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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 29 October 2009 (29.10.2009) WO 2009/132050 A2 (51) International Patent Classification: 61/101,1 12 29 September 2008 (29.09.2008) US A61K 39/395 (2006.01) A61K 47/34 (2006.01) 61/140,033 22 December 2008 (22. 12.2008) US A61P 27/16 (2006.01) A61K 9/06 (2006.01) 61/160,233 13 March 2009 (13.03.2009) US (21) International Application Number: (71) Applicants (for all designated States except US): OTON- PCT/US2009/041320 OMY, INC. [US/US]; 5626 Oberlin Drive, Suite 100, San Diego, CA 92121 (US). THE REGENTS OF THE (22) International Filing Date: UNIVERSITY OF CALIFORNIA [US/US]; 1111 2 1 April 2009 (21 .04.2009) Franklin Street, 12th Floor, Oakland, CA 94607 (US). (25) Filing Language: English (72) Inventors; and (26) Publication Language: English (75) Inventors/Applicants (for US only): LICHTER, Jay [US/US]; P.O. Box 676244, Rancho Santa Fe, CA 92067 (30) Priority Data: (US). VOLLRATH, Benedikt [DE/US]; 4704 Niagara 61/046,543 2 1 April 2008 (21 .04.2008) US Avenue, San Diego, CA 92107 (US). TRAMMEL, An¬ 61/048,878 29 April 2008 (29.04.2008) US drew, M. [US/US]; 12485 South Alden Circle, Olathe, 61/127,7 13 14 May 2008 (14.05.2008) us KS 66062 (US). DURON, Sergio, G. [US/US]; 1605 61/055,625 23 May 2008 (23.05.2008) us Neale Street, San Diego, CA 92103 (US). PIU, Fabrice 61/060,425 10 June 2008 (10.06.2008) us [FR/US]; 11859 Stonedale Ct., San Diego, CA 92131 61/073,7 16 18 June 2008 (18.06.2008) us (US). DELLAMARY, Luis, A. [US/US]; 829 Quiet Hills 61/074,583 20 June 2008 (20.06.2008) us Dr, San Marcos, CA 92069 (US). YE, Qiang [US/US]; 61/076,576 27 June 2008 (27.06.2008) us 7395 Mannix Court, San Diego, CA 92129 (US). 61/076,567 27 June 2008 (27.06.2008) us LEBEL, Carl [US/US]; 23256 Mariposa De Oro St., 61/082,450 2 1 July 2008 (21 .07.2008) us Malibu, CA 90265 (US). SCAIFE, Michael, Christo¬ 61/083,871 25 July 2008 (25.07.2008) us pher [US/US]; 60 Marvin Avenue, Los Altos, CA 94022 61/083,830 25 July 2008 (25.07.2008) us 61/086,105 4 August 2008 (04.08.2008) us (US). HARRIS, Jeffrey, P. [US/US]; 7717 Sierra Mar 61/086,094 4 August 2008 (04.08.2008) us Drive, La Jolla, CA 92037 (US). 61/087,905 11 August 2008 ( 11.08.2008) us (74) Agents: AKHAVAN, Ramin et al; 650 Page Mill Road, 61/087,951 11 August 2008 ( 11.08.2008) us Palo Alto, CA 94304 (US). 61/088,275 12 August 2008 (12.08.2008) us 61/094,384 4 September 2008 (04.09.2008) us [Continued on nextpage] (54) Title: AURIS FORMULATIONS FOR TREATING OTIC DISEASES AND CONDITIONS (57) Abstract: Disclosed herein are compositions and methods for the treatment of otic disorders with immunomodulating agents and auris pressure modulators. In these methods, the auris compositions and formulations are administered locally to an individual afflicted with an otic disorder, through direct application of the immunomodulating and/or auris pressure modulating composi tions and formulations onto the auris media and/or auris interna target areas, or via perfusion into the auris media and/or auris in terna structures. (81) Designated States (unless otherwise indicated, for every GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, kind of national protection available): AE, AG, AL, AM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MR, NE, SN, TD, TG). MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, Published: NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, — without international search report and to be republished UG, US, UZ, VC, VN, ZA, ZM, ZW. upon receipt of that report (Rule 48.2(g)) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, AURIS FORMULATIONS FOR TRE-VTING OTIC DISEASES AND CONDITIONS RELATED APPUCATIONS [0001] This patent application claims the benefit of U.S. Provisional Application Ser. Nos. 61/087,905, filed on August 11, 2008, 61/055,625 filed on May 23, 2008, 61/086,105 filed on August 04, 2008, 61/073,716 filed on June 18, 2008 61/140,033 filed on December 22, 2008, 61/127,713 filed on May 14, 2008, 61/101,1 12 filed on September 29, 2008, 61/094,384 filed on September 04, 2008, 61/074,583 filed on June 20, 2008, 61/060,425 filed on June 10, 2008, 61/048,878 filed on April 29 2008, 61/046,543 filed on April 2 1, 2008, 61/076,567 filed on June 27, 2008, 61/076,576 filed on June 27, 2008, 61/160,233 filed on March 13, 2009, 61/086,094 filed on August 04, 2008, 61/083,830 filed on July 25, 2008. 61/083,871 filed on July 25, 2008, 61/087,951 filed on August 11, 2008, 61/088,275 filed on August 12, 2008, the disclosures of all of which are herein incorporated by reference in their entirety. BACKGROUND OF THE INVENTION [0002] Described herein are formulations for enhanced drug delivery into the external, middle and/or inner ear, including the cochlea and vestibular labyrinth; preferably with little or no systemic release of the drug. SUMMARY OF THE INVENTION 10003} The auris formulations and therapeutic methods described herein have numerous advantages that overcome the previously-unrecognized limitations of formulations and therapeutic methods described io prior art. Sterility [0004] The environment of the inner ear is an isolated environment. The endolymph and the perilymph are static fluids and are not in contiguous contact with the circulatory system. The blood - labyrinth - barrier (BLB), which includes a blood-endolymph barrier and a blood-perilymph barrier, consists of tight junctions between specialized epithelial cells i the labyrinth spaces (i.e., the vestibular and cochlear spaces). The presence of the BLB limits delivery of active agents (e.g., imraunomodulators, aural pressure modulators, antimicrobials) to the isolated microenvironment of the inner ear. Aaris hair cells are bathed in endolymphatic or perilymphatic fluids and cochlear recycling of potassium ions is important for hair cell function. When the inner ear is infected, there is n influx of leukocytes and/or immunoglobins (e.g. in response to a microbial infection) into the endolymph and/or the perilymph and the delicate ionic composition of inner ear fluids is upset by the influx of leukocytes and/or immunoglobins. In certain instances, a change in the ionic composition of inner ear fluids results in hearing loss, loss of balance and/or ossification of auditory structures. In certain instances, even trace amounts of pyrogens and/or microbes can trigger infections and related physiological changes in the isolated microenvironment of the inner ear. [0005] Due to the susceptibilty of the inner ear to infections, auris formulations require a level of sterility that has not been recognized hitherto in prior art. Provided herein are auris formulations that are sterilized with stringent sterilty requiremenls and are suitable for administration to the middle and/or inner ear. In some embodiments, the auris compatible compositions described herein are substantially free of pyrogens and/or microbes. Compatibility with Inner Ear Environment [00061 Described herein are otic formulations with an ionic balance that is compatible with the perilymph and/or the endolymph and does not cause any change in cochlear potential . In specific embodiments, osmolarity/osraolality of the present formulations is adjusted, for example, by the use of appropriate salt concentrations (eg,, concentration of sodium salts) or the use of tonicity agents which renders, the formulations endolyrαph-compatibie and/or perilymph-compatible (i.e. isotonic with the endolymph and/or perilymph). In some instances, the endolymph-compatible and/or perilymph-compatible formulations described herein cause minimal disturbance to the environment of the inner ear and cause minimum discomfort (e.g, vertigo) to a mammal (e.g., a human) upon adminstration. Further, the formulations comprise polymers that are biodegradable and/or dispersable, and/or otherwise non-toxic to the inner ear environment. In some embodiments, the formulations described herein are free of preservatives and cause minimal disturbance (e.g., change in pH or osmolality, irritation) in auditory structures, In some embodiments, the formulations described herein comprise antioxidants that are non-irritating and/or non-toxic to otic structures. Dosing Frequency [0007] The current standard of care for auris formulations requires multiple administrations of drops or injections (e.g. intratympauie injections) over several days (e.g., up to two weeks), including schedules of receiving multiple injections per day.
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    British Journal of DOI:10.1111/bph.12787 www.brjpharmacol.org BJP Pharmacology Themed Section: Animal Models in Psychiatry Research Correspondence Jeffrey W Dalley, Department of Psychology, University of REVIEW Cambridge, Downing St, Cambridge CB2 3EB, UK. E-mail: [email protected] Convergent ---------------------------------------------------------------- Received 20 February 2014 pharmacological Revised 2 May 2014 Accepted mechanisms in impulsivity 12 May 2014 and addiction: insights from rodent models B Jupp1,2 and J W Dalley1,3 1Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK, 2Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia, and 3Department of Psychiatry, University of Cambridge, Cambridge, UK Research over the last two decades has widely demonstrated that impulsivity, in its various forms, is antecedent to the development of drug addiction and an important behavioural trait underlying the inability of addicts to refrain from continued drug use. Impulsivity describes a variety of rapidly and prematurely expressed behaviours that span several domains from impaired response inhibition to an intolerance of delayed rewards, and is a core symptom of attention deficit hyperactivity disorder (ADHD) and other brain disorders. Various theories have been advanced to explain how impulsivity interacts with addiction both causally and as a consequence of chronic drug abuse; these acknowledge the strong overlaps in neural circuitry and mechanisms between impulsivity and addiction and the seemingly paradoxical treatment of ADHD with stimulant drugs with high abuse potential. Recent years have witnessed unprecedented progress in the elucidation of pharmacological mechanisms underpinning impulsivity. Collectively, this work has significantly improved the prospect for new therapies in ADHD as well as our understanding of the neural mechanisms underlying the shift from recreational drug use to addiction.