WO2012062691A1

WO2012062691A1 - Pharmaceutical compositions for treating hcv infections

Info

Publication number: WO2012062691A1
Application number: PCT/EP2011/069507
Authority: WO
Inventors: Michael Thomas Brandl; Karen Elizabeth Olocco
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 2010-11-09
Filing date: 2011-11-07
Publication date: 2012-05-18
Also published as: TW201300106A; AR083792A1

Abstract

The present inventions related to new pharmaceutical solid tablet and capsule formulations which used the HCV polymerase inhibitor 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5- hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (Ia).

Description

PHARMACEUTICAL COMPOSITIONS FOR TREATING HCV INFECTIONS

The present invention provides novel formulations for the treatment of HCV infections containing 4-amino- l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl- tetrahydro-furan-2-yl)- lH-pyrimidin-2-one (la: PSI-6130) and at least one additional antiviral agent wherein la is a diluent that replaces conventional biologically inactive excipients with a HCV polymerase inhibitor and allows higher doses of active pharmaceutical ingredients (API) in a easily ingested dosage form.

The development of commercially manufacturable pharmaceutical formulations that provide convenient therapy for the patient is a critical step of the drug development process. The compressed tablet is a common, convenient and well-accepted dosage form. The safety, efficacy and acceptability of drug can be significantly influenced by the physico-chemical, and biopharmaceutical properties of the therapeutically active agent that can limit formulation options. Direct compression of blended ingredients is a simple process but is frequently unsuccessful due to problems related to flow, content uniformity, and compression of powders. Frequently used approaches to resolve the biopharmaceutical issues include, but are not limited to, particle size modification, lipid solution, solid dispersions, or the use of amorphous forms. Manufacturing technologies such as wet or dry granulation, fluid bed granulation, hot melt extrusion and high shear granulation are commonly used approaches to resolve manufacturing difficulties. Granulation is the process of aggregating flocculent poorly compressible powders. Accordingly, novel approaches are frequently employed to achieve optimal results with respect to manufacturability, stability, bioavailability, and patient convenience.

Conventional tablets manufactured by common tablet compression and coating techniques often require the use of relatively large percentages of excipients in addition to the active agent(s) to optimize the physical properties of the ingredients that allow convenient manufacture of the tablet and produce a final product which is readily administered to the patient. These excipients may include fillers, binders, disintegrants, lubricants, anti- adherents, glidants, colorants, polymer coatings and plasticizers,. Fillers or diluents are inert bulking agents to provide sufficient material to compress a powder into a tablet. Well-established processes to manage poor particulate properties, e.g., flow and compaction properties, also include processing steps such as granulation, lyophilization and sizing of the particles. However, the excipient levels can, in some cases, exceed 90% of the tablet weight, depending on the drug properties and the intended use of the tablet. When high dose levels of the API are required for acceptable therapy, this can result in large tablets that are difficult to ingest by some patients or requiring ingestion of multiple tablets both of which can negatively impact patient compliance. Thus it is desirable to identify new dosage forms which accommodate higher dosage levels of active pharmaceutical ingredient(s).

The present invention provides a solid oral tablet or capsule composition comprising granules containing 4-amino-l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl- tetrahydro-furan-2-yl)-lH-pyrimidin-2-one (la) and at least one

additional pharmaceutically active anti- viral ingredient selected from the group consisting of -4- fluoro- 1 ,3-dihydro-isoindole-2-carboxylic acid (Z)-( 1 S ,4R,6S , 14S , 18R)- U-tert- butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3 , 16-diaza- tricyclo[14.3.0.0⁴'⁶]nonadec-7-en-18-yl ester (II), isobutyric acid (2R,3R,4R,5R)-5-(4-amino-2- oxo-2H-pyrimidin-l-yl)-4-fluoro-2-isobutyryloxymethyl-4-methyl-tetrahydro-furan-3-yl ester isobutyric acid (lb) or (2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidin-l-yl)-2-azido-3,4-bis- isobutyryloxy-tetrahydro-furan-2-ylmethyl ester (III) and a binder. The invention affords formulations which produce improved systemic levels of HCV polymerase and/or protease inhibitors useful for treating patients suffering from HCV infections.

In another aspect of the present invention there is provided a solid oral tablet or capsule composition comprising granules containing la and at least one additional pharmaceutically active anti-viral ingredient and a binder which produce improved systemic levels of an antiviral medication and an HCV polymerase inhibitor useful for treating patients suffering from HCV infections.

Figure la depicts the release of la from a tablet comprising granules containing la and lb. Figure lb depicts the release of II from a tablet comprising granules containing la and lb.

Solid tablet and capsule dosage forms containing low doses of the active pharmaceutical ingredient (API) are typically be made by tablet compression or encapsulation of the powder in hard gelatin capsules. With a relatively low concentration of API, excipients can be added which provide for compactability, fluidity and lubricity required for effective tableting or encapsulation and stable solid dosage forms. Typically these excipients optionally include diluents, binders, disintegrants, lubricants, glidants, coloring agents, coating agents and flavoring agents. Direct compression is the simplest procedures; however, problems providing uniform distribution of the API throughout the dosage form are often encountered.

When direct compression is not practical because large doses are required, or the mixture is poorly compacted and/or poorly flowing, granulation technology can frequently be

advantageously employed. Wet granulation is a process wherein a liquid or a liquid containing a binder or adhesive is added to the API and excipients and the resulting mixture is homogenized forming denser granules. The damp granules which result can be milled or sieved to a uniform size, dried and then compressed along with other excipients which contribute to the properties of the final dosage form. Inert fillers which are added in the granulation process to provide sufficient mass to compress typically include lactose, mannitol, sucrose, cellulose,

microcrystalline cellulose, dried starch, powdered sugar, kaolin, dicalcium phosphate, calcium sulfate and sodium chloride. (E. Rudnic, Oral Solid Dosage Forms in Remington: The Science and Practice of Pharmacy, 19^th Edition,A. R. Gennaro, Ed.; Mack Publishing Company: Easton, Pa., 1995, Vol. II p.1617) A disintegrant is frequently included which facilitates disintegration of the compressed formulation after ingestion. Lubricants are often added prevent adhesion to the tablet press and reduce interparticle friction.

Hot-melt extrusion is an alternative technique to prepare granules suitable for further processing into a final formulation in which a homogenous molten mixture of API and excipients are extruded to produce a solid solution or suspension which can be further processed. (J.

Breitenbach "Melt Extrusion: from Process to Drug Delivery", Eur. J. Pharmaceutics and Biopharmaceutics 2002 54: 107-117; F.A. Alvarez-Nunez et al. "Formulation of a Poorly Soluble Drug Using a Hot Melt Extrusion" Amer. Pharm. Rev. 2004 7(4):88-92; K. Coppens et al.

"Evaluation of Formulations Produced via Hot Melt Extrusion that Contain high API Loading and Exhibit Controlled Release, 2007 AASP Meeting and Exposition, San Diego, CA, November 11-15, 2007; M. Brandl et al. "Early Clinical and Preclinical Formulations of R1626", 2008 AASP Meeting and Exposition, Atlanta, GA, November 16-20, 2008).

In contrast when high doses (> 250 mg) of the API are required the opportunity to add diluents or excipients to impart specific properties is constrained by the physical size of the tablet or capsule. In the specific case of antiviral medications, large doses are frequently used to maintain high blood levels of the API to diminish the risk of generating resistant populations. Recent trials have used doses of up to 1500 mg BID and QID of (lb: R7128). (S. Le Pogam et al., "Evidence of R7128 Drug Resistance After Up To 4 Weeks Treatment of GT1,2 and 3 Hepatitis C Virus Infected Individuals", 44th Annual Meeting of the European Association for the Study of the Liver (EASL), Copenhagen, Denmark, Apr 22-Apr 26, 2009).

Ib is a HCV polymerase inhibitor which inhibits HCV replication and currently is undergoing Phase II trials. (B.-K. Chun et al., WO2007065829 published June 14, 2007 which is hereby incorporated by reference in its entirety) Ib has variable bulk density requiring addition of excipients and extensive processing to prepare powders wherein the bulk density is adequate to use in a table press.

Antiviral therapy commonly employs multidrug treatment regimes and in these situations patient compliance can be enhanced if the components can be combined in a single tablet or capsule or if the number of tablets required can be minimized. The HCV protease inhibitor II (R7227) (L. Blatt et al., WO2005/037214 published April 15, 2005 which is hereby incorporated by reference in its entirety) inhibits HCV replication. However, II exhibits poor intrinsic solubility and dissolution properties (intrinsic solubility is 0.004 mg/mL). The intrinsic dissolution rate for II (Lot No. TXMH001) was determined in pH 7.4 simulated gastric fluid (SIF) without pancreatin and found to be 0.14 mg«cm^" min^" which renders it difficult to compress into tablet. The limited solubility of lb (0.18 mg/mL)and II limits oral bioavailability. Ib is a prodrug of la (J. Clark, WO2005003147 A3, published January 13, 2005 which is hereby incorporated by reference in its entirety). Ib has better permeability across gastrointestinal membranes but poorer solubility than the parent nucleoside la (aqueous solubility 60 mg/mL) but enhanced permeability throughout the gut. Lower water solubility limits the quantity of API in solution available for transport across GI membranes. It has now been surprisingly found that la can be employed as a water soluble filler in solid oral HCV formulations thereby replacing inert excipients to provide smaller tablets and improved manufacturability while simultaneously contributing to higher systemic levels of the HCV polymerase.

As used herein, the following terms have the meanings set out below. The term "API" refers to the active pharmaceutical ingredient.

The term "excipients" refers to an inactive substance used as a carrier for an active

pharmaceutical ingredient. Excipients may be used to aid in the absorption of the active pharmaceutical ingredient, to bulk up formulations to aid in the manufacturing process, or to help stabilize the active pharmaceutical ingredient. Non-limiting illustrative examples of excipients include antiadherents, binders, coatings, disintegrants, fillers/diluents, flavors and colors, glidants, lubricants, preservatives, sorbents, and sweeteners.

The term "diluent" or "filler" as used herein refers to an inert excipient added to adjust the bulk in order to produce a size practical for compression. Common diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride starch and powdered sugar. Diluents such as mannitol, lactose, sorbitol, sucrose and inositol in sufficient quantities aid disintegration of the tablet and are frequently used in chewable tablets.

Microcrystalline cellulose (AVICEL^®) has been used as an excipient in wet granulation and direct compression formulations. The term "binder" as used herein refers to an excipient added to impart cohesive qualities to the powder which allows the compressed tablet to retain its integrity. Materials commonly used as binders include starch, gelatin and sugars such as sucrose, glucose, dextrose, molasses and lactose. Natural and synthetic gums including acacia, sodium alginate, panwar gum, ghatti gum, carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, ethyl cellulose and

hypromellose have also be used binders in some formulations.

The term "lubricants" as used herein refers to an excipient added to prevent adhesion of the tablet material to the surface of dyes and punches. Commonly used lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and PEG. Water soluble lubricants include sodium benzoate, mixtures of sodium benzoate and sodium acetate, sodium chloride, leucine and Carbowax 4000.

The term "glidant" as used herein refers to an excipient added to improve the flow characteristics of the tablet powder. Colloidal silicon dioxide (AEROSIL^®) is a common glidant. Talc may serve as a combined lubricant/glidant.

The term "disintegrant" as used herein refers to a excipient added to facilitate breakup or disintegrate after administration. Dried and powdered corn starch or potato starch are popular disintegrants. They have a high affinity for water and swell when moistened leading to rupture of the tablet. A group of materials known as super-disintegrants include croscarmellose sodium, a cross-linked cellulose, crosprovidone, a cross-linked polymer and sodium starch glycolate, a cross- linked starch. Crosprovidone (POLYPLASDONE^®) is a synthetic, insoluble, but rapidly swellable cross-linked N-vinyl-pyrrolidone homopolymer.

The term "pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.

The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base- addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides, such as for example,

tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (i.e., drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, and solubility of compounds. See, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6^th Ed. 1995) at pp. 196 and 1456-1457.

The term "prodrug" refers to compounds, which undergo transformation prior to exhibiting their pharmacological effects. The chemical modification of drugs to overcome pharmaceutical problems has also been termed "drug latentiation." Drug latentiation is the chemical

modification of a biologically active compound to form a new compound, which will liberate the parent compound in vivo. The chemical alterations of the parent compound are such that the change in physicochemical properties will affect the absorption, distribution and enzymatic metabolism. The terms prodrugs, latentiated drugs, and bio-reversible derivatives are used interchangeably. The term prodrug is a generic term for agents, which undergo in vivo transformation prior to exhibiting their pharmacological actions.

The term "extragranular" refers to the tablet ingredients added to a hot melt or wet granular mixture (i.e., the first granular component) of la and lb, II or III and a binder. For the sake of clarity a tablet or capsule, however, can contain more than one granular component.

In one embodiment of the present invention there is provided a solid oral tablet or capsule composition comprising a first granular component containing 4-amino-l-((2R,3R,4R,5R)-3- fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)- lH-pyrimidin-2-one (la) and at least one additional pharmaceutically active anti- viral ingredient selected from the group consisting of 4-fluoro-l,3-dihydro-isoindole-2-carboxylic acid (Z)-(lS,4R,6S, 14S,18R)- 14-ieri- butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza- tricyclo[14.3.0.0⁴'⁶]nonadec-7-en- 18-yl ester (II), isobutyric acid (2R,3R,4R,5R)-5-(4-amino-2- oxo-2H-pyrimidin-l-yl)-4-fluoro-2-isobutyryloxymethyl-4-methyl-tetrahydro-furan-3-yl ester isobutyric acid(Ib) or (2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidin- l-yl)-2-azido-3,4-bis- isobutyryloxy-tetrahydro-furan-2-ylmethyl ester (III) and a binder.

In a second embodiment of the present invention there is provided a solid oral tablet or capsule composition comprising granules containing 4-amino- l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5- hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-lH-pyrimidin-2-one (la) wherein said additional pharmaceutically active antiviral ingredient is (II) and a binder.

In a third embodiment of the present invention there is provided a solid oral tablet or capsule composition comprising granules containing 4-amino- l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5- hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-lH-pyrimidin-2-one (la) wherein said additional pharmaceutically active antiviral ingredient is (II) and poloxomer as binder.

In a fourth embodiment of the present invention there is provided a solid oral tablet or capsule composition wherein said first granular component is comprised of 20-40% wt/wt of II, 40 to 60% wt/et of la and 15-30% wt/wt of poloxomer 188.

In a fifth embodiment of the present invention there is provided a solid oral tablet or capsule composition wherein said first granular component is comprised of 25-30% wt/wt of II, 50 to 60% wt/et of la and 17-23% wt/wt of poloxomer 188.

In a sixth embodiment of the present invention there is provided a solid oral tablet or capsule composition wherein said first granular component is comprised of 27% wt/wt of II, 53% wt/et of la and 20% wt/wt of poloxomer 188.

In a seventh embodiment of the present invention there is provided a solid oral tablet or capsule composition containing a first granular component is comprised of4-amino- l-((2R,3R,4R,5R)-3- fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)- lH-pyrimidin-2-one (la), (II) and poloxomer and a second granular component containing a third antiviral compound and at least one additional diluent, carrier and/or excipient.

In a eighth embodiment of the present invention there is provided a solid oral tablet or capsule composition comprising granules containing 4-amino- l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5- hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-lH-pyrimidin-2-one (la), (II) and poloxomer and the extra-granular components further comprise a lb and at least one additional diluent, carrier and/or excipient.

In a ninth embodiment of the present invention there is provided a solid oral tablet or capsule composition comprising 191 mg of granules containing 53% (la), 27% of(II) and 20% of poloxomer 188 and the extra-granular components further comprise 449 mg of (lb), 15 mg croscarmellose sodium, 18 mg of microcrystalline cellulose (ΡΗ102), 20 mg of talc and 7 mg of sodium stearyl fumarate. In a tenth embodiment of the present invention there is provided a solid oral tablet or capsule composition comprising granules containing (la) wherein said additional pharmaceutically active antiviral ingredient is (III) and a binder.

In an eleventh embodiment of the present invention there is provided A solid oral tablet or capsule composition comprising a first granular component containing 4-amino- l-

((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)- lH- pyrimidin-2-one (la) and at least one additional pharmaceutically active anti- viral ingredient and a binder.

In an twelfth embodiment of the present invention there is provided A solid oral tablet or capsule composition comprising a first granular component containing 4-amino-l-((2R,3R,4R,5R)-3- fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)- lH-pyrimidin-2-one (la) and at least one additional pharmaceutically active anti- viral ingredient and a poloxomer as a binder.

The following examples illustrate the preparation of solid tablets and capsules within the scope of the invention. These examples and preparations which follow are provided to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. The skilled pharmaceutical scientist will be aware of excipients, diluents and carriers which can be used interchangeably and these variations do not depart from the spirit of the invention.

Example 1

Hot Melt Granular Tablets containing HCV protease inhibitor II and HCV polymerase inhibitor

la

The melt ingredients are first blended using a Turbula mixer and then melted and extruded using an American Leistritz model Micro- 18/62/40D extruder. The extrudate was milled using a mill to pass through an 18 mesh screen. The extrudate granules were blended with extragranular excipients with the following composition:

Tablets were prepared from powder blends containing each of the hot melt granules using a Carver press at 2000 lbs, 0 seconds dwell time and flat oval concave punches, approximately 0.304" x 0.576" in dimension. Representative tablets from different batches of extrudate weighed 471 and 436 mg and contained 92 and 93 mg of II and 100 and 196 mg of la

respectively.

Example 2

Hot Melt Granular Tablets containing HCV protease inhibitor II and HCV polymerase inhibitors la and lb

Wet Granulation of lb

Granules of lb were prepared by blending dry ingredients using a Turbula mixer. Water was added dropwise and mixed in using a spatula until a satisfactory granulation was obtained. The granulation was dried at 50°C for 21 hours, cooled and milled using a mortar and pestle to pass through a 20 mesh screen.

Two different II/Ia/Ib combination tablet formulations were prepared by blending the two different Il/Ia granules with the lb granules plus extra- granular excipients. Tablets were prepared using a Carver press at 2000 lbs, 0 seconds dwell time and flat oval concave punches, approximately 0.328" x 0.619" in dimension. Ingredient mg/tablet¹ mg/tablet

89% lb granules 25 27

25% 11/25% la granules 206 0

25% 11/25% la granules 0 191

croscarmellose sodium 15 15

microcrystalline cellulose (PH102) 18 18

talc 20 20

sodium stearyl fumarate 7 7

1. 400 mg lb/ 50 mg la/ 48 mg II

2. 400 mg lb/ 100 la/ 48 mg II

Example 3

Tablets of III in combination with la

The melt ingredients are first blended using a Turbula mixer and then melted and extruded using an American Leistritz model Micro- 18/62/40D extruder. The extrudate was milled to pass through an 18 mesh screen. The extrudate granules were then blended with extragranular excipients.

Three 500 mg III (as free base) tablet formulations having 0 mg (control), 77 mg and 177 mg of la were prepared. The tablet compositions are listed in following tables. The highest loading of la was produced by replacing extragranular mannitol with la in one of the formulations. Tablets were prepared using a Carver press at 2000 lbs, 0 seconds dwell time and modified capsule shaped concave punches, approximately 0.325" x 0.7874" in dimension.

Example 4

Wet granulation of a composition containing lb and la as a filler replacing microcrystalline cellulose. The intragranular ingredients for a 6 gram batch size were weighed out. The API and intragranular croscarmellose sodium were blended together and transferred to an agate mortar and pestle. The povidone K30 and sodium lauryl sulfate were dissolved in 1.8 g granulating fluid, added to the API blend and mixed using mortar and pestle. The wet granulations were transferred to pans and dried over night at 50°C. The dried granulations were milled through an 18 mesh screen and weighed

The extra-granular colloidal silicon dioxide and the magnesium stearate were passed through a 30 mesh screen prior to dispensing to each lot. All the extragranular excipients except the magnesium stearate were added to the dried and milled granules and mixed on a Turbula mixer for 2 minutes. The magnesium stearate was then added to the powder blend and mixed on the Turbula mixer for an additional 2 minutes.

Example 5

Dissolution testing

Dissolution testing of the HCV combination tablets carried out in a Vankel VK7000 Dissolution System with peristaltic pump and Vankel VK8000 SamplingStation. Varian filters with a 10 μιη cut off were used. The sampling times were 10, 20, 30, 45 and 60 min at 50 RPM followed by a 15 min final spin at 250 RPM Sample volumes of 5 mL were collected at each time point and 60 sec priming and purges were employed prior to sample collection. The dissolution media was 1 L of 20 mM phosphate buffer, pH 6.8 degassed with helium maintained at 37 °C. Sample analysis was accomplished by HPLC analysis using a 4.6 x 100 mm Mac Mod

Analytical, Halo C18 (2.7 μιη) eluting with the following gradient while maintaining the sample and column at 37 °C. The flow rate was 1.5 mL/min. The run time was 5 min with 2 min re- equilibration

Figure la and lb contain normalized data for the release demonstrating the efficient release of la and II, respectively, from granules prepared as described in Example 1

The features disclosed in the foregoing description, or the following claims, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for attaining the disclosed result, as appropriate, may, separately, or in any combination of such features, be utilized for realizing the invention in diverse forms thereof.

The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

The patents, published applications, and scientific literature referred to herein establish the knowledge of those skilled in the art and are hereby incorporated by reference in their entirety to the same extent as if each was specifically and individually indicated to be incorporated by reference. Any conflict between any reference cited herein and the specific teachings of this specifications shall be resolved in favor of the latter. Likewise, any conflict between an art- understood definition of a word or phrase and a definition of the word or phrase as specifically taught in this specification shall be resolved in favor of the latter.

Claims

A solid oral tablet or capsule composition comprising a first granular component containing 4-amino- l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl- tetrahydro-furan-2-yl)- lH-pyrimidin-2-one (la) and at least one additional

pharmaceutically active anti- viral ingredient selected from the group consisting of -4- fluoro- 1 ,3-dihydro-isoindole-2-carboxylic acid (Z)-( 1 S ,4R,6S , 14S , 18R) - 14-ieri- butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza- tricyclo[14.

3.0.0⁴'⁶]nonadec-7-en- 18-yl ester-(II), isobutyric acid (2R,3R,4R,5R)-5-(4- amino-2-oxo-2H-pyrimidin- l-yl)-4-fluoro-2-isobutyryloxymethyl-4-methyl-tetrahydro- furan-3-yl ester isobutyric acid(Ib) or (2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidin-l- yl)-2-azido-3,4-bis-isobutyryloxy-tetrahydro-furan-2-ylmethyl ester (III) and a binder.

A composition according to claim 1 wherein said additional pharmaceutically active antiviral ingredient is (II).

A composition according to claim 2 further comprising a poloxamer.

4. A composition according to claim 3 wherein said first granular component is comprised of 20-40% wt/wt of II, 40 to 60% wt/wt of la and 15-30 % wt/wt of poloxamer 188.

5. A composition according to claim 3 wherein said first granular component is comprised of 25-30% wt/wt of II, 50 to 60% wt/wt of la and 17-23 % wt/wt of poloxamer 188.

6. A composition according to claim 5 wherein said first granular component is comprised of 27 %wt/wt of II, 53% wt/wt of la and 20 % wt/wt of poloxamer 188.

7. A composition according to claim 3 further comprising a second granular component containing a third antiviral compound and at least one additional diluent, carrier and/or excipient.

8. A composition according to claim 7 wherein said third antiviral compound is a compound according to formula lb.

9. A composition according to claim 8 said composition comprising:

10. A composition according to claim 1 wherein said additional pharmaceutically active antiviral ingredient is isobutyric acid (2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidin- l- yl)-2-azido-3,4-bis-isobutyryloxy-tetrahydro-furan-2-ylmethyl ester (III)

11. A solid oral tablet or capsule composition comprising a first granular component is

comprised ofamino- l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl- tetrahydro-furan-2-yl)- lH-pyrimidin-2-one (la) and at least one additional

pharmaceutically active anti- viral ingredient and a binder. A solid oral tablet or capsule composition according to claim 11 wherein the binder is a poloxomer.

Use of a composition according to any one of claims 1 to 12 for the treatment of HCV infections.