Hypotonic hydrogel formulations for enhanced transport of active agents at mucosal surfaces

Abstract

Hypotonic formulations of hydrogel forming polymers, preferably poloxamers, have been developed for enhanced delivery through mucosa of therapeutic, diagnostic, prophylactic or other agents, to epithelial tissues, especially those having a mucosal coating. The polymers are administered at a concentration above, at or less than their critical gelling concentration (CGC) under isotonic conditions. The hypotonicity of the formulation is adjusted so that the polymer gels at the lower concentration. A Poloxamer gel administered into the vagina or colorectum at its CGC will form a “plug” of gel in the lumen.

1 . A formulation for use as a barrier and/or in the delivery of a therapeutic, prophylactic, diagnostic or nutraceutical agent to the eye comprising
 a gel-forming polymer at a concentration at or above the critical gel concentration (CGC) of the polymer under isotonic conditions and a temperature between room temperature and body temperature (25 to 37° C.), and   excipients to form a hypotonic formulation of the polymer.   
     
     
         2 . The formulation of  claim 1 , wherein the gel-forming polymer is present at a concentration above the minimum gel concentration of the polymer (MGC). 
     
     
         3 . The formulation of  claim 1 , wherein the gel-forming polymer is a thermosensitive gel-forming polymer. 
     
     
         4 . The formulation of  claim 3 , wherein the thermosensitive gel-forming polymer has a lower critical solution temperature that is below 30° C., preferably below 21° C. 
     
     
         5 . The formulation of  claim 4  wherein the polymer is a poloxamer. 
     
     
         6 . The formulation of  claim 1 , wherein the polymer in combination with excipient forms a depo or barrier gel on a mucosal or epithelial surface on the ocular surface of the eye. 
     
     
         7 . (canceled) 
     
     
         8 . The formulation of  claim 1 , wherein the hypotonic solution further comprises a therapeutic, prophylactic, or diagnostic agent. 
     
     
         9 . The formulation of  claim 6 , wherein the gel releases the therapeutic, prophylactic, or diagnostic agent at the epithelial surface over a period of at least 24 hours. 
     
     
         10 . The formulation of  claim 1 , wherein the gel-forming polymer is between greater than 12 and less than 24% F98 in an aqueous excipient. 
     
     
         11 . The formulation of  claim 1 , wherein the gel-forming polymer is between 10 and 18% F127. 
     
     
         12 . (canceled) 
     
     
         13 . The formulation of  claim 1 , wherein the gel comprises a therapeutic, prophylactic, or diagnostic agent selected from the group consisting of small-molecule drugs, peptides, proteins, sugars, polysaccharides, nucleotides, and nucleic acids. 
     
     
         14 . The formulation of  claim 13  wherein the agent is a small molecule having a molecular weight less than 2000, 1500, 1000, 750, or 500 atomic mass units or a nucleic acid molecule. 
     
     
         15 . The formulation of  claim 1 , wherein the polymer formulation is provided in a multiple dosage unit administration. 
     
     
         16 . A method for administering an agent to a mucosal or epithelial ocular surface comprising administrating to a site in need thereof the formulation of  claim 1 . 
     
     
         17 . The method of  claim 16  wherein the formulation is administered at or above the critical gel concentration (CGC) of the polymer under isotonic conditions and a temperature between room temperature and body temperature (25 to 37° C.). 
     
     
         18 . The method of  claim 16  wherein the formulation is administered below the critical gel concentration (CGC) of the polymer under isotonic conditions and a temperature between room temperature and body temperature (25 to 37° C.). 
     
     
         19 . The method of  claim 16  for delivery of a therapeutic, prophylactic, or diagnostic selected from the group consisting of small-molecule drugs, peptides, proteins, sugars, polysaccharides, nucleotides, and nucleic acids. 
     
     
         20 . The method of  claim 16  for formation of a barrier.