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„ Wo 2011/049958 A2 (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 28 April 2011 (28.04.2011) WO 2011/049958 A2 (51) International Patent Classification: (74) Agents: WILSON SONSINI GOODRICH & ROSATI A61K 47/34 (2006.01) A61K 9/06 (2006.01) et al; 650 Page Mill Road, Palo Alto, California 94304 A61K 47/30 (2006.01) A61P 27/16 (2006.01) (US). A61K 31/56 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US2010/053214 AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 19 October 2010 (19.10.2010) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (25) Filing Language: English KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (26) Publication Langi English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (30) Priority Data: SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 61/253,782 2 1 October 2009 (21 .10.2009) US TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 61/255,379 27 October 2009 (27. 10.2009) US (84) Designated States (unless otherwise indicated, for every 61/255,783 28 October 2009 (28. 10.2009) us kind of regional protection available): ARIPO (BW, GH, 61/255,780 28 October 2009 (28. 10.2009) us GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 61/297,1 70 2 1 January 2010 (21 .0 1.2010) us ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 61/297,1 38 2 1 January 2010 (21 .0 1.2010) us TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 61/364,288 14 July 2010 (14.07.2010) us EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 61/366,677 22 July 2010 (22.07.2010) us LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (71) Applicant (for all designated States except US): OTON- SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, OMY, INC. [US/US]; 5626 Oberlin Drive, Suite 100, GW, ML, MR, NE, SN, TD, TG). San Diego, California 92 121 (US). Declarations under Rule 4.17 : (72) Inventors; and — as to applicant's entitlement to apply for and be granted (75) Inventors/Applicants (for US only): YE, Qiang a patent (Rule 4.1 7(H)) [US/US]; 13484 El Presidio Trail, San Diego, California — as to the applicant's entitlement to claim the priority of 92130 (US). DELLAMARY, Luis, A. [US/US]; 829 the earlier application (Rule 4.17(Hi)) Quiet Hills Dr, San Marcos, California 92069 (US). PIU, Fabrice [FR/US]; 11859 Stonedale C , San Diego, Cali Published: fornia 921 3 1 (US). — without international search report and to be republished upon receipt of that report (Rule 48.2(g)) ∞< © o (54) Title: MODULATION OF GEL TEMPERATURE OF POLOXAMER-CONTAINING FORMULATIONS (57) Abstract: Disclosed herein are methods for modulation of gel temperature of poloxamer-containing formulations. Also de scribed herein are sustained release pharmaceutical formulations that gel upon contact with the body and are administered by di rect application of these compositions and formulations onto or via perfusion into the targeted structure(s). MODULATION OF GEL TEMPERATURE OF POLOXAMER-CONTAINING FORMULATIONS CROSS-REFERENCE [0001] This patent application claims the benefit of U.S. Provisional Application Ser. No. 61/253,782 filed October 2 1, 2009: U.S. Provisional Application Ser. No. 61/255,379 filed October 27, 2009;U.S. Provisional Application Ser. No. 61/255,780 filed October 28. 2009: U.S. Provisional Application Ser. No. 61/255,783 filed October 28, 2009; U.S. Provisional Application Ser. No. 61/297,138 filed January 21. 2010; U.S. Provisional Application Ser. No. 61/297,170 filed January 21, 2010; U.S. Provisional Application Ser. No. 61/364,288 filed July 14, 2010; and U.S. Provisional Application Ser. No 61/366,677 filed. July 22, 2010; all of which are incorporated by reference herein in their entirety. BACKGROUND OF THE INVENTION [0002] Sustained release formulations that gel upon contact with the body are used in a variety of therapeutic applications. SUMMARY OF THE INVENTION [0003] Described herein are sustained release formulations comprising thermosensitive polymers. Also described herein are methods wherein gelation temperature of formulations comprising thermosensitive polymers is manipulated with the addition of one or more gel temperature modifying agents to achieve a desired therapeutically relevant gelation temperature (e.g. a formulation that gels upon contact with the body). [000 Provided herein, in some embodiments, are pharmaceutical formulations comprising an active agent, a thermosensitive polymer comprising polyoxyethylene and polyoxypropylene copolymers, and a) having a syringable viscosity at time of administration suitable for administration via a 25 - 31 gauge needle; b) having a gelation temperature between about 14 °C and about 42 °C ; c)providing in vivo sustained release of a therapeutically effective amount of the active agent for a period of at least 3 days; and (d) having less than 50 cfu of microbial agents per gram of the formulation; provided that (i) the formulation comprises less than 14.5% of the thermosensitive polymer by weight of the formulation and further comprises one or more gelation temperature increasing agents; or (ii) the formulation comprises more than 25% of the thermosensitive polymer by weight of the formulation and further comprises one or more gelation temperature decreasing agents; or (iii) the formulation comprises between about 5% and about 20% of the thermosensitive polymer by weight of the formulation, wherein the thermosensitive polymer has been purified, and optionally further comprises one or more gelation temperature increasing or gelation temperature decreasing agents; or (iv) the formulation comprises between about 14.5% and about 25% of the thermosensitive polymer by weight of the formulation and further comprises one or more gelation temperature increasing or gelation temperature decreasing agents. [0005] In some embodiments, the formulation provides an in vivo sustained release of a therapeutically effective amount of the active agent for a period of at least 5 days. In some embodiments, the formulation provides an in vivo sustained release of a therapeutically effective amount of the active agent for a period of at least 7 days. In some embodiments, the formulation provides an in vivo sustained release of a therapeutically effective amount of the active agent for a period of at least 10 days. In some embodiments, the formulation provides an in vivo sustained release of a therapeutically effective amount of the active agent for a period of at least 14 days. [0006] In some embodiments, the formulation is administered at or in the vicinity of the round window membrane of the ear. In some embodiments, the in vivo sustained release occurs in the inner ear. [0007] In some embodiments, the formulation is administered in the middle ear, away from the round window membrane. In some embodiments, the in vivo sustained release occurs in the middle ear. [0008] In some embodiments, the formulation is administered into or in the vicinity of one or more sinonasal cavities. In some embodiments, the in vivo sustained release occurs in one or more sinona l i i i h i i i f i l i i [0009] In some embodiments, the thermosensitive polymer is P407. In some embodiments, the formulation is substantially free of additional preservatives. In some embodiments, the formulation is substantially free of pyrogens. In some embodiments, the formulation comprises less than about 5 endotoxin units (EU) per kg of body weight of a subject. In some embodiments, the formulation is substantially free of additional tonicity agents. [0010] In some embodiments, the formulation comprises a suspension of one or more multiparticulate active agents. In some embodiments, the multiparticulate active agent is a micronized active agent sterilized by dry-heat, irradiation or steam sterilization. [0011] In some embodiments, the formulation has any individual product related impurity of no more than 1% by weight of the formulation. In some embodiments, the formulation has total product related impurities of no more than 2% by weight of the formulation. [0012] In some embodiments, the active agent is a corticosteroid, or a salt or prodrug or solvate thereof. [0013] In some embodiments, the corticosteroid is 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, or triamcinolone hexacetonide, or salt or prodrug thereof. [0014] In some embodiments, the corticosteroid is dexamethasone, prednisolone, methylprednisolone, triamcinolone, or a salt or prodrug or solvate thereof, or a combination thereof. In some embodiments, the corticosteroid is dexamethasone, or a salt or prodrug or solvate thereof. In some embodiments, the dexamethasone is dexamethasone sodium phosphate or dexam h [0015] In some embodiments, the dexamethasone, or salt or prodrug or solvate thereof, is present in an amount from about 0.05% to about 40% by weight of the formulation.
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