US 2010.0015228A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0015228A1 LCHTER et al. (43) Pub. Date: Jan. 21, 2010 (54) CONTROLLED RELEASE ION CHANNEL (21) Appl. No.: 12/506,664 MODULATOR COMPOSITIONS AND METHODS FOR THE TREATMENT OF OTC (22) Filed: Jul. 21, 2009 DSORDERS Related U.S. Application Data (75) Inventors: Jay LICHTER, Rancho Santa Fe, (60) Provisional application No. 61/082,450, filed on Jul. CA (US); Benedikt VOLLRATH, 21, 2008, provisional application No. 61/094,384, San Diego, CA (US); Sergio G. filed on Sep. 4, 2008, provisional application No. DURON, San Diego, CA (US); 61/101,112, filed on Sep. 29, 2008, provisional appli Carl LEBEL, Malibu, CA (US); cation No. 61/140,033, filed on Dec. 22, 2008, provi Fabrice PIU, San Diego, CA (US); sional application No. 61/088,275, filed on Aug. 12, Qiang YE, San Diego, CA (US); 2008. Luis A. DELLAMARY, San Marcos, CA (US); Andrew M. Publication Classification TRAMMEL Olathe, KS (US); (51) Int. C. MichOSAILOS, crees, ; Jerey S.E. P. A69/10 (2006.01) HARRIS, La Jolla, CA (US) (52) U.S. Cl. ........................................................ 424/484 (57) ABSTRACT Correspondence Address: WILSON, SONSINI, GOODRICH & ROSATI Disclosed herein are compositions and methods for the treat 650 PAGE MILL ROAD ment of otic disorders with ion channel modulators. In these PALO ALTO, CA 94304-1050 (US) methods, the ion channel modulator compositions and for mulations are administered locally to an individual afflicted (73) Assignees: OTONOMY, INC., San Diego, CA with an otic disorder, through direct application of the ion (US): THE REGENTS OF THE channel modulator compositions and formulations onto the UNIVERSITY OF auris interna target areas, or via perfusion into the auris CALIFORNIA, Oakland, CA (US) interna structures. Patent Application Publication Jan. 21, 2010 Sheet 1 of 5 US 2010/OO15228A1 1000 -H NOn-Sustained release 100--- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Cmax --H Sustained release s s S. 10 ---,s -H BimOdal release 1 s - - - Cmin 0.1 H Time (days) FIG. 1 Patent Application Publication Jan. 21, 2010 Sheet 2 of 5 US 2010/OO15228A1 1OOOO / 7 L 1000 W / 100 W/ 10 1/ 2 3 4 5 6 Percent CMC, by Weight-o- FIG. 2 Patent Application Publication Jan. 21, 2010 Sheet 3 of 5 US 2010/OO15228A1 100,000so III. toogoo,| 50,000 ep | 15,000 H / 15,000 I AV 40 /M l s s || //M Y /Q Ht-1 L 21 t % METHOCEL Cellulose Ether FIG. 3 Patent Application Publication Jan. 21, 2010 Sheet 4 of 5 US 2010/OO15228A1 Semi circular Canals eliptical window pinna Circular Window 1-1 Vestibular nerve malleuS - auditory nerve COChlea tympanic cavity tympanic membrane auditory (eardrum) Stapes euStaChian tube Canal FIG. 4 Patent Application Publication Jan. 21, 2010 Sheet 5 of 5 US 2010/OO15228A1 1000 Non-micronized otic agent 10 Solution Micronized otic agentSolution Non-micronized Otic agent + gelling agent Crmin Micronized otic agent+ gelling agent Time (days) FIG. 5 US 2010/0015228A1 Jan. 21, 2010 CONTROLLED RELEASE ON CHANNEL nel agonist or antagonist. In some embodiments, the agonist MODULATOR COMPOSITIONS AND of a potassium channel is nicorandil; minoxidil, levcro METHODS FOR THE TREATMENT OF OTC makalim; lemakalim; cromakalim; L-735,334; retigabine; DISORDERS flupirtine; BMS-204352: DMP-543; or combinations thereof. In some embodiments, the antagonist of a potassium channel CROSS-REFERENCE is linopirdine; XE991: 4-AP: 3,4-DAP; E-4031: DIDS: Way 123,398; CGS-12066A: dofetilide; Sotalol; apamin; amio 0001. This patent application claims the benefit of U.S. darone; azimilide; bretylium; clofilium; tedisamil: ibutilide; Provisional Application Ser. No. 61/082,450 filed Jul. 21, sematilide; nifekalant; tamulustoxin; or combinations 2008; U.S. Provisional Application Ser. No. 61/088,275 filed thereof. In some embodiments, the ion channel modulator is Aug. 12, 2008; U.S. Provisional Application Ser. No. 61/094, a purigenic receptor agonist or antagonist. In some embodi 384 filed Sep. 4, 2008; U.S. Provisional Application Ser. No. ments, the agonist of a purigenic receptor is ATP; ADP; UTP: 61/101,112 filed Sep. 29, 2008; and U.S. Provisional Appli UDP, UDP-glucose: adenosine: 2-MeSATP; 2-MeSADP; cation Ser. No. 61/140,033 filed Dec. 22, 2008; all of which ofmeATP, dATPCS: ATPYS; Bz-ATP, MRS2703; denufosol are incorporated by reference herein in their entirety. tetrasodium; MRS2365; MRS 2690; PSB 0474; or combina tions thereof. In some embodiments, the antagonist of a puri BACKGROUND OF THE INVENTION genic receptor is A-3 17491; RO-3 (Roche); Suramin; PPADS: 0002 Vertebrates have a pair of ears, placed symmetri PPNDS; DIDS; pyridoxal-5-phosphate, 5-(3-bromophenyl)- cally on opposite sides of the head. The ear serves as both the 1,3-dihydro-2H-benzofuro-3,2-e-1,4-diazepin-2-one: ciba sense organ that detects Sound and the organ that maintains cron blue; basilen blue; ivermectin: A-438079; A-74.0003: balance and body position. The ear is generally divided into NF023; NF449; NF110, NF157; MRS 2179; NF279; MRS three portions: the outer ear, auris media (or middle ear) and 2211; MRS 2279; MRS 2500 tetrasodium salt; TNP-ATP: the auris interna (or inner ear). tetramethylpyrazine; IpsI: By-carboxymethylene ATP: By-chlorophosphomethylene ATP; KN-62; spinorphin; or SUMMARY OF THE INVENTION combinations thereof. 0003. Described herein are compositions, formulations, 0007. In one aspect, the controlled release composition manufacturing methods, therapeutic methods, uses, kits, and further comprises an additional therapeutic agent, including a delivery devices for the controlled release of desired agents to diuretic, an anti-emetic agent, an anti-vertigo agent, an anti at least one structure or region of the ear. anxiety agent, a corticosteroid, an anti-histamine or combi 0004 Controlled release formulations are disclosed nations thereof. In some embodiments, the composition fur hereinfordelivering ion channel modulating agents to the ear. ther comprises a modulator of ion channels as an immediate In some embodiments, the ion channel modulating agents release agent wherein the immediate release modulator of ion target fluid homeostasis control in the inner ear, or auris channels is the same agent as the controlled-release agent, a interna. In other embodiments the ion channel modulating different modulator of ion channels, an additional therapeutic agents target fluid homeostasis control in the middle ear, or agent, or a combination thereof. In some embodiments, the auris media. In some embodiments, the ion channel modula additional therapeutic agent is an immediate release agent. In tors are KCNQ channel modulators or P2X receptor modu Some embodiments, the additional therapeutic agent is a con lators. In some embodiments, the ion channel modulators are trolled release agent. epithelial sodium channel (ENaC) modulators or Na/K 0008 Disclosed herein are controlled release formula ATPase modulators. In some embodiments, the ion channel tions for delivering an ion channel modulating agent to the modulating agents are inhibitors of KCNO channel or P2X ear. In some embodiments, the composition is administered receptor function in the ear. In some embodiments, the ion so that the composition is in contact with the crista fenestrae channel modulating agents are inhibitors of ENaC modula cochleae, the round window or the tympanic cavity. In one tors or Na/K ATPase function in the ear. In some embodi aspect the composition is administered by intratympanic ments, the controlled release formulations further comprise a injection. rapid or immediate release component for delivering ion 0009. The auris formulations and therapeutic methods channel modulating agents to the auris interna. All formula described herein have numerous advantages that overcome tions comprise excipients that are auris-interna acceptable. the previously-unrecognized limitations of formulations and 0005 Also disclosed herein are methods and composi therapeutic methods described in prior art. tions for the treatment of otic disorders by administration of 0010 Sterility controlled release formulations comprising ion channel 0011. The environment of the inner ear is an isolated envi modulating agents. In some embodiments, the otic disorder is ronment. The endolymph and the perilymph are static fluids a fluid homeostasis disorder. Also disclosed herein is the local and are not in contiguous contact with the circulatory system. delivery of controlled release ion channel modulating com The blood labyrinth barrier (BLEB), which includes a positions and formulations to Suppress or ameliorate auditory blood-endolymph barrier and a blood-perilymph barrier, con and vestibular impairment as a result of a fluid homeostasis sists of tight junctions between specialized epithelial cells in disorder, such as Meniere's disease. In another aspect, the the labyrinth spaces (i.e., the vestibular and cochlear spaces). composition is administered so that the composition is in The presence of the BLB limits delivery of active agents (e.g., contact with the crista fenestrae cochleae, the round window ion channel modulating agents) to the isolated microenviron or the tympanic cavity. ment of the inner ear. Auris hair cells are bathed in endolym 0006. In some embodiments, the ion channel modulating phatic or perilymphatic fluids and cochlear recycling of agent has limited or no systemic release, systemic toxicity, potassium ions is important for hair cell function. When the poor pK characteristics,