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(12) Patent Application Publication (10) Pub. No.: US 2009/0324552 A1 LCHTER Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0324552 A1 LCHTER Et Al US 20090324552A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0324552 A1 LCHTER et al. (43) Pub. Date: Dec. 31, 2009 (54) CONTROLLED RELEASE CYTOTOXIC (21) Appl. No.: 12/493,611 AGENT COMPOSITIONS AND METHODS FOR THE TREATMENT OF OTC (22) Filed: Jun. 29, 2009 DSORDERS Related U.S. Application Data (75) Inventors: Jay LICHTER, Rancho Santa Fe, CA (US); Benedikt VOLLRATH, (60) Provisional application No. 61/076,576, filed on Jun. San Diego, CA (US); Sergio G. 27, 2008, provisional application No. 61/082,450, DURON, San Diego, CA (US); filed on Jul. 21, 2008, provisional application No. Carl LEBEL, Malibu, CA (US); 61/094,384, filed on Sep. 4, 2008, provisional applica Fabrice PIU, San Diego, CA (US); tion No. 61/101,112, filed on Sep. 29, 2008, provi Qiang YE, San Diego, CA (US); sional application No. 61/140,033, filed on Dec. 22, Luis A. DELLAMARY, San 2008. Marcos, CA (US); Andrew M. TRAMMEL, Olathe, KS (US); Publication Classification Michael Christopher SCAIFE, (51) Int. Cl. Los Altos, CA (US); Jeffrey P. A6II 35/74 (2006.01) HARRIS, La Jolla, CA (US) (52) U.S. Cl. ....................................................... 424/93.4 Correspondence Address: WILSON, SONSINI, GOODRICH & ROSATI (57) ABSTRACT 650 PAGE MILL ROAD PALO ALTO, CA 94304-1050 (US) Disclosed herein are compositions and methods for the treat ment of otic diseases or conditions with cytotoxic agent com (73) Assignees: OTONOMY, INC., San Diego, CA positions and formulations administered locally to an indi (US): THE REGENTS OF THE vidual afflicted with an otic disease or condition, through UNIVERSITY OF direct application of these compositions and formulations CALIFORNLA, Oakland, CA (US) onto or via perfusion into the targeted auris structure(s). Patent Application Publication Dec. 31, 2009 Sheet 1 of 4 US 2009/0324552 A1 Figure 1 i: www.www.www.www.ww. :38-3:8:8::s: Si:388 - - - - - - - - - - - - - - - - - - ------------- 3:38 Ya-- 8:::::::::::::::::: :: :: i.e. 88ays Patent Application Publication Dec. 31, 2009 Sheet 2 of 4 US 2009/0324552 A1 Figure 2 Patent Application Publication Dec. 31, 2009 Sheet 3 of 4 US 2009/0324552 A1 Figure 3 180,000 rp-poorr;" I 8 : 8 5.0 - 8, 838 war i:8:8 &- H l/ : isi 3.30 XX III,// A. (3)C. : f s / // 8. T8::::::::::8::::::: Patent Application Publication Dec. 31, 2009 Sheet 4 of 4 US 2009/0324552 A1 Figure 4 Se::::::::::ia: Ea:8:S 3. 8:3tia sixties: g888 y&S:::::::3:33:38a -- &:38:y 388 3883 tygaga is cavity ty spanie rest are 388x3:y 23:3: Stages 8:S388:38: 8:8 &3:8: US 2009/0324552 A1 Dec. 31, 2009 CONTROLLED RELEASE CYTOTOXC closed herein include acridine carboxamide, actinomycin, AGENT COMPOSITIONS AND METHODS 17-N-allylamino-17-demethoxygeldanamycin, amsacrine, FOR THE TREATMENT OF OTC aminopterin, anthracycline, antineoplastic, antineoplaston, DISORDERS 5-azacytidine, azathioprine, BL22, bendamustine, biricodar, bleomycin, bortezomib. bryostatin, buSulfan, calyculin, CROSS-REFERENCE camptothecin, capecitabine, carboplatin, chlorambucil, cispl atin, cladribine, clofarabine, cytarabine, dacarbazine, dasat 0001. This application claims the benefit of U.S. Provi inib, daunorubicin, decitabine, dichloroacetic acid, discoder sional Application No. 61/076,576 filed Jun. 27, 2008, U.S. mollide, docetaxel, doxorubicin, epirubicin, epothilone, Provisional Application No. 61/082,450 filed Jul. 21, 2008, eribulin, estramustine, etoposide, exatecan, exisulind, fer U.S. Provisional Application No. 61/094,384 filed Sep. 4, ruginol, floxuridine, fludarabine, fluorouracil, fosfestrol, 2008, U.S. Provisional Application No. 61/101,112 filed Sep. fotemustine, gemcitabine, hydroxyurea, IT-101. idarubicin, 29, 2008, and U.S. Provisional Application No. 61/140,033 ifosfamide, imiquimod, irinotecan, irofulven, ixabepilone, filed Dec. 22, 2008, all of which are incorporated herein in laniquidar, lapatinib, lenalidomide, lomustine, lurtotecan, their entirety. mafosfamide, masoprocol, mechlorethamine, melphalan, mercaptopurine, mitomycin, mitotane, mitoxantrone, nelara BACKGROUND OF THE INVENTION bine, nilotinib, oblimersen, oxaliplatin, PAC-1, paclitaxel, 0002 Vertebrates have a pair of ears, placed symmetri pemetrexed, pentostatin, pipobroman, pixantrone, plicamy cally on opposite sides of the head. The ear serves as both the cin, procarbazine, proteasome inhibitors (e.g., bortezomib), sense organ that detects Sound and the organ that maintains raltitrexed, rebeccamycin, rubitecan, SN-38, salinospora balance and body position. The ear is generally divided into mide A, satraplatin, Streptozotocin, Swainsonine, tariquidar, three portions: the outer ear, auris media (or middle ear) and taxane, tegafur-uracil, temozolomide, testolactone, the auris interna (or inner ear). thioTEPA, tioguanine, topotecan, trabectedin, tretinoin, tri platin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, SUMMARY OF THE INVENTION uracil mustard, valrubicin, vinblastine, Vincristine, Vinorel 0003. Described herein are compositions, formulations, bine, Vorinostat, and ZoSuquidar. Also disclosed herein is the manufacturing methods, therapeutic methods, uses, kits, and local delivery of controlled release cytotoxic agent composi delivery devices for the controlled release or delivery of at tions and formulations to suppress or ameliorate auditory and least one cytotoxic agent to at least one structure or region of vestibular impairment as a result of AIED, which may be the ear. In certain embodiments, the cytotoxic agent is an provoked by other autoimmune conditions, including Anky antimetabolite, an antifolate, an alkylating agent and/or a losing Spondylitis, Systemic Lupus Erythematosis (SLE), DNA intercalator. In certain embodiments, the cytotoxic Sjögren's Syndrome, Cogan's disease, ulcerative colitis, agent is a protein, an antibody, DNA, a carbohydrate, an Wegener's granulomatosis, rheumatoid arthritis, Scleroderma inorganic compound, or an organic compound. In certain and Behcet's disease (also known as Bechet's disease and embodiments, the cytotoxic agent is an organic Small mol adamantiades). In other embodiments, the otic disorder is ecule. In certain specific embodiments, the cytotoxic Small otitis media. molecule is methotrexate, cyclophosphamide, or thalido 0007. In some embodiments, the compositions described mide, a metabolite, salt, polymorph, prodrug, analogue, or herein are administered so that the composition is in contact derivative thereof. In certain embodiments, preferred with the crista fenestrae cochleae, the round window or the metabolites of cyclophosphamide are 4-hydroxycyclophos tympanic cavity. phamide, aldophosphamide, phosphoramide mustard, and 0008. The auris formulations and therapeutic methods combinations thereof. described herein have numerous advantages that overcome 0004. In some embodiments, the target portion of the ear is the previously-unrecognized limitations of formulations and the middle ear or auris media. In other embodiments, the therapeutic methods described in prior art. target portion of the ear is the inner ear, or auris interna. In 0009 Sterility other embodiments, the target portion of the ear is the middle 0010. The environment of the inner ear is an isolated envi ear, or auris media. In still other embodiments, the target ronment. The endolymph and the perilymph are static fluids portion of the ear is both the auris media and the auris interna. and are not in contiguous contact with the circulatory system. In some embodiments, the controlled release formulations The blood-labyrinth-barrier (BLEB), which includes a blood further comprise a rapid or immediate release component for endolymph barrier and a blood-perilymph barrier, consists of delivering a cytotoxic agent to the auris media and/or the auris tight junctions between specialized epithelial cells in the interna. All formulations comprise excipients that are auris labyrinth spaces (i.e., the vestibular and cochlear spaces). The media and/or auris-interna acceptable. presence of the BLB limits delivery of active agents (e.g., 0005 Also disclosed herein are methods for inducing cytotoxic agents) to the isolated microenvironment of the selective cellular toxicity within the auris media or auris inner ear. Auris hair cells are bathed in endolymphatic or interna comprising administration of the cytotoxic agent con perilymphatic fluids and cochlear recycling of potassium ions trolled release formulations described herein. is important for hair cell function. When the inner ear is 0006. Also disclosed herein are methods for the treatment infected, there is an influx of leukocytes and/or immunoglo of otic disorders comprising administration of cytotoxic bins (e.g. in response to a microbial infection) into the agent controlled release formulations. In some embodiments, endolymph and/or the perilymph and the delicate ionic com the otic disorder is an autoimmune inner ear disease (AIED). position of inner ear fluids is upset by the influx of leukocytes In other embodiments, the otic disorder is cancer of the ear. and/or immunoglobins. In certain instances, a change in the Cytotoxic agents that are also suitable for the treatment of ionic composition of inner ear fluids results in hearing loss, cancer of the ear in the formulations and compositions dis loss of balance and/or ossification of auditory structures. In US 2009/0324552 A1 Dec. 31, 2009 certain instances, even trace amounts of pyrogens and/or totoxicity, cardiotoxicity, gastrointestinal side effects, renal microbes can trigger infections and related physiological
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