HAS-active ingredient conjugates

Abstract

The invention relates to compounds comprising a conjugate of hydroxyalkyl starch (HAS) and an active agent, whereby the hydroxyalkyl starch is either directly covalently bonded to the active agent, or by means of a linker. The invention further relates to methods for the production of a covalent HAS-active agent conjugate, whereby HAS and an active agent are reacted in a reaction medium, characterised in that the reaction medium is water or a mixture of water and an organic solvent, comprising at least 10 wt. % water.

1 - 72 . (canceled)  
     
     
         73 . A process for the preparation of a nucleic acid conjugate, the method comprising coupling HAS and a nucleic acid in a reaction medium, wherein the reaction medium is (a) water or (b) a mixture of water with an organic solvent, the mixture comprising at least 10 weight-% water.  
     
     
         74 . The process according to  claim 73 , wherein the HAS is coupled to the nucleic acid either directly or via a linker.  
     
     
         75 . The process according to  claim 73 , wherein the nucleic acid is a D- or L-nucleic acid.  
     
     
         76 . The process according to  claim 75 , wherein the amino acid is D-DNA, L-DNA, D-RNA, or L-RNA.  
     
     
         77 . The process according to  claim 73 , wherein the HAS is hydroxyethyl starch.  
     
     
         78 . The process according to  claim 73 , wherein the hydroxyethyl starch has an average molecular weight of 1-300 kDa.  
     
     
         79 . The process according to  claim 78 , wherein the hydroxyethyl starch has an average molecular weight of 5-200 kDa.  
     
     
         80 . The process according to  claim 78 , wherein the hydroxyethyl starch has a molar degree of substitution of 0.1-0.8 and a relation of C2:C6 substitution in the range of 2-20, each relative to the hydroxyethyl groups.  
     
     
         81 . The process according to  claim 73 , wherein the HAS is oxidized before coupling to the nucleic acid.  
     
     
         82 . The process according to  claim 81 , wherein the HAS has an oxidizing end and a reducing end, and wherein the reducing end group is selectively oxidized.  
     
     
         83 . The process according to  claim 82 , wherein the oxidized reducing end group of the HAS is coupled to an amino group of the nucleic acid, thus producing an amide.  
     
     
         84 . The process according to  claim 73 , further comprising adding an activator to the reaction medium.  
     
     
         85 . The process according to  claim 84 , wherein the activator is ethyldimethyl-aminopropyl-carbodiimide.  
     
     
         86 . A HAS-nucleic acid conjugate obtained by the process of  claim 73 .  
     
     
         87 . The conjugate according to  claim 86 , wherein the HAS is coupled to the nucleic acid either directly or via a linker.  
     
     
         88 . The conjugate according to  claim 86 , wherein the nucleic acid is a D- or L-nucleic acid.  
     
     
         89 . The conjugate according to  claim 88 , wherein the nucleic acid is D-DNA, L-DNA, D-RNA or L-RNA.  
     
     
         90 . The conjugate according to  claim 86 , wherein the HAS is hydroxyethyl starch.  
     
     
         91 . The conjugate according to  claim 90 , wherein the hydroxyethyl starch has an average molecular weight of 1-300 kDa.  
     
     
         92 . The conjugate according to  claim 90 , wherein the hydroxyethyl starch has an average molecular weight of 5-200 kDa.  
     
     
         93 . The conjugate according to  claim 90 , wherein the hydroxyethyl starch has a molar degree of substitution of 0.1-0.8 and a relation of C2:C6 substitution in the range of 2-20, each relative to the hydroxyethyl groups.  
     
     
         94 . A pharmaceutical composition comprising the conjugate according to  claim 86.