TW201300106A - Pharmaceutical compositions for treating HCV infections - Google Patents

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 composition for treating HCV infection

The present invention provides a 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydrofuran-containing compound for the treatment of HCV infection. Novel formulation of 2-yl)-1H-pyrimidin-2-one (Ia: PSI-6130) and at least one other antiviral agent, wherein Ia is a replacement of commonly used bioinactive excipients with HCV polymerase inhibitors A higher dose of a diluent for the active pharmaceutical ingredient (API) of the digestible dosage form is permitted.

The development of commercially viable pharmaceutical formulations that provide appropriate therapies for patients is a critical step in the drug development process. Compressed tablets are a versatile, convenient and widely accepted dosage form. The safety, efficacy, and acceptability of a drug are significantly affected by the physicochemical and biopharmaceutical properties of the therapeutically active agent selected for the limited formulation. Direct compression of the blended component is a simple process but often unsuccessful due to problems associated with powder flow, content uniformity and compression. Common methods for solving biomedical problems include, but are not limited to, particle size modification, lipid solution, solid dispersion, or amorphous use. Manufacturing techniques such as wet or dry granulation, fluidized bed granulation, hot melt extrusion, and high shear granulation are commonly used to solve manufacturing problems. Granulation is a process in which a flocculent powder having poor compressibility is aggregated. Therefore, novel methods are often used to achieve optimal results in manufacturability, stability, bioavailability, and patient convenience.

Conventional lozenges made by conventional tablet compression and coating techniques often require the use of a relatively high percentage of excipients other than the active agent to optimize the ease of manufacture of the lozenge and the manufacture of the final product which is readily administered to the patient. Physical properties. Such excipients can include fillers, binders, decomposers, lubricants, anti-adherents, glidants, colorants, polymeric coatings, and plasticizers. The filler or diluent is an inert filler to provide sufficient material to compress the powder into a tablet. Well-defined methods for handling poor particle properties, such as flow and compression properties, also include processing steps such as granulation, freeze drying, and particle grading. However, in some cases, the amount of excipient may exceed the weight of the lozenge by more than 90% depending on the nature of the drug and the intended use of the tablet. When an acceptable regimen requires a high dose of API, this can result in a large lozenge that is negatively affected by the patient's ability to be digested by some patients or that requires digestion of multiple lozenges. Therefore, it is desirable to identify novel dosage forms that can hold higher dose concentrations of active pharmaceutical ingredients.

The present invention provides a method comprising 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydrofuran-2-yl)- Solid oral lozenge or capsule composition of 1H-pyrimidin-2-one (Ia) and at least one granule selected from the group consisting of additional pharmaceutically active antiviral components and binders: 4-fluoro-1,3-di Hydrogen-isoindole-2-carboxylic acid (Z)-(1S,4R,6S,14S,18R)-14-t-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-tertiaryoxy-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]19- 7-en-1-yl ester (II), isobutyric acid (2R, 3R, 4R, 5R)-5-(4-Amino-2-epoxy-2H-pyrimidin-1-yl)-4-fluoro-2-isobutyloxymethyl-4-methyl-tetrahydrofuran-3-yl Ester (Ib) or isobutyric acid (2R, 3S, 4R, 5R)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3,4 - Biisobutyloxy-tetrahydrofuran-2-ylmethyl ester (III). The present invention provides a formulation that produces a systemic concentration of an improved HCV polymerase and/or protease inhibitor suitable for treating a patient infected with HCV.

In another aspect of the invention, there is provided a solid oral lozenge or capsule composition comprising granules comprising Ia and at least one additional pharmaceutically active antiviral component and a binder which produces improved antiviral drugs and HCV protease inhibition The systemic concentration of the agent is suitable for the treatment of patients with HCV infection.

Solid lozenges and capsules containing low doses of the active pharmaceutical ingredient (API) are generally prepared by compressing the tablet or encapsulating the powder in a hard gelatin capsule. For relatively low levels of API, excipients that provide the potency, flow and lubricity required to effectively tablet or encapsulate and stabilize the solid dosage form can be added. Such excipients typically include diluents, binders, disintegrants, lubricants, glidants, colorants, coating agents, and flavoring agents as needed. Direct compression is the simplest program; however, there is often a problem with uniform distribution of APIs to dosage forms.

Granulation techniques are often applied when large doses are required, or when the mixture is not sufficiently compact and/or fluid is not practical and cannot be directly compressed. Wet granulation is a process in which a liquid or a liquid comprising a binder or an adhesive is added to an API and an excipient to homogenize the resulting mixture to form denser granules. The resulting moist particles can be ground or screened to a uniform size, dried and then compressed with other excipients that result in the properties of the final dosage form. An inert filler is added during the granulation to provide a quality sufficient for compression, which generally includes lactose, mannitol, sucrose, cellulose, microcrystalline cellulose, dry 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, 19th ed., A. R. Gennaro, Ed.; Mack Publishing Company: Easton, Pa., 1995, Vol. II, p. 1617). It is often included as a disintegrant that facilitates disintegration of the compressed formulation after ingestion. Lubricants are often added to prevent sticking to the tablet machine and reduce friction between the particles.

Hot melt extrusion is an alternative technique for making granules suitable for further processing into a final formulation wherein a homogeneous molten mixture of API and excipients is extruded to produce a solid solution or suspension that can be further processed. (J. Breitenbach "Melt Extrusion: from Process to Drug Delivery", Eur. J. Pharmaceutics and Biopharmaceutics 2002 54: 107-117; FA 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 a high dose (>250 mg) of API is required, the possibility of adding a diluent or excipient to impart a particular property is limited by the physical size of the tablet or capsule. In the specific case of antiviral drugs, large doses are often used to maintain high blood content APIs to reduce the risk of developing resistant populations. A dose of up to 1500 mg (Ib: R7128) of BID and QID has been used in recent trials. (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, April 22-4, 26, 2009).

Ib is an HCV polymerase inhibitor that inhibits HCV replication and is currently undergoing Phase II trials. (B.-K. Chun et al., WO 2007065829, issued Jun. 14, 2007, the entire disclosure of which is incorporated herein by reference. Ib has a variable bulk density, requires the addition of excipients and extensive processing to produce a powder, wherein the bulk density is sufficient for use in a tablet machine.

Antiviral therapies typically employ a multi-drug treatment regimen and, under such conditions, can be improved if the components can be combined in a single tablet or capsule or if the desired amount of tablet is minimized. HCV Protease Inhibitor II (R7227) (L. Blatt et al., WO 2005/037214, filed on Apr. 15, 2005, the entire disclosure of which is incorporated herein by reference). However, II exhibited poor intrinsic solubility and solubility (intrinsic solubility of 0.004 mg/mL). The intrinsic dissolution rate of II (batch number: TXMH001) was determined to be difficult to compress into tablets when it was determined to be 0.14 mg.cm ^-2 min ^-1 in pH 7.4 simulated gastric juice (SIF) without trypsin. The limited solubility of Ib (0.18 mg/mL) and II limits oral bioavailability. Ib is a prodrug of Ia (J. Clark, WO2005003147 A3, issued Jan. 13, 2005, the entire disclosure of which is incorporated herein by reference). Ib has better digestive membrane permeability but poor solubility than parent nucleoside Ia (water solubility: 60 mg/mL), but intestinal permeability is enhanced. Lower water solubility limits the amount of API dissolved that can be delivered through the GI membrane.

It has now surprisingly been found that Ia can be used as a water soluble filler in solid oral HCV formulations to replace inert excipients to provide smaller tablets and improved manufacturability while resulting in higher systemic concentrations of HCV polymerase.

As used herein, the following terms have the meanings set forth below.

The term "API" means an active pharmaceutical ingredient.

The term "excipient" means an inert substance used as a carrier for an active pharmaceutical ingredient. Excipients can be used to promote absorption of the active pharmaceutical ingredient, swelling the formulation to aid in the manufacture or aid in stabilizing the active pharmaceutical ingredient. Non-limiting illustrative examples of excipients include anti-adhesives, binders, coating agents, disintegrants, fillers/diluents, perfumes and pigments, glidants, lubricants, preservatives, adsorbents, and sweeteners. Agent.

As used herein, the term "diluent" or "filler" is used to mean the inert excipient added to adjust the volume to produce the actual compressed size. Typical diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride starch, and powdered sugar. A sufficient amount of diluent, such as mannitol, lactose, sorbitol, sucrose, and inositol, aids in the disintegration of the tablet and is commonly used in chewable tablets. Microcrystalline cellulose Used as an excipient in wet granulation and direct compression formulations.

The term "binder" as used herein is used to mean an excipient that is added to impart viscosity to the powder to maintain its integrity. Substances commonly used as binders include starch, gelatin and sugars such as sucrose, glucose, dextrose, molasses and lactose. Natural and synthetic gums can also be used as binders in some formulations, including gum arabic, sodium alginate, panwar gum, ghatti gum, carboxymethylcellulose, methylcellulose, polyethylene. Pyrrolidone, ethyl cellulose and hydroxypropyl methylcellulose.

The term "lubricant" as used herein refers to an excipient added to prevent the tablet material from sticking to the dye and the surface of the punch. Commonly used lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, 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 a tablet powder. Colloidal cerium oxide Is a common glidant. Talc can be used as a lubricant/glidant combination.

The term "disintegrant" as used herein refers to an excipient that is added to promote rupture or disintegration after administration. Dry powdered corn starch or potato starch is a common disintegrant. They have a high water affinity and swell when wet, causing the tablet to rupture. A material group called a super disintegrant includes croscarmellose sodium, crosslinked cellulose, crospovidone, crosslinked polymer, and sodium starch glycolate, crosslinked starch. Cross-linked povidone Is a synthetic, insoluble, but rapidly expandable crosslinked N-vinyl-pyrrolidone homopolymer.

The term "pharmaceutically acceptable", such as a pharmaceutically acceptable carrier, excipient, and the like, is meant to be pharmaceutically acceptable and substantially non-toxic to the individual to whom the particular compound is administered.

The term "pharmaceutically acceptable salts" refers to conventional acid addition or base addition salts which retain the biological effectiveness and properties of the compounds of the invention and which are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid addition salt samples include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, and nitric acid, and such as from p-toluenesulfonic acid, salicylic acid, A winner of organic acids of methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base addition salt samples include those obtained from ammonium, potassium, sodium, and quaternary ammonium hydroxides such as, for example, tetramethylammonium hydroxide. Chemically modifying a pharmaceutical compound (ie, a drug) into a technique well known to salt medicinal chemists to obtain improved physical and chemical stability, hygroscopicity, and solubility of the compound. See, for example, H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed., 1995) at pages 196 and 1456-1457.

The term "prodrug" means a compound that exhibits its pharmacological action after conversion. The medicinal chemical modification to overcome medical problems is also known as "drug potential." The drug is submerged into a chemical modification of the biologically active compound to form a novel compound that will release the parent compound in vivo. Chemical changes in the parent compound cause changes in physicochemical properties that affect absorption, distribution, and enzymatic metabolism. The terms prodrug, latent drug, and bioreversible derivative are used interchangeably. The term prodrug is a generic term for a drug that exhibits its pharmacological effects upon transformation in vivo.

The term "extragranular" means the tablet component of a hot melt or wet particulate mixture (i.e., the first particulate component) added to Ia and Ib, II or III and a binder. However, for the sake of clarity, the tablet or capsule may contain more than one particulate component.

In one embodiment of the invention, there is provided a method comprising 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl- Solid oral lozenge or capsule combination of tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (Ia) and at least one additional pharmaceutically active antiviral component selected from the group consisting of the first granule component of a binder and a first granule component of a binder Compound: 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (Z)-(1S,4R,6S,14S,18R)-14-t-butoxycarbonylamino-4- Cyclopropanesulfonylaminocarbonyl-2,15-di-oxy-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]19--7-en-18-yl ester (II) Isobutyric acid (2R,3R,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-fluoro-2-isobutyloxymethyl 4-methyl-tetrahydrofuran-3-yl ester (Ib) or isobutyric acid (2R, 3S, 4R, 5R)-5-(4-amino-2-yloxy-2H-pyrimidin-1-yl 2-azido-3,4-bisisobutyloxy-tetrahydrofuran-2-ylmethyl ester (III).

In a second embodiment of the invention, there is provided a process comprising 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl A solid oral lozenge or capsule composition of granules of tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (Ia) wherein the additional pharmaceutically active antiviral component is (II) and a binder.

In a third embodiment of the present invention, there is provided a method comprising 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl a solid oral ingot of tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (Ia) (wherein the additional pharmaceutically active antiviral component is (II)) and poloxomer as a binder particle Agent or capsule composition.

In a fourth embodiment of the present invention, there is provided a solid oral lozenge or capsule composition, wherein the first particulate component comprises 20-40% wt/wt II, 40 to 60% wt/wt Ia and 15 -30% wt/wt of poloxamer 188.

In a fifth embodiment of the present invention, there is provided a solid oral lozenge or capsule composition, wherein the first particulate component comprises 25-30% wt/wt II, 50 to 60% wt/wt Ia and 17 -23% wt/wt of poloxamer 188.

In a sixth embodiment of the present invention, there is provided a solid oral lozenge or capsule composition, wherein the first particulate component comprises 27% wt/wt II, 53% wt/wt Ia and 20% wt/wt Polosham 188.

In a seventh embodiment of the present invention, there is provided a method comprising 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl a first particulate component of -tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (Ia), (II) and poloxamer and comprising a third antiviral compound and at least one additional diluent, carrier and / or a solid oral lozenge or capsule composition of the second granule component of the excipient.

In an eighth embodiment of the present invention, there is provided a method comprising 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl Solid oral lozenges or capsule compositions and extragranular components of granules of tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (Ia), (II) and poloxamer further comprising Ib and at least one additional Diluent, carrier and/or excipient.

In a ninth embodiment of the present invention, there is provided a solid oral lozenge or capsule composition comprising 191 mg of granules containing 53% (Ia), 27% (II) and 20% poloxamer 188 and an extragranular group The preparation further comprises 449 mg (Ib), 15 mg of croscarmellose sodium, 18 mg of microcrystalline cellulose (pH 102), 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 lozenge or capsule composition comprising granules comprising (Ia) wherein the additional pharmaceutically active antiviral component is (III) and a binder.

In an eleventh embodiment of the present invention, there is provided a method comprising 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl Solid oral lozenge or capsule composition of the first granule component of benzyl-tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (Ia) and at least one additional pharmaceutically active antiviral component and binder.

In a twelfth embodiment of the present invention, there is provided a method comprising 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl Solid oral lozenge or capsule combination of base-tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (Ia) and at least one additional pharmaceutically active antiviral component and poloxamer as the first granule component of the binder Things.

The following examples illustrate the preparation of solid tablets and capsules within the scope of the invention. The following examples and methods are provided to enable those skilled in the art to more clearly understand and practice the invention. They are not to be considered as limiting the scope of the invention, A skilled medical scientist will recognize that the excipients, diluents, and carriers are used interchangeably and that such changes do not depart from the spirit of the invention.

Example 1 Hot melt granule lozenge comprising HCV protease inhibitor II and HCV polymerase inhibitor Ia

The molten components were first blended with a Turbula mixer and subsequently melted and extruded using a US Leistritz model Micro-18/62/40D extruder. The extrudate was ground using a grinder to pass through a 18 mesh screen. The extrudate particles are blended with an extragranular excipient having the following composition:

A tablet was prepared from a powder blend containing each of the hot melt particles using a Carver press with an embossing punch of 2000 lbs, 0 seconds dwell time and a size of about 0.304" x 0.576". Representative tablets from different batches of extrudate weighed 471 and 436 mg and contained 92 and 93 mg II and 100 and 196 mg Ia, respectively.

Example 2

Hot melt granule lozenge comprising HCV protease inhibitor II and HCV polymerase inhibitors Ia and Ib

I b wet granulation

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

Two different II/Ia/Ib combination lozenge formulations were prepared by blending two different II/Ia particles with Ib particles and extragranular excipients. Tablets were prepared using a Carver press at 2000 lbs, 0 second dwell time, and an oblate circular punch having a size of about 0.328" x 0.619".

Example 3 Lozenges in combination with III and Ia

The molten components were first blended with a Turbula mixer and subsequently melted and extruded using a US Leistritz model Micro-18/62/40D extruder. The extrudate was ground to pass through a 18 mesh screen. The extrudate particles are then blended with the extragranular excipients.

Three 500 mg III (as free base) lozenge formulations including 0 mg (control), 77 mg, and 177 mg Ia were prepared. Tablet compositions are listed in the table below. The highest loading of Ia is produced by replacing the extragranular mannitol with Ia in a formulation. Tablets were prepared using a Carver press with a modified capsule type concave punch of 2000 lbs, 0 second residence time and a size of approximately 0.325" x 0.7874".

Example 4

Wet granulation comprising a composition of Ib and Ia as a filler in place of microcrystalline cellulose

Weigh 6 g batch size of the granules. The API was blended with intragranular croscarmellose sodium and transferred to an agate mortar and pestle. Povidone K30 and sodium lauryl sulfate were dissolved in 1.8 g of granulation fluid, added to the API blend and mixed using a mortar and pestle. The wet granules were transferred to a pan and dried overnight at 50 °C. The dried particles were ground through a 18 mesh and weighed.

The extragranular colloidal cerium oxide and magnesium stearate were passed through a 30 mesh screen and then distributed to each group. All extragranular excipients except magnesium stearate were added to the mill dried granules and mixed for 2 minutes in a Turbula mixer. Magnesium stearate was then added to the powder blend and the Turbula mixer was mixed for an additional 2 minutes.

Example 5 Dissolution test

The dissolution test of the HCV combination tablet was carried out in a Vankel VK7000 dissolution system with a peristaltic pump and a Vankel VK8000 sampling station. A Varian filter with a cutoff of 10 μm was used. The sampling time at 50 RPM was 10, 20, 30, 45, and 60 min, followed by a final spin at 15 RPM for 15 min. A 5 mL sample volume was collected at each time point and purged and purged for 60 seconds, and the samples were collected. The dissolution medium was 1 L of 20 mM phosphate buffer (pH 6.8, degassed with helium, maintained at 37 ° C).

Sample analysis was performed by HPLC analysis using 4.6 x 100 mm Mac Mod Analytical, Halo C18 (2.7 μm), eluting with the following gradient while maintaining the sample and column at 37 °C. The flow rate was 1.5 mL/min. The operating time was 5 min, of which 2 min was rebalanced.

Figures 1a and 1b include normalized data for release indicating the effective release of particles prepared by Ia and II, respectively, as described in Example 1.

The features disclosed in the above or in the following patent applications, in the form of their specific forms or implementations of the disclosed functions, or the methods or process representations used to obtain the disclosed results, may be individually or in accordance with the features. Any combination is used to implement the various forms of the invention.

For the purposes of brevity and understanding, the foregoing has been explained in some detail by way of illustration and example. It will be apparent to those skilled in the art that changes and modifications can be implemented within the scope of the attached patent application. Therefore, it should be understood that the above discussion is intended to be illustrative rather than limiting. Therefore, the scope of the invention should not be determined by the above description, but should be determined by the full scope of the attached technical solutions and equivalents of such technical solutions.

The patents, publications, and scientific literature referenced herein are incorporated by reference in their entirety to the extent of the disclosure of the disclosures of Any conflict between any reference cited in the text and the specific teachings of the description is intended to facilitate the latter. Similarly, any conflict between the definition of a technical understanding of a word or idiom and the definition of a particular teaching or idiom in that description is intended to facilitate the latter.

Figure 1a depicts the results of the release of Ia from a lozenge comprising particles comprising Ia and Ib.

Figure 1b depicts the results of II release from a lozenge comprising particles comprising Ia and Ib.

(no component symbol description)

Claims (13)

A solid oral lozenge or capsule composition comprising 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl- a first granule component of tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (Ia) and at least one additional pharmaceutically active antiviral component and binder selected from the group consisting of 4-fluoro-1,3 -Dihydro-isoindole-2-carboxylic acid (Z)-(1S,4R,6S,14S,18R)-14-t-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl- 2,15-di-oxy-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]dodec-7-en-18-yl ester (II), isobutyric acid (2R, 3R, 4R,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-4-fluoro-2-isobutyloxymethyl-4-methyl-tetrahydrofuran-3 -yl ester (Ib) or isobutyric acid (2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3 ,4-bisisobutyloxy-tetrahydrofuran-2-ylmethyl ester (III) The composition of claim 1, wherein the additional pharmaceutically active antiviral component is (II). The composition of claim 2, further comprising a poloxamer. The composition of claim 3, wherein the first particulate component comprises 20-40% wt/wt II, 40 to 60% wt/wt Ia, and 15-30% wt/wt poloxamer 188. The composition of claim 3, wherein the first particulate component comprises 25-30% wt/wt II, 50 to 60% wt/wt Ia, and 17-23% wt/wt poloxamer 188. The composition of claim 5, wherein the first particulate component comprises 27% wt/wt II, 53% wt/wt Ia, and 20% wt/wt poloxamer 188. The composition of claim 3, further comprising a second particulate component comprising a third antiviral compound and at least one additional diluent, carrier and/or excipient. The composition of claim 7, wherein the third antiviral compound is a compound of formula Ib. The composition of claim 8 which comprises: The composition of claim 1, wherein the additional pharmaceutically active antiviral component is isobutyric acid (2R, 3S, 4R, 5R)-5-(4-amino-2-oxo-2H-pyrimidin-1- 2-Azido-3,4-bisisobutyloxy-tetrahydrofuran-2-ylmethyl ester (III). A solid oral lozenge or capsule composition comprising a first particulate component comprising 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl 3-methyl-tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (Ia) and at least one additional pharmaceutically active antiviral component and binder. The solid oral lozenge or capsule composition of claim 11, wherein the binder is a poloxamer. Use of a composition according to any one of claims 1 to 12 for the manufacture of a medicament for the treatment of HCV infection.