WO 2017/004012 Al 5 January 2017 (05.01.2017) P O P C T
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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 WO 2017/004012 Al 5 January 2017 (05.01.2017) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 9/24 (2006.01) A61K 31/513 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/505 (2006.01) A61K 31/675 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/US20 16/039762 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 28 June 2016 (28.06.2016) 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. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/187,102 30 June 2015 (30.06.2015) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 62/296,524 17 February 2016 (17.02.2016) US TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (71) Applicants: GILEAD SCIENCES, INC. [US/US]; 333 LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Lakeside Drive, Foster City, CA 94404 (US). JANSSEN SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, SCIENCES IRELAND UC [IE/IE]; Eastgate Village, GW, KM, ML, MR, NE, SN, TD, TG). Eastgate, Little Island, County Cork (IE). Declarations under Rule 4.17 : (72) Inventors: KOZIARA, Joanna; c/o Gilead Sciences, Inc., — as to applicant's entitlement to apply for and be granted a 333 Lakeside Drive, Foster City, CA 94404 (US). SPER- patent (Rule 4.1 7(H)) GER, Diana; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404 (US). — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.1 7(in)) (74) Agents: HARTRUM, J., Elin et al; Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404 (US). Published: (81) Designated States (unless otherwise indicated, for every — with international search report (Art. 21(3)) kind of national protection available): AE, AG, AL, AM, (54) Title: PHARMACEUTICAL FORMULATIONS (57) Abstract: The invention provides a solid oral dosage form comprising rilpivirine or a pharmaceutically acceptable salt thereof, tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and emtncitabine or a pharmaceutically acceptable salt thereof. This invention provides pharmaceutical formulations suitable for treating viral infections such as HIV, and in particular solid oral dosage forms including rilpivirine, emtricitabine and tenofovir alafenamide. BACKGROUND Human immunodeficiency virus, type 1 (HIV-1) infection is a life-threatening and serious disease of major public health significance, with approximately 35 million people infected worldwide (Joint United Nations Programme on HIV/AIDS (UNAIDS). Global report: UNAIDS report on the global AIDS epidemic, 2013). Standard of care for the treatment of HIV-1 infection uses combination antiretrovirai therapy (ART) to suppress viral replication to below detectable limits, increase CD4 cell counts, and halt disease progression. The success of potent and well-tolerated ART means that morbidity and mortality in the HIV- infected population is increasingly driven by non-AIDS associated comorbidities. Clinical attention has become more focused on optimizing toierabiiity, long-term safety, and adherence (Costagliola D . Demographics of HIV and aging Curr. Opin. HIV AIDS, 2014, 9(4), 294). There remains a significant medical need for safe and effective new therapies that take into consideration the aging patient population, non-HlV -related comorbidities, virologic resistance, and regimen simplification. SUMMARY All the compositions and oral dosage forms herein include rilpivirine or a pharmaceutically acceptable salt thereof. The inventors have successfully formulated an oral dosage form containing rilpivirine, tenofovir alafenamide and emtricitabine. This oral dosage form is suitable for use in medicine, and in particular in treating viral infections such as HIV. In one aspect, a solid oral dosage form comprising rilpivirine or a pharmaceutically acceptable salt thereof, tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and emtricitabine or a pharmaceutically acceptable salt thereof is provided. For instance, in certain embodiments, the dosage fonn comprises 25 g rilpivirine as a pharmaceutically acceptable salt thereof, 25 mg tenofovir alafenamide as a pharmaceutically acceptable salt thereof, and 200 mg emtricitabine. In certain embodiments, the dosage form comprises 27.5 g rilpivirine hydrochloride, 28 mg tenofovir alafenamide hemifumarate, and 200 mg emtricitabine. The inventors have found thai it is possible to formulate solid oral dosage forms that are pharmaceutically acceptable (i.e. pharmacologically efficacious and physically acceptable) while reducing the total amount of excipients necessary to achieve stability. Accordingly, in one aspect the invention provides a solid oral dosage form comprising 25 mg rilpivirine or a pharmaceutically acceptable salt thereof, 25 mg tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and 200 mg emtricitabine or a pharmaceutically acceptable salt thereof, wherein the dosage form has a total weight of less than 850 mg (e.g. less than 800 mg or less than 700 mg). The inventors have demonstrated that it is possible to formulate stable compositions containing tenofovir alafenamide and emtricitabine that exhibit acceptable stability. Accordingly, in another aspect the invention provides a composition comprising (a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (b) emtricitabine or a pharmaceutically acceptable salt thereof, where the total quantity of degradation products derived from the tenofovir alafenamide or the pharmaceutically acceptable salt thereof is less than 3% after storage for one month at 40°C/75% RH in open conditions. Such compositions may further comprise rilpivirine or a pharmaceutically acceptable salt thereof. In another aspect, a coated tablet comprising 25 mg rilpivirine or a pharmaceutically acceptable salt thereof, 25 mg tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and 200 mg emtricitabine or a pharmaceutically acceptable salt thereof is provided. In another aspect, a tablet comprising 27.5 mg rilpivirine hydrochloride, 28 mg tenofovir alafenamide hemifumarate, and 200 mg emtricitabine is provided. In another aspect, a tablet comprising (a) 25 mg rilpivirine or a pharmaceutically acceptable salt thereof, (b) 25 mg tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (c) 200 mg emtricitabine or a pharmaceutically acceptable salt thereof is provided, wherein (a) and (b) are segregated, and wherein the tablet has a total weight of less than about .5 g . Typically, (a) and (b) are present within separate layers in a multilayer tablet. In another aspect, a tablet comprising from 2.5-4 5 % w/w rilpivirine or a pharmaceutically acceptable salt thereof, 2.5-4.5 % w w tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and 27-33 % w/w emtricitabine or a pharmaceutically acceptable salt thereof is provided, where the weight percentages denote a proportion of the whole tablet. In some embodiments, (a) the rilpivirine is present as rilpivirine hydrochloride and/or (b) the tenofovir alafenamide is present as tenofovir alafenamide hemifumarate. Typically, the rilpivifine will be present as rilpivirine hydrochloride and the tenofovir alafenamide w ll be present as tenofovir alafenamide hemifumarate. The inventors have found that the use of multilayer tablets may assist in achieving appropriate pharmacokinetic parameters and/or adequate tablet stability . Accordingly, in another aspect a multilayer tablet comprising (a) rilpivirine or a pharmaceutically acceptable salt thereof, (b) tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (c) emtricitabine or a pharmaceutically acceptable salt thereof is provided. The inventors have a so found that there is a relationship between the stability of tenofovir alafenamide and the concentration of tenofovir alafenamide within a given composition. Accordingly, in another aspect a solid composition comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof is provided wherein the proportion of tenofovir alafenamide or a pharmaceutically acceptable salt thereof in the composition is from about 4% to about 12% by weight. Another aspect provides a solid composition comprising from about 5% to about 15% by weight tenofovir alafenamide hemifumarate. In another aspect, a dry granulated mixture of (a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (b) emtricitabine or a pharmaceutically acceptable salt thereof is provided. In another aspect, a kit comprising (a) a tablet comprising rilpivirine or a pharmaceutically acceptable salt thereof, tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and emtricitabine or a pharmaceutically acceptable salt thereof, and (b) a desiccant (e.g.