Auris Formulations for Treating Otic Diseases and Conditions

Abstract

Disclosed herein are compositions and methods for the treatment of otic disorders with immunomodulating agents and auris pressure modulators. In these methods, the auris compositions and formulations are administered locally to an individual afflicted with an otic disorder, through direct application of the immunomodulating and/or auris pressure modulating compositions and formulations onto the auris media and/or auris interna target areas, or via perfusion into the auris media and/or auris interna structures.

We claim: 
     
         1 . A pharmaceutical formulation for use in the treatment of an otic disease or condition formulated to provide a therapeutically effective amount of an immunomodulating agent, the formulation comprising:
 between about 0.2% to about 6% by weight of an immunomodulating agent, or pharmaceutically acceptable prodrug or salt thereof;   between about 16% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106;   sterile water, q.s., buffered to provide a perilymph-suitable pH between about 6.0 and about 7.6;   and substantially low degradation products of the immunomodulating agent;   
       wherein the pharmaceutical formulation has a perilymph-suitable osmolarity between about 250 and 320 mOsm/L, 
       less than about 50 colony forming units (cfu) of microbiological agents per gram of formulation, and less than about 5 endotoxin units (EU) per kg of body weight of a subject. 
     
     
         2 . The composition of  claim 1 , wherein the immunomodulating agent is released from the formulation for a period of at least 3 days. 
     
     
         3 . The composition of  claim 2 , wherein the pharmaceutical formulation is an auris-acceptable thermoreversible gel. 
     
     
         4 . The composition of  claim 1 , further comprising a penetration enhancer. 
     
     
         5 . The composition of  claim 1 , further comprising a dye. 
     
     
         6 . The composition of  claim 1 , further comprising a drug delivery device selected from a needle and syringe, a pump, a microinjection device, a wick, an in situ forming spongy material or combinations thereof. 
     
     
         7 . The composition of  claim 3 , wherein the immunomodulating agent is essentially in the form of micronized particles. 
     
     
         8 . The composition of  claim 1 , wherein the immunomodulating agent is an anti-TNF agent, a calcineurin inhibitor, an IKK inhibitor, an interleukin inhibitor, a TNF-a converting enzyme (TACE) inhibitor, or a toll-like receptor inhibitor. 
     
     
         9 . The composition of  claim 1 , further comprising an immunomodulating agent, or pharmaceutically acceptable salt thereof, as an immediate release agent. 
     
     
         10 . The composition of  claim 1 , wherein the otic disease or condition is Meniere's disease, sudden sensorineural hearing loss, noise induced hearing loss, age related hearing loss, auto immune ear disease or tinnitus. 
     
     
         11 . A pharmaceutical formulation for use in the treatment of an otic disease or condition formulated to provide a therapeutically effective amount of an aural pressure modulating, the formulation comprising:
 between about 0.2% to about 6% by weight of an aural pressure modulating agent, or pharmaceutically acceptable prodrug or salt thereof;   between about 16% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106;   sterile water, q.s., buffered to provide a perilymph-suitable pH between about 6.0 and about 7.6;   and substantially low degradation products of the aural pressure modulating agent;   
       wherein the pharmaceutical formulation has a perilymph-suitable osmolarity between about 250 and 320 mOsm/L, 
       less than about 50 colony forming units (cfu) of microbiological agents per gram of formulation, and less than about 5 endotoxin units (EU) per kg of body weight of a subject. 
     
     
         12 . The composition of  claim 11 , wherein the aural pressure modulating agent is released from the formulation for a period of at least 3 days. 
     
     
         13 . The composition of  claim 12 , wherein the pharmaceutical formulation is an auris-acceptable thermoreversible gel. 
     
     
         14 . The composition of  claim 11 , further comprising a penetration enhancer. 
     
     
         15 . The composition of  claim 11 , further comprising a dye. 
     
     
         16 . The composition of  claim 11 , further comprising a drug delivery device selected from a needle and syringe, a pump, a microinjection device, a wick, an in situ forming spongy material or combinations thereof. 
     
     
         17 . The composition of  claim 13 , wherein the aural pressure modulating agent is essentially in the form of micronized particles. 
     
     
         18 . The composition of  claim 11 , wherein the aural pressure modulating agent is a modulator of aquaporin, an estrogen related receptor beta modulator, a gap junction protein modulator, an NMDA receptor modulator, an osmotic diuretic, a progesterone receptor modulator, a prostaglandin modulator, or a vasopressin receptor modulator. 
     
     
         19 . The composition of  claim 11 , further comprising an aural pressure modulating agent, or pharmaceutically acceptable salt thereof, as an immediate release agent. 
     
     
         20 . The composition of  claim 11 , wherein the otic disease or condition is Meniere's disease, sudden sensorineural hearing loss, noise induced hearing loss, age related hearing loss, auto immune ear disease or tinnitus.