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WO 2015/030853 Al 5 March 2015 (05.03.2015) P O P C T

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WO 2015/030853 Al 5 March 2015 (05.03.2015) 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 2015/030853 Al 5 March 2015 (05.03.2015) P O P C T (51) International Patent Classification: (74) Agents: TANNER, Lorna, L. et al; Sheppard Mullin A61K 9/16 (2006.01) A61K 31/4188 (2006.01) Richter & Hampton LLP, 379 Lytton Avenue, Palo Alto, A61K 9/20 (2006.01) A61K 31/513 (2006.01) CA 94301-1479 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US2014/013930 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) Date: International Filing BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 30 January 2014 (30.01 .2014) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (26) Publication Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (30) Priority Data: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 61/870,712 27 August 2013 (27.08.2013) US SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 61/898,690 1 November 2013 (01. 11.2013) US TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 61/907,308 2 1 November 2013 (21. 11.2013) US ZW. (71) Applicant: GILEAD PHARMASSET LLC [US/US]; (84) Designated States (unless otherwise indicated, for every 333 Lakeside Drive, Foster City, CA 94404 (US). kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (72) Inventors: GORMAN, Eric; c/o Gilead Pharmasset LLC, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 333 Lakeside Drive, Foster City, CA 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, CA 94404 (US). OLIYAI, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Reza; c/o Gilead Pharmasset LLC, 333 Lakeside Drive, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Foster City, CA 94404 (US). STEFANIDIS, Dimitrios; KM, ML, MR, NE, SN, TD, TG). c/o Gilead Pharmasset LLC, 333 Lakeside Drive, Foster City, CA 94404 (US). WISER, Lauren; c/o Gilead Declarations under Rule 4.17 : Pharmasset LLC, 333 Lakeside Drive, Foster City, CA — of inventorship (Rule 4.17(iv)) 94404 (US). ZIA, Vahid; c/o Gilead Pharmasset LLC, 333 Lakeside Drive, Foster City, CA 94404 (US). Published: — with international search report (Art. 21(3)) (54) Title: COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS o (I) © (57) Abstract: Disclosed are pharmaceutical compositions comprising Compound I, having the formula (I): and an effective amount o of sofosbuvir wherein the sofosbuvir is substantially crystalline. Also disclosed are methods of use for the pharmaceutical composi o tion. 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 61/870,712, filed on August 27, 2013, U.S. Provisional Application Number 61/898,690, filed on November 1, 2013, and U.S. Provisional Application Number 61/907,308, filed on November 21, 2013, the entirety of which are 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] The compounds methyl {(2S)-l-[(2S,5S)-2-(9-{2-[(2S,4S)-l-{(2R)-2- [(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-lH- imidazol-5-yl} -1,1 1-dihydroisochromeno[4',3':6,7]naphtho[ 1,2-d]imidazol-2-yl)-5- methylpyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl} carbamate, designated herein as Compound I and (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, designated herein as sofosbuvir, are known to be an effective anti-HCV agents, as described for example in U.S. Patent Nos. 7,964,580 and 8,575,135. However, the therapeutic benefits of the administration of Compound I and crystalline sofosbuvir were not heretofore known. SUMMARY [0004] Compound I (see, for example, WO 2013/075029 and U.S. Patent No. 8,575,135) has the following chemical structure: I. [0005] Sofosbuvir is a selective inhibitor of non-structural protein 5B (NS5B) (see, for example, WO 2010/132601 and U.S. Patent No. 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: [0006] Aspects of the disclosure relate to pharmaceutical composition comprising: a) an effective amount of Compound I, wherein the Compound I is substantially amorphous; and b) an effective amount of sofosbuvir, wherein the sofosbuvir is substantially crystalline. [0007] Further aspects 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. [0008] It is contemplated that the solid dispersions disclosed herein would demonstrate one or more of increased bioavailability, elimination of or reduced food-effect, reduced negative drug-drug interaction with acid suppressive therapies, reduced variability across patient populations, and/or improved dose linearity at higher doses when compared with administration of Compound I and/or sofosbuvir alone. DETAILED DESCRIPTION 1. Definitions [0009] 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. [0010] As used herein, the term "about" used in the context of quantitative measurements means the indicated amount ± 10%. For example, "about 2:8" would mean 1.8-2.2:7.2-8.8. [0011] The term "amorphous" refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (glass transition). [0012] The term "crystalline" refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (melting point). [0013] The term "substantially amorphous" as used herein is intended to mean that greater than 50%; or greater than 55%; or greater than 60%; or greater than 65%; or greater than 70%; or greater than 75%; or greater than 80%; or greater than 85%; or greater than 90%; or greater than 95%, or greater than 99% of the compound present in a composition is in amorphous form. "Substantially amorphous" can also refer to material which has no more than about 20% crystallimty, or no more than about 10% crystallimty, or no more than about 5% crystallimty, or no more than about 2% crystallimty. [0014] The term "substantially crystalline" as used herein is intended to mean that greater than 50%; or greater than 55%; or greater than 60%; or greater than 65%; or greater than 70%; or greater than 75%; or greater than 80%; or greater than 85%; or greater than 90%; or greater than 95%, or greater than 99% of the compound present in a composition is in crystalline form. "Substantially crystalline" can also refer to material which has no more than about 20%, or no more than about 10%, or no more than about 5%, or no more than about 2% in the amorphous form. [0015] The term "polymer matrix" as used herein is defined to mean compositions comprising one or more polymers in which the active agent is dispersed or included within the matrix. [0016] The term "solid dispersion" refers to the dispersion of one or more active agents in a polymer matrix at solid state prepared by a variety of methods, including spray drying, the melting (fusion), solvent, or the melting-solvent method. [0017] The term "amorphous solid dispersion" as used herein, refers to stable solid dispersions comprising an amorphous active agent and a polymer. By "amorphous active agent," it is meant that the amorphous solid dispersion contains active agent in a substantially amorphous solid state form. [0018] The term "pharmaceutically acceptable" indicates that the material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration.
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