Biocompatible crosslinked hydrogels, drug-loaded hydrogels and methods of using the same

Abstract

Disclosed are hydrogel compositions formed by the mixture of a tetramethylmethane substituted with one or more polyethylene glycols, and wherein each polyethylene glycol substituent is independently further substituted with one or more electrophilic groups, and a tetramethylmethane substituted with one or more polyethylene glycols, and wherein each polyethylene glycol substituent is independently further substituted with one or more nucleophilic groups. Disclosed are also methods of preparing the above hydrogels. The hydrogel compositions can further comprise pharmaceuticals, such as analgesics or local anesthetics. Disclosed are also methods of sealing a wound, preventing post-surgical adhesion, and reducing post-surgical pain using the disclosed hydrogels.

1 . A composition comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein
 each R 1  is independently selected from the group consisting of hydrogen, alkyl, —C(═O)R 3 , and —C(═O)OR 3 ; 
 each R 2  is independently selected from the group consisting hydrogen, alkyl, and —(CH 2 CH 2 O) n —R 4 , 
 R 3  is selected from the group consisting of hydrogen, halogen, amino, monoalkylamino, dialkylamino, alkyl, carbocyclyl, and heterocyclyl; 
 each R 4  is independently selected from the group consisting hydrogen, alkyl, —CH 2 CH 2 OH, and —CH 2 CH 2 OR 1 ; 
 each n is independently an integer greater than 1; 
 wherein at least one of R 1  is not hydrogen or alkyl. 
 
       
     
     
         2 - 7 . (canceled) 
     
     
         8 . A composition of  claim 1  comprising a compound of Formula III: 
       
         
           
           
               
               
           
         
         wherein
 each R 5  is independently selected from the group consisting of hydrogen, alkyl, —OR 4 , —SR 7 , and —N(R 7 ) 2 ; 
 each R 6  is independently selected from the group consisting hydrogen, alkyl, and —(CH 2 CH 2 O) n —R 8 ; 
 each R 7  is independently selected from the group consisting of hydrogen, alkyl, carbocyclyl, and heterocyclyl; 
 each R 8  is independently selected from the group consisting hydrogen, alkyl, and —CH 2 CH 2 R 5 ; 
 each n is independently an integer greater than 1; 
 wherein at least one of —R 5  is not hydrogen or alkyl, with the proviso that when both R 6  are —(CH 2 CH 2 O) n —R 8  and both R 8  are —CH 2 CH 2 R 5 , R 5  cannot all be —OH, or R 5  cannot all be —OCH 3 , or R 5  cannot all be —SH in all four arms, or R 5  cannot all be —NH 2 . 
 
       
     
     
         9 - 13 . (canceled) 
     
     
         14 . A hydrogel composition produced by a method comprising
 mixing a first compound and a second compound to obtain a first mixture,   adding a first aqueous solution to the first mixture to obtain a first solution,   adding a second aqueous solution to the first solution, wherein   the first compound is a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein
 each R 1  is independently selected from the group consisting of hydrogen, alkyl, —C(═O)R 3 , and —C(═O)OR 3 ; 
 each R 2  is independently selected from the group consisting hydrogen, alkyl, and —(CH 2 CH 2 O) n —R 4 , 
 R 3  is selected from the group consisting of hydrogen, halogen, amino, monoalkylamino, dialkylamino, alkyl, carbocyclyl, and heterocyclyl; 
 each R 4  is independently selected from the group consisting hydrogen, alkyl, —CH 2 CH 2 OH, and —CH 2 CH 2 OR 1 ; 
 each n is independently an integer greater than 1; 
 wherein at least one of R 1  is not hydrogen or alkyl; and 
 the second compound is a compound of Formula III: 
 
       
         
           
           
               
               
           
         
       
       wherein
 each R 5  is independently selected from the group consisting of hydrogen, alkyl, —OR 4 , —SR 7 , and —N(R 7 ) 2 ; 
 each R 6  is independently selected from the group consisting hydrogen, alkyl, and —(CH 2 CH 2 O) n —R 8 ; 
 each R 7  is independently selected from the group consisting of hydrogen, alkyl, carbocyclyl, and heterocyclyl; 
 each R 8  is independently selected from the group consisting hydrogen, alkyl, and —CH 2 CH 2 R 5 ; 
 each n is independently an integer greater than 1; 
 wherein at least one of —R 5  is not hydrogen or alkyl. 
 
     
     
         15 . The hydrogel of  claim 14 , wherein the first solution is an acidic solution. 
     
     
         16 . The hydrogel of  claim 14 , wherein the first solution is buffered. 
     
     
         17 . The hydrogel of  claim 14 , wherein the first solution comprises hydrochloric acid. 
     
     
         18 . The hydrogel of  claim 14 , wherein the second solution is basic. 
     
     
         19 . The hydrogel of  claim 14 , wherein the second solution is buffered. 
     
     
         20 . The hydrogel of  claim 14 , wherein the first compound is a compound of Formula I.1: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The hydrogel of  claim 14 , wherein the first compound is a compound of Formula I.2: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The hydrogel of  claim 14 , wherein at least one of —OR 1  is 
       
         
           
           
               
               
           
         
       
     
     
         23 . The hydrogel of  claim 14 , wherein the first compound is a compound of Formula II.1: 
       
         
           
           
               
               
           
         
         wherein each n is independently an integer greater than 1. 
       
     
     
         24 . The hydrogel of  claim 14 , wherein the first compound is a compound of Formula II.2: 
       
         
           
           
               
               
           
         
         wherein each n is independently an integer greater than 1. 
       
     
     
         25 . The hydrogel of  claim 14 , wherein the first compound is a compound of Formula II.3: 
       
         
           
           
               
               
           
         
         wherein each n is independently an integer greater than 1. 
       
     
     
         26 . The hydrogel of  claim 14 , wherein the second compound is a compound of Formula III.1: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The hydrogel of  claim 14 , wherein the second compound is a compound of Formula III.2: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The hydrogel of  claim 14 , wherein the second compound is selected from a compound of Formula IV.1, Formula IV.2, Formula IV.3, IV.4 and IV.5: 
       
         
           
           
               
               
           
         
         wherein each n is independently an integer greater than 1. 
       
     
     
         29 - 47 . (canceled) 
     
     
         48 . A method of sealing a wound comprising administering to the wound a biocompatible hydrogel, wherein the biocompatible hydrogel is produced by a method comprising;
 mixing a first compound and a second compound to obtain a first mixture,   adding a first aqueous solution to the first mixture to obtain a first solution,   adding a second aqueous solution to the first solution, wherein   the first compound is a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein
 each R 1  is independently selected from the group consisting of hydrogen, alkyl, —C(═O)R 3 , and —C(═O)OR 3 ; 
 each R 2  is independently selected from the group consisting hydrogen, alkyl, and —(CH 2 CH 2 O) n —R 4 , 
 R 3  is selected from the group consisting of hydrogen, halogen, amino, monoalkylamino, dialkylamino, alkyl, carbocyclyl, and heterocyclyl; 
 each R 4  is independently selected from the group consisting hydrogen, alkyl, —CH 2 CH 2 OH, and —CH 2 CH 2 OR 1 ; 
 each n is independently an integer greater than 1; 
 wherein at least one of R 1  is not hydrogen or alkyl; and 
 the second compound is a compound of Formula III: 
 
       
         
           
           
               
               
           
         
       
       wherein
 each R 5  is independently selected from the group consisting of hydrogen, alkyl, —OR 4 , —SR 7 , and —N(R 7 ) 2 ; 
 each R 6  is independently selected from the group consisting hydrogen, alkyl, and —(CH 2 CH 2 O) n —R 8 ; 
 each R 7  is independently selected from the group consisting of hydrogen, alkyl, carbocyclyl, and heterocyclyl; 
 each R 8  is independently selected from the group consisting hydrogen, alkyl, and —CH 2 CH 2 R 5 ; 
 each n is independently an integer greater than 1; 
 wherein at least one of —R 5  is not hydrogen or alkyl. 
 
     
     
         49 . The method of  claim 48 , wherein the hydrogel is administered after the wound has been sutured. 
     
     
         50 . The method of  claim 48 , wherein the wound is a surgically-induced wound. 
     
     
         51 - 115 . (canceled)