Film-coated tablet containing tofacitinib

Abstract

To provide a tablet containing tofacitinib or a pharmaceutically acceptable salt thereof which exhibits resistance to yellowing and enhanced stability.SOLUTION: The present invention provides a film-coated tablet that comprises an uncoated tablet, containing tofacitinib or a pharmaceutically acceptable salt thereof as an active ingredient, and a film coating layer, where the film-coated tablet is free of polyethylene glycol (provided that sustained-release preparations are excluded).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to film-coated tablets containing tofacitinib or a pharma- ceutically acceptable salt thereof, in particular to immediate release film-coated tablets containing tofacitinib citrate. [Background technology]

[0002] Tofacitinib, 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile, is an inhibitor of the Janus kinase (JAK) family that exhibits high selectivity among human kinases, and tofacitinib citrate is commercially available as Xeljanz (registered trademark) tablets 5 mg for the treatment of rheumatoid arthritis and ulcerative colitis.

[0003] Patent Document 1 discloses a once-daily sustained-release formulation containing tofacitinib citrate, and cites oral sustained-release of tofacitinib as a useful therapy as an immunosuppressant for organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, infectious arthritis, type I diabetes and diabetic complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, ankylosing spondylitis, juvenile idiopathic arthritis, Crohn's disease, Alzheimer's disease, leukemia, and other indications in which immunosuppression may be desirable.

[0004] Furthermore, Patent Document 2 discloses an orally disintegrating tablet containing tofacitinib that combines a sweetener and a disintegrant. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2014-181234 A [Patent Document 2] Special Publication No. 2018-521040 Summary of the Invention [Problem to be solved by the invention]

[0006] Xeljanz® 5 mg tablets are white, film-coated tablets that tend to turn yellow depending on storage time and conditions. There is also room for improvement regarding the stability of tofacitinib in the formulation.

[0007] Patent Document 1 discloses not only sustained release formulations but also immediate release film-coated tablets containing tofacitinib citrate. However, the immediate release film-coated tablets of Patent Document 1 tend to turn yellow depending on the storage period and storage conditions, similar to the above-mentioned Xeljanz (registered trademark) tablets. Patent Document 1 does not disclose any description of yellowing. Patent Document 2 does not disclose any description of yellowing or film-coated tablets.

[0008] Therefore, an objective of the present invention is to provide a film-coated tablet containing tofacitinib or a pharma- ceutical acceptable salt thereof, which is inhibited from yellowing and has improved stability. [Means for solving the problem]

[0009] The present inventors have discovered that yellowing can be suppressed and stability can be improved by forming an oral formulation containing tofacitinib or a pharma- ceutically acceptable salt thereof (excluding sustained-release formulations) into a film-coated tablet using a formulation that does not use polyethylene glycol, and have thus completed the present invention.

[0010] That is, the present invention provides [1] A film-coated tablet consisting of an uncoated tablet containing tofacitinib or a pharma- ceutically acceptable salt thereof as an active ingredient and a film-coating layer, the film-coated tablet not containing polyethylene glycol (excluding sustained-release preparations), [2] The film-coated tablet according to [1] above, wherein the film-coating layer contains triacetin as a plasticizer; and [3] The film-coated tablet according to [1] or [2] above, which is an immediate-release formulation. Regarding. Effect of the Invention

[0011] According to the present invention, by forming an oral formulation containing tofacitinib or a pharma- ceutically acceptable salt thereof (excluding sustained-release formulations) into a film-coated tablet using a formulation that does not use polyethylene glycol, it is possible to obtain a formulation that is inhibited from yellowing and has improved stability. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 is a graph showing the stability of tofacitinib citrate in film-coated tablets. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present invention is characterized in that polyethylene glycol is not contained in a film-coated tablet containing tofacitinib or a pharma- cetically acceptable salt thereof as an active ingredient. This can suppress yellowing of an oral formulation of tofacitinib, and can further improve the stability of tofacitinib. As described below, the present inventors have found that tofacitinib citrate is not stable to magnesium stearate and polyethylene glycol (these additives are used in existing formulations such as Xeljanz (registered trademark) tablets), and turns yellow. As described below, when a plain tablet containing magnesium stearate but not polyethylene glycol was tested at 60°C, 75% RH, and unpackaged, yellowing was confirmed after a storage period of 3 weeks. When such a plain tablet was film-coated with a formulation not using polyethylene glycol, yellowing was not confirmed even after a storage period of 3 weeks. In addition, in this film-coated tablet, the production of total related substances of tofacitinib was also suppressed, and stability was improved. Thus, it is surprising that not only was yellowing suppressed but also stability was improved simply by removing polyethylene glycol from the film coating layer, without removing magnesium stearate, which is believed to have a larger contact area with tofacitinib citrate.

[0014] The film-coated tablet of the present invention is an oral preparation, and is not a sustained release preparation but an immediate release preparation. In this specification, the term "immediate release preparation" for oral administration means a preparation in which the release of the active ingredient from the preparation is not particularly controlled, and generally shows a dissolution behavior according to the solubility of the active ingredient.

[0015] (Uncoated tablet) Tofacitinib and pharma- ceutically acceptable salts of tofacitinib are not particularly limited and commercially available salts can be used, and pharma- ceutically acceptable salts of tofacitinib may be derived from tofacitinib by methods commonly used in the art.

[0016] Examples of pharma- ceutically acceptable salts of tofacitinib include pharma- ceutically acceptable non-toxic organic and inorganic acid addition salts such as citrate, acid citrate, hydrochloride, sulfate, nitrate, bisulfate, phosphate, superphosphate, acetate, hydroiodide, hydrobromide, lactate, tartrate, acid tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate, etc. Among these, the citrate of tofacitinib is particularly preferred.

[0017] The amount of tofacitinib or a pharma- ceutically acceptable salt thereof in the uncoated tablet is usually preferably 5 mg of tofacitinib per tablet.

[0018] The content of the active ingredient in the uncoated tablet is preferably 1.5% by mass or more, more preferably 2.0% by mass or more, as tofacitinib. By making the content of the active ingredient in the uncoated tablet 1.5% by mass or more, the formulation uniformity (i.e., the content uniformity of the active ingredient between individual formulations) tends to be good. In addition, the content of the active ingredient in the uncoated tablet is preferably 3.5% by mass or less, more preferably 3.0% by mass or less, as tofacitinib. By making the content of the active ingredient in the uncoated tablet 3.5% by mass or less, the manufacturability tends to be good.

[0019] In addition to the active ingredient, tofacitinib or a pharma- ceutically acceptable salt thereof, the uncoated tablet may contain additives commonly used in this field, such as excipients, disintegrants, flow agents, lubricants, surfactants, binders, stabilizers, and coloring agents.

[0020] The excipient is not particularly limited, but examples thereof include celluloses (such as crystalline cellulose, ethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose) and derivatives thereof, starch (such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, hydroxypropyl starch and derivatives thereof), sugars (such as glucose, lactose, sucrose, refined sucrose, powdered sugar, trehalose, dextran, dextrin and hydrates thereof), sugar alcohols (such as D-mannitol, xylitol, sorbitol, erythritol), glycerin fatty acid esters, inorganic powders (magnesium aluminometasilicate, synthetic hydrotalcite), anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, calcium silicate, calcium hydrogen phosphate hydrate, and inorganic salts such as sodium hydrogen carbonate. Among these, celluloses such as crystalline cellulose and sugars such as lactose and lactose hydrate are preferred, and it is particularly preferred to use crystalline cellulose in combination with lactose. When crystalline cellulose and lactose are used in combination, the weight ratio of crystalline cellulose:lactose is preferably 2:1 to 1:6, and from the viewpoint of facilitating obtaining a suitable tablet hardness, 1:1 is particularly preferable. The excipients may be used alone or in combination of two or more kinds.

[0021] When an excipient is used, the amount of the excipient used in the uncoated tablet is not particularly limited, but from the viewpoints of manufacturability such as flowability and tableting problems, and tablet physical properties such as hardness and friability, the amount of the excipient used is preferably 60% by mass or more, and more preferably 70% by mass or more, relative to the total mass of the uncoated tablet, and from the viewpoint of formulation uniformity, the amount of the excipient used is preferably 96% by mass or less, and more preferably 95% by mass or less.

[0022] The disintegrant is not particularly limited, but examples thereof include crospovidone, sodium carboxystarch, sodium carboxymethyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium citrate, light anhydrous silicic acid, crystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose, croscarmellose sodium, calcium carboxymethyl cellulose, carmellose, hydroxypropyl starch, etc. Among these, low-substituted hydroxypropyl cellulose, croscarmellose sodium, etc. are preferred from the viewpoint of suppressing an increase in related substances, etc. The disintegrant may be used alone or in combination of two or more kinds.

[0023] When a disintegrant is used, the amount used in the uncoated tablet varies depending on the intended disintegration rate of the uncoated tablet and the type of disintegrant used, and is not particularly limited. In general, from the viewpoint of tablet disintegrability, the amount is preferably 1.0% by mass or more, and more preferably 2.0% by mass or more, relative to the total mass of the uncoated tablet, and from the viewpoint of tablet physical properties such as hardness and thickness under humidified conditions, the amount is preferably 5.0% by mass or less, and more preferably 4.5% by mass or less.

[0024] The fluidizing agent is not particularly limited, but examples thereof include silicates such as calcium silicate, anhydrous silicic acid such as light anhydrous silicic acid, hydrous silicon dioxide, talc, titanium oxide, stearic acid, magnesium stearate, calcium stearate, magnesium aluminometasilicate, etc. Among these, light anhydrous silicic acid is preferred from the viewpoint of suppressing an increase in related substances. These may be used alone or in combination of two or more.

[0025] When a fluidizer is used, the amount used in the uncoated tablets should be an amount that allows the powder additive described above to flow smoothly during the production of the uncoated tablets. This amount varies depending on the type of fluidizer used, and is not particularly limited. From the viewpoint of fluidity, the amount is usually preferably 0.1% by mass or more, and more preferably 0.3% by mass or more, relative to the total mass of the uncoated tablet, and from the viewpoint of manufacturability, the amount is preferably 1.0% by mass or less, and more preferably 0.7% by mass or less.

[0026] The lubricant is not particularly limited, but examples thereof include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, light anhydrous silicic acid, hardened oil, glycerin fatty acid ester, talc, etc. Among them, calcium stearate and magnesium stearate are preferred because of their high lubricity. These may be used alone or in combination of two or more.

[0027] When a lubricant is used, the amount used in the uncoated tablets is an amount that can prevent the various additives mentioned above from adhering to the equipment (punches and dies) used to manufacture the uncoated tablets. This amount varies depending on the type of lubricant used, and is not particularly limited. However, from the viewpoint of preventing tableting problems, the amount is usually preferably 0.5% by mass or more, and more preferably 0.7% by mass or more, relative to the total mass of the uncoated tablets, and from the viewpoint of preventing an increase in related substances, the amount is preferably 2.0% by mass or less, and more preferably 1.5% by mass or less.

[0028] (Film coating layer) Film-coated tablets are preparations in which a film (film-coating layer) is applied to the surface of a tablet using a film-coating base such as a polymer or sugar. By applying a film coating, effects such as masking bitterness and bad odor, improving the stability of the active ingredient against external conditions such as moisture, light, or oxygen, improving the appearance, and increasing the commercial value can be expected. The film-coating layer is generally composed of a base, a plasticizer, a colorant, a lubricant, and a solvent (solvent), and the already commercially available Xeljanz (registered trademark) tablet uses polyethylene glycol as a plasticizer. In the present invention, by applying a film coating that does not contain polyethylene glycol, it is possible to suppress yellowing of the tablet and improve the stability of the active ingredient.

[0029] The base for film coating is not particularly limited, but includes polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), carmellose sodium, polyvinylpyrrolidone, and polyvinyl alcohol; and sugars such as lactose hydrate, sucrose, refined sucrose, powdered sugar, and glucose. Among them, hypromellose and lactose hydrate are preferred from the viewpoints of manufacturability and film strength. These bases may be used alone or in combination of two or more.

[0030] The content of the film coating base in the film coating layer is preferably 55 to 90% by mass, more preferably 60 to 85% by mass, and even more preferably 65 to 82% by mass, from the viewpoint of film strength.

[0031] Examples of the plasticizer include propylene glycol, triacetin, triethyl citrate, and the like. There is no particular limitation other than the absence of polyethylene glycol, but among these, it is preferable to use triacetin.

[0032] The content of the plasticizer in the film coating layer is preferably 1 to 20% by mass, more preferably 3 to 15% by mass, and even more preferably 4 to 10% by mass, in order to ensure the plasticity of the base.

[0033] In addition, colorants such as titanium oxide, ferric oxide, and aluminum lake, lubricants such as talc, and glossing agents such as carnauba wax can be appropriately added to the film coating layer as necessary. In particular, depending on the ratio of other components forming the film coating layer, such as the base of the film coating, it is preferable to use talc as a lubricant to prevent tablets from sticking to each other.

[0034] (Manufacturing method of uncoated tablets) The method for producing uncoated tablets can be a method generally used in the art, and is not particularly limited. For example, tofacitinib or a pharma- ceutical acceptable salt thereof is mixed with an appropriate excipient, disintegrant, lubricant, flow agent, etc., as described above, to obtain a mixture. The obtained mixture can be tableted, for example, using a tableting mortar, an upper punch for tableting, and a lower punch for tableting, by a hydraulic hand press, a single punch tableting machine, a rotary tableting machine, or the like, to obtain uncoated tablets. Tabletting may be performed at a tableting pressure such that the obtained tablets have an appropriate hardness, and the tableting pressure is appropriately adjusted depending on the tableting method, the equipment used for tableting, the size of the tablets, the type of medicinal ingredient, and the like.

[0035] The obtained uncoated tablets preferably have an appropriate hardness, specifically, from the viewpoint of preventing cracking or chipping during the tablet production, the hardness is preferably 40 to 200 N, more preferably 80 to 150 N. In particular, to prepare film-coated tablets, it is preferable to ensure a certain degree of hardness so that the uncoated tablets are not worn or damaged (defective) during film coating. The hardness is a value measured by a general method using a tablet hardness tester.

[0036] The shape of the obtained plain tablet is not particularly limited, and may be, for example, a disk, a donut, a polygonal plate, a sphere, an ellipse, a caplet, etc. In terms of size, for example, in the case of a disk shape, the diameter is preferably about 8 mm from the viewpoint of ingestibility, and the thickness is preferably 3.5 to 5 mm. The mass depends on the content of the active ingredient, but in the case of 5 mg of tofacitinib, it is preferably about 170 to 220 mg.

[0037] The uncoated tablets thus obtained are film-coated with a coating agent that does not contain polyethylene glycol by a method commonly used in the art.

[0038] (Film coating method) The film coating method for the uncoated tablets can be a method for producing a film-coated tablet that is generally used in the art. For example, the uncoated tablets containing tofacitinib or a pharma- ceutically acceptable salt thereof are loaded into a film coating machine, and the uncoated tablets are sprayed with a coating liquid prepared by dissolving or dispersing the base and additives of the film coating in an appropriate solvent such as purified water, an organic solvent such as ethanol, or a mixture thereof (e.g., a mixture of purified water / ethanol) and then dried to coat the tablets.

[0039] In the obtained film-coated tablet, the mass of the film-coating layer is not particularly limited as long as it is an amount sufficient to cover the entire uncoated tablet. However, in order to allow the tofacitinib or a pharma- ceutically acceptable salt thereof to be rapidly dissolved from the uncoated tablet after ingestion, it is preferable that the mass of the film-coating layer be 1 to 5%, and more preferably 2 to 4%, of the total mass of the uncoated tablet taken as 100%.

[0040] The hardness of the obtained film-coated tablet is not particularly limited, but it is preferable that the film-coated tablet has an appropriate hardness. Specifically, the film-coated tablet has a hardness of preferably 40 to 250N, more preferably 80 to 220N, from the viewpoint of preventing cracking or chipping during transportation or storage of the product, prescription at a hospital or pharmacy, or handling by a patient. Furthermore, since the thickness of the film-coating layer is thin, the size of the film-coated tablet is similar to the size of the uncoated tablet described above, and the preferred range is the same as that of the uncoated tablet, for example, in the case of a disk-shaped tablet, the diameter is preferably about 8 mm from the viewpoint of ease of administration, and the thickness is preferably 3.5 to 5 mm. The mass depends on the content of the active ingredient, but in the case of 5 mg of tofacitinib, it is preferably about 170 to 220 mg.

[0041] The film-coated tablet of the present invention is useful for treating rheumatoid arthritis, ulcerative colitis, and the like.

[0042] The present invention will now be described in detail with reference to examples, but it is not intended that the present invention be limited to these examples. EXAMPLES

[0043] Details of the reagents used in the examples are given below. Tofacitinib Citrate Lactose monohydrate: Japanese Pharmacopoeia XVIII Microcrystalline cellulose: Japanese Pharmacopoeia XVIII Croscarmellose sodium: Japanese Pharmacopoeia XVIII Light anhydrous silicic acid: Japanese Pharmacopoeia XVIII Magnesium stearate: Japanese Pharmacopoeia XVIII Hypromellose: Japanese Pharmacopoeia XVIII Titanium oxide: Japanese Pharmacopoeia XVIII Polyethylene glycol 4000 (Macrogol 4000): Japanese Pharmacopoeia XVIII Triacetin: Pharmaceutical Additives Regulations Talc: Japanese Pharmacopoeia XVIII

[0044] In the above, JP XVIII refers to the 18th Edition of the Japanese Pharmacopoeia, and Yakuhin Ki refers to Pharmaceutical Excipients Standards 2018 and its supplements.

[0045] Test example 1: Contact stability test Tofacitinib citrate was placed in a test tube with lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hypromellose, polyethylene glycol 4000, or titanium oxide in a 1:1 mass ratio and mixed with a spatula. After storing at 60°C, 75% RH, and in an open system, samples containing magnesium stearate and macrogol 4000 showed clear yellowing when visually observed after 3 weeks.

[0046] Example 1 (Manufacturing of uncoated tablets) According to the formulation in Table 1, tofacitinib citrate, lactose monohydrate, crystalline cellulose, croscarmellose sodium, and light anhydrous silicic acid were mixed in a bag, except for the lubricant. Magnesium stearate was added to the resulting mixture and further mixed. The resulting mixture was then placed in a rotary tablet press (VIRG0512SS2AZ, manufactured by Kikusui Seisakusho Co., Ltd.) and tableted at a tableting pressure of 6 kN to obtain 290 g of plain tablets (diameter: 8 mm, thickness: 3.8 mm). The hardness of the plain tablets was 136 N.

[0047] (Manufacturing of film-coated tablets) 100 g of the obtained plain tablets and 100 g of placebo tablets (prepared in the same manner as in Example 1 (production of plain tablets) except that no active ingredient was contained, the diameter was 6.5 mm, and the tablet weight was 125 mg) were added to a film coating machine (PRC-GTXmini, manufactured by Powrex Corporation). Meanwhile, hypromellose, titanium oxide, triacetin, and talc were dissolved and suspended in water (60.0 g) to prepare a coating liquid (solid concentration 13.8% w / w). The coating liquid was sprayed onto the plain tablets in the film coating machine to coat them, and then dried to obtain a total of 103 g of tablets (205.98 mg per tablet). The hardness of the tablets was 207 N.

[0048] [Table 1]

[0049] Example 2 (Manufacturing of uncoated tablets) According to the formulation in Table 1, tofacitinib citrate, lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium were mixed in a bag except for the lubricant. Magnesium stearate was added to the resulting mixture and further mixed. The resulting mixture was then compressed with a tableting simulator (PSY3R0010, MEDELPHARM) at a tableting pressure of 6 kN to obtain uncoated tablets (diameter: 8 mm, thickness: 3.7 mm). The hardness of the uncoated tablets was 114 N.

[0050] (Manufacturing of film-coated tablets) 30 g of the obtained plain tablets and 170 g of placebo tablets (same as the placebo tablets used in Example 1) used as bulk enhancers were placed in a film coating machine in the same manner as in Example 1, and coating was performed in the same manner as in Example 1 using the film coating layer recipe shown in Table 1 to obtain film-coated tablets (total weight 31 g (208.00 mg per tablet)). The hardness of the film-coated tablets was 142 N.

[0051] Comparative Examples 1 and 2 Film-coated tablets (total weight 31 g (208.00 mg per tablet)) were obtained in the same manner as in Example 2, except that the formulation of the film-coating layer was as shown in Table 1. The hardness of the film-coated tablets was 133 N for Comparative Example 1 and 162 N for Comparative Example 2, respectively.

[0052] Test example 2: Color difference measurement The tablets immediately after production in Examples 1-2 and Comparative Examples 1-2 were stored unpackaged at 60°C and 75% RH, and the lightness (L*) and chromaticity (a*, b*) indicating hue and saturation of each tablet (at the start of storage: n=3, storage period 1 week: n=1, storage period 3 weeks: n=3) were measured using a colorimeter CR-400 manufactured by Konica Minolta, Inc., at the start of storage, after 1 week of storage, and after 3 weeks of storage. Note that as Reference Example 1, measurements were also taken on the plain tablets immediately after production in Example 1. The color difference was measured using the L*a*b* color space (CIE 1976) as the chromaticity value. From this result and the initial value, the color difference (ΔE* ab Yellowing was also evaluated using Δb*. ΔE* ab = {(ΔL*) 2 +(Δa*) 2 +(Δb*) 2} 1 / 2

[0053] The results are shown in Table 2.

[0054] [Table 2]

[0055] From Table 2, it can be seen that yellowing is suppressed by film coating that does not contain polyethylene glycol. Furthermore, in consideration of Reference Example 1, it can be seen that film coating that contains polyethylene glycol actually promotes yellowing.

[0056] Test Example 4: Stability test Tablets immediately after production in Examples 1 and 2 and Comparative Examples 1 and 2 were stored for 14 days in an unpackaged environment at 60°C and 75% RH. At the start of storage, and at 1 week, 2 weeks, and 3 weeks of storage, the amount of tofacitinib related substances, which are decomposition products of tofacitinib citrate, was measured by HPLC for each tablet (n=1 for each). The results are shown in Table 3 and Figure 1 as the content (%) of total related substances relative to the amount of tofacitinib citrate. The HPLC analysis conditions were as follows.

[0057] (HPLC analysis conditions) Detector: Ultraviolet spectrophotometer (measurement wavelength: 285 nm) Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm was packed with 3.5 μm octadecylsilylated silica gel for liquid chromatography. Column temperature: constant temperature around 40℃ Mobile phase A: Dissolve 2.31 g of ammonium acetate in water to make 3000 mL. Add formic acid to this solution to adjust the pH to 4.0. Mobile phase B: Acetonitrile for liquid chromatography TIFF2025018790000003.tif39121Flow rate: 1.0mL / min Area measurement range: After sample injection, from the solvent peak to 30 minutes after injection Injection volume: 10μL Diluent: Water / acetonitrile mixture (4:1)

[0058] [Table 3]

[0059] From Table 3 and FIG. 1, it can be seen that Examples 1 and 2, which do not contain Macrogol 4000, have improved storage stability compared to Comparative Examples 1 and 2.

Claims

1. A film-coated tablet consisting of an uncoated tablet containing tofacitinib or a pharma- ceutically acceptable salt thereof as an active ingredient and a film coating layer, the film-coated tablet not containing polyethylene glycol (excluding sustained-release preparations).

2. 2. The film-coated tablet according to claim 1, wherein the film-coating layer contains triacetin as a plasticizer.

3. 3. The film-coated tablet according to claim 1 or 2, which is an immediate release formulation.

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