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WO 2015/120110 A2 13 August 2015 (13.08.2015) P O P C T

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WO 2015/120110 A2 13 August 2015 (13.08.2015) P O P C T (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 WO 2015/120110 A2 13 August 2015 (13.08.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/28 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US2015/014545 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 5 February 2015 (05.02.2015) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/937,189 7 February 2014 (07.02.2014) US (84) Designated States (unless otherwise indicated, for every 61/990,061 7 May 2014 (07.05.2014) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: AUSPEX PHARMACEUTICALS, INC. TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, [US/US]; 33 N. Torrey Pines Court, Suite 400, La Jolla, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, CA 92037 (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors: SOMMER, Andreas; 3333 N. Torrey Pines SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Court, Suite 400, La Jolla, CA 92037 (US). ZHANG, GW, KM, ML, MR, NE, SN, TD, TG). Chengzhi; 3333 N . Torrey Pines Court, Suite 400, La Jolla, CA 92037 (US). CARTER, John; 3333 N. Torrey Published: Pines Court, Suite 400, La Jolla, CA 92037 (US). AR¬ — without international search report and to be republished THUR, John; 3333 N. Torrey Pines Court, Suite 400, La upon receipt of that report (Rule 48.2(g)) Jolla, CA 92037 (US). BRADBURY, Margaret; 3333 N. Torrey Pines Court, Suite 400, La Jolla, CA 92037 (US). (74) Agent: BENNETT, Dennis, A.; GLOBAL PATENT GROUP, LLC, 1005 N.. Warson Road, Suite 404, St. Louis, MO 63 132 (US). (54) Title: NOVEL PHARMACEUTICAL FORMULATIONS (57) Abstract: The present invention relates to new extended release pharmaceutical compositions and methods of use thereof for the treatment of disorders. NOVEL PHARMACEUTICAL FORMULATIONS [0001] This application claims the benefit of priority of United States provisional applications No. 61/937,189, filed February 7, 2014 and No. 61/990,061, filed May 7, 2014, the disclosures of which are hereby incorporated by reference as if written herein in their entireties. [0002] Disclosed herein are new pharmaceutical compositions, formulations, and methods of use thereof for the treatment of disorders. [0003] The administration of various drugs can be complicated by unfavorable pharmacodynamic and/or pharmacokinetic properties such as poor absorption or low bioavailability, short half-life or Tmax, high maximal plasma concentration, low minimal plasma concentrations, or unfavorable food effects. [0004] Thus, there is a need to develop extended release pharmaceutical formulations that provide improved drug delivery properties, such as increased half- life, increased Tmax, reduced Cmax and/or dose-normalized Cmax, while maintaining acceptable bioavailability and moderate food effects. [0005] Novel pharmaceutical compositions have been discovered, together with methods of synthesizing and using the compositions, including methods for the treatment of disorders in a patient by administering the compositions as disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS [0006] FIG. 1: Method of preparation of tetrabenazine extended release formulations. [0007] FIG. 2 : Dimensions of Gastro-Retentive Extended Release Large Tablet. [0008] In certain embodiments, disclosed herein is an extended-release pharmaceutical formulation comprising, in a solid dosage form for oral delivery of between about 100 mg and about 1 g total weight: between about 2 and about 18% of an active ingredient; between about 70% and about 96% of one or more diluents; between about 1% and about 10% of a water-soluble binder ; and between about 0.5 and about 2% of a surfactant. [0009] In certain embodiments, the diluent or diluents are chosen from mannitol, lactose, and microcrystalline cellulose; the binder is a polyvinylpyrrolidone; and the surfactant is a polysorbate. [0010] In certain embodiments, the extended-release pharmaceutical formulation comprises between about 2.5% and about 11% of an active ingredient. [00 11] In certain embodiments, the extended-release pharmaceutical formulation comprises: between about 60% and about 70% mannitol or lactose; between about 15% and about 25% microcrystalline cellulose about 5% of polyvinylpyrrolidone K29/32; and between about 1 and about 2% of Tween 80. [0012] In certain embodiments, the extended-release pharmaceutical formulation comprises: between about 4% and about 9% of an active ingredient; between about 60% and about 70% mannitol or lactose; between about 20% and about 25% microcrystalline cellulose about 5% of polyvinylpyrrolidone K29/32; and about 1.4% of Tween 80. [0013] In certain embodiments, disclosed herein is an extended-release pharmaceutical formulation comprising, in a solid dosage form for oral delivery of between about 100 mg and about 1 g total weight: between about 70 and about 95% of a granulation of an active ingredient, wherein the active ingredient comprises between about 1 and about 15% of the granulation; between about 5% and about 15% of one or more diluents; between about 5% and about 20% of sustained-release polymer; and between about 0.5 and about 2% of a lubricant. [0014] In certain embodiments, the extended-release pharmaceutical formulation comprises: between about 5% and about 15% of one or more spray-dried mannitol or spray-dried lactose; between about 5% and about 20% of sustained-release polymer; and between about 0.5 and about 2% of a magnesium stearate. [0015] In certain embodiments, the sustained-release polymer is chosen from a polyvinyl acetate-polyvinylpyrrolidone mixture and a poly(ethylene oxide) polymer. [0016] In certain embodiments, the sustained-release polymer is chosen from Kollidon® SR, POLYOX® N60K, and Carbopol®. [0017] In certain embodiments, the sustained-release polymer is Kollidon® SR. [0018] In certain embodiments, the sustained-release polymer is POLYOX® N60K. [0019] In certain embodiments, the sustained-release polymer is Carbopol®. [0020] In certain embodiments, the extended-release pharmaceutical formulation comprises from about 5 mg to about 250 mg of an active ingredient. [0021] In certain embodiments, the active ingredient is selected from the group consisting of tetrabenazine, dihydrotetrabenazine, ketamine, pirfenidone, phenylephrine, ethambutol, venlafaxine, zolipidem, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, sitaxentan, codeine, hydrocodone, morphine, oxycodone, almotriptan, eletriptan, naratriptan, sumatriptan, zolmitriptan, ranolazine, desmethylvenlafaxine, mirabegron, ticagrelor, darapladib, rilapladib, nilotinib, tofacitinib, apixaban, lumiracoxib, solabegron, riociguat, cariprazine, neratinib, pelitinib, fostamatinib, R-406, dihydrotetrabenazine, NBI- 98854, nintedanib, F-351, agomelatine, almorexant, alogliptin, anastrozole, aripiprazole, atomoxetine, bosentan, brivaracetam, bupropion, cediranib, cinacalcet, clemizole, dextromethorphan, dimeboline, donepezil, duloxetine, fingolimod, gefitinib, imatinib, ITMN-191, ivabradine, linezolid, lonafarnib, maraviroc, mosapride, nateglinide, oxybutynin, paroxetine, pazopanib, quetiapine, rilpivirine, rimonabant, rolofylline, sitagliptin, tolterodine, udenafil, valproic acid, vandetanib, vildagliptin, alpha-lipoic acid, ambrisentan, anacetrapib, apremilast, atazanavir, bardoxolone, baricitinib, boceprevir, brecanavir, carfilzomib, carmofur, cilostazol, conivaptan, crizotinib, darunavir, dasatinib, dimethylcurcumin, dolutegravir, elvitegravir, erlotinib, etravirine, felbamate, filibuvir, gliclazide, ibudilast, ibrutinib, idebenone, iloperidone, iloprost, indiplon, ivacaftor, L-838417, lacosamide, lapatinib, lenalidomide, lorcaserin, mibefradil, milnacipran, N-butyl bumetanide, NTP-2014, niacin, niacin prodrugs, NS1 1394, NS-304, MRE-304, MRE-269, pagoclone, pentifylline, pentoxifylline, pentoxifylline metabolites, PLX4032, pomalidomide, ponatinib, PPL- 100, praziquantel, preladenant, primaquine, radequinil, raltegravir, rigosertib, rivaroxaban, ruxolitinib, safinamide, silodosin, sodium oxybate, 4-hydroxybutyrate, sorafenib, telcagepant, thalidomide, tigecycline, omadacycline, tizanidine, TPA-023, treprostinil, varespladib, vercirnon, vicriviroc, levodopa, carbidopa, levodopa in combination with carbidopa , amantadine, dipraglurant, nintedanib, and pridopidine. [0022] In certain embodiments, the active ingredient is selected from the group consisting of a deuterated analog of tetrabenazine, a deuterated analog of dihydrotetrabenazine, a deuterated analog of ketamine, a deuterated analog of pirfenidone, a deuterated analog of phenylephrine, a deuterated analog of ethambutol, a deuterated analog of venlafaxine, a deuterated analog of zolipidem, a deuterated analog
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