%. 
     
     
         41 . A method according to  claim 6  wherein the lipase is not immobilized. 
     
     
         42 . A method according to  claim 25  wherein the lipase is not immobilized. 
     
     
         43 . A method according to  claim 1  wherein the fatty alcohol ester of α-hydroxy carboxylic acid is lauryl mandelate. 
     
     
         44 . A method according to  claim 1  wherein the fatty alcohol ester of α-hydroxy carboxylic acid is 3,7-dimethyl-1-octyl lactate. 
     
     
         45 . A method according to  claim 1  wherein the fatty alcohol ester of α-hydroxy carboxylic acid is cetyl lactate. 
     
     
         46 . A method according to  claim 1  wherein the fatty alcohol ester of α-hydroxy carboxylic acid is ethyl lactate. 
     
     
         47 . A method according to  claim 1  wherein an absorbing agent is added to the reaction. 
     
     
         48 . A method according to  claim 24  wherein an absorbing agent is added to the reaction. 
     
     
         49 . A method according to  claim 1  wherein a solvent is added to the reaction. 
     
     
         50 . A method according to  claim 49  wherein the solvent is selected from a group consisting of the following: acetone, acetonitrile, dioxane, heptane, hexanes and tetrahydrofuran. 
     
     
         51 . A method according to  claim 24  wherein a solvent is added to the reaction. 
     
     
         52 . A method according to  claim 51  wherein the solvent is selected from a group consisting of the following: acetone, acetonitrile, dioxane, heptane, hexanes and tetrahydrofuran. 
     
     
         53 . A fatty alcohol ester of α-hydroxy carboxylic acid formed by converting a lower alkyl ester of α-hydroxy carboxylic acid into a fatty alcohol ester of α-hydroxy carboxylic acid via transesterification, wherein the transesterification process is an equilibrium reaction that is shifted in the desired direction to produce the desired product. 
     
     
         54 . A high-purity lauryl lactate formed by (1) providing a lower-alkyl ester of an α-hydroxy carboxylic acid; an alcohol; and an enzyme; and (2) converting the lower-alkyl ester of an α-hydroxy carboxylic acid into lauryl lactate through transesterification, wherein the transesterification process is an equilibrium reaction that is shifted in the desired direction to produce the desired product.