EP4565213A1 - Formulation pharmaceutique orale stable contenant de l'hémifumarate de ruxolitinib - Google Patents

Formulation pharmaceutique orale stable contenant de l'hémifumarate de ruxolitinib

Info

Publication number
EP4565213A1
EP4565213A1 EP23748998.4A EP23748998A EP4565213A1 EP 4565213 A1 EP4565213 A1 EP 4565213A1 EP 23748998 A EP23748998 A EP 23748998A EP 4565213 A1 EP4565213 A1 EP 4565213A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical formulation
solid oral
release pharmaceutical
oral immediate
weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23748998.4A
Other languages
German (de)
English (en)
Inventor
Isabel FERNÁNDEZ GARROSA
I-Teng Montserrat NG CHOI
Ernesto DURÁN LÓPEZ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medichem SA
Original Assignee
Medichem SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medichem SA filed Critical Medichem SA
Publication of EP4565213A1 publication Critical patent/EP4565213A1/fr
Pending legal-status Critical Current

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Classifications

    • 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.

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Abstract

La présente invention concerne des formulations solides orales à libération immédiate d'hémifumarate de ruxolitinib (composé II) qui présentent une solubilité identique ou supérieure à celle des comprimés commerciaux de phosphate de ruxolitinib. Ces nouvelles formulations solides orales à libération immédiate peuvent être obtenues selon un procédé qui comprend une granulation par voie humide.
EP23748998.4A 2022-08-03 2023-07-26 Formulation pharmaceutique orale stable contenant de l'hémifumarate de ruxolitinib Pending EP4565213A1 (fr)

Applications Claiming Priority (2)

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EP22382753 2022-08-03
PCT/EP2023/070782 WO2024028193A1 (fr) 2022-08-03 2023-07-26 Formulation pharmaceutique orale stable contenant de l'hémifumarate de ruxolitinib

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EP4565213A1 true EP4565213A1 (fr) 2025-06-11

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EP (1) EP4565213A1 (fr)
AU (1) AU2023318885A1 (fr)
CA (1) CA3263118A1 (fr)
WO (1) WO2024028193A1 (fr)

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TR2024005656A1 (tr) * 2024-05-09 2025-11-21 Abdi̇ İbrahi̇m İlaç Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇ Ruksolitin'in direkt baskı bir farmasötik tableti.
CN118986907B (zh) * 2024-08-19 2025-07-08 青岛国信制药有限公司 一种磷酸芦可替尼片及其制备方法

Family Cites Families (11)

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Publication number Priority date Publication date Assignee Title
EP2455382B1 (fr) 2005-12-13 2016-10-26 Incyte Holdings Corporation Pyrrolo[2,3-b]pyridines et pyrrolo[2,3-b]pyrimidines à substitution hétéroaryle en tant qu'inhibiteurs de la janus kinase
EP3070090B1 (fr) 2007-06-13 2018-12-12 Incyte Holdings Corporation Utilisation des sels de l'inhibiteur de janus kinase (r)-3-(4- (7h-pyrrolo [2,3-d] pyrimidin-4-yl)-1h-pyrazol-1-yl) -3-cyclopentylpropanenitrile
US20150246043A1 (en) * 2012-07-27 2015-09-03 Ratiopharm Gmbh Oral dosage forms for modified release comprising ruxolitinib
CN113384546A (zh) * 2012-11-15 2021-09-14 因赛特公司 鲁索利替尼的缓释剂型
WO2016026974A1 (fr) 2014-08-21 2016-02-25 Ratiopharm Gmbh Sel d'oxalate de ruxolitinib
WO2016026975A1 (fr) 2014-08-21 2016-02-25 Ratiopharm Gmbh Sel de (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-lh-pyrazol-l-yl)-3-cyclopentylpropanenitrile avec de l'acide benzènesulfonique
WO2016063294A2 (fr) 2014-10-20 2016-04-28 Msn Laboratories Private Limited Procédé de préparation de phosphate de (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile et de ses polymorphes
CZ2014773A3 (cs) 2014-11-10 2016-05-18 Zentiva, K.S. Soli (3R)-3-cyklopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propannitrilu
CZ2015496A3 (cs) 2015-07-14 2017-01-25 Zentiva, K.S. Krystalické formy solí (3R)-3-cyklopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propannitrilu a jejich příprava
CZ201629A3 (cs) 2016-01-22 2017-08-02 Zentiva, K.S. Krystalické modifikace solí (3R)-3-cyklopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propannitrilu a způsoby jejich přípravy
CA3139457A1 (fr) 2021-11-19 2023-05-19 Apotex Inc. Nouveaux sels de ruxolitinib et formes cristallines connexes

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AU2023318885A1 (en) 2025-02-13
WO2024028193A1 (fr) 2024-02-08

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