Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
  • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

• 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.
• API active pharmaceutical ingredients
• 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.
• 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.
• 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.
• 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.
• the present invention provides a solid oral tablet or capsule composition
• 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[14.3.0.0 4 ' 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-amin
• 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 are typically be made by tablet compression or encapsulation of the powder in hard gelatin capsules.
• excipients can be added which provide for compactability, fluidity and lubricity required for effective tableting or encapsulation and stable solid dosage forms.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• API refers to the active pharmaceutical ingredient.
• excipients refers to an inactive substance used as a carrier for an active
• 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.
• diluent 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.
• lubricants 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.
• glidant refers to an excipient added to improve the flow characteristics of the tablet powder.
• Colloidal silicon dioxide AEROSIL ®
• Talc may serve as a combined lubricant/glidant.
• disintegrant 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 ®
• 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.
• compositions of the present invention 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.
• prodrug refers to compounds, which undergo transformation prior to exhibiting their pharmacological effects.
• drug latentiation The chemical modification of drugs to overcome pharmaceutical problems has also been termed “drug latentiation.” Drug latentiation is the chemical
• prodrugs are used interchangeably.
• prodrug is a generic term for agents, which undergo in vivo transformation prior to exhibiting their pharmacological actions.
• 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.
• a tablet or capsule can contain more than one granular component.
• 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[14.3.0.0 4 ' 6 ]nonadec-7-en- 18-yl ester (II), isobutyric acid (2R,3R,4R,5R
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 ( ⁇ 102), 20 mg of talc and 7 mg of sodium stearyl fumarate.
• a solid oral tablet or capsule composition comprising granules containing (la) wherein said additional pharmaceutically active antiviral ingredient is (III) and a binder.
• a solid oral tablet or capsule composition comprising a first granular component containing 4-amino- l-
• 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 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
• 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/tablet 1 mg/tablet
• 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.
• 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.
• 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 ⁇ 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
• 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

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Virology (AREA)
• Molecular Biology (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Biotechnology (AREA)
• Biophysics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=45044542

Family Applications (1)

Country Status (3)

Cited By (1)

Citations (6)

• 2011
  • 2011-11-07 WO PCT/EP2011/069507 patent/WO2012062691A1/en active Application Filing
  • 2011-11-07 TW TW100140577A patent/TW201300106A/zh unknown
  • 2011-11-08 AR ARP110104158A patent/AR083792A1/es not_active Application Discontinuation

Patent Citations (6)

Non-Patent Citations (7)

Also Published As

Similar Documents

Legal Events