Tofacitinib-containing tablet and method for producing the same, and method for improving quality of tofacitinib-containing tablet

Abstract

To provide a tofacitinib-containing tablet with superior stability, which suppresses an increase of tofacitinib-related substances even when produced by a wet granulation process, and a method for producing the tofacitinib-containing tablet, as well as a method for improving the quality of a tofacitinib-containing tablet.SOLUTION: A tofacitinib-containing tablet comprises tofacitinib or a pharmaceutically acceptable salt thereof and a sugar alcohol, wherein the sugar alcohol is at least one selected from the group consisting of mannitol, erythritol, xylitol, sorbitol, maltitol, and isomalt.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a tofacitinib-containing tablet, a method for producing the same, and a method for improving the quality of a tofacitinib-containing tablet.

Background Art

[0002] Tofacitinib is a compound represented by the following structural formula (chemical name: 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile). Tofacitinib is an active ingredient of a Janus kinase (JAK) inhibitor and is used as a therapeutic agent for rheumatoid arthritis and ulcerative colitis.

Chemical formula

[0003] In Japan, "Xeljanz (registered trademark) tablets", which are tofacitinib citrate tablets, are on the market.

[0004] "Xeljanz (registered trademark) tablets" contain 8.078 mg of tofacitinib citrate (5 mg as tofacitinib) per tablet and, as additives, lactose hydrate, crystalline cellulose, hypromellose, croscarmellose sodium, magnesium stearate, titanium oxide, macrogol 4000, and a film-coated tablet containing triacetin (see Non-Patent Document 1). According to the review report of the European Medicines Agency, at least "Xeljanz (registered trademark) tablets" sold in Europe employ dry granulation as a manufacturing method. In addition, it has been confirmed that the tablets discolor under various storage conditions in the interview form of "Xeljanz (registered trademark) tablets" (see Non-Patent Document 2).

[0005] In the production of pharmaceutical tablets, granulation is widely performed. The granulation methods are roughly classified into a dry granulation method for producing granules without using a solvent and a wet granulation method for producing granules using a solvent.

[0006] The dry granulation method is a technique that compresses a powder containing an active pharmaceutical ingredient (API) and then crushes it to obtain API granules with a larger particle size than the API alone. Since there is no solvent in dry granulation, it has advantages such as being applicable to moisture-sensitive materials and heat-unstable APIs. However, it has drawbacks such as the generation of a large amount of fine powder and a decrease in tabletability due to the compression of the granulated material.

[0007] On the other hand, the wet granulation method is a technique that grows particles by mixing a solvent in which a binder is dissolved as needed with a powder containing an API, and then obtains API granules by drying. Although multiple steps are required and there are also demerits due to them, in many cases, fluidity, tabletability, content uniformity, dissolution properties, etc. can be obtained to be superior to those of the dry granulation method. The solvent for dissolving the binder can be either a polar or non-polar solvent. In recent years, from the viewpoints of explosion prevention, environmental protection, and residual solvents, it is desirable to use water as the solvent.

[0008] As another method for producing tablets, there is the direct compression method in which the API and excipients are simply mixed and compressed. However, a large amount of excipients may be required to ensure fluidity and tablet hardness, which may lead to an increase in the size of the tablets.

[0009] In the wet granulation method, since the binder is efficiently coated on the particle surface, the required amount of the binder is small, and relatively the same binding property can be obtained, so it can be applied in the same way from those with a low drug content to those with a high drug content. On the other hand, in the case of dry or direct compression, depending on the properties of the API, it may be difficult to keep it in a simple formulation, and it often happens that it is necessary to increase the amount of additives and high-content tablets cannot be obtained. Furthermore, since the physical properties of the powder such as the particle size of the content are directly related to tabletability, great care is required for the variation between lots.

[0010] As described above, when manufacturing pharmaceutical tablets, granulation may or may not be performed, and the granulation method may be selected. However, the wet granulation method, which can obtain API granules with excellent fluidity, tabletability, content uniformity, and dissolution, is the mainstream in Japan.

[0011] On the other hand, it has been reported that tofacitinib hydrolyzes (the amount of related substances increases) upon contact with water (see, for example, Non-Patent Document 3). Therefore, as a manufacturing method, a method that does not use water, such as dry granulation or direct tableting, is considered preferable instead of the wet granulation method that involves contact with water.

Prior Art Documents

Non-Patent Documents

[0012]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0013] As described above, tofacitinib is considered to be preferably produced by a method that does not use a solvent such as water, such as dry granulation or direct compression. However, even when produced by a wet granulation method, if the increase in related substances can be suppressed, API granules excellent in fluidity, tableting property, content uniformity, and dissolution property can be obtained, and a tofacitinib-containing tablet excellent in stability can be obtained. Therefore, there is a strong demand for the prompt provision of a tofacitinib-containing tablet excellent in stability that can suppress the increase in related substances of tofacitinib even when produced by a wet granulation method.

[0014] An object of the present invention is to solve the above-mentioned various problems and achieve the following objects. That is, the present invention aims to provide a tofacitinib-containing tablet excellent in stability that can suppress the increase in related substances of tofacitinib even when produced by a wet granulation method, a method for producing the same, and a method for improving the quality of a tofacitinib-containing tablet.

Means for Solving the Problems

[0015] As a result of intensive studies to solve the above problems, the present inventors unexpectedly found that by blending a specific sugar alcohol, even when produced by a wet granulation method, the increase in related substances of tofacitinib can be suppressed, and the change in the tablet color tone can also be suppressed.

[0016] The present invention is based on the above findings of the present inventors, and the means for solving the above problems are as follows. That is, <1> A tofacitinib-containing tablet comprising tofacitinib or a pharmaceutically acceptable salt thereof and a sugar alcohol, wherein the sugar alcohol is at least one selected from the group consisting of mannitol, erythritol, xylitol, sorbitol, maltitol, and isomalt. <2> The tofacitinib-containing tablet according to <1>, further comprising a binder. <3> The tofacitinib-containing tablets according to <2> above, which contain a wet granulated product containing the tofacitinib or a pharmaceutically acceptable salt thereof, the sugar alcohol, and the binder. <4> The tofacitinib-containing tablets according to any one of <2> to <3> above, wherein the binder is at least one selected from the group consisting of hydroxypropyl cellulose and hypromellose. <5> The tofacitinib-containing tablets according to any one of <1> to <4> above, which do not contain saccharides. <6> A wet granulation step of wet granulating a raw material for wet granulation containing tofacitinib or a pharmaceutically acceptable salt thereof and a sugar alcohol to obtain a wet granulated product, A tableting step of tableting a raw material for tableting containing the wet granulated product to obtain tablets, A method for producing a tofacitinib-containing tablet, characterized in that the sugar alcohol is at least one selected from the group consisting of mannitol, erythritol, xylitol, sorbitol, maltitol, and isomalt. <7> The method for producing a tofacitinib-containing tablet according to <6> above, wherein the raw material for wet granulation further contains a binder. <8> The method for producing a tofacitinib-containing tablet according to <7> above, wherein the binder is at least one selected from the group consisting of hydroxypropyl cellulose and hypromellose. <9> The method for producing a tofacitinib-containing tablet according to any one of <6> to <8> above, wherein the tofacitinib-containing tablet does not contain saccharides. <10> A method for improving the quality of a tofacitinib-containing tablet, including a wet granulation step of wet granulating a raw material for wet granulation containing tofacitinib or a pharmaceutically acceptable salt thereof and a sugar alcohol to obtain a wet granulated product, The sugar alcohol is at least one selected from the group consisting of mannitol, erythritol, xylitol, sorbitol, maltitol, and isomalt. <11> The method for improving the quality of a tofacitinib-containing tablet according to <10> above, wherein the raw material for wet granulation further contains a binder. <12> The method for improving the quality of the tofacitinib-containing tablets according to <11> above, wherein the binder is at least one selected from the group consisting of hydroxypropyl cellulose and hypromellose. <13> The method for improving the quality of the tofacitinib-containing tablets according to any one of <10> to <12> above, wherein the tofacitinib-containing tablets do not contain saccharides.

Advantages of the Invention

[0017] According to the present invention, the above-mentioned various problems in the prior art can be solved, the above-mentioned object can be achieved, and even when produced by the wet granulation method, an increase in related substances of tofacitinib can be suppressed, and a tofacitinib-containing tablet excellent in stability, a method for producing the same, and a method for improving the quality of the tofacitinib-containing tablet can be provided.

Embodiments for Carrying Out the Invention

[0018] (Tofacitinib-containing Tablets and Method for Producing the Same) The tofacitinib-containing tablets of the present invention contain at least tofacitinib or a pharmaceutically acceptable salt thereof and a sugar alcohol, and may further contain other components as necessary. The method for producing the tofacitinib-containing tablets of the present invention is not particularly limited and can be appropriately selected according to the purpose, but can be preferably produced by the method for producing the tofacitinib-containing tablets of the present invention. Hereinafter, the tofacitinib-containing tablets of the present invention will also be described in conjunction with the description of the method for producing the tofacitinib-containing tablets of the present invention.

[0019] The method for producing the tofacitinib-containing tablets of the present invention includes at least a wet granulation step and a tableting step, and may further include other steps as necessary.

[0020] <Wet Granulation Step> The wet granulation step is a step of wet granulating a raw material for wet granulation containing tofacitinib or a pharmaceutically acceptable salt thereof and a sugar alcohol to obtain a wet granulated product.

[0021] <<Raw materials for wet granulation>> The raw materials for wet granulation include at least tofacitinib or a pharmaceutically acceptable salt thereof and a sugar alcohol, and may include other components as required.

[0022] -Tofacitinib or a pharmaceutically acceptable salt thereof- The tofacitinib is a compound represented by the following structural formula (chemical name: 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile). [Chemical formula]

[0023] The pharmaceutically acceptable salts of the tofacitinib are not particularly limited and can be appropriately selected according to the purpose. For example, citrate, acid citrate, hydroiodide, hydrobromide, hydrochloride, sulfate, nitrate, bisulfate, phosphate, acetate, perphosphate, lactate, tartrate, acid tartrate, succinate, maleate, fumarate, malate, gluconate, oxalate, L-aspartate, ascorbate, mesylate, tosylate, sulfamate, cinnamate, saccharate, benzoate, ethanesulfonate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, pamoate, etc. can be mentioned. These can be used alone or in combination of two or more. Among the pharmaceutically acceptable salts of the tofacitinib, citrate is preferred.

[0024] The particle size distribution of the tofacitinib or a pharmaceutically acceptable salt thereof is not particularly limited and can be appropriately selected according to the purpose. For example, the 10% particle size (D10) can be 1 - 5 μm, the 50% particle size (D50) can be 5 - 20 μm, and the 90% particle size (D90) can be 20 - 30 μm. The particle size distribution refers to the volume-based particle size distribution measured by the laser diffraction method. In principle, particles of a certain volume are sieved in ascending order of size, and the particle diameter at the time when the particles corresponding to 10% of the volume are separated is defined as D10, the particle diameter at the time when the particles corresponding to 50% of the volume are separated is defined as D50, and the particle diameter at the time when the particles corresponding to 90% of the volume are separated is defined as D90.

[0025] For the tofacitinib or a pharmaceutically acceptable salt thereof, those produced by known methods may be used, or commercially available products may be used.

[0026] There is no particular limitation on the content of the tofacitinib or a pharmaceutically acceptable salt thereof in the raw material for wet granulation, and it can be appropriately selected according to the content in the tofacitinib-containing tablets and the like.

[0027] There is no particular limitation on the content of the tofacitinib or a pharmaceutically acceptable salt thereof in the tofacitinib-containing tablets, and it can be appropriately selected according to the purpose. For example, as tofacitinib, 0.1 to 10% by mass and the like can be mentioned.

[0028] -Sugar alcohol- The sugar alcohol is at least one selected from the group consisting of mannitol (hereinafter, may also be referred to as "D-mannitol"), erythritol, xylitol, sorbitol, maltitol, and isomalt. These may be used alone or in combination of two or more. Among these sugar alcohols, mannitol and erythritol are preferred, and mannitol alone is more preferred in terms of being able to more suppress the total amount of related substances.

[0029] For the sugar alcohol, those produced by known methods may be used, or commercially available products may be used.

[0030] The content of the sugar alcohol in the raw material for wet granulation is not particularly limited and can be appropriately selected according to the content in the tofacitinib-containing tablets and the like.

[0031] The content of the sugar alcohol in the tofacitinib-containing tablets is not particularly limited and can be appropriately selected according to the purpose. However, 10 to 80% by mass is preferable, 20 to 70% by mass is more preferable, and 30 to 60% by mass is particularly preferable. Being within the preferable range is advantageous in that an increase in related substances of tofacitinib and a change in the tablet color tone can be more suppressed.

[0032] When the mannitol and the erythritol are used in combination, the mass ratio of the two (mannitol:erythritol) is not particularly limited and can be appropriately selected according to the purpose. However, 90:10 to 40:60 is preferable, 80:20 to 40:60 is more preferable, 70:30 to 40:60 is particularly preferable, and 60:40 to 40:60 is most preferable. Being within the preferable range is advantageous in that an increase in related substances of tofacitinib and a change in the tablet color tone can be more suppressed, and the shape retention of the tablets is also excellent.

[0033] -Other components- The other components in the raw material for wet granulation are not particularly limited as long as the effects of the present invention are not impaired, and additives commonly used in the pharmaceutical field can be appropriately selected according to the purpose. The raw material for wet granulation preferably contains a binder as the other component. Examples of the other components other than the binder will be described in the item of other components in the tofacitinib-containing tablets described later.

[0034] --Binder-- The binder is not particularly limited, and additives commonly used in the pharmaceutical field can be appropriately selected. For example, hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, hypromellose phthalate, ethyl cellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol graft copolymer, etc. can be mentioned. These may be used alone or in combination of two or more. Among these binders, at least one selected from the group consisting of hydroxypropyl cellulose and hypromellose is preferable in that it can more effectively suppress the increase in related substances of tofacitinib and the change in tablet color tone.

[0035] The binder may be produced by a known method or a commercially available product may be used.

[0036] The content of the binder in the raw material for wet granulation is not particularly limited and can be appropriately selected according to the content in the tofacitinib-containing tablets, etc.

[0037] The content of the binder in the tofacitinib-containing tablets is not particularly limited and can be appropriately selected according to the purpose. However, 0.1 to 5% by mass is preferable, 1 to 4% by mass is more preferable, and 2 to 3% by mass is particularly preferable. Being within the preferable range is advantageous in that it can more effectively suppress the increase in related substances of tofacitinib and the change in tablet color tone.

[0038] <<Granulation>> In the production method of the present invention, the raw material for wet granulation is wet granulated to obtain a wet granulated product.

[0039] The method of the wet granulation is not particularly limited, and known wet granulation methods can be appropriately selected. For example, stirring granulation, fluidized bed granulation, rolling granulation, extrusion granulation, etc. can be mentioned. More specifically, for example, after mixing the raw materials for the wet granulation other than the granulation liquid, the granulation liquid can be added to the mixture for granulation.

[0040] The solvent used in the granulation liquid is not particularly limited as long as it can be used in the production of pharmaceuticals, and can be appropriately selected according to the purpose. For example, water, ethanol, propanol, isopropanol, dichloromethane, etc. can be mentioned. Among these, water is preferred from the viewpoints of explosion prevention, environmental protection, and residual solvents.

[0041] The granulation liquid can contain arbitrary components as necessary, but preferably contains the binder described above. The content of the binder in the granulation liquid is not particularly limited and can be appropriately selected according to the purpose.

[0042] The amount of the granulation liquid used is not particularly limited and can be appropriately selected according to the purpose.

[0043] The wet granulated product may be dried and sieved as necessary.

[0044] The tofacitinib-containing tablets preferably contain a wet granulated product containing the tofacitinib or a pharmaceutically acceptable salt thereof, the sugar alcohol, and the binder.

[0045] <Tablet pressing step> The tablet pressing step is a step of tablet pressing (hereinafter, also referred to as "compression molding") the tablet pressing raw material containing the wet granulated product to obtain tablets.

[0046] <<Tablet pressing raw material>> The tablet pressing raw material (hereinafter, also referred to as "tablet pressing powder") contains at least the wet granulated product and may contain other components as necessary.

[0047] -Wet granulated product- The wet granulated product is a granulated product obtained in the above-described wet granulation process.

[0048] The content of the wet granulated product in the raw material for tableting is not particularly limited, and can be appropriately selected according to the content in the tofacitinib-containing tablet of each component contained in the wet granulated product and the like.

[0049] -Other components- The other components in the raw material for tableting are not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected according to the purpose from additives usually used in the pharmaceutical field. Examples of the other components in the raw material for tableting will be described in the item of other components in the tofacitinib-containing tablet described later.

[0050] <<Tableting>> The method of tableting is not particularly limited, and a known tableting method can be appropriately selected, for example, a method using a desktop precision universal testing machine (Autograph), a method using a rotary tableting machine, and the like. The conditions for tableting are not particularly limited and can be appropriately selected according to the purpose.

[0051] <Other processes> The other processes in the method for producing the tofacitinib-containing tablet are not particularly limited as long as the effects of the present invention are not impaired, and known processes usually performed in the pharmaceutical field can be appropriately selected according to the purpose.

[0052] <Tofacitinib-containing tablet> The tofacitinib-containing tablet can be, for example, a plain tablet, a chewable tablet, a film-coated tablet, a sugar-coated tablet, or an orally disintegrating tablet.

[0053] The shape, structure, size, weight, hardness, etc. of the tofacitinib-containing tablet are not particularly limited and can be appropriately selected according to the purpose.

[0054] The tofacitinib-containing tablets of the present invention preferably do not contain saccharides. In the present specification, the saccharides refer to monosaccharides and disaccharides. Examples of the monosaccharides include glucose, fructose, and the like. Examples of the disaccharides include sucrose, lactose, maltose, and the like.

[0055] - Other components in the tofacitinib-containing tablets - Other components in the tofacitinib-containing tablets are not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected according to the purpose from additives commonly used in the pharmaceutical field. For example, excipients, disintegrants, fluidizing agents, solubilizing agents, lubricants, flavoring agents, fragrances, coating agents, plasticizers, coloring agents, gloss agents, and the like can be mentioned. These may be used alone or in combination of two or more. In addition, other components in the raw materials for wet granulation and other components in the raw materials for tableting can be appropriately selected according to the purpose from among other components in the tofacitinib-containing tablets.

[0056] - Excipients - The excipients are not particularly limited and can be appropriately selected according to the purpose. For example, crystalline cellulose, calcium hydrogen phosphate hydrate, anhydrous calcium hydrogen phosphate, corn starch, wheat starch, talc, purified gelatin, hydroxypropyl starch, polyvinylpyrrolidone, calcium silicate, and the like can be mentioned. These may be used alone or in combination of two or more.

[0057] The mass ratio of the sugar alcohol to the excipient (sugar alcohol: excipient) is not particularly limited and can be appropriately selected according to the purpose, but is preferably 20:80 to 65:35, and more preferably 30:70 to 50:50.

[0058] - Disintegrants - The disintegrant is not particularly limited and can be appropriately selected according to the purpose. For example, corn starch, pregelatinized starch, partial pregelatinized starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, sodium carboxymethyl starch, etc. can be mentioned. These may be used alone or in combination of two or more.

[0059] -Glidant- The glidant is not particularly limited and can be appropriately selected according to the purpose. For example, light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate, talc, etc. can be mentioned. These may be used alone or in combination of two or more.

[0060] -Solubilizer- The solubilizer is not particularly limited and can be appropriately selected according to the purpose. For example, sodium lauryl sulfate, sodium oleate, polyoxyl 40 stearate, polysorbate 80, etc. can be mentioned. These may be used alone or in combination of two or more.

[0061] -Lubricant- The lubricant is not particularly limited and can be appropriately selected according to the purpose. For example, stearic acid, calcium stearate, magnesium stearate, sodium stearyl fumarate, glycerin fatty acid ester, sucrose fatty acid ester, light anhydrous silicic acid, talc, etc. can be mentioned. These may be used alone or in combination of two or more.

[0062] -Flavoring agent- The flavoring agent is not particularly limited and can be appropriately selected according to the purpose. For example, sucralose, aspartame, acesulfame potassium, thaumatin, ascorbic acid, etc. can be mentioned. These may be used alone or in combination of two or more.

[0063] - Perfume The perfume is not particularly limited and can be appropriately selected according to the purpose. For example, l-menthol, vanillin, orange oil, yogurt micron, etc. can be mentioned. These may be used alone or in combination of two or more.

[0064] - Coating agent The coating agent is not particularly limited and can be appropriately selected according to the purpose. For example, hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, hypromellose phthalate, ethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl alcohol·acrylic acid·methyl methacrylate copolymer, polyvinyl alcohol·polyethylene glycol graft copolymer, etc. can be mentioned. These may be used alone or in combination of two or more.

[0065] - Plasticizer The plasticizer is not particularly limited and can be appropriately selected according to the purpose. For example, triethyl citrate, triacetin, propylene glycol, macrogol 6000, concentrated glycerin, etc. can be mentioned. These may be used alone or in combination of two or more.

[0066] - Colorant The colorant is not particularly limited and can be appropriately selected according to the purpose. For example, titanium oxide, yellow iron sesquioxide, iron sesquioxide, edible blue No. 1, etc. can be mentioned. These may be used alone or in combination of two or more.

[0067] - Glazing agent The glazing agent is not particularly limited and can be appropriately selected according to the purpose. For example, carnauba wax, beeswax, titanium oxide, magnesium stearate, etc. can be mentioned. These may be used alone or in combination of two or more.

[0068] For the other components in the tofacitinib-containing tablets, those produced by known methods may be used, or commercially available products may be used.

[0069] The content of the other components in the tofacitinib-containing tablets is not particularly limited and can be appropriately selected according to the purpose.

[0070] According to the production method of the present invention, even when produced by the wet granulation method, the increase in related substances of tofacitinib can be suppressed, and the tofacitinib-containing tablets of the present invention with excellent stability can be efficiently produced.

[0071] (Method for improving the quality of tofacitinib-containing tablets) The method for improving the quality of the tofacitinib-containing tablets of the present invention includes at least a wet granulation step, and further includes other steps as necessary.

[0072] (Wet granulation step) The wet granulation step is a step of wet granulating a raw material for wet granulation containing tofacitinib or a pharmaceutically acceptable salt thereof and a sugar alcohol to obtain a wet granulated product, which is the same as that described in the item of the <wet granulation step> of the production method of the tofacitinib-containing tablets of the present invention described above, and the preferred embodiments are also the same.

[0073] (Other steps) As other steps in the method for improving the quality of the tofacitinib-containing tablets, there is no particular limitation as long as the effects of the present invention are not impaired, and known steps usually performed in the pharmaceutical field can be appropriately selected according to the purpose. For example, a tableting step and the like can be mentioned. The tableting step can be carried out in the same manner as described in the item of the <tableting step> of the production method of the tofacitinib-containing tablets of the present invention described above.

[0074] The tofacitinib-containing tablets are the same as the tofacitinib-containing tablets of the present invention described above, and the preferred embodiments are also the same.

[0075] Examples of quality improvement in the quality improvement method include improvement of the stability of tofacitinib (suppression of increase in related substances) and suppression of discoloration of tofacitinib-containing tablets.

Examples

[0076] Hereinafter, the present invention will be described more specifically based on test examples, but the present invention is not limited to these test examples.

[0077] (Test Example 1) <Example 1> 80.9 mg of tofacitinib citrate (10% particle size (D10) = 2.5 μm, 50% particle size (D50) = 8.1 μm, 90% particle size (D90) = 29 μm), 1,226.0 mg of crystalline cellulose (UF-711, manufactured by Asahi Kasei), and 612.9 mg of D-mannitol (Mannitol P, manufactured by Mitsubishi Corporation Life Sciences) were combined and mixed using an agate mortar to obtain a mixed product. Then, 480 mg of purified water was added to the mixed product and granulated until uniform to obtain a granulated product. The granulated product was dried in a dryer set at 40°C for 3 hours to obtain a dried product. The dried product was sieved through a sieve with an aperture of 710 μm (22 mesh) to obtain a sieved product. To the sieved product (total amount), 59.7 mg of croscarmellose sodium (Ac-Di-Sol, manufactured by DuPont) and 20.0 mg of magnesium stearate (Magnesium stearate-S, manufactured by NOF Corporation) were added and mixed to obtain a tableting powder. The tableting powder was compression molded with a tableting pressure of 6.0 kN using a single-shot tableting machine (HANDTAB-200, manufactured by Ichihashi Seiki) to obtain tablets of 200 mg per tablet.

[0078] <Example 2> 80.8 mg of tofacitinib citrate (the same as that used in Example 1), 1,226.2 mg of crystalline cellulose (the same as that used in Example 1), and 612.8 mg of erythritol (Erythritol 100M, manufactured by Fujiproducts Food Science) were combined and mixed using an agate mortar to obtain a mixture. Then, 480 mg of purified water was added to the mixture and granulated until uniform to obtain granulated product. The granulated product was dried in a dryer set at 40 °C for 3 hours to obtain a dried product. The dried product was sieved through a sieve with an opening size of 710 μm (22 mesh) to obtain a sieved product. To the sieved product (total amount), 60.3 mg of croscarmellose sodium (the same as that used in Example 1) and 20.0 mg of magnesium stearate (the same as that used in Example 1) were added and mixed to obtain a tableting powder. The tableting powder was compression molded at a tableting pressure of 3.0 kN using a single-shot tableting machine (the same as that used in Example 1) to obtain tablets of 200 mg per tablet.

[0079] <Example 3> 80.7 mg of tofacitinib citrate (the same as that used in Example 1), 1,226.5 mg of crystalline cellulose (the same as that used in Example 1), 306.5 mg of D-mannitol (the same as that used in Example 1), and 306.3 mg of erythritol (the same as that used in Example 2) were combined and mixed using an agate mortar to obtain a mixture. Then, 480 mg of purified water was added to the mixture and granulated until uniform to obtain granulated product. The granulated product was dried in a dryer set at 40 °C for 3 hours to obtain a dried product. The dried product was sieved through a sieve with an opening size of 710 μm (22 mesh) to obtain a sieved product. To the sieved product (total amount), 60.0 mg of croscarmellose sodium (the same as that used in Example 1) and 19.7 mg of magnesium stearate (the same as that used in Example 1) were added and mixed to obtain a tableting powder. The tableting powder was compression molded at a tableting pressure of 3.1 kN using a single-shot tableting machine (the same as that used in Example 1) to obtain tablets of 200 mg per tablet.

[0080] <Comparative Example 1> 80.8 mg of tofacitinib citrate (the same as that used in Example 1), 1,226.3 mg of crystalline cellulose (the same as that used in Example 1), and 612.9 mg of lactose hydrate (lactose 200M, manufactured by DFE pharma) were combined and mixed using an agate mortar to obtain a mixture. Thereafter, 576 mg of purified water was added to the mixture and granulated until uniform to obtain granulated product. The granulated product was dried in a dryer set at 40°C for 3 hours to obtain a dried product. The dried product was sieved through a sieve with an opening size of 710 μm (22 mesh) for the entire amount to obtain a sieved product. To the sieved product (entire amount), 59.8 mg of croscarmellose sodium (the same as that used in Example 1) and 20.0 mg of magnesium stearate (the same as that used in Example 1) were added and mixed to obtain tableting powder. The tableting powder was compression molded with a tableting pressure of 6.0 kN using a single-shot tableting machine (the same as that used in Example 1) to obtain tablets of 200 mg per tablet.

[0081] <Comparative Example 2> 80.9 mg of tofacitinib citrate (the same as that used in Example 1), 1,226.1 mg of crystalline cellulose (the same as that used in Example 1), and 613.4 mg of lactose hydrate (the same as that used in Comparative Example 1) were combined and mixed using an agate mortar to obtain a mixture. The mixture was dried in a dryer set at 40°C for 3 hours to obtain a dried product. To the dried product (entire amount), 60.0 mg of croscarmellose sodium (the same as that used in Example 1) and 19.6 mg of magnesium stearate (the same as that used in Example 1) were added and mixed to obtain tableting powder. The tableting powder was compression molded with a tableting pressure of 6.0 kN using a single-shot tableting machine (the same as that used in Example 1) to obtain tablets of 200 mg per tablet.

[0082] <Comparative Example 3> Tofacitinib citrate (the same as that used in Example 1) 80.9 mg, crystalline cellulose (the same as that used in Example 1) 1,226.1 mg, D-mannitol (the same as that used in Example 1) 613.3 mg were mixed using an agate mortar to obtain a mixture. The mixture was dried in a dryer set at 40 °C for 3 hours to obtain a dried product. To the dried product (total amount), croscarmellose sodium (the same as that used in Example 1) 60.5 mg and magnesium stearate (the same as that used in Example 1) 20.2 mg were added and mixed to obtain a tableting powder. The tableting powder was compression molded at a tableting pressure of 3.5 kN using a single-shot tableting machine (the same as that used in Example 1) to obtain tablets of 200 mg per tablet.

[0083] <Comparative Example 4> Tofacitinib citrate (the same as that used in Example 1) 80.9 mg, crystalline cellulose (the same as that used in Example 1) 1,226.6 mg, erythritol (the same as that used in Example 2) 613.4 mg were mixed using an agate mortar to obtain a mixture. The mixture was dried in a dryer set at 40 °C for 3 hours to obtain a dried product. To the dried product (total amount), croscarmellose sodium (the same as that used in Example 1) 59.7 mg and magnesium stearate (the same as that used in Example 1) 20.0 mg were added and mixed to obtain a tableting powder. The tableting powder was compression molded at a tableting pressure of 3.6 kN using a single-shot tableting machine (the same as that used in Example 1) to obtain tablets of 200 mg per tablet.

[0084] <Comparative Example 5> Tofacitinib citrate (the same as that used in Example 1) 80.7 mg, crystalline cellulose (the same as that used in Example 1) 1,226.0 mg, D-mannitol (the same as that used in Example 1) 306.3 mg, erythritol (the same as that used in Example 2) 306.6 mg were mixed using an agate mortar to obtain a mixture. The mixture was dried in a dryer set at 40°C for 3 hours to obtain a dried product. To the dried product (total amount), 59.9 mg of croscarmellose sodium (the same as that used in Example 1) and 20.1 mg of magnesium stearate (the same as that used in Example 1) were added and mixed to obtain a tableting powder. The tableting powder was compression-molded at a tableting pressure of 3.5 kN using a single-punch tableting machine (the same as that used in Example 1) to obtain tablets of 200 mg per tablet.

[0085] The composition of each tablet manufactured in Test Example 1 is shown in Tables 1 to 2.

[0086]

Table 1

[0087]

Table 2

[0088] <Evaluation> The tablets manufactured in Test Example 1 were stored under open conditions at 60°C and a relative humidity of 75% for 2 weeks, and the total amount of related substances and color difference (color tone change) were evaluated as follows.

[0089] -Total amount of related substances- For the tablets immediately after manufacture (hereinafter sometimes referred to as "0W"), after 1 week of storage (hereinafter sometimes referred to as "1W"), or after 2 weeks of storage (hereinafter sometimes referred to as "2W"), the amounts of tofacitinib and its total related substances were measured by high-performance liquid chromatography. The amount (%) of the total related substances of tofacitinib was defined as the ratio of the total peak area of peaks other than tofacitinib to the peak area derived from tofacitinib citrate raw drug. The results are shown in Table 3.

[0090] --Measurement conditions for total related substances-- As a column for high performance liquid chromatography, a YMC Triart C18 column (4.6 mm × 250 mm, 5 μm) or its equivalent was used and maintained at 35°C. As mobile phase A, a 0.1% ammonium acetate solution (pH 4.0) was used, and as mobile phase B, acetonitrile was used. The sample solution used was a dilution with a 50% aqueous acetonitrile solution so that the concentration of tofacitinib citrate was 1 mg / mL. The flow rate was adjusted to 1 mL / min with the gradient program shown below, and related substances were measured with an ultraviolet absorption photometer (wavelength: 280 nm). · Gradient program (Solution A: Solution B) 0 min (95:5) → 5 min (95:5) → 40 min (50:50) → 40.1 min (95:5) → 45 min (95:5)

[0091] - Color difference - Using a spectrophotometer (CM-5, manufactured by Konica Minolta), the color difference (ΔE * ab) from immediately after manufacture (at the start of storage) was measured for tablets after 1 week of storage (hereinafter sometimes referred to as "1W") or after 2 weeks of storage (hereinafter sometimes referred to as "2W"). The results are shown in Table 3.

[0092]

Table 3

[0093] From Comparative Example 1 and Comparative Example 2, it was found that when saccharides were used and when manufactured by the wet granulation method, the total amount of related substances increased and the value of the color difference also increased compared to the manufacturing method without adding water. Therefore, it is considered that tofacitinib causes an increase in related substances and discoloration by wet granulation, and as a manufacturing method, a manufacturing method that does not come into contact with water during the granulation process, such as dry granulation or direct compression, is considered preferable rather than the wet granulation method that comes into contact with water during the granulation process. On the other hand, in Examples 1 to 3 produced by the wet granulation method using at least one of D-mannitol and erythritol, which are sugar alcohols, instead of saccharides, the total amount of related substances and the value of color difference showed lower values compared to Comparative Example 1. Therefore, it was found that by using at least one of D-mannitol and erythritol, which are sugar alcohols, it is possible to suppress the increase of related substances and discoloration even when produced by the wet granulation method. In addition, it was found that the discoloration suppression effect in the mixture of D-mannitol and erythritol is higher than that of the sugar alcohol alone.

[0094] (Test Example 2) <Example 4> 80.9 mg of tofacitinib citrate (the same as that used in Example 1), 1,186.0 mg of crystalline cellulose (the same as that used in Example 1), and 613.5 mg of D-mannitol (the same as that used in Example 1) were combined and mixed using an agate mortar to obtain a mixture. Then, 520 mg of a granulating solution prepared by dissolving 4.0 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) in 48.0 g of purified water was added to the mixture and granulated until uniform to obtain granulated products. The granulated products were dried in a dryer set at 40°C for 3 hours to obtain dried products. The dried products were sieved through a sieve with an aperture of 710 μm (22 mesh) to obtain sieved products. To the sieved products (total amount), 59.8 mg of croscarmellose sodium (the same as that used in Example 1) and 20.0 mg of magnesium stearate (the same as that used in Example 1) were added and mixed to obtain tableting powder. The tableting powder was compression molded at a tableting pressure of 5.3 kN using a single-shot tableting machine (the same as that used in Example 1) to obtain tablets of 200 mg per tablet.

[0095] <Example 5> 80.6 mg of tofacitinib citrate (the same as that used in Example 1), 1,186.0 mg of crystalline cellulose (the same as that used in Example 1), and 613.5 mg of D-mannitol (the same as that used in Example 1) were combined and mixed using an agate mortar to obtain a mixture. Then, 520 mg of a granulation solution prepared by dissolving 4.0 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.) in 48.0 g of purified water was added to the mixture and granulated until uniform to obtain granulated product. The granulated product was dried in a dryer set at 40 °C for 3 hours to obtain a dried product. The dried product was sieved through a sieve with an opening size of 710 μm (22 mesh) to obtain a sieved product. To the sieved product (total amount), 60.1 mg of croscarmellose sodium (the same as that used in Example 1) and 20.0 mg of magnesium stearate (the same as that used in Example 1) were added and mixed to obtain a tableting powder. The tableting powder was compression molded at a tableting pressure of 6.1 kN using a single-shot tableting machine (the same as that used in Example 1) to obtain tablets of 200 mg per tablet.

[0096] The composition in one tablet of each tablet manufactured in Test Example 2 is shown in Table 4.

[0097]

Table 4

[0098] <Evaluation> The tablets manufactured in Test Example 2 were stored at 60 °C, 75% relative humidity, and open conditions for 2 weeks, and evaluated for the total amount of related substances and color difference in the same manner as in Test Example 1. The results are shown in Table 5.

[0099]

Table 5

[0100] In Examples 4 and 5 using a binder, the total amount of related substances and color tone changes could be suppressed as compared with Example 1 of Test Example 1 without using a binder. Also, good results were obtained in Examples 4 and 5 as compared with the directly compressed product using lactose (Comparative Example 2 of Test Example 1). Therefore, it was clarified that when manufacturing by the wet granulation method, using a binder enables suppression of an increase in related substances and suppression of discoloration.

[0101] (Test Example 3) <Example 6> 12.10 g of tofacitinib citrate (the same as that used in Example 1), 174.91 g of crystalline cellulose (PH-101, manufactured by Asahi Kasei), and 92.01 g of D-mannitol (the same as that used in Example 1) were combined and mixed to obtain a mixed product. The above mixed product (total amount) was charged into a fluidized bed granulator (FD-MP-01D, manufactured by Powrex) and preheated at an intake air temperature of 70°C. When the exhaust temperature reached 40°C, the preheating was terminated, and 180.0 g of a granulation liquid prepared by dissolving 27.0 g of hydroxypropyl cellulose (the same as that used in Example 4) in 513.0 g of purified water was sprayed to perform granulation. After completion of spraying of the granulation liquid, drying was performed at an intake air temperature of 70°C until the exhaust temperature reached 40°C to obtain a granulated product. To 250.0 g of the granulated product, 7.80 g of croscarmellose sodium (the same as that used in Example 1) and 2.60 g of magnesium stearate (the same as that used in Example 1) were added and mixed to obtain a tableting powder. The above tableting powder was compression-molded with a tableting pressure of 4.8 kN using a rotary tableting machine (VIRGO, manufactured by Kikusui Seisakusho) to obtain tablets of 200 mg per tablet.

[0102] <Example 7> 12.10 g of tofacitinib citrate (the same as that used in Example 1), 92.01 g of crystalline cellulose (the same as that used in Example 6), and 174.91 g of D-mannitol (the same as that used in Example 1) were combined and mixed to obtain a mixed product. The above-mentioned mixture (total amount) was charged into a fluidized bed granulator (similar to that used in Example 6), and preheated at an intake air temperature of 70°C. When the exhaust temperature reached 40°C, the preheating was terminated, and 180.0 g of a granulation liquid obtained by dissolving 27.0 g of hydroxypropyl cellulose (similar to that used in Example 4) in 513.0 g of purified water was sprayed to perform granulation. After completion of the spraying of the granulation liquid, drying was carried out at an intake air temperature of 70°C until the exhaust temperature reached 40°C to obtain granulated products. To 249.9 g of the granulated products, 7.81 g of croscarmellose sodium (similar to that used in Example 1) and 2.63 g of magnesium stearate (similar to that used in Example 1) were added and mixed to obtain tableting powder. The above-mentioned tableting powder was compression-molded at a tableting pressure of 6.3 kN using a rotary tableting machine (similar to that used in Example 6) to obtain tablets of 200 mg per tablet.

[0103] The composition in one tablet of each tablet manufactured in Test Example 3 is shown in Table 6.

[0104]

Table 6

[0105] <Evaluation> The tablets manufactured in Test Example 3 were stored under open conditions at 60°C and a relative humidity of 75% for 2 weeks, and evaluated for the total amount of related substances and color difference in the same manner as in Test Example 1. The results are shown in Table 7.

[0106]

Table 7

[0107] In Examples 6 and 7 produced by fluidized bed granulation using a binder, the total amount of related substances and color tone changes could be suppressed as compared with Example 1 of Test Example 1 without using a binder. Therefore, it was clarified that even when produced by fluidized bed granulation using a binder, it is possible to suppress the increase of related substances and discoloration. Furthermore, from the results of Example 6 and Example 7, it was revealed that even when the blending ratio of the sugar alcohol and the excipient was changed, it was possible to suppress the increase in related substances and discoloration.

Claims

1. A tofacitinib-containing tablet comprising tofacitinib or a pharma- ceutically acceptable salt thereof and a sugar alcohol, A tofacitinib-containing tablet, characterized in that the sugar alcohol is at least one selected from the group consisting of mannitol, erythritol, xylitol, sorbitol, maltitol, and isomalt.

2. The tofacitinib-containing tablet of claim 1 further comprising a binder.

3. The tofacitinib-containing tablet according to claim 2, comprising a wet granulation comprising the tofacitinib or a pharma- ceutically acceptable salt thereof, the sugar alcohol, and the binder.

4. The tofacitinib-containing tablet according to any one of claims 2 to 3, wherein the binder is at least one selected from the group consisting of hydroxypropyl cellulose and hypromellose.

5. The tofacitinib-containing tablet according to any one of claims 1 to 2, which does not contain sugar.

6. A wet granulation step of wet granulating a raw material for wet granulation, the raw material including tofacitinib or a pharma- ceutically acceptable salt thereof and a sugar alcohol, to obtain a wet granulated product; and a tableting step of tableting the tableting raw material containing the wet granulation to obtain tablets. A method for producing a tofacitinib-containing tablet, characterized in that the sugar alcohol is at least one selected from the group consisting of mannitol, erythritol, xylitol, sorbitol, maltitol, and isomalt.

7. The method for producing a tofacitinib-containing tablet according to claim 6, wherein the wet granulation raw material further comprises a binder.

8. The method for producing a tofacitinib-containing tablet according to claim 7, wherein the binder is at least one selected from the group consisting of hydroxypropyl cellulose and hypromellose.

9. The method for producing a tofacitinib-containing tablet according to any one of claims 6 to 7, wherein the tofacitinib-containing tablet does not contain sugar.

10. The method includes a wet granulation step of wet granulating a raw material for wet granulation, the raw material including tofacitinib or a pharma- ceutically acceptable salt thereof and a sugar alcohol, to obtain a wet granulated product, A method for improving the quality of a tofacitinib-containing tablet, characterized in that the sugar alcohol is at least one selected from the group consisting of mannitol, erythritol, xylitol, sorbitol, maltitol, and isomalt.

11. The method for improving the quality of a tofacitinib-containing tablet according to claim 10, wherein the wet granulation raw material further contains a binder.

12. The method for improving the quality of a tofacitinib-containing tablet according to claim 11, wherein the binder is at least one selected from the group consisting of hydroxypropyl cellulose and hypromellose.

13. A method for improving the quality of a tofacitinib-containing tablet according to any one of claims 10 to 11, wherein the tofacitinib-containing tablet does not contain sugar.

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