Details for Patent: 9,427,472

Title:	Controlled release compositions for modulating free-radical induced damage and methods of use thereof
Abstract:	Disclosed herein are compositions and methods for the treatment of otic diseases or conditions with free-radical modulating agent compositions and formulations administered locally to an individual afflicted with an otic disease or condition, through direct application of these compositions and formulations onto or via perfusion into the targeted auris structure(s).
Inventor(s):	Lichter; Jay (Rancho Santa Fe, CA), Trammel; Andrew M. (Olathe, KS), Piu; Fabrice (San Diego, CA), Ye; Qiang (San Diego, CA), Duron; Sergio G. (San Diego, CA), Dellamary; Luis A. (San Marcos, CA), Lebel; Carl (Malibu, CA), Harris; Jeffrey P. (La Jolla, CA)
Assignee:	OTONOMY, INC. (San Diego, CA) THE REGENTS OF THE UNIVERSITY OF CALIFORNIA (Oakland, CA)
Filing Date:	May 01, 2014
Application Number:	14/267,677
Claims:	1. An intratympanic composition for use in the treatment of an otic disease or condition associated with free-radical induced damage, the intratympanic composition comprising a micronized free-radical modulating agent, or pharmaceutically acceptable prodrug or salt thereof; and an auris acceptable gel, wherein the micronized free-radical modulating agent, or pharmaceutically acceptable prodrug or salt thereof is not provided as polymer-containing particles, and is suspended in the auris acceptable gel; and wherein sustained release of the free-radical modulating agent into the ear occurs for a period of at least 5 days after a single administration. 2. The intratympanic composition of claim 1, wherein the auris acceptable gel is an auris acceptable hydrogel. 3. The intratympanic composition of claim 1, wherein the auris acceptable gel has a gelation viscosity between about 15,000 cP and about 1,000,000 cP. 4. The intratympanic composition of claim 1, wherein the auris acceptable gel is capable of being injected by a narrow gauge needle or cannula through the tympanic membrane. 5. The intratympanic composition of claim 1, wherein the intratympanic composition has an osmolarity of from about 100 mOsm/L to about 1000 mOsm/L. 6. The intratympanic composition of claim 1, wherein the intratympanic composition has a pH between 7.0 and 8.0. 7. The intratympanic composition of claim 1, wherein the free-radical modulating agent is selected from an antioxidant, an iron chelator, a mitochondrial modulator, a sirtuin modulator, a nitric oxide (NO) modulators, a nitric oxide synthase (NOS) modulators, an iNOS modulators, or combinations thereof. 8. The intratympanic composition of claim 7, wherein the antioxidant is selected from N-acetylcysteine, vitamin E, vitamin C, vitamin A, lutein, selenium glutathione, melatonin, a polyphenol, a carotenoid, coenzyme Q-10, 2-phenyl-1,2-benzisoselenazol-3 (2H)-one, L-methionine, azulenyl nitrones, L-(+)-Ergothioneine, caffeic acid phenethyl ester, dimethylthiourea, dimethylsulfoxide, disufenton sodium, pentoxifylline, MCI-186, Ambroxol, U-83836E, mitoquinone mesylate, 2-(10-hydroxydecyl)-5,6-dimethoxy-3-methyl-cyclohexa-2,5-diene-1,4-dione, or combinations thereof. 9. The intratympanic composition of claim 7, wherein the iron chelator is selected from desferrioxamine, hydroxybenzyl ethylene diamine, fullerenol-1, pyrrolidine dithiocarbamate, or combinations thereof. 10. The intratympanic composition of claim 7, wherein the mitochondrial modulator is selected from acetylcarnitine, lipoic acid, or combinations thereof. 11. The intratympanic composition of claim 7, wherein the sirtuin modulator is selected from a stilbene, a chalcone, a flavone, an isoflavone, a flavanones, an anthocyanidin, a catechin, isonicotinamide, dipyridamole, ZM 336372, camptothecin, coumestrol, nordihydroguaiaretic acid, esculetin, SRT-1720, SRT-1460, SRT-2183, or combinations thereof. 12. The intratympanic composition of claim 7, wherein the NO modulator is selected from aminoguanidine, 1-Amino-2-hydroxyguanidine p-toluensulfate, GED, bromocriptine mesylate, idebenone, SDMA, ADMA, L-NMMA, L-NMEA, D-MMA, L-NIL, L-NNA, L-NPA, L-NAME, L-VNIO, diphenyleneiodonium chloride, 2-ethyl-2-thiopseudourea, haloperidol, L-NIO, MEG, SMT, SMTC, 7-Ni, nNOS inhibitor, 1,3-PBITU, L-thiocitrulline, TRIM, MTR-105, BBS-1, BBS-2, ONO-1714, GW273629, GW 274150, PPA250, AR-R17477, AR-R18512, spiroquinazolone, 1400W, S-NC, NTG, SNP, thapsigargin, VEGF, bradykinin, ATP, sphingosine-1-phosphate, estrogen, angiopoietin, acetylcholine, SIN-1, GEA 3162, GEA, GEA 5024, GEA 5538, SNAP, molsidomine, CNO-4, CNO-5, DEA/NO, IPA/NO, SPER/NO, SULFI/NO, OXI/NO, DETA/NO, or combinations thereof. 13. The intratympanic composition of claim 1, wherein the otic disease or condition is ototoxicity, excitotoxicity, sensorineural hearing loss, presbycusis, or combinations thereof. 14. The intratympanic composition of claim 1, wherein sustained release of the free-radical modulating agent into the ear occurs for a period of at least 10 days after a single administration. 15. The intratympanic composition of claim 1, wherein sustained release of the free-radical modulating agent into the ear occurs for a period of at least 14 days after a single administration.