In vivo gelling pharmaceutical pre-formulation

Abstract

Provided herein are in vivo gelling pharmaceutical pre-formulations forming biocompatible hydrogel polymers that are polymerized in vivo and kits comprising at least one nucleophilic compound or monomer unit, at least one electrophilic compound or monomer unit, and optionally at least one therapeutic agent. The biocompatible hydrogel polymer is bioabsorbable and releases the therapeutic agent at a target site, avoiding systemic exposure.

1 . An in vivo gelling pharmaceutical pre-formulation, comprising:
 (a) at least one water soluble first compound comprising more than one nucleophilic group;   (b) at least one water soluble second compound comprising more than one electrophilic group;   (c) an aqueous buffer in the pH range of 5.0 to 9.0; and   (d) optionally, one or more therapeutic agents;   wherein mixing the first compound, the second compound, and the optional therapeutic agent in the aqueous buffer and delivering the mixture to a target site in the human body generates the in vivo gelling pharmaceutical pre-formulation such that the in vivo gelling pharmaceutical pre-formulation at least in part polymerizes and gels at the target site to form a biocompatible hydrogel polymer.   
     
     
         2 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the nucleophilic group is a thiol or amino group. 
     
     
         3 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the first compound is a glycol, trimethylolpropane, pentaerythritol, hexaglycerol, or tripentaerythritol derivative. 
     
     
         4 . The in vivo gelling pharmaceutical pre-formulation of  claim 3 , wherein the first compound is a pentaerythritol or hexaglycerol derivative. 
     
     
         5 . The in vivo gelling pharmaceutical pre-formulation of  claim 3 , wherein the first compound further comprises one or more polyethylene glycol sections. 
     
     
         6 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the first compound is selected from the group consisting of ethoxylated pentaerythritol ethylamine ether, ethoxylated pentaerythritol propylamine ether, ethoxylated pentaerythritol amino acetate, ethoxylated hexaglycerol ethylamine ether, ethoxylated hexaglycerol propylamine ether, and ethoxylated hexaglycerol amino acetate. 
     
     
         7 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the first compound is selected from the group consisting of trimethylolpropane trimercaptoacetate, trimethylolpropane tri-3-mercaptopropionate, pentaerythritol tetramercaptoacetate, pentaerythritol tetra-3-mercaptopropionate, ethoxylated trimethylolpropane trimercaptoacetate, ethoxylated trimethylolpropane tri-3-mercaptopropionate, ethoxylated pentaerythritol tetramercaptoacetate, and ethoxylated trimethylolpropane tri-3-mercaptopropionate. 
     
     
         8 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the molecular weight of the first compound is between about 1000 and 20000. 
     
     
         9 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the electrophilic group is an epoxide, N-succinimidyl succinate, N-succinimidyl glutarate, N-succinimidyl succinamide or N-succinimidyl glutaramide. 
     
     
         10 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the second compound is a trimethylolpropane, glycerol, diglycerol, pentaerythritol, sorbitol, hexaglycerol, tripentaerythritol, or polyglycerol derivative. 
     
     
         11 . The in vivo gelling pharmaceutical pre-formulation of  claim 10 , wherein the second compound is a trimethylolpropane, pentaerythritol, or hexaglycerol derivative. 
     
     
         12 . The in vivo gelling pharmaceutical pre-formulation of  claim 10 , wherein the second compound further comprises one or more polyethylene glycol sections. 
     
     
         13 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the second compound is selected from the group consisting of ethoxylated pentaerythritol succinimidyl succinate, ethoxylated pentaerythritol succinimidyl glutarate, ethoxylated pentaerythritol succinimidyl glutaramide, ethoxylated hexaglycerol succinimidyl succinate, ethoxylated hexaglycerol succinimidyl glutarate, and ethoxylated hexaglycerol succinimidyl glutaramide. 
     
     
         14 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the second compound is selected from the group consisting of sorbitol polyglycidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, glycerol polyglycidyl ether, and trimethylolpropane polyglycidyl ether. 
     
     
         15 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the molecular weight of the second compound is between about 1000 and 20000. 
     
     
         16 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the therapeutic agent is independently selected from the group consisting of an anticancer agent, an antiviral agent, an antibacterial agent, antifungal agent, an immunosuppressant agent, an hemostasis agent, and an anti-inflammatory agent. 
     
     
         17 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the gelling time of the biocompatible hydrogel polymer is controlled by the pH of the aqueous buffer. 
     
     
         18 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the gelling time is between about 20 seconds and 5 minutes. 
     
     
         19 . The in vivo gelling pharmaceutical pre-formulation of  claim 1 , wherein the pH of the aqueous buffer is from about 6.9 to about 7.9. 
     
     
         20 . The in vivo gelling pharmaceutical pre-formulation of  claim 19 , wherein the pH of the aqueous buffer is about 7.4. 
     
     
         20 - 83 . (canceled)