Tofacitinib-containing tablets

Abstract

The present invention provides tofacitinib-containing tablets having excellent stability and dissolution properties, and a method for producing said tablets. [Solution] A tofacitinib-containing tablet comprising tofacitinib, an excipient, a disintegrant, and a lubricant, wherein the water content of the tablet is 2.5% or less.

Description

Technical Field

[0001] The present invention relates to tablets containing tofacitinib as an active ingredient and a method for producing the same.

Background Art

[0002] Tofacitinib citrate (chemical name: 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile monocitrate) has Janus kinase inhibitory activity and is commercially available under the name "Xeljanz (registered trademark) tablets 5 mg" as an oral drug for rheumatoid arthritis and ulcerative colitis (hereinafter also referred to as "pre-approved preparation"). The pre-approved preparation is a film-coated tablet obtained by coating a core tablet composed of tofacitinib citrate, lactose hydrate, crystalline cellulose, hypromellose, croscarmellose sodium and magnesium stearate with a coating agent composed of hypromellose, lactose hydrate, titanium oxide, macrogol 4000 and triacetin (Non-Patent Document 1).

[0003]

Chemical formula

[0004] Tablets containing tofacitinib citrate include, for example, tablets made by mixing and compressing tofacitinib citrate, crystalline cellulose, lactose, croscarmellose sodium, colloidal silica, and magnesium stearate, and then film-coating them, in order to improve solubility and disintegration (Patent Document 1); tablets made by mixing and compressing tofacitinib citrate, microcrystalline cellulose and lactose granules, croscarmellose sodium, and silicon dioxide, and then film-coating them (Patent Document 2); tablets made by mixing and compressing tofacitinib citrate, lactose, crystalline cellulose, croscarmellose sodium, and magnesium stearate, and then film-coating them (Patent Document 3); and tablets made by mixing and compressing tofacitinib citrate, crystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate. Furthermore, the following have been disclosed: a film-coated tablet (Patent Document 4), a tablet made by stirring 8% by mass of tofacitinib citrate, 48.5% by mass of mannitol, 31% by mass of lactose, 2.5% by mass of hydroxymethylcellulose, 3.5% by mass of croscarmellose sodium, 4.5% by mass of povidone, and 2% by mass of magnesium stearate to form intermediate particles, compressing them, and then film-coating the tablet; a tablet made by wet-granulating tofacitinib citrate, microcrystalline cellulose, pregelatinized starch, and povidone, drying them to reduce the moisture content to 5% or less, then mixing and compressing them with hydroxymethylcellulose, hypromellose, and magnesium stearate, and then film-coating the tablet (Patent Document 5); and a tofacitinib film-coated tablet (Patent Document 6) in which the film does not contain polyethylene glycol and suppresses yellowing of the tablet. However, there have been no previous reports on the relationship between the water content in tablets containing tofacitinib and tofacitinib-related substances. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2023 / 086066 [Patent Document 2] China Public Gazette No. 106176640 [Patent Document 3] China Public Gazette No. 105878202 [Patent Document 4] China Public Gazette No. 110946834 [Patent Document 5] China Public Gazette No. 111358795 [Patent Document 6] Japanese Patent Publication No. 2025-18780 [Non-patent literature]

[0006] [Non-Patent Document 1] Xeljanz® Tablets 5mg Interview Form, Revised September 2024 (19th Edition) [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] The present invention relates to providing tofacitinib-containing tablets having excellent stability and dissolution properties, and a method for producing the same. [Means for solving the problem]

[0008] As a result of investigations to solve the above problems, the present inventors found that in tablets containing tofacitinib, the generation of tofacitinib-related substances is related to the amount of water in the formulation, and that by setting the amount of water in the tablet to 2.5% by mass or less, the generation of related substances can be effectively suppressed, and a tablet with excellent stability can be provided.

[0009] In other words, the present invention relates to the following: 1) A tofacitinib-containing tablet comprising tofacitinib, an excipient, a disintegrant, and a lubricant, wherein the water content of the tablet is 2.5% or less. 2) The tablet according to 1), wherein the total relative abundance ratio of tofacitinib, calculated by 100 × (total related substances / tofacitinib) after storage at 50°C under open conditions for one month, is 0.5% or less, and the total related substances are a group of substances that appear in a high-performance liquid chromatography chart with a relative retention time of 0.5 to 1.5, when the relative retention time of the peak shown by tofacitinib is set to 1. 3) The tablet described in 1), further comprising a silicate compound. 4) The tablet according to 1) or 2), wherein the excipient is one or more selected from anhydrous lactose, lactose monohydrate, D-mannitol, or crystalline cellulose. 5) The tablet according to 1) or 2), wherein the amount of excipients is 60 to 95% by mass of the entire tablet. 6) The tablet according to 1) or 2), wherein the disintegrant is one or more selected from croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, or sodium starch glycolate. 7) A tablet according to 1) or 2), wherein the amount of disintegrant is 0.1 to 10% by mass relative to the total weight of the tablet. 8) A tablet according to 1) or 2), wherein the lubricant is one or more selected from magnesium stearate, calcium stearate, and sodium stearyl fumarate. 9) A tablet according to 1) or 2), wherein the amount of lubricant is 0.1 to 10% by mass relative to the total weight of the tablet. 10) A tablet according to 1) or 2), wherein tofacitinib is tofacitinib citrate. 11) A tablet according to 1) or 2), wherein the tofacitinib content is 5 mg per tablet. 12) The tablet described in 3), wherein the amount of silicate compound is 0.1 to 10% by mass relative to the total weight of the tablet. 13) A tablet as described in 1) or 2), having a moisture content of 2% or less. 14) A film-coated tablet as described in 1) or 2). 15) A method for producing tofacitinib-containing tablets, comprising the steps of obtaining granules by dry granulation of tofacitinib, an excipient, a disintegrant, and a lubricant, and a drying step. 16) Further, a step of mixing an excipient, a disintegrant, and a lubricant with the granulated product and tableting to obtain a core tablet, and a step of spraying and drying a film base solution onto the core tablet to obtain a film-coated tablet are included, the method according to 15). 17) The method according to 15) or 16), wherein a silicate compound is added in the granulation step. 18) The tofacitinib-containing tablet according to 1) or 2) is contained in a PTP package composed of a plastic sheet and an aluminum sheet including at least one layer selected from a polychlorotrifluoroethylene layer, a polyvinylidene chloride layer, and a polychlorotetrafluoroethylene layer, and further the PTP package is contained in an aluminum pillow package formed of a film having an aluminum layer. 19) A method for improving the storage stability of a tofacitinib-containing tablet by setting the moisture content in the tablet to 2.5% or less.

Effects of the Invention

[0010] The tofacitinib-containing tablet of the present invention effectively suppresses the generation of analogs of tofacitinib and has excellent stability and dissolution properties.

Brief Description of the Drawings

[0011] [Figure 1] A diagram showing the dissolution behavior of Example 1 and Comparative Example 2.

Modes for Carrying Out the Invention

[0012] In the present invention, "tofacitinib" refers to free tofacitinib or a salt of tofacitinib. Examples of salts of tofacitinib include pharmaceutically acceptable salts of tofacitinib, preferably acid-added salts, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, bisulfate, succinate, maleate, fumarate, malic acid, gluconate, saccharinate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate. In the present invention, tofacitinib is preferably tofacitinib citrate.

[0013] The tofacitinib used in the present invention is not particularly limited, but for example, tofacitinib produced by known methods such as those described in International Publication No. 2001 / 042246 or International Publication No. 2002 / 096909 can be used. In addition, tofacitinib citrate produced by methods such as those described in International Publication No. 2003 / 048162 can be used. From the viewpoint of dissolution, a smaller particle size is preferable for tofacitinib, while a relatively larger particle size is preferable from the viewpoint of content uniformity and ease of manufacture. For example, for an average particle size d50, particles with a size of 0.1 to 20 μm, preferably 2 to 12 μm, and for an average particle size d90, particles with a size of 0.2 to 30 μm, preferably 5 to 20 μm, can be used. The particle size measurement method is based on the volume-based particle size distribution of the "Particle Size Measurement Method by Laser Diffraction and Scattering" or the "Particle Size Measurement Method in Liquid by Dynamic Light Scattering" in the Japanese Pharmacopoeia. As for the particle shape, needle-shaped, rod-shaped, or cubic (by crushing these) particles can be used. From the viewpoint of tableting properties, adhesion, and dissolution properties, it is preferable to use cubic particles obtained by crushing needle-shaped or rod-shaped particles.

[0014] Multiple crystalline forms have been reported for tofacitinib citrate, and the type A crystal is used in approved formulations. The type A crystal described in International Publication 2003 / 048162 can be used. This type A crystal has characteristic peaks represented by an angle of 2θ at 5.7±0.2, 16.1±0.2, 20.2±0.2, and 20.5±0.2 in its X-ray powder diffraction pattern.

[0015] The amount of tofacitinib contained in the tofacitinib tablets of the present invention is 5 mg as free tofacitinib. For example, in the case of tofacitinib citrate, one tablet contains 8.078 mg. The tofacitinib content in the tablets of the present invention is 2 to 10% by mass, preferably 3 to 8% by mass, and more preferably 3 to 5% by mass, based on the total weight of the tablet.

[0016] The tofacitinib-containing tablets of the present invention contain, in addition to tofacitinib, excipients, disintegrants, and lubricants. Examples of excipients include anhydrous lactose, lactose monohydrate, sucrose, D-mannitol, D-sorbitol, xylitol, inositol, maltose, isomaltose monohydrate, starch, pregelatinized starch, dextrin, crystalline cellulose, acacia gum, pullulan, anhydrous calcium hydrogen phosphate, and calcium hydrogen phosphate. One or more of these excipients may be used. Preferably, from the viewpoint of water content, anhydrous lactose, lactose monohydrate, D-mannitol, or xylitol is used, and from the viewpoint of moldability, crystalline cellulose is used, and more preferably, anhydrous lactose or lactose monohydrate and crystalline cellulose are used. Furthermore, to improve the moldability of the tablets, these excipients may include granules or amorphous materials. Of these excipients, those with a drying loss exceeding 2.5% by mass can be dried or otherwise modified to reduce the drying loss to 2.5% by mass or less, preferably 2% by mass. Examples of such excipients with a drying loss exceeding 2.5% by mass include sucrose, D-sorbitol, maltose, isomalt hydrate, starch, pregelatinized starch, dextrin, crystalline cellulose, gum arabic, pullulan, and calcium hydrogen phosphate. The drying loss is measured using an infrared moisture meter as described later or according to the drying loss method of the Japanese Pharmacopoeia.

[0017] The amount of excipients is 60 to 95% by mass of the total tablet, preferably 65 to 92% by mass, and more preferably 70 to 90% by mass. When anhydrous lactose, lactose monohydrate, or crystalline cellulose is added, the amounts are 15 to 50% by mass of lactose and 22 to 80% by mass of crystalline cellulose, preferably 17 to 42% by mass of lactose and 25 to 75% by mass of crystalline cellulose, relative to the total tablet. Furthermore, the excipient is preferably used in a ratio of 16 to 27 parts by mass, more preferably 18 to 25 parts by mass, and even more preferably 20 to 23 parts by mass, per 1 part by mass of tofacitinib. When the excipient is lactose and crystalline cellulose, it is preferably used in a ratio of 3 to 12 parts by mass of lactose and 10 to 20 parts by mass of crystalline cellulose per 1 part by mass of tofacitinib, more preferably 4 to 10 parts by mass of lactose and 12 to 18 parts by mass of crystalline cellulose.

[0018] Examples of disintegrants include croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium starch glycolate, crospovidone, carboxymethylcellulose, calcium carboxymethylcellulose, and sodium carboxymethyl starch. One or more of these disintegrants can be included. Croscarmellose sodium, low-substituted hydroxypropylcellulose, and sodium starch glycolate are preferred, and croscarmellose sodium is more preferred.

[0019] The amount of disintegrant added is 0.1 to 10% by mass of the total tablet weight, preferably 1 to 8% by mass, and more preferably 1.5 to 5% by mass. Furthermore, the disintegrant is preferably used in a ratio of 0.4 to 2 parts by mass per 1 part by mass of tofacitinib, more preferably 0.5 to 1.5 parts by mass, and even more preferably 0.6 to 1.3 parts by mass.

[0020] Examples of lubricants include magnesium stearate, calcium stearate, sucrose fatty acid esters, and sodium stearyl fumarate. One or more of these lubricants can be included in the mixture. Preferably, magnesium stearate and sodium stearyl fumarate are used, and more preferably, magnesium stearate. Furthermore, the lubricant is preferably used in a ratio of 0.05 to 1 part by mass per 1 part by mass of tofacitinib, more preferably 0.1 to 0.8 parts by mass, and even more preferably 0.2 to 0.6 parts by mass.

[0021] The amount of lubricant added is 0.1 to 10% by mass of the total tablet weight, preferably 0.5 to 8% by mass, and more preferably 1 to 5% by mass.

[0022] In the tofacitinib-containing tablets of the present invention, it is preferable to add a silicate compound to suppress the adhesion of tofacitinib to the equipment during tablet manufacturing and to improve content uniformity and content. The silicate compound is silicic acid or a salt thereof, and examples include light anhydrous silicic acid, hydrated silicon dioxide, magnesium aluminometasilicate, magnesium aluminometasilicate, calcium silicate, synthetic aluminum silicate, magnesium aluminum silicate, or talc. One or more of these silicate compounds can be blended. Preferably, it is light anhydrous silicic acid, hydrated silicon dioxide, magnesium aluminometasilicate, or talc, and more preferably light anhydrous silicic acid.

[0023] The amount of silicate compound included is 0.1 to 10% by mass of the total tablet weight, preferably 0.5 to 8% by mass, and more preferably 1 to 6% by mass. Furthermore, the silicate compound is preferably used in a ratio of 0.1 to 2.5 parts by mass, more preferably 0.4 to 2 parts by mass, and even more preferably 0.5 to 1.5 parts by mass, per 1 part by mass of tofacitinib.

[0024] The tofacitinib-containing tablets of the present invention have a water content of 2.5% by mass or less relative to the total weight of the tablet, which may be, for example, 0.1-2.2% by mass, 0.2-2.0% by mass, or 0.4-1.8% by mass. The water content here refers to adhering water or attached water, not structural water such as crystal water. In this invention, the moisture content is measured using an infrared moisture meter (for example, the FD-660 infrared moisture meter manufactured by Kett Scientific Co., Ltd.), and the specific measurement conditions are shown in the examples below. Any method for obtaining the same measurement results may be used, such as the method for measuring loss on drying specified in the Japanese Pharmacopoeia.

[0025] The moisture content is adjusted by drying the tablets at one of the stages of manufacturing so that the moisture content in the tablets after manufacturing is 2.5% by mass or less. Examples include (1) drying before mixing excipients, disintegrants, etc., (2) drying after preparing the mixed powder, (3) drying after granulation, (4) drying after tableting, (5) drying before film coating, and (6) drying after film coating. However, from the viewpoint of effectively suppressing related substances, it is preferable to dry the added components in advance. The drying process may be carried out using equipment used in pharmaceutical manufacturing, such as a shelf dryer, rotary vacuum dryer, fluidized bed granulator, or tablet film coating apparatus, or it may be carried out by sealing with a desiccant.

[0026] As shown in the examples described later, stability can be improved by reducing the water content in the tablets to 2.5% by mass or less, that is, the relative abundance of tofacitinib's total related substances (100 × (total related substances / tofacitinib)) can be suppressed to 0.5% or less. Stability can be measured under accelerated conditions. For example, to observe the effect of temperature, storage can be performed at 50°C for one month under open conditions, or to observe the effect of humidity, storage can be performed at 40°C for one month at 75% RH. Under these conditions, the relative abundance of total related substances (100 × (total related substances / tofacitinib)) can be reduced to 0.5% or less. Fluidizers and antistatic agents such as light anhydrous silicic acid, and lubricants such as magnesium stearate, are components that increase the production of tofacitinib-related substances. However, by keeping the water content in the tablet below 2.5% by mass, it becomes possible to incorporate these components. This allows for the suppression of low tofacitinib citrate content, content uniformity, suppression of tableting problems such as capping and binding during tableting, and favorable settings for tablet hardness, abrasion resistance, disintegration time, and dissolution.

[0027] Related substances include degradation products and by-products of tofacitinib, or degradation products and products derived from the raw materials, intermediates, and by-products of tofacitinib. These include known related substances and unknown related substances with unknown structures, and the total number of related substances is the sum of these. The total number of related substances corresponds to the group of substances that appear in the region of 0.5 to 1.5 relative retention times (relative retention time when the relative retention time of the peak shown by tofacitinib is set to 1) in the high-performance liquid chromatography (HPLC) chart obtained under the following measurement conditions, excluding those detected in tofacitinib and blank solutions. In particular, it suppresses the increase of related substances with relative retention times of 0.79, 0.80, 0.81, 0.88, 0.89, 1.21, and 1.22. The total amount of related substances can be expressed, for example, in an HPLC chart, as the total peak area of ​​the peaks excluding tofacitinib, where the relative retention time of the peak shown by tofacitinib is set to 1, and the relative retention time of the peaks excluding tofacitinib is between 0.5 and 1.5. <Measurement conditions> • Detector: Ultraviolet absorbance meter (measurement wavelength: 289 nm) • Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm is packed with 3 μm C18 octylsilylated silica gel for liquid chromatography. • Column temperature: A constant temperature of around 40°C Mobile phase A: 25mM ammonium acetate buffer:acetonitrile = 95:5 Mobile phase B: 25mM ammonium acetate buffer:acetonitrile = 5:95 Mobile phase delivery: 100% of mobile phase A from 0 to 15 minutes, 100% of mobile phase A to 40% of mobile phase A and 60% of mobile phase B from 15 to 45 minutes, and 40% of mobile phase A and 60% of mobile phase B from 45 to 50 minutes. • Flow rate: 1.0 mL per minute • Area measurement range: Approximately 50 minutes

[0028] In one embodiment, the tofacitinib-containing tablets of the present invention have a total relative abundance ratio (%) of the above-mentioned total relative substances, calculated as 100 × (total relative substances / tofacitinib) after storage for one month at 50°C under open conditions (severe test), of 0.5% or less, preferably 0.3% or less, and more preferably 0.2% or less. The relative abundance of such total related substances is far lower than that of previously approved formulations measured under the same conditions, indicating that the tofacitinib-containing tablets of the present invention have higher storage stability.

[0029] Furthermore, the dissolution properties of the tofacitinib-containing tablets of the present invention are similar to or equivalent to those of previously approved formulations and are sufficiently superior. Specifically, in the dissolution test of the Japanese Pharmacopoeia, the dissolution properties were 86±15% in 30 minutes for the first test solution and 85±15% in 30 minutes for the second test solution.

[0030] The tofacitinib-containing tablets of the present invention may contain other pharmaceutical additives besides those mentioned above, such as binders, colorants, light-shielding agents, stabilizers, and sweeteners. These additives are added to adjust other tablet properties while maintaining the desired physical properties of the tablets of the present invention.

[0031] Examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, pullulan, gelatin, acacia gum, crystalline cellulose, sucrose, pregelatinized starch, sucrose, D-mannitol, trehalose, and dextrin. Polyvinylpyrrolidone and hydroxypropylcellulose are preferred.

[0032] The stabilizer is not particularly limited as long as it can avoid affecting the dissolution behavior. Examples include dibutylhydroxytoluene, propyl gallate, butylhydroxyanisole, ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, sodium bisulfite, sodium pyrosulfite, citric acid, and sodium edetate. Other embodiments include dibutylhydroxytoluene, propyl gallate, and sodium ascorbate, and a further embodiment is dibutylhydroxytoluene. These antioxidants are expected to suppress oxidation of tofacitinib and discoloration of the tablets due to oxidizing components such as oxygen.

[0033] Examples of coloring agents include Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Red No. 2, Food Red No. 3, Food Blue No. 1 aluminum lake, Food Blue No. 2 aluminum lake, Food Red No. 2 aluminum lake, iron(III) oxide (red), titanium dioxide, yellow iron(III) oxide, caramel, and talc. These coloring agents are expected to suppress the degradation of tofacitinib by light and the discoloration of the tablets.

[0034] Examples of light-shielding agents include iron oxides such as yellow iron(III) oxide, iron(III) oxide, and black iron(III) oxide, titanium dioxide, calcium carbonate, zinc oxide, talc, Yellow No. 5, and Red No. 102, with titanium dioxide and calcium carbonate being preferred. These light-shielding agents are expected to suppress the decomposition of tofacitinib and discoloration of the tablets due to light.

[0035] Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia.

[0036] The tofacitinib-containing tablets may be film-coated to prevent contact with other drugs, prevent drug dispersion, suppress the increase of related substances, or color the tablets. The film coating can typically be applied using film coating agents and their additives commonly used in pharmaceutical formulations. For example, film coating agents, plasticizers, lubricants, colorants, and light-shielding agents may be included. Here, the film coating agent is not particularly limited, but examples include cellulose-based film coating agents such as hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, carboxymethylcellulose, lumellose, carmellose sodium, and carmellose calcium, as well as acacia powder, gelatin pullulan, dextrin, carboxymethyl starch sodium, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. Cellulose-based film coating agents are preferred, and hypromellose is more preferred.

[0037] The plasticizer is not particularly limited, but examples include polyethylene glycol (e.g., polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, etc.), triethyl citrate, glycerin, castor oil, propylene glycol hydrogenated castor oil, polysorbate 80, macrogol, lauromacrogol, triacetin, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and triacetin is preferred.

[0038] The lubricant for film coating is not particularly limited, but examples include talc, hydrated silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, and magnesium stearate, with talc being preferred.

[0039] Examples of dyes for film coating include those listed above as colorants, with titanium dioxide being preferred.

[0040] Examples of solvents for dissolving / suspending film coating agents include alcohols such as methanol, ethanol, and isopropyl alcohol, acetone, toluene, hexane, methyl ethyl ketone, and water, or mixtures thereof. Ethanol and water are preferred, and water is more preferred.

[0041] In the film-coated tablets, there are no clear limitations on the amount of film coating, but for example, it is preferable that a 200 mg / tablet uncoated tablet is coated with a film coating in the range of 2 to 10 mg / tablet, and more preferably in the range of 3 to 7 mg / tablet.

[0042] The tofacitinib-containing tablets of the present invention have a hardness of 20 to 120 N, preferably 30 to 100 N, and a disintegration time of 30 to 180 seconds, preferably 40 to 150 seconds.

[0043] The tofacitinib-containing tablets of the present invention can be manufactured by either a method of compressing tablets after mixing all components (direct compression method), or a method of dry or wet granulation followed by the addition of additives as necessary before compression (dry granulation method, wet granulation method). Granulation is preferred from the viewpoint of moldability and uniformity of content. In the direct compression method, the uncoated tablet is a tablet in which the active ingredient and pharmaceutical excipients are uniformly mixed. In the granulation method, the tablet is a tablet in which granulated particles, which are uniformly mixed with the active ingredient and pharmaceutical excipients, are uniformly mixed with the pharmaceutical excipients.

[0044] Tablets produced by direct compression can be manufactured by appropriately selecting and mixing tofacitinib, excipients, disintegrants, and lubricants, as well as silicate compounds and other pharmaceutical additives as needed, and then compressing the mixture. Mixing can be carried out by commonly used mixing methods, such as mixing, kneading, and granulation. Mixing can be performed using, for example, a high-speed agitator, a universal kneader, a fluidized bed granulator, a V-type mixer, a tumbler mixer, a double-cone mixer, a ribbon mixer, a swirling screw mixer, or manual mixing in bags.

[0045] Compression molding can be performed using rotary tablet presses or the like commonly used in pharmaceuticals. The molding pressure during tableting varies depending on the size of the tablet, but for example, for a φ8mm tablet, it is 2 to 15kN, preferably 3 to 12kN. Furthermore, when using an external lubrication method during compression molding, a tablet can be obtained by mixing tofacitinib, excipients and disintegrants, and, if necessary, silicate compounds and other pharmaceutical additives, and then applying a lubricant during compression molding.

[0046] Tablet granulation can be carried out using either a solvent-based granulation and drying method, known as wet granulation, or a compaction followed by crushing and disintegration method, known as dry granulation. Since the use of solvents tends to affect the formation of tofacitinib-related substances, dry granulation is preferred.

[0047] In the dry granulation method, tofacitinib, excipients, disintegrants, and lubricants, as well as silicate compounds, binders, and other pharmaceutical additives as needed, are added, compacted, and then crushed and granulated to obtain tofacitinib granules. Dry granulation is a method of granulation in which the compounding components are compacted, then crushed and broken down, without intentionally adding any external solutions such as water. Compaction methods include roll compression using a roller compactor and slug compression using a conventional tablet press. Roll compression is preferred from the standpoint of manufacturing efficiency. The conditions for the roller compactor, such as roll pressure, roll rotation speed, and powder supply screw rotation speed, vary depending on the size and type of equipment. For example, for Freund Industrial Co.'s TF-mini or TF-208, a roll pressure of 2 to 20 MPa, a roll rotation speed of 2 to 30 rpm, and a powder supply screw rotation speed of 5 to 80 rpm are preferred. The flakes obtained by the roller compactor may be crushed and sized to a predetermined particle size using a crusher or pulverizer such as an oscillator, co-mill, quick mill, or power mill.

[0048] Wet granulation is a method of obtaining granules by wet granulation of tofacitinib, excipients, and optionally disintegrants and binders. Wet granulation is a method commonly used in the pharmaceutical field and includes, for example, fluidized bed granulation, agitation granulation, toppling granulation, and kneading granulation, with fluidized bed granulation being preferred as it minimizes contact time with water.

[0049] The obtained tofacitinib granules are mixed with pharmaceutical additives such as lubricants and excipients, and then compressed to obtain uncoated tablets. The compression molding conditions are the same as those for the direct compression method described above. Furthermore, the obtained tofacitinib granules can be mixed with pharmaceutical additives such as excipients, and an external lubrication method can be performed in which a lubricant is applied to the die during compression molding.

[0050] The tofacitinib-containing tablets of the present invention are preferably film-coated tablets obtained by film-coating the uncoated tablets manufactured as described above in accordance with common methods in the pharmaceutical field.

[0051] Film-coated tablets can be manufactured using methods commonly employed in the pharmaceutical field. A suspension of film coating agents, plasticizers, lubricants, light-shielding agents, colorants, etc., dissolved and dispersed in a solvent such as water or ethanol is sprayed into a coating pan containing uncoated tablets at a constant supply air temperature of approximately 70°C and exhaust temperature of approximately 40-60°C. The film coating is uniformly applied to the surface of the uncoated tablets, and then dried as necessary to form a film coating layer.

[0052] The process of reducing the moisture content of the tofacitinib-containing tablets of the present invention to 2.5% by mass or less may be performed at any stage of the manufacturing process, or simultaneously at each stage. The drying process can be carried out by any of the following methods: (1) pre-drying the excipients, disintegrants, etc., before mixing; (2) drying after preparing the mixed powder; (3) drying after granulation; (4) drying after tableting; (5) drying before film coating; or (6) drying after film coating. From the viewpoint of suppressing the generation of related substances during the manufacturing process, pre-drying the added components as in (1) is preferable, and from the viewpoint of simplicity of the process, drying before film coating using a coating apparatus as in (5) is preferable.

[0053] The tofacitinib-containing tablets of the present invention are preferably packaged in a PTP (Press-Through Packaging) body sealed with an aluminum sheet after the tablets have been placed in the pockets, formed from a plastic sheet containing one or more layers selected from a polychlorotrifluoroethylene layer, a polyvinylidene chloride layer, a polychlorotetrafluoroethylene layer, and a cycloolefin copolymer layer.

[0054] The above-mentioned plastic sheet, other than the polychlorotrifluoroethylene layer, polyvinylidene chloride layer (PVDC), polychlorotetrafluoroethylene (PCTFE) layer, or cycloolefin copolymer (COC) layer, may use resins as the constituent layers, such as polyethylene, polypropylene, olefin resins such as ethylene-vinyl acetate copolymer (EVA), ethylene-vinyl alcohol copolymer, ionomer resin (IO), and ethylene-methacrylic acid copolymer (EMAA); and chlorine-containing resins such as polyvinyl chloride (PVC). These resins can be used individually or in combination of two or more. The average thickness of the PTP sheet is, for example, 0.05 to 3 mm, preferably 0.1 to 1 mm, and more preferably 0.15 to 0.5 mm.

[0055] The aluminum sheet may be aluminum foil, a laminate of aluminum foil and a resin layer, or an aluminum vapor-deposited film. The average thickness of the aluminum sheet is, for example, 0.03 to 1 mm, preferably 0.05 to 0.5 mm, and more preferably 0.1 to 0.3 mm.

[0056] Furthermore, it is preferable to seal the PTP packaging containing the tofacitinib-containing tablets with aluminum pillow packaging. The aluminum pillow packaging may be any pillow packaging made of a film having an aluminum layer, and may be a pillow packaging made of a laminated film of aluminum foil and a plastic film, or a pillow packaging made of a plastic film having an aluminum vapor-deposited film. Examples of plastic films include films made of polyolefins such as polyethylene and polypropylene; films made of polyester such as polyethylene terephthalate; and polyamide films made of polyamides such as polyamide 6.

[0057] The aluminum pillow packaging may contain a desiccant and / or oxygen absorber in addition to the oral solid dosage form. Conventional desiccants can be used, such as silica gel, calcium chloride, or zeolite. Conventional oxygen absorbers can also be used, such as iron-based or organic oxygen absorbers. [Examples]

[0058] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way to the examples described below.

[0059] (Measurement of moisture content) In the following examples and comparative examples, the moisture content in the tablets was measured using an infrared moisture meter FD-660 manufactured by Kett Scientific Co., Ltd. 25 tablets were crushed in a mortar and pestle, and the measurement was performed using approximately 5g of powder at 80°C for 15 minutes.

[0060] (Example 1) 8.078 parts by mass of tofacitinib citrate, 37.922 parts by mass of lactose monohydrate (lactose 200M), 100 parts by mass of crystalline cellulose (Asahi Kasei Corporation, Ceolus® PH-302), 4 parts by mass of croscarmellose sodium (Nichirin Chemical Industry Co., Ltd., Kikkolate® ND-2HS), 4 parts by mass of light anhydrous silicic acid (Freund Industrial Co., Ltd., Adzolider® 101), and 1.5 parts by mass of magnesium stearate were mixed, and then compacted in a rotor compactor under conditions of roll pressure 5 MPa, screw rotation speed 15 rpm, and roll rotation speed 7 rpm to obtain ribbons. These were then crushed and granulated using an oscillator with a mesh opening of 20 M to obtain tofacitinib granules. 155.5 parts by mass of the granules, 40 parts by mass of crystalline cellulose, 2 parts by mass of croscarmellose sodium, and 2.5 parts by mass of magnesium stearate were mixed and compressed using a rotary tablet press with a φ8 mm R12 punch at a set hardness of 60 N to obtain 200 mg uncoated tablets. The tablets were then dried in a film coating apparatus at an exhaust temperature of 55°C for 15 minutes.

[0061] (Example 2) 8.078 parts by mass of tofacitinib citrate, 55.922 parts by mass of lactose monohydrate, 80 parts by mass of crystalline cellulose, 6 parts by mass of croscarmellose sodium, 2 parts by mass of light anhydrous silicic acid, and 1.5 parts by mass of magnesium stearate were mixed and compacted in a rotor compactor under conditions of roll pressure of 5 MPa, screw rotation speed of 15 rpm, and roll rotation speed of 7 rpm to obtain ribbons. These were then crushed and granulated using an oscillator with a mesh opening of 20 M to obtain tofacitinib granules. 153.5 parts by mass of these granules, 40 parts by mass of crystalline cellulose, 4 parts by mass of croscarmellose sodium, and 2.5 parts by mass of magnesium stearate were mixed and compressed using a rotary tablet press with a φ8 mm R12 punch at a set hardness of 60 N to obtain 200 mg uncoated tablets. These were then dried in a film coating apparatus at an exhaust temperature of 55°C for 10 minutes.

[0062] (Example 3) 8.078 parts by mass of tofacitinib citrate (D50: 6.3 μm, D90: 11.9 μm), 53.922 parts by mass of anhydrous lactose (manufactured by DEF Pharma, SuperTab® 24AN), 60 parts by mass of crystalline cellulose, 5 parts by mass of croscarmellose sodium, 10 parts by mass of light anhydrous silicic acid (manufactured by Freund Industrial Co., Adzolider® 101), and 1 part by mass of magnesium stearate were mixed. The mixture was then compacted in a rotor compactor under conditions of roll pressure of 5 MPa, screw rotation speed of 15 rpm, and roll rotation speed of 6 rpm to obtain ribbons. These ribbons were then crushed and granulated using an oscillator with a mesh opening of 20 M to obtain tofacitinib granules. 138 parts by mass of the granules, 60 parts by mass of crystalline cellulose, and 2 parts by mass of magnesium stearate were mixed and compressed using a rotary tablet press with a φ8 mm R12 punch at a set hardness of 60 N to obtain 200 mg uncoated tablets. Then, the tablets were dried in a film coating apparatus at an exhaust temperature of 55°C for 10 minutes.

[0063] (Example 4) 8.078 parts by mass of tofacitinib citrate, 78.922 parts by mass of anhydrous lactose (DEF Pharma, SuperTab® 21AN), 65 parts by mass of crystalline cellulose, 5 parts by mass of croscarmellose sodium, and 1 part by mass of magnesium stearate were mixed, compacted in a rotary compactor, and crushed and sized in an oscillator to obtain granules. 158 parts by mass of these granules, 40 parts by mass of crystalline cellulose, and 2 parts by mass of magnesium stearate were mixed and compressed using a rotary tablet press with a φ8 mm R12 punch at a set hardness of 60 N to obtain 200 mg uncoated tablets. Then, they were dried in a film coating apparatus at an exhaust temperature of 55°C for 10 minutes.

[0064] (Example 5) 8.078 parts by mass of tofacitinib citrate, 74.922 parts by mass of anhydrous lactose (DEF Pharma, SuperTab® 21AN), 65 parts by mass of crystalline cellulose, 5 parts by mass of croscarmellose sodium, 4 parts by mass of talc, and 1 part by mass of calcium stearate were mixed, compacted in a rotary compactor, and then crushed and granulated in an oscillator to obtain granules. 158 parts by mass of these granules, 40 parts by mass of crystalline cellulose, and 2 parts by mass of calcium stearate were mixed and compressed using a rotary tablet press with a φ8 mm R12 punch at a set hardness of 60 N to obtain 200 mg uncoated tablets. Next, the tablets were dried in a film coating apparatus at an exhaust temperature of 55°C for 10 minutes.

[0065] (Example 6) 100 parts by mass of crystalline cellulose (Asahi Kasei Corporation, Ceolus® PH-302) was dried overnight at 80°C (moisture content 1.1%), then 8.078 parts by mass of tofacitinib citrate, 37.922 parts by mass of lactose monohydrate (lactose 200M), 4 parts by mass of croscarmellose sodium (Nichirin Chemical Industry Co., Ltd., Kikkolate® ND-2HS), 4 parts by mass of light anhydrous silicic acid (Freund Industrial Co., Ltd., Adzolider® 101), and 1.5 parts by mass of magnesium stearate were mixed. The mixture was then compacted in a rotor compactor under conditions of roll pressure 5 MPa, screw rotation speed 15 rpm, and roll rotation speed 7 rpm to obtain ribbons, which were then crushed and granulated using an oscillator with a mesh opening of 20 M to obtain tofacitinib granules. 155.5 parts by mass of the granules, 40 parts by mass of crystalline cellulose, 2 parts by mass of croscarmellose sodium, and 2.5 parts by mass of magnesium stearate were mixed and compressed using a rotary tablet press with a set hardness of 60N and a punch of diameter φ8 mm R12 to obtain 200 mg uncoated tablets with a moisture content of 2.5% or less. The moisture content was 1.63% by mass.

[0066] (Example 7) In Example 1, a coating solution consisting of 3.55 parts by mass of hypromellose, 0.45 parts by mass of triacetin, 0.5 parts by mass of titanium dioxide, 0.5 parts by mass of talc, and 45 parts by mass of water was sprayed onto the tofacitinib tablets using a coating apparatus at an exhaust temperature of approximately 55°C to perform film coating. After drying in the apparatus, film-coated tablets with a weight of 205 mg and a moisture content of 1.72% by mass were obtained.

[0067] (Example 8) In Example 3, a coating solution consisting of 2.15 parts by mass of polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, 2.15 parts by mass of talc, 0.7 parts by mass of titanium dioxide, and 28.33 parts by mass of water was sprayed onto the tofacitinib tablets using a coating apparatus at an exhaust temperature of approximately 55°C to perform film coating. After film coating, the tablets were dried in the apparatus to obtain film-coated tablets with a weight of 205 mg and a moisture content of 1.41% by mass.

[0068] (Examples 9-13) In Example 6, tofacitinib tablets were coated with a film coating solution having the composition shown in Table 1 below, using a coating apparatus, at an exhaust temperature of approximately 55°C. Film coating was then performed to obtain 205 mg film-coated tablets.

[0069] [Table 1]

[0070] (Example 14) In Example 6, the tofacitinib tablets were coated with a coating solution (1) consisting of 2 parts by mass of hypromellose and 26.6 parts by mass of water using a coating apparatus to provide an undercoat. Then, a coating solution (2) consisting of 2.1 parts by mass of hypromellose, 0.2 parts by mass of triacetin, 0.3 parts by mass of talc, 0.3 parts by mass of titanium dioxide, 0.1 parts by mass of polyethylene glycol 6000, and 27 parts by mass of water was sprayed onto the tablets to provide a film coating, resulting in 205 mg film-coated tablets.

[0071] (Comparative Example 1) 8.078 parts by mass of tofacitinib citrate, 67.922 parts by mass of lactose monohydrate, 100 parts by mass of crystalline cellulose, 4 parts by mass of croscarmellose sodium, 10 parts by mass of light anhydrous silicic acid, and 10 parts by mass of calcium stearate were mixed. The mixture was then compressed using a rotary tablet press with a φ8 mm R12 punch at a set hardness of 70 N to obtain 200 mg uncoated tablets. The moisture content was 2.94% by mass.

[0072] (Comparative Example 2) Comparative Example 2 was Xeljanz® tablets (aluminum / polyvinyl chloride PTP packaging) containing 8.078 mg of tofacitinib citrate, lactose monohydrate, crystalline cellulose, hypromellose, croscarmellose sodium, and magnesium stearate in the tablet portion, and titanium dioxide, macrogol 4000, lactose monohydrate, and triacetin in the coating portion.

[0073] [Table 2]

[0074] (Stability test) The tablets of Comparative Examples and Examples 1-4, and Comparative Examples 1-2 were each packaged in PTP blister packs and stored for one month at a temperature of 40°C and a humidity of 75% RH or at a temperature of 50°C. The amount of related substances in each tablet immediately after manufacturing and after storage was measured as follows. The tablets were extracted with a fixed amount of dissolving solution (water:acetonitrile = 50:50) and filtered through a membrane filter to obtain the sample solution. Each sample solution was analyzed by liquid chromatography under the following conditions. The peak area of ​​each sample solution was measured by automated integration, and the sum of the peak areas of tofacitinib and each related substance with a relative retention time of 0.5 to 1.5 was calculated by the area percentage method, and the relative abundance of all related substances (100 × (sum of peak areas of related substances / peak area of ​​tofacitinib)) was calculated.

[0075] <Test Conditions> Detector: UV absorbance spectrophotometer (measurement wavelength: 280 nm) Column: YMC-Triart C18, 4.6 mm × 25 cm, 5 μm Column temperature: Constant temperature around 40°C Flow rate: 1.0 mL per minute Area measurement range: Approximately 50 minutes Mobile phase A: 25 mM ammonium acetate buffer:acetonitrile = 95:5 Mobile phase B: 25 mM ammonium acetate buffer:acetonitrile = 5:95 Mobile phase delivery: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 3.

[0076] [Table 3]

[0077] (Stability test) Table 4 shows the results of stability tests conducted for each tablet and specific PTP packaging over one month under conditions of 50°C and 40°C / 75%RH, and the relative abundance [%] of total related substances was measured.

[0078] [Table 4]

[0079] (Leaching test) Dissolution tests were performed using Japanese Pharmacopoeia Solution 1 (pH 1.2) and Japanese Pharmacopoeia Solution 2 (pH 6.8) under the paddle method at a rotation speed of 50 rpm, in accordance with the dissolution test method of the Japanese Pharmacopoeia. Tofacitinib was measured by HPLC under the following conditions. Table 5 shows the rate of decrease in dissolution rate after 30 minutes for each solution.

[0080] <Test Conditions> Detector: UV absorbance spectrophotometer (measurement wavelength: 289 nm) Column: YMC-Triart C18 4.6 mm × 15 cm, 3 μm Column temperature: Constant temperature around 30°C Mobile phase: 50 mM phosphate buffer (pH 3.5): methanol = 60:40

[0081] [Table 5]

[0082] In Examples 2, 4, 5, 7, and 8, the tofacitinib formulations showed a total relative abundance of 0.3% or less under all conditions of 50°C, 40°C, and 75% RH humidity for one month, which was sufficiently low. In contrast, the formulation of Comparative Example 1 with a moisture content of 2.94% by mass and the previously approved formulation of Comparative Example 2 with a moisture content of 2.83% by mass showed a high relative abundance of 0.49% or more. Furthermore, in terms of packaging materials, the total relative abundance of related substances in PTP packaging containing a polyvinylidene chloride layer, a polychlorotrifluoroethylene layer, and a cycloolefin copolymer layer was 0.1% or less, which sufficiently suppressed the generation of related substances compared to PTP packaging containing a polyvinyl chloride layer. The dissolution properties of the tofacitinib formulations in Comparative Example 2 (an approved formulation) and Examples 7 and 8 were equivalent, suggesting bioequivalence. Furthermore, the dissolution properties of the tofacitinib formulations in Examples 7 and 8 remained unchanged after a one-month accelerated testing period.

[0083] (Example of formulation 1) Wet granulation was performed by stirring according to the ingredients and proportions shown in Table 6, and the added components were mixed and compressed to obtain uncoated tablets. Film coating was then performed in the same manner as in Example 7 to produce tofacitinib citrate tablets.

[0084] [Table 6]

[0085] (Formulation Example 2) Tofacitinib citrate tablets are manufactured by following the same procedure as in Example 1, using the ingredients and proportions shown in Table 7, and then film-coating them using the same procedure as in Example 6.

[0086] [Table 7]

Claims

1. A tablet containing tofacitinib, an excipient, a disintegrant, and a lubricant, wherein the water content of the tablet is adjusted to 0.2 to 2.0% by mass. Tofacitinib-containing tablets, wherein the excipients are anhydrous lactose or lactose monohydrate and crystalline cellulose, the relative abundance of total related substances determined by 100 × (total related substances / tofacitinib) after storage for one month at 50°C under open conditions is 0.5% or less, and the total related substances are a group of substances that appear in a high-performance liquid chromatography chart with a relative retention time of 0.5 to 1.5, when the relative retention time of the peak shown by tofacitinib is set to 1.

2. The tablet according to claim 1, further comprising a silicate compound.

3. The tablet according to claim 1 or 2, wherein the amount of excipients is 60 to 95% by mass of the entire tablet.

4. The tablet according to claim 1 or 2, wherein the disintegrant is one or more selected from croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, or sodium starch glycolate.

5. The tablet according to claim 1 or 2, wherein the amount of disintegrant is 0.1 to 10% by mass relative to the total weight of the tablet.

6. The tablet according to claim 1 or 2, wherein the lubricant is one or more selected from magnesium stearate, calcium stearate, and sodium stearyl fumarate.

7. The tablet according to claim 1 or 2, wherein the amount of lubricant is 0.1 to 10% by mass relative to the total weight of the tablet.

8. The tablet according to claim 1 or 2, wherein tofacitinib is tofacitinib citrate.

9. The tablet according to claim 1 or 2, wherein the tofacitinib content is 5 mg per tablet.

10. The tablet according to claim 3, wherein the amount of silicate compound included is 0.1 to 10% by mass of the entire tablet.

11. The tablet according to claim 1 or 2, which is a film-coated tablet.

12. A method for producing tofacitinib-containing tablets according to claim 1, comprising the steps of granulating tofacitinib, an excipient, a disintegrant, and a lubricant by a dry granulation method to obtain granules, and a drying step.

13. The method according to claim 12, further comprising the steps of mixing an excipient, a disintegrant, and a lubricant with the granules, compressing them into tablets to obtain uncoated tablets, and spraying and drying a film base solution onto the uncoated tablets to obtain film-coated tablets.

14. The method according to claim 12 or 13, wherein a silicate compound is added in the granulation step.

15. A tofacitinib-containing tablet according to claim 1 or 2, contained in a PTP packaging made of a plastic sheet containing one or more layers selected from a polychlorotrifluoroethylene layer, a polyvinylidene chloride layer, and a polychlorotetrafluoroethylene layer, and an aluminum sheet, and further contained in an aluminum pillow packaging made of a film having an aluminum layer.

16. A method for improving the storage stability of tofacitinib-containing tablets, which involves adjusting the water content in the tablets to 0.2 to 2.0% by mass.

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