Stabilized 3-Hydroxyflavan Compositions and Methods Therefor

Abstract

Compositions and methods are directed to covalent adducts between reducing agents and optionally substituted 3-hydroxyflavans, wherein the reducing agent is covalently bound to the B-ring of the 3-hydroxyflavan. Such adducts exhibit markedly increased stability towards oxidation as compared to the unmodified 3-hydroxyflavan. Particularly preferred 3-hydroxyflavans include green tea catechins, and especially EGCG, while especially preferred reducing agents include NAC and glutathione.

1 . A composition comprising:
 a reducing agent in a first quantity, and a 3-hydroxyflavan in a second quantity, wherein the 3-hydroxyflavan has an A-Ring and a B-ring;   wherein the reducing agent is selected from the group consisting of an N-substituted cysteine, glutathione, dithiothreitol, dithioerythrol, mercaptoethanol, and Tris(2-carboxyethyl)phosphine;   wherein the first quantity is a predetermined function of the second quantity such that the reducing agent is present in an amount effective to reduce discoloration of the composition;   wherein the discoloration is due to at least one of a non-enzymatic oxidation, a non-enzymatic dimerization, a non-enzymatic oligomerization, and a non-enzymatic polymerization of the 3-hydroxyflavan;   wherein the reducing agent has a structure to allow reaction with an atom in the B-ring of the 3-hydroxyflavan to form a covalent adduct to thereby reduce the discoloration, with the proviso that   (a) where the 3-hydroxyflavan is catechin, then the reducing agent is not glutathione or glutamine-cysteine dipeptide;   (b) where the 3-hydroxyflavan is epicatechin, then the reducing agent is not dithiothreitol or glutamine-cysteine dipeptide.   
     
     
         2 . The composition of  claim 1  wherein the reducing agent is present in at least stoichiometric quantity relative to the 3-hydroxyflavan. 
     
     
         3 . The composition of  claim 1  wherein the composition is a cosmetic formulation for topical administration to skin. 
     
     
         4 . The composition of  claim 1  wherein the composition is a nutritional formulation for enteral administration to a mammal. 
     
     
         5 . The composition of  claim 1  wherein the composition is an intermediate in a process for isolation of a 3-hydroxyflavan. 
     
     
         6 . The composition of  claim 1  wherein the 3-hydroxyflavan is selected from the group consisting of (−)-Epigallocatechin gallate, (−)-Gallocatechin gallate, (+)-Epigallocatechin gallate, (+)-Gallocatechin gallate, (−)-Epigallocatechin, (−)-Gallocatechin, (+)-Epigallocatechin, (+)-Gallocatechin, (−)-Epicatechin gallate, (−)-Catechin gallate, (+)-Epicatechin gallate, (+)-Catechin gallate, (−)-Epicatechin, (−)-Catechin, (+)-Epicatechin, and (+)-Catechin. 
     
     
         7 . The composition of  claim 1  wherein the 3-hydroxyflavan is selected from the group consisting of (−)-Epigallocatechin gallate, (−)-Gallocatechin gallate, (+)-Epigallocatechin gallate, (+)-Gallocatechin gallate, (−)-Epigallocatechin, (−)-Gallocatechin, (+)-Epigallocatechin, and (+)-Gallocatechin. 
     
     
         8 . The composition of  claim 1  wherein the 3-hydroxyflavan is selected from the group consisting of (−)-Epigallocatechin gallate, (−)-Gallocatechin gallate, (+)-Epigallocatechin gallate, and (+)-Gallocatechin gallate. 
     
     
         9 . The composition of  claim 1  having a pH between 4.0 and 6.0, inclusive 
     
     
         10 . The composition of  claim 1  wherein the reducing agent is selected from the group consisting of glutathione and N-acetyl cysteine. 
     
     
         11 . A method of reducing non-enzymatic discoloration of a 3-hydroxyflavan-containing composition, wherein the non-enzymatic discoloration is due to at least one of an oxidation, a dimerization, a oligomerization, and a polymerization of the 3-hydroxyflavan, comprising:
 combining the 3-hydroxyflavan with a reducing agent selected from the group consisting of an N-substituted cysteine, glutathione, dithiothreitol, dithioerythrol, mercaptoethanol, and Tris(2-carboxyethyl)phosphine under conditions that allow reaction of the reducing agent with an atom in the B-ring of the 3-hydroxyflavan to form a covalent adduct to thereby reduce the discoloration;   with the proviso that   (a) where the 3-hydroxyflavan is catechin, then the reducing agent is not glutathione or glutamine-cysteine dipeptide;   (b) where the 3-hydroxyflavan is epicatechin, then the reducing agent is not dithiothreitol or glutamine-cysteine dipeptide.   
     
     
         12 . The method of  claim 11  wherein the reducing agent is present in a stoichiometric quantity relative to the 3-hydroxyflavan. 
     
     
         13 . The method of  claim 11  wherein the 3-hydroxyflavan is selected from the group consisting of (−)-Epigallocatechin gallate, (−)-Gallocatechin gallate, (+)-Epigallocatechin gallate, (+)-Gallocatechin gallate, (−)-Epigallocatechin, (−)-Gallocatechin, (+)-Epigallocatechin, (+)-Gallocatechin, (−)-Epicatechin gallate, (−)-Catechin gallate, (+)-Epicatechin gallate, (+)-Catechin gallate, (−)-Epicatechin, (−)-Catechin, (+)-Epicatechin, and (+)-Catechin. 
     
     
         14 . The method of  claim 11  wherein the 3-hydroxyflavan is selected from the group consisting of (−)-Epigallocatechin gallate, (−)-Gallocatechin gallate, (+)-Epigallocatechin gallate, (+)-Gallocatechin gallate, (−)-Epigallocatechin, (−)-Gallocatechin, (+)-Epigallocatechin, and (+)-Gallocatechin. 
     
     
         15 . The method of  claim 11  wherein the 3-hydroxyflavan is selected from the group consisting of (−)-Epigallocatechin gallate, (−)-Gallocatechin gallate, (+)-Epigallocatechin gallate and (+)-Gallocatechin gallate. 
     
     
         16 . The method of  claim 11  further comprising a step of adjusting the pH of the composition to 4.0 to 6.0, inclusive. 
     
     
         17 . The composition of  claim 11  wherein the reducing agent is selected from the group consisting of glutathione and N-acetyl cysteine.