Controlled Release Ion Channel Modulator Compositions and Methods for the Treatment of Otic Disorders

Abstract

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

1 - 20 . (canceled) 
     
     
         21 . A method of treating otic disorders selected from the group consisting of Meniere's Disease, endolymphatic hydrops, progressive hearing loss, dizziness, vertigo and tinnitus in an individual in need thereof comprising intratympanic administration of a sterile pharmaceutical composition into the ear, the composition comprising:
 a multiparticulate ion channel modulating agent such that sustained release of the ion channel modulating agent into the ear occurs for a period of at least 5 days;   provided that the ion channel modulating agent is a non-corticosteroid ion channel modulating agent.   
     
     
         22 . The method of  claim 21 , wherein the ion channel modulating agent comprises micronized particles. 
     
     
         23 . The method of  claim 21 , wherein the ion channel modulating agent comprises non-sized particles. 
     
     
         24 . The method of  claim 21 , wherein the sustained release of the ion channel modulating agent into the ear occurs for a period of at least 7 days. 
     
     
         25 . The method of  claim 21 , wherein the ion channel modulator is a potassium channel modulator. 
     
     
         26 . The method of  claim 21 , wherein the potassium channel modulator is a potassium channel agonist. 
     
     
         27 . The method of  claim 26 , wherein the potassium channel agonist is selected from L-735,334 (14-hydroxy CAF-603 oleate); retigabine; flupirtine; BMS-204352 (3S)-(+)-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one); or DMP-543 (10,10-bis((2-fluoro-4-pyridinyl)methyl)-9(10H)-anthracenone). 
     
     
         28 . The method of  claim 21 , wherein the potassium channel modulator is a potassium channel antagonist. 
     
     
         29 . The method of  claim 28 , wherein the potassium channel antagonist is selected from linopirdine; XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone); 4-AP (4-aminopyridine); 3,4-DAP (3,4-Diaminopyridine); E-4031 (4′-[[1-[2-(6-methyl-2-pyridyl)ethyl]-4-piperidinyl]carbonyl]-methanesulfonanilide); DIDS (4,4′-diisothiocyanostilbene-2,2′-disulfonic acid); Way 123,398 (N-methyl-N-(2-(methyl(1-methyl-1H-benzimidazol-2-yl)amino)ethyl)-4-((methylsulfonyl)amino)benzenesulfonamide HCl); CGS-12066A (7-Trifluoromethyl-4-(4-methyl-1-piperazinyl)pyrrolo-[1,2-a]quinoxaline); dofetilide; sotalol; apamin; amiodarone; azimilide; bretylium; clofilium; tedisamil; ibutilide; sematilide; nifekalant; or tamulustoxin. 
     
     
         30 . The method of  claim 21 , wherein the ion channel modulator is a purigenic receptor modulator. 
     
     
         31 . The method of  claim 30 , wherein the purinergic receptor modulator is a purinergic receptor agonist. 
     
     
         32 . The method of  claim 31 , wherein the purigenic receptor agonist is selected from ATP; ADP; UTP; UDP; UDP-glucose; adenosine; 2-MeSATP; 2-MeSADP; αβmeATP; dATPaS; ATPγS; Bz-ATP; MRS2703 (2-MeSADP with the beta-phosphate group blocked by a 1-(3,4-dimethyloxyphenyl)eth-1-yl phosphoester)); denufosol tetrasodium; MRS2365 ([[(1R,2R,3S,4R,5S)-4-[6-amino-2-(methylthio)-9H-purin-9-yl]-2,3-dihydroxybicyclo[3.1.0]hex-1-yl]methyl]diphosphoric acid mono ester trisodium salt); MRS 2690 (diphosphoric acid 1-a-D-glucopyranosyl ester 2-[(4′-methylthio)uridin-5″-yl]ester disodium salt); PSB 0474 (3-(2-oxo-2-phenylethyl)-uridine-5′-diphosphate disodium salt); or combinations thereof. 
     
     
         33 . The method of  claim 30 , wherein the purigenic receptor modulator is a purigenic receptor antagonist. 
     
     
         34 . The method of  claim 33 , wherein the purigenic receptor antagonist is selected from A-317491 ((5-([(3-Phenoxybenzyl) [(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl)-1,2,4-benzenetricarboxylic acid)); RO-3 (Roche); suramin; PPADS (pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid); PPNDS (Pyridoxal-5′-phosphate-6-(2′-naphthylazo-6′-nitro-4′,8′-disulfonate)tetrasodium salt); DIDS; pyridoxal-5-phosphate; 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro-[3,2-e]-1,4-diazepin-2-one; cibacron blue; basilen blue; ivermectin; A-438079 (3-[[5-(2,3-Dichlorophenyl)-1H-tetrazol-1-yl]methyl]pyridine hydrochloride); A-740003 ((N-(1-{[(cyanoimino)(5-quinolinylamino)methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide); NF449 (4,4′,4″,4′″-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid); NF110 (para-4,4′,4″,4′″-(carbonylbis(imino-5,1,3-benzenetriylbis carbonylimino)))tetrakis-benzenesulfonic acid); MRS 2179 (2′-Deoxy-N6-methyladenosine 3′,5′-bisphosphate tetrasodium salt); MRS 2211 (2-[(2-chloro-5-nitrophenyl)azo]-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-4-pyridinecarboxaldehyde disodium salt); MRS 2279 ((1R,2S,4S,5S)-4-[2-chloro-6-(methylamino)-9H-purin-9-yl]-2-(phosphonooxy)bicyclo[3.1.0]hexane-1-methanol dihydrogen phosphate ester diammonium salt); MRS 2500 tetrasodium salt ((1R,2S,4S,5S)-4-[2-Iodo-6-(methylamino)-9H-purin-9-yl]-2-(phosphonooxy)bicyclo[3.1.0]hexane-1-methanol dihydrogen phosphate ester tetraammonium salt); NF157 (8,8′-[carbonylbis[imino-3,1-phenylenecarbonylimino(4-fluoro-3,1-phenylene)carbonylimino]]bis-1,3,5-naphthalene trisulfonic acid hexasodium salt); TNP-ATP; tetramethylpyrazine; Ip 5 I; βγ-carboxymethylene ATP; βγ-chlorophosphomethylene ATP; KN-62 (4-[(2S)-2-[(5-isoquinolinylsulfonyl)methylamino]-3-oxo-3-(4-phenyl-1-piperazinyl)propyl]phenyl isoquinolinesulfonic acid ester); NF023 (8,8′-[carbonylbis(imino-3,1-phenylenecarbonylimino)]bis-1,3,5-naphthalene-trisulphonic acid, hexasodium salt); NF279 (8,8′-[Carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt); spinorphin; or combinations thereof. 
     
     
         35 . The method of  claim 21 , wherein the ion channel modulating agent is a Na/K ATPase modulator or an epithelial sodium channel modulator. 
     
     
         36 . The method of  claim 35  wherein the ion channel modulating agent is selected from nimodipine, ouabain, furosemide and amelioride. 
     
     
         37 . A method of treating otic disorders selected from the group consisting of Meniere's Disease, endolymphatic hydrops, progressive hearing loss, dizziness, vertigo and tinnitus in an individual in need thereof comprising intratympanic administration of a sterile pharmaceutical composition into the ear, the composition comprising:
 a mutliparticulate ion channel modulating agent selected from linopirdine; XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone); 4-AP (4-aminopyridine); 3,4-DAP (3,4-Diaminopyridine); E-4031 (4′-[[1-[2-(6-methyl-2-pyridyl)ethyl]-4-piperidinyl]carbonyl]-methanesulfonanilide); DIDS (4,4′-diisothiocyanostilbene-2,2′-disulfonic acid); Way 123,398 (N-methyl-N-(2-(methyl(1-methyl-1H-benzimidazol-2-yl)amino)ethyl)-4-((methylsulfonyl)amino)benzenesulfonamide HCl); CGS-12066A (7-Trifluoromethyl-4-(4-methyl-1-piperazinyl)pyrrolo-[1,2-a]quinoxaline); dofetilide; sotalol; apamin; amiodarone; azimilide; bretylium; clofilium; tedisamil; ibutilide; sematilide; nifekalant; or tamulustoxin, such that sustained release of the ion channel modulating agent into the ear occurs for a period of at least 3 days.