Formulations of biologics for intravesical instillation

Abstract

Pharmaceutical formulations comprising a clostridial derivative and a permeabilizing agent for intravesical instillation are disclosed.

We claim: 
     
         1 . A pharmaceutical composition comprising a therapeutically effective amount of a clostridial derivative and at least one permeabilizing agent, wherein:
 the at least one permeabilizing agent is present in an amount effective to substantially and reversibly increase the permeability of the bladder wall to the clostridial derivative; wherein   the clostridial derivative is a botulinum toxin; and wherein the at least one permeabilizing agent comprises a surfactant; and wherein the surfactant is present in an amount from about 0.005% to about 10% (w/v); and wherein the surfactant is a non-ionic surfactant.   the mucoadhesive comprises chitosan; and   the surfactant comprises octoxynol-9.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the at least one permeabilizing agent further comprises a muchoadhesive. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the at least one permeabilizing agent comprises octoxynol-9. 
     
     
         4 . The pharmaceutical composition of  claim 2 , wherein the mucoadhesive comprises chitosan. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the mucoadhesive is present in an amount ranging from about 0.01% to about 5% (w/v). 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the mucoadhesive is present in an amount of about 1% (w/v). 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the clostridial derivative is a botulinum toxin type A. 
     
     
         8 . The pharmaceutical composition of  claim 3 , wherein the surfactant is present in an amount of 0.1% (w/v). 
     
     
         9 . A method of treating a patient with a neurogenic bladder dysfunction in a patient in need thereof, comprising intravesically instilling to the bladder wall of the patient a pharmaceutical composition, wherein:
 the pharmaceutical composition comprising comprises a therapeutically effective amount of a clostridial derivative and at least one permeabilizing agent present in an amount effective to substantially increase the permeability of the bladder wall to the botulinum neurotoxin at a therapeutically effective rate; wherein   the clostridial derivative is a botulinum toxin; and wherein   the at least one permeabilizing agent comprises a non-ionic surfactant; and wherein   the non-ionic surfactant is present in an amount ranging from about 0.05% to about 10% (w/v).   
     
     
         10 . The method of  claim 9 , wherein at least one permeabilizing agent further comprises a muchoadhesive. 
     
     
         11 . The method of  claim 9 , wherein the at least one permeabilizing agent comprises octoxynol-9. 
     
     
         12 . The method of  claim 9 , wherein the mucoadhesive comprises chitosan. 
     
     
         13 . The method of  claim 9 , wherein the mucoadhesive is present in an amount ranging from about 0.01% to about 5% (w/v). 
     
     
         14 . The method of  claim 9 , wherein the mucoadhesive is present in an amount of about 1% (w/v). 
     
     
         15 . The method of  claim 9 , wherein the clostridial derivative is a botulinum toxin type A. 
     
     
         16 . The method of  claim 11 , wherein the surfactant is present in an amount of 0.1% (w/v). 
     
     
         17 . A pharmaceutical composition comprising a therapeutically effective amount of a clostridial derivative and at least one permeabilizing agent, wherein:
 the at least one permeabilizing agent is present in an amount of 0.005-10% (w/v) to substantially and reversibly increase the permeability of the bladder wall to the clostridial derivative; wherein   the clostridial derivative is a botulinum toxin; wherein   the at least one permeabilizing agent comprises a non-ionic surfactant and a mucoadhesive,   
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the surfactant is a non-ionic surfactant octoxynol-9 and the mucoadhesive is a cationic polymer chitosan. 
     
     
         19 . The composition of  claim 18 , wherein the surfactant is present at about 0.1% (w/v) and the mucoadhesive is present at about 1% (w/v). 
     
     
         20 . A method of treating a neurogenic bladder dysfunction in a patient in need thereof, comprising intravesically instilling to the bladder wall of the patient a pharmaceutical composition of  claim 17 .