Controlled-release cns modulating compositions and methods for the treatment of otic disorders

Abstract

Disclosed herein are compositions and methods for the treatment of otic disorders with CNS modulating agent compositions and compositions administered locally to an individual afflicted with an otic disorder, through direct application of these compositions and compositions onto or via perfusion into the targeted auris structure(s).

We claim: 
     
         1 . A pharmaceutical composition or device, comprising: a therapeutically effective amount of a CNS inhibitory agent having substantially low degradation products; and wherein the composition or device comprises two or more characteristics selected from:
 (i) between about 0.1% to about 10% by weight of the CNS inhibitory agent, or pharmaceutically acceptable prodrug or salt thereof,   (ii) between about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106;   (iii) sterile water, q.s., buffered to provide a pH between about 5.5 and about 8.0;   (iv) multiparticulate CNS inhibitory agent;   (v) a gelation temperature between about 19° C. to about 42° C.;   (vi) less than about 50 colony forming units (cfu) of microbiological agents per gram of composition, and   (vii) less than about 5 endotoxin units (EU) per kg of body weight of a subject.   
     
     
         2 . The pharmaceutical composition or device of  claim 1 , wherein the composition comprises:
 (i) between about 0.1% to about 10% by weight of the CNS inhibitory agent, or pharmaceutically acceptable prodrug or salt thereof,   (ii) between about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106;   (iii) multiparticulate the CNS inhibitory agent; and   (iv) a gelation temperature between about 19° C. to about 42° C.   
     
     
         3 . The pharmaceutical composition or device of  claim 1  wherein the composition or device provides a practical osmolarity between about 200 and 400 mOsm/L. 
     
     
         4 . The pharmaceutical composition or device of  claim 1 , wherein the CNS inhibitory agent is released for a period of at least 3 days. 
     
     
         5 . The pharmaceutical composition or device of  claim 1 , wherein the pharmaceutical composition is an auris-acceptable thermoreversible gel. 
     
     
         6 . The pharmaceutical composition or device of  claim 1 , further comprising a dye. 
     
     
         7 . The pharmaceutical composition or device of  claim 1 , wherein the CNS inhibitory agent is an antihistamine, a GABA receptor modulator, a neurotransmitter reuptake inhibitor, a local anesthetic, an anticholinergic, a sodium channel blocker, a calcium channel blocker, a thyrotropin-releasing hormone, combinations thereof. 
     
     
         8 . The composition or device of  claim 1 , further comprising the CNS inhibitory agent, or pharmaceutically acceptable salt thereof, prodrug or combination thereof as an immediate release agent. 
     
     
         9 . The pharmaceutical composition or device of  claim 1 , wherein the CNS inhibitory agent comprises multiparticulates. 
     
     
         10 . The pharmaceutical composition or device of  claim 1 , wherein the CNS inhibitory agent is essentially in the form of micronized particles. 
     
     
         11 . The pharmaceutical composition or device of  claim 1 , wherein the pH of the composition or device is between about 6.0 to about 7.6. 
     
     
         12 . The pharmaceutical composition or device of  claim 1 , wherein the otic disease or condition is endolymphatic hydrops, kinetosis, labyrinthitis, mal de debarquement, Meniere's disease, Meniere's syndrome, Ramsay Hunt's syndrome (Herpes zoster infection), recurrent vestibulopathy, tinnitus, vertigo, microvascular compression syndrome, utricular dysfunction, vestibular neuronitis, benign paroxysmal positional vertigo, or combinations thereof. 
     
     
         13 . A method of treating an otic disease or condition characterized by an excess of nerve impulses comprising administering to an individual in need thereof an intratympanic composition or device comprising a therapeutically effective amount of a CNS inhibitory agent, wherein the CNS inhibitory agent is in the form of a substantially low degradation product; and wherein the composition or device comprises two or more characteristics selected from:
 (i) between about 0.1% to about 10% by weight of the CNS inhibitory agent, or pharmaceutically acceptable prodrug or salt thereof,   (ii) between about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106;   (iii) sterile water, q.s., buffered to provide a pH between about 5.5 and about 8.0;   (iv) multiparticulate the CNS inhibitory agent;   (v) a gelation temperature between about 19° C. to about 42° C.;   (vi) less than about 50 colony forming units (cfu) of microbiological agents per gram of composition, and   (vii) less than about 5 endotoxin units (EU) per kg of body weight of a subject.   
     
     
         14 . The method of  claim 13 , wherein the CNS inhibitory agent is released from the composition for a period of at least 3 days. 
     
     
         15 . The method of  claim 13 , wherein the CNS inhibitory agent is essentially in the form of micronized particles. 
     
     
         16 . The method of  claim 13 , wherein the CNS inhibitory agent inhibits the transmission of a nerve impulse. 
     
     
         17 . The method of  claim 13 , wherein the CNS inhibitory agent inhibits the release of a neurotransmitter. 
     
     
         18 . The method of  claim 13 , wherein the CNS inhibitory agent agonizes the activity of a GABA receptor 
     
     
         19 . The method of  claim 13 , wherein the CNS inhibitory agent partially or fully inhibits the repolarization of a neuron. 
     
     
         20 . The method of  claim 13 , wherein the CNS inhibitory agent disrupts the conduction of an ion channel.