Zwitterionic polymer-insulin compositions and related methods

Abstract

Zwitterionic polymer-insulin-saccharide compositions glucose-responsive zwitterionic polymer-insulin-saccharide compositions and are provided by the present disclosure which include a zwitterionic polymer, an insulin moiety, and a saccharide moiety. Methods of use include administration to human patients to alleviate conditions, such as diabetes, which are responsive to administration of insulin.

1 . The zwitterionic polymer-insulin composition of  claim 25 , further comprising:
 a covalently bonded saccharide moiety or saccharide monomer forming a zwitterionic polymer-insulin-saccharide composition.   
     
     
         2 . The zwitterionic polymer-insulin-saccharide composition of  claim 1 , comprising a polymerization reaction product of a zwitterionic monomer, an insulin-containing monomer, and a saccharide-containing monomer. 
     
     
         3 .- 5 . (canceled) 
     
     
         6 . The zwitterionic polymer-insulin-saccharide composition of  claim 1  wherein the saccharide moiety or saccharide monomer comprises a saccharide selected from the group consisting of: mannose, fucose, a bisaccharide, a trisaccharide, a tetrasaccharide, a branched trisaccharide, bimannose, trimannose, tetramannose, branched trimannose, glucosamine, a derivative of any thereof, and a combination of any two or more thereof. 
     
     
         7 .- 8 . (canceled) 
     
     
         9 . The zwitterionic polymer-insulin-saccharide composition of  claim 1 , further comprising:
 a saccharide binding molecule, wherein the saccharide binding molecule binds to the saccharide of the zwitterionic polymer-insulin-saccharide composition, forming a glucose-responsive zwitterionic polymer-insulin-saccharide composition.   
     
     
         10 . The glucose-responsive zwitterionic polymer-insulin-saccharide composition of  claim 9  wherein the saccharide binding molecule is a lectin, a saccharide binding fragment thereof or a combination of any two or more thereof. 
     
     
         11 .- 20 . (canceled) 
     
     
         21 . The glucose-responsive zwitterionic polymer-insulin-saccharide composition of  claim 9 , further comprising a hydrogel carrier, where the glucose-responsive zwitterionic polymer-insulin-saccharide composition is encapsulated by the hydrogel carrier, producing a hydrogel encapsulated glucose-responsive zwitterionic polymer-insulin-saccharide composition. 
     
     
         22 .- 24 . (canceled) 
     
     
         25 . A zwitterionic polymer-insulin composition. 
     
     
         26 . The zwitterionic polymer-insulin composition of  claim 25 , wherein the composition comprises a reaction product selected from the group consisting of: a (poly)carboxybetaine polymer comprising reactive groups that react with primary amines, and insulin; a (poly)sulfobetaine polymer comprising reactive groups that react with primary amines, and insulin; and a (poly)phosphobetaine polymer comprising reactive groups that react with primary amines, and insulin. 
     
     
         27 . The zwitterionic polymer-insulin composition of  claim 26 , wherein the (poly)carboxybetaine polymer comprising reactive groups that react with primary amines is selected from the group consisting of (poly)carboxybetaine acrylamide comprising reactive groups that react with primary amines; (poly)carboxybetaine methacrylate comprising reactive groups that react with primary amines; (poly)carboxybetaine methacrylamide comprising reactive groups that react with primary amines; (poly)carboxybetaine acrylate comprising reactive groups that react with primary amines; (poly)carboxybetaine vinyl comprising reactive groups that react with primary amines; (poly)sulfobetaine acrylamide comprising reactive groups that react with primary amines; (poly)sulfobetaine methacrylate comprising reactive groups that react with primary amines; (poly)sulfobetaine methacrylamide comprising reactive groups that react with primary amines; (poly)sulfobetaine acrylate comprising reactive groups that react with primary amines; (poly)sulfobetaine vinyl comprising reactive groups that react with primary amines; (poly)phosphobetaine acrylamide comprising reactive groups that react with primary amines; (poly)phosphobetaine methacrylate comprising reactive groups that react with primary amines; (poly)phosphobetaine methacrylamide comprising reactive groups that react with primary amines; (poly)phosphobetaine acrylate comprising reactive groups that react with primary amines; (poly)phosphobetaine vinyl comprising reactive groups that react with primary amines; and any two or more thereof. 
     
     
         28 . The zwitterionic polymer-insulin composition of  claim 26 , wherein the reactive groups that react with primary amines are selected from the group consisting of: isothiocyanates, isocyanates, acyl azides, NHS esters, sulfonyl chlorides, aldehydes, glyoxals, epoxides, oxiranes, carbonates, aryl halides, imidoesters, carbodiimides, anhydrides, and fluorophenyl esters. 
     
     
         29 . The zwitterionic polymer-insulin composition of  claim 25 , wherein the composition comprises a reaction product of an NHS ester terminated (poly)carboxybetaine polymer and insulin. 
     
     
         30 . The zwitterionic polymer-insulin composition of  claim 25 , wherein the composition comprises a reaction product of insulin and an NHS ester terminated (poly)carboxybetaine polymer selected from the group consisting of: NHS ester terminated (poly)carboxybetaine acrylamide; NHS ester terminated (poly)carboxybetaine methacrylate; NHS ester terminated (poly)carboxybetaine methacrylamide; NHS ester terminated (poly)carboxybetaine acrylate; NHS ester terminated (poly)carboxybetaine vinyl; NHS ester terminated (poly)sulfobetaine acrylamide; NHS ester terminated (poly)sulfobetaine methacrylate; NHS ester terminated (poly)sulfobetaine methacrylamide; NHS ester terminated (poly)sulfobetaine acrylate; NHS ester terminated (poly)sulfobetaine vinyl; NHS ester terminated (poly)phosphobetaine acrylamide; NHS ester terminated (poly)phosphobetaine methacrylate; NHS ester terminated (poly)phosphobetaine methacrylamide; NHS ester terminated (poly)phosphobetaine acrylate; NHS ester terminated (poly)phosphobetaine vinyl; and two or more thereof. 
     
     
         31 . The zwitterionic polymer-insulin composition of  claim 25 , wherein the composition comprises a reaction product of: a (poly)carboxybetaine polymer comprising reactive groups that react with primary amines; and insulin. 
     
     
         32 . The zwitterionic polymer-insulin composition of  claim 25  comprising:
 a polymerization reaction product of a zwitterionic monomer and an insulin-containing monomer. 
 
     
     
         33 . The zwitterionic polymer-insulin composition of  claim 32 , wherein the zwitterionic monomer has the structural formula: 
       
         
           
           
               
               
           
         
       
       where R 1 , R 2 , and R 3  are each independently selected from hydrogen, alkyl, and aryl groups; L 1  is a linker that covalently couples a cationic center to a polymer backbone; L 2  is a linker that covalently couples the cationic center to an anionic group; A(═O)O −  is the anionic group; X −  is the counter ion associated with the cationic center, and M +  is a metal cation, an ammonium cation, or an organic cation. 
     
     
         34 . The zwitterionic polymer-insulin composition of  claim 32 , wherein the zwitterionic monomer is selected from the group consisting of: carboxybetaine acrylamide; carboxybetaine methacrylate; carboxybetaine methacrylamide; carboxybetaine acrylate; carboxybetaine vinyl; sulfobetaine acrylamide; sulfobetaine methacrylate; sulfobetaine methacrylamide; sulfobetaine acrylate; sulfobetaine vinyl; phosphobetaine acrylamide; phosphobetaine methacrylate; phosphobetaine methacrylamide; phosphobetaine acrylate; phosphobetaine vinyl; and two or more thereof. 
     
     
         35 . The zwitterionic polymer-insulin composition of  claim 32  wherein the insulin monomer comprises a terminal acryloyl functional group. 
     
     
         36 . (canceled) 
     
     
         37 . A method of treatment of a subject in need of insulin, comprising:
 administering a composition selected from the group consisting of: a zwitterionic polymer-insulin composition, a zwitterionic polymer-insulin-saccharide composition, a glucose-responsive zwitterionic polymer-insulin composition, and a combination of any two or more thereof, of  claim 25 .   
     
     
         38 . (canceled) 
     
     
         39 . The method of  claim 37 , wherein the subject has type 1 diabetes, type 2 diabetes, gestational diabetes or pre-diabetes. 
     
     
         40 . A medical device comprising a composition selected from the group consisting of: a zwitterionic polymer-insulin composition, a zwitterionic polymer-insulin-saccharide composition, a glucose-responsive zwitterionic polymer-insulin composition, and a combination of any two or more thereof, according to  claim 25 . 
     
     
         41 .- 53 . (canceled)