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WO 2014/120981 Al 7 August 2014 (07.08.2014) P O P C T

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WO 2014/120981 Al 7 August 2014 (07.08.2014) 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 2014/120981 Al 7 August 2014 (07.08.2014) P O P C T (51) International Patent Classification: Gilead Pharmasset LLC, 333 Lakeside Drive, Foster City, A61K 9/16 (2006.01) A61K 31/501 (2006.01) California 94404 (US). A61K 9/20 (2006.01) A61K 31/513 (2006.01) (74) Agents: TANNER, Lorna L. et al; Sheppard Mullin (21) International Application Number: Richter & Hampton Lip, 379 Lytton Avenue, Palo Alto, PCT/US2014/013953 California 94301-1479 (US). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 30 January 2014 (30.01 .2014) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (25) Filing Language: English BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (26) Publication Language: English 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, (30) Priority Data: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 61/759,320 31 January 2013 (3 1.01.2013) US MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 61/772,292 4 March 2013 (04.03.2013) US OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 61/828,899 30 May 2013 (30.05.2013) US SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 61/870,729 27 August 2013 (27.08.2013) US TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 61/897,793 30 October 20 13 (30. 10.20 13) US ZW. 61/907,332 2 1 November 2013 (21. 11.2013) US (84) Designated States (unless otherwise indicated, for every (71) Applicant: GILEAD PHARMASSET LLC [US/US]; kind of regional protection available): ARIPO (BW, GH, 333 Lakeside Drive, Foster City, California 94404 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (72) Inventors: CHAL, Ben; c/o Gilead Pharmasset LLC, 333 UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, Lakeside Drive, Foster City, California 94404 (US). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, MOGALIAN, Erik; c/o Gilead Pharmasset LLC, 333 EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Lakeside Drive, Foster City, California 94404 (US). PAK- MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, DAMAN, Rowchanak; c/o Gilead Pharmasset LLC, 333 TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Lakeside Drive, Foster City, California 94404 (US). KM, ML, MR, NE, SN, TD, TG). OLIYAI, Reza; c/o Gilead Pharmasset LLC, 333 Lakeside Published: Drive, Foster City, California 94404 (US). STEFANIDIS, — with international search report (Art. 21(3)) Dimitrios; c/o Gilead Pharmasset LLC, 333 Lakeside Drive, Foster City, California 94404 (US). ZIA, Vahid; c/o 00 © o (54) Title: COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS (57) Abstract: Disclosed are pharmaceutical compositions having an effective amount of substantially amorphous ledipasvir and an effective amount of substantially crystalline sofosbuvir. COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 61/759,320, filed on January 31, 2013, U.S. Provisional Application Number 61/772,292, filed on March 4, 2013, U.S. Provisional Application Number 61/828,899, filed on May 30, 2013, U.S. Provisional Application Number 61/870,729, filed on August 27, 2013, U.S. Provisional Application Number 61/897,793, filed on October 30, 2013, and U.S. Provisional Application Number 61/907,332, filed on November 21, 2013, the entirety of which are all incorporated herein by reference. BACKGROUND [0002] Hepatitis C is recognized as a chronic viral disease of the liver which is characterized by liver disease. Although drugs targeting the liver are in wide use and have shown effectiveness, toxicity and other side effects have limited their usefulness. Inhibitors of hepatitis C virus (HCV) are useful to limit the establishment and progression of infection by HCV as well as in diagnostic assays for HCV. [0003] Ledipasvir is a selective inhibitor of non-structural protein 5A (NS5A), which has been described previously (see, for example, WO 2010/132601). The chemical name of ledipasvir is (l-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5- aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-lH-benzoimidazol-2-yl]-2-aza- bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester. [0004] Sofosbuvir (SOF) is a selective inhibitor of non-structural protein 5B (NS5B) (see, for example, WO 2010/132601 and U.S. Patent 7,964,580). The chemical name of sofosbuvir is (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-4-fluoro-3 -hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino) propanoate. SUMMARY [0005] The present disclosure provides, in some embodiments, a pharmaceutical composition comprising ledipasvir in a substantially amorphous form and sofosbuvir in a substantially crystalline form. [0006] Ledipasvir has the chemical name of (l-{3-[6-(9,9-difluoro-7-{2-[5-(2- methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H- fluoren-2-yl)-lH-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl- propyl)-carbamic acid methyl ester, and has the following chemical formula: [0007] Sofosbuvir (SOF) has the chemical name of (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)- 5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate and has the following chemical formula: [0008] In some embodiments, provided is a pharmaceutical composition comprising: a) an effective amount of ledipasvir, wherein ledipasvir is substantially amorphous; and b) an effective amount of sofosbuvir wherein sofosbuvir is substantially crystalline. [0009] Further embodiments of the disclosure relate to pharmaceutical dosage forms and tablets. The disclosure also provides methods for using the combination in the treatment of hepatitis C. BRIEF DESCRIPTION OF THE DRAWINGS [0010] FIG. 1 is a XRPD pattern of the solid dispersion formulation of ledipasvir comprising copovidone in a drug:polymer ratio of 1:1. As shown by the XRPD, the solid dispersion is in the amorphous state. [0011] FIG. 2 is a modulated differential scanning calorimetry (DSC) curve of the solid dispersion of ledipasvir comprising copovidone in a drug:polymer ratio of 1:1. The glass transition temperature of the solid dispersion is about 140 °C. [0012] FIG. 3 shows a solid state characterization of the solid dispersion formulation of ledipasvir comprising copovidone in a drug:polymer ratio of 1:1by solid state nuclear magnetic resonance (SS-NMR). [0013] FIG. 4 is a Fourier-transformed Raman spectra of the solid dispersion of ledipasvir comprising copovidone in a drug:polymer ratio of 1:1. [0014] FIG. 5 shows the dissolution of sofosbuvir in the sofosbuvir (400 mg)/ledipasvir (90 mg) combination described in Example 7. [0015] FIG. 6 shows the dissolution of ledipasvir in the sofosbuvir (400 mg)/ledipasvir (90 mg) combination formulation described in Example 3. [0016] FIG. 7A-D shows the HCV RNA levels during 1 weeks of treatment and 24 weeks post-treatment for treatment na ve (FIG. 7A) or null responder (FIG. 7B) patients treated with sofosbuvir (SOF) and ribavirin (RBV) and for treatment na ve (FIG. 7C) or null responder (FIG. 7D) patients treated with sofosbuvir (SOF), ledipasvir and ribavirin (RBV). This data and experimental method are further described in Example 5. [0017] FIG. 8A-B present charts to show that all three formulations had comparable dissolution performance, similar to that of the single-agent controls. This is more thoroughly described in Example 7. [0018] FIG. 9 presents the pH-solubility profile of ledipasvir at room temperature (RT). The line is the nonlinear least-square regression fit using equation PK L PH (pKal+pKa2 2 pH) µ π ST = SO [(i+i 0 - +10 - - )] with an intrinsic solubility (S0) of 0.04 and a weakly basic pKal and pKa2 values of 5.0 and 4.0, respectively. This is more thoroughly described in Example 8. [0019] FIG. 10 shows the study design for treatment naive (non-cirrhotic) and for null responders (50% cirrhotic) for patients treated with a fixed dose combination of sofosbuvir (SOF) and ledipasvir, with and without ribavirin (RBV) for 8 and 12 weeks. The data and experimental method are described in Example 9. [0020] FIG. 11 shows the results for treatment naive (non-cirrhotic) and for null responders (50%> cirrhotic) for patients treated with a fixed dose combination of sofosbuvir (SOF) and ledipasvir, with and without ribavirin (RBV) for 8 and 1 weeks. This data and experimental method are further described in Example 9. DETAILED DESCRIPTION 1. Definitions [0021] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. [0022] As used herein, the term "about" used in the context of quantitative measurements means the indicated amount ± 10%, or alternatively ± 5%, or ± 1%. For example, with a ± 10% range, "about 2:8" can mean 1.8-2.2:7.2-8.8.
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