WO2024028193A1 - Stable oral pharmaceutical formulation containing ruxolitinib hemifumarate - Google Patents

Stable oral pharmaceutical formulation containing ruxolitinib hemifumarate Download PDF

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Publication number
WO2024028193A1
WO2024028193A1 PCT/EP2023/070782 EP2023070782W WO2024028193A1 WO 2024028193 A1 WO2024028193 A1 WO 2024028193A1 EP 2023070782 W EP2023070782 W EP 2023070782W WO 2024028193 A1 WO2024028193 A1 WO 2024028193A1
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WIPO (PCT)
Prior art keywords
pharmaceutical formulation
solid oral
release pharmaceutical
oral immediate
weight
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Application number
PCT/EP2023/070782
Other languages
French (fr)
Inventor
Isabel FERNÁNDEZ GARROSA
I-Teng Montserrat NG CHOI
Ernesto DURÁN LÓPEZ
Original Assignee
Medichem, S.A.
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Application filed by Medichem, S.A. filed Critical Medichem, S.A.
Publication of WO2024028193A1 publication Critical patent/WO2024028193A1/en

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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
    • A61K9/20—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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention relates to stable pharmaceutical formulations of ruxolitinib hemifumarate which show the same or higher solubility compared to the commercial tablets containing ruxolitinib phosphate.
  • Ruxolitinib phosphate (Compound I) is the international commonly accepted nonproprietary name (INN) of (3R)-3-cyclopentyl-3-[4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)pyrazol- 1 -yl]propanenitrile phosphate, has empirical formula of C17H18N6 H3PO4 and its molecular weight is 404.37 g/mol.
  • Ruxolitinib and pharmaceutically acceptable salts thereof have a selective inhibitor activity on the Janus Associated Kinase 1 (JAKI) and Janus Associated Kinase 2 (JAK2) enzymes. These kinases mediate the signaling of a number of cytokines and growth factors important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression.
  • STATs signal transducers and activators of transcription
  • ruxolitinib phosphate Tablets containing ruxolitinib phosphate (Compound I) have been approved in the US and Europe for the treatment of myelofibrosis, polycythemia vera and graft-versus-host disease. These tablets, marketed as Jakavi® in Europe and as Jakafi® in the US, are immediate-release tablets.
  • Ruxolitinib phosphate (Compound I) is described as a Biopharmaceutics Classification system (BCS) Class I active ingredient with rapid oral absorption and a short half-life of about 3 hours. See, Shi et al, J. Clin. Pharmacol. 2012 Jun, 52(6), 809-818.
  • Ruxolitinib and its pharmaceutically acceptable salts thereof were first disclosed in W02007070514A1.
  • Example 67 describes the preparation of ruxolitinib base.
  • ruxolitinib different salts of ruxolitinib, apart from the commercial ruxolitinib phosphate (Compound I), have been disclosed in the literature.
  • W02008157208A2 discloses, apart from ruxolitinib phosphate (Compound I), salts of ruxolitinib with maleic acid and sulfuric acid.
  • WO2016026974A1 discloses the oxalate salt of ruxolitinib and tablets comprising the same.
  • WO2016026975A1 discloses the besylate salt of ruxolitinib.
  • WO2016063294A2 reports crystalline forms of salts of ruxolitinib with (+)-dibenzoyl tartaric acid and hydrochloric acid.
  • W02016074650A1 discloses amorphous salts of ruxolitinib with hydrobromic acid, hydrochloric acid, citric acid, fumaric acid, L-tartaric acid, p- toluenesulfonic acid, benzoic acid, benzenesulfonic acid, ethanesulfonic acid, 2- naphthalenesulfonic acid and 4-chlorobenzenesulfonic acid.
  • W02017008772A1 reports several crystalline forms of ruxolitinib salt with hydrobromic and hydrochloric acid.
  • WO2017125097A1 describes specific crystalline forms of salts of ruxolitinib with hydrochloric acid, fumaric acid and L-tartaric acid.
  • IN202141008799A1 discloses a crystalline form of ruxolitinib benzoate and IN202141017096A1 discloses a crystalline form of ruxolitinib tartrate.
  • W02023087101A1 reports sulfonate salts, concretely a mesylate salt, an edisylate salt, a napadisylate salt and an acesulfamate salt, of ruxolitinib and crystalline forms thereof.
  • Different salts and polymorphic forms thereof (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties may provide a basis for improving certain aspects of the active ingredient and their pharmaceutical formulations, for example, by facilitating better processing or handling of by improving solubility and in consequence bioavailability.
  • the present invention relates to a solid oral immediate-release pharmaceutical formulation comprising ruxolitinib hemifumarate (Compound II) which provides the same or higher solubility compared to the commercial tablets JakavP which contain ruxolitinib phosphate (Compound I).
  • a first aspect of the invention relates to a solid oral immediate-release pharmaceutical formulation comprising a therapeutically effective amount of ruxolitinib hemifumarate (Compound II) and one or more pharmaceutically acceptable excipients.
  • Compound II ruxolitinib hemifumarate
  • the pharmaceutical formulations herein disclosed can be easily manufactured into solid dosage forms, such as tablets, having good stability and the desired dissolution profiles.
  • the pharmaceutical formulations herein disclosed have the technological properties for being manufactured at an industrial scale (flowability, compaction, hardness, disintegration, content uniformity, friability, dissolution and stability).
  • the present invention also provides a process for preparing the solid oral immediate- release pharmaceutical formulations of ruxolitinib hemifumarate (compound II) which comprises granulation, for example wet granulation.
  • Another aspect of the invention relates to the solid oral immediate-release pharmaceutical formulation of ruxolitinib hemifumarate (compound II) as defined herein, for use in treating a disease in a patient, wherein said disease is associated with JAK activity.
  • Another aspect of the invention relates to the solid oral immediate-release pharmaceutical formulation of ruxolitinib hemifumarate (compound II) as defined herein, for use in treating a myeloproliferative disorder.
  • Figure 2 depicts the dissolution profile of the tablets of the example 1 of the present invention compared with the dissolution profile of the commercial tablets Jakavi® in 500 mL of 0.1 N HCI at 37°C ⁇ 0.5°C using USP apparatus 2 (paddle) at 50 rpm.
  • Figure 3 depicts the dissolution profile of the tablets of the example 2 of the present invention compared with the dissolution profile of the commercial tablets Jakavi® in 500 mL of 0.1 N HCI at 37°C ⁇ 0.5°C using USP apparatus 1 (basket) at 100 rpm.
  • Figure 4 depicts the molecular structure of ruxolitinib hemifumarate (Compound II) as obtained in Example A, step 6, with the atom-labeling scheme.
  • An aspect of the present invention provides a solid oral immediate-release pharmaceutical formulation comprising a therapeutically effective amount of ruxolitinib hemifumarate (Compound II) and one or more pharmaceutically acceptable excipients.
  • therapeutically effective amount refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed.
  • the specific dose of the compound of the invention to obtain a therapeutic benefit may vary depending on the particular circumstances of the individual patient including, among others, the size, weight, age and sex of the patient, the nature and stage of the disease, the aggressiveness of the disease.
  • pharmaceutically acceptable excipients refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • the term “about” when used in the present invention preceding a number and referring to it, is meant to designate any value which lies within the range defined by the number ⁇ 10% of its value, preferably a range defined by the number ⁇ 5%, more preferably a range defined by the number ⁇ 2%, still more preferably a range defined by the number ⁇ 1%.
  • “about 10” should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
  • stable refers to a pharmaceutical formulation comprising ruxolitinib hemifumarate (Compound II) wherein the total content of impurities originated from the degradation of ruxolitinib hemifumarate (Compound II) does not exceed 5%, preferably 3%, more preferably 2%, most preferably 1%, and even most preferably 0.5%, as determined by a liquid chromatography method (HPLC method) if such a formulation is stored for at least 3 months, preferably at least 6 months, at 40 ⁇ 2°C and 75 ⁇ 5% relative humidity (RH) and for at least 3 months, preferably at least 6 months, more preferably at least 9 months, even more preferably for at least 1 year at 25 ⁇ 2°C and 60 ⁇ 5% relative humidity (RH).
  • HPLC method liquid chromatography method
  • the solid oral immediate-release pharmaceutical formulation of the present invention can be in the form of powder, a granule, a pellet, a mini-tablet, a tablet, a capsule, a capsule filled with granules or pellets and the like.
  • the solid oral immediate-release pharmaceutical formulation of the present invention is a tablet.
  • the solid oral immediate-release pharmaceutical formulation as herein disclosed has to be understood as a solid oral pharmaceutical formulation, preferably a tablet, having a dissolution performance such as at least about 75% of the ruxolitinib hemifumarate (Compound II) of the solid oral immediate-release pharmaceutical formulation of the present invention dissolves in 30 minutes, when the solid oral immediate-release pharmaceutical formulation is placed in 500 mL of 0.1 N HCI at 37°C ⁇ 0.5°C using USP apparatus 2 (paddle) at 50 rpm or in 500 mL of 0.1 N HCI at 37°C ⁇ 0.5°C using USP apparatus 1 (basket) at 100 rpm.
  • a dissolution performance such as at least about 75% of the ruxolitinib hemifumarate (Compound II) of the solid oral immediate-release pharmaceutical formulation of the present invention dissolves in 30 minutes, when the solid oral immediate-release pharmaceutical formulation is placed in 500 mL of 0.1 N HCI at 37°C ⁇ 0.5°C using
  • ruxolitinib hemifumarate (Compound II) of the solid oral immediate-release pharmaceutical formulation of the present invention dissolves in 15 minutes, when the solid oral immediate-release pharmaceutical formulation is placed in 500 mL of 0.1 N HCI at 37°C ⁇ 0.5°C using USP apparatus 2 (paddle) at 50 rpm or in 500 mL of 0.1 N HCI at 37°C ⁇ 0.5°C using USP apparatus 1 (basket) at 100 rpm.
  • the solid oral immediate-release pharmaceutical formulation comprises ruxolitinib hemifumarate (compound II) and one or more excipients selected from the group consisting of wetting agents, fillers, disintegrants, antioxidants, binders, chelating agents, glidants, lubricants, and mixtures thereof.
  • Non-limiting examples of wetting agents which can be used in the formulation of the present invention are poloxamer (e.g. Kolliphor® P407), polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polysorbates, such as polysorbate 80, cetyl alcohol, glycerol fatty acid esters (e.g.
  • triacetin triacetin, glycerol monostearate and the like), polyoxymethylene stearate, sodium dodecyl sulfate, sorbitan fatty acid esters, sucrose fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, docusate sodium, and mixtures thereof.
  • Non-limiting examples of fillers which can be used in the formulation of the present invention are microcrystalline cellulose (e.g., Avicel® PH101), silicified microcrystalline cellulose (e.g. Prosolv® HD90), pregelatinized starch, starches (such as maize starch, potato starch, rice starch, wheat starch), lactitol, lactose (e.g. lactose monohydrate), maltose, trehalose, a suitable inorganic calcium salt, sucrose, glucose, sugar alcohols (such as mannitol, sorbitol and xylitol), silicic acid, and mixtures thereof.
  • the formulation of the present invention comprises microcrystalline cellulose (e.g., Avicel® PH 101) and lactose (e.g. lactose monohydrate).
  • Non-limiting examples of disintegrants which can be used in the formulation of the present invention are low substituted hydroxypropyl cellulose (L-HPC), carboxymethylcellulose calcium, carboxymethylcellulose sodium, cellulose powdered, chitosan, docusate sodium, glycine, sodium alginate, crospovidone (e.g. Polyplasdone® XL), croscarmellose sodium (e.g. Vivasol®), sodium starch glycolate (e.g. Explotab® CLV), and mixtures thereof.
  • the formulation of the present invention comprises sodium starch glycolate (e.g. Explotab® CLV).
  • Non-limiting examples of antioxidants which can be used in the formulation of the present invention are ascorbic acid and salts and esters thereof, citric acid and salts and esters thereof, butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), tocopherols (e.g., alpha-tocopherol, beta-tocopherol, gamma-tocopherol and delta-tocopherol), tocopherol acetate (e.g. alpha-tocopherol acetate, beta-tocopherol), carotenoids (e.g., vitamin A, lutein, and zeaxanthin), and mixtures thereof.
  • antioxidants which can be used in the formulation of the present invention are ascorbic acid and salts and esters thereof, citric acid and salts and esters thereof, butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), tocopherols (e.g., al
  • Non-limiting examples of binders which can be used in the formulation of the present invention are povidone (e.g., Plasdone® K29/32 or Kolloidon®), hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, Klucel® EF), hydroxypropyl methyl cellulose, gelatin, starch, sucrose, mannitol, polyethylene glycol, acacia, guar gum, maltodextrin, methylcellulose, ethylcellulose, and mixtures thereof.
  • the formulation of the present invention comprises povidone (e.g., Plasdone® K29/32) and hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF).
  • Non-limiting examples of chelating agents which can be used in the formulation of the present invention are ethylenediaminetetraacetic acid (EDTA) and derivatives thereof (e.g. edetate calcium disodium), ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA) and derivatives thereof, diethylenetriaminepentaacetic acid (DTPA) and derivatives thereof, N,N-bis(carboxymethyl)glycine (NTA) and derivatives thereof, nitrilotriacetic acid and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, sodium desoxycholate and derivatives thereof, and mixtures thereof.
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid
  • DTPA diethylenetriaminepent
  • Non-limiting examples of glidants which can be used in the formulation of the present invention are colloidal silicon dioxide (e.g. Aerosil® 200), silica gel, fumed silica, talc, magnesium carbonate, magnesium silicate, calcium silicate, calcium phosphate tribasic, bentonite, and mixtures thereof.
  • the formulation of the present invention comprises colloidal silicon dioxide (e.g. Aerosil® 200).
  • Non-limiting examples of lubricants which can be used in the formulation of the present invention are stearic acid (e.g, Kolliwax® S Fine), and stearic acid derivatives such as sodium stearate, calcium stearate, zinc stearate, magnesium stearate, sodium oleate, polyethylene glycol, talc, mineral oil, sodium lauryl sulfate, sodium stearyl fumarate, castor oils, sodium benzoate, sodium acetate, sodium chloride, and mixtures thereof.
  • the formulation of the present invention comprises magnesium stearate (e.g. Ligamed®MF-2-V).
  • the solid oral immediate-release pharmaceutical formulation preferably a tablet, comprises ruxolitinib hemifumarate (Compound II) and at least one filler, preferably microcrystalline cellulose (e.g. Avicel® PH 101) and/or lactose (e.g. lactose monohydrate), at least one disintegrant, preferably sodium starch glycolate (e.g. Explotab® CLV), at least one binder, preferably povidone (e.g. Plasdone® K29/32) and/or hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF), at least one glidant, preferably colloidal silicon dioxide (e.g. Aerosil® 200), and at least one lubricant, preferably magnesium stearate (e.g. Ligamed® MF-2-V).
  • ruxolitinib hemifumarate Compound II
  • filler preferably microcrystalline cellulose (e.
  • the solid oral immediate-release pharmaceutical formulation comprises ruxolitinib hemifumarate (Compound II), microcrystalline cellulose (e.g., Avicel® PH 101), lactose (e.g. lactose monohydrate), sodium starch glycolate (e.g. Explotab® CLV), povidone (e.g. Plasdone® K29/32), hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF), colloidal silicon dioxide (e.g. Aerosil® 200) and magnesium stearate (e.g. Ligamed® MF-2-V).
  • Compound II ruxolitinib hemifumarate
  • microcrystalline cellulose e.g., Avicel® PH 101
  • lactose e.g. lactose monohydrate
  • sodium starch glycolate e.g. Explotab® CLV
  • povidone e.g. Plasdone® K29
  • the solid oral immediate-release pharmaceutical formulation preferably a tablet, comprises or consists of ruxolitinib hemifumarate (Compound II) and at least one filler, preferably microcrystalline cellulose (e.g. Avicel® PH 101) and/or lactose (e.g. lactose monohydrate), at least one disintegrant, preferably sodium starch glycolate (e.g. Explotab® CLV), at least one binder, preferably povidone (e.g. Plasdone® K29/32) and/or hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g.
  • ruxolitinib hemifumarate Compound II
  • filler preferably microcrystalline cellulose (e.g. Avicel® PH 101) and/or lactose (e.g. lactose monohydrate), at least one disintegrant, preferably sodium starch glycolate (e.g. Explotab® CLV), at least one bin
  • Klucel® EF at least one glidant, preferably colloidal silicon dioxide (e.g. Aerosil® 200), and at least one lubricant, preferably magnesium stearate (e.g. Ligamed® MF-2-V), wherein:
  • the weight of ruxolitinitb hemifumarate in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 2.0% to 6.0%, preferably from 2.5% to 4.5%, for example 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1.%, 3.2.%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, or 4.5%, more preferably from 3.0% to 4.0%, even more preferably from 3.5% to 4.0%;
  • the weight of the at least one filler preferably microcrystalline cellulose (e.g. Avicel® PH 101) and/or lactose (e.g. lactose monohydrate), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 70% to 95%, for example 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, or 95%, preferably from 80% to 90%;
  • microcrystalline cellulose e.g. Avicel® PH 101
  • lactose e.g. lactose monohydrate
  • the weight of the at least one disintegrant, preferably sodium starch glycolate (e.g. Explotab® CLV), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 1 .0% to 8.0% or from 2.0% to 8.0%, preferably from 2.0% to 5.0% or from 3.0% to 5.0%, for example 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1 %, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5.0%;
  • sodium starch glycolate e.g. Explotab® CLV
  • the weight of the at least one binder preferably povidone (e.g. Plasdone® K29/32) and/or hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.5% to 7.0%, preferably from 3.5% to 5.5%, for example 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1 %, 5.2%, 5.3%, 5.4%, or 5.5%;
  • povidone e.g. Plasdone® K29/32
  • hydroxypropylcellulose e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF
  • the weight of the at least one glidant, preferably colloidal silicon dioxide (e.g. Aerosil® 200), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.1 % to 2.5%, for example 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, or 2.5%, preferably from 0.5% to 1.5%; and
  • the weight of the at least one lubricant, preferably magnesium stearate (e.g. Ligamed® MF-2-V), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.2% to 6.5% or from 0.4% to 6.5%, preferably from 0.4% to 3.0% or from 1 .0% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
  • the weight of the at least one lubricant preferably magnesium stearate (e.g. Ligamed® MF-2-V)
  • the weight of the at least one lubricant preferably magnesium stearate (e.g. Liga
  • the solid oral immediate-release pharmaceutical formulation comprises or consists of ruxolitinib hemifumarate (Compound II), microcrystalline cellulose (e.g. Avicel® PH 101), lactose (e.g. lactose monohydrate), sodium starch glycolate (e.g. Explotab® CLV), povidone (e.g. Plasdone® K29/32), hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF), colloidal silicon dioxide (e.g. Aerosil® 200) and magnesium stearate (e.g. Ligamed® MF-2-V), wherein:
  • the weight of ruxolitinib hemifumarate in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 2.0% to 6.0%, preferably from 2.5% to 4.5%, for example 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1.%, 3.2.%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, or 4.5%, more preferably from 3.0% to 4.0%, even more preferably from 3.5% to 4.0%;
  • the sum of the weights of microcrystalline cellulose (e.g. Avicel® PH 101) and lactose (e.g. lactose monohydrate), in relation to the total weight of the solid oral immediate- release pharmaceutical formulation of the present invention is from 70% to 95%, for example 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%, preferably from 80% to 90%;
  • the weight of sodium starch glycolate in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 1.0% to 8.0% or from 2.0% to 8.0%, preferably from 2.0% to 5.0% or from 3.0% to 5.0%, for example 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5.0%;
  • the sum of weights of povidone (e.g. povidone K30) and hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.5% to 7.0%, preferably from 3.5% to 5.5%, for example 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, or 5.5%;
  • the weight of colloidal silicon dioxide (e.g. Aerosil® 200) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.1 % to 2.5%, for example 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, or 2.5%, preferably from 0.5% to 1.5%, and
  • the weight of magnesium stearate (e.g. Ligamed® MF-2-V) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.2% to 6.5% or from 0.4% to 6.5%, preferably from 0.4% to 3.0% or from 1.0% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
  • 0.4% to 3.0% preferably from 0.4% to 3.0% or from 1.0% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%
  • the solid oral immediate-release pharmaceutical formulation comprises or consists of ruxolitinib hemifumarate (Compound II), microcrystalline cellulose (e.g. Avicel® PH 101), lactose (e.g. lactose monohydrate), sodium starch glycolate (e.g. Explotab® CLV), povidone (e.g. Plasdone® K29/32), hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF), colloidal silicon dioxide (e.g. Aerosil® 200) and magnesium stearate (e.g. Ligamed® MF-2-V), wherein:
  • the weight of ruxolitinib hemifumarate in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 2.0% to 6.0%, preferably from 2.5% to 4.5%, for example 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1.%, 3.2.%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, or 4.5%, more preferably from 3.0% to 4.0%, even more preferably from 3.5% to 4.0%;
  • the weight of microcrystalline cellulose in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 25% to 60% or from 35% to 60%, preferably from 30% to 50%, for example 30%, 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%, more preferably from 38% to 45%;
  • the weight of lactose in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 25% to 60% or from 35% to 60%, preferably from 30% to 50%, for example 30%, 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%, more preferably from 40% to 48%;
  • the weight of sodium starch glycolate in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 1.0% to 8.0% or from 2.0% to 8.0%, preferably from 2.0% to 5.0% or from 3.0% to 5.0%, for example 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5.0%;
  • the weight of povidone in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.5% to 6.5%, preferably from 1.5% to 2.5%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, or 2.5%;
  • the weight of hydroxypropylcellulose in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.5% to 6.5%, preferably from 1.5% to 3.5% or from 1.5% to 3.0%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1 %, 3.2%, 3.3%, 3.4%, or 3.5%, more preferably from 2.0% to 3.0%;
  • the weight of colloidal silicon dioxide (e.g. Aerosil® 200) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.1 % to 2.5%, for example 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, or 2.5%, preferably from 0.5% to 1.5%; and
  • the weight of magnesium stearate (e.g. Ligamed® MF-2-V) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.2% to 6.5% or from 0.4% to 6.5%, preferably from 0.4% to 3.0% or from 1.0% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
  • 0.4% to 3.0% preferably from 0.4% to 3.0% or from 1.0% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%
  • the solid oral immediate-release pharmaceutical formulation comprises or consists of ruxolitinib hemifumarate (compound II), microcrystalline cellulose (e.g. Avicel® PH101), lactose (e.g. lactose monohydrate), sodium starch glycolate (e.g. Explotab® CLV), povidone (e.g. Plasdone® K29/32), hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF), colloidal silicon dioxide (e.g. Aerosil® 200) and magnesium stearate (e.g. Ligamed® MF-2-V), wherein:
  • the weight of ruxolitinib hemifumarate (Compound II), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 3.5% to 4.0%, for example 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, or 4.0%;
  • the weight of microcrystalline cellulose in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 38% to 45%, for example 38%, 39%, 40%, 41%, 42%, 43%, 44%, or 45%;
  • the weight of lactose in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 40% to 48%, for example 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, or 48%;
  • the weight of sodium starch glycolate in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 2.0% to 5.0%, for example 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1 %, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5.0%;
  • the weight of povidone in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 1.5% to 2.5%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, or 2.5%;
  • hydroxypropylcellulose e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF
  • weight of hydroxypropylcellulose in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 2.0% to 3.0%, for example 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%;
  • the weight of colloidal silicon dioxide (e.g. Aerosil® 200) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.5% to 1.5%, for example 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, or 1.5%; and
  • the weight of magnesium stearate (e.g. Ligamed® MF-2-V) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.4% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
  • the solid oral immediate-release tablet is not coated.
  • the solid oral immediate-release tablet can be coated preferably with a coating comprising hydroxypropylmethyl cellulose such as Opadry® Clear (Colorcon®, Inc.) or hydroxypropyl methyl cellulose E3 or with a PVA-based film coating (e.g. Opadry® II White 85F18422, Opadry® II White 32F280008 or Opadry® Pink 03B240053), preferably with a PVA-based film coating (e.g. Opadry® II White 85F18422, Opadry® II White 32F280008 or Opadry® Pink 03B240053).
  • a coating comprising hydroxypropylmethyl cellulose such as Opadry® Clear (Colorcon®, Inc.) or hydroxypropyl methyl cellulose E3
  • a PVA-based film coating e.g. Opadry® II White 85F18422, Opadry® II White 32F280008 or Opadry® Pink 03B240053
  • a PVA-based film coating
  • the solid oral immediate-release pharmaceutical formulation, preferably a tablet, of the present invention can be packaged in any type of container and/or packaging component that prevents water absorption and degradation (such as bottles, flasks, plastic bags, and blister packs).
  • the formulation of the present invention preferably a tablet, can contain the amount of ruxolitinib hemifumarate (Compound II) equivalent to 5, 10, 15, 20 and 25 mg of ruxolitinib free base, respectively.
  • Compound II ruxolitinib hemifumarate
  • the formulation of the present invention can be obtained by processes which can involve different techniques used in pharmaceutical development such as direct compression, dry granulation, wet granulation, melt-granulation, spraydrying, extrusion or hot melt extrusion, preferably wet granulation.
  • the solid immediate-release pharmaceutical formulation of the present invention preferably a tablet, is obtainable by a process comprising a granulation step, preferably wet granulation, more preferably aqueous wet granulation.
  • the process for preparing the formulations of the present invention comprises an aqueous wet granulation.
  • the process for preparing the immediate-release tablets of the present invention comprises the following steps: 1) ruxolitinib hemifumarate (Compound II) and the intragranular components are weighed, sieved, for example by a 0.8 mm wire mesh screen, and mixed;
  • a binder solution is added to the mixture obtained in step 1), and granulation is performed.
  • the binder solution is separately and previously prepared by heating water at a temperature of between 40°C to 60°C, preferably about 50°C, and gradually adding the at least one binder, preferably povidone and/or hydroxypropylcellulose, with constant stirring until complete dissolution;
  • step 2) the mixture obtained in step 2) is sieved, for example by a 2.0 mm or 4.0 mm wire mesh screen, and dried at a temperature not higher than about 40°C until a specific moisture content, for example of less than 3% w/w;
  • step 4) the dried granules obtained in step 3) are sieved, for example by a 0.8 mm wire mesh screen;
  • the extragranular components are sieved, for example by a 0.8 mm wire mesh screen;
  • step 6) the dried granules obtained in step 4) are mixed with the extragranular components obtained in step 5);
  • step 6) the mixture obtained in step 6) is compressed.
  • all of the binders are added in solution or, alternatively, one or some of them are added in solid form and the rest in solution.
  • the at least one binder preferably povidone and/or hydroxypropylcellulose, is added in solid form as intragranular component or components in the step 1) above, so that no binder solution is prepared.
  • water preferably at room temperature, is added to the mixture obtained in step 1) and afterwards the process continues according to the above steps 3) to 7).
  • the intragranular components comprise at least one filler, at least one disintegrant and at least one binder and the extragranular components comprise the rest of excipients, for example at least one glidant and at least one lubricant.
  • the solid oral immediate-release pharmaceutical formulation preferably a tablet
  • the solid oral immediate-release pharmaceutical formulation is prepared by a process comprising a granulation step, preferably wet granulation, more preferably aqueous wet granulation, apart from the ruxolitinib hemifumarate (Compound II)
  • the intragranular components comprise part of the filler or fillers, part of the disintegrant or disintegrants and the binder or binders
  • the extragranular components comprise the rest of the filler or fillers, the rest of the disintegrant or disintegrants, the glidant or glidants, and the lubricant or lubricants. Therefore, fillers and disintegrants can form part of the intragranular and the extragranular mixture.
  • the solid oral immediate-release pharmaceutical formulation preferably a tablet
  • the solid oral immediate-release pharmaceutical formulation is prepared by a process comprising a granulation step, preferably wet granulation, more preferably aqueous wet granulation, at least one filler, preferably microcrystalline cellulose, and the disintegrant, preferably sodium starch glycolate, form part of the intragranular and the extragranular mixture.
  • the solid oral immediate-release pharmaceutical formulation preferably a tablet
  • the relation between the weight of the intragranular filler or fillers, preferably microcrystalline cellulose (e.g. Avicel® PH101) and lactose (e.g. lactose monohydrate), with respect of the weight of the extragranular filler or fillers, preferably microcrystalline cellulose (e.g. Avicel® PH101), is of about 4 to 5, for example 4.0, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0.
  • the solid oral immediate-release pharmaceutical formulation preferably a tablet
  • the relation between the weight of the intragranular filler, preferably microcrystalline cellulose, and the weight of the same extragranular filler, preferably microcrystalline cellulose is from about 1 to 2, for example about 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0
  • the relation between the weight of the intragranular disintegrant, preferably sodium starch glycolate, and the extragranular disintegrant, preferably sodium starch glycolate is from about 0.5 to 1.5, for example about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, or 1.5.
  • the solid oral immediate-release pharmaceutical formulation preferably a tablet
  • the solid oral immediate-release pharmaceutical formulation comprises or consists of intragranular components which comprise or consist of ruxolitinib hemifumarate (Compound II), microcrystalline cellulose (e.g. Avicel® PH 101), lactose (e.g. lactose monohydrate), sodium starch glycolate (e.g. Explotab® CLV), povidone (e.g. Plasdone® K29/32) and hydroxypropylcellulose (e.g.
  • Compound II ruxolitinib hemifumarate
  • microcrystalline cellulose e.g. Avicel® PH 101
  • lactose e.g. lactose monohydrate
  • sodium starch glycolate e.g. Explotab® CLV
  • povidone e.g. Plasdone® K29/32
  • hydroxypropylcellulose e.g.
  • hydroxypropylcellulose 300 to 600 cps e.g. Klucel® EF
  • extragranular components which comprise or consist of microcrystalline cellulose (e.g. Avicel® PH 101), sodium starch glycolate (e.g. Explotab® CLV), colloidal silicon dioxide (e.g. Aerosil® 200) and magnesium stearate (e.g. Ligamed® MF-2-V), wherein:
  • the weight of ruxolitinib hemifumarate (Compound II) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 2.0% to 6.0%, preferably from 2.5% to 4.5%, for example 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1.%, 3.2.%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, or 4.5%, more preferably from 3.0% to 4.0%, even more preferably from 3.5% to 4.0%;
  • the weight of intragranular microcrystalline cellulose (e.g. Avicel® PH 101) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 15% to 35%, preferably from 20% to 30%, for example 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%;
  • the weight of lactose in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 25% to 60%, preferably from 30% to 50%, for example 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 22%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%, more preferably from 40% to 48%;
  • the weight of intragranular sodium starch glycolate (e.g. Explotab® CLV) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.5% to 3.5%, preferably from 1.0% to 2.5%, for example 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, or 2.5%;
  • the weight of povidone (e.g. Plasdone® K29/32) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.5% to 6.5%, preferably from 1.5% to 2.5%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, or 2.5%;
  • the weight of hydroxypropylcellulose in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.5% to 6.5%, preferably from 1.5% to 3.5%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, or 3.5%, more preferably from 2.0% to 3.0%;
  • the weight of extragranular microcrystalline cellulose (e.g. Avicel® PH 101) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 5% to 25%, preferably from 10% to 20%, for example 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%;
  • the weight of extragranular sodium starch glycolate (e.g. Explotab® CLV) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.5% to 3.5%, more preferably from 1.0% to 2.5%, for example 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, or 2.5%;
  • the weight of colloidal silicon dioxide (e.g. Aerosil® 200) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.1% to 2.5%, for example 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, or 2.5, preferably from 0.5% to 1.5%; and
  • the weight of magnesium stearate (e.g. Ligamed® MF-2-V) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.2% to 6.5%, preferably from 0.4% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
  • 0.4% to 3.0% for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%
  • the solid oral immediate-release pharmaceutical formulation preferably a tablet
  • the solid oral immediate-release pharmaceutical formulation comprises or consists of intragranular components which comprise or consist of ruxolitinib hemifumarate (Compound II), microcrystalline cellulose (e.g. Avicel® PH 101), lactose (e.g. lactose monohydrate), sodium starch glycolate (e.g. Explotab® CLV), povidone (e.g. Plasdone® K29/32) and hydroxypropylcellulose (e.g.
  • Compound II ruxolitinib hemifumarate
  • microcrystalline cellulose e.g. Avicel® PH 101
  • lactose e.g. lactose monohydrate
  • sodium starch glycolate e.g. Explotab® CLV
  • povidone e.g. Plasdone® K29/32
  • hydroxypropylcellulose e.g.
  • hydroxypropylcellulose 300 to 600 cps e.g. Klucel® EF
  • extragranular components which comprise or consist of microcrystalline cellulose (e.g. Avicel® PH 101), sodium starch glycolate (e.g. Explotab® CLV), colloidal silicon dioxide (e.g. Aerosil® 200) and magnesium stearate (e.g. Ligamed® MF-2-V), wherein:
  • the weight of ruxolitinib hemifumarate (Compound II) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 3.5% to 4.0%, for example 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, or 4.0%;
  • the weight of intragranular microcrystalline cellulose in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 20% to 30%, for example 20%, 21 %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%;
  • the weight of lactose in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 40% to 48%, for example 42%, 43%, 44%, 45%, 46%, 47%, or 48%;
  • the weight of intragranular sodium starch glycolate (e.g. Explotab® CLV) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 1.0% to 2.5%, for example 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, or 2.5%;
  • the weight of povidone (e.g. Plasdone® K29/32) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 1.5% to 2.5%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, or 2.5%;
  • the weight of hydroxypropylcellulose in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 2.0% to 3.0%, for example 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%;
  • the weight of extragranular microcrystalline cellulose (e.g. Avicel® PH 101) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 10% to 20%, for example 10%, 11%, 12%, 13%, 14%, 15%, 16% , 17% , 18% , 19% , or 20% ;
  • the weight of extragranular sodium starch glycolate (e.g. Explotab® CLV) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 1.0% to 2.5%, for example 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, or 2.5%;
  • the weight of colloidal silicon dioxide (e.g. Aerosil® 200) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.5% to 1.5%, for example 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%, and
  • the weight of magnesium stearate (e.g. Ligamed® MF-2-V) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.4% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
  • Non-limiting examples of the wetting agents, fillers, antioxidants, disintegrants, chelating agents, glidants or lubricants used in the process of the present invention are the same as those given for the solid oral immediate-release formulations of the present invention.
  • the ruxolitinib hemifumarate (Compound II) used for the preparation of the solid oral immediate-release formulation of the present invention preferably a tablet, can be crystalline or amorphous or a mixture of a crystalline and amorphous forms.
  • the ruxolitinib hemifumarate (Compound II) used for the preparation of the solid immediate-release formulation of the present invention shows a X-Ray Powder Diffractogram (XRPD) that comprises characteristic peaks at an angle of diffraction 2 theta (20) of 5.6, 6.5, 16.2 and 18.1 ( ⁇ 0.2), preferably at an angle of diffraction 2 theta (20) of 5.6, 6.5, 10.2, 10.5, 13.1, 15.5, 16.2 and 18.1 ( ⁇ 0.2), more preferably at an angle of diffraction 2 theta (20) of 5.6, 6.5, 10.2, 10.5, 13.1, 15.2, 15.5, 16.2, 16.7, 18.1 , 19.4, 19.7, 20.0, 22.0, 22.7, 23.1 , 23.9, 25.5 and 26.5 ( ⁇ 0.2) as measured in a X-ray diffractometer with Cu Ka radiation (1.54056 A).
  • XRPD X-Ray Powder Diffractogram
  • the ruxolitinib hemifumarate (Compound II) used for the preparation of the solid immediate-release formulation of the present invention shows a X-Ray Powder Diffractogram (XRPD) as shown in Figure 1.
  • the solid oral immediate-release formulation of the present invention preferably a tablet, contains ruxolitinib hemifumarate (Compound II) which shows a X-Ray Powder Diffractogram (XRPD) that comprises characteristic peaks at an angle of diffraction 2 theta (20) of 5.6, 6.5, 16.2 and 18.1 ( ⁇ 0.2), preferably at an angle of diffraction 2 theta (20) of 5.6, 6.5, 10.2, 10.5, 13.1 , 15.5, 16.2 and 18.1 ( ⁇ 0.2), more preferably at an angle of diffraction 2 theta (20) of 5.6, 6.5, 10.2, 10.5, 13.1, 15.2, 15.5, 16.2, 16.7, 18.1, 19.4, 19.7, 20.0, 22.0, 22.7, 23.1, 23.9, 25.5 and 26.5 ( ⁇ 0.2) as measured in a X-ray diffractometer with Cu Ka radiation (1.54056 A).
  • the solid oral immediate-release formulation of the present invention contains
  • the basic crystallographic data for a single crystal of the ruxolitinib hemifumarate (Compound I) used for the preparation of the solid immediate-release formulation of the present invention is as follows:
  • the ruxolitinib hemifumarate (Compound II) used for the preparation of the solid oral immediate-release formulation of the present invention preferably a tablet, has a D90 value from 30 to 300 pm, preferably a D90 value from 40 to 200 pm, and more preferably a D90 value from 50 to 100 pm, as determined by laser diffraction.
  • the ruxolitinib hemifumarate (Compound II) used for the preparation of the solid oral immediate-release formulation of the present invention preferably a tablet, has a D90 value from 50 to 100 pm, a D50 value from 18 to 40 pm, and a D10 value from 3 to 15 pm, as determined by laser diffraction.
  • the ruxolitinib hemifumarate (Compound II) used for the preparation of the solid oral immediate-release formulation of the present invention preferably a tablet, can be prepared by reacting ruxolitinib base with fumaric acid.
  • Ruxolitinib base can be prepared according to any process disclosed in the prior art.
  • One aspect of the present invention provides a process for preparing ruxolitinib hemifumarate (Compound II).
  • Scheme 1 shows the synthetic pathway for preparing ruxolitinib hemifumarate (Compound II) of the present invention:
  • (A) reacts with 2-(chloromethoxy)ethyl)trimethylsilane (SEM-CI) in the presence of a base which is an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium terf-butoxide, potassium methoxide, potassium ethoxide, potassium terf-butoxide and the like, preferably potassium or sodium terf-butoxide, in a polar aprotic solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, preferably in dimethyl sulfoxide.
  • a base which is an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium terf-butoxide, potassium methoxide, potassium ethoxide, potassium terf-butoxide and the like, preferably potassium or sodium terf-butoxide
  • a polar aprotic solvent such as dimethylformamide, dimethylacet
  • (B) reacts with 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1/7-pyrazole (C) in the presence of a catalyst, preferably a palladium catalyst, in the presence of a suitable base and in a suitable solvent to obtain 4-(1/7-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7/7-pyrrolo[2,3-c(]pyrimidine (D).
  • the palladium catalyst can be tetrakis(triphenylphosphine)palladium (0).
  • 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)- 7/7-pyrrolo[2,3-c(]pyrimidine (B) reacts with 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1/7-pyrazole (C) in the presence of tetrakis(triphenylphosphine)palladium (0) and sodium or potassium acetate in a suitable solvent, for example a polar aprotic solvent such as acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, preferably acetonitrile, to obtain 4-(1/7-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7/7-pyrrolo[2,3-c(]pyrimidine (D).
  • a suitable solvent for example a polar aprotic solvent such as acetonitrile, dimethylform
  • the catalyst tetrakis(triphenylphosphine)palladium (0) is generated in situ.
  • 4-chloro-7-((2- (trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidine (B) reacts with 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1/7-pyrazole (C) in the presence of palladium acetate, triphenylphosphine and sodium or potassium acetate in a suitable solvent, preferably a mixture of ethyl acetate, acetonitrile and water.
  • the obtained 4-(1 /7-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3- d]pyrimidine (D) can be preferably purified by recrystallization or slurrying in a suitable organic solvent.
  • the obtained 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7/7- pyrrolo[2,3-d]pyrimidine (D) is purified by slurrying in acetonitrile.
  • 3-cyclopentylacrylonitrile (E) consists of (2E)-3- cyclopentylacrylonitrile, (2Z)-3-cyclopentylacrylonitrile, or a mixture thereof.
  • the 2-(trimethylsilyl)ethoxymethyl) protecting group is removed from 3- cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c]pyrimidin-4-yl)-1/7- pyrazol-1-yl)propanenitrile (F).
  • the protecting group is removed by treating with trifluoroacetic acid, a fluoride ion (e.g., tetrabutylammonium fluoride), hydrochloric acid, pyridinium p-toluenesulfonic acid, boron trifluoride diethyl etherate or a Lewis acid (e.g.
  • the treating comprises treating with a Lewis acid followed by treating with a base, e.g., alkali metal hydroxide such as sodium or potassium hydroxide, ammonia in a solvent such as water or an alcoholic solvent, e.g., methanol.
  • a base e.g., alkali metal hydroxide such as sodium or potassium hydroxide, ammonia in a solvent such as water or an alcoholic solvent, e.g., methanol.
  • 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7/7- pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol-1-yl)propanenitrile (F) is treated with a Lewis acid, preferably aluminium chloride, in a suitable solvent, preferably an ether solvent such as tetra hydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl terf-butyl ether, dioxane and the like, preferably 2-methyltetrahydrofuran, followed by the treatment with ammonia to obtain 3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3- cyclopentylpropanenitrile (G).
  • a Lewis acid preferably aluminium chloride
  • a suitable solvent preferably an ether solvent such as tetra hydrofuran
  • the chiral acid is selected from optically active forms of mandelic acid, 2-chloromandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, dibenzoyl tartaric acid, di-p-toluoyltartaric acid, 2-amino-7,7-dimethylbicyclop[2,2,1]heptan-1-methylene sulfonic acid, and 2-acrylamide-7,7-dimethylbicyclo[2,2,l] heptan-1 -methylene sulfonic acid.
  • the chiral acid is (+)-dibenzoyl-D-tartaric acid, also known as (2S,3S)-2,3-bis(benzoyloxy)succinic acid ((+)-DBTA).
  • the suitable solvent to form the chiral salt comprises acetonitrile, tetra hydrofuran, acetone, alcoholic solvent, such as methanol, ethanol, isopropanol, n- propanol, butanol and the like, or combination thereof.
  • a product comprising an enantiomeric excess of the (R)-enantiomer of 3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H- pyrazol-1-yl)-3-cyclopentylpropanenitrile (2S,3S)-2,3-bis(benzoyloxy)succinate (H) is isolated by filtration.
  • 3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)- 1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile (G) reacts with (2S,3S)-2,3- bis(benzoyloxy)succinic acid ((+)-DBTA) in a mixture of acetonitrile and an alcoholic solvent, preferably isopropanol, to form a product comprising an enantiomeric excess of (R)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile (2S,3S)-2,3-bis(benzoyloxy)succinate (H) which is isolated by filtration.
  • the obtained and isolated (R)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3- cyclopentylpropanenitrile (2S,3S)-2,3-bis(benzoyloxy)succinate (H) can be purified by means of recrystallization or slurrying in a suitable solvent or mixture of solvents, preferably in mixtures of acetonitrile and an alcoholic solvent, preferably isopropanol. The purifications can be repeated until the desired chiral purity is achieved, e.g., until the amount of the (S)-enantiomer is not more than 0.15% as analyzed by a chiral HPLC method.
  • (F?)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3-cyclopentyl- propanenitrile, i.e., ruxolitinib base is converted to (F?)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4- yl)-1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile hemifumarate, i.e., ruxolitinib hemifumarate (Compound II) by reacting (F?)-3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7- pyrazol-1-yl)-3-cyclopentylpropanenitrile, i.e., ruxolitinib base, with fumaric acid in a suitable solvent.
  • (F?)-3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7- pyrazol-1-yl)-3-cyclopentylpropanenitrile, i.e., ruxolitinib base reacts with fumaric acid in an alcohol solvent such as methanol, ethanol, isopropanol, n-propanol, butanol, and the like, preferably isopropanol to form (F?)-3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol- 1-yl)-3-cyclopentylpropanenitrile hemifumarate, i.e. ruxolitinib hemifumarate (Compound II).
  • an alcohol solvent such as methanol, ethanol, isopropanol, n-propanol, butanol, and the like
  • mother liquors obtained in the fifth step disclosed hereinbefore which are enriched in the undesired enantiomer (S)-3-(4-(7/7-pyrrolo[2,3- d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile (2S,3S)-2,3- bis(benzoyloxy)succinate, i.e., H wherein ruxolitinib has (S) configuration, can be reprocessed as it follows: a) Solvent from mother liquors obtained in the fifth step disclosed hereinbefore is evaporated and the resulting residue X is treated with a suitable base in a suitable solvent to produce a product with an enantiomeric excess of (S)-3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-
  • the resulting residue X is treated with an alkali metal carbonate or bicarbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate, lithium carbonate or bicarbonate and the like, preferably sodium bicarbonate, in a mixture of an ester solvent such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, preferably ethyl acetate, and water to obtain a product with an enantiomeric excess of (S)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)- 1/7-pyrazol-1-yl)-3-cyclopentyl-propanenitrile, i.e.
  • an alkali metal carbonate or bicarbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate, lithium carbonate or bicarbonate and the like, preferably sodium bicarbonate
  • (S)-ruxolitinib base The product with an enantiomeric excess of (S)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)- 1/7-pyrazol-1-yl)-3-cyclopentyl-propanenitrile, i.e., (S)-ruxolitinib base, reacts with 2-(chloromethoxy)ethyl)trimethylsilane (SEM-CI) in the presence of 1 ,8-diazabicyclo(5.4.0)undec-7-ene (DBU) in acetonitrile.
  • SEM-CI 2-(chloromethoxy)ethyl)trimethylsilane
  • the retro- Michael reaction occurs in the presence of a base which is an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium terf-butoxide, potassium methoxide, potassium ethoxide, potassium terf-butoxide and the like, preferably sodium terf-butoxide, in a polar aprotic solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, preferably in dimethyl sulfoxide.
  • a base which is an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium terf-butoxide, potassium methoxide, potassium ethoxide, potassium terf-butoxide and the like, preferably sodium terf-butoxide
  • a polar aprotic solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, preferably in dimethyl sulfoxide.
  • the obtained 4-(1/7-pyrazol-4-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-d]pyrimidine (D) can be preferably purified by recrystallization or slurrying in a suitable organic solvent.
  • the obtained 4- (1 /7-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidine (D) is purified by slurrying in acetonitrile.
  • This compound D can be introduced in the synthetic procedure indicated in the scheme 1.
  • suitable solvents used in the present invention is selected from, but are not limited to “alcohol solvents” such as methanol, ethanol, isopropanol, n- propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n- butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, “ether solvents” such as tetra hydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl fert-butyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like; “halogenated solvents” such as dichloromethane, ethylene dichloromethane, ethylene dichlor
  • suitable base used herein the present invention until unless specified is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium terf-butoxide, potassium methoxide, potassium ethoxide, potassium terf-butoxide and the like; triethylamine, methylamine, ethylamine, 1 ,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicy
  • Another aspect of the present invention provides a solid oral immediate-release formulation comprising ruxolitinib hemifumarate (Compound II), obtainable by any one of the processes of the present invention.
  • Compound II ruxolitinib hemifumarate
  • Another aspect of the present invention provides the solid oral immediate-release formulation of the invention, for use in treating a disease in a patient, wherein said disease is associated with JAK activity, for example allograft rejection or graft versus host disease, an autoimmune disease, a skin disorder, a viral disease, cancer, a disease characterized by a mutant JAK2, a myeloproliferative disorder, an inflammatory disease, ischemia reperfusion or related to an ischemic event, anorexia or cachexia resulting from or associated with cancer, fatigue resulting from or associated with cancer.
  • JAK activity for example allograft rejection or graft versus host disease, an autoimmune disease, a skin disorder, a viral disease, cancer, a disease characterized by a mutant JAK2, a myeloproliferative disorder, an inflammatory disease, ischemia reperfusion or related to an ischemic event, anorexia or cachexia resulting from or associated with cancer, fatigue resulting from or associated with cancer.
  • Non-limiting examples of myeloproliferative disorders are polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), or systemic mast cell disease (SMCD).
  • PV polycythemia vera
  • E essential thrombocythemia
  • MMM myeloid metaplasia with myelofibrosis
  • CML chronic myelogenous leukemia
  • CMML chronic myelomonocytic leukemia
  • HES hypereosinophilic syndrome
  • SMCD systemic mast cell disease
  • Step 1 Preparation of a solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-cf]pyrimidine (B)
  • Step 3 Preparation of 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-oQpyrimidin-4-yl)-1 H-pyrazol-1 -yl)propanenitrile (F)
  • the aqueous layer was removed from the resulting biphasic solution, and after two consecutive aqueous acidic washes using a solution of hydrochloric acid 0.1 N and a final aqueous neutral wash, the resulting organic layer was dried with sodium sulphate anhydrous, filtered and a 2-methyltetrahydrofuran solution of 3-cyclopentyl-3-(4-(7-((2- (trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol-1- yl)propanenitrile (F) was obtained. Yield: 100.0%. Purity (UPLC method): 91.99%.
  • Step 4a Preparation of 3-(4-(7H-pyrrolo[2,3-oQpyrimidin-4-yl)-1H-pyrazol-1-yl)-3- cyclopentylpropanenitrile (G) 650.3 mL of 2-methyltetrahydrofuran were added to 212.37 g of 2-methyltetrahydrofuran solution of 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3- d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)propanenitrile (F) (containing 55.37 g (0.127 mol) of 3- cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7- pyrazol-1-yl)propanenitrile (F) (100% equivalent
  • Step 4b Preparation of 3-(4-(7H-pyrrolo[2,3-oQpyrimidin-4-yl)-1H-pyrazol-1-yl)-3- cyclopentylpropanenitrile (G)
  • Step 5 Preparation of (/?)-3-(4-(7H-pyrrolo[2,3-oQpyrimidin-4-yl)-1H-pyrazol-1-yl)-3- cyclopentylpropanenitrile (2S,3S)-2,3-bis(benzoyloxy)succinate (H)
  • the obtained solid was recrystallized repeatedly from a mixture of acetonitrile and isopropanol until a solid with the desired chiral purity (e.g., (S)-isomer not more than 0.15% as analyzed by a chiral HPLC method) was obtained.
  • the desired chiral purity e.g., (S)-isomer not more than 0.15% as analyzed by a chiral HPLC method
  • Step 6 Preparation of (/?)-3-(4-(7H-pyrrolo[2,3-oQpyrimidin-4-yl)-1H-pyrazol-1-yl)-3- cyclopentylpropanenitrile hemifumarate, i.e., ruxolitinib hemifumarate (Compound II).
  • Table 1 shows the measured solubility (mg/mL) of ruxolitinib hemifumarate (Compound II) according to the present invention at 37° C and pH 1.2 in comparison with the solubility in mg/mL of ruxolitinib phosphate (Compound I) as reported in WO2016026974A1 :
  • Table 1 shows that ruxolitinib hemifumarate (Compound II) is less soluble than ruxolitinib phosphate at 37°C and pH 1.2.
  • the diffraction pattern was recorded including values of 20 that range from 2 to 50° with a sampling rate of 0.02° per second and a step time of 1 second per step.
  • the powdered sample was pressed between two glass plates, forming a film.
  • DIFFRAC Plus measurement software with EVA evaluation software (Bruker) was used to record the data and for a primary analysis of the diffraction pattern. The equipment was periodically calibrated using quartz and silicon.
  • Example A A colourless prism-like specimen as obtained in Example A, step 6, with approximate dimensions 0.185 mm x 0.066 mm x 0.056 mm, was used for the X-ray crystallographic analysis.
  • the frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm.
  • the goodness-of-fit was 1.018.
  • the largest peak in the final difference electron density synthesis was 0.737 e?A 3 and the largest hole was -0.644 e7A 3 with an RMS deviation of 0.062 e7A 3 .
  • the calculated density was 1.374 g/cm 3 and F(000), 768 e.
  • HCI 0.1 N 8.36 mL of HCI 37% were diluted to 1000 mL with Milli-Q water.
  • Paddles USP type 2.
  • the pH was adjusted to pH 8.5 ⁇ 0.05 with formic acid or ammonia 30%.
  • solutions were obtained directly withdrawing samples from the dissolution test at the time-points indicated above and were filtered through 0.45 pm PVDF filter before injecting them.
  • HCI 0.1 N 8.36 mL of HCI 37% were diluted to 1000 mL with Milli-Q water.
  • the pH was adjusted to pH 2.6 ⁇ 0.05 with ortho-phosphoric acid or potassium hydroxide.
  • solutions were obtained directly withdrawing samples from the dissolution test at the time-points indicated above and were filtered through 0.45 pm PVDF filter before injecting them.
  • Example 1 Immediate-release tablet of ruxolitinib hemifumarate (Compound II) was prepared:
  • compositions of example 1 were manufactured by following a manufacturing process which includes the following steps:
  • Ruxolitinib hemifumarate Compound II
  • intragranular microcrystalline cellulose Avicel® PH 101
  • lactose monohydrate and intragranular sodium starch glycolate (Explotab® CLV) were weighed and sieved by a 0.8 mm wire mesh screen.
  • step 3 The rest of the intragranular components were added to the premix obtained in step 2) and everything was mixed for 10 minutes at a speed of 15 rpm.
  • step 5 The granules obtained in step 4) were sieved by a 2 mm wire mesh screen and then dried at a temperature not higher than 40°C until reaching a moisture content less than 3% (w/w). 6) The dry granules mixture obtained in step 5) was sieved by a 0.8 mm wire mesh screen.
  • extragranular microcrystalline cellulose (Avicel® PH 101), extragranular sodium starch glycolate (Explotab® CLV), colloidal silicon dioxide (Aerosil® 200) and magnesium stearate (Ligamed® MF-2-V) were weighed and sieved by a 0.8 mm wire mesh screen.
  • step 6) The dry granules obtained in step 6) were mixed with the extragranular microcrystalline cellulose (Avicel® PH 101) and the extragranular sodium starch glycolate (Explotab® CLV) obtained is step 7) for 10 minutes at a speed of 12 rpm.
  • step 9) Colloidal silicon dioxide (Aerosil® 200) and magnesium stearate (Ligamed® MF-2-V) obtained in step 7) were added to the mixture of step 8) and mixed for 2 minutes at a speed of 12 rpm.
  • step 10) the mixture obtained in step 9) was compressed obtaining tablets with a hardness of 100 N.
  • Hydroxypropylcellulose (Klucel® EF) was slowly added to the 70 mL of purified water previously heated to 50°C. Once all the hydroxypropylcellulose (Klucel® EF) was dispersed, the heating was stopped, and 30 mL of purified water were added. The mixture was stirred until a transparent solution was obtained.
  • Povidone K29/32 (Plasdone® K29/32) was slowly added to the above solution until its complete dissolution.
  • Tables 3 and 4 depict stability data of the tablets of example 1 in open dish at 25 ⁇ 2°C and 60 ⁇ 5% relative humidity (RH) and in open dish at 40 ⁇ 2°C and 75 ⁇ 5% relative humidity (RH) respectively.
  • Example 2 Immediate-release tablet of ruxolitinib hemifumarate (Compound II) was prepared: Pharmaceutical tablets of example 2 were manufactured by following a manufacturing process which includes the following steps:
  • Ruxolitinib hemifumarate Compound II
  • intragranular microcrystalline cellulose Avicel® PH 101
  • lactose monohydrate intragranular sodium starch glycolate
  • Explotab® CLV intragranular sodium starch glycolate
  • hydroxypropylcellulose Kermel® EF
  • povidone K29/32 povidone K29/32
  • step 3 The rest of the intragranular components were added to the premix obtained in step 2) and everything was mixed for 10 minutes at a speed of 15 rpm.
  • step 5 The granules obtained in step 4) were sieved by a 4 mm wire mesh screen and then dried at a temperature not higher than 40°C until reaching a moisture content less than 3% (w/w).
  • step 6) The dry granules mixture obtained in step 5) was sieved by a 0.8 mm wire mesh screen.
  • extragranular microcrystalline cellulose (Avicel® PH 101), extragranular sodium starch glycolate (Explotab® CLV), colloidal silicon dioxide (Aerosil® 200) and magnesium stearate (Ligamed® MF-2-V) were weighed and sieved by a 0.8 mm wire mesh screen.
  • step 6) The dry granules obtained in step 6) were mixed with the extragranular microcrystalline cellulose (Avicel® PH 101) and the extragranular sodium starch glycolate (Explotab® CLV) obtained is step 7) for 10 minutes at a speed of 12 rpm.
  • step 9) Colloidal silicon dioxide (Aerosil® 200) and magnesium stearate (Ligamed® MF-2-V) obtained in step 7) were added to the mixture of step 8) and mixed for 2 minutes at a speed of 12 rpm.
  • step 10) the mixture obtained in step 9) was compressed obtaining tablets with a hardness of 100 N.
  • immediate-release tablets comprising ruxolitinib hemifumarate (Compound II) of the present invention show a slightly higher dissolution profile than the commercial tablets Jakavi® of ruxolitinib phosphate, even when the solubility of ruxolitinib hemifumarate (Compound II) is lower than the solubility of ruxolitinib phosphate (Compound I).
  • Stability data of the tablets of example 2 Tables 6 and 7 depict stability data of the tablets of Example 2 in blister of PCTFE and Hard foil aluminim at 25 ⁇ 2°C and 60 ⁇ 5% relative humidity (RH) and in in blister of PCTFE and Hard foil aluminim at 40 ⁇ 2°C and 75 ⁇ 5% relative humidity (RH) respectively.

Abstract

The present invention provides solid oral immediate-release formulations of ruxolitinib hemifumarate (Compound II) which show the same or higher solubility than the commercial tablets of ruxolitinib phosphate. These novel solid oral immediate-release formulations can be obtained by a process which comprises wet granulation.

Description

STABLE ORAL PHARMACEUTICAL FORMULATION CONTAINING RUXOLITINIB HEMIFUMARATE
FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical formulations of ruxolitinib hemifumarate which show the same or higher solubility compared to the commercial tablets containing ruxolitinib phosphate.
BACKGROUND OF THE INVENTION
Ruxolitinib phosphate (Compound I) is the international commonly accepted nonproprietary name (INN) of (3R)-3-cyclopentyl-3-[4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)pyrazol- 1 -yl]propanenitrile phosphate, has empirical formula of C17H18N6 H3PO4 and its molecular weight is 404.37 g/mol.
Figure imgf000002_0001
Compound I
Ruxolitinib and pharmaceutically acceptable salts thereof have a selective inhibitor activity on the Janus Associated Kinase 1 (JAKI) and Janus Associated Kinase 2 (JAK2) enzymes. These kinases mediate the signaling of a number of cytokines and growth factors important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression.
Tablets containing ruxolitinib phosphate (Compound I) have been approved in the US and Europe for the treatment of myelofibrosis, polycythemia vera and graft-versus-host disease. These tablets, marketed as Jakavi® in Europe and as Jakafi® in the US, are immediate-release tablets. Ruxolitinib phosphate (Compound I) is described as a Biopharmaceutics Classification system (BCS) Class I active ingredient with rapid oral absorption and a short half-life of about 3 hours. See, Shi et al, J. Clin. Pharmacol. 2012 Jun, 52(6), 809-818.
Ruxolitinib and its pharmaceutically acceptable salts thereof were first disclosed in W02007070514A1. Example 67 describes the preparation of ruxolitinib base.
Different salts of ruxolitinib, apart from the commercial ruxolitinib phosphate (Compound I), have been disclosed in the literature. W02008157208A2 discloses, apart from ruxolitinib phosphate (Compound I), salts of ruxolitinib with maleic acid and sulfuric acid. WO2016026974A1 discloses the oxalate salt of ruxolitinib and tablets comprising the same. WO2016026975A1 discloses the besylate salt of ruxolitinib. WO2016063294A2 reports crystalline forms of salts of ruxolitinib with (+)-dibenzoyl tartaric acid and hydrochloric acid. W02016074650A1 discloses amorphous salts of ruxolitinib with hydrobromic acid, hydrochloric acid, citric acid, fumaric acid, L-tartaric acid, p- toluenesulfonic acid, benzoic acid, benzenesulfonic acid, ethanesulfonic acid, 2- naphthalenesulfonic acid and 4-chlorobenzenesulfonic acid. W02017008772A1 reports several crystalline forms of ruxolitinib salt with hydrobromic and hydrochloric acid. WO2017125097A1 describes specific crystalline forms of salts of ruxolitinib with hydrochloric acid, fumaric acid and L-tartaric acid. IN202141008799A1 discloses a crystalline form of ruxolitinib benzoate and IN202141017096A1 discloses a crystalline form of ruxolitinib tartrate. W02023087101A1 reports sulfonate salts, concretely a mesylate salt, an edisylate salt, a napadisylate salt and an acesulfamate salt, of ruxolitinib and crystalline forms thereof.
None of these documents provide examples of pharmaceutical formulations, in particular solid oral immediate-release tablets, containing ruxolitinib hemifumarate.
Different salts and polymorphic forms thereof (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties may provide a basis for improving certain aspects of the active ingredient and their pharmaceutical formulations, for example, by facilitating better processing or handling of by improving solubility and in consequence bioavailability.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to a solid oral immediate-release pharmaceutical formulation comprising ruxolitinib hemifumarate (Compound II) which provides the same or higher solubility compared to the commercial tablets JakavP which contain ruxolitinib phosphate (Compound I).
Figure imgf000004_0001
Compound II
As illustrated in the examples, the authors of the present invention have found that although the solubility of ruxolitinib hemifumarate (Compound II) is lower than the solubility of ruxolitinib phosphate (Compound I), the solid oral immediate-release pharmaceutical formulations comprising ruxolitinib hemifumarate (Compound II) of the present invention show the same or higher solubility than the commercial tablets Jakavi® containing ruxolitinib phosphate (Compound I).
Thus, a first aspect of the invention relates to a solid oral immediate-release pharmaceutical formulation comprising a therapeutically effective amount of ruxolitinib hemifumarate (Compound II) and one or more pharmaceutically acceptable excipients.
The pharmaceutical formulations herein disclosed can be easily manufactured into solid dosage forms, such as tablets, having good stability and the desired dissolution profiles. The pharmaceutical formulations herein disclosed have the technological properties for being manufactured at an industrial scale (flowability, compaction, hardness, disintegration, content uniformity, friability, dissolution and stability).
The present invention also provides a process for preparing the solid oral immediate- release pharmaceutical formulations of ruxolitinib hemifumarate (compound II) which comprises granulation, for example wet granulation.
Another aspect of the invention relates to the solid oral immediate-release pharmaceutical formulation of ruxolitinib hemifumarate (compound II) as defined herein, for use in treating a disease in a patient, wherein said disease is associated with JAK activity.
Another aspect of the invention relates to the solid oral immediate-release pharmaceutical formulation of ruxolitinib hemifumarate (compound II) as defined herein, for use in treating a myeloproliferative disorder. BRIEF DESCRIPTION OF DRAWINGS
Figure 1 X-Ray Powder Diffractogram (XRPD) of ruxolitinib hemifumarate (Compound II) as obtained in Example A, step 6.
Figure 2 depicts the dissolution profile of the tablets of the example 1 of the present invention compared with the dissolution profile of the commercial tablets Jakavi® in 500 mL of 0.1 N HCI at 37°C ± 0.5°C using USP apparatus 2 (paddle) at 50 rpm.
Figure 3 depicts the dissolution profile of the tablets of the example 2 of the present invention compared with the dissolution profile of the commercial tablets Jakavi® in 500 mL of 0.1 N HCI at 37°C ± 0.5°C using USP apparatus 1 (basket) at 100 rpm.
Figure 4 depicts the molecular structure of ruxolitinib hemifumarate (Compound II) as obtained in Example A, step 6, with the atom-labeling scheme.
DETAILED DESCRIPTION OF THE INVENTION
An aspect of the present invention provides a solid oral immediate-release pharmaceutical formulation comprising a therapeutically effective amount of ruxolitinib hemifumarate (Compound II) and one or more pharmaceutically acceptable excipients.
The expression "therapeutically effective amount" as used herein, refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed. The specific dose of the compound of the invention to obtain a therapeutic benefit may vary depending on the particular circumstances of the individual patient including, among others, the size, weight, age and sex of the patient, the nature and stage of the disease, the aggressiveness of the disease.
The expression "pharmaceutically acceptable excipients" refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio. The term “about” when used in the present invention preceding a number and referring to it, is meant to designate any value which lies within the range defined by the number ±10% of its value, preferably a range defined by the number ±5%, more preferably a range defined by the number ±2%, still more preferably a range defined by the number ±1%. For example, “about 10” should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
The pharmaceutical formulations as disclosed herein are stable. The term "stable" as used herein refers to a pharmaceutical formulation comprising ruxolitinib hemifumarate (Compound II) wherein the total content of impurities originated from the degradation of ruxolitinib hemifumarate (Compound II) does not exceed 5%, preferably 3%, more preferably 2%, most preferably 1%, and even most preferably 0.5%, as determined by a liquid chromatography method (HPLC method) if such a formulation is stored for at least 3 months, preferably at least 6 months, at 40±2°C and 75±5% relative humidity (RH) and for at least 3 months, preferably at least 6 months, more preferably at least 9 months, even more preferably for at least 1 year at 25±2°C and 60±5% relative humidity (RH).
The solid oral immediate-release pharmaceutical formulation of the present invention can be in the form of powder, a granule, a pellet, a mini-tablet, a tablet, a capsule, a capsule filled with granules or pellets and the like. Preferably, the solid oral immediate-release pharmaceutical formulation of the present invention is a tablet.
The solid oral immediate-release pharmaceutical formulation as herein disclosed has to be understood as a solid oral pharmaceutical formulation, preferably a tablet, having a dissolution performance such as at least about 75% of the ruxolitinib hemifumarate (Compound II) of the solid oral immediate-release pharmaceutical formulation of the present invention dissolves in 30 minutes, when the solid oral immediate-release pharmaceutical formulation is placed in 500 mL of 0.1 N HCI at 37°C ± 0.5°C using USP apparatus 2 (paddle) at 50 rpm or in 500 mL of 0.1 N HCI at 37°C ± 0.5°C using USP apparatus 1 (basket) at 100 rpm. More preferably at least about 85% of the ruxolitinib hemifumarate (Compound II) of the solid oral immediate-release pharmaceutical formulation of the present invention dissolves in 15 minutes, when the solid oral immediate-release pharmaceutical formulation is placed in 500 mL of 0.1 N HCI at 37°C ± 0.5°C using USP apparatus 2 (paddle) at 50 rpm or in 500 mL of 0.1 N HCI at 37°C ± 0.5°C using USP apparatus 1 (basket) at 100 rpm.
The authors of the present invention have surprisingly found that the solid oral immediate- release formulation of ruxolitinib hemifumarate (Compound II) of the present invention shows the same or even higher solubility than the commercial immediate-release tablets Jakavi® of ruxolitinib phosphate (Compound I), so that bioavailability can be improved.
In an embodiment of the present invention the solid oral immediate-release pharmaceutical formulation comprises ruxolitinib hemifumarate (compound II) and one or more excipients selected from the group consisting of wetting agents, fillers, disintegrants, antioxidants, binders, chelating agents, glidants, lubricants, and mixtures thereof.
Non-limiting examples of wetting agents which can be used in the formulation of the present invention are poloxamer (e.g. Kolliphor® P407), polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polysorbates, such as polysorbate 80, cetyl alcohol, glycerol fatty acid esters (e.g. triacetin, glycerol monostearate and the like), polyoxymethylene stearate, sodium dodecyl sulfate, sorbitan fatty acid esters, sucrose fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, docusate sodium, and mixtures thereof.
Non-limiting examples of fillers which can be used in the formulation of the present invention are microcrystalline cellulose (e.g., Avicel® PH101), silicified microcrystalline cellulose (e.g. Prosolv® HD90), pregelatinized starch, starches (such as maize starch, potato starch, rice starch, wheat starch), lactitol, lactose (e.g. lactose monohydrate), maltose, trehalose, a suitable inorganic calcium salt, sucrose, glucose, sugar alcohols (such as mannitol, sorbitol and xylitol), silicic acid, and mixtures thereof. In a preferred embodiment, the formulation of the present invention comprises microcrystalline cellulose (e.g., Avicel® PH 101) and lactose (e.g. lactose monohydrate).
Non-limiting examples of disintegrants which can be used in the formulation of the present invention are low substituted hydroxypropyl cellulose (L-HPC), carboxymethylcellulose calcium, carboxymethylcellulose sodium, cellulose powdered, chitosan, docusate sodium, glycine, sodium alginate, crospovidone (e.g. Polyplasdone® XL), croscarmellose sodium (e.g. Vivasol®), sodium starch glycolate (e.g. Explotab® CLV), and mixtures thereof. In a preferred embodiment, the formulation of the present invention comprises sodium starch glycolate (e.g. Explotab® CLV).
Non-limiting examples of antioxidants which can be used in the formulation of the present invention are ascorbic acid and salts and esters thereof, citric acid and salts and esters thereof, butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), tocopherols (e.g., alpha-tocopherol, beta-tocopherol, gamma-tocopherol and delta-tocopherol), tocopherol acetate (e.g. alpha-tocopherol acetate, beta-tocopherol), carotenoids (e.g., vitamin A, lutein, and zeaxanthin), and mixtures thereof.
Non-limiting examples of binders which can be used in the formulation of the present invention are povidone (e.g., Plasdone® K29/32 or Kolloidon®), hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, Klucel® EF), hydroxypropyl methyl cellulose, gelatin, starch, sucrose, mannitol, polyethylene glycol, acacia, guar gum, maltodextrin, methylcellulose, ethylcellulose, and mixtures thereof. In a preferred embodiment, the formulation of the present invention comprises povidone (e.g., Plasdone® K29/32) and hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF).
Non-limiting examples of chelating agents which can be used in the formulation of the present invention are ethylenediaminetetraacetic acid (EDTA) and derivatives thereof (e.g. edetate calcium disodium), ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA) and derivatives thereof, diethylenetriaminepentaacetic acid (DTPA) and derivatives thereof, N,N-bis(carboxymethyl)glycine (NTA) and derivatives thereof, nitrilotriacetic acid and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, sodium desoxycholate and derivatives thereof, and mixtures thereof.
Non-limiting examples of glidants which can be used in the formulation of the present invention are colloidal silicon dioxide (e.g. Aerosil® 200), silica gel, fumed silica, talc, magnesium carbonate, magnesium silicate, calcium silicate, calcium phosphate tribasic, bentonite, and mixtures thereof. In a preferred embodiment, the formulation of the present invention comprises colloidal silicon dioxide (e.g. Aerosil® 200).
Non-limiting examples of lubricants which can be used in the formulation of the present invention are stearic acid (e.g, Kolliwax® S Fine), and stearic acid derivatives such as sodium stearate, calcium stearate, zinc stearate, magnesium stearate, sodium oleate, polyethylene glycol, talc, mineral oil, sodium lauryl sulfate, sodium stearyl fumarate, castor oils, sodium benzoate, sodium acetate, sodium chloride, and mixtures thereof. In a preferred embodiment, the formulation of the present invention comprises magnesium stearate (e.g. Ligamed®MF-2-V).
In a preferred embodiment of the present invention, the solid oral immediate-release pharmaceutical formulation, preferably a tablet, comprises ruxolitinib hemifumarate (Compound II) and at least one filler, preferably microcrystalline cellulose (e.g. Avicel® PH 101) and/or lactose (e.g. lactose monohydrate), at least one disintegrant, preferably sodium starch glycolate (e.g. Explotab® CLV), at least one binder, preferably povidone (e.g. Plasdone® K29/32) and/or hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF), at least one glidant, preferably colloidal silicon dioxide (e.g. Aerosil® 200), and at least one lubricant, preferably magnesium stearate (e.g. Ligamed® MF-2-V).
In a preferred embodiment of the present invention, the solid oral immediate-release pharmaceutical formulation, preferably a tablet, comprises ruxolitinib hemifumarate (Compound II), microcrystalline cellulose (e.g., Avicel® PH 101), lactose (e.g. lactose monohydrate), sodium starch glycolate (e.g. Explotab® CLV), povidone (e.g. Plasdone® K29/32), hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF), colloidal silicon dioxide (e.g. Aerosil® 200) and magnesium stearate (e.g. Ligamed® MF-2-V).
In a preferred embodiment of the present invention, the solid oral immediate-release pharmaceutical formulation, preferably a tablet, comprises or consists of ruxolitinib hemifumarate (Compound II) and at least one filler, preferably microcrystalline cellulose (e.g. Avicel® PH 101) and/or lactose (e.g. lactose monohydrate), at least one disintegrant, preferably sodium starch glycolate (e.g. Explotab® CLV), at least one binder, preferably povidone (e.g. Plasdone® K29/32) and/or hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF), at least one glidant, preferably colloidal silicon dioxide (e.g. Aerosil® 200), and at least one lubricant, preferably magnesium stearate (e.g. Ligamed® MF-2-V), wherein:
- the weight of ruxolitinitb hemifumarate (Compound II), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 2.0% to 6.0%, preferably from 2.5% to 4.5%, for example 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1.%, 3.2.%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, or 4.5%, more preferably from 3.0% to 4.0%, even more preferably from 3.5% to 4.0%;
- the weight of the at least one filler, preferably microcrystalline cellulose (e.g. Avicel® PH 101) and/or lactose (e.g. lactose monohydrate), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 70% to 95%, for example 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, or 95%, preferably from 80% to 90%;
- the weight of the at least one disintegrant, preferably sodium starch glycolate (e.g. Explotab® CLV), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 1 .0% to 8.0% or from 2.0% to 8.0%, preferably from 2.0% to 5.0% or from 3.0% to 5.0%, for example 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1 %, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5.0%;
- the weight of the at least one binder, preferably povidone (e.g. Plasdone® K29/32) and/or hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.5% to 7.0%, preferably from 3.5% to 5.5%, for example 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1 %, 5.2%, 5.3%, 5.4%, or 5.5%;
- the weight of the at least one glidant, preferably colloidal silicon dioxide (e.g. Aerosil® 200), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.1 % to 2.5%, for example 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, or 2.5%, preferably from 0.5% to 1.5%; and
- the weight of the at least one lubricant, preferably magnesium stearate (e.g. Ligamed® MF-2-V), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.2% to 6.5% or from 0.4% to 6.5%, preferably from 0.4% to 3.0% or from 1 .0% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
In a preferred embodiment of the present invention, the solid oral immediate-release pharmaceutical formulation, preferably a tablet, comprises or consists of ruxolitinib hemifumarate (Compound II), microcrystalline cellulose (e.g. Avicel® PH 101), lactose (e.g. lactose monohydrate), sodium starch glycolate (e.g. Explotab® CLV), povidone (e.g. Plasdone® K29/32), hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF), colloidal silicon dioxide (e.g. Aerosil® 200) and magnesium stearate (e.g. Ligamed® MF-2-V), wherein:
- the weight of ruxolitinib hemifumarate (Compound II), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 2.0% to 6.0%, preferably from 2.5% to 4.5%, for example 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1.%, 3.2.%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, or 4.5%, more preferably from 3.0% to 4.0%, even more preferably from 3.5% to 4.0%;
- the sum of the weights of microcrystalline cellulose (e.g. Avicel® PH 101) and lactose (e.g. lactose monohydrate), in relation to the total weight of the solid oral immediate- release pharmaceutical formulation of the present invention, is from 70% to 95%, for example 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%, preferably from 80% to 90%;
- the weight of sodium starch glycolate (e.g. Explotab® CLV) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 1.0% to 8.0% or from 2.0% to 8.0%, preferably from 2.0% to 5.0% or from 3.0% to 5.0%, for example 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5.0%;
- the sum of weights of povidone (e.g. povidone K30) and hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.5% to 7.0%, preferably from 3.5% to 5.5%, for example 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, or 5.5%;
- the weight of colloidal silicon dioxide (e.g. Aerosil® 200) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.1 % to 2.5%, for example 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, or 2.5%, preferably from 0.5% to 1.5%, and
- the weight of magnesium stearate (e.g. Ligamed® MF-2-V) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.2% to 6.5% or from 0.4% to 6.5%, preferably from 0.4% to 3.0% or from 1.0% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
In a preferred embodiment of the present invention, the solid oral immediate-release pharmaceutical formulation, preferably a tablet, comprises or consists of ruxolitinib hemifumarate (Compound II), microcrystalline cellulose (e.g. Avicel® PH 101), lactose (e.g. lactose monohydrate), sodium starch glycolate (e.g. Explotab® CLV), povidone (e.g. Plasdone® K29/32), hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF), colloidal silicon dioxide (e.g. Aerosil® 200) and magnesium stearate (e.g. Ligamed® MF-2-V), wherein:
- the weight of ruxolitinib hemifumarate (Compound II), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 2.0% to 6.0%, preferably from 2.5% to 4.5%, for example 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1.%, 3.2.%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, or 4.5%, more preferably from 3.0% to 4.0%, even more preferably from 3.5% to 4.0%;
- the weight of microcrystalline cellulose (e.g. Avicel® PH 101) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 25% to 60% or from 35% to 60%, preferably from 30% to 50%, for example 30%, 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%, more preferably from 38% to 45%;
- the weight of lactose (e.g. lactose monohydrate) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 25% to 60% or from 35% to 60%, preferably from 30% to 50%, for example 30%, 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%, more preferably from 40% to 48%;
- the weight of sodium starch glycolate (e.g. Explotab® CLV) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 1.0% to 8.0% or from 2.0% to 8.0%, preferably from 2.0% to 5.0% or from 3.0% to 5.0%, for example 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5.0%;
- the weight of povidone (e.g. Plasdone® K29/32) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.5% to 6.5%, preferably from 1.5% to 2.5%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, or 2.5%;
- the weight of hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.5% to 6.5%, preferably from 1.5% to 3.5% or from 1.5% to 3.0%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1 %, 3.2%, 3.3%, 3.4%, or 3.5%, more preferably from 2.0% to 3.0%;
- the weight of colloidal silicon dioxide (e.g. Aerosil® 200) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.1 % to 2.5%, for example 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, or 2.5%, preferably from 0.5% to 1.5%; and
- the weight of magnesium stearate (e.g. Ligamed® MF-2-V) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.2% to 6.5% or from 0.4% to 6.5%, preferably from 0.4% to 3.0% or from 1.0% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
In a preferred embodiment of the present invention, the solid oral immediate-release pharmaceutical formulation, preferably a tablet, comprises or consists of ruxolitinib hemifumarate (compound II), microcrystalline cellulose (e.g. Avicel® PH101), lactose (e.g. lactose monohydrate), sodium starch glycolate (e.g. Explotab® CLV), povidone (e.g. Plasdone® K29/32), hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF), colloidal silicon dioxide (e.g. Aerosil® 200) and magnesium stearate (e.g. Ligamed® MF-2-V), wherein:
- the weight of ruxolitinib hemifumarate (Compound II), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 3.5% to 4.0%, for example 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, or 4.0%;
- the weight of microcrystalline cellulose (e.g. Avicel® PH 101) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 38% to 45%, for example 38%, 39%, 40%, 41%, 42%, 43%, 44%, or 45%;
- the weight of lactose (e.g. lactose monohydrate) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 40% to 48%, for example 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, or 48%;
- the weight of sodium starch glycolate (e.g. Explotab® CLV) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 2.0% to 5.0%, for example 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1 %, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5.0%;
- the weight of povidone (e.g. Plasdone® K29/32) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 1.5% to 2.5%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, or 2.5%;
- the weight of hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 2.0% to 3.0%, for example 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%;
- the weight of colloidal silicon dioxide (e.g. Aerosil® 200) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.5% to 1.5%, for example 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, or 1.5%; and
- the weight of magnesium stearate (e.g. Ligamed® MF-2-V) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention, is from 0.4% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
In an embodiment of the present invention the solid oral immediate-release tablet is not coated.
Alternatively, the solid oral immediate-release tablet can be coated preferably with a coating comprising hydroxypropylmethyl cellulose such as Opadry® Clear (Colorcon®, Inc.) or hydroxypropyl methyl cellulose E3 or with a PVA-based film coating (e.g. Opadry® II White 85F18422, Opadry® II White 32F280008 or Opadry® Pink 03B240053), preferably with a PVA-based film coating (e.g. Opadry® II White 85F18422, Opadry® II White 32F280008 or Opadry® Pink 03B240053).
The solid oral immediate-release pharmaceutical formulation, preferably a tablet, of the present invention can be packaged in any type of container and/or packaging component that prevents water absorption and degradation (such as bottles, flasks, plastic bags, and blister packs).
The formulation of the present invention, preferably a tablet, can contain the amount of ruxolitinib hemifumarate (Compound II) equivalent to 5, 10, 15, 20 and 25 mg of ruxolitinib free base, respectively.
The formulation of the present invention, preferably a tablet, can be obtained by processes which can involve different techniques used in pharmaceutical development such as direct compression, dry granulation, wet granulation, melt-granulation, spraydrying, extrusion or hot melt extrusion, preferably wet granulation. In a preferred embodiment, the solid immediate-release pharmaceutical formulation of the present invention, preferably a tablet, is obtainable by a process comprising a granulation step, preferably wet granulation, more preferably aqueous wet granulation.
In a preferred embodiment of the present invention, the process for preparing the formulations of the present invention, preferably a tablet, comprises an aqueous wet granulation.
In a preferred embodiment, the process for preparing the immediate-release tablets of the present invention comprises the following steps: 1) ruxolitinib hemifumarate (Compound II) and the intragranular components are weighed, sieved, for example by a 0.8 mm wire mesh screen, and mixed;
2) under constant agitation, a binder solution is added to the mixture obtained in step 1), and granulation is performed. The binder solution is separately and previously prepared by heating water at a temperature of between 40°C to 60°C, preferably about 50°C, and gradually adding the at least one binder, preferably povidone and/or hydroxypropylcellulose, with constant stirring until complete dissolution;
3) the mixture obtained in step 2) is sieved, for example by a 2.0 mm or 4.0 mm wire mesh screen, and dried at a temperature not higher than about 40°C until a specific moisture content, for example of less than 3% w/w;
4) the dried granules obtained in step 3) are sieved, for example by a 0.8 mm wire mesh screen;
5) the extragranular components are sieved, for example by a 0.8 mm wire mesh screen;
6) the dried granules obtained in step 4) are mixed with the extragranular components obtained in step 5);
7) the mixture obtained in step 6) is compressed.
In the embodiment wherein more than one binder is used, all of the binders are added in solution or, alternatively, one or some of them are added in solid form and the rest in solution.
In another embodiment, the at least one binder, preferably povidone and/or hydroxypropylcellulose, is added in solid form as intragranular component or components in the step 1) above, so that no binder solution is prepared. In this alternative process, in the step 2), water, preferably at room temperature, is added to the mixture obtained in step 1) and afterwards the process continues according to the above steps 3) to 7).
In one embodiment of the invention, apart from ruxolitinib hemifumarate (Compound II), the intragranular components comprise at least one filler, at least one disintegrant and at least one binder and the extragranular components comprise the rest of excipients, for example at least one glidant and at least one lubricant.
In the embodiment of the invention wherein the solid oral immediate-release pharmaceutical formulation, preferably a tablet, is prepared by a process comprising a granulation step, preferably wet granulation, more preferably aqueous wet granulation, apart from the ruxolitinib hemifumarate (Compound II), the intragranular components comprise part of the filler or fillers, part of the disintegrant or disintegrants and the binder or binders, and the extragranular components comprise the rest of the filler or fillers, the rest of the disintegrant or disintegrants, the glidant or glidants, and the lubricant or lubricants. Therefore, fillers and disintegrants can form part of the intragranular and the extragranular mixture.
Preferably, in the embodiment of the invention wherein the solid oral immediate-release pharmaceutical formulation, preferably a tablet, is prepared by a process comprising a granulation step, preferably wet granulation, more preferably aqueous wet granulation, at least one filler, preferably microcrystalline cellulose, and the disintegrant, preferably sodium starch glycolate, form part of the intragranular and the extragranular mixture.
Preferably, in the embodiment of the invention wherein the solid oral immediate-release pharmaceutical formulation, preferably a tablet, is prepared by a process comprising a granulation step, preferably wet granulation, more preferably aqueous wet granulation, the relation between the weight of the intragranular filler or fillers, preferably microcrystalline cellulose (e.g. Avicel® PH101) and lactose (e.g. lactose monohydrate), with respect of the weight of the extragranular filler or fillers, preferably microcrystalline cellulose (e.g. Avicel® PH101), is of about 4 to 5, for example 4.0, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0.
Preferably, in the embodiment of the invention wherein the solid oral immediate-release pharmaceutical formulation, preferably a tablet, is prepared by a process comprising a granulation step, preferably wet granulation, more preferably aqueous wet granulation, the relation between the weight of the intragranular filler, preferably microcrystalline cellulose, and the weight of the same extragranular filler, preferably microcrystalline cellulose, is from about 1 to 2, for example about 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0, and the relation between the weight of the intragranular disintegrant, preferably sodium starch glycolate, and the extragranular disintegrant, preferably sodium starch glycolate, is from about 0.5 to 1.5, for example about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, or 1.5.
Preferably, in the embodiment of the invention wherein the solid oral immediate-release pharmaceutical formulation, preferably a tablet, is prepared by a process comprising a granulation step, preferably wet granulation, more preferably aqueous wet granulation, the solid oral immediate-release pharmaceutical formulation, preferably a tablet, comprises or consists of intragranular components which comprise or consist of ruxolitinib hemifumarate (Compound II), microcrystalline cellulose (e.g. Avicel® PH 101), lactose (e.g. lactose monohydrate), sodium starch glycolate (e.g. Explotab® CLV), povidone (e.g. Plasdone® K29/32) and hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF); and extragranular components which comprise or consist of microcrystalline cellulose (e.g. Avicel® PH 101), sodium starch glycolate (e.g. Explotab® CLV), colloidal silicon dioxide (e.g. Aerosil® 200) and magnesium stearate (e.g. Ligamed® MF-2-V), wherein:
- the weight of ruxolitinib hemifumarate (Compound II) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 2.0% to 6.0%, preferably from 2.5% to 4.5%, for example 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1.%, 3.2.%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, or 4.5%, more preferably from 3.0% to 4.0%, even more preferably from 3.5% to 4.0%;
- the weight of intragranular microcrystalline cellulose (e.g. Avicel® PH 101) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 15% to 35%, preferably from 20% to 30%, for example 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%;
- the weight of lactose (e.g. lactose monohydrate) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 25% to 60%, preferably from 30% to 50%, for example 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 22%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%, more preferably from 40% to 48%;
- the weight of intragranular sodium starch glycolate (e.g. Explotab® CLV) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.5% to 3.5%, preferably from 1.0% to 2.5%, for example 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, or 2.5%;
- the weight of povidone (e.g. Plasdone® K29/32) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.5% to 6.5%, preferably from 1.5% to 2.5%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, or 2.5%;
- the weight of hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.5% to 6.5%, preferably from 1.5% to 3.5%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, or 3.5%, more preferably from 2.0% to 3.0%;
- the weight of extragranular microcrystalline cellulose (e.g. Avicel® PH 101) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 5% to 25%, preferably from 10% to 20%, for example 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%;
- the weight of extragranular sodium starch glycolate (e.g. Explotab® CLV) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.5% to 3.5%, more preferably from 1.0% to 2.5%, for example 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, or 2.5%;
- the weight of colloidal silicon dioxide (e.g. Aerosil® 200) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.1% to 2.5%, for example 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, or 2.5, preferably from 0.5% to 1.5%; and
- the weight of magnesium stearate (e.g. Ligamed® MF-2-V) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.2% to 6.5%, preferably from 0.4% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
Preferably, in the embodiment of the invention wherein the solid oral immediate-release pharmaceutical formulation, preferably a tablet, is prepared by a process comprising a granulation step, preferably wet granulation, more preferably aqueous wet granulation, the solid oral immediate-release pharmaceutical formulation, preferably tablets, comprises or consists of intragranular components which comprise or consist of ruxolitinib hemifumarate (Compound II), microcrystalline cellulose (e.g. Avicel® PH 101), lactose (e.g. lactose monohydrate), sodium starch glycolate (e.g. Explotab® CLV), povidone (e.g. Plasdone® K29/32) and hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF); and extragranular components which comprise or consist of microcrystalline cellulose (e.g. Avicel® PH 101), sodium starch glycolate (e.g. Explotab® CLV), colloidal silicon dioxide (e.g. Aerosil® 200) and magnesium stearate (e.g. Ligamed® MF-2-V), wherein:
- the weight of ruxolitinib hemifumarate (Compound II) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 3.5% to 4.0%, for example 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, or 4.0%;
- the weight of intragranular microcrystalline cellulose (e.g. Avicel® PH 101) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 20% to 30%, for example 20%, 21 %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%;
- the weight of lactose (e.g. lactose monohydrate) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 40% to 48%, for example 42%, 43%, 44%, 45%, 46%, 47%, or 48%;
- the weight of intragranular sodium starch glycolate (e.g. Explotab® CLV) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 1.0% to 2.5%, for example 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, or 2.5%;
- the weight of povidone (e.g. Plasdone® K29/32) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 1.5% to 2.5%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, or 2.5%;
- the weight of hydroxypropylcellulose (e.g. hydroxypropylcellulose 300 to 600 cps, e.g. Klucel® EF) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 2.0% to 3.0%, for example 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%;
- the weight of extragranular microcrystalline cellulose (e.g. Avicel® PH 101) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 10% to 20%, for example 10%, 11%, 12%, 13%, 14%, 15%, 16% , 17% , 18% , 19% , or 20% ;
- the weight of extragranular sodium starch glycolate (e.g. Explotab® CLV) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 1.0% to 2.5%, for example 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, or 2.5%;
- the weight of colloidal silicon dioxide (e.g. Aerosil® 200) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.5% to 1.5%, for example 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%, and
- the weight of magnesium stearate (e.g. Ligamed® MF-2-V) in relation to the total weight of the solid oral immediate-release pharmaceutical formulation of the present invention is from 0.4% to 3.0%, for example 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
Non-limiting examples of the wetting agents, fillers, antioxidants, disintegrants, chelating agents, glidants or lubricants used in the process of the present invention are the same as those given for the solid oral immediate-release formulations of the present invention.
The ruxolitinib hemifumarate (Compound II) used for the preparation of the solid oral immediate-release formulation of the present invention, preferably a tablet, can be crystalline or amorphous or a mixture of a crystalline and amorphous forms. In a preferred embodiment of the present invention the ruxolitinib hemifumarate (Compound II) used for the preparation of the solid immediate-release formulation of the present invention shows a X-Ray Powder Diffractogram (XRPD) that comprises characteristic peaks at an angle of diffraction 2 theta (20) of 5.6, 6.5, 16.2 and 18.1 (± 0.2), preferably at an angle of diffraction 2 theta (20) of 5.6, 6.5, 10.2, 10.5, 13.1, 15.5, 16.2 and 18.1 (± 0.2), more preferably at an angle of diffraction 2 theta (20) of 5.6, 6.5, 10.2, 10.5, 13.1, 15.2, 15.5, 16.2, 16.7, 18.1 , 19.4, 19.7, 20.0, 22.0, 22.7, 23.1 , 23.9, 25.5 and 26.5 (± 0.2) as measured in a X-ray diffractometer with Cu Ka radiation (1.54056 A). In a preferred embodiment of the present invention the ruxolitinib hemifumarate (Compound II) used for the preparation of the solid immediate-release formulation of the present invention shows a X-Ray Powder Diffractogram (XRPD) as shown in Figure 1.
In an embodiment of the present invention, the solid oral immediate-release formulation of the present invention, preferably a tablet, contains ruxolitinib hemifumarate (Compound II) which shows a X-Ray Powder Diffractogram (XRPD) that comprises characteristic peaks at an angle of diffraction 2 theta (20) of 5.6, 6.5, 16.2 and 18.1 (± 0.2), preferably at an angle of diffraction 2 theta (20) of 5.6, 6.5, 10.2, 10.5, 13.1 , 15.5, 16.2 and 18.1 (± 0.2), more preferably at an angle of diffraction 2 theta (20) of 5.6, 6.5, 10.2, 10.5, 13.1, 15.2, 15.5, 16.2, 16.7, 18.1, 19.4, 19.7, 20.0, 22.0, 22.7, 23.1, 23.9, 25.5 and 26.5 (± 0.2) as measured in a X-ray diffractometer with Cu Ka radiation (1.54056 A). In a preferred embodiment the solid oral immediate-release formulation of the present invention contains ruxolitinib hemifumarate (Compound II) which shows a X-Ray Powder Diffractogram (XRPD) as shown in Figure 1.
In a preferred embodiment of the present invention, the basic crystallographic data for a single crystal of the ruxolitinib hemifumarate (Compound I) used for the preparation of the solid immediate-release formulation of the present invention, preferably a tablet, is as follows:
Figure imgf000020_0001
In an embodiment of the present invention, the ruxolitinib hemifumarate (Compound II) used for the preparation of the solid oral immediate-release formulation of the present invention, preferably a tablet, has a D90 value from 30 to 300 pm, preferably a D90 value from 40 to 200 pm, and more preferably a D90 value from 50 to 100 pm, as determined by laser diffraction.
In a preferred embodiment of the present invention, the ruxolitinib hemifumarate (Compound II) used for the preparation of the solid oral immediate-release formulation of the present invention, preferably a tablet, has a D90 value from 50 to 100 pm, a D50 value from 18 to 40 pm, and a D10 value from 3 to 15 pm, as determined by laser diffraction.
The ruxolitinib hemifumarate (Compound II) used for the preparation of the solid oral immediate-release formulation of the present invention, preferably a tablet, can be prepared by reacting ruxolitinib base with fumaric acid. Ruxolitinib base can be prepared according to any process disclosed in the prior art.
One aspect of the present invention provides a process for preparing ruxolitinib hemifumarate (Compound II). Scheme 1 shows the synthetic pathway for preparing ruxolitinib hemifumarate (Compound II) of the present invention:
Figure imgf000021_0001
Scheme 1 In the first step, 4-chloro-7/7-pyrrolo[2,3-d]pyrimidine (A) reacts with 2- (chloromethoxy)ethyl)trimethylsilane (SEM-CI) in presence of a suitable base in a suitable solvent to provide 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidine (B).
In a preferred embodiment of the present invention, 4-chloro-7/7-pyrrolo[2,3-d]pyrimidine
(A) reacts with 2-(chloromethoxy)ethyl)trimethylsilane (SEM-CI) in the presence of a base which is an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium terf-butoxide, potassium methoxide, potassium ethoxide, potassium terf-butoxide and the like, preferably potassium or sodium terf-butoxide, in a polar aprotic solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, preferably in dimethyl sulfoxide. The obtained 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7/7- pyrrolo[2,3-d/pyrimidine (B) can be used in the subsequent step without isolation, i.e., in solution.
In the second step 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidine
(B) reacts with 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1/7-pyrazole (C) in the presence of a catalyst, preferably a palladium catalyst, in the presence of a suitable base and in a suitable solvent to obtain 4-(1/7-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7/7-pyrrolo[2,3-c(]pyrimidine (D). The palladium catalyst can be tetrakis(triphenylphosphine)palladium (0).
In an embodiment of the present invention 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)- 7/7-pyrrolo[2,3-c(]pyrimidine (B) reacts with 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1/7-pyrazole (C) in the presence of tetrakis(triphenylphosphine)palladium (0) and sodium or potassium acetate in a suitable solvent, for example a polar aprotic solvent such as acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, preferably acetonitrile, to obtain 4-(1/7-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7/7-pyrrolo[2,3-c(]pyrimidine (D).
In a preferred embodiment of the present invention the catalyst tetrakis(triphenylphosphine)palladium (0) is generated in situ. Thus, 4-chloro-7-((2- (trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidine (B) reacts with 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1/7-pyrazole (C) in the presence of palladium acetate, triphenylphosphine and sodium or potassium acetate in a suitable solvent, preferably a mixture of ethyl acetate, acetonitrile and water.
The obtained 4-(1 /7-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3- d]pyrimidine (D) can be preferably purified by recrystallization or slurrying in a suitable organic solvent. Preferably, the obtained 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7/7- pyrrolo[2,3-d]pyrimidine (D) is purified by slurrying in acetonitrile.
In the third step 4-(1/7-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3- c]pyrimidine (D) reacts with 3-cyclopentylacrylonitrile (E) in the presence of a suitable base in a suitable solvent to obtain 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)- 7/7-pyrrolo[2,3-d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)propanenitrile (F). In a preferred embodiment of the present invention 4-(1/7-pyrazol-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-d]pyrimidine (D) reacts with 3- cyclopentylacrylonitrile (E) in the presence of 1 ,8-diazabicyclo(5.4.0)undec-7-ene (DBU) in acetonitrile. The obtained 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7/7- pyrrolo[2,3-d]pyrimidin-4-yl)-1/7-pyrazol-1- yl)propanenitrile (F) is preferably used in the subsequent step without isolation, i.e. , in solution.
In a preferred embodiment, 3-cyclopentylacrylonitrile (E) consists of (2E)-3- cyclopentylacrylonitrile, (2Z)-3-cyclopentylacrylonitrile, or a mixture thereof.
In the fourth step the 2-(trimethylsilyl)ethoxymethyl) protecting group is removed from 3- cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c]pyrimidin-4-yl)-1/7- pyrazol-1-yl)propanenitrile (F). The protecting group is removed by treating with trifluoroacetic acid, a fluoride ion (e.g., tetrabutylammonium fluoride), hydrochloric acid, pyridinium p-toluenesulfonic acid, boron trifluoride diethyl etherate or a Lewis acid (e.g. lithium tetrafluoroborate, aluminium chloride or magnesium bromide). In some embodiments, the treating comprises treating with a Lewis acid followed by treating with a base, e.g., alkali metal hydroxide such as sodium or potassium hydroxide, ammonia in a solvent such as water or an alcoholic solvent, e.g., methanol.
In a preferred embodiment, 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7/7- pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol-1-yl)propanenitrile (F) is treated with a Lewis acid, preferably aluminium chloride, in a suitable solvent, preferably an ether solvent such as tetra hydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl terf-butyl ether, dioxane and the like, preferably 2-methyltetrahydrofuran, followed by the treatment with ammonia to obtain 3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3- cyclopentylpropanenitrile (G).
In a fifth step 3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3- cyclopentylpropanenitrile (G) reacts with a chiral acid in a suitable solvent to form a chiral salt. Any chiral acid useful for chiral resolution can be used. In some embodiments, the chiral acid is selected from optically active forms of mandelic acid, 2-chloromandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, dibenzoyl tartaric acid, di-p-toluoyltartaric acid, 2-amino-7,7-dimethylbicyclop[2,2,1]heptan-1-methylene sulfonic acid, and 2-acrylamide-7,7-dimethylbicyclo[2,2,l] heptan-1 -methylene sulfonic acid. In a preferred embodiment, the chiral acid is (+)-dibenzoyl-D-tartaric acid, also known as (2S,3S)-2,3-bis(benzoyloxy)succinic acid ((+)-DBTA).
In some embodiments the suitable solvent to form the chiral salt comprises acetonitrile, tetra hydrofuran, acetone, alcoholic solvent, such as methanol, ethanol, isopropanol, n- propanol, butanol and the like, or combination thereof.
In an embodiment, after crystallization of the chiral salt, a product comprising an enantiomeric excess of the (R)-enantiomer of 3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H- pyrazol-1-yl)-3-cyclopentylpropanenitrile (2S,3S)-2,3-bis(benzoyloxy)succinate (H) is isolated by filtration.
Figure imgf000024_0001
In a preferred embodiment of the present invention 3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)- 1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile (G) reacts with (2S,3S)-2,3- bis(benzoyloxy)succinic acid ((+)-DBTA) in a mixture of acetonitrile and an alcoholic solvent, preferably isopropanol, to form a product comprising an enantiomeric excess of (R)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile (2S,3S)-2,3-bis(benzoyloxy)succinate (H) which is isolated by filtration.
The obtained and isolated (R)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3- cyclopentylpropanenitrile (2S,3S)-2,3-bis(benzoyloxy)succinate (H) can be purified by means of recrystallization or slurrying in a suitable solvent or mixture of solvents, preferably in mixtures of acetonitrile and an alcoholic solvent, preferably isopropanol. The purifications can be repeated until the desired chiral purity is achieved, e.g., until the amount of the (S)-enantiomer is not more than 0.15% as analyzed by a chiral HPLC method. In a sixth step, (R)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3- cyclopentylpropanenitrile (2S,3S)-2,3-bis(benzoyloxy)succinate (H) is treated with a suitable base in a suitable solvent to produce a product with an enantiomer excess of (/?)-
3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile, i.e., ruxolitinib base. In a preferred embodiment (R)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H- pyrazol-1-yl)-3-cyclopentylpropanenitrile (2S,3S)-2,3-bis(benzoyloxy)succinate (H) is treated with an alkali metal carbonate or bicarbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate and the like, preferably sodium carbonate or sodium bicarbonate, in a mixture of an ester solvent such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, preferably ethyl acetate and water to obtain (F?)-3-(4-(7/7- pyrrolo[2,3-d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile, i.e., ruxolitinib base.
Finally, (F?)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3-cyclopentyl- propanenitrile, i.e., ruxolitinib base, is converted to (F?)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4- yl)-1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile hemifumarate, i.e., ruxolitinib hemifumarate (Compound II) by reacting (F?)-3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7- pyrazol-1-yl)-3-cyclopentylpropanenitrile, i.e., ruxolitinib base, with fumaric acid in a suitable solvent. In a preferred embodiment, (F?)-3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7- pyrazol-1-yl)-3-cyclopentylpropanenitrile, i.e., ruxolitinib base, reacts with fumaric acid in an alcohol solvent such as methanol, ethanol, isopropanol, n-propanol, butanol, and the like, preferably isopropanol to form (F?)-3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol- 1-yl)-3-cyclopentylpropanenitrile hemifumarate, i.e. ruxolitinib hemifumarate (Compound II).
In order to increase overall yields, mother liquors obtained in the fifth step disclosed hereinbefore, which are enriched in the undesired enantiomer (S)-3-(4-(7/7-pyrrolo[2,3- d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile (2S,3S)-2,3- bis(benzoyloxy)succinate, i.e., H wherein ruxolitinib has (S) configuration, can be reprocessed as it follows: a) Solvent from mother liquors obtained in the fifth step disclosed hereinbefore is evaporated and the resulting residue X is treated with a suitable base in a suitable solvent to produce a product with an enantiomeric excess of (S)-3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-
4-yl)-1/7-pyrazol-1-yl)-3-cyclopentyl-propanenitrile, i.e., (S)-ruxolitinib base.
In a preferred embodiment the resulting residue X is treated with an alkali metal carbonate or bicarbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate, lithium carbonate or bicarbonate and the like, preferably sodium bicarbonate, in a mixture of an ester solvent such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, preferably ethyl acetate, and water to obtain a product with an enantiomeric excess of (S)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)- 1/7-pyrazol-1-yl)-3-cyclopentyl-propanenitrile, i.e. , (S)-ruxolitinib base. b) The product with an enantiomeric excess of (S)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)- 1/7-pyrazol-1-yl)-3-cyclopentyl-propanenitrile, i.e., (S)-ruxolitinib base, reacts with 2-(chloromethoxy)ethyl)trimethylsilane (SEM-CI) in the presence of 1 ,8-diazabicyclo(5.4.0)undec-7-ene (DBU) in acetonitrile. The obtained product with an enantiomeric excess of (S)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7/7- pyrrolo[2,3-d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)propanenitrile, i.e., (S)-enantiomer of F, is preferably used in the subsequent step without isolation, i.e., in solution. c) The 3-cyclopentylpropanenitrile group is removed from the product with an enantiomeric excess of (S)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7/7- pyrrolo[2,3-d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)propanenitrile, i.e., (S)-enantiomer of F. The retro- Michael reaction occurs in the presence of a base which is an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium terf-butoxide, potassium methoxide, potassium ethoxide, potassium terf-butoxide and the like, preferably sodium terf-butoxide, in a polar aprotic solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, preferably in dimethyl sulfoxide. The obtained 4-(1/7-pyrazol-4-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-d]pyrimidine (D) can be preferably purified by recrystallization or slurrying in a suitable organic solvent. Preferably, the obtained 4- (1 /7-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidine (D) is purified by slurrying in acetonitrile. This compound D can be introduced in the synthetic procedure indicated in the scheme 1.
As used herein, the term “suitable solvents” used in the present invention is selected from, but are not limited to “alcohol solvents” such as methanol, ethanol, isopropanol, n- propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n- butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, “ether solvents” such as tetra hydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl fert-butyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like; “halogenated solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone and the like; water, or mixtures thereof. The term “suitable base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium terf-butoxide, potassium methoxide, potassium ethoxide, potassium terf-butoxide and the like; triethylamine, methylamine, ethylamine, 1 ,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium diisopropylamine (LDA), n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine (DIPA), diisopropylethylamine (DIPEA), N-methylmorpholine (NMP), N- ethylmorpholine, piperidine, dimethyl aminopyridine (DMAP), morpholine, pyridine, 2,6- lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1 ,2,4-triazole, 1,4- diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.
Another aspect of the present invention provides a solid oral immediate-release formulation comprising ruxolitinib hemifumarate (Compound II), obtainable by any one of the processes of the present invention.
Another aspect of the present invention provides the solid oral immediate-release formulation of the invention, for use in treating a disease in a patient, wherein said disease is associated with JAK activity, for example allograft rejection or graft versus host disease, an autoimmune disease, a skin disorder, a viral disease, cancer, a disease characterized by a mutant JAK2, a myeloproliferative disorder, an inflammatory disease, ischemia reperfusion or related to an ischemic event, anorexia or cachexia resulting from or associated with cancer, fatigue resulting from or associated with cancer.
Non-limiting examples of myeloproliferative disorders are polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), or systemic mast cell disease (SMCD).
Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word “comprise” encompasses the case of “consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.
Examples
Example A: Preparation of ruxolitinib hemifumarate (Compound II)
Step 1 : Preparation of a solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-cf]pyrimidine (B)
80.0 g (0.521 mol) of 4-chloro-7/7-pyrrolo[2,3-c(]pyrimidine (A) were dissolved in 400 mL of dimethyl sulfoxide at 20-25 °C, under nitrogen atmosphere. The mixture was cooled down to about 15 °C and 70.09 g (0.729 mol) of sodium terf-butoxide were added and stirred at a temperature below 25 °C. The reaction mixture was stirred at 20-25 °C for 20 minutes before cooling the mixture down to about 10 °C. 108.56 g (0.651 mol) of 2- (chloromethoxy)ethyl)trimethylsilane (SEM-CI) were then added to the resulting mixture at a temperature below 25 °C, and the resulting reaction mixture was stirred for 2 hours at 20-25 °C. After cooling it down to about 10 °C, 640.0 mL of ethyl acetate and 600.0 mL of deionised water were added. The resulting biphasic mixture was extracted and the organic layer was washed twice with an aqueous solution of sodium bicarbonate 5% (w/w) and with deionized water. The resulting organic layer was collected and partially concentrated under reduced pressure. The resulting solution was filtered and an ethyl acetate solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidine (B) was obtained. Yield: 91.30%. Purity (UPLC method): 92.56% (% area).
Step 2: Preparation of 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-cf]pyrimidine (D)
3.17 g (0.014 mol) of palladium acetate (47.14% Pd content) Johnson Matthey type Pd- 111 , 7.32 g (0.028 mol) of triphenylphosphine and 91.63 g (0.472 mol) of 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1/7-pyrazole (C) were dissolved in 264.1 mL of acetonitrile at 20-25 °C, under nitrogen atmosphere. An ethyl acetate solution containing 132.06 g (0.465 mol) of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3- d]pyrimidine (B) in 143.0 g of ethyl acetate was diluted with 253.2 mL of acetonitrile and was added to the reaction mixture and stirred at 15-20 °C for 30 minutes. A solution of 57.08 g of potassium acetate in 330.2 mL of deionised water was then added and the resulting mixture was heated up to reflux temperature (about 80 °C) and stirred for 6 hours at this temperature. After cooling it down to 20-25 °C, 1.0 L of 2-methyltetrahydrofuran and 528.2 mL of deionised water were added. The aqueous layer was extracted and washed with 528.2 mL of 2-methyltetrahydrofuran. The resulting organic layers were collected and washed twice with sodium bicarbonate 5% (w/w) aqueous solution and brine. Charcoal and sodium sulphate were added to the resulting organic layer and stirred at 20-25 °C for 2 hours. After filtration of the resulting mixture, the organic solvent was removed under reduced pressure and 356.5 mL of acetonitrile were added. The suspension was heated up to reflux temperature (about 80 °C) and stirred for 2 hours at this temperature. The resulting suspension was cooled down to 20-25 °C and stirred for 1 hour at this temperature. The precipitated solid was filtered and washed with acetonitrile to obtain 4-(1 /7-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3- d]pyrimidine (D). Yield: 78.32%. Purity (LIPLC method): 98.57% (% area).
356.5 mL of acetonitrile were added to 131 .48 g of the obtained wet 4-(1/7-pyrazol-4-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidine (D) at 20-25 °C. The resulting mixture was stirred at 20-25 °C, heated up to reflux temperature and stirred for 2 hours at this temperature. Then, the resulting suspension was cooled down to 20-25 °C and stirred for 1 hour at this temperature. The resulting suspension was filtered, washed with acetonitrile and dried under vacuum until constant weight to obtain 4-(1/7-pyrazol-4-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidine (D).
Yield: 73.92%. Purity (UPLC method): 98.81%.
Step 3: Preparation of 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-oQpyrimidin-4-yl)-1 H-pyrazol-1 -yl)propanenitrile (F)
14.48 g (0.095 mol) of 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added dropwise to a mixture of 40.0 g (0.127 mol) of 4-(1/7-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7/7-pyrrolo[2,3-c(]pyrimidine (D) in 220.0 mL of acetonitrile at 20-25 °C under nitrogen atmosphere. The mixture was heated up to 40-45 °C and the resulting mixture was stirred at this temperature. 21.51 g (0.178 mol) of 3-cyclopentylacrylonitrile (E) and 60.0 mL of acetonitrile were then added dropwise at 40-45 °C. The reaction mixture was stirred at 40- 45 °C for 16 to 22 hours. The resulting organic solvent was removed under vacuum at a temperature below 30 °C before cooling the reaction down to 20-25 °C After cooling, 320.0 mL of 2-methyltetrahydrofuran and 180.0 mL of deionised water were added. The aqueous layer was removed from the resulting biphasic solution, and after two consecutive aqueous acidic washes using a solution of hydrochloric acid 0.1 N and a final aqueous neutral wash, the resulting organic layer was dried with sodium sulphate anhydrous, filtered and a 2-methyltetrahydrofuran solution of 3-cyclopentyl-3-(4-(7-((2- (trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol-1- yl)propanenitrile (F) was obtained. Yield: 100.0%. Purity (UPLC method): 91.99%.
Step 4a: Preparation of 3-(4-(7H-pyrrolo[2,3-oQpyrimidin-4-yl)-1H-pyrazol-1-yl)-3- cyclopentylpropanenitrile (G) 650.3 mL of 2-methyltetrahydrofuran were added to 212.37 g of 2-methyltetrahydrofuran solution of 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3- d]pyrimidin-4-yl)-1/7-pyrazol-1-yl)propanenitrile (F) (containing 55.37 g (0.127 mol) of 3- cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7- pyrazol-1-yl)propanenitrile (F) (100% equivalent) and 157.0 g (180.3 mL) of 2- methyltetrahydrofuran) at 20-25 °C under nitrogen atmosphere and stirred at this temperature until homogeneous mixture. After cooling it down to 10-15 °C, 42.27 g (0.317 mol) of aluminium chloride were added portion wise at a temperature below 20-25 °C. The reaction mixture was heated up to reflux temperature (about 80 °C) and stirred for 3 hours at this temperature. After cooling it down to 10-15 °C, 387.6 mL of deionised water was dropwise added at a temperature below 20-25 °C. The resulting biphasic mixture was stirred for 30 minutes, filtered through celite pad, and the organic layer was extracted and washed with sodium bicarbonate 5% (w/w) aqueous solution and deionised water. After that, the resulting organic layer was concentrated under vacuum and the resulting crude mixture was dissolved in 55.4 mL of acetonitrile and 166.1 mL of deionised water at 20-25 °C. 18.25 mL (0.288 mol) of ammonia 30% (w/w) solution were added dropwise at 20-25 °C. The resulting reaction mixture was stirred at 20-25 °C overnight. After this time, 387.6 mL of 2-methyltetrahydrofuran and 276.9 mL of deionised water were added to the reaction mixture, stirred for 30 minutes and the organic layer was extracted. 165 mL of deionised water were added to the resulting organic layer and the pH was adjusted to pH 2 by adding hydrochloric acid 6M aqueous solution to extract the desired product 3-(4- (7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile (G) into the aqueous acidic layer. Then, 2-methyltetrahydrofuran was added to the aqueous acidic layers, and the pH was then adjusted to pH 9-10 using sodium bicarbonate aqueous solution. The organic layer was extracted and washed with deionised water and the resulting solution was concentrated under vacuum to give 3-(4-(7/7-pyrrolo[2,3- c(]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile (G). Yield: 82.96%. Purity (UPLC method): 97.61%.
Step 4b: Preparation of 3-(4-(7H-pyrrolo[2,3-oQpyrimidin-4-yl)-1H-pyrazol-1-yl)-3- cyclopentylpropanenitrile (G)
462.8 mL of 2-methyltetrahydrofuran were added to a mixture of 44.03 g (0.101 mol) of 3- cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7- pyrazol-1-yl)propanenitrile (F) and 168.65 g (197.5 mL) of 2-methyltetrahydrofuran at 20- 25 °C under nitrogen atmosphere and stirred at this temperature until homogeneous mixture. After cooling it down to 10-15 °C, 33.61 g (0.252 mol) of aluminium chloride were added portion wise at a temperature below 20-25 °C. The reaction mixture was heated up to reflux temperature (about 80 °C) and stirred for 5 hours at this temperature. After cooling it down to 10-15 °C, 308.2 mL of deionised water was dropwise added at a temperature below 20-25 °C. The resulting biphasic mixture was stirred for 30 minutes, filtered through celite pad, and the organic layer was extracted and washed with sodium bicarbonate 5% (w/w) aqueous solution and with deionised water. After that, the resulting organic layer was concentrated under vacuum and the resulting crude mixture was dissolved in 44.1 mL of acetonitrile and 132.1 mL of deionised water at 20-25 °C. 15.4 mL (0.244 mol) of ammonia 30% (w/w) aqueous solution were added dropwise at 20-25 °C. The resulting reaction mixture was stirred at 20-25 °C overnight. After this time, 396.3 mL of ethyl acetate and 220.2 mL of deionised water were added to the reaction mixture, stirred for 30 minutes and the organic layer was washed two consecutive times with 220.2 mL of deionised water and 220.2 mL of brine.
The resulting organic layer was dried with sodium sulphate anhydrous, filtered and a ethyl acetate solution of 3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3- cyclopentylpropanenitrile (G) was obtained. Yield: 90.45%. Purity (UPLC method): 92.05%.
Step 5: Preparation of (/?)-3-(4-(7H-pyrrolo[2,3-oQpyrimidin-4-yl)-1H-pyrazol-1-yl)-3- cyclopentylpropanenitrile (2S,3S)-2,3-bis(benzoyloxy)succinate (H)
16.50 g (0.539 mol) of 3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3- cyclopentylpropanenitrile (G) were suspended in 283.1 mL of acetonitrile and 38.6 mL of isopropanol at 20-25 °C, under nitrogen atmosphere. The resulting mixture was heated up to about 65 °C and stirred at this temperature until a homogeneous solution is obtained. A solution of 16.54 g of (2S,3S)-2,3-bis(benzoyloxy)succinic acid ((+)-DBTA) in 49.5 mL of acetonitrile was added dropwise at about 65 °C. After cooling the resulting mixture down to about 55 °C, stirred at this temperature for 1 hour, cooling down to about 45 °C and stirred at this temperature for 1 hour, the resulting suspension was gradually cooled down to 25-27 °C overnight and stirred at this temperature for 1 more hour. The precipitated solid was filtered and washed with acetonitrile to obtain (R)-3-(4-(7/7-pyrrolo[2,3- c(]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile (2S,3S)-2,3- bis(benzoyloxy)succinate (H). Yield: 44.80%. Purity (HPLC chiral method): 86.49%.
The obtained solid was recrystallized repeatedly from a mixture of acetonitrile and isopropanol until a solid with the desired chiral purity (e.g., (S)-isomer not more than 0.15% as analyzed by a chiral HPLC method) was obtained.
Step 6: Preparation of (/?)-3-(4-(7H-pyrrolo[2,3-oQpyrimidin-4-yl)-1H-pyrazol-1-yl)-3- cyclopentylpropanenitrile hemifumarate, i.e., ruxolitinib hemifumarate (Compound II). Ethyl acetate and water were added to (R)-3-(4-(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)-1/7- pyrazol-1-yl)-3-cyclopentylpropanenitrile (2S,3S)-2,3-bis(benzoyloxy)succinate (H) at 20- 25 °C and stirred at 20-25 °C until a biphasic clear solution was obtained. The resulting mixture was basified to pH > 9 with sodium carbonate aqueous solution at 20-25 °C. After stirring the resulting biphasic solution at 20-25 °C for 30 minutes, the organic layer was extracted and washed twice with deionised water. The resulting solution was concentrated under vacuum to give (R)-3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3- cyclopentylpropanenitrile free base, i.e. , ruxolitinib base.
450.0 mL of isopropanol were added to 50 g (0.163 mol) of the resulting (R)-3-(4-(7/7- pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7-pyrazol-1-yl)-3-cyclopentylpropanenitrile, i.e., ruxolitinib base, at 20-25 °C. After heating the mixture up to 50-55 °C, a clear solution was obtained. Then, 20.16 g (0.173 mol) of fumaric acid were added portion wise at 50-55 °C and stirred at this temperature for at least 1 hour. The resulting suspension was gradually cooled down to 0-5 °C overnight. The precipitated solid was filtered, washed with isopropanol and dried at 35-40 °C under vacuum to obtain (R)-3-(4-(7/7-pyrrolo[2,3-c(]pyrimidin-4-yl)-1/7- pyrazol-1-yl)-3-cyclopentylpropanenitrile hemifumarate (Compound II) as a white solid. Yield: 88%. X-Ray Powder Diffraction as shown in Figure 1. Solubility: see table 1.
Solubility of ruxolitinib hemifumarate (Compound II)
Table 1 shows the measured solubility (mg/mL) of ruxolitinib hemifumarate (Compound II) according to the present invention at 37° C and pH 1.2 in comparison with the solubility in mg/mL of ruxolitinib phosphate (Compound I) as reported in WO2016026974A1 :
Figure imgf000032_0001
Table 1
Table 1 shows that ruxolitinib hemifumarate (Compound II) is less soluble than ruxolitinib phosphate at 37°C and pH 1.2.
X-Ray Powder Diffraction (XRPD):
The XRPD pattern was recorded on a Siemens D5000 diffractometer equipped with two symmetrically mounted vertical goniometers (Bragg-Brentano geometry) with horizontal sample stages, a X-ray tube, a high voltage generator (working at 45 kV and 35 mA) and standard scintillation detectors. Ni-filtered Cu-anode source was used and diffracted radiation was further monochromatized with a graphite crystal to avoid fluorescence effects Cu Ka = 1.54056 A. The diffraction pattern was recorded including values of 20 that range from 2 to 50° with a sampling rate of 0.02° per second and a step time of 1 second per step. The powdered sample was pressed between two glass plates, forming a film. DIFFRAC Plus measurement software with EVA evaluation software (Bruker) was used to record the data and for a primary analysis of the diffraction pattern. The equipment was periodically calibrated using quartz and silicon.
Single crystal X-Ray Diffraction (SC-XRD):
Sample preparation
A colourless prism-like specimen as obtained in Example A, step 6, with approximate dimensions 0.185 mm x 0.066 mm x 0.056 mm, was used for the X-ray crystallographic analysis.
Instrument and experimental conditions:
The X-ray intensity data were measured at 100K on a D8 Venture system equipped with a multilayer monochromator and a Mo microfocus (A = 0.71073 A). The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. The integration of the data using a triclinic unit cell yielded a total of 84065 reflections to a maximum 0 angle of 30.60° (0.70 A resolution), of which 21574 were independent (average redundancy 3.897, completeness = 99.9%, Rint = 9.17%, Rsig = 9.23%) and 15585 (72.24%) were greater than 2o(F2). The final cell constants of a = 7.7423(3) A, b = 14.9939(6) A, c = 17.1009(7) A, a = 111.400(2)°, = 97.898(2)°, y = 101.554(2)°, volume = 1762.00(12) A3, are based upon the refinement of the XYZ-centroids of reflections above 20 o(l). Data were corrected for absorption effects using the multi-scan method (SADABS). The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.6275 and 0.7461.
The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P1, with Z = 2 for the formula unit, C38H40N12O4. The final anisotropic full-matrix least-squares refinement on F2 with 970 variables converged at R1 = 6.27% for the observed data and wR2 = 14.31% for all data. The goodness-of-fit was 1.018. The largest peak in the final difference electron density synthesis was 0.737 e?A3 and the largest hole was -0.644 e7A3 with an RMS deviation of 0.062 e7A3. On the basis of the final model, the calculated density was 1.374 g/cm3 and F(000), 768 e.
Dissolution Test by HPLC for ruxolitinib in ruxolitinib hemifumarate tablets and ruxolitinib phosphate tablets (Jakavi®}. Dissolution conditions used for the tablets of example 1
- Dissolution medium HCI 0.1 N: 8.36 mL of HCI 37% were diluted to 1000 mL with Milli-Q water.
- Dissolution apparatus: Paddles (USP type 2).
- Volume of medium/vessel: 500 mL.
- Batch Temperature: 37°C ± 0.5°C.
- Paddles rotation speed: 50 rpm.
- Sample withdrawal timings: 5, 10, 15, 20, 25, 30, 45 and 60 minutes without replacing withdrawn volume.
5 mL each time was taken and filtered immediately through 0.45 pm PVDF filter.
Chromatographic system used for the tablets of example 1
- Column: Atlantis T3 3 pm, 4.6 x 150 mm, or equivalent (L1 packing)
- Mode: Isocratic (60% Mobile phase A: 40% Mobile Phase B)
- Mobile phase A: Buffer Ammonium formate 10 mM, pH 8.5.
Preparation for 1 L. 0.64 g of Ammonium acetate were weighed and dissolved in 1 L of HPLC-grade water.
The pH was adjusted to pH 8.5 ± 0.05 with formic acid or ammonia 30%.
- Mobile phase B: HPLC-grade Acetonitrile.
- Flow rate: 1 mL/min
- UV/Visible detector configuration:
Wavelength: 230 nm
Injection volume: 10 pL
- Column temperature: 40°C
- Sample temperature: 8°C
- Run time: 7 minutes
Solutions
- Diluent A: HPLC-grade water: HPLC-grade Acetonitrile (50:50 v/v).
- Diluent B/Blank: Dissolution medium filtered through 0.45 pm PVDF filter.
- Standard solution 100% (a) (approximately 40 pg/mL ruxolitinib base): 24 mg of ruxolitinib hemifumarate Reference Standard were weighed in a 100.0 mL volumetric flask and diluted up to volume with diluent A. 5.0 mL of the previous solution were transferred to a 25.0 mL volumetric flask and diluted up with diluent B. The solution was filtered through PVDF 0.45 pm filter.
- Standard solution 100% (b) (approximately 40 pg/mL ruxolitinib base): 27 mg of ruxolitinib phosphate Reference Standard were weighed in a 100.0 mL volumetric flask and diluted up to volume with diluent A. 5.0 mL of the previous solution were transferred to a 25.0 mL volumetric flask and diluted up with diluent B. The solution was filtered through PVDF 0.45 pm filter.
- Test solution preparation for a dissolution profile sampling: solutions were obtained directly withdrawing samples from the dissolution test at the time-points indicated above and were filtered through 0.45 pm PVDF filter before injecting them.
Dissolution conditions used for the tablets of example 2
- Dissolution medium HCI 0.1 N: 8.36 mL of HCI 37% were diluted to 1000 mL with Milli-Q water.
- Dissolution apparatus: Baskets (USP type 1).
- Volume of medium/vessel: 500 mL.
- Batch Temperature: 37°C ± 0.5°C.
- Paddles rotation speed: 100 rpm
- Sample withdrawal timings: 5, 10, 15, 20, 25, 30, 45 and 60 minutes without replacing withdrawn volume.
5 mL each time was taken and filtered immediately through 0.45 pm PVDF filter.
Chromatographic system used for the tablets of Example 2
- Column: Atlantis T3 3 pm, 4.6 x 150 mm, or equivalent (L1 packing)
- Mode: Isocratic (58% Mobile phase A: 42% Mobile Phase B)
- Mobile phase A: Buffer potassium dihydrogen phosphate 10 mM, pH 2.6.
Preparation for 1 L. 1.36 g of potassium dihydrogen phosphate were weighed and dissolved in 1 L of HPLC-grade water.
The pH was adjusted to pH 2.6 ± 0.05 with ortho-phosphoric acid or potassium hydroxide.
- Mobile phase B: HPLC-grade Acetonitrile.
- Flow rate: 1 mL/min
- UV/Visible detector configuration:
Wavelength: 230 nm
Injection volume: 10 pL
- Column temperature: 40°C
- Sample temperature: 8°C
- Run time: 5 minutes
Solutions
- Diluent A/Blank: Dissolution medium filtered through 0.45 pm PVDF filter.
- Standard solution 100% (a) (approximately 40 pg/mL ruxolitinib base): 24 mg of ruxolitinib hemifumarate Reference Standard were weighed in a 100.0 mL volumetric flask and diluted up to volume with diluent A. 5.0 mL of the previous solution were transferred to a 25.0 mL volumetric flask and diluted up with diluent. The solution was filtered through PVDF 0.45 pm filter. - Standard solution 100% (b) (approximately 40 pg/mL ruxolitinib base): 27 mg of ruxolitinib phosphate Reference Standard were weighed in a 100.0 mL volumetric flask and diluted up to volume with diluent A. 5.0 mL of the previous solution were transferred to a 25.0 mL volumetric flask and diluted up with diluent B. The solution was filtered through PVDF 0.45 pm filter.
- Test solution preparation for a dissolution profile sampling: solutions were obtained directly withdrawing samples from the dissolution test at the time-points indicated above and were filtered through 0.45 pm PVDF filter before injecting them.
Preparation of tablets according to the invention
Example 1 : Immediate-release tablet of ruxolitinib hemifumarate (Compound II) was prepared:
Figure imgf000036_0001
Manufacturing procedure:
Pharmaceutical tablets of example 1 were manufactured by following a manufacturing process which includes the following steps:
A. Granules preparation:
1) Ruxolitinib hemifumarate (Compound II), intragranular microcrystalline cellulose (Avicel® PH 101), lactose monohydrate and intragranular sodium starch glycolate (Explotab® CLV) were weighed and sieved by a 0.8 mm wire mesh screen.
2) The ruxolitinib hemifumarate (Compound II) and one part of the microcrystalline cellulose (1 :10) were mixed for 10 minutes at a speed of 12 rpm.
3) The rest of the intragranular components were added to the premix obtained in step 2) and everything was mixed for 10 minutes at a speed of 15 rpm.
4) Granulation: under constant stirring at a speed of 15 rpm the binder solution was added to the mixture obtained in step 3).
5) The granules obtained in step 4) were sieved by a 2 mm wire mesh screen and then dried at a temperature not higher than 40°C until reaching a moisture content less than 3% (w/w). 6) The dry granules mixture obtained in step 5) was sieved by a 0.8 mm wire mesh screen.
B. Tablets preparation
7) All the extragranular components: extragranular microcrystalline cellulose (Avicel® PH 101), extragranular sodium starch glycolate (Explotab® CLV), colloidal silicon dioxide (Aerosil® 200) and magnesium stearate (Ligamed® MF-2-V) were weighed and sieved by a 0.8 mm wire mesh screen.
8) The dry granules obtained in step 6) were mixed with the extragranular microcrystalline cellulose (Avicel® PH 101) and the extragranular sodium starch glycolate (Explotab® CLV) obtained is step 7) for 10 minutes at a speed of 12 rpm.
9) Colloidal silicon dioxide (Aerosil® 200) and magnesium stearate (Ligamed® MF-2-V) obtained in step 7) were added to the mixture of step 8) and mixed for 2 minutes at a speed of 12 rpm.
10) the mixture obtained in step 9) was compressed obtaining tablets with a hardness of 100 N.
Preparation of the binder solution: 100 mL
Hydroxypropylcellulose (Klucel® EF) was slowly added to the 70 mL of purified water previously heated to 50°C. Once all the hydroxypropylcellulose (Klucel® EF) was dispersed, the heating was stopped, and 30 mL of purified water were added. The mixture was stirred until a transparent solution was obtained.
Povidone K29/32 (Plasdone® K29/32) was slowly added to the above solution until its complete dissolution.
Dissolution profiles of the tablets of Example 1 compared with commercial tablets JakavP, tablets of ruxolitinib phosphate, 20 mg equivalent base are shown in Table 2:
Figure imgf000037_0001
Table 2 As it can be observed in Table 2 and Figure 2 immediate-release tablets comprising ruxolitinib hemifumarate (Compound II) of the present invention show a higher dissolution profile than the commercial tablets Jakavi® of ruxolitinib phosphate, even when the solubility of ruxolitinib hemifumarate (Compound II) is lower than the solubility of ruxolitinib phosphate (Compound I).
Stability data of the tablets of Example 1
Tables 3 and 4 depict stability data of the tablets of example 1 in open dish at 25±2°C and 60±5% relative humidity (RH) and in open dish at 40±2°C and 75±5% relative humidity (RH) respectively.
Figure imgf000038_0001
Table 3
Figure imgf000038_0002
Table 4
Example 2: Immediate-release tablet of ruxolitinib hemifumarate (Compound II) was prepared:
Figure imgf000038_0003
Pharmaceutical tablets of example 2 were manufactured by following a manufacturing process which includes the following steps:
A. Granules preparation:
1) Ruxolitinib hemifumarate (Compound II), intragranular microcrystalline cellulose (Avicel® PH 101), lactose monohydrate, intragranular sodium starch glycolate (Explotab® CLV), hydroxypropylcellulose (Klucel® EF) and povidone K29/32 (Plasdone® K29/32) were weighed and sieved by a 0.8 mm wire mesh screen.
2) The ruxolitinib hemifumarate (Compound II) and one part of the microcrystalline cellulose (1 :10) were mixed for 10 minutes at a speed of 12 rpm.
3) The rest of the intragranular components were added to the premix obtained in step 2) and everything was mixed for 10 minutes at a speed of 15 rpm.
4) Granulation: water was added to the mixture obtained in step 3) in continuous flow rate with impeller/mixer at 150 rpm and chopper at 300 rpm,
5) The granules obtained in step 4) were sieved by a 4 mm wire mesh screen and then dried at a temperature not higher than 40°C until reaching a moisture content less than 3% (w/w).
6) The dry granules mixture obtained in step 5) was sieved by a 0.8 mm wire mesh screen.
B. Tablets preparation
7) All the extragranular components: extragranular microcrystalline cellulose (Avicel® PH 101), extragranular sodium starch glycolate (Explotab® CLV), colloidal silicon dioxide (Aerosil® 200) and magnesium stearate (Ligamed® MF-2-V) were weighed and sieved by a 0.8 mm wire mesh screen.
8) The dry granules obtained in step 6) were mixed with the extragranular microcrystalline cellulose (Avicel® PH 101) and the extragranular sodium starch glycolate (Explotab® CLV) obtained is step 7) for 10 minutes at a speed of 12 rpm.
9) Colloidal silicon dioxide (Aerosil® 200) and magnesium stearate (Ligamed® MF-2-V) obtained in step 7) were added to the mixture of step 8) and mixed for 2 minutes at a speed of 12 rpm.
10) the mixture obtained in step 9) was compressed obtaining tablets with a hardness of 100 N.
Dissolution profiles of the tablets of example 2 compared with commercial tablets Jakavi®, tablets of ruxolitinib phosphate, 20 mg equivalent base are shown in Table 5:
Figure imgf000039_0001
Figure imgf000040_0001
Table 5
As it can be observed in Table 5 and Figure 3 immediate-release tablets comprising ruxolitinib hemifumarate (Compound II) of the present invention show a slightly higher dissolution profile than the commercial tablets Jakavi® of ruxolitinib phosphate, even when the solubility of ruxolitinib hemifumarate (Compound II) is lower than the solubility of ruxolitinib phosphate (Compound I).
Stability data of the tablets of example 2 Tables 6 and 7 depict stability data of the tablets of Example 2 in blister of PCTFE and Hard foil aluminim at 25±2°C and 60±5% relative humidity (RH) and in in blister of PCTFE and Hard foil aluminim at 40±2°C and 75±5% relative humidity (RH) respectively.
Figure imgf000040_0002
Table 6
Figure imgf000040_0003
Table 7

Claims

1. A solid oral immediate-release pharmaceutical formulation comprising a therapeutically effective amount of ruxolitinib hemifumarate (Compound II) and one or more pharmaceutically acceptable excipients.
Figure imgf000041_0001
Compound II
2. The solid oral immediate-release pharmaceutical formulation according to claim 1, which is in the form of powder, a granule, a pellet, a mini-tablet, a tablet, a capsule, a capsule filled with granules or pellets.
3. The solid oral immediate-release pharmaceutical formulation according to claim 2, which is in the form of a tablet.
4. The solid oral immediate-release pharmaceutical formulation according to any one of claims 1 or 3, wherein the excipients are selected from the group consisting of wetting agents, fillers, disintegrants, antioxidants, binders, chelating agents, glidants, lubricants, and mixtures thereof.
5. The solid oral immediate-release pharmaceutical formulation according to claim 4, wherein: the wetting agents are selected from the group consisting of poloxamers, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers, polysorbates, such as polysorbate 80, cetyl alcohol, glycerol fatty acid esters, polyoxymethylene stearate, sodium dodecyl sulfate, sorbitan fatty acid esters, sucrose fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, docusate sodium, and mixtures thereof; the fillers are selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch, starches, lactitol, lactose, maltose, trehalose, a suitable inorganic calcium salt, sucrose, glucose, sugar alcohols, silicic acid, and mixtures thereof; the disintegrants are selected from the group consisting of low substituted hydroxypropyl cellulose (L-HPC), carboxymethylcellulose calcium, carboxymethylcellulose sodium, cellulose powdered, chitosan, docusate sodium, glycine, sodium alginate, crospovidone, croscarmellose sodium, sodium starch glycolate, and mixtures thereof; the antioxidants are selected from the group consisting of ascorbic acid and salts and esters thereof, citric acid and salts and esters thereof, butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), tocopherols, tocopherol acetate, carotenoids, and mixtures thereof; the binders are selected from the group consisting of povidone, hydroxypropylcellulose, hydroxypropylmethyl cellulose, gelatin, starch, sucrose, mannitol, polyethylene glycol, acacia, guar gum, maltodextrin, methylcellulose, ethylcellulose, and mixtures thereof; the chelating agents are selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), diethylenetriaminepentaacetic acid (DTPA), N,N-bis(carboxymethyl)glycine (NTA), nitrilotriacetic acid, citric acid, niacinamide, sodium desoxycholate and mixtures thereof; the glidants are selected from the group consisting of colloidal silicon dioxide, silica gel, fumed silica, talc, magnesium carbonate, magnesium silicate, calcium silicate, calcium phosphate tribasic, bentonite, and mixtures thereof; and the lubricants are selected from the group consisting of stearic acid, sodium stearate, calcium stearate, zinc stearate, magnesium stearate, sodium oleate, polyethylene glycol, talc, mineral oil, sodium lauryl sulfate, sodium stearyl fumarate, castor oils, sodium benzoate, sodium acetate, sodium chloride, and mixtures thereof.
6. The solid oral immediate-release pharmaceutical formulation according to any one of claims 1 to 5, wherein the solid oral immediate-release pharmaceutical formulation comprises at least one filler, at least one disintegrant, at least one binder, at least one glidant, and at least one lubricant.
7. The solid oral immediate-release pharmaceutical formulation according to claim 6, wherein:
- the weight of ruxolitinitb hemifumarate (Compound II), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 2.0% to 6.0%;
- the weight of the at least one filler, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 70% to 95%; - the weight of the at least one disintegrant, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 1.0% to 8.0%;
- the weight of the at least one binder, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 0.5% to 7.0%;
- the weight of the at least one glidant, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 0.1% to 2.5%; and
- the weight of the at least one lubricant, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 0.2% to 6.5%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
8. The solid oral immediate-release pharmaceutical formulation according to claim 7, wherein:
- the weight of ruxolitinitb hemifumarate (Compound II), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 2.5% to 4.5%;
- the weight of the at least one filler, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 80% to 90%;
- the weight of the at least one disintegrant, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 2.0% to 5.0%;
- the weight of the at least one binder, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 3.5% to 5.5%;
- the weight of the at least one glidant, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 0.5% to 1.5%; and
- the weight of the at least one lubricant, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 0.4% to 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
9. The solid oral immediate-release pharmaceutical formulation according to claims 7 or 8, wherein the filler is microcrystalline cellulose and/or lactose, the disintegrant is sodium starch glycolate, the binder is povidone and/or hydroxypropylcellulose, the glidant is colloidal silicon dioxide, and the lubricant is magnesium stearate.
10. The solid oral immediate-release pharmaceutical formulation according to claim 9, wherein the filler is microcrystalline cellulose and lactose, and the binder is povidone and hydroxypropylcellulose and wherein:
- the weight of ruxolitinitb hemifumarate (Compound II), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 3.5% to 4.5%; - the weight of microcrystalline cellulose, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 38% to 45%;
- the weight of lactose, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 40% to 48%;
- the weight of povidone, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 1.5% to 2.5%;
- the weight of hydroxypropylcellulose, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 2.0% to 3.0%; being the sum of all the components of the solid oral immediate-release pharmaceutical formulation of 100% by weight.
11. The solid oral immediate-release pharmaceutical formulation according to any one of claims 1 to 10, wherein the solid oral immediate-release pharmaceutical formulation is obtainable by a process comprising a granulation step, preferably wet granulation, more preferably aqueous wet granulation.
12. The solid oral immediate-release pharmaceutical formulation according to claim 11, wherein the solid oral immediate-release pharmaceutical formulation is a tablet and the tablet comprises intragranular and extragranular components, wherein the intragranular components comprise ruxolitinib hemifumarate (Compound II), microcrystalline cellulose, lactose, sodium starch glycolate, povidone and hydroxypropylcellulose; and the extragranular components comprise microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate, wherein:
- the weight of ruxolitinib hemifumarate (Compound II), in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 3.5% to 4.0%;
- the weight of intragranular microcrystalline cellulose, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 20% to 30%;
- the weight of lactose, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 40% to 48%;
- the weight of intragranular sodium starch glycolate, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 1.0% to 2.5%;
- the weight of povidone, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 1.5% to 2.5%:
- the weight of hydroxypropylcellulose, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 2.0% to 3.0%:
- the weight of extragranular microcrystalline cellulose, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 10% to 20%;
- the weight of extragranular sodium starch glycolate, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 1.0% to 2.5%; - the weight of colloidal silicon dioxide, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 0.5% to 1.5%; and
- the weight of magnesium stearate, in relation to the total weight of the solid oral immediate-release pharmaceutical formulation, is from 0.4% to 3.0%; being the sum of all the components of the immediate-release tablet of 100% by weight.
13. The solid oral immediate-release formulation according to any one of claims 1 to 12, wherein the ruxolitinib hemifumarate (Compound II) shows a X-Ray Powder Diffractogram (XRPD) that comprises characteristic peaks at an angle of diffraction 2 theta (20) of 5.6, 6.5, 16.2 and 18.1 (± 0.2) as measured in a X-ray diffractometer with Cu Ka radiation (1.54056 A).
14. The solid oral immediate-release pharmaceutical formulation according to any one of claims 1 to 13 for use in treating a disease in a patient, wherein said disease is associated with JAK activity.
15. The solid oral immediate-release pharmaceutical formulation according to claim 14, wherein said disease is allograft rejection or graft versus host disease.
16. The solid oral immediate-release pharmaceutical formulation according to any one of claims 1 to 13, for use in treating a myeloproliferative disorder.
17. The solid oral immediate-release pharmaceutical formulation according to claim 16, wherein the myeloproliferative disorder (MPD) is selected from the group consisting of polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), and systemic mast cell disease (SMCD).
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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007070514A1 (en) 2005-12-13 2007-06-21 Incyte Corporation Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors
WO2008157208A2 (en) 2007-06-13 2008-12-24 Incyte Corporation Salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile
WO2014016396A1 (en) * 2012-07-27 2014-01-30 Ratiopharm Gmbh Oral dosage forms for modified release comprising ruxolitinib
WO2014078486A1 (en) * 2012-11-15 2014-05-22 Incyte Corporation Sustained-release dosage forms of ruxolitinib
WO2016026975A1 (en) 2014-08-21 2016-02-25 Ratiopharm Gmbh Salt of (r)-3-(4-(7h-pyrrolo [2,3-d] pyrimidin-4-yl)-lh-pyrazol-l-yl)-3-cyclopentylpropanenitrile with benzenesulfonic acid
WO2016026974A1 (en) 2014-08-21 2016-02-25 Ratiopharm Gmbh Oxalate salt of ruxolitinib
WO2016063294A2 (en) 2014-10-20 2016-04-28 Msn Laboratories Private Limited Process for the preparation of (r)-3-(4-(7h-pyrrolo[2,3-d], pyrimidin-4-yl)-1 h-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate and its polymorphs thereof
WO2016074650A1 (en) 2014-11-10 2016-05-19 Zentiva, K.S. Salts of (3r)-3-cyclopentyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile
WO2017008772A1 (en) 2015-07-14 2017-01-19 Zentiva, K.S. Crystalline forms of (3r)-3-cyclopentyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile salts and preparation thereof
WO2017125097A1 (en) 2016-01-22 2017-07-27 Zentiva, K.S. Crystalline forms of (3r)-3-cyclopentyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile salts and preparation thereof
WO2023087101A1 (en) 2021-11-19 2023-05-25 Apotex Inc Salts of ruxolitinib and crystalline forms thereof

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007070514A1 (en) 2005-12-13 2007-06-21 Incyte Corporation Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors
WO2008157208A2 (en) 2007-06-13 2008-12-24 Incyte Corporation Salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile
WO2014016396A1 (en) * 2012-07-27 2014-01-30 Ratiopharm Gmbh Oral dosage forms for modified release comprising ruxolitinib
WO2014078486A1 (en) * 2012-11-15 2014-05-22 Incyte Corporation Sustained-release dosage forms of ruxolitinib
WO2016026975A1 (en) 2014-08-21 2016-02-25 Ratiopharm Gmbh Salt of (r)-3-(4-(7h-pyrrolo [2,3-d] pyrimidin-4-yl)-lh-pyrazol-l-yl)-3-cyclopentylpropanenitrile with benzenesulfonic acid
WO2016026974A1 (en) 2014-08-21 2016-02-25 Ratiopharm Gmbh Oxalate salt of ruxolitinib
WO2016063294A2 (en) 2014-10-20 2016-04-28 Msn Laboratories Private Limited Process for the preparation of (r)-3-(4-(7h-pyrrolo[2,3-d], pyrimidin-4-yl)-1 h-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate and its polymorphs thereof
WO2016074650A1 (en) 2014-11-10 2016-05-19 Zentiva, K.S. Salts of (3r)-3-cyclopentyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile
WO2017008772A1 (en) 2015-07-14 2017-01-19 Zentiva, K.S. Crystalline forms of (3r)-3-cyclopentyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile salts and preparation thereof
WO2017125097A1 (en) 2016-01-22 2017-07-27 Zentiva, K.S. Crystalline forms of (3r)-3-cyclopentyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile salts and preparation thereof
WO2023087101A1 (en) 2021-11-19 2023-05-25 Apotex Inc Salts of ruxolitinib and crystalline forms thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FDA: "FDA Jakafi Label", 1 November 2011 (2011-11-01), XP093096965, Retrieved from the Internet <URL:https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202192lbl.pdf> [retrieved on 20231031] *
SHI ET AL., J. CLIN. PHARMACOL., vol. 2, no. 6, 5 June 2012 (2012-06-05), pages 809 - 818

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