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

1. A composition comprising a biocompatible hydrogel and an analgesic, wherein the analgesic is uniformly distributed in the hydrogel as in situ generated particles, and wherein the biocompatible hydrogel is produced by a method comprising:

mixing a first compound and a second compound to obtain a first mixture,

adding an acidic aqueous solution and the analgesic to the first mixture to obtain a first solution,

adding a basic 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 7 , —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, and

wherein the analgesic is a local anesthetic selected from the group consisting of bupivacaine, levobupivacaine, ropivacaine, lidocaine, mepivacaine, prilocaine, cinchocaine, etidocaine, articaine and salts thereof.

2. The composition of claim 1 , wherein the compound of Formula I is a compound of Formula I.2:

wherein at least one of —OR 1 is

3. The composition of claim 1 , wherein the compound of Formula I is a compound of Formula II.3:

wherein each n is independently an integer greater than 1.

4. The composition of claim 1 , wherein the compound of Formula III is a compound of Formula IV.1, Formula IV.2 Formula IV.3, Formula IV.4 or Formula IV.5:

wherein each n is independently an integer greater than 1.

5. The composition of claim 1 , wherein the particles of the analgesic are 1 -50 microns in sizes.