(51) International Patent Classification: Declarations Under Rule 4.17
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) ( (51) International Patent Classification: Declarations under Rule 4.17: A61K9/00 (2006.01) A61K 31/675 (2006.01) — as to applicant's entitlement to apply for and be granted a A61K9/14 (2006.01) A61K 31/683 (2006.01) patent (Rule 4.17(H)) A61K9/16 (2006.01) — as to the applicant's entitlement to claim the priority of the (21) International Application Number: earlier application (Rule 4.17(iii)) PCT/US2020/046758 Published: (22) International Filing Date: — with international search report (Art. 21(3)) 18 August 2020 (18.08.2020) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/888,959 19 August 2019 (19.08.2019) US (71) Applicant: GILEAD SCIENCES, INC. [US/US]; 333 Lakeside Drive, Foster City, California 94404 (US). (72) Inventors: BANE, Jessica M.; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404 (US). NEJATI, Elham; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404 (US). STEFANIDIS, Dimitrios; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404 (US). (74) Agent: BAJPAI, Reena et al.; Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, IT, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 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, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (54) Title: PHARMACEUTICAL FORMULATIONS OF TENOFOVIR ALAFENAMIDE (57) Abstract: Long-acting formulations comprising isopropyl ((S)-((((R)-l-(6-amino-9//-purin-9- yl)propan-2-yl)oxy)methyl)(phe noxy)phosphoryl)-L-alaninate, or a pharmaceutically acceptable salt thereof, and a biodegradable polymer, e.g. poly(lactic-co-gly colic acid) (PLGA), are described, as are methods of making the long acting formulations and uses thereof. PHARMACEUTICAL FORMULATIONS OF TENOFOVIR ALAFENAMIDE CROSS-REFERENCE [0001] This application claims priority to U.S. Provisional Patent Application No. 62/888,959, fried August 19, 2020, which is incorporated here in entirety for all purposes. FIELD [0002] Pharmaceutical formulations that may be used for treating or preventing human immunodeficiency virus (HIV) infection are described. In particular, long acting formulations of tenofovir alafenamide (TAF), methods for their preparation, and uses thereof as therapeutic or prophylactic agents are described. BACKGROUND [0003] For certain patients, for example, those with difficult or limited access to health care, adherence to daily oral treatment or prophylactic regimens can be challenging. Drugs and formulations that offer favorable pharmaceutical properties (for example, improved potency, long- acting pharmacokinetics, low solubility, low clearance, and/or other properties) are amenable to less frequent administration and provide for better patient compliance. SUMMARY [0004] Provided herein are pharmaceutical compositions comprising: (i) a compound of Formula F Formula I , or a pharmaceutically acceptable salt thereof, and (ii) a biodegradable polymer. In some embodiments, the compositions described herein consist essentially of the compound of Formula I, or the pharmaceutically acceptable salt thereof and the biodegradable i polymer. In some embodiments, the compositions described herein consist of the compound of Formula I, or the pharmaceutically acceptable salt thereof and a biodegradable polymer. [0005] In some embodiments, the pharmaceutical compositions comprise sucrose acetate isobutyrate in an amount less than 5% w/w. In some embodiments, the pharmaceutical compositions comprise sucrose acetate isobutyrate in an amount less than 0.5% w/w. In some embodiments, the pharmaceutical compositions comprise sucrose acetate isobutyrate in an amount less than 0.1% w/w. In some embodiments, the pharmaceutical compositions described herein do not comprise sucrose acetate isobutyrate. In some embodiments, the pharmaceutical compositions are free of sucrose acetate isobutyrate. [0006] In some embodiments, the compositions described herein further comprise an additional therapeutic agent. In some embodiments, the additional therapeutic agent in an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent is a steroid. In some embodiments the additional therapeutic agent is a corticosteroid. In some embodiments the additional therapeutic agent is a dexamethasone. [0007] Also provided herein are pharmaceutical formulations comprising the compositions described herein and a suspending vehicle. In some embodiments, the suspending vehicle comprises (i) a suspending agent, (ii) a wetting agent, and (iii) a buffer. [0008] Further provided herein are methods for treating a human immunodeficiency virus (HIV) infection, the methods comprising administering to a subject in need thereof a composition or a pharmaceutical formulation described herein. [0009] Additionally provided herein are methods for treating an HBV infection, the methods comprising administering to a subject in need thereof a composition or a pharmaceutical formulation described herein. [0010] Also described herein are methods of making the compositions described herein, the methods comprising: (i) mixing the compound of Formula I : Formula I , or the pharmaceutically acceptable salt thereof, and a biodegradable polymer, and (ii) hot melt extrusion of a mixture comprising the compound of Formula I and the biodegradable polymer. There are also provided pharmaceutical compositions obtainable by these methods. There are also further provided pharmaceutical compositions prepared by hot melt extrusion. BRIEF DESCRIPTION OF THE DRAWINGS [0011] Figure 1. Shows a flow diagram for an exemplary method of making microspheres comprising the TAF drug substance and PLGA. [0012] Figure 2. Shows a flow diagram for an exemplary method of making spray-dried dispersions comprising the TAF drug substance and PLGA. [0013] Figure 3a. Shows SEM images of the three types of compositions ((i) microspheres, (ii) spray-dried dispersions, and (iii) hot melt extruded pharmaceutical compositions) descried in Example 1. [0014] Figure 3b. Shows the chemical stability of the three types of compositions ((i) microspheres, (ii) spray-dried dispersions, and (iii) hot melt extruded pharmaceutical compositions) descried in Example 1. [0015] Figure 4a. Shows a flow diagram for an exemplary method of making hot melt extruded pharmaceutical compositions comprising TAF and PLGA. [0016] Figure 4b. Shows overlaps of XRPD spectrums of the crystalline Form I of TAF free base starting material and two exemplary pharmaceutical formulations prepared by the hot-melt extrusion methods described herein (i) 30% TAF (free base (FB), crystalline Form I, and micronized) and 70% PLGA8515 and (ii) 30% TAF (free base (FB), crystalline Form I, and micronized) and 70% PLGA7525. [0017] Figure 5. Shows a comparison of the (i) chemical stability studies and (ii) dog PK studies of compositions comprising (a) 30% crystalline TAF bis-xinafoate (micronized) and 70% PLGA7525 and (b) 30% crystalline Form I of TAF free base (micronized) and 70% PLGA7525. [0018] Figure 6. Shows a comparison of the dog PK studies of compositions comprising (a) 30% crystalline Form I of TAF free base (micronized) and 70% PLGA7525 and (b) 30% crystalline TAF vanillate (micronized) and 70% PLGA7525. [0019] Figure 7. Shows a comparison of the dog PK studies of compositions comprising (a) 20% crystalline Form I of TAF free base (micronized) and 80% PLGA8515 and (b) 20% crystalline TAF sebacate Form I (micronized) and 80% PLGA8515. [0020] Figure 8. Shows the (i) chemical stability studies and (ii) dog PK studies on a composition comprising (a) 30% crystalline TAF orotate Form I (micronized) and 70% PLGA8515. [0021] Figure 9. Shows a comparison of the dog PK studies on compositions comprising (i) 30% TAF free base (crystalline Form I) and 70% PLGA5050 and (ii) TAF free base (amorphous) and 70% PLGA5050. [0022] Figure 10. Shows a comparison of the dog PK studies on compositions comprising (i) 30% TAF free base (crystalline Form I) and 70% PLGA5050 and (ii) TAF free base (amorphous) and 70% PLGA5050. [0023] Figure 11. Shows comparison of dog PK studies of two compositions (i) 30% crystalline Form I of TAF free base and 70%PLGA5050 and (ii) ) 30% amorphous TAF free base and 70%PLGA5050. [0024] Figure 12. Shows a comparison of the (i) chemical stability and (ii) dog PK studies of compositions comprising (a) 30% crystalline TAF Form I of free base (unmicronized) and 70% PLGA7525 and (b) 30% crystalline Form I of TAF free base (micronized) and 70% PLGA7525. [0025] Figure 13. Shows a comparison of the (i) chemical stability and (ii) dog PK studies of compositions comprising (a) 40% crystalline Form I of TAF free base and 60% PLGA7525 with dio = 42 µι , dso = 101 µι , and d o = 202 µιη and (b) 50% crystalline Form I of TAF free base and 50% PLGA7525 with dio = 6 µιη, dso = 19 µιη, and d90 = 8 1 µιη . [0026] Figure 14. Shows a comparison of the (i) chemical stability and (ii) dog PK studies of compositions comprising (a) 40% crystalline Form I o f TAF free base and 60% PLGA7525 with dio = 42 pm, dso = 101 pm, and d o = 202 pm and (b) 50% crystalline Form I of TAF free base and 50% PLGA7525 with dio = 6 pm, dso = 19 pm, and d90 = 8 1 pm.