Ruxolitinib-containing solid dosage forms

Abstract

The main objective is to provide a new ruxolitinib-containing solid formulation that has pharmaceutically acceptable stability. [Solution] The present invention includes, for example, a pharmaceutical solid formulation comprising ruxolitinib or a pharmaceutically acceptable salt thereof and sodium stearyl fumarate. The pharmaceutical solid formulation preferably further comprises low-substituted hydroxypropyl cellulose, and more preferably does not comprise at least one of magnesium stearate, polyvinylpyrrolidone, and sodium starch glycolate, particularly does not comprise sodium starch glycolate.

Description

[Technical Field]

[0001] The present invention belongs to the technical field of pharmaceutical formulations. In the technical field, the present invention relates to a solid formulation containing ruxolitinib or a pharmaceutically acceptable salt thereof, or a method for producing the same. [Background technology]

[0002] Myelofibrosis (MF) is a type of hematopoietic malignancy characterized by widespread bone marrow fibrosis, splenomegaly, and other clinical symptoms. Activation of Janus kinase (JAK) 2, which is involved in the differentiation and proliferation of blood cells, and JAK1, which contributes to inflammatory interleukin signaling, are thought to be involved in the debilitating systemic symptoms.

[0003] Ruxolitinib, with the chemical name (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile and the structure shown below (1), is a Janus kinase (JAK) inhibitor developed by Incyte Pharmaceuticals, Inc., that exhibits selectivity for JAK1 and JAK2. Jakavi® tablets, which contain ruxolitinib as the active ingredient, were developed for the oral treatment of myeloproliferative neoplasms (MPNs) and other conditions (Patent Documents 1 and 2). MPN is a general term for a group of diseases consisting of polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF), and other conditions.

[0004] [ka]

[0005] Ruxolitinib phosphate is highly selective for JAK1 and JAK2 (IC 50Ruxolitinib showed a potency of <5 nM and inhibited JAK / STAT signaling and proliferation in cell lines expressing a constitutively activated JAK2 mutant gene (JAK2V617F). Its JAK inhibitory effects were also confirmed in vivo, with mice inoculated with JAK2V617F mutant gene-expressing cells showing reduced splenomegaly, life extension, and reduced blood levels of inflammatory cytokines. In humans, the Cmax and AUC were approximately dose-proportional, the half-life was approximately 3 hours, and the primary elimination pathway was metabolic. Two pivotal Phase III clinical trials in MF patients were conducted overseas. Ruxolitinib administered at a starting dose of 15 mg twice daily or 20 mg twice daily significantly reduced splenomegaly compared with the control group, and also demonstrated improvements in clinical symptoms and a reduced risk of death. Similar efficacy and tolerability were also demonstrated in a Phase II trial in Asian patients, including Japanese, leading to its marketing approval for the treatment of MF in Japan in July 2014 (Non-Patent Document 1). In Japan, tablets containing 5 mg or 10 mg of ruxolitinib (ruxolitinib phosphate) are manufactured and sold under the trade name Jakavi (registered trademark) Tablets.

[0006] It has been reported that the related substances RRT0.30 and RRT0.97 produced by the decomposition of ruxolitinib increase when it reacts with povidone and magnesium stearate under heat and moisture conditions according to the following reaction formula (Non-Patent Document 2).

[0007] [ka] [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Special Publication 2009-519340 [Patent Document 2] Special Publication 2010-529209 [Non-patent literature]

[0009] [Non-Patent Document 1] Japanese Journal of Pharmacology, 146, 54-61(2015) [Non-patent document 2] Michal Dousa et.al., “Detection and structural elucidation of the new degradation impurities in the pharmaceutical formulations of ruxolitinib hydrobromide”, Journal of Pharmaceutical and Biomedical Analysis, 186(2020) 113266, pages 3-6 Summary of the Invention [Problem to be solved by the invention]

[0010] The main object of the present invention is to provide a new ruxolitinib-containing solid formulation that has a different composition from the already commercially available Jakavi (registered trademark) tablets, a solid formulation, and that ensures pharmaceutically acceptable stability, as well as to provide a method for producing such a ruxolitinib-containing solid formulation. [Means for solving the problem]

[0011] As a result of extensive research, the present inventors have found that the above problems can be solved by using a specific additive or excipient, and have thus completed the present invention.

[0012] The present invention can include, for example, the following aspects. [1] A pharmaceutical solid formulation comprising ruxolitinib or a pharmaceutically acceptable salt thereof and sodium stearyl fumarate. [2] The pharmaceutical solid formulation according to the above [1], which contains low-substituted hydroxypropyl cellulose. [3] The pharmaceutical solid formulation according to [2] above, which does not contain sodium starch glycolate. [4] The pharmaceutical solid formulation according to any one of the above [1] to [3], which does not contain at least one of magnesium stearate, polyvinylpyrrolidone, and sodium starch glycolate. [5] The pharmaceutical solid formulation according to [1] above, which is a tablet.

[0013] [6] A method for producing a pharmaceutical solid formulation containing ruxolitinib or a pharmaceutically acceptable salt thereof, comprising the step of adding sodium stearyl fumarate to a mixture containing ruxolitinib or a pharmaceutically acceptable salt thereof. [7] A method for stabilizing a pharmaceutical solid formulation containing ruxolitinib or a pharmaceutically acceptable salt thereof, wherein sodium stearyl fumarate is used as a lubricant. [Effects of the Invention]

[0014] According to the present invention, a new solid formulation containing ruxolitinib or a pharmaceutically acceptable salt thereof, which has guaranteed stability, can be provided. [Brief explanation of the drawings]

[0015] [Figure 1] This shows the change in the amount of related substance RRT0.3 produced over time. The vertical axis represents the amount of related substance produced (%), and the horizontal axis represents the period (months). Cross marks (x) represent the results of Example 1, open triangles represent the results of Example 2, asterisks (*) represent the results of Example 3, filled circles represent the results of Example 4, open diamonds represent the results of Example 5, open squares represent the results of Example 6, filled squares (dotted line) represent the results of Example 7, filled squares represent the results of Comparative Example 1, filled diamonds represent the results of Comparative Example 2, and filled triangles represent the results of Comparative Example 3. The horizontal line at 0.400% on the vertical axis indicates the threshold point at which safety confirmation is required. [Figure 2]This shows the change in the amount of related substance RRT0.97 produced over time. The vertical axis represents the amount of related substance produced (%), and the horizontal axis represents the period (months). Cross marks (x) represent the results of Example 1, open triangles represent the results of Example 2, asterisks (*) represent the results of Example 3, filled circles represent the results of Example 4, open diamonds represent the results of Example 5, open squares represent the results of Example 6, filled squares (dotted line) represent the results of Example 7, filled squares represent the results of Comparative Example 1, filled diamonds represent the results of Comparative Example 2, and filled triangles represent the results of Comparative Example 3. The horizontal line at 0.400% on the vertical axis indicates the threshold point at which safety confirmation is required. DETAILED DESCRIPTION OF THE INVENTION

[0016] 1. Solid preparation according to the present invention The solid preparation according to the present invention (hereinafter referred to as "the preparation of the present invention") is characterized by containing ruxolitinib or a pharmaceutically acceptable salt thereof and sodium stearyl fumarate. Furthermore, the preparation of the present invention containing low-substituted hydroxyprocellulose is preferred, and the preparation of the present invention containing low-substituted hydroxyprocellulose but not containing sodium starch glycolate is more preferred.

[0017] 1.1 Essential ingredients The formulation of the present invention contains at least ruxolitinib or a pharmaceutically acceptable salt thereof as an active ingredient, and sodium stearyl fumarate as an additive (filler or lubricant).

[0018] Ruxolitinib as a free base is a known compound and can be obtained commercially by those skilled in the art, or can be produced according to the method described in Patent Document 1.

[0019] The pharmaceutically acceptable salt of ruxolitinib is not particularly limited as long as it is an acid addition salt, and includes salts with inorganic acids or salts with organic acids.Specific examples include salts with inorganic acids such as hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, and nitrate; and salts with organic acids such as acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, amino acid salt, and besylate.Among these, phosphate is preferred.

[0020] Pharmaceutically acceptable salts of ruxolitinib, such as phosphate salts, are known compounds, and some phosphate salts are commercially available to those skilled in the art and can be easily prepared by conventional methods. For example, ruxolitinib can be prepared by dissolving ruxolitinib and a desired acid (e.g., phosphoric acid) in an appropriate solution such as alcohol, contacting the two in the liquid phase, and then isolating the solid salt product from the reaction solution (e.g., by crystallization, precipitation, evaporation, etc.). Alternatively, it can be prepared according to the method described in Patent Document 2.

[0021] The content of ruxolitinib or a pharmaceutically acceptable salt thereof in the formulation of the present invention is not particularly limited, but is suitably within the range of 0.1 to 10% by mass, preferably 1 to 6% by mass, more preferably 2 to 5% by mass, and particularly preferably 3 to 4% by mass, of ruxolitinib as a free base. If the content is less than 0.1% by mass, a bulky formulation may be required to achieve efficacy.

[0022] The content of sodium stearyl fumarate in the formulation of the present invention can be an appropriate amount as a lubricant, specifically, for example, in the range of 0.1 to 5% by mass, preferably in the range of 0.5 to 2% by mass, and more preferably in the range of 0.7 to 1.5% by mass. If the content of sodium stearyl fumarate is less than 0.1% by mass, it may not function as a lubricant.

[0023] 1.2 Optional ingredients (additives) The formulation of the present invention may contain appropriate amounts of additives commonly used in the field of pharmaceutical formulations, provided that the effects of the present invention are not impaired.Specific examples include excipients, binders, disintegrants, lubricants, etc., and, if necessary, plasticizers, antioxidants, colorants, flavoring agents, sweeteners, fragrances, preservatives, pH adjusters, surfactants, stabilizers, fluidizing agents, etc. As exemplified below, it is preferable not to include, for example, magnesium stearate, polyvinylpyrrolidone (povidone), and sodium starch glycolate, as they may accelerate the decomposition of ruxolitinib in the presence of heat and moisture.

[0024] Examples of excipients include lactose, D-mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose hydrate, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch, modified corn starch, potato starch, wheat starch, rice starch, dextrin / dextrates, maltodextrin, calcium citrate; inorganic salts such as calcium phosphate, calcium aluminometasilicate, calcium carbonate, dicalcium phosphate, and calcium sulfate; and cellulose derivatives such as crystalline cellulose and wood cellulose. Among these, crystalline cellulose and lactose hydrate are preferred in the present invention. Examples of crystalline cellulose include Ceolus PH-101 and Ceolus UF-702 (both manufactured by Asahi Kasei Corporation). Among these, Ceolus UF-702 is particularly preferred from the viewpoint of dissolution properties of the formulation. The excipient may be contained in granules such as granulated powder, or may be contained in the final component. Alternatively, the excipient may be contained in both the granules and the final component. From the viewpoint of dissolution properties of the formulation, it is preferable that the excipient be contained in both the granules and the final component. The composition may contain one type of excipient or any two or more types of excipients.

[0025] The content of crystalline cellulose in the formulation of the present invention can be an appropriate amount as an excipient, specifically, for example, in the range of 1 to 60% by mass, preferably in the range of 5 to 55% by mass, more preferably in the range of 8 to 50% by mass. From the viewpoint of formulation stability (suppression of related substances), the range of 9 to 11% by mass is preferred.

[0026] Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch, polyvinylpyrrolidone, gum arabic, starch (e.g., wheat starch, rice starch, corn starch, potato starch), sodium alginate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, gelatin, dextrin, hydroxypropyl starch, pullulan, and polyvinyl alcohol. Among these, hydroxypropyl cellulose is preferred in the present invention. When polyvinylpyrrolidone is contained, as described above, there is a risk of promoting the decomposition of ruxolitinib in the presence of heat and moisture. Therefore, the content of polyvinylpyrrolidone in the formulation of the present invention is preferably 2% by mass or less, more preferably 1.5% by mass or less, and particularly preferably zero. The binder may be contained in one kind or in any combination of two or more kinds.

[0027] Examples of disintegrants include starch (e.g., wheat starch, rice starch, potato starch, corn starch), sodium starch glycolate (sodium carboxymethyl starch), hydroxypropyl starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose calcium, crospovidone, low-substituted hydroxypropylcellulose, partially pregelatinized starch, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, magnesium aluminometasilicate, calcium silicate, and sodium lauryl sulfate. Among these, low-substituted hydroxypropylcellulose is preferred in the present invention. Examples of low-substituted hydroxypropylcellulose include the LH series manufactured by Shin-Etsu Chemical Co., Ltd., specifically LH-21 and LH-B1. Among these, LH-B1 is preferred from the viewpoint of dissolution properties of the formulation. Furthermore, in the present invention, sodium starch glycolate can also be contained as a disintegrant. However, when sodium starch glycolate is contained, as described above, there is a risk that the decomposition of ruxolitinib may be accelerated in the presence of heat and moisture. Therefore, the content of sodium starch glycolate in the formulation of the present invention is preferably 10% by mass or less, more preferably 5% by mass or less, and it is particularly preferable that no sodium starch glycolate is contained. The disintegrant may be contained alone or in any combination of two or more kinds.

[0028] Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, and sodium stearyl fumarate. The lubricant may be one type or any two or more types, but it is preferable that magnesium stearate is not contained, and it is more preferable that sodium stearyl fumarate is contained as the only lubricant.

[0029] Examples of plasticizers include polyethylene glycol 400 (macrogol 400), polyethylene glycol 600 (macrogol 600), polyethylene glycol 1500 (macrogol 1500), polyethylene glycol 4000 (macrogol 4000), polyethylene glycol 6000 (macrogol 6000), propylene glycol, isopropyl myristate, triacetin, glycerin, glycerin fatty acid esters (e.g., glycerin monostearate, etc.), triethyl citrate, polysorbate 80, diethyl phthalate, and dibutyl phthalate. The plasticizer may be contained alone or in any combination of two or more kinds.

[0030] Suitable examples of antioxidants include sulfites, ascorbic acid, sodium edetate, erythorbic acid, tocopherol, anhydrous citric acid, citric acid hydrate, soybean lecithin, dibutylhydroxytoluene, and propyl gallate. The antioxidant may be contained alone or in any combination of two or more kinds.

[0031] Examples of coloring agents include carotenoids, iron oxides, and chlorophyll. Examples of coloring agents also include food color red No. 2 and No. 3, food color yellow No. 4 and No. 5, food color green No. 3, food color blue No. 1 and No. 2, aluminum lakes of these food colors, iron sesquioxide, and yellow iron sesquioxide. The colorant may be contained alone or in any combination of two or more kinds.

[0032] Examples of flavoring agents include erythritol, xylitol, refined sucrose, D-sorbitol, lactose hydrate, sucrose, glucose, D-mannitol, aspartame, cocoa powder, reduced maltose syrup, reduced syrup, licorice, licorice extract, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, succinic acid, saccharin, saccharin sodium hydrate, tartaric acid, sucralose, purified stevia extract, peppermint oil, anhydrous citric acid, l-menthol, and DL-malic acid. The flavoring agent may be contained in one kind or in any combination of two or more kinds.

[0033] Examples of sweeteners include xylitol, refined sucrose, D-sorbitol, lactose hydrate, sucrose, glucose, D-mannitol, aspartame, reduced maltose syrup, licorice, licorice extract, saccharin, saccharin sodium hydrate, sucralose, purified stevia extract, maltitol, acesulfame potassium, and thaumatin. The sweetener may contain one kind or any two or more kinds.

[0034] Examples of flavorings include peppermint oil, 1-menthol, and vanillin. The fragrance may contain one kind or any two or more kinds of the fragrances.

[0035] Examples of preservatives include parabens (e.g., methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, etc.), citric acid hydrate, sodium benzoate, sodium edetate hydrate, and dibutylhydroxytoluene. The preservative may be contained alone or in any combination of two or more kinds.

[0036] Examples of pH adjusters include citric acid, magnesium carbonate, magnesium aluminometasilicate, magnesium oxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, sodium carbonate, aluminum silicate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and sodium acetate. The pH adjuster may be contained alone or in any combination of two or more kinds.

[0037] Examples of surfactants include sodium lauryl sulfate, sodium stearate, polyoxyethylene sorbitan monooleate, and sucrose fatty acid esters. The surfactant may be contained alone or in any combination of two or more kinds.

[0038] Examples of stabilizers include ascorbic acid, sodium edetate, erythorbic acid, and tocopherol. The stabilizer may be contained alone or in any combination of two or more kinds.

[0039] Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, and talc. Of these, it is preferred in the present invention that the fluidizing agent contains light anhydrous silicic acid. The fluidizing agent may be contained alone or in any combination of two or more kinds.

[0040] 2. Manufacturing method and form of the present formulation The formulation of the present invention can be produced, for example, by adding and mixing a desired amount of additives to a desired amount of ruxolitinib or a pharmaceutically acceptable salt thereof and a desired amount of sodium stearyl fumarate, and then processing the mixture or granules into a desired form according to a conventional method.

[0041] One aspect of the present invention is a method for producing a pharmaceutical solid formulation containing ruxolitinib or a pharmaceutically acceptable salt thereof, the method comprising the step of adding sodium stearyl fumarate to a mixture containing ruxolitinib or a pharmaceutically acceptable salt thereof. The mixture referred to here may be a powder containing ruxolitinib or a pharmaceutically acceptable salt thereof, or a granulated powder containing ruxolitinib or a pharmaceutically acceptable salt thereof.

[0042] Specific forms of the preparation (solid preparation) of the present invention include tablets such as plain tablets, coated tablets, OD tablets, and multi-layer tablets, granules, powders, fine granules, pills, and capsules. Among these, the tablet form is preferred.

[0043] The planar shape (surface shape) of the tablet is not particularly limited, and examples thereof include a circle, an oval, and a polygon (such as a square, a rectangle, or a hexagon), with a circle being preferred.

[0044] The tablet diameter (average diameter) of the tablet is, for example, suitably within the range of 5 to 15 mm, preferably within the range of 5.5 to 12 mm, and more preferably within the range of 7 to 10 mm. The tablet thickness is, for example, suitably within the range of 2 to 6 mm, preferably within the range of 2.5 to 5 mm, and more preferably within the range of 3 to 4.5 mm.

[0045] To improve identifiability, the surface of the tablet may be engraved or printed with information such as the product number, name of the active ingredient, content of the active ingredient, dosage form, product number, QR code (registered trademark), and barcode. Engraving or printing may be performed directly on the surface of the plain tablet or film-coated tablet. An appropriate printing method can be selected from, for example, ink printing methods using plate-type transfer printing, gravure printing, offset printing, and inkjet printing, and laser printing. The ink used for printing can be selected from edible inks containing dyes and / or pigments, and the ink color may be one color or two or more colors from the perspective of identifiability, etc.

[0046] The formulation of the present invention may be packaged in an appropriate packaging material. Examples of such packaging include press-through packages (PTPs), strip packages, bottles, and aluminum packages. Specific examples of materials for PTP packages containing tablets include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, and polycarbonate, as well as metals such as aluminum. These materials may be used alone or in combination. Specific examples of material combinations include laminates of polyvinyl chloride and polyvinylidene chloride, and laminates of polyvinyl chloride and polychlorotrifluoroethylene. Tablets can be packaged in PTPs by forming a resin sheet with pockets using a known method, placing tablets in the pockets, and then covering them with aluminum foil. The PTP package may be secondary packaged in an aluminum pillow. A desiccant and / or oxygen scavenger may also be contained in the aluminum pillow. Specific examples of desiccants include calcium chloride, calcium oxide, magnesium oxide, silica gel, and zeolite. Specific examples of oxygen scavengers include iron-based oxygen scavengers such as iron powder, and organic oxygen scavengers such as ascorbic acid, isoascorbic acid, hydroquinone, and catechol. The desiccants and / or desiccants may be used alone or in combination. A combination of desiccants and desiccants may also be used. PharmaKeep (registered trademark) (manufactured by Mitsubishi Gas Chemical Company, Inc.) is a specific example of a product combining a desiccant and an desiccant. Among these, from the viewpoint of ensuring stability, the packaging form of the formulation of the present invention is preferably a press-through package (PTP) made of a laminate of polyvinyl chloride and polychlorotrifluoroethylene, or a polyvinyl chloride PTP package further packaged in an aluminum pillow bag.

[0047] The formulation of the present invention may be filled in a glass or plastic bottle. Specific examples of the material for the plastic bottle include those resins exemplified above for PTP packaging.

[0048] The formulation of the present invention may be packaged in individual doses in aluminum packaging. The aluminum packaging may be secondary packaged in an aluminum pillow. The aluminum pillow may further contain the above-mentioned desiccant and / or oxygen scavenger.

[0049] The various components can be mixed using a mixer used in the pharmaceutical formulation field, and specific examples include a V-type mixer, a double cone type mixer, a ribbon type mixer, a conical screw type mixer, and a tumbler mixer.

[0050] When granulation is carried out in producing the formulation of the present invention, the granulation method may be any of wet methods (e.g., extrusion granulation, stirring granulation, fluidized bed granulation, tumbling granulation), dry methods (compression granulation (roller compactor method), briquette granulation (compression granulation)), and spray granulation. The machine used for granulation is not particularly limited, and examples include extrusion granulators (extrusion methods include, for example, screw extrusion, plunger extrusion, and roller extrusion), stirring granulators, fluidized bed granulators, tumbling granulators, and dry granulators. Production by granulation methods is superior to production not using granulation methods in that it can suppress tableting problems such as sticking. Of these, fluidized bed granulation is preferred.

[0051] When the formulation of the present invention is a tablet, the tableting method is not particularly limited, and may be any of the following: a direct compression method in which a mixture of ingredients is compressed as is; a semi-direct compression method in which an active ingredient is mixed with pre-granulated additives and compressed; a dry granulation compression method in which dry granulation is performed and then the granulated product is compressed; and a wet granulation compression method in which dried granulation prepared in a wet method is compressed.

[0052] For molding the preparation of the present invention into tablets, for example, a single punch tablet press, a rotary tablet press, etc. can be used. When a single punch tablet press, a rotary tablet press, etc. is used, the tableting pressure should be 1 to 50 kN / cm. 2 It is appropriate to use a tableting pressure in the range of 5 to 35 kN / cm. 2 Furthermore, it is preferable to use a tapered die for the purpose of preventing tableting problems such as capping.

[0053] The water content of the formulation of the present invention is not particularly limited, but is suitably, for example, 5% by mass or less, and more preferably 3% by mass or less. The lower limit of the water content is not particularly limited, and may be 0% by mass. In this specification, the water content of the formulation of the present invention can be measured, for example, by the Karl Fischer method or loss on drying (LOD) method.

[0054] When the preparation of the present invention is a coated tablet, it can be produced by coating the plain tablet of the preparation of the present invention with sugar coating, film coating or the like in accordance with a conventional method. The components of the coating agent include, for example, a coating base and a coating additive, which can be appropriately selected and used in appropriate amounts according to conventional methods.

[0055] Examples of coating bases include sugar coating bases, water-soluble film coating bases, enteric film coating bases, and sustained-release film coating bases. These may be used alone or in combination of any two or more.

[0056] Examples of sugar-coating bases include sugar alcohols such as sucrose, refined sucrose, and erythritol. Furthermore, one or more of the following may be used in combination: talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc.

[0057] Examples of water-soluble film coating bases include cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, and polyvinylpyrrolidone; and polysaccharides such as pullulan. These may be used alone or in combination of two or more.

[0058] Examples of enteric film coating bases include cellulose polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic acid polymers such as methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S; and natural products such as shellac. These may be used alone or in combination of any two or more.

[0059] Examples of sustained-release film coating bases include cellulose-based polymers such as ethyl cellulose, and acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS ​​and ethyl acrylate-methyl methacrylate copolymer suspensions. These may be used alone or in combination of two or more.

[0060] Examples of coating additives include light-blocking agents such as titanium oxide, fluidizing agents such as talc, and / or colorants such as ferric oxide and yellow ferric oxide, plasticizers such as polyethylene glycol, propylene glycol, triethyl citrate, castor oil, and polysorbates, and organic acids such as citric acid, tartaric acid, malic acid, and ascorbic acid. These may be used alone or in combination of any two or more.

[0061] 3. Use, dosage, and other information of the present invention The formulation of the present invention is useful as a pharmaceutical, and specifically, it can be administered, for example orally, to humans and non-human mammals (e.g., mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.) for the purpose of regulating the activity of JAK (particularly JAK1 and JAK2) possessed by ruxotinib or a pharmaceutically acceptable salt thereof, which is the active ingredient of the formulation of the present invention, or for the treatment or prevention of diseases associated with JAK activity.

[0062] The compounds can be used to treat or prevent diseases related to the regulation of JAK (particularly JAK1 and JAK2) activity or JAK activity, such as immune-related diseases, skin disorders, myeloproliferative disorders, cancer, and other diseases. Specific diseases or symptoms include, for example, the following:

[0063] Autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type 1 diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, autoimmune thyroid disorders, and autoimmune bullous skin disorders (e.g., pemphigus vulgaris (PV) or bullous pemphigoid (BP)). Allergic conditions, such as asthma, food allergies, atopic dermatitis and rhinitis.

[0064] Viral diseases, such as those caused by Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV-1, varicella-zoster virus (VZV) and human papillomavirus (HPV). Skin disorders, such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), etc.

[0065] Solid tumors, such as prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, melanoma, etc. Blood cancers, such as lymphoma, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia (AML), multiple myeloma, etc. Skin cancers, including cutaneous T-cell lymphoma (CTCL) (e.g., Sézary syndrome and mycosis fungoides), cutaneous B-cell lymphoma.

[0066] Myeloproliferative disorders (MPDs), such as polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), and systemic mast cell disease (SMCD). Inflammatory diseases, such as ocular inflammatory diseases (e.g., iritis, uveitis, scleritis, conjunctivitis, or related diseases), respiratory inflammatory diseases (e.g., of the upper respiratory tract, including the nose and paranasal sinuses (e.g., rhinitis or sinusitis), or the lower respiratory tract (e.g., bronchitis, chronic obstructive pulmonary disease, etc.)), inflammatory muscle diseases such as myocarditis, systemic inflammatory response syndrome (SIRS), septic shock, etc.

[0067] The dosage of ruxolitinib or a pharmaceutically acceptable salt thereof varies depending on the condition, age, weight, etc. of the patient to be administered, but typically ranges from 2 mg to 60 mg of ruxolitinib per day for adults, preferably from 5 mg to 25 mg. This is administered once or twice daily (every 12 hours) in divided doses. Oral administration is preferred.

[0068] When the formulation of the present invention is a tablet containing 5 mg or 10 mg of ruxolitinib per tablet, similar to Jakavi® tablets, it is effective in humans in the same way as Jakavi® tablets. In this case, similar to Jakavi® tablets, for myelofibrosis, the formulation of the present invention is preferably orally administered to adults twice daily, approximately every 12 hours. The appropriate dose ranges from 5 mg to 25 mg of ruxolitinib, and may be adjusted appropriately depending on the patient's condition. For polycythemia vera, the formulation of the present invention is preferably orally administered to adults twice daily, approximately every 12 hours, starting at 10 mg of ruxolitinib, although this may be adjusted appropriately depending on the patient's condition. For graft-versus-host disease after hematopoietic stem cell transplantation, the formulation of the present invention is preferably orally administered to adults and children aged 12 years or older at 10 mg of ruxolitinib twice daily, approximately every 12 hours, although this may be adjusted appropriately depending on the patient's condition. [Example]

[0069] The present invention will be explained below with reference to examples and test examples, but the present invention is not limited to these examples in any way.

[0070] [Examples 1 to 6, Comparative Examples 1 to 3] The ingredients shown in Tables 1 and 2 were mixed to prepare a tableting powder, and the obtained tableting powder was directly compressed using a single-punch tableting machine to produce a solid formulation (tablet) containing ruxolitinib phosphate.

[0071] [Example 7] A mixture containing the ingredients from ruxolitinib phosphate to low-substituted hydroxypropyl cellulose shown in Table 2 was wet granulated in a mortar, dried, and sieved through a 30M sieve (500 μm mesh size) to obtain a granulated product. Light anhydrous silicic acid and sodium stearyl fumarate were added to the obtained granulated product, and the mixture was compressed into tablets using a single-punch tablet press to produce a solid preparation (tablet) containing ruxolitinib phosphate.

[0072] [Table 1]

[0073] [Table 2]

[0074] The tablets manufactured in Examples 1 to 7 and Comparative Examples 1 to 3 were placed in a petri dish and stored in the open at 40°C and 75% relative humidity (RH) to measure the increase in the amount of related substances (RRT 0.3 and RRT 0.97), which are degradation products of ruxolitinib, over time. The measurements were performed using the area percentage method.

[0075] The results are shown in Figures 1 and 2. As is clear from the figure, the production of related substances was suppressed and stability was ensured in all of the tablets of Examples 1 to 7, which are formulations of the present invention. In all of the tablets of Comparative Examples 1 to 3, the production amount of related substances with an RRT of 0.3 exceeded the safety limit (0.4% or less) in less than two weeks, and the RRT of 0.97 also tended to increase compared to the tablets of the Examples.

[0076] Furthermore, the figure shows that even with the formulation of the present invention, the formulation that does not contain povidone tends to suppress the production of related substances, and furthermore, the formulation that does not contain sodium starch glycolate and uses low-substituted hydroxypropyl cellulose as a substitute tends to suppress the production of related substances.

[0077] [Examples 8 and 9] According to the component amounts shown in Table 3, ruxolitinib phosphate, lactose hydrate, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose were placed in a fluidized bed granulation dryer, and a solution of hydroxypropyl cellulose was sprayed onto the mixture of raw materials to granulate, dry, and sieve. The resulting granules were mixed with microcrystalline cellulose, light anhydrous silicic acid, and sodium stearyl fumarate. The mixture was tableted using a rotary tablet press while adding sodium stearyl fumarate using an external lubricator to produce a solid formulation (tablet) containing ruxolitinib phosphate.

[0078] [Table 3]

[0079] The tablets prepared in Examples 8 and 9 were placed in a petri dish and stored in the open at 50°C and 75% relative humidity (RH) for one week, after which the increase in the amount of related substances (RRT0.3 and RRT0.97), which are degradation products of ruxolitinib, was measured by the area percentage method.

[0080] The results are shown in Table 4. As is clear from the table, it was confirmed that the production of related substances was suppressed and stability was ensured for both the tablets of Example 8 and Example 9.

[0081] [Table 4]

[0082] [Packaging example 1] The tablets of Examples 8 and 9 were each packaged in a PTP package using a laminate of polyvinyl chloride and polychlorotrifluoroethylene.

[0083] [Packaging example 2] The tablets of Examples 8 and 9 were each packaged in a PTP package using a polyvinyl chloride sheet, and then further packaged in an aluminum pillow bag as a second package. [Industrial Applicability]

[0084] INDUSTRIAL APPLICABILITY The present invention can provide a new pharmaceutical composition containing ruxolitinib or a pharmaceutically acceptable salt thereof, and is therefore useful in the pharmaceutical industry.

Claims

1. A pharmaceutical solid formulation comprising ruxolitinib or a pharmaceutically acceptable salt thereof and sodium stearyl fumarate.

2. 2. The pharmaceutical solid formulation according to claim 1, comprising low-substituted hydroxypropyl cellulose.

3. 3. The pharmaceutical solid formulation according to claim 2, which does not contain sodium starch glycolate.

4. 4. The pharmaceutical solid formulation according to claim 1, which does not contain at least any of magnesium stearate, polyvinylpyrrolidone, and sodium starch glycolate.

5. The pharmaceutical solid formulation according to claim 1, which is a tablet.

6. A method for producing a pharmaceutical solid formulation containing ruxolitinib or a pharmaceutically acceptable salt thereof, comprising the step of adding sodium stearyl fumarate to a mixture containing ruxolitinib or a pharmaceutically acceptable salt thereof.

7. A method for stabilizing a pharmaceutical solid formulation containing ruxolitinib or a pharmaceutically acceptable salt thereof, characterized by using sodium stearyl fumarate as a lubricant.

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