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Details for Patent: 8,399,018

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Details for Patent: 8,399,018

Title: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.
Inventor(s): Lichter; Jay (Rancho Santa Fe, CA), Vollrath; Benedikt (San Diego, CA), Duron; Sergio G. (San Diego, CA), Lebel; Carl (Malibu, CA), Piu; Fabrice (San Diego, CA), Ye; Qiang (San Diego, CA), Dellamary; Luis A. (San Marcos, CA), Trammel; Andrew M. (Olathe, KS), Scaife; Michael Christopher (Los Altos, CA), Harris; Jeffrey P. (La Jolla, CA)
Assignee: Otonomy, Inc. (San Diego, CA) The Regents of The University of California (Oakland, CA)
Filing Date:Jul 21, 2009
Application Number:12/506,664
Claims:1. 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: an auris acceptable thermoreversible aqueous gel comprising a copolymer of polyoxyproplene and polyoxyethylene in an amount sufficient to provide a non-gelation viscosity that allows injection at or about room temperature with a needle having a gauge in the range of 18-31 through the tympanic membrane to an area on or near the round window membrane, and with a gelation viscosity between about 15,000 cP and about 1,000,000 cP and a gelation temperature of between about room temperature and about body temperature; and 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.

2. The method of claim 1, wherein the ion channel modulating agent comprises micronized particles.

3. The method of claim 1, wherein the ion channel modulating agent comprises non-sized particles.

4. The method of claim 1, wherein the copolymer of polyoxypropylene and polyoxyethylene is Poloxamer 407.

5. The method of claim 1, wherein the sustained release of the ion channel modulating agent into the ear occurs for a period of at least 7 days.

6. The method of claim 1, wherein the ion channel modulator is a potassium channel modulator.

7. The method of claim 6, wherein the potassium channel modulator is a potassium channel agonist.

8. The method of claim 7, 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-(trifluorometh- yl)-2H-indole-2-one); and DMP-543 (10,10-bis((2-fluoro-4-pyridinyl)methyl)-9(10H)-anthracenone).

9. The method of claim 6, wherein the potassium channel modulator is a potassium channel antagonist.

10. The method of claim 9, 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]-methanesulf- onanilide); 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; and tamulustoxin.

11. The method of claim 1, wherein the ion channel modulator is a purigenic receptor modulator.

12. The method of claim 11, wherein the purinergic receptor modulator is a purinergic receptor agonist.

13. The method of claim 12, wherein the purigenic receptor agonist is selected from ATP; ADP; UTP; UDP; UDP-glucose; adenosine; 2-MeSATP; 2-MeSADP; aPmeATP; dATP.alpha.S; ATP.gamma.S; 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); and PSB 0474 (3-(2-Oxo-2-phenylethyl)-uridine-5''-diphosphate disodium salt); or combinations thereof.

14. The method of claim 11, wherein the purigenic receptor modulator is a purigenic receptor antagonist.

15. The method of claim 14, wherein the purigenic receptor antagonist is selected from A-317491 ((5-([(3-Phenoxybenzyl)[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carb- onyl)-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)tetr- asodium 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(carbonylimi- no)))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-N-6-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)b- icyclo[3.1.0]hexane-1-methanol dihydrogen phosphate ester tetraammonium salt); NF157 (8,8'-[carbonylbis[imino-3,1-phenylenecarbonylimino(4-fluoro-3,1-phenylen- e)carbonylimino]]bis-1,3,5-naphthalene trisulfonic acid hexasodium salt); TNP-ATP; tetramethylpyrazine; Ip.sub.51; .beta..gamma.-carboxymethylene ATP; .beta..gamma.-chlorophosphomethylene ATP; KN-62 (4-[(2S)-2-[(5-isoquinolinylsulfonyl)methylamino]-3-oxo-3-(4-phenyl-1-pip- erazinyl)propyl]phenyl isoquinolinesulfonic acid ester); NF023 (8,8'-[carbonylbis(imino-3,1-phenylenecarbonylimino)]bis-1,3,5-naphthalen- e-trisulphonic acid, hexasodium salt); NF279 (8,8'-[Carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonyl- imino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt); and spinorphin; or combinations thereof.

16. The method of claim 1, wherein the ion channel modulating agent is a Na/K ATPase modulator or an epithelial sodium channel modulator.

17. The method of claim 16 wherein the ion channel modulating agent is selected from nimodipine, ouabain, furosemide and amelioride.

18. 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: an auris acceptable thermoreversible aqueous gel having a gelation viscosity between about 15,000 cP and about 1,000,000 cP comprising of a copolymer of polyoxyproplene and polyoxyethylene and a multiparticle 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]-methanesulf- onanilide); 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; and tamulustoxin, such that sustained release of the ion channel modulating agent into the ear occurs for a period of at least 3 days.
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