Multiple controlled-release tablet compositions of ruxolitinib and methods of preparing same

Abstract

The present invention relates to a multiple controlled-release tablet composition of ruxolitinib or a pharmaceutically acceptable salt thereof, which is useful for treating Janus kinase-associated diseases such as myeloproliferative disorders, and a method for producing the same. More specifically, the present invention relates to a multiple controlled-release tablet composition and a method for producing the same, which exhibits a maximum drug blood concentration similar to that of commercially available immediate-release formulations, while controlling the drug release rate so as to efficiently maintain the drug at or above the effective blood concentration in the body, thereby enabling once-daily administration, unlike commercially available formulations that are administered twice daily.

Description

[Technical Field]

[0001] The present invention relates to a multiple controlled-release tablet composition of ruxolitinib or a pharmaceutically acceptable salt thereof, which is useful for treating Janus kinase-associated diseases such as myeloproliferative disorders, and a method for producing the same. More specifically, the present invention relates to a multiple controlled-release tablet composition and a method for producing the same, which exhibits a maximum drug blood concentration similar to that of commercially available immediate-release formulations, while controlling the drug release rate so as to efficiently maintain the drug at or above the effective blood concentration in the body, thereby enabling once-daily administration, unlike commercially available formulations that are administered twice daily. [Background technology]

[0002] Ruxolitinib ((3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile) is the first FDA-approved Janus kinase (JAK) inhibitor and the first drug approved for the treatment of myelofibrosis. It is marketed in Korea under the trade name Jakavi® and is taken twice daily.

[0003] Ruxolitinib is a BCS class I molecule with rapid oral absorption and a short half-life of approximately 3 hours (see Non-Patent Document 1). These properties result in a maximum peak / trough plasma concentration ratio in human subjects, requiring multiple daily doses for optimal treatment, potentially contributing to problems with patient compliance and unwanted side effects. Ruxolitinib therapy is often associated with the side effects of thrombocytopenia (low platelet count) and anemia (low hemoglobin). Thrombocytopenia is dose-dependent and considered a dose-limiting toxic effect. Therefore, there is a need for new and improved formulations of ruxolitinib that not only reduce side effects in patients but also still achieve therapeutic efficacy and further facilitate drug administration by reducing the number of doses required to achieve therapeutic benefit.

[0004] Patent Document 1 discloses a sustained-release formulation of ruxolitinib intended for once-daily administration. However, the formulation disclosed in this document contains hydroxypropyl methylcellulose, which may result in a rapid initial release of the drug. Furthermore, due to the physicochemical properties of ruxolitinib, which has higher solubility at low pH, there are problems in that the initial release is not efficiently controlled when exposed to gastric acid, etc. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Korea Patent No. 10-2015-0085833 [Non-patent literature]

[0006] [Non-Patent Document 1] Shiet al., J. Clin. Pharmacol. 2012 Jun;52(6):809-18. Epub 2011 May 20 Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention aims to solve the problems of the prior art as described above, and aims to provide a multiple controlled-release formulation of ruxolitinib, which solves the problem of rapid initial release of conventional ruxolitinib sustained-release formulations, and which can efficiently maintain an effective blood concentration of the drug in the body or higher by adjusting the drug release rate while showing a maximum drug blood concentration and a bioavailability at the same level as commercially available immediate-release formulations, and which can effectively improve the pharmacokinetic properties of ruxolitinib, as well as a method for producing the same. [Means for solving the problem]

[0008] In order to solve the above technical problems, one aspect of the present invention provides an oral multiple controlled-release tablet comprising: (a) one or more immediate-release portions containing ruxolitinib as an active ingredient and a fast-acting excipient; and (b) one or more sustained-release portions containing ruxolitinib as an active ingredient and a sustained-release agent.

[0009] The sustained-release agent is a "sustained-release polymer or base" and refers to a substance used to release a drug over a long period of time.

[0010] In one embodiment, the sustained-release agent may be selected from the group consisting of, but not limited to, polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl acetate-polyvinylpyrrolidone (Kollidon SR), ammonio methacrylate copolymer (Eudragit RS series, Eudragit RL series), ethyl acrylate-methyl methacrylate copolymer (Eudragit NE series), methacrylic acid copolymer (Eudragit L, Eudragit S), amino methacrylate (Eudragit E), sodium alginate, propylene glycol alginate, xanthan gum, locust bean gum, and mixtures thereof.

[0011] More specifically, the sustained release agent may be polyethylene oxide.

[0012] More specifically, the sustained-release agent may be polyethylene oxide having a viscosity of 1000 cP to 10000 cP based on a 1 to 5% (wt / wt) aqueous solution at 25°C.

[0013] In one embodiment, the fast-acting excipient may be one or more selected from the group consisting of gelling starch, sugar alcohols, low-substituted hydroxypropyl cellulose, lactose hydrate, and microcrystalline cellulose.

[0014] In one embodiment, the sustained-release portion may further include a sustained-release auxiliary.

[0015] In one embodiment, the sustained release aid may be selected from polyethylene glycol, povidone, hydroxypropyl cellulose, sugar alcohols, glyceryl behenate, ethyl cellulose, ammonium methacrylate copolymer, shellac, hydroxypropyl methylcellulose phthalate (HPMC-P), waxes, gums, and combinations thereof.

[0016] In one embodiment, the oral multiple controlled-release tablet of the present invention may exhibit a dissolution pattern in which the active ingredient of the immediate-release portion is completely released within 3 hours after the start of drug dissolution in purified water, based on the uncoated tablet.

[0017] In one embodiment, the oral multiple controlled-release tablet of the present invention has a coefficient of determination R obtained by linear regression analysis of the dissolution time-dissolution rate curve from the time 1 hour after the start of drug dissolution in purified water to the time when the drug dissolution rate reaches 90% or more, based on the uncoated tablet. 2 may exhibit an elution pattern in which the β-glucan group is 0.95 or higher.

[0018] Another aspect of the present invention provides a method for producing oral multiple controlled-release tablets, comprising: (1) preparing a mixture containing ruxolitinib as active ingredients and a fast-acting excipient; (2) preparing a mixture containing ruxolitinib as active ingredients and a sustained-release agent; and (3) compressing one or more of the mixtures obtained in step (1) and one or more of the mixtures obtained in step (2) into multiple controlled-release tablets, wherein the mixtures do not mix with each other during compression in step (3).

[0019] In one embodiment, in the method for manufacturing oral multiple controlled-release tablets of the present invention, the mixture containing ruxolitinib and a sustained-release agent may be a sustained-release core tablet, and the mixture containing ruxolitinib and a fast-acting excipient may be an outer layer surrounding the core tablet.

[0020] In one embodiment, the mixture prepared in step (2) of the method for preparing oral multiple controlled-release tablets of the present invention may further contain a sustained-release auxiliary agent as described above. [Effects of the Invention]

[0021] The oral multiple controlled-release tablets of ruxolitinib provided by the present invention do not have a rapid initial release of the drug, and while they exhibit the same maximum drug blood concentration and bioavailability as commercially available immediate-release formulations, they can effectively improve the pharmacokinetic properties of ruxolitinib by adjusting the drug release rate to efficiently maintain the effective blood concentration of the drug in the body or higher, and can be administered once daily, unlike commercially available formulations that are administered twice daily. [Brief explanation of the drawings]

[0022] [Figure 1] This shows the results of a pharmacokinetic (PK) study conducted in Test Example 2 of the present invention, comparing the results when the multiple controlled-release tablets of the present invention (bilayer tablets Examples 4 to 7) are administered once daily with the results when the commercially available control drug (Jakavi (registered trademark) tablets) is administered twice daily. [Figure 2] This is based on the results of the pharmacokinetic (PK) test conducted in Test Example 3 of the present invention, and is intended to compare the results when the multiple controlled-release tablet of the present invention is administered once a day with the results when a commercially available control drug is administered twice a day. The graphs for the first (1st) dose of the tablet of the present invention (bilayer tablet Example 8) and the control drug are the same as the results of the pharmacokinetic (PK) test conducted in Test Example 3 of the present invention, and the graph for the second (2nd) dose of the control drug is shown on the assumption that the same PK results as those for the first dose of the control drug are obtained. BEST MODE FOR CARRYING OUT THE INVENTION

[0023] Throughout this specification, unless otherwise specified, the terms "comprise" or "contain" mean the inclusion of a particular component (or components) without any particular limitation, and are not to be construed as excluding the addition of other components (or components).

[0024] As used herein, the term "multiple controlled-release tablet" refers to a formulation prepared by combining multiple granules with different properties in separate layers and compressing them into a single tablet, or by placing a core tablet with different release properties inside the tablet and then compressing granules with different release properties on the outside. Multiple controlled-release tablets include combination formulations in which the type of drug is different in each layer, immediate-release / extended-release formulations in which the type of drug is the same but the drug release rate is different in each layer, and formulations in which a structure for regulating drug release or imparting functionality is combined with a drug layer. The oral multiple controlled-release tablet of ruxolitinib according to the present invention belongs to the immediate-release / extended-release formulations.

[0025] The oral multiple controlled-release tablet of ruxolitinib according to the present invention comprises (a) one or more immediate-release portions comprising ruxolitinib as an active ingredient and a fast-acting excipient; and (b) one or more sustained-release portions comprising ruxolitinib as an active ingredient and a sustained-release agent.

[0026] In one embodiment, the oral multiple controlled-release tablet of ruxolitinib according to the present invention may be a bilayer tablet comprising one immediate-release layer as the immediate-release portion and one sustained-release layer as the sustained-release portion.

[0027] In one embodiment, the oral multiple controlled-release tablet of ruxolitinib according to the present invention may be a double-layered tablet comprising: (a) a sustained-release core tablet containing ruxolitinib as an active ingredient and a sustained-release agent; and (b) an outer layer surrounding the core tablet containing ruxolitinib as an active ingredient and a fast-acting excipient. The outer layer preferably has a faster disintegration rate than the core tablet. In this case, the sustained-release core tablet corresponds to the sustained-release portion, and the outer layer corresponds to the fast-release portion.

[0028] In one embodiment, the oral multiple controlled-release tablet for ruxolitinib according to the present invention may be a double-layered tablet comprising: (a) an enteric-coated core tablet containing ruxolitinib as an active ingredient and an enteric coating base; and (b) an outer layer surrounding the core tablet containing ruxolitinib as an active ingredient and a fast-acting excipient. The outer layer preferably has a faster disintegration rate than the core tablet. The enteric-coated core tablet is a delayed-release tablet that is resistant to gastric juice and intended to release its active ingredient(s) into the intestinal medium.

[0029] In the present invention, the "ruxolitinib" may be a free base of ruxolitinib (a base drug without a separate salt), or a pharmaceutically acceptable salt thereof (e.g., a phosphate salt), or an isomer thereof, or a mixture thereof. It may also be a compound that forms various hydrates and various crystal forms, respectively. For example, ruxolitinib may be an anhydrous form, various hydrates such as hemihydrate, monohydrate, dihydrate, trihydrate, or various solvates, or a mixture thereof.

[0030] In one embodiment, the "ruxolitinib or a pharmaceutically acceptable salt thereof" may be ruxolitinib phosphate salt.

[0031] In one embodiment, the content ratio of ruxolitinib in the immediate-release portion and the sustained-release portion may be, per 1 part by weight of ruxolitinib in the immediate-release portion, 0.2 parts by weight or more, 0.3 parts by weight or more, 0.4 parts by weight or more, 0.5 parts by weight or more, 0.6 parts by weight or more, 0.7 parts by weight or more, 0.8 parts by weight or more, 0.9 parts by weight or more, or 1 part by weight or more of ruxolitinib in the sustained-release portion, or may be, but is not limited to, 9 parts by weight or less, 8 parts by weight or less, 7 parts by weight or less, 6 parts by weight or less, 5 parts by weight or less, 4 parts by weight or less, 3 parts by weight or less, or 2 parts by weight or less.

[0032] In one embodiment, the content ratio of the immediate-release portion to the sustained-release portion in the ruxolitinib oral multiple controlled-release tablet according to the present invention may be, but is not limited to, 0.2 parts by weight or more, 0.3 parts by weight or more, 0.4 parts by weight or more, 0.5 parts by weight or more, 0.6 parts by weight or more, 0.7 parts by weight or more, 0.8 parts by weight or more, 0.9 parts by weight or more, or 1 part by weight or more of the sustained-release portion per 1 part by weight of the immediate-release portion. The content ratio of the immediate-release portion to the sustained-release portion can be adjusted to control the drug release rate and efficiently maintain an effective blood concentration of the drug in the body above that of the effective blood concentration.

[0033] In the present invention, the fast-acting excipient is not particularly limited as long as it can rapidly release the drug from the formulation. In one embodiment, the fast-acting excipient may be one or more selected from the group consisting of gelling starch, sugar alcohols, low-substituted hydroxypropyl cellulose, lactose hydrate, and microcrystalline cellulose, but is not limited thereto.

[0034] In one embodiment, the content of the fast-acting excipient in the immediate-release portion may be, relative to 1 part by weight of ruxolitinib in the immediate-release portion, 1 part by weight or more, 3 parts by weight or more, 5 parts by weight or more, 7 parts by weight or more, 9 parts by weight or more, or 10 parts by weight or more, or may be 40 parts by weight or less, 35 parts by weight or less, 30 parts by weight or less, 25 parts by weight or less, 20 parts by weight or less, or 15 parts by weight or less, more specifically, 1 to 40 parts by weight, 5 to 30 parts by weight, or 10 to 20 parts by weight, but is not limited thereto. The sustained-release agent is a "sustained-release polymer or base" and refers to a substance used to release a drug over a long period of time.

[0035] In one embodiment, the sustained-release agent may be selected from the group consisting of, but is not limited to, polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl acetate-polyvinylpyrrolidone (Kollidon SR), ammonio methacrylate copolymer (Eudragit RS series, Eudragit RL series), ethyl acrylate-methyl methacrylate copolymer (Eudragit NE series), methacrylic acid copolymer (Eudragit L, Eudragit S), amino methacrylate (Eudragit E), sodium alginate, propylene glycol alginate, xanthan gum, locust bean gum, and mixtures thereof.

[0036] More specifically, the sustained release agent may be polyethylene oxide.

[0037] In one embodiment, the polyethylene oxide used as a sustained-release agent component is not particularly limited as long as it can control the release of the drug from the formulation. In one embodiment, such polyethylene oxide (hereinafter sometimes abbreviated as "PEO") may be, for example, POLYOX WSR 303, POLYOX WSR 301, POLYOX WSR N60K, POLYOX WSR 205, POLYOX WSR N80, or a combination thereof, but is not limited thereto. In the present invention, two or more PEOs with different molecular weights and grades may be used in combination.

[0038] In one embodiment, the viscosity average molecular weight (g / mol) of the PEO (when two or more PEOs are used in combination, this refers to the viscosity average molecular weight of the combination) may be, for example, 50,000 or more, 100,000 or more, 150,000 or more, or 200,000 or more, and may be 7,000,000 or less, 6,000,000 or less, 5,000,000 or less, 4,000,000 or less, 3,000,000 or less, or 2,000,000 or less, and more specifically, may be, but is not limited to, 100,000 to 4,000,000 g / mol, 150,000 to 3,000,000 g / mol, or 200,000 to 2,000,000 g / mol. If the viscosity average molecular weight of the PEO is too low, the drug release in the sustained-release portion may be too rapid, making it meaningless as a sustained-release portion. Conversely, if the viscosity average molecular weight of the PEO is too high, the formulation may show a high blood concentration even 24 hours after in vivo administration, and repeated administration may result in accumulation of the drug concentration in the blood.

[0039] In one embodiment, the viscosity of the PEO (when two or more PEOs are used in combination, this means the viscosity of the combination) may be, for example, 1000 cP or more, 1100 cP or more, 1200 cP or more, 1300 cP or more, 1400 cP or more, or 1500 cP or more, or 10,000 cP or less, 9,000 cP or less, 8,000 cP or less, 7,000 cP or less, or 6,000 cP or less, based on a 1 to 5% (wt / wt) aqueous solution at 25° C. In one embodiment, the viscosity of the PEO may be 1000 cP to 10,000 cP based on a 1 to 5% (wt / wt) aqueous solution at 25° C. For example, the viscosity of PEO may be, but is not limited to, 1000 cP to 6000 cP in a 1% (wt / wt) aqueous solution at 25° C., 1500 cP to 7000 cP in a 2% (wt / wt) aqueous solution at 25° C., or 4000 cP to 10000 cP in a 5% (wt / wt) aqueous solution at 25° C. If the viscosity of PEO is lower than the above levels, the drug release in the sustained-release portion may be too rapid, making it useless as a sustained-release portion. Conversely, if the viscosity is higher than the above levels, the formulation may show high blood concentrations even 24 hours after in vivo administration, and repeated administration may result in accumulation of blood drug concentrations.

[0040] In one embodiment, the content of the sustained-release agent in the sustained-release portion may be, relative to 1 part by weight of ruxolitinib in the sustained-release portion, 1 part by weight or more, 2 parts by weight or more, 3 parts by weight or more, 4 parts by weight or more, or 5 parts by weight or more, or may be 30 parts by weight or less, 25 parts by weight or less, 20 parts by weight or less, 15 parts by weight or less, or 10 parts by weight or less, more specifically, 1 to 30 parts by weight, 3 to 20 parts by weight, or 5 to 10 parts by weight, but is not limited to these.

[0041] In one embodiment, when the PEO is used as a sustained-release agent component, it exhibits a phenomenon in which it dissolves and gels immediately upon contact with organic solvents, such as alcohol, particularly ethanol, and therefore cannot be subjected to wet granulation using such solvents followed by drying, sieving, and tableting processes.

[0042] Therefore, in one embodiment, the oral multiple controlled-release tablet of the present invention does not contain an organic solvent (e.g., an alcohol such as ethanol). That is, in one embodiment, the oral multiple controlled-release tablet of the present invention is manufactured by a dry process that does not use an organic solvent (e.g., an alcohol such as ethanol).

[0043] In one embodiment, the sustained-release portion may further include a sustained-release auxiliary.

[0044] In one embodiment, the sustained release aid can be selected from polyethylene glycol, povidone, hydroxypropyl cellulose, sugar alcohols, glyceryl behenate, ethyl cellulose, ammonium methacrylate copolymer, shellac, hydroxypropyl methylcellulose phthalate (HPMC-P), waxes, gums, and combinations thereof.

[0045] In one embodiment, the number average molecular weight (g / mol) of the polyethylene glycol (for example, trade name Macrogol) may be, but is not limited to, 1,000 to 10,000 g / mol.

[0046] In one embodiment, the sugar alcohols may be, but are not limited to, sorbitol, maltitol, xylitol, erythritol, or combinations thereof.

[0047] The glyceryl behenate serves as a suitable lubricant during the dry granulation process and the compression molding process, and also serves to maintain the tablet form and delay the drug release due to its strong non-aqueous properties.

[0048] In one embodiment, the ammonium methacrylic acid copolymer may be, but is not limited to, poly(ethyl acrylate / methyl methacrylate / trimethylammonium chloride methacrylate) (e.g., Eudragit® RL or Eudragit® RS, Evonik).

[0049] In one embodiment, the waxes may be carnauba wax, beeswax, microcrystalline wax or combinations thereof, and the gums may be, but are not limited to, guar gum, locust bean gum, tragacanth, carrageenan, acacia gum, gum arabic, gellan gum, xanthan gum or combinations thereof.

[0050] In one embodiment, the content of the sustained-release auxiliary agent in the sustained-release portion may be, but is not limited to, 0.05 parts by weight or more, 0.1 parts by weight or more, 0.12 parts by weight or more, or 0.15 parts by weight or more, or 5 parts by weight or less, 4 parts by weight or less, 3 parts by weight or less, or 2 parts by weight or less, relative to 1 part by weight of ruxolitinib in the sustained-release portion. When the sustained-release auxiliary agent also functions as a lubricant, its content may be 5 w / w% to 20 w / w%, 10 w / w% to 20 w / w%, or 10 w / w% to 15 w / w% relative to the total tablet weight.

[0051] In one embodiment, one or more of the immediate-release portion and the sustained-release portion may further contain, if necessary, one or more pharmaceutically acceptable carriers or additives in addition to the components described above.

[0052] In one embodiment, one or more of the immediate release portion and the sustained release portion may further comprise a diluent.

[0053] In one embodiment, the diluent may be selected from the group consisting of sugars, sugar alcohols, cellulose, starch, inorganic salts, and mixtures thereof, and more specifically, may be selected from the group consisting of lactose (anhydrous or hydrated, e.g., monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, gelatinized starch, calcium carbonate, cyclodextrin, calcium sulfate, calcium silicate, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, potassium chloride, sodium chloride, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dextrates, dextrin, and mixtures thereof.

[0054] In one embodiment, the diluent may also serve as a binder.

[0055] In one embodiment, when a diluent is used in one or more of the immediate-release portion and the sustained-release portion, the amount used may be, relative to 1 part by weight of ruxolitinib contained in the immediate-release portion or the sustained-release portion, 0.5 parts by weight or more, 1 part by weight or more, or 1.5 parts by weight or more, and may be, but is not limited to, 400 parts by weight or less, 200 parts by weight or less, 100 parts by weight or less, 50 parts by weight or less, or 20 parts by weight or less.

[0056] In one embodiment, one or more of the immediate release portion and the sustained release portion may further comprise a lubricant.

[0057] In one embodiment, the lubricant can be selected from the group consisting of soluble lubricants, insoluble lubricants, and mixtures thereof, and more specifically, can be selected from the group consisting of magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, sucrose fatty acid esters, starch, talc, colloidal silica, magnesium oxide, magnesium carbonate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate, hydrogenated vegetable oil, hard liquid paraffin, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, glyceryl triacetate, sucrose monolaurate, and mixtures thereof.

[0058] In one embodiment, when a lubricant is used in one or more of the immediate-release portion and the sustained-release portion, the amount used may be, relative to 1 part by weight of ruxolitinib contained in the immediate-release portion or the sustained-release portion, 0.005 parts by weight or more, 0.01 parts by weight or more, or 0.05 parts by weight or more, and may be, but is not limited to, 10 parts by weight or less, 5 parts by weight or less, or 1 part by weight or less.

[0059] In one embodiment, one or more of the immediate release portion and the sustained release portion may further comprise a binder.

[0060] In one embodiment, the binder may be selected from the group consisting of povidone, polyvinylpyrrolidone, polyvinyl alcohol, carbopol, hydroxypropyl methylcellulose, hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (HPC-L), carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, pullulan, carboxyvinyl polymer polyethylene glycol or derivatives thereof, and mixtures thereof.

[0061] In one embodiment, when a binder is used in one or more of the immediate-release portion and the sustained-release portion, the amount used may be, but is not limited to, 0.005 parts by weight or more, 0.01 parts by weight or more, or 0.05 parts by weight or more, relative to 1 part by weight of ruxolitinib contained in the immediate-release portion and the sustained-release portion.

[0062] In one embodiment, the immediate release portion may further comprise a disintegrant.

[0063] In one embodiment, the disintegrant may be selected from the group consisting of croscarmellose sodium (CrosCMC-Na), carboxymethylcellulose, crospovidone (cross-linked polyvinylpyrrolidone), low-substituted hydroxypropyl cellulose (L-HPC), starch, pregelatinized starch, sodium carboxymethyl starch, sodium starch glycolate, partially hydrolyzed starch, and mixtures thereof.

[0064] In one embodiment, when a disintegrant is used in the immediate-release portion, the amount used may be, relative to 1 part by weight of ruxolitinib contained in the immediate-release portion, 0.005 parts by weight or more, 0.01 parts by weight or more, or 0.05 parts by weight or more, and may be, but is not limited to, 10 parts by weight or less, 5 parts by weight or less, or 1 part by weight or less.

[0065] The oral multiple controlled-release tablet of the present invention may further comprise a coating layer.

[0066] In one embodiment, the coating base forming the coating layer can be selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinyl alcohol, macrogol-polyvinyl alcohol graft copolymer, polymers of acrylic acid and salts thereof, polymethacrylate, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer, vinylpyrrolidone-vinyl acetate copolymer, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof.

[0067] In one embodiment, when the oral multiple controlled-release tablet of the present invention further comprises a coating layer, the content thereof may be, but is not limited to, 1 part by weight or more, 2 parts by weight or more, 3 parts by weight or more, 4 parts by weight or more, 5 parts by weight or more, or 6 parts by weight or more, per 100 parts by weight of the tablet before coating (plain tablet).

[0068] Coating is performed to improve the stability of the uncoated tablet and prevent drug loss. Therefore, a second coating can be applied after the first coating if necessary, and the coating thickness can be selected appropriately. However, as mentioned above, the coating must not delay drug dissolution, so an appropriate range must be selected. Other ingredients and methods required for coating can be selected appropriately by those of ordinary skill in the art.

[0069] In one embodiment, the hardness of the uncoated tablets (uncoated tablets) of the oral multiple controlled-release tablets of the present invention may be 50 N to 400 N. More specifically, the minimum average hardness of the uncoated tablets of the oral multiple controlled-release tablets of the present invention may be 50 N, 100 N, 150 N, or 200 N, and the maximum average hardness may be 400 N, 350 N, 300 N, or 250 N.

[0070] In one embodiment, the oral multiple controlled-release tablet of the present invention can exhibit a dissolution pattern in which the active ingredient in the immediate-release layer is completely released within 3 hours, more specifically within 2 hours, and even more specifically within 1 hour, after the start of drug dissolution in purified water (e.g., purified water at 37°C and at 50 rpm) relative to the uncoated tablet.

[0071] In one embodiment, the oral multiple controlled-release tablet of the present invention has a coefficient of determination R obtained by linear regression analysis of the dissolution time-dissolution rate curve from the point 1 hour after the start of drug dissolution in purified water (e.g., at 37°C and 50 rpm) to the point at which the drug dissolution rate reaches 90% or more, based on the uncoated tablet. 2 More specifically, the coefficient of determination R 2 may be 0.96 or greater, 0.97 or greater, 0.98 or greater, 0.99 or greater, or 0.995 or greater (R 2 The maximum value of is 1).

[0072] The dissolution pattern may be determined, for example, by Method 2 (paddle, 50 rpm) of the Korean Pharmacopoeia Dissolution Test.

[0073] The coefficient of determination R 2R indicates the degree of difference between the dissolution time (X)-dissolution rate (Y) trend line derived from the dissolution time-dissolution rate curve through linear regression analysis (linear regression model) to examine the linearity of the drug release pattern from 1 hour after the start of drug dissolution until the drug dissolution rate reaches 90% or more, and the actual measured value. It is an index showing how well the linear regression model is fitted linearly. 2 The closer to 1, the better all the response variables fit with the predictor variables. In other words, the R 2 The closer the value is to 1, the more zero-order release control is possible, which means that the drug is released at the same rate in the body, effectively maintaining the drug concentration in the blood. 2 is calculated by the following formula:

number

[0074] In one embodiment, the shape of the oral multiple controlled-release tablet of the present invention may be various shapes such as rectangular, oval, diamond, circular, polygonal (e.g., triangular, square, pentagonal, hexagonal, etc.). The shape of the tablet may be determined by comprehensively considering factors such as convenience for patients to take the tablet, ease of punch production and management, ease of manufacturing such as tablet compression, coating, packaging, and handling, whether the dissolution pattern can be adjusted, and ease of adjusting variables related to physical properties such as tablet hardness, friability, and disintegration. In addition, an appropriate shape may be selected depending on the respective doses.

[0075] In one embodiment, the total weight of the tablets (uncoated tablets) of the oral multiple controlled-release tablets of the present invention before coating, especially in the case of the maximum dose, is preferably an average tablet weight of not more than 1100 mg, more preferably not more than 1000 mg, even more preferably not more than 900 mg, even more preferably not more than 800 mg, and even more preferably not more than 700 mg.

[0076] In one embodiment, the oral multiple controlled-release tablets of the present invention are useful for treating anuskinin-associated disorders, more particularly myeloproliferative disorders.

[0077] Another aspect of the present invention provides a method for producing oral multiple controlled-release tablets, comprising: (1) preparing a mixture containing ruxolitinib as active ingredients and a fast-acting excipient; (2) preparing a mixture containing ruxolitinib as active ingredients and a sustained-release agent; and (3) compressing one or more of the mixtures obtained in step (1) and one or more of the mixtures obtained in step (2) into multiple controlled-release tablets, wherein the mixtures do not mix with each other during compression in step (3).

[0078] In the method for producing oral multiple controlled-release tablets of the present invention, the phrase "the mixtures are not mixed with each other during tableting" means that the mixture obtained in step (1) and the mixture obtained in step (2) are not intentionally mixed during tableting, and does not exclude the inevitable mixing of one mixture into another mixture at the boundary between the layers.

[0079] In one embodiment, in the method for manufacturing oral multiple controlled-release tablets of the present invention, the mixture containing ruxolitinib and a sustained-release agent can be a sustained-release core tablet, and the mixture containing ruxolitinib and a fast-acting excipient can be an outer layer surrounding the core tablet. In one embodiment, the mixture prepared in step (2) of the method for preparing oral multiple controlled-release tablets of the present invention may further contain a sustained-release auxiliary.

[0080] In the method for preparing oral multiple controlled-release tablets, the active ingredient ruxolitinib, the fast-acting excipient, the sustained-release agent, and the additional ingredient sustained-release auxiliary are as described above.

[0081] In one embodiment, the mixture produced in any one or more of step (1) and step (2) may further contain a diluent, where usable diluents are as described above.

[0082] In one embodiment, the mixture produced in any one or more of step (1) and step (2) may further contain a lubricant, where usable lubricants are as described above.

[0083] In one embodiment, the mixture produced in any one or more of step (1) and step (2) may further contain a binder, where usable binders are as described above.

[0084] In one embodiment, the mixture produced in step (1) may further contain a disintegrant, and usable disintegrants are as described above.

[0085] In one embodiment, the method for producing oral tablets of the present invention may further include (4) a step of coating the surfaces of the multiple controlled-release tablets (plain tablets) obtained by tableting in the step (3) with a coating base, and usable coating bases are as described above.

[0086] In each of the above steps, the particle size of the mixture can be made uniform by sieving, which can improve the flowability and compression moldability of the mixture.

[0087] In one embodiment, the multiple controlled-release tablets of the present invention can be manufactured by weighing the raw materials, optionally granulating them, mixing them, compressing them into a multi-layer formulation, and coating them. Granulation can be performed by methods such as dry granulation or wet granulation.

[0088] In one embodiment, when granulating using wet granulation, a binder solution is prepared, and the drug and diluents are added and mixed together to form a mixture. The mixture is then mixed with the binder solution to form granules, which are then sieved and dried to obtain the granules. The remaining ingredients are then mixed and compressed into tablets. The binder solution is as described above, and while water can be used as a binder solvent, PEO is not suitable for use in organic solvents, such as alcohol, especially ethanol, because it dissolves and gels immediately when in contact with such solvents.

[0089] In one embodiment, when dry granulation is used, a mixture of a drug and a diluent is compressed using a roller granulator or the like, and then sieved. The remaining ingredients are then mixed in a post-mixing process, followed by tableting.

[0090] Examples are given below to aid in understanding the present invention, but the following examples are for illustrative purposes only and are not intended to limit the present invention.

[0091] Example <Fast-acting excipients used> Microcrystalline cellulose ·Lactose hydrate

[0092] <Sustained-release ingredients used> Polyethylene oxide - POLYOX WSR N80: Viscosity average molecular weight: 200,000 g / mol, Viscosity (1% aqueous solution at 25°C): 65-115 cP Polyethylene oxide - POLYOX WSR 205: Viscosity average molecular weight: 600,000 g / mol, Viscosity (5% aqueous solution at 25°C): 4500-8800 cP Polyethylene oxide - POLYOX WSR N60K: Viscosity average molecular weight: 2,000,000 g / mol, Viscosity (2% aqueous solution at 25°C): 2000-4000 cP

[0093] <Other additives used> Sustained-release agent: Macrogol 4000 (polyethylene glycol with a number-average molecular weight of 4000 g / mol) Disintegrant: Sodium starch glycolate Binder: Low-substituted hydroxypropyl cellulose (HPC-L), povidone (K-30) Lubricants: Magnesium stearate, silica (SiO2)

[0094] Comparative Example 1 (immediate-release single-layer tablet) Ruxolitinib phosphate (26.4 g), microcrystalline cellulose (17.84 g), lactose hydrate (18.5 g), sodium starch glycolate (1.3 g), povidone (K-30) (0.8 g), and low-substituted hydroxypropyl cellulose (0.8 g) were sieved and mixed, then an appropriate amount of purified water was added to granulate, dried at 50°C to evaporate the solvent, and sieved to obtain granules. Hard anhydrous silicic acid (0.42 g) and magnesium stearate (0.2 g) were added to the sieved granules and mixed. This mixture was compressed using a rectangular punch at a weight basis of 425.0 mg per tablet. The hardness of the uncoated tablets was approximately 140 N.

[0095] Example 1 <Manufacturing of sustained-release layer granules> Ruxolitinib phosphate (3.3 g), POLYOX WSR N80 (5.0 g), POLYOX WSR 205 (16.25 g), macrogol 4000 (6.25 g), and HPC-L (1.225 g) were sieved and mixed, and then magnesium stearate (0.475 g) was added and mixed (lubrication process) to produce sustained-release layer granules.

[0096] <Manufacturing of Rapid-Release Granules> Using the ingredients of the types and amounts shown in Table 1, the same granulation process as in Comparative Example 1 was carried out to produce layered immediate-release granules.

[0097] <Manufacturing of bilayer tablets (uncoated tablets)> The sustained-release layer granules were weighed at 325.0 mg per tablet, and the immediate-release layer granules were weighed at 318.8 mg per tablet. The tablets were then compressed with a rectangular punch using an Autotab-200TR (Ichihoshiseiki Co., Ltd.) to prevent the two granules from mixing. The total weight of the bilayer tablets was 643.8 mg, and the hardness was 200-220 N.

[0098] Examples 2 and 3 Using the ingredients of the types and amounts shown in Table 1, bilayer tablets were produced in the same manner as in Example 1.

[0099] Manufacturing of coated tablets For the plain tablets of Examples 1 to 3, Opadry 20A (manufactured by Colorcon) was dispersed in 80% ethanol to coat 6.0 mg of Opadry 20A per tablet as a primary coating, and then Opadry 200F (manufactured by Colorcon) was dispersed in purified water to coat 15.0 mg of Opadry 200F per tablet to produce coated tablets.

[0100] [Table 1]

[0101] [Test Example 1: Dissolution test of Comparative Example 1 and Examples 1 to 3] The uncoated tablet of Comparative Example 1 and each of the coated tablets of Examples 1 to 3 were subjected to a dissolution test using the paddle method according to the Korean Pharmacopoeia, 10th Edition, under the following conditions (n=3). The results are shown in Table 2 below.

[0102] <Dissolution test method> Elution solution: purified water 900 mL / Rotation speed: 50 rpm / Temperature: 37°C Dissolution test solution sampling times: 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 16 hours Analysis method: HPLC analysis method Evaluation criteria for dissolution rate: The concentration of ruxolitinib phosphate 52.8 mg / 900 mL purified water is 100%.

[0103] [Table 2]

[0104] Comparative Example 1 was the highest dose of a commercially available once-daily formulation, and the final dissolution rate was approximately 50%. In Examples 1 to 3, the ratio of the active ingredient in the immediate-release layer of the bilayer tablet was 37.5% of the total active ingredient in the tablet, and all of the active ingredient in the immediate-release layer was dissolved within 1 hour without affecting the formulation in the sustained-release layer, confirming that the time point at which the dissolution rate reached 80% in Examples 1 to 3 could be adjusted by the sustained-release layer configuration.

[0105] Comparative Example 2 (sustained-release single-layer tablet) Ruxolitinib phosphate (5.28 g), POLYOX WSR 205 (17.0 g), POLYOX WSR N60K (17.0 g), macrogol 4000 (10.0 g), and HPC-L (1.96 g) were sieved and mixed, then magnesium stearate (0.76 g) was added and mixed (lubrication process) to produce granules. These granules were compressed into tablets using rectangular punches at a weight basis of 520 mg per tablet. The hardness of the uncoated tablets was 200-220 N.

[0106] Examples 4 to 7 <Manufacturing of sustained-release layer granules> The same granulation process as in Comparative Example 2 was carried out using the ingredients of the types and amounts shown in Table 3 to produce sustained-release layer granules.

[0107] <Manufacturing of Rapid-Release Granules> Using the ingredients of the types and amounts shown in Table 3, the same granulation process as in Comparative Example 1 was carried out to produce layered immediate-release granules.

[0108] <Manufacturing of bilayer tablets (uncoated tablets)> Using the produced sustained-release layer granules and rapid-release layer granules, bilayer tablets were produced in the same manner as in Example 1.

[0109] Manufacturing of coated tablets For the plain tablets of Comparative Example 2 and Examples 4 to 7, Opadry 20A (manufactured by Colorcon) was dispersed in 80% ethanol to form a primary coating so that 6.0 mg of Opadry 20A was coated per tablet. Subsequently, Opadry 200F (manufactured by Colorcon) was dispersed in purified water to form coated tablets so that 15.0 mg of Opadry 200F was coated per tablet.

[0110] [Table 3-1] [Table 3-2]

[0111] Example 5 has the same composition as Example 2, and the sustained-release and immediate-release granules of Examples 5 and 6 were manufactured using the same granules, with only the ratio of the main ingredients in each layer being changed. The weight ratio of the active ingredients in the sustained-release layer to the immediate-release layer in each formulation (sustained-release layer: immediate-release layer) was 20:20 in Example 4, 25:15 in Example 5, 30:10 in Example 6, and 35:15 in Example 7.

[0112] Test Example 2: Dissolution test and linearity evaluation of dissolution patterns in Comparative Example 2 and Examples 4 to 7, and evaluation of pharmacokinetic properties in Examples 4 to 7 1.Dissolution test For each of the coated tablets of Comparative Example 2 and Examples 4 to 7, a dissolution test was carried out using the paddle method according to the Korean Pharmacopoeia, 10th Edition, under the following conditions (n=3). The results are shown in Table 4 below.

[0113] <Dissolution test method> Elution solution: purified water 900 mL / Rotation speed: 50 rpm / Temperature: 37°C Dissolution test solution sampling times: 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours Analysis method: HPLC analysis method Evaluation criteria for dissolution rate: The concentration of ruxolitinib phosphate 52.8 mg / 900 mL purified water is 100%.

[0114] [Table 4]

[0115] Comparative Example 2, which did not have an immediate-release layer, showed no active ingredient rapidly released within 1 hour after the start of dissolution, and exhibited a zero-order release pattern. On the other hand, the bilayer tablets of Examples 4 to 7, which had an immediate-release layer, rapidly released the active ingredient within 1 hour after the start of dissolution, and it was confirmed that the amount of release could be adjusted by the composition of the immediate-release layer.

[0116] 2. Linearity evaluation of dissolution pattern From the results of the dissolution test conducted on the coated tablets of Comparative Example 2, a linear regression model was performed on the dissolution curve from 0 hour after the start of dissolution to approximately 90% dissolution, and an equation between dissolution time (X) and dissolution rate (Y) was calculated as a trend line. From the results of the dissolution test conducted on each of the coated tablets of Examples 4 to 7, a linear regression model was performed on the dissolution curve from 1 hour after the start of dissolution (i.e., the time when it is determined that there is no effect of the immediate-release layer) to approximately 90% dissolution, and an equation between dissolution time (X) and dissolution rate (Y) was calculated as a trend line. The results are shown in Table 5 below.

[0117] [Table 5]

[0118] From the above results, it was confirmed that each of the bilayer tablets in Examples 4 to 7 exhibited a zero-order release pattern from 1 hour onwards, when the dissolution rate of the immediate-release layer was no longer considered to have any effect. The release rates of all the formulations were confirmed to have similar slope values ​​around 5.5, since the sustained-release portion had the same molecular weight.

[0119] 3. Pharmacokinetic (PK) studies A nonclinical pharmacokinetic (PK) study was conducted in beagle dogs to compare the in vivo pharmacokinetic properties of commercially available Jakavi® tablets (20 mg of ruxolitinib) and the coated bilayer tablets (40 mg of ruxolitinib) prepared in Examples 4 to 7. Beagle dogs (N=12) were administered the drug with water in a fasted state, and blood samples were taken at regular intervals for up to 24 hours. The commercially available Jakavi® tablets were administered twice daily at 12-hour intervals, while the bilayer tablets of Examples 4 to 7 were administered once daily. The blood samples collected for each subject were frozen after plasma separation and then analyzed for concentration using an LC / MS / MS system to obtain blood concentrations over time. The AUC, Cmax, and half-life were calculated from the data, and the results are summarized in Table 6 below.

[0120] [Table 6]

[0121] As a result of the test, the bilayer tablets of Examples 4 to 7 exhibited pharmacokinetic properties that showed excellent half-life extension effects compared to the control drug, Jakavi (registered trademark) tablets.

[0122] Example 8 <Manufacturing of sustained-release layer granules> Ruxolitinib phosphate (5.28 g), POLYOX WSR205 (29.0 g), POLYOX WSR N60K (5.0 g), macrogol 4000 (10.12 g), and HPC-L (2.0 g) were sieved and mixed, and then magnesium stearate (0.6 g) was added and mixed (lubrication process) to produce sustained-release layer granules.

[0123] <Manufacturing of Rapid-Release Granules> The same types and contents of ingredients as in Comparative Example 1 were used and the same granulation process was carried out to produce rapid-release layered granules.

[0124] <Manufacturing of bilayer tablets (uncoated tablets)> The sustained-release layer granules were weighed at 455.0 mg per tablet, and the immediate-release layer granules were weighed at 106.25 mg per tablet. The two granules were then compressed into bilayer tablets using an Autotab-200TR device (manufactured by Ichihoshiseiki Co., Ltd.) with a rectangular punch, taking care not to mix the two granules. The total weight of the bilayer tablets was 561.25 mg, and the hardness was 200-220 N.

[0125] Manufacturing of coated tablets For the plain tablets of Example 8, Opadry 20A (manufactured by Colorcon) was dispersed in 80% ethanol to coat 6.0 mg of Opadry 20A per tablet as a primary coating, and then Opadry 200F (manufactured by Colorcon) was dispersed in purified water to coat 15.0 mg of Opadry 200F per tablet to produce coated tablets.

[0126] [Table 7]

[0127] Test Example 3: Dissolution test and pharmacokinetic property evaluation of Example 8 1.Dissolution test The coated tablets of Example 8 were subjected to a dissolution test using the paddle method of the Korean Pharmacopoeia, 10th Edition, under the following conditions (n=3). The results are shown in Table 8 below.

[0128] <Dissolution test method> Elution solution: purified water 900 mL / Rotation speed: 50 rpm / Temperature: 37°C Dissolution test solution sampling times: 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 16 hours Analysis method: HPLC analysis method Dissolution rate evaluation criteria: The concentration of ruxolitinib phosphate 52.8 mg / 900 mL purified water is adjusted to 100%.

[0129] [Table 8]

[0130] 2. Pharmacokinetic (PK) studies A nonclinical pharmacokinetic (PK) study was conducted in beagle dogs to compare the in vivo pharmacokinetic properties of commercially available Jakavi® tablets (20 mg of ruxolitinib) and the coated bilayer tablets of Example 8 (40 mg of ruxolitinib). Beagle dogs (N=5) were administered the drug with water in a fasted state, and blood samples were collected at regular intervals up to 48 hours. Plasma was separated from the collected blood samples, which were then frozen and analyzed for concentration using an LC / MS / MS system to obtain blood concentrations over time. The AUC, Cmax, and half-life were calculated from the data, and the results are summarized in Table 9 below.

[0131] [Table 9]

[0132] The test results confirmed that, compared to the control drug, Jakavi (registered trademark) tablets, the bilayer tablet of Example 8 exhibited pharmacokinetic properties that showed a similar level of Cmax, twice the AUC, and approximately 2.8 times the half-life extension effect.

[0133] In addition, to compare the once-daily administration of the multiple controlled-release tablet of the present invention with the twice-daily administration of a commercially available control drug, the pharmacokinetic (PK) test results were performed after the first (1st) administration of the tablet of the present invention (bilayer tablet Example 8) and the control drug (Jakavi (registered trademark) tablet), and the results after the second (2nd) administration of the control drug, assuming that the same PK results would be obtained as after the first administration of the control drug, are also shown in Figure 2.

[0134] Thus, the ruxolitinib multiple controlled-release tablets of the present invention can maintain the drug concentration in the body at or above the effective blood concentration for a long period of time without a rapid initial release of the drug, thereby reducing the number of drug administrations compared to commercially available products. For example, compared to commercially available products that require twice-daily administration of a 20 mg formulation, the number of daily administrations can be reduced to one, i.e., a single administration of 40 mg.

[0135] Examples 9 to 11 <Manufacturing of the core tablet (sustained-release portion)> Ruxolitinib phosphate and sustained-release agent components in the amounts shown in Table 10 were sieved and mixed, and then magnesium stearate in the amount shown in Table 10 was added and mixed (lubrication step). This mixture was compressed into tablets using a circular punch based on a weight of 110.0 mg per tablet. The hardness was 50 to 60 N.

[0136] <Manufacturing of outer layer (immediate release) granules> Ruxolitinib phosphate, microcrystalline cellulose, lactose hydrate, sodium starch glycolate, povidone (K-30), and low-substituted hydroxypropyl cellulose (HPC-L) in the amounts shown in Table 10 were sieved and mixed, and then an appropriate amount of purified water was added to granulate, which was dried at 50°C to evaporate the solvent and then sieved to obtain granules. Hard anhydrous silicic acid (SiO2) and magnesium stearate in the amounts shown in Table 10 were added to the sieved granules and mixed (lubrication step).

[0137] <Manufacturing of dry-coated tablets> An appropriate amount of outer layer (immediate-release portion) granules was placed in a circular punch, the previously prepared inner core tablet (sustained-release portion) was placed in the center of the outer core, and the outer layer (immediate-release portion) granules were filled in so that the outer layer (immediate-release portion) per dry-coated tablet was 640.0 mg, and then the dry-coated tablets were compressed using an Autotab-200TR device manufactured by Ichihoshiseiki Co., Ltd. The total weight of the compressed dry-coated tablets was 750.0 mg, and the hardness was 170-180 N.

[0138] [Table 10]

[0139] Test Example 4: Dissolution test of Examples 9 to 11 1.Dissolution test For each of the tablets produced in Examples 9 to 11, a dissolution test was carried out using the paddle method according to the Korean Pharmacopoeia, 10th Edition, under the following conditions (n=3). The results are shown in Table 11 below.

[0140] <Dissolution test method> Elution solution: purified water 900 mL / Rotation speed: 50 rpm / Temperature: 37°C Dissolution test solution sampling times: 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours Analysis method: HPLC analysis method Dissolution rate evaluation criteria: The concentration of ruxolitinib phosphate 52.8 mg / 900 mL purified water is adjusted to 100%.

[0141] [Table 11]

[0142] The test results confirmed that multiple release control (immediate / sustained release) is possible using the same polymer for dry-coated tablets, and that the drug release rate of the inner core (sustained release part) can be controlled depending on the molecular weight (viscosity) of the polymer.

Claims

1. (a) one or more immediate-release portions comprising ruxolitinib as an active ingredient and immediate-release excipients; and (b) one or more sustained-release portions comprising ruxolitinib as an active ingredient and a sustained-release agent; 1. An oral multiple controlled-release tablet comprising:

2. 2. The oral multiple controlled-release tablet according to claim 1, wherein the sustained-release agent is selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl acetate-polyvinylpyrrolidone, ammonio methacrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, methacrylic acid copolymer, amino methacrylate, sodium alginate, propylene glycol alginate, xanthan gum, locust bean gum, and mixtures thereof.

3. 2. The oral multiple controlled release tablet according to claim 1, wherein the sustained release agent is polyethylene oxide.

4. 4. The oral multiple controlled-release tablet according to claim 3, wherein the viscosity of the polyethylene oxide is 1,000 cP to 10,000 cP in a 1 to 5% (wt / wt) aqueous solution at 25°C.

5. 2. The oral multiple controlled-release tablet according to claim 1, wherein the content ratio of ruxolitinib in the immediate-release portion and the sustained-release portion is 0.5 to 9 parts by weight of ruxolitinib in the sustained-release portion per 1 part by weight of ruxolitinib in the immediate-release portion.

6. 2. The oral multiple controlled-release tablet according to claim 1, wherein the sustained-release portion further comprises a sustained-release auxiliary.

7. 7. The oral multiple controlled-release tablet according to claim 6, wherein the sustained-release aid is selected from the group consisting of polyethylene glycol, povidone, hydroxypropyl cellulose, sugar alcohols, glyceryl behenate, ethyl cellulose, ammonium methacrylate copolymer, shellac, hydroxypropylmethylcellulose phthalate (HPMC-P), waxes, gums, and combinations thereof.

8. The oral multiple controlled-release tablet according to any one of claims 1 to 7, which exhibits a dissolution pattern in which the active ingredient of the immediate-release portion is completely released within 3 hours after the start of drug dissolution in purified water, based on the uncoated tablet.

9. The coefficient of determination R was obtained by linear regression analysis of the dissolution time-dissolution rate curve from the time 1 hour after the start of drug dissolution in purified water to the time when the drug dissolution rate reached 90% or more, using the uncoated tablet as a reference. 2 The oral multiple controlled-release tablet according to any one of claims 1 to 7, which exhibits a dissolution pattern in which the β-amyloid ratio is 0.95 or more.

10. (1) preparing a mixture comprising ruxolitinib as an active ingredient and a fast-acting excipient; (2) producing a mixture containing ruxolitinib as an active ingredient and a sustained-release agent; and (3) compressing one or more mixtures obtained in step (1) and one or more mixtures obtained in step (2) into multiple controlled-release tablets; Including, Here, the method for producing oral multiple controlled-release tablets, wherein the mixtures do not mix with each other during tableting in step (3).

11. 11. The method for producing an oral multiple controlled-release tablet according to claim 10, wherein the sustained-release agent is selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl acetate-polyvinylpyrrolidone, ammonio methacrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, methacrylic acid copolymer, amino methacrylate, sodium alginate, propylene glycol alginate, xanthan gum, locust bean gum, and mixtures thereof.

12. 11. The method for producing oral multiple controlled release tablets according to claim 10, wherein the sustained-release agent is polyethylene oxide.

13. 13. The method for producing oral multiple controlled-release tablets according to claim 12, wherein the viscosity of the polyethylene oxide is 1,000 cP to 10,000 cP in a 1 to 5% (wt / wt) aqueous solution at 25°C.

14. 11. A method for producing an oral multiple controlled-release tablet according to claim 10, wherein a mixture containing ruxolitinib and a sustained-release agent forms a sustained-release core tablet, and a mixture containing ruxolitinib and a fast-acting excipient forms an outer layer surrounding the core tablet.

15. The method for producing oral multiple controlled-release tablets according to claim 10, wherein the mixture produced in step (2) further comprises a sustained-release auxiliary.

16. 16. The method for producing oral multiple controlled-release tablets according to claim 15, wherein the sustained-release auxiliary is selected from the group consisting of polyethylene glycol, povidone, hydroxypropyl cellulose, sugar alcohols, glyceryl behenate, ethyl cellulose, ammonium methacrylate copolymer, shellac, hydroxypropylmethylcellulose phthalate (HPMC-P), waxes, gums, and combinations thereof.

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