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(12) Patent Application Publication (10) Pub. No.: US 2014/0364510 A1 Lichter Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0364510 A1 Lichter Et Al US 20140364510A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0364510 A1 Lichter et al. (43) Pub. Date: Dec. 11, 2014 (54) CONTROLLED RELEASE AURAL PRESSURE filed on Jun. 20, 2008, provisional application No. MODULATOR COMPOSITIONS AND 61/082,450, filed on Jul. 21, 2008, provisional appli METHODS FOR THE TREATMENT OF OTC cation No. 61/086,105, filed on Aug. 4, 2008, provi DSORDERS sional application No. 61/094,384, filed on Sep. 4, 2008, provisional application No. 61/101,112, filed on (71) Applicants: Otonomy, Inc., San Diego, CA (US); Sep. 29, 2008, provisional application No. 61/140,033, The Regents of the University of filed on Dec. 22, 2008. California, Oakland, CA (US) Publication Classification (72) Inventors: Jay Lichter, Rancho Santa Fe, CA (US); Andrew M. Trammel, Olathe, KS (US); (51) Int. C. Fabrice Piu, San Diego, CA (US); A647/34 (2006.01) Qiang Ye, San Diego, CA (US); Michael A 6LX3/5377 (2006.01) Christopher Scaife, Los Altos, CA 469/14 (2006.01) (US); Benedikt Vollrath, San Diego, CA A 6LX3/557 (2006.01) (US); Sergio G. Duron, San Diego, CA (52) U.S. C. (US); Luis A. Dellamary, San Marcos, CPC ............. A61K 47/34 (2013.01); A61 K3I/5517 CA (US); Carl Lebel, Malibu, CA (US); (2013.01); A61 K3I/5377 (2013.01); A61 K Jeffrey P. Harris, La Jolla, CA (US) 9/14 (2013.01) USPC ....................................................... 514/772.1 (21) Appl. No.: 14/465,153 (57) ABSTRACT (22) Filed: Aug. 21, 2014 Disclosed herein are compositions and methods for the treat Related U.S. Application Data ment of otic diseases or conditions with aural pressure modu lating agent compositions and formulations administered (63) Continuation of application No. 12/486,697, filed on locally to an individual afflicted with an otic disease or con Jun. 17, 2009, now Pat. No. 8,846,770. dition, through direct application of these compositions and (60) Provisional application No. 61/073,716, filed on Jun. formulations onto or via perfusion into the targeted auris 18, 2008, provisional application No. 61/074,583, structure(s). Patent Application Publication Dec. 11, 2014 Sheet 1 of 4 US 2014/0364510 A1 1000 - Non-Sustained release 100---------------------------------------------------- Cmax -- Sustained release W as s 10 s s -- Bimodal release Time (days) FIG. 1 Patent Application Publication Dec. 11, 2014 Sheet 2 of 4 US 2014/0364510 A1 10000 7 L 1000 % / 100 /// 10 1/ 2 3 4 5 6 |Percent CMC, by weight-o- FIG. 2 Patent Application Publication Dec. 11, 2014 Sheet 3 of 4 US 2014/0364510 A1 100,000so II || || | | | | | | | || | 10:0// / / / 50,000 of / 7 | | | I//i?/ML). / / / 400 / / I/// 7 50 III///IMY / / / / / ZY M / III/// 4Z 1. t Y e 1 M/ an // 1 1 e Y 21Y - 10 2241 1.sal 3 4 5 6 7 % METHOCEL Cellulose Ether FIG. 3 Patent Application Publication Dec. 11, 2014 Sheet 4 of 4 US 2014/0364510 A1 Semi Circular Canals eliptical window pinna Circular window -vestibular nerve malleuS 1- auditory nerve COChlea tympanic cavity tympanic membrane auditory (eardrum) Stapes eustachian tube Canal FIG. 4 US 2014/03.64510 A1 Dec. 11, 2014 CONTROLLED RELEASE AURAL PRESSURE is administered so that the composition is in contact with the MODULATOR COMPOSITIONS AND crista fenestrae cochleae, the round window or the tympanic METHODS FOR THE TREATMENT OF OTC cavity. DISORDERS 0006 Disclosed herein are controlled release formula tions for delivering an aural pressure modulating agent to the CROSS-REFERENCE ear. In some embodiments, the target portion of the ear is the middle ear or auris media. In some embodiments, the target 0001. This application claims the benefit of U.S. patent portion of the ear is the inner ear, or auris interna. In other application Ser. No. 12/486,697, filed Jun. 17, 2009; which embodiments, the target portion of the ear is both the auris claims benefite of Provisional Application No. 61/073,716 media and the auris interna. filed Jun. 18, 2008, U.S. Provisional Application No. 61/074, 0007. The auris formulations and therapeutic methods 583 filed Jun. 20, 2008, U.S. Provisional Application No. described herein have numerous advantages that overcome 61/082,450 filed Jul. 21, 2008, U.S. Provisional Application the previously-unrecognized limitations of formulations and No. 61/086,105 filed Aug. 4, 2008, U.S. Provisional Appli therapeutic methods described in prior art. cation No. 61/094,384 filed Sep. 4, 2008, U.S. Provisional Application No. 61/101,112 filed Sep. 29, 2008, and U.S. 0008 Sterility 0009. The environment of the inner ear is an isolated envi Provisional Application No. 61/140,033 filed Dec. 22, 2008, ronment. The endolymph and the perilymph are static fluids all of which are incorporated herein in their entirety. and are not in contiguous contact with the circulatory system. The blood labyrinth barrier (BLEB), which includes a BACKGROUND OF THE INVENTION blood-endolymph barrier and a blood-perilymph barrier, con 0002 Vertebrates have a pair of ears, placed symmetri sists of tight junctions between specialized epithelial cells in cally on opposite sides of the head. The ear serves as both the the labyrinth spaces (i.e., the vestibular and cochlear spaces). sense organ that detects Sound and the organ that maintains The presence of the BLB limits delivery of active agents (e.g., balance and body position. The ear is generally divided into aural pressure modulators) to the isolated microenvironment three portions: the outer ear, auris media (or middle ear) and of the inner ear. Auris hair cells are bathed in endolymphatic the auris interna (or inner ear). or perilymphatic fluids and cochlear recycling of potassium ions is important for hair cell function. When the inner ear is SUMMARY OF THE INVENTION infected, there is an influx of leukocytes and/or immunoglo bins (e.g. in response to a microbial infection) into the 0003. Described herein are compositions, formulations, endolymph and/or the perilymph and the delicate ionic com manufacturing methods, therapeutic methods, uses, kits, and position of inner ear fluids is upset by the influx of leukocytes delivery devices for the controlled release or delivery of at and/or immunoglobins. In certain instances, a change in the least one aural pressure modulating agent to at least one ionic composition of inner ear fluids results in hearing loss, structure or region of the ear. loss of balance and/or ossification of auditory structures. In 0004. In some embodiments, the aural pressure modulat certain instances, even trace amounts of pyrogens and/or ing agents target imbalance in aural pressure in the ear. In microbes can trigger infections and related physiological Some embodiments, the aural pressure modulating agents changes in the isolated microenvironment of the inner ear. target fluid homeostasis control in the inner ear, or auris 0010. Due to the susceptibility of the inner ear to infec interna. In other embodiments, the aural pressure modulating tions, auris formulations require a level of sterility (e.g., low agents target fluid homeostasis control in the middle ear, or bioburden) that has not been recognized hitherto in prior art. auris media. In some embodiments, the aural pressure modu Provided herein are auris formulations that are manufactured lators are vasopressin receptor modulators, prostaglandins or with low bioburden or sterilized with stringent sterilty estrogen-related receptor modulators. In some embodiments, requirements and are suitable for administration to the middle the aural pressure modulating agents are inhibitors of vaso and/or inner ear. In some embodiments, the auris compatible pressin receptor function, prostaglandin receptor orestrogen compositions described herein are substantially free of pyro related receptor function in the ear. In some embodiments, the gens and/or microbes. aural pressure modulating agents are osmotic diuretic agents. 0011 Compatibility with Inner Ear Environment In some embodiments, the controlled release formulations 0012. Described herein are otic formulations with an ionic further comprise a rapid or immediate release component for balance that is compatible with the perilymph and/or the delivering aural pressure modulating agents to the auris endolymph and does not cause any change in cochlear poten interna. All formulations comprise excipients that are auris tial. In specific embodiments, osmolarity/oSmolality of the interna acceptable. present formulations is adjusted, for example, by the use of 0005 Also disclosed herein are methods and composi appropriate salt concentrations (e.g., concentration of sodium tions for the treatment of otic diseases or conditions associ salts) or the use of tonicity agents which renders the formu ated with an imbalance in aural pressure by administration of lations endolymph-compatible and/or perilymph-compatible controlled release formulations comprising aural pressure (i.e. isotonic with the endolymph and/or perilymph). In some modulating agents. In some embodiments, the otic disease or instances, the endolymph-compatible and/or perilymph condition associated with an imbalance in aural pressure is a compatible formulations described herein cause minimal dis fluid homeostasis disorder. Also disclosed herein is the local turbance to the environment of the inner ear and cause mini delivery of controlled release aural pressure modulating com mum discomfort (e.g., vertigo) to a mammal (e.g., a human) positions and formulations to Suppress or ameliorate auditory upon administration. Further, the formulations comprise and vestibular impairment as a result of an imbalance inaural polymers that are biodegradable and/or dispersable, and/or pressure and/or imbalance in fluid homeostasis in the ear, otherwise non-toxic to the inner ear environment. In some Such as Meniere's disease. In another aspect, the composition embodiments, the formulations described herein are free of US 2014/03.64510 A1 Dec. 11, 2014 preservatives and cause minimal disturbance (e.g., change in auris-acceptable foam, an auris-acceptable microsphere or pH or osmolarity, irritation) in auditory structures.
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