Crosslinkable polysaccharide derivative, process for producing the same, crosslinkable polysaccharide composition, and medical treatment material

Abstract

A process for producing an uncrosslinked, crosslinkable polysaccharide derivative having an active ester group, said process including: dissolving an acid-containing polysaccharide having a carboxy group and/or a carboxyalkyl group which are originally possessed or which have been introduced, in its non-salt form, into an aprotic polar solvent at a temperature of 60° C. to 120° C., and reacting it with an N-hydroxylamine-based electrophilic group-introducing reagent at a temperature between 0° C. and 70° C. in the presence of a dehydrating-condensing agent selected from the group consisting of 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride and 1-cyclohexyl-(2-morphonyl-4-ethyl)-carbodiimide-meso-p-toluenesulfonate, and thereby converting at least part of said carboxy group and/or carboxyalkyl group into active esters bearing an N-hydroxylamine-based electrophilic group.

1 . A process for producing an uncrosslinked, crosslinkable polysaccharide derivative having an active ester group, said process comprising:
 dissolving an acid-containing polysaccharide having a carboxy group and/or a carboxyalkyl group which are originally possessed or which have been introduced, in its non-salt form, into an aprotic polar solvent at a temperature of 60° C. to 120° C., and   reacting it with an N-hydroxylamine-based electrophilic group-introducing reagent at a temperature between 0° C. and 70° C. in the presence of a dehydrating-condensing agent selected from the group consisting of 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride and 1-cyclohexyl-(2-morphonyl-4-ethyl)-carbodiimide-meso-p-toluenesulfonate, and thereby converting at least part of said carboxy group and/or carboxyalkyl group into active esters bearing an N-hydroxylamine-based electrophilic group.   
   
   
       2 . The process according to  claim 1 , wherein the acid-containing polysaccharide contains said carboxy group and/or carboxyalkyl group in an amount of 0.1 to 5 mmol/g based on dry weight. 
   
   
       3 . The process according to  claim 1 , wherein said dehydrating-condensing agent is used in an amount (Z mmol) defined by 0.1<(Z/X)<50, where X denotes the amount (X mmol) of the carboxy group and/or the carboxyalkyl group in said acid-containing polysaccharide present in the reaction system. 
   
   
       4 . The process according to  claim 1 , which further comprises a step of purifying and/or drying the previously obtained polysaccharide derivative. 
   
   
       5 . A crosslinkable polysaccharide composition comprising an uncrosslinked polysaccharide derivative (A) and a polymer (C) selected from the group consisting of a polyalkylene glycol derivative, a polypeptide, a polysaccharide and a derivative thereof,
 wherein said polysaccharide derivative (A) has at least one active ester group containing a N-hydroxylamine-based electrophilic moiety which is introduced to a carboxy group at a side chain of the acid-containing polysaccharide, and may form a covalent bond through a reaction with an active hydrogen-containing group selected from the group consisting of a hydroxy group, an amino group, and a thiol group under alkaline conditions in the presence of moisture.   
   
   
       6 . A crosslinkable polysaccharide composition comprising an uncrosslinked polysaccharide derivative (A) and a pH adjusting agent (B),
 wherein said polysaccharide derivative (A) has at least one active ester group containing a N-hydroxylamine-based electrophilic moiety which is introduced to a carboxy group at a side chain of the acid-containing polysaccharide, and may form a covalent bond through a reaction with an active hydrogen-containing group selected from the group consisting of a hydroxy group, an amino group, and a thiol group under alkaline conditions in the presence of moisture.   
   
   
       7 . The composition according to  claim 6 , which further comprises a polymer other than said polysaccharide derivative (A). 
   
   
       8 . A medical treatment material which comprises the composition according to  claim 5 . 
   
   
       9 . The medical treatment material according to  claim 8 , which is a hemostatic agent and/or biomedical adhesive. 
   
   
       10 . The process according to  claim 1 , wherein the acid-containing polysaccharide is a polysaccharide which does not originally possess a carboxyl group and a carboxyalkyl group. 
   
   
       11 . The process according to  claim 1 , wherein the N-hydroxylamine-based electrophilic group-introducing reagent is selected from the group consisting of N-hydroxysuccinimide, N-hydroxynorbornene-2,3-dicarboxylic imide, ethyl ester of 2-hydroxyimino-2-cyanoacetate, 2-hydroxyimino-2-cyanoacetic amide, and N-hydroxypiperidine. 
   
   
       12 . The process according to  claim 1 , wherein the dehydrating-condensing agent is 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride. 
   
   
       13 . The composition according to  claim 6 , wherein the uncrosslinked polysaccharide derivative (A) is obtained by a process for producing an uncrosslinked, crosslinkable polysaccharide derivative having an active ester group, said process comprising:
 dissolving an acid-containing polysaccharide having a carboxy group and/or a carboxyalkyl group which are originally possessed or which have been introduced, in its non-salt form, into an aprotic polar solvent at a temperature of 60° C. to 120° C., and   reacting it with an N-hydroxylamine-based electrophilic group-introducing reagent at a temperature between 0° C. and 70° C. in the presence of a dehydrating-condensing agent selected from the group consisting of 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride and 1-cyclohexyl-(2-morphonyl-4-ethyl)-carbodiimide-meso-p-toluenesulfonate, and thereby converting at least part of said carboxy group and/or carboxyalkyl group into active esters bearing an N-hydroxylamine-based electrophilic group.   
   
   
       14 . The composition according to  claim 6 , wherein pH of the alkaline conditions is from 7.5 to 12. 
   
   
       15 . The composition according to  claim 6 , wherein the pH adjusting agent (B) is selected from the group consisting of sodium hydrogencarbonate in the form of an aqueous solution or powder, phosphate buffer, and acetic acid-ammonia buffer. 
   
   
       16 . The composition according to  claim 6 , wherein the N-hydroxylamine-based electrophilic group is introduced from a compound selected from the group consisting of N-hydroxysuccinimide, N-hydroxynorborene-2,3-dicarboxylic imide, ethyl ester of 2-hydroxyimino-2-cyanoacetate, 2-hydroxyimino-2-cyanoacetic amide, and N-hydroxypiperidine. 
   
   
       17 . The composition according to  claim 16 , wherein the compound is N-hydroxysuccinimide. 
   
   
       18 . The composition according to  claim 7 , wherein the polysaccharide derivative contains the active ester group in an amount of 0.1 to 2 mmol/g based on dry weight. 
   
   
       19 . The composition according to  claim 6 , wherein the carboxy group and/or the carboxyalkyl group that are not esterified are free acid. 
   
   
       20 . The composition according to  claim 6 , wherein the polysaccharide derivative (A) is an aqueous solution containing 1 to 80% (w/v) of the polysaccharide derivative and the pH adjusting agent (B) is water adjusted to a pH of 7.5 to 10.5. 
   
   
       21 . The composition according to  claim 6 , wherein said active hydrogen-containing group is that on the surface of a living organism, and said polysaccharide is capable of adhesion to the surface of a living organism. 
   
   
       22 . A medical treatment material which comprises the composition according to  claim 6 . 
   
   
       23 . The medical treatment material according to  claim 22 , which is a hemostatic agent and/or biomedical adhesive. 
   
   
       24 . The composition according to  claim 6 , wherein the composition is a two-component composition. 
   
   
       25 . The composition according to  claim 24 , wherein the phosphate buffer comprises disodium hydrogenphosphate and potassium dihydrogenphosphate. 
   
   
       26 . A method of hemostasis and/or adhesion of a living organism by applying a polysaccharide derivative (A) to react at a desired part of the living organism in the presence of water under alkaline condition, said polysaccharide derivative (A) comprising at least one active ester group containing a N-hydroxylamine-based electrophilic moiety which is introduced to a carboxy group at a side chain of the acid-containing polysaccharide. 
   
   
       27 . The method according to  claim 26 , further comprising applying a pH adjusting agent (B). 
   
   
       28 . The method according to  claim 26 , further comprising applying a polymer (C) selected from the group consisting of a polyalkylene glycol derivative, a polypeptide, a polysaccharide and a derivative thereof. 
   
   
       29 . A method of applying a polysaccharide derivative (A) to a living organism, comprising applying the polysaccharide derivative (A) to react at a desired part of the living organism in the presence of water under alkaline condition, said polysaccharide derivative (A) comprising at least one active ester group containing a N-hydroxylamine-based electrophilic moiety which is introduced to a carboxy group at a side chain of the acid-containing polysaccharide. 
   
   
       30 . The method according to  claim 29 , wherein the polysaccharide derivative (A) is applied by spraying. 
   
   
       31 . The method according to  claim 29 , further comprising applying a pH adjusting agent (B). 
   
   
       32 . The method according to  claim 29 , further comprising applying a polymer (C) selected from the group consisting of a polyalkylene glycol derivative, a polypeptide, a polysaccharide and a derivative thereof.