Coupling Low-Molecular Substances To A Modified Polysaccharide

Abstract

The invention relates to a method for coupling low-molecular substances to a starch-derived modified polysaccharide. The binding interaction between the modified polysaccharide and the low-molecular substance is based on a covalent bond which is the result of a coupling reaction between the terminal aldehyde group or a functional group of the modified polysaccharide molecule resulting from the chemical reaction of this aldehyde group and a functional group of the low-molecular substance which reacts with this aldehyde group or with the resulting functional group of the polysaccharide molecule. The bond directly resulting from the coupling reaction can be optionally modified by a further reaction to the aforementioned covalent bond. The invention further relates to pharmaceutical compositions that comprise conjugates formed in this coupling process and to the use of said conjugates and compositions for the prophylaxis or therapy of the human or animal body.

1 - 36 . (canceled) 
     
     
         37 . A method for preparing a conjugate of hydroxyalkylstarch and a low molecular weight substance, wherein the binding interaction between the hydroxyalkylstarch molecule and the low molecular weight substance is based on a covalent bonding which is the result of a coupling reaction between (i) the terminal aldehyde group, or a functional group derived from this aldehyde group by chemical reaction, of the hydroxyalkylstarch molecule and (ii) a functional group, which is able to react with this aldehyde group or functional group derived therefrom of the hydroxyalkylstarch molecule, of the low molecular weight substance, where the bonding resulting directly in the coupling reaction can be modified where appropriate by a further reaction to give the abovementioned covalent bonding, the method comprising:
 carrying out a coupling reaction between the terminal aldehyde group, or a functional group derived from this aldehyde group by chemical reaction, of the hydroxyalkylstarch molecule and a functional group, able to react with this aldehyde group or functional group derived therefrom of the hydroxyalkylstarch molecule, of the low molecular weight substance, wherein the bonding resulting directly in the coupling reaction is modified where appropriate by a further reaction.   
     
     
         38 . The method of  claim 37 , wherein the functional group of the low molecular weight substance is one of the functional groups of a bifunctional linker molecule which has been coupled to the low molecular weight substance 
     
     
         39 . The method of  claim 37 , wherein the functional group derived from the terminal aldehyde group is one of the functional groups of a bifunctional linker molecule with which the terminal aldehyde group or a functional group derived therefrom has been reacted. 
     
     
         40 . The method of  claim 38 , wherein the functional group derived from the terminal aldehyde group is one of the functional groups of a bifunctional linker molecule with which the terminal aldehyde group or a functional group derived therefrom has been reacted. 
     
     
         41 . The method of  claim 37 , wherein the terminal aldehyde group of the hydroxyalkylstarch molecule is converted by selective oxidation into the corresponding lactone group, and the latter is subsequently reacted with a primary amino group of the low molecular weight substance so that the hydroxyalkylstarch molecule is linked to the low molecular weight substance by an amide linkage. 
     
     
         42 . The method of  claim 38 , wherein the coupling reaction is carried out in the presence of carbodiimide. 
     
     
         43 . The method of  claim 42 , wherein the carbodiimide is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. 
     
     
         44 . The method of  claim 37 , wherein the coupling reaction is carried out in heterogeneous phase. 
     
     
         45 . The method of  claim 37 , wherein the coupling reaction is carried out in homogeneous phase in DMSO or N-methylpyrrolidone or glycol. 
     
     
         46 . The method of  claim 37 , wherein the coupling reaction is carried out in DMSO or N-methylpyrrolidone or glycol in the absence of an activator. 
     
     
         47 . The method of  claim 37 , wherein the terminal aldehyde group of the hydroxyalkylstarch molecule is coupled to a primary amino group of the low molecular weight substance to form a Schiff's base, and the Schiff's base is then reduced to an amine so that the hydroxyethylstarch molecule is linked by an amine linkage to the low molecular weight substance. 
     
     
         48 . The method of  claim 47 , wherein the Schiff's base is reduced the amine with a reducing agent selected from the group consisting of sodium borohydride, sodium cyanoborohydride, and an organic boron complex. 
     
     
         49 . The method of  claim 37 , wherein the HAS molecule has a molecular weight in the range from about 70 to about 1000 kD. 
     
     
         50 . The method of  claim 37 , wherein the HAS molecule has a molecular weight of about 130 kD. 
     
     
         51 . The method of  claim 37 , wherein the HAS molecule has a degree of substitution of from about 0.3 to about 0.7. 
     
     
         52 . The method of  claim 37 , wherein the HAS molecule has a ratio of C 2  to C 6  substitution of from 8 to 12. 
     
     
         53 . The method of  claim 37 , wherein the HAS molecule is a hydroxyethylstarch molecule. 
     
     
         54 . The method of  claim 37 , wherein the low molecular weight substance is an active pharmaceutical ingredient. 
     
     
         55 . The method of  claim 54 , wherein the active pharmaceutical ingredient is selected from the group composed of antibiotics, antidepressants, antidiabetics, antidiuretics, anticholinergics, antiarrhythmics, antiemetics, antiepileptics, antihistamines, antimycotics, antisympathotonics, antithrombotics, androgens, antiandrogens, estrogens, antiestrogens, antiosteoporotics, antitumor agents, vasodilators, other antihypertensive agents, antipyretic agents, analgesics, antiinflammatory agents, β-blockers, immunosuppressants, and vitamins. 
     
     
         56 . The method of  claim 53 , wherein the functional group of the active pharmaceutical ingredient involved in the coupling reaction is an amino group and the active pharmaceutical ingredient is selected from the group consisting of albuterol, alendronate, amikazin, aminopenicillin, amoxicillin, atenolol, azathioprine, cefaclor, cefadroxil, cefotaxime,