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WO2019030387A1 - Composition solide comprenant du sofosbuvir amorphe et du daclatasvir amorphe - Google Patents

Composition solide comprenant du sofosbuvir amorphe et du daclatasvir amorphe Download PDF

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Publication number
WO2019030387A1
WO2019030387A1 PCT/EP2018/071773 EP2018071773W WO2019030387A1 WO 2019030387 A1 WO2019030387 A1 WO 2019030387A1 EP 2018071773 W EP2018071773 W EP 2018071773W WO 2019030387 A1 WO2019030387 A1 WO 2019030387A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
weight
solid composition
sofosbuvir
Prior art date
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Ceased
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PCT/EP2018/071773
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English (en)
Inventor
Thorsten Wilhelm
Olga SCHÖNE
Hans-Peter SPITZENSTÄTTER
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Sandoz AG
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Sandoz AG
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Ceased legal-status Critical Current

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    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/7072—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 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • 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

Definitions

  • Solid Composition Comprising Amorphous Sofosbuvir and Amorphous Daclatasvir
  • the present invention relates to a solid composition comprising amorphous sofosbuvir and amorphous daclatasvir and optionally at least one pharmaceutically acceptable matrix compound and to a process for the preparation of the solid composition.
  • the present invention further relates to a pharmaceutically acceptable composition comprising the solid composition.
  • the present invention relates the solid composition and the pharmaceutically acceptable composition comprising the solid composition for use in the treatment of hepatitis C.
  • sofosbuvir is described as a compound instable to moisture.
  • RH relative humidity
  • sofosbuvir deliquesces after a few hours.
  • Amorphous sofosbuvir compared to its crystalline forms, is even less stable to moisture and deliquesces at relative humidity above about 50 %.
  • amorphous sofosbuvir has the desirable property of a higher solubility.
  • Daclatasvir is a compound of formula (II)
  • the IUPAC name is methyl N-[(2S)-l-[(2S)-2-[5-[4-[4-[2-[(2S)-l-[(2S)-2- (methoxycarbonylamino)-3 -methylbutanoyl]pyrro lidin-2-yl] - 1 H-imidazo 1-5 - yl]phenyl]phenyl]- lH-imidazol-2-yl]pyrrolidin- 1 -yl] -3 -methyl- 1 -oxobutan-2-yl]carbamate. It is a Hepatitis C Virus NS5A Inhibitor.
  • the problem underlying the present invention is the provision of a stable composition comprising amorphous sofosbuvir and amorphous daclatasvir.
  • amorphous sofosbuvir and amorphous daclatasvir are stable when comprised in a solid composition.
  • the solid composition according to the invention comprises amorphous sofosbuvir and amorphous daclatasvir.
  • the solid composition further comprises at least one pharmaceutically acceptable matrix compound. Stable in the context of the invention means that the amorphous form, preferably the amorphous form of sofosbuvir does not deliquescence and does not crystallize.
  • the present invention relates to a solid composition
  • a solid composition comprising sofosbuvir according to formula (I)
  • sofosbuvir or a pharmaceutically acceptable salt thereof and daclatasvir or a pharmaceutically acceptable salt thereof comprised in the solid composi- tion are in amorphous form.
  • the present invention relates to a process for the preparation of said solid composition. Further, the present invention relates to a pharmaceutically acceptable composition comprising said solid composition and least one pharmaceutically acceptable excipient and a process for preparing said pharmaceutically acceptable composition.
  • the present invention relates to said solid composition or said pharmaceutically ac- ceptable composition for use in a method for treating hepatitis C in a human. Further the present invention relates to the use of said solid composition or of said pharmaceutically acceptable composition for the preparation of a medicament for treating hepatitis C in a human.
  • the present invention relates to a solid composition of sofosbuvir according to formula (I)
  • compositions of sofosbuvir include acid addition salts, formed with inorganic acids such as hydrochloric acid, hydro bromic acid, sulfuric acid, nitric acid, phosphoric acid, or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesul- fonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chiorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsul- fonic acid, la
  • the reference to pharmaceutically acceptable salts includes sol- vent addition forms (solvates) or crystal forms (polymorphs) of the same acid addition salt.
  • pharmaceutically acceptable salts of daclatasvir include acid addition salts, formed with inorganic acids such as hydrochloric, hydrobromic, sulphuric, or with organic acid such as 2- naphthalenesulfonic, toluenesulfonic, methanesulfonic, benzenesulfonic, maleic and fumaric acids.
  • the salt is daclatasvir dihydrochloride, preferably in its amorphous form.
  • Daclatasvir or the pharmaceut ically acceptable salt thereof comprised in the solid composition are in amorphous form. For example at least 35 weight-%, or at least 40 weight-%, or at least 45 weight-%, or at least 50 weight-%, or at least 55 weight-%, or at least 60 weight-%, or at least 65 weight-%, or at least 70 weight-%. or at least 75 weight-%, or at least 80 weight-%, or at least 85 weight-%.
  • At least 90 weight-%, or at least 95 weight-%, or at least 96 weight-%., or at least 97 weight-%, or at least 98 weight-%, or at least 99 weight-%, or at least 99 weight-%, or 1 00 weight-% of daclatasvir or the pharmaceutically acceptable salt thereof comprised in the solid composit ion are in amorphous form.
  • at least 97 weight-%, more preferably at least 98 weight-%, more preferably at least 99.9 weight-% of daclatasvir or the pharmaceut ically acceptable salt thereof comprised in the solid composit ion are in amorphous form.
  • Sofosbuvir or the pharmaceut ically acceptable salt thereof comprised in the solid composit ion are in amorphous form.
  • sofosbuvir or the pharmaceutically acceptable salt thereof comprised in the solid composit ion are in amorphous form.
  • at least 97 weight-%, more preferably at least 98 weight-%, more preferably at least 99.9 weight-%. of sofosbuvir or the pharmaceutically acceptable salt thereof comprised in the solid composit ion are in amorphous form.
  • Sofosbuvir or the pharmaceut ically acceptable salt thereof and daclatasvir or the pharmaceut ically acceptable salt thereof are present in the in the solid composit ion in a certain weight ratio.
  • the weight ratio of sofosbuvir or of the pharmaceutically acceptable salt thereof relative to daclatasvir or the pharmaceut ical ly acceptable salt thereof in the sol id composit ion is in the range of from 3 : 1 to 8 : 1 .
  • At least 90 weight-%, or at least 95 weight-%, or at least 96 weight-%, or at least 97 weight-%. or at least 98 weight-%, or at least 99 weight- %, or 1 00 weight-% of daclatasvir or the pharmaceut ical ly acceptable salt thereof are in amorphous form and at least 90 weight-%. or at least 95 weight-%, or at least 96 weight-%, or at least 97 weight-%, or at least 98 weight-%.
  • sofosbuvir or the pharmaceutically acceptable salt thereof are in amorphous form
  • w herein the weight ratio of sofosbuvir or of the pharmaceutical ly acceptable salt thereof relat ive to daclatasvir or the pharmaceutically acceptable salt thereof is in the range of from 3 : 1 to 8 : 1.
  • at least 97 weight-% of sofosbuvir or the pharmaceut ically acceptable salt thereof comprised in the solid composit ion are in amorphous form and at least 97 weight-%.
  • daclatasvir or the pharmaceutically acceptable salt thereof comprised in the solid composit ion are in amorphous form and the weight ratio of sofosbuv i o of the pharmaceut ically acceptable salt thereof relat iv e to daclatasv ir o the pharmaceut ically acceptable salt thereof is in the range of from 5 : 1 to 6.5 : 1 .
  • At least 99 weight-% of sofosbuv ir or the pharmaceut ically acceptable salt thereof comprised in the solid composit ion arc in amorphous form and at least 99 weight-% of daclatasvir or the pharmaceutically acceptable salt thereof comprised in the solid composition are in amorphous form and the weight ratio of sofosbuvir or of the pharmaceutical ly acceptable salt thereof relat ive to daclatasv ir or the pharmaceut ically acceptable salt thereof is in the range of from 5 : 1 to 6.5 : 1.
  • At least 75 weight-% or at least 90 weight-% or at least 95 weight-% or at least 96 weight-% or at least 97 weight-% o at least 98 weight-% or at least 99 weight-% or 100 weight-% of the solid composition consists of
  • At least 97 weight-%, more preferably at least 98 weight-% of the solid composition consists of
  • the solid composition may further comprise at least one pharmaceutically acceptable matrix compound. Therefore the present invention is further directed to solid composition comprising
  • sofosbuvir or a pharmaceutically acceptable salt thereof
  • At least 75 weight-% or at least 90 weight-% or at least 95 weight-% or at least 96 weight-% or at least 97 weight-% or at least 98 weight-% or at least 99 weight-% or 100 weight-% of the solid composition consists of
  • sofosbuvir or a pharmaceutically acceptable salt thereof
  • sofosbuvir or a pharmaceutically acceptable salt thereof
  • the solid composition is preferably a solid dispersion.
  • the at least one pharmaceutically acceptable matrix compound it was found that in particular hydrophilic polymers, preferably hydrophilic water-soluble polymers and silicon- based inorganic adsorbents are suitable pharmaceutically acceptable matrix compounds for stabilizing the amorphous sofosbuvir and the amorphous daclatasvir.
  • the at least one pharmaceutically acceptable matrix compound is a hydrophilic water-soluble polymer, a silicon-based inorganic adsorbent and a combination of two or more thereof.
  • At least one pharmaceutically acceptable matrix compound is selected from the group consisting of hydrophilic polymers, preferably hydrophilic water-soluble polymers, and combinations of two or more thereof; or from the group consisting of silicon-based inorganic adsorbents and combinations of two or more thereof; or from the group consisting of combinations of at least one hydrophilic polymer, preferably hydrophilic water-soluble polymer, and at least one silicon-based inorganic adsorbent.
  • the solid composition comprises at least one hydrophilic, preferably a water-soluble polymer as the pharmaceutically acceptable matrix compound. More preferably, the solid composition of the present invention comprises, as the pharmaceutically acceptable matrix compound, one, two, or three, preferably one or two, more preferably one hydrophilic, preferably water-soluble, polymer(s).
  • hydrophilic polymers include, but are not restricted to, polysaccharides, preferably cellulose derivatives, polyvinylpyrrolidones, polyethylene glycols, polyethylene glycol based copolymers, polyacrylic acids, salts of polyacrylic acids, polyvinyl alco- hols, polyacrylamide copolymers, methacrylic acid copolymers, methacrylate copolymers, pectines, chitin derivatives, chitosan derivatives, polyphosphates, polyoxazolines, and mixtures of two or more thereof.
  • polysaccharides preferably cellulose derivatives, polyvinylpyrrolidones, polyethylene glycols, polyethylene glycol based copolymers, polyacrylic acids, salts of polyacrylic acids, polyvinyl alco- hols, polyacrylamide copolymers, methacrylic acid copolymers, methacrylate copolymers, pectines, chitin derivatives, chitos
  • hydrophilic polymers include, but are not restricted to, cellulose derivatives selected from the group consisting of alkylcellulose, preferably methylcellulose, ethylcellulose, or propylcellulose; hydroxalkylcellulose, preferably hydroxymethylcellulose, hydroxyethylcellulose, or hydroxypropylcellulose; hydroxy- alkylalkylcellulose, preferably hydroxyethylmethylcellulose (HEMC), or hydroxypropylmethylcellulose (HPMC); carboxyalkylcellulose, preferably carboxymethylcellulose (CMC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxyethylcarboxymethylcellulose (HECMC); sodium carboxymethylcellulose, cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose acetate (HPMCA), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and a mixture of two or more thereof. More specific examples of hydrophilic polymers further include vinyl pyrrol
  • the at least one hydrophilic, preferably water-soluble, polymer has a solubility in water of at least 10 g/1, more preferably of at least 15 g/1, more preferably of at least 20 g/1, more preferably of at least 25 g/1, more preferably of at least 30 g/1, in each case at 23 °C at atmospheric pressure.
  • polysaccharides and derivatives of polysaccharides are preferred.
  • the polysaccharides can be homoglycans or heteroglycans. Further, the polysaccharides can be naturally occurring compounds or synthesized compounds.
  • compounds are preferred which are derivatized at one or more hydroxyl groups of the monosaccharide units of the polysaccharides.
  • Polysaccharides and derivatives of polysaccharides include, but are not restricted to, cellulose and cellulose derivatives, such as alkylcellulose, such as methylcellulose, ethylcellulose, or propylcellulose; hydroxalkylcellulose, such as hydroxymethylcellulose, hydroxyethylcellulose, or hydroxypropylcellulose; hydroxyalkylalkylcellulose, such as hydroxyethylmethylcellulose (HEMC), or hydroxypropylmethylcellulose (HPMC); carboxyalkylcellulose, such as carboxymethylcellulose (CMC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxyethylcarbox- ymethylcellulose (HECMC); sodium carboxymethylcellulose, cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose acetate (HPMCA), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and a mixture or combination of two or more thereof.
  • alkylcellulose such
  • the at least one hydrophilic, preferably water-soluble, polymer comprises, preferably consists of a cellulose derivative selected from the group consisting of hydroxy alky lalkyl- celluloses and a mixture of two or more thereof. More preferably, the at least one hydrophilic, preferably water-soluble, polymer comprises, more preferably consists of, hydroxypropylme- thylcellulose (HPMC).
  • HPMC hydroxypropylme- thylcellulose
  • the weight average molecular weight (M w ) of the cellulose derivative is in the range of from 7 to 225 kDa, more preferably in the range of from 7 to 100 kDa, more preferably in the range of from 7 to 30 kDa.
  • the solid composition contains two or more cellulose derivative, preferably two or more hydroxy- alkylalkylcelluloses, more preferably two or more hydroxypropylmethylcelluloses which differ only in the weight average molecular weight M w .
  • the molecular degree of substitution (DS) of the cellulose derivative is in the range of from 0.3 to 2.8, more preferably in the range of from 0.6 to 2.5, more preferably in the range of from 1.0 to 2.3, more preferably in the range of from 1.3 to 2.0.
  • the solid composition contains two or more cellulose derivative, preferably two or more hydroxyalkylalkylcelluloses, more preferably two or more hydroxypropylmethylcelluloses which differ only in the molecular degree of substitution.
  • the parameter DS describes the number of hydroxyalkylalkylated sites per anhydro-glucose unit of a given hydroxyalkylalkylcellulose.
  • the solid composition contains two or more cellulose derivatives, preferably two or more hydroxyalkylalkylcelluloses, more preferably two or more hydroxypropylmethylcelluloses which differ in the molecular degree of substitution and the weight average molecular weight M w .
  • the present invention is further directed to a solid composition wherein at least 95 weight-% or at least 96 weight-% or at least 97 weight-% or at least 98 weight-% or at least 99 weight-% or 100 weight-% of the solid composition consists of
  • sofosbuvir or a pharmaceutically acceptable salt thereof
  • the pharmaceutically acceptable matrix compound is a hydrophilic polymer selected from a vinyl pyrrolidone-vinyl acetate copolymers, preferably copovidone and cellulose derivatives selected from the group consisting of alkylcellulose, preferably methylcellulose, ethylcellulose, or propylcellulose; hydroxalkylcellulose, preferably hydroxymethylcellulose, hydroxyethylcellulose, or hydroxypropylcellulose; hydroxyalkylalkylcellulose, preferably hydroxyethylmethylcellulose (HEMC), or hydroxypropylmethylcellulose (HPMC); carboxyalkylcellulose, preferably car- boxymethylcellulose (CMC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxyethylcarboxymethylcellulose (HECMC); sodium carboxymethylcellulose, cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose acetate (HPM- CA), hydroxypropylmethylcellulose phthalate (HPMCP),
  • CAP hydroxypropylmethylcellulose
  • the at least one pharmaceutically acceptable matri compound is copov idonc or h y d ro y p ro p y 1 m e t h y 1 - cellulose (HPMC).
  • the weight ratio of sofosbuvir or the pharmaceut ically acceptable salt thereof relative to daclatasvir or the pharmaceutically acceptable salt thereof is in the range of from 5 : 1 to 6.5 : 1 and p eferably the weight ratio of the sofosbuvir or a pharmaceutically acceptable salt thereof and daclatasvir or the pharmaceutically acceptable salt thereof relative to the at least one pharmaceutically acceptable matrix compound is in the range of from 2.3 : 1 to 5 : 1.
  • the solid composition is a solid dispersion. b) silicon based inorganic adsorbents
  • the at least one pharmaceutically acceptable matrix compound may comprise at least one silicon-based inorganic adsorbent.
  • the at least one silicon-based inorganic adsorbent has an oil adsorbance in the range of from 1.0 to 5.0 ml/g, preferably in the range of from 1.3 to 4.5 ml/g, more preferably in the range of from 1.5 to 4.0 ml/g.
  • the solid composition of the present invention contains at least one silicon-based inorganic adsorbent having an oil adsorbance in the above-defined preferred ranges and at least one silicon-based inorganic adsorbent having an oil adsorbance outside these ranges.
  • all silicon-based inorganic adsorbents comprised in the solid composition of the present invention have an oil adsorbance in the above-defined preferred ranges.
  • the least one silicon-based inorganic adsorbent has a bulk density in the range of from 10 to 500 g/ml, preferably in the range of from 30 to 400 g/ml, more preferably in the range of from 50 to 300 g/ml.
  • the solid composition of the present invention contains at least one silicon-based inorganic adsorbent having a bulk density in the above-defined preferred ranges and at least one silicon-based inorganic adsorbent having a bulk density outside these ranges.
  • all silicon-based inorganic adsorbents comprised in the solid composition of the present invention have having a bulk density in the above-defined preferred ranges.
  • the least one silicon-based inorganic adsorbent has a pH in the range of from 6.0 to 9.0, preferably in the range of from 6.5 to 8.5, more preferably in the range of from 7.0 to 8.0.
  • the at least one silicon-based inorganic adsorbent there is no particular limitation as to the at least one silicon-based inorganic adsorbent provided that the above conditions as to the oil adsorbance, the bulk density and the pH are met.
  • the at least one silicon-based inorganic adsorbent is selected from the group consisting of silica, silicates, and a combination of two or more thereof. It is further contemplated that at least 90 weight-%, preferably at least 95 weight-%, more preferably at least 99 weight- % of the at least one silicon-based inorganic adsorbent is in amorphous form.
  • the silica is selected from the group consisting of fumed silica, precipitated silica, gel silica, colloidal silica, and a combination of two or more thereof, such as a combination of fumed silica and precipitated silica or a combination of fumed silica and colloidal silica or a combination of fumed silica and gel silica or a combination of precipitated silica and gel silica or a combination of precipitated silica and colloidal silica or a combination of gel silica and colloidal silica or a combination of fumed silica and precipitated silica and gel silica or a combination or fumed silica and gel silica and colloidal silica or a combination of precipitated silica and gel silica and colloidal silica or a combination of fumed silica and colloidal silica or a combination of fumed silica and colloidal silica or a combination of fumed silica and colloidal silica or a combination
  • the silicate is an alumino silicate which, more preferably, additionally contains at least one alkali metal element selected from the group consisting of Li, Na, K, Rb, Cs and a combination of two or more thereof, preferably from the group consisting of Li, Na, K, and a combination of two or more thereof, more preferably from the group consisting of Na, K, and a combination of two or more thereof, and/or at least one alkaline earth metal element selected from the group consisting of Mg, Ca, Sr, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, and a combination of two or more thereof.
  • the silicate is an aluminosilicate which additionally contains at least one alkaline earth metal element selected from the group consisting of Mg, Ca, Sr, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, and a combination of two or more thereof. More preferably, the silicate is an aluminosilicate which additionally contains Mg.
  • Preferred silicates include, but are not restricted to, the commercial- ly available compounds Neusilin® UFL2, Neusilin® US2, both from Fuji Chemical Industry Co., Ltd.
  • the present invention also relates to the solid composition as described above, wherein the at least one silicon-based inorganic adsorbent is selected from the group consisting of silica, silicates, and a combination of two or more thereof, wherein the silica is preferably selected from the group consisting of fumed silica, precipitated silica, gel silica, colloidal silica, and a combination of two or more thereof, and wherein the silicates are preferably alu- minosilicates preferably comprising at least one alkali metal element and/or at least one alka- line earth metal element, more preferably at least one alkaline earth metal element, more preferably magnesium.
  • the silica and/or the silicate can be in crystalline or amorphous form. It is further contemplated that at least 90 weight-%, preferably at least 95 weight-%, more preferably at least 99 weight-% of the the silica and/or the silicate is in amorphous form.
  • the present invention is for example directed to a solid composition wherein at least 95 weight-% or at least 96 weight-% or at least 97 weight-% or at least 98 weight-% or at least 99 weight-% or 100 weight-% of the solid composition consists of
  • sofosbuvir or a pharmaceutically acceptable salt thereof
  • At least one pharmaceutically acceptable matrix compound wherein the matrix compound is a silicon-based inorganic adsorbent such as an amorphous silica or colloidal silica
  • weight ratio of sofosbuvir or of the pharmaceutically acceptable salt thereof relative to daclatasvir or the pharmaceut ically acceptable salt thereof ranges from 3 : 1 to 8 : 1
  • weight ratio of the sofosbuvir o the pharmaceutically acceptable salt thereof and daclatasvir o the pharmaceutically acceptable salt thereof relative to the at least one pharmaceutically acceptable matrix compound is at least 1.2 : 1.
  • the weight ratio of sofosbuvir or the pharmaceutically acceptable salt thereof relative to daclatasvir or the pharmaceutically acceptable salt thereof is in the range o from 5 : 1 to 6.5 : 1 and preferably the weight ratio of the sofosbuvi o the pharmaceut ically acceptable salt thereof and daclatasvir o the pharmaceutically acceptable salt thereof relative to the at least one pharmaceutically acceptable matri compound is in the range of from 2.3 : 1 to 5 : 1.
  • the solid composition is a solid dispersion.
  • the present invention also relates to the preparation of a solid composition comprising amorphous sofosbuvir or an amorphous pharmaceutically acceptable salt thereof and amorphous daclatasvir or an amorphous pharmaceutically acceptable salt thereof, preferably the solid composition of the invention as described above wherein the solid composition more preferably comprises at least one pharmaceutically acceptable matrix compound.
  • the present invention is directed to a process for the preparation of a solid composition, comprising sofosbuvir according to formula (I)
  • the process comprises embedding sofosbuvir or a pharmaceutically acceptable salt thereof and daclatasvir or a pharmaceutically acceptable salt thereof in a matrix consisting of the at least one pharmaceutically acceptable matrix compound, starting from a solution or a suspension of the sofosbuvir or the pharmaceutically acceptable salt thereof and daclatasvir or the pharmaceutically acceptable salt thereof in at least one solvent.
  • the solution or the suspension of sofosbuvir or the pharmaceutically acceptable salt thereof and daclatasvir or the pharmaceutically acceptable salt thereof used as the starting material for the preparation of the solid composition can be prepared according to all conceivable means.
  • the solution or the suspension can be prepared from amorphous sofosbuvir, from crystalline sofosbuvir in one or more crystalline forms, from a sofosbuvir salt, from a sofosbuvir solvate, from a sofosbuvir hydrate, or from a combination of two or more thereof.
  • the solution can be prepared from amorphous daclatasvir, from crystalline daclatasvir in one or more crystalline forms, from a daclatasvir salt, from a daclatasvir solvate, from a daclatasvir hydrate, or from a combination of two or more thereof.
  • sofosbuvir such as crystalline form 1.
  • crystalline form 1 of sofosbuvir is described, for example, in patent application WO2011/123645 A.
  • crystalline daclatasvir it is possible to start from a solution prepared from crystalline daclatasvir.
  • the preparation of crystalline daclatasvir 2HC1 is described, for example, in patent application WO2009/020828A.
  • the present invention also relates to a process as described above, wherein the solution of the sofosbuvir in at least one solvent is prepared from sofosbuvir wherein at least 95 weight-%, preferably at least 99 weight-%, more preferably at least 99.9 weight-% of sofosbuvir is in amorphous form.
  • a method for preparing amorphous sofosbuvir is disclosed herein below. Further, it is possible to start from a solution prepared from amorphous daclatasvir.
  • the present invention also relates to a process as described above, wherein the solution of the daclatasvir in at least one solvent is prepared from daclatasvir wherein at least 95 weight-%, preferably at least 99 weight-%, more preferably at least 99.9 weight-% of daclatasvir is in amorphous form.
  • a method for preparing amorphous daclatasvir 2HC1 is disclosed in patent application US20160194352.
  • the weight ratio of sofosbuvir or a pharmaceutically acceptable salt thereof and daclatasvir or a pharmaceutically acceptable salt thereof relative to the at least one pharmaceutically acceptable matrix compound is at least 1.5 : 1, preferably in the range of from 1.5 : 1 to 9 : 1, more preferably in the range of from 2.3 : 1 to 5 : 1.
  • the at least one solvent is selected from the group consisting of water, an organic solvent, and a combination of two or more thereof, wherein the organic solvent is preferably selected from the group consisting of C1-C3 ketones such as acetone, Cl- C2 halogenated hydrocarbons, C1-C4 alcohols, C2-C6 ethers, C3-C5 esters, and a combina- tion of two or more thereof.
  • the at least one solvent is selected from the group consisting of water and a C1-C4 alcohol or a combination thereof.
  • the C1-C4 alcohol is preferably selected from the group consisting of methanol, ethanol, propanol, isopropanol, buta- nol, more preferably the C1-C4 alcohol is methanol. It is also preferred that the solvent is a mixture of water and methanol.
  • the embedding comprises subjecting the solution or the suspension to drying.
  • the drying is carried out by lyophilizing the solution or the suspension or spray-drying the solution or the suspension or evaporating to dry, or by melt evaporation.
  • the embedding comprises spray-drying the solution or the suspension.
  • the present invention also relates to the process as described above, wherein the process comprises subjecting the solution or the suspension of the sofosbuvir, the daclatasvir or the pharmaceutically acceptable salts thereof and the at least one pharmaceutically acceptable matrix compound to drying by spray-drying the solution or the suspension or by evaporating and optionally vacuum-drying the solution or the suspension, more preferably by spray-drying the solution or the suspension.
  • the solution comprising sofosbuvir or a pharmaceutically acceptable salt thereof and daclatasvir or a pharmaceutically acceptable salt thereof is incorporated directly into the melt pharmaceutically acceptable matrix compound and evaporation is followed.
  • At least 99 weight-%, preferably at least 99.9 weight-%, more preferably at least 99.9 weight-% of the at least one solvent is removed and the solid composition is obtained.
  • the solid composition obtained is preferably a solid dispersion.
  • the present invention is preferably directed to a process for the preparation of a solid composition, comprising sofosbuvir according to formula (I)
  • At least one pharmaceutically acceptable matrix compound preferably for the preparation of a solid composition as disclosed herein above in the chapter "The solid composition”.
  • Said process comprises preparing a solution or a suspension of the sofosbuvir or a pharmaceutically acceptable salt thereof, daclatasvir or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable matrix compound in at least one solvent, subjecting the solution or the suspension to drying, preferably by spray-drying or by evaporating to dry, more preferably by spray-drying, wherein the solvent is preferably methanol or a mixture of water and methanol.
  • the solid composition obtained is a solid dispersion.
  • the at least one pharmaceutically acceptable matrix compound is hydroxypropylmethylcellulose (HPMC) or copovidone
  • the present invention is further directed to a process for the preparation of a solid composition, comprising
  • At least one pharmaceutically acceptable matrix compound preferably for the preparation of a solid composition as disclosed herein above in the chapter "The solid composition”.
  • Said process comprises embedding sofosbuvir or a pharmaceutically acceptable salt thereof and daclatasvir or a pharmaceutically acceptable salt thereof in a matrix consisting of the at least one pharmaceutically acceptable matrix compound by melting the at least one pharmaceutically acceptable matrix compound in solid form together with the sofosbuvir or a pharmaceutically acceptable salt thereof in solid form and daclatasvir or a pharmaceutically acceptable salt thereof in solid form.
  • the weight ratio of sofosbuvir or the pharmaceutically acceptable salt thereof and daclatasvir or the pharmaceutically acceptable salt thereof relative to the at least one pharmaceutically acceptable matrix compound is at least 1.5 : 1, preferably is in the range of from 1.5 : 1 to 9 : 1, more preferably is in the range of from 2.3 : 1 to 5 : 1 .
  • the solid composition obtained is a solid dispersion.
  • the melting is carried out by a hot-melt method, more preferably by a hot- melt extrusion method.
  • a hot melt extrusion method the active ingredients and the at least one pharmaceutically acceptable matrix compound are mixed and melted, homogenized, extruded and shaped to the desired form.
  • the at least one pharmaceutically acceptable matrix compound is as disclosed above in the chapter "The solid composition”.
  • the present invention is further directed to a process for the preparation of a solid composition, comprising sofosbuvir according to formula (I)
  • a solid composition for the preparation of a solid composition preferably a solid composition as disclosed above in the chapter "The solid composition", wherein the at least 97 weight-%, preferably at least 99 weight-%, more preferably 99.9 weight-%) of the solid composition consist of sofosbuvir or a pharmaceutically acceptable salt thereof and daclatasvir or a pharmaceutically acceptable salt thereof.
  • said solid composition does not comprise the at least one pharmaceutically acceptable compound.
  • Said process comprises preparing a solution or a suspension of the sofosbuvir or a pharmaceutically acceptable salt thereof and daclatasvir or a pharmaceutically acceptable salt thereof in at least one solvent, subjecting the solution or the suspension to drying, preferably by lyophilization, or by spray-drying or by spray granulation or by evaporating to dry, more preferably by spray-drying.
  • the solid composition obtained is a solid dispersion.
  • the at least one solvent is selected from the group consisting of water, an organic solvent, and a combination of two or more thereof.
  • the organic solvent is preferably selected from the group consisting of C1-C2 halogenated hydrocarbons, C1-C4 alcohols, C2-C6 ethers, C3-C5 esters, and a combination of two or more thereof.
  • the at least one solvent is a Cl- C4 alcohol.
  • the C1-C4 alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, more preferably the C1-C4 alcohol is methanol.
  • the process of the invention as disclosed hereinabove may further comprises the preparation of sofosbuvir in amorphous form.
  • the process comprises
  • sofosbuvir in at least one crystalline form or as a mixture of at least one crystalline form and amorphous form
  • step (i) at least 95 weight-%, more preferably at least 99 weight-%, more preferably at least 99.9 weight-% of sofosbuvir is in at least one crystalline form.
  • the at least one solvent according to (ii) is selected from the group consisting of water, C1-C3 ketones, C1-C2 halogenated hydrocarbons, C1-C4 alcohols, C2-C6 ethers, C3- C5 esters, and a combination of two or more thereof. More preferably the at least one solvent according to (ii) is selected from the group consisting of water, C1-C4 alcohols, C1-C3 ketones, and a combination of two or more thereof.
  • the at least one solvent comprises, preferably consists of, water and a C1-C4 alcohol, preferably water and ethanol, or the at least one solvent comprises, more preferably consists of, acetone.
  • at least 95 weight-%, preferably at least 99 weight-%, more preferably at least 99.9 weight-% of sofosbuvir is obtained in its amorphous form.
  • the rapid-drying according to (iii) is carried out by spray-drying or spray- granulation, preferably by spray-drying.
  • the spray-drying is preferably carried out at an inlet temperature in the range of from 50 to 100 °C, and at an outlet temperature in the range of from 20 to 70 °C.
  • a further method for the preparation of amorphous sofosbuvir is contemplated.
  • the process of the invention as disclosed hereinabove may further comprises the preparation of amorphous sofosbuvir.
  • the process comprises
  • step (i') at least 95 weight-%o, more preferably at least 99 weight-%o, more pref- erably at least 99.9 weight-% of sofosbuvir is in at least one crystalline form.
  • step ( ⁇ ') at least 95 weight-%), preferably at least 99 weight-%o, more preferably at least 99.9 weight-%o of sofosbuvir is obtained in its amorphous form.
  • the present invention is directed to a solid composition obtainable or obtained by a process for preparing a solid composition wherein the solid composition is as disclosed herein above in chapter "The solid composition”.
  • compositions and preparation of a pharmaceutically acceptable composition are provided.
  • the present invention further relates to a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising the solid composition as described herein above and at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable composition is in the form of an oral dosage form for example a compressed or a non-compressed dosage form.
  • the oral dosage form according to the present invention is a compressed dosage form.
  • the oral dosage form of the present invention is a granule, a capsule, for example a capsule filled with gran- ules, a sachet, a pellet, a dragee, a lozenge, a troche, a pastille, or a tablet, such as an uncoated tablet, a coated tablet, an effervescent tablet, a soluble tablet, a dispersible tablet, an orodis- persible tablet, a tablet for use in the mouth, a chewable tablet or an extrudate.
  • the oral dosage form of the present invention is a tablet.
  • the tablets contain, in addition to the solid composition of the present invention, at least one pharmaceutically acceptable excipient.
  • Any pharmaceutically acceptable excipient can be employed as long as it does not detrimentally affect the properties of the pharmaceutically acceptable composition.
  • pharmaceutically acceptable excipients comprise carriers such as solid carriers like magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methycellulose, sodium carboxy-methylcellulose and wax; or liquid carriers such as water, aqueous or nonaqueous liquids, vehicles, diluents, solvents, binders, adjuvants, solubilizers, thickening agents, stabilizers, disintegrants, glidants, lubricating agents, buffering agents, emulsifiers, wetting agents, suspending agents, sweetening agents, colorants, flavors, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers, additives to make
  • pharmaceutically acceptable excipient and “pharmaceutical excipient” as used in this context of the present invention refer to a compound that is used to prepare a pharmaceutically acceptable composition, and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
  • the pharmaceutically acceptable composition comprises the solid composition of the present invention, and at least one excipient selected from the group consisting of at least one of a diluent, at least one disin- tegrant, at least one glidant, at least one lubricant, and a combination of two or more thereof.
  • the diluent may be selected from the group consisting of calcium carbonate, dicalcium phosphate, dry starch, calcium sulfate, cellulose, compressible sugars, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmi- tostearate, hydrogenated vegetable oil, inositol, kaolin, lactose, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, powdered sugar, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, and combinations of two or more thereof.
  • the disintegrant may be selected from the group consisting of agar, alginic acid, bentonite, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethyl- cellulose, cellulose, a cation exchange resin, cellulose, gums, citrus pulp, colloidal silicon dioxide, corn starch, croscarmellose sodium crospovidone, guar gum, hydrous aluminum silicate, an ion exchange resin such as polyacrin potassium, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, modified cellulose gum, modified corn starch, montmorillonite clay, natural sponge, polyacrilin potassium, potato starch, powdered cellulose, povidone, pregelatinized starch, sodium alginate, sodium bicarbonate in admixture with an acidulant such as tartaric acid or citric acid, sodium starch glycolate, starch, silicates such as, and combinations of two or more thereof.
  • an acidulant such as tartaric acid or citric acid, sodium starch glycolate, star
  • the glidant may be selected from the group consisting of colloidal silicon dioxide, talc, starch, starch derivatives, and combinations of two or more thereof.
  • the lubricant may be selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium ben- zoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, and combinations thereof.
  • the pharmaceutically acceptable composition of the present invention in particular in form of a tablet, may further comprise a coating agent which may further comprise a taste-masking agent.
  • the coating agent may be formed from an aqueous film coat composi- tion, wherein the aqueous film coat composition may comprise a film-forming polymer, water and/or an alcohol as a vehicle, and optionally one or more adjuvants such as are known in the film-coating art.
  • the coating agent may be selected from among hydroxypropylmethylcellu- lose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, cellulose acetate phthalate, sodium ethyl cellulose sulfate, carboxymethyl cellulose, polyvinylpyr- rolidone, zein, and an acrylic polymer such as methacrylic acid/methacrylic acid ester copolymers such as methacrylic acid/methylmethacrylate copolymers, etc., and a polyvinyl alcohol.
  • film-forming polymers are typically provided in either aqueous or organic solvent-based solutions or aqueous dispersions.
  • the polymers may be also provided in dry form, alone or in a powdery mixture with other components such as a plasti- cizer and/or a colorant, which may be made into a solution or dispersion.
  • the aqueous film coat composition may further comprise water as a vehicle for the other components.
  • the vehicle may optionally further comprise one or more water soluble solvents, such as an alcohol and/or a ketone.
  • Conceivable examples of an alcohol include but are not limited to methanol, isopropanol, propanol, etc.
  • a non-limiting example for the ketone may be acetone.
  • Suitable aqueous film coating compositions may include those commercially available from Colorcon, Inc. of West Point, Pa., under the trade name OPADRY and OPADRY II.
  • the present invention is further directed to a process for the preparation of a pharmaceutically acceptable composition, preferably an oral dosage form, more preferably a tablet, preferably as disclosed herein above.
  • a pharmaceutically acceptable composition preferably an oral dosage form, more preferably a tablet, preferably as disclosed herein above.
  • the process comprises
  • the solid composition provided in (a) is the solid composition disclosed in the chapter "The solid composition” herein above or the solid composition is the solid composition obtained or obtainable according to the processes disclosed herein above.
  • the solid composition provided in (a) comprises the at least a pharmaceutically acceptable matrix compound.
  • the solid composition provided in (a) is a solid dispersion.
  • the at least one pharmaceutically acceptable excipient is as disclosed herein above.
  • any conceivable method for preparing a pharmaceutically acceptable composition can be used for preparing the pharmaceutically acceptable composition of the invention.
  • the pharmaceutically acceptable composition of the invention can be prepared by direct compression of the mixture of (b) comprising the solid composition of the invention and the at least one pharmaceutically acceptable excipient or by granulation of an intragranular composition comprising the solid composition of the invention and optionally at least one pharmaceutically acceptable excipient with an extragranular composition.
  • the present invention is further directed to a solid composition as disclosed herein above or to a pharmaceutically acceptable composition as disclosed herein above, for use in a method for treating hepatitis C in a human.
  • the present invention is further directed to a solid composition as disclosed herein above or to a pharmaceutically acceptable composition as disclosed herein above for the preparation of a medicament for treating hepatitis C in a human.
  • the present invention is further directed to a method for treating hepatitis C comprising administering a solid composition as disclosed herein above or to a pharmaceutically acceptable composition as disclosed herein above
  • a solid composition comprising sofosbuvir or a pharmaceutically acceptable salt thereof, daclatasvir or a pharmaceutically acceptable salt thereof and optionally at least one pharmaceutically acceptable matrix compound, wherein at least 35 weight-%, or at least 40 weight-%, or at least 45 weight-%, or at least 50 weight-%, or at least 55 weight-%, or at least 60 weight-%.. or at least 65 weight-%, or at least 70 weight-%, or at least 75 weight-%, or at least 80 weight-%. or at least 85 weight-%.. or at least 90 weight-%, or at least 95 weight-%, or at least 96 weight-%.
  • sofosbuvir or the pharmaceutically acceptable salt thereof comprised in the solid composition is in amorphous form.
  • the solid composition of any one of embodiments 1 to 3, wherein at least 97 weight-%, preferably at least 98 weight-%, more preferably at least 99.9 weight-% of sofosbiiv ir or the pharmaceutically acceptable salt thereof comprised in the solid composition is in amorphous form.
  • the solid composition of any one of embodiments 1 to 6, wherein at least 75 weight-% or at least 90 weight-% or at least 95 weight-% or at least 96 weight-% or at least 97 weight-%, preferably at least 98 weight-% more preferably at least 99.9 weight-% of the solid composition consists of
  • sofosbiivir or a pharmaceutically acceptable salt thereof
  • the solid composition of any one of embodiments 1 to 8, wherein at least 75 weight-% or at least 90 weight-% or at least 95 weight-% or at least 96 weight-% or at least 97 weight-%, preferably at least 98 weight-% more preferably at least 99.9 weight-% of the solid composition consists of
  • sofosbiivir or a pharmaceutically acceptable salt thereof
  • the solid composition of embodiment 10 or 11, wherein the at least one hydrophilic water-soluble polymer comprises, preferably consists of a cellulose derivative selected from the group consisting of hydroxyalkylalkylcelluloses and a mixture of two or more thereof, the at least one hydrophilic water-soluble polymer preferably comprising, more preferably consisting of, hydro xypropylmethylcellulose (HPMC).
  • HPMC hydro xypropylmethylcellulose
  • the solid composition of embodiment 12 wherein the cellulose derivative has a degree of substitution (DS) in the range of from 0.3 to 2.8, preferably in the range of from 0.6 to 2.5, more preferably in the range of from 1.0 to 2.3, more preferably in the range of from 1.3 to 2.0.
  • DS degree of substitution
  • the solid composition of embodiment 15, wherein the at least one silicon-based inorganic adsorbent has an oil adsorbance in the range of from 1.0 to 5.0 ml/g, preferably in the range of from 1.5 to 4.0 ml/g.
  • the solid composition of embodiment 15 or 16, wherein the at least one silicon-based inorganic adsorbent has a bulk density in the range of from 10 to 500 g/ml, preferably in the range of from 30 to 400 g/ml, more preferably in the range of from 50 to 300 g/ml.
  • the at least one silicon-based inorganic adsorbent is selected from the group consisting of silica, silicates, and a combination of two or more thereof, wherein the silica is preferably selected from the group consisting of fumed silica, precipitated silica, gel silica, colloidal silica, and a combination of two or more thereof, and wherein the silicates are preferably aluminosilicates preferably comprising at least one alkali metal element and/or at least one alkaline earth metal element, more preferably at least one alkaline earth metal element, more preferably magnesium, wherein more preferably, at least 90 weight-%, more preferably at least 95 weight-%, more preferably at least 99 weight-% of the at least one silicon-based inorganic adsorbent is in amorphous form.
  • the solid composition of any one of embodiments 1 to 18, wherein the weight ratio of the sofosbuvir or the pharmaceutically acceptable salt thereof and of daclatasvir or the pharmaceutically acceptable salt thereof relative to the at least one pharmaceutically acceptable matrix compound is at least 1.2 : 1, preferably in the range of from 1.5 : 1 to 9 : 1, more preferably in the range of from 2.3 : 1 to 5 : 1.
  • a pharmaceutically acceptable composition comprising the solid composition according to any one of embodiments 1 to 21.
  • compositions of embodiment 22, wherein the pharmaceutically acceptable composition is an oral dosage form, preferably an oral dosage form selected from the group consisting of tablet, capsule, dragee (sugar coated tablet), powder, granules, and sachets.
  • At least one pharmaceutically acceptable matrix compound preferably for the preparation of a solid composition according to any one of embodiments 1 to 21,
  • said process comprising embedding sofosbuvir or the pharmaceutically acceptable salt thereof and daclatasvir or the pharmaceutically acceptable salt thereof in a matrix consisting of the at least one pharmaceutically acceptable matrix compound, starting from a solution or a suspension of the sofosbuvir or the pharmaceutically acceptable salt thereof and daclatasvir or the pharmaceutically acceptable salt thereof in at least one solvent, wherein the weight ratio of sofosbuvir or of the pharmaceutically acceptable salt thereof and of daclatasvir or of the pharmaceutically acceptable salt thereof relative to the at least one pharmaceutically acceptable matrix compound is at least 1.5 : 1, preferably in the range of from 1.5 : 1 to 9 : 1 , more preferably in the range of from 2.3 : 1 to 5 : 1.
  • a process for the preparation of a solid composition comprising
  • weight ratio of the sofosbuvir or of the pharmaceutically acceptable salt thereof and of daclatasvir or of the pharmaceutically acceptable salt thereof relative to the at least one pharmaceutically acceptable matrix compound is at least 1.5 : 1, preferably in the range of from 1.5 : 1 to 9 : 1, more preferably in the range of from 2.3: 1 to 5 : 1. 27.
  • the at least one pharmaceutically acceptable matrix compound is selected from the group consisting of hydrophilic water- soluble polymers, silicon-based inorganic adsorbents and a combination of two or more thereof, preferably wherein the at least one pharmaceutically acceptable matrix compound is copovidone or hydroxypropylmethylcellulose (HPMC), more preferably the at least one pharmaceutically acceptable matrix compound is hydroxypropylmethylcellulose (HPMC).
  • At least one pharmaceutically acceptable matrix compound has a pH in the range of from 6.0 to 9.0, preferably in the range of from 6.5 to 8.5, more preferably in the range of from 7.0 to 8.0.
  • the process of embodiment 31 wherein the at least one solvent is a combination of water and methanol.
  • the embedding comprises subjecting the solution or the suspension to drying, preferably by lyophilizing the solution or spray-drying the solution or evaporating to dry, more preferably by spray- drying.
  • a solid composition preferably for the preparation of a solid composition according to any one of embodiments 1 to 7, wherein at least 98 weight-% more preferably at least 99.9 weight-% of the solid composition consists of sofosbuvir or the pharmaceutically acceptable salt thereof and of daclatasvir or the pharmaceut ically acceptable salt thereof, said process comprising preparing a solution or a suspension of the sofosbuvir or the pharmaceutically acceptable salt thereof and daclatasvir or the pharmaceutically acceptable salt thereof in at least one solvent, subjecting the solution or the suspension to drying, preferably by lyophilization, or by spray-drying or by spray granulation or by evaporating to dry, more preferably by spray-drying.
  • the at least one solvent is selected from the group consisting of water, an organic solvent, and a combination of two or more thereof, wherein the organic solvent is preferably selected from the group consisting of Cl- C2 halogenated hydrocarbons, C1-C4 alcohols, C2-C6 ethers, C3-C5 esters, and a combination of two or more thereof.
  • the at least one solvent is a C1-C4 alcohol preferably selected from the group consisting of methanol, ethanol, propanol, iso- propanol, butanol, more preferably the C1-C4 alcohol is methanol.
  • sofosbuvir in at least one crystalline form or as a mixture of at least one crystalline form and amorphous form, preferably providing sofosbuvir wherein at least 95 weight-%, preferably at least 99 weight-%, more preferably at least 99.9 weight-% of sofosbuvir is in at least one crystalline form;
  • the at least one solvent according to (ii) is selected from the group consisting of water, C1-C3 ketones, C1-C2 halogenated hydrocarbons, C1-C4 alcohols, C2-C6 ethers, C3-C5 esters, and a combination of two or more thereof, more preferably from the group consisting of water, C1-C4 alcohols, Cl- C3 ketones, and a combination of two or more thereof, wherein more preferably, the at least one solvent comprises, more preferably consists of, water and a C1-C4 alcohol, preferably water and ethanol, or comprises, more preferably consists of, acetone.
  • sofosbuvir in at least one crystalline form or in amorphous form or as a mixture of at least one crystalline form and amorphous form, preferably providing sofosbuvir wherein at least 95 weight-%, preferably at least 99 weight-%, more preferably at least 99.9 weight-% of sofosbuvir is in at least one crystalline form; ( ⁇ ') subjecting the sofosbuvir provided in (i') to a melt method, preferably a hot-melt method, more preferably a hot-melt extrusion method, obtaining the sofosbuvir of wherein at least 95 weight-%, preferably at least 99 weight-%, more preferably at least 99.9 weight-%) of sofosbuvir is in its amorphous form.
  • a melt method preferably a hot-melt method, more preferably a hot-melt extrusion method
  • a process for the preparation of a pharmaceutically acceptable composition preferably an oral dosage form, more preferably a tablet, said process comprising
  • a solid composition obtainable or obtained by a process according to any one of embodiments 25 to 41.
  • a pharmaceutically acceptable composition obtainable or obtained by a process according to embodiment 42.
  • a method for treating hepatitis C comprising administering a solid composition according to any one of embodiments 1 to 21 or 43, or a pharmaceutically acceptable composition according to any one of embodiments 22 to 24 or 44, to a human patient in need thereof.
  • Reference Example 1 Characterization of amorphousness via XRD analysis
  • the solid compositions obtained according to Examples 1.1 and 1.2 herein below were sub- jected to XRD analysis as follows: the X-ray powder diffraction pattern (XRPD) was obtained with a PA alytical X'Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, programmable XYZ stage with well plate holder, Cu-Kalphal,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector.
  • XRPD X-ray powder diffraction pattern
  • the patterns were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a step size of 0.013 ° 2-theta with 40 s per step (255 channels) in the angular range of 2 ° to 40 ° 2-theta at ambient conditions.
  • the XRD patters showed that sofosbuvir and daclatasvir in the solid composition were in amorphous form.
  • Example 1 Preparation of a solid composition comprising amorphous sofosbuvir and amorphous daclatasvir and a hydrophilic water-soluble polymer as the matrix compound

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Abstract

La présente invention concerne une composition solide comprenant du sofosbuvir amorphe et du daclatasvir amorphe et un procédé de préparation de la composition solide. La présente invention concerne en outre une composition pharmaceutiquement acceptable comprenant la composition solide. De plus, la présente invention concerne l'utilisation de la composition solide et de la composition pharmaceutiquement acceptable comprenant la composition solide pour le traitement de l'hépatite C.
PCT/EP2018/071773 2017-08-11 2018-08-10 Composition solide comprenant du sofosbuvir amorphe et du daclatasvir amorphe Ceased WO2019030387A1 (fr)

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