Aryl/Alkyl Succinic Anhydride Hyaluronan Derivatives

Abstract

The present invention relates to the modification of hyaluronic acid (HA) with aryl/alkyl succinic anhydrides (ASA) to produce aryl/alkyl succinic anhydride HA derivatives, to the derivatives as such, and to their applications and uses, particularly in the cosmetic and biomedical industries. The ASA-HA derivatives are expected to have interesting properties that can be used for advanced formulation (bind stronger to the skin compared to non-modified HA), possibly also in delivery systems for actives or drugs by encapsulation (nano/micro capsules) or formation of nano/micro spheres. Further, the low MW ASA-HA derivatives are expected to penetrate the skin more efficiently than non-modified HA of the same MW.

1 . A process of producing a hyaluronic acid derivative or a salt thereof comprising n repeating units of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 (a) in at least one repeating unit, one or more of the R1, R2, R3, and R4 groups is an alkyl-/aryl-succinic acid of formula (II): 
 
       
         
           
           
               
               
           
         
       
       wherein at least one of the R5, R6, R7, and R8 groups is an alkyl- or aryl-group and the other R5, R6, R7, and R8 groups are hydrogen, and the oxygen labelled “ester” forms an ester bond with structure (I); and
 (b) in the other repeating units, the R1, R2, R3, and R4 groups are hydroxyl groups; 
 
       the process comprising the steps of:
 (1) reacting hyaluronic acid (HA) or a salt thereof in an aqueous solution with one or more alkyl-/aryl-succinic anhydride (ASA) of formula (III): 
 
       
         
           
           
               
               
           
         
       
       wherein at least one of the R5, R6, R7, and R8 groups is an alkyl- or aryl-group and the other R5, R6, R7, and R8 groups are hydrogen; and
 (2) recovering the hyaluronic acid derivative. 
 
     
     
         2 . The process of  claim 1 , wherein one of the R1, R2, R3, and R4 groups is an alkyl-succinic acid of formula (II). 
     
     
         3 . The process of  claim 1 , wherein two of the R1, R2, R3, and R4 groups are an alkyl-succinic acid of formula (II). 
     
     
         4 . The process of  claim 1 , wherein three of the R1, R2, R3, and R4 groups are an alkyl-succinic acid of formula (II). 
     
     
         5 . The process of  claim 1 , wherein at least one of the R1, R2, R3, and R4 groups is an alkyl-succinic acid of formula (II), wherein the alkyl group is a C 1 -C 20  alkyl group. 
     
     
         6 . The process of  claim 1 , wherein at least one of the R1, R2, R3, and R4 groups is an alkyl-succinic acid of formula (II), wherein the alkyl group is a propyl, 2-octenyl, 2-dodecenyl, 2-hexadecenyl, or 2-octadecenyl group. 
     
     
         7 . The process of  claim 1 , wherein one of the R1, R2, R3, and R4 groups is an aryl-succinic acid of formula (II). 
     
     
         8 . The process of  claim 1 , wherein two of the R1, R2, R3, and R4 groups are an aryl-succinic acid of formula (II). 
     
     
         9 . The process of  claim 1 , wherein three of the R1, R2, R3, and R4 groups are an aryl-succinic acid of formula (II). 
     
     
         10 . The process of  claim 1 , wherein at least one of the R1, R2, R3, and R4 groups is an aryl-succinic acid of formula (II), wherein the aryl-group is phenyl. 
     
     
         11 . The process of  claim 1 , wherein the hyaluronic acid derivative or salt thereof has an average molecular weight of between 10,000 and 1,500,000 Da. 
     
     
         12 . The process of  claim 1 , wherein the hyaluronic acid derivative or salt thereof has an average molecular weight of between 20,000 and 50,000 Da. 
     
     
         13 . The process of  claim 1 , wherein the hyaluronic acid derivative or salt thereof has an average molecular weight of between 50,000 and 500,000 Da. 
     
     
         14 . The process of  claim 1 , wherein the hyaluronic acid derivative or salt thereof has an average molecular weight of between 80,000 and 300,000 Da. 
     
     
         15 . The process of  claim 1 , wherein the hyaluronic acid derivative or salt thereof has a Degree of Substitution (DS) in the range of 1-90%. 
     
     
         16 . The process of  claim 1 , wherein the hyaluronic acid derivative or salt thereof has a Degree of Substitution (DS) in the range of 10-50%. 
     
     
         17 . The process of  claim 1 , wherein the hyaluronic acid derivative or salt thereof has a Degree of Substitution (DS) in the range of 14-40%. 
     
     
         18 . The process of  claim 1 , wherein the hyaluronic acid derivative or salt thereof has a Degree of Substitution (DS) in the range of 18-25%. 
     
     
         19 . The process of  claim 1 , further comprising recombinantly producing the hyaluronic acid (HA) or salt thereof. 
     
     
         20 . The process of  claim 19 , wherein the hyaluronic acid (HA) or salt thereof is recombinantly produced in a  Bacillus  host.