Modulation of Heparin-binding Epidermal Growth Factor Activity for Tympanic Membrane Healing

Abstract

Compositions and methods are provided for the generation or treatment of chronic tympanic membrane perforation by modulation of HB-EGF activity.

What is claimed is: 
     
         1 . A method of improving healing of a chronic tympanic membrane perforation in an individual, the method comprising:
 contacting a site of chronic tympanic membrane perforation with a formulation comprising an effective dose of an agent that provides heparin binding epidermal growth factor (HB-EGF) activity, for a period of time sufficient to substantially close the perforation.   
     
     
         2 . The method of  claim 1 , wherein the agent that provides HB-EGF activity is a soluble form of HB-EGF protein. 
     
     
         3 . The method of  claim 2 , wherein the individual is a human, and the HB-EGF is human HB-EGF. 
     
     
         4 . The method of  claim 1 , wherein the formulation comprising an effective dose of HB-EGF is contacted with the affected tympanic membrane for a period of at least 7 days. 
     
     
         5 . The method of  claim 1 , wherein the formulation comprising an effective dose of HB-EGF is contacted with the affected tympanic membrane for a period of at least 2 weeks. 
     
     
         6 . The method of  claim 4  or  5 , wherein formulation is administered at least daily. 
     
     
         7 . The method of  claim 4  or  5 , wherein the formulation provides for sustained release of the HB-EGF. 
     
     
         8 . The method of  claim 1 , wherein the formulation is provided as an aqueous solution, a gel, a lotion, a balm, paste or other vehicle. 
     
     
         9 . The method of  claim 1 , wherein the composition is administered by a spray. 
     
     
         10 . The method of  claim 1 , wherein the composition is administered as a liquid that then solidifies to stay adjacent to the tympanic membrane. 
     
     
         11 . The method of  claim 1 , wherein the formulation is a sustained release gel comprising a cross-linked copolymer of chitosan and polylactide. 
     
     
         12 . The method of  claim 1 , wherein the sustained release gel further comprises fibrinogen. 
     
     
         13 . The method of  claim 1 , wherein the formulation is delivered by a device that provides for sustained release of the HB-EGF. 
     
     
         14 . The method of  claim 1 , wherein the formulation further comprises at least one additional active agent. 
     
     
         15 . A pharmaceutical formulation comprising an effective dose of HB-EGF for use in the method of any one of  claims 1 - 14 . 
     
     
         16 . Use of an agent with HB-EGF activity in the manufacture of a medicament for the treatment of a chronic perforation of the TM, wherein the medicament is administered to a patient having a chronic perforation of the TM for a period of time and dose sufficient to effect a closure of the perforation. 
     
     
         17 . A method of inhibiting healing of a tympanic membrane perforation in an individual, the method comprising:
 contacting a site of tympanic membrane perforation with a formulation comprising an effective dose of an agent that inhibits HB-EGF activity.   
     
     
         18 . The method of  claim 17 , comprising the step of generating a perforation in the tympanic membrane prior to the contacting step. 
     
     
         19 . The method of  claim 17 , wherein the individual is a human. 
     
     
         20 . The method of  claim 17 , wherein the formulation is provided as an aqueous solution, a gel, a lotion, a balm, paste or other vehicle. 
     
     
         21 . The method of  claim 17 , wherein the composition is administered as a liquid that then solidifies to stay adjacent to the tympanic membrane. 
     
     
         22 . The method of  claim 17 , wherein the formulation is a sustained release gel comprising a cross-linked copolymer of chitosan and polylactide. 
     
     
         23 . The method of  claim 17 , wherein the sustained release gel further comprises fibrinogen. 
     
     
         24 . The method of  claim 1 , wherein the formulation is delivered by a device that provides for sustained release of the HB-EGF inhibitor.