Selexipag-containing tablet and method for producing the same

Abstract

To provide a selexipag-containing tablet that has high storage stability, and a method for producing the same.SOLUTION: A selexipag-containing tablet of the present invention contains, in a core tablet portion, (a) at least one selected from the group consisting of selexipag, a salt of selexipag, and a solvate of selexipag, and (b) carnauba wax. The core tablet portion has granules, and it is preferable that the granules contain the component (a) and the component (b) inside the granules. The selexipag-containing tablet may further contain (c) at least one selected from the group consisting of polyvinyl alcohol and macrogol.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a tablet containing selexipag and a method for producing the same. [Background technology]

[0002] Selexipag (chemical name: 2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide) is a prostacyclin agonist represented by the following formula (1), and is manufactured and sold as a pharmaceutical effective in treating pulmonary hypertension (see, for example, Non-Patent Document 1).

[0003] [ka]

[0004] In order for tablets containing selexipag to be widely used as pharmaceuticals, it is necessary to further improve their storage stability.

[0005] There are several known formulation technologies for selexipag, such as a drug with a specific surface area of ​​1.0 m 2 It has been reported that a stabilized solid preparation can be provided by containing D-mannitol with a solubility of 1000 mg / g or less (see, for example, Patent Document 1).

[0006] Furthermore, it has been reported that a solid preparation containing a granulated material containing starch and at least one binder selected from the group consisting of hydroxypropyl cellulose and hypromellose in specific proportions has high storage stability and good disintegrability (see, for example, Patent Document 2).

[0007] Furthermore, it is known that the commercially available selexipag tablet, Uptravi (registered trademark), has an uncoated tablet portion consisting of mannitol, corn starch, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and magnesium stearate, and a film-coated portion consisting of hypromellose, propylene glycol, carnauba wax, etc. (see, for example, Non-Patent Document 2).

[0008] However, the specific configuration is different from that of the present invention. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2017 / 098998 Brochure [Patent Document 2] International Publication No. 2021 / 206159 Brochure [Non-patent literature]

[0010] [Non-Patent Document 1] Uptravi Tablets Package Insert August 2021 (4th Edition) [Non-patent document 2] Australian Public Assessment Report for Selexipag (November 2016) Summary of the Invention [Problem to be solved by the invention]

[0011] The present invention has been made in light of the above-mentioned problems, and an object of the present invention is to provide a selexipag-containing tablet having high storage stability and a method for producing the same. [Means for solving the problem]

[0012] The selexipag-containing tablet of the present invention contains, in the uncoated tablet portion, (a) at least one member selected from the group consisting of selexipag, a salt of selexipag, and a solvate of selexipag, and (b) carnauba wax.

[0013] The method for producing a selexipag-containing tablet of the present invention includes a tableting step of tableting a mixture containing (a) at least one selected from the group consisting of selexipag, a salt of selexipag, and a solvate of selexipag, and (b) carnauba wax to form a core tablet. [Effects of the Invention]

[0014] According to the present invention, the uncoated tablet portion contains (a) at least one selected from the group consisting of selexipag, a salt of selexipag, and a solvate of selexipag, and (b) carnauba wax, thereby improving storage stability.

[0015] Furthermore, if the uncoated tablet portion contains granules, and the granules contain component (a) and component (b), a higher effect can be obtained.

[0016] Furthermore, if the uncoated tablet contains at least one member selected from the group consisting of polyvinyl alcohol and macrogol as component (c), dissolution and disintegration properties can be improved.

[0017] In addition, if the uncoated tablet contains sodium starch glycolate as component (d), dissolution can be improved.

[0018] Furthermore, disintegration properties can be improved by adding lactose hydrate as component (e) to the uncoated tablet portion.

[0019] In addition, the selexipag-containing tablet of the present invention can be easily obtained by tableting a mixture containing component (a) and component (b) to form a core tablet. DETAILED DESCRIPTION OF THE INVENTION

[0020] Hereinafter, embodiments of the present invention will be described in detail.

[0021] [Composition of selexipag-containing tablets] The selexipag-containing tablet according to this embodiment contains, in its uncoated tablet portion, (a) at least one selected from the group consisting of selexipag, a salt of selexipag, and a solvate of selexipag, and (b) carnauba wax. The (a) component, selexipag, is a prostacyclin agonist, and its chemical name is 2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide, and is represented by the following formula (1). The (b) component, carnauba wax, primarily contributes to storage stability.

[0022] [ka]

[0023] The form of the selexipag-containing tablet may be an uncoated tablet consisting of only an uncoated tablet portion, a film-coated tablet containing an uncoated tablet portion and a film-coated portion, a sugar-coated tablet, a dry-coated tablet, etc. The uncoated tablet portion refers to the tablet portion that is formed into a tablet shape during the tableting process and is not coated with a film coating, sugar coating, or the like.

[0024] The uncoated tablet portion has granules, and preferably contains component (a) and component (b) inside the granules. The granules are preferably composite particles, and preferably dry composite particles. In the present invention, composite particles refer to particles in which all or part of a mother particle is coated with child particles, and dry composite particles refer to composite particles produced by a dry method, and can be produced using Nobilta (registered trademark; manufactured by Hosokawa Micron Corporation) or the like. In the granules, component (a) and component (b) are preferably contained in the child particles of the composite particle. This is because a higher effect can be obtained. Note that component (a) and a part of component (b) may be contained in the mother particle of the composite particle. Furthermore, it is preferable that all or part of component (a) is coated with component (b). This is because a higher effect can be obtained.

[0025] Component (a) includes the free form of selexipag, as well as its pharmaceutically acceptable salts and solvates, with the free form of selexipag being preferred. Selexipag may be amorphous or crystalline, with crystalline being preferred. The content of component (a) relative to the total tablet mass is preferably 0.1% to 10% by mass, more preferably 0.1% to 5% by mass, even more preferably 0.1% to 1% by mass, and particularly preferably 0.1% to 0.5% by mass. The content of component (a) relative to the total granule mass is preferably 0.1% to 20% by mass, more preferably 0.5% to 10% by mass, even more preferably 0.5% to 5% by mass, and particularly preferably 1% to 3% by mass.

[0026] The content of component (a) per tablet is not particularly limited, and can be appropriately selected based on the clinically used dose. Specifically, the content is usually 0.05 mg to 10 mg, preferably 0.05 mg to 5 mg, and more preferably 0.1 mg to 2.5 mg, calculated as the free form of selexipag. When used as a therapeutic agent for pulmonary hypertension, it is particularly preferable that the content be, for example, 0.1 mg to 0.5 mg, calculated as the free form of selexipag.

[0027] The content of component (b) in the uncoated tablet is preferably from 0.1 to 20% by mass, more preferably from 0.2 to 10% by mass, and particularly preferably from 0.4 to 5% by mass, of the total mass of the uncoated tablet, from the viewpoint of balancing dissolution, disintegration, storage stability, etc. When component (b) is contained inside a granule, the content of component (b) inside the granule is preferably from 0.5 to 50% by mass, more preferably from 1 to 30% by mass, and particularly preferably from 5 to 30% by mass, of the total mass inside the granule.

[0028] The uncoated tablet portion preferably further contains a base particle component that will become the base particle of the granules. The base particle component is preferably one that does not react with component (a). Preferred examples of the base particle component include starches such as partially pregelatinized starch, corn starch, potato starch, rice starch, and sodium starch glycolate; sugars such as lactose hydrate, anhydrous lactose, sucrose, mannitol, erythritol, sorbitol, xylitol, trehalose, and sucrose; celluloses such as crystalline cellulose and low-substituted hydroxypropyl cellulose; and inorganic salts such as light anhydrous silicic acid, anhydrous calcium hydrogen phosphate, and calcium carbonate. These may be used alone or in combination of two or more. Among these, starches are preferred, and partially pregelatinized starch is more preferred.

[0029] The selexipag-containing tablet according to this embodiment may further contain (c) at least one selected from the group consisting of polyvinyl alcohol and macrogol. Polyvinyl alcohol and macrogol contribute to improving dissolution and disintegration properties. From the viewpoint of disintegration properties, it is more preferable to contain polyvinyl alcohol. When the selexipag-containing tablet contains component (c), component (c) is preferably contained in the uncoated tablet portion, and more preferably contained inside the granules.

[0030] When polyvinyl alcohol is contained in the selexipag-containing tablet, the content of polyvinyl alcohol in the tablet is preferably 0.1% by mass to 20% by mass, more preferably 0.5% by mass to 10% by mass, and particularly preferably 1% by mass to 5% by mass, based on the total mass of the tablet, from the viewpoint of the balance between dissolution and disintegration properties. When polyvinyl alcohol is contained inside the granule, the content of polyvinyl alcohol inside the granule is preferably 0.5% by mass to 50% by mass, more preferably 1% by mass to 35% by mass, and particularly preferably 5% by mass to 35% by mass, based on the total mass of the granule, from the viewpoint of the balance between dissolution and moldability.

[0031] When macrogol is contained in the selexipag-containing tablet, the average molecular weight of the macrogol is, from the viewpoint of dissolution property, preferably from 500 to 25,000, more preferably from 1,000 to 15,000, and even more preferably from 2,500 to 10,000. Macrogol 6,000 is particularly preferred.

[0032] When macrogol is contained in the selexipag-containing tablet, the content of macrogol in the tablet is preferably 0.02% by mass to 10% by mass, more preferably 0.05% by mass to 2% by mass, and particularly preferably 0.1% by mass to 0.5% by mass, based on the total mass of the tablet, from the viewpoint of the balance between dissolution and disintegration. When macrogol is contained inside the granule, the content of macrogol inside the granule is preferably 0.1% by mass to 30% by mass, more preferably 0.2% by mass to 15% by mass, and particularly preferably 0.5% by mass to 8% by mass, based on the total mass of the granule, from the viewpoint of the balance between dissolution and compactibility.

[0033] When the selexipag-containing tablet contains macrogol, the granules may contain low-substituted hydroxypropyl cellulose. From the viewpoint of the balance between dissolution property and moldability, the content of low-substituted hydroxypropyl cellulose inside the granules is preferably 0.2% by mass or more and 50% by mass or less, more preferably 0.5% by mass or more and 30% by mass or less, and particularly preferably 2% by mass or more and 30% by mass or less, based on the total mass of the granules.

[0034] When macrogol and low-substituted hydroxypropyl cellulose are contained inside the granule, the total content of macrogol and low-substituted hydroxypropyl cellulose inside the granule is preferably from 0.5% by mass to 50% by mass, more preferably from 1% by mass to 30% by mass, and particularly preferably from 5% by mass to 30% by mass, based on the total mass of the granule, from the viewpoint of the balance between dissolution property and moldability.

[0035] The selexipag-containing tablet according to this embodiment may further contain (d) sodium starch glycolate. Sodium starch glycolate contributes to improving dissolution. When sodium starch glycolate is contained in the selexipag-containing tablet, it is preferably contained in the uncoated tablet portion, and from the viewpoint of manufacturing, it is more preferably contained outside the granules. From the viewpoint of the balance between disintegration property and moldability, the content of sodium starch glycolate in the tablet is preferably 1% by mass or more and 40% by mass or less, more preferably 1% by mass or more and 30% by mass or less, and particularly preferably 1% by mass or more and 5% by mass or less, relative to the total mass of the tablet.

[0036] The selexipag-containing tablet according to this embodiment may further contain (e) lactose. Lactose contributes to improving disintegration. The lactose is preferably lactose hydrate. When the selexipag-containing tablet contains lactose, it is preferably contained in the uncoated tablet, and more preferably contained outside the granules from the viewpoint of disintegration. From the viewpoint of a balance between disintegration, storage stability, moldability, etc., the lactose content in the tablet is preferably 30% by mass or more and 90% by mass or less, more preferably 30% by mass or more and 85% by mass or less, and even more preferably 30% by mass or more and 80% by mass or less, based on the total mass of the tablet.

[0037] The selexipag-containing tablet according to the present embodiment may further contain an additive. The additive may be any pharmaceutically acceptable additive, such as a filler, binder, surfactant, lubricant, colorant, fluidizer, preservative, sweetener, flavoring agent, flavoring agent, stabilizer, etc. One of these additives may be used alone, or two or more may be used in combination.

[0038] Examples of excipients include sugar alcohol excipients such as mannitol, erythritol, sorbitol, maltitol, lactitol, and xylitol; starch excipients such as corn starch, potato starch, pregelatinized starch, and partially pregelatinized starch; calcium hydrogen phosphate hydrate, anhydrous calcium hydrogen phosphate, calcium silicate, lactose, lactose hydrate, anhydrous lactose, fructose, sucrose, glucose, crystalline cellulose, powdered cellulose, and low-substituted hydroxypropyl cellulose. These excipients may be used alone or in combination of two or more.

[0039] Examples of lubricants include hardened oil, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, etc. These lubricants may be used alone or in combination of two or more.

[0040] Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, corn starch, magnesium aluminometasilicate, synthetic aluminum silicate, etc., and light anhydrous silicic acid is preferred. These fluidizing agents may be used alone or in combination of two or more.

[0041] [Method for producing selexipag-containing tablets] The method for producing selexipag-containing tablets according to this embodiment includes a tableting step of forming a core tablet by tableting a mixture containing (a) at least one selected from the group consisting of selexipag, a salt of selexipag, and a solvate of selexipag, and (b) carnauba wax. It is also preferable to include a granulation step, prior to the tableting step, of granulating a composition (also referred to as a granulation composition) containing component (a) and component (b) to form granules.

[0042] In the granulation step, the granulation composition can be granulated into granules, for example, according to a known granulation method described in the General Provisions for Preparations of the Japanese Pharmacopoeia, Seventeenth Edition. In addition to components (a) and (b), other components may be added to the granulation composition. Examples of such other components include at least one selected from the group consisting of base particle components, (c) polyvinyl alcohol, and macrogol.

[0043] The granulation composition can be prepared, for example, by mixing component (a), component (b), and, if necessary, other components, or by kneading component (a), component (b), and, if necessary, other components with a solvent such as water or aqueous alcohol. Component (a) may be pulverized prior to preparing the granulation composition. Component (b) is preferably added in multiple batches; it is preferable to add component (b) and, if necessary, other components to component (a) and granulate, and then add additional component (b) and granulate. This is to coat all or part of component (a) with component (b).

[0044] The granulation in the granulation step may be carried out by wet granulation or dry granulation, but dry granulation is preferred, and granulation using a dry compounding device is more preferred. As the dry compounding device, Nobilta (registered trademark; manufactured by Hosokawa Micron Corporation) can be used.

[0045] In the tableting step, for example, it is preferable to add other ingredients as necessary to the granules obtained in the granulation step, mix them, and then tablet them. Examples of other ingredients include (d) sodium starch glycolate, (e) lactose, and the above-mentioned additives. Tableting in the tableting step may be carried out according to a conventional method using a rotary tableting machine, a single-punch tableting machine, or the like. Uncoated tablets (plain tablets) are obtained by the tableting step.

[0046] Furthermore, the uncoated tablets obtained in the tableting step may be film-coated with a film-coating agent and, if necessary, one or more selected from a plasticizer and a colorant.

[0047] As described above, according to this embodiment, the uncoated tablet portion contains (a) at least one selected from the group consisting of selexipag, a salt of selexipag, and a solvate of selexipag, and (b) carnauba wax, thereby improving storage stability.

[0048] Furthermore, if the uncoated tablet portion contains granules, and the granules contain component (a) and component (b), a higher effect can be obtained.

[0049] Furthermore, if the uncoated tablet contains at least one member selected from the group consisting of polyvinyl alcohol and macrogol as component (c), dissolution and disintegration properties can be improved.

[0050] In addition, if the uncoated tablet contains sodium starch glycolate as component (d), dissolution can be improved.

[0051] Furthermore, disintegration properties can be improved by adding lactose hydrate as component (e) to the uncoated tablet portion.

[0052] In addition, the selexipag-containing tablet of the present invention can be easily obtained by tableting a mixture containing component (a) and component (b) to form a core tablet. [Example]

[0053] The present invention will be explained in more detail below by way of examples, but the present invention is not limited thereto.

[0054] The measurement conditions for each measurement in this example are as follows. <Impurity measurement test> Using high performance liquid chromatography (HPLC), the amount of impurities derived from selexipag was calculated from the peak area ratio to that of a selexipag standard solution. <Disintegration test> Using an orally disintegrating tablet measuring device (Tricoop Tester, manufactured by Okada Seiko Co., Ltd.), the disintegration time was measured by dropping a fixed amount of water onto a tablet sandwiched between meshes with a load of 40 g at a rate of 6 mL / min and a drop height of 80 mm. <Dissolution test> One tablet was added to 900 mL of dissolution test solution 1, and a dissolution test was performed using the paddle method at 50 revolutions per minute. The test solution was sampled at each sampling time point (5, 10, 15, 30, 45, 60, 90, and 120 minutes), and the dissolution rate of selexipag was measured by high-performance liquid chromatography (HPLC).

[0055] In the examples, unless otherwise specified, the following ingredients were used: lactose hydrate, crystalline cellulose, partially pregelatinized starch, macrogol, low-substituted hydroxypropyl cellulose, sodium starch glycolate, sodium stearyl fumarate, carnauba wax, polyvinyl alcohol, stearic acid, sucrose fatty acid ester, hydrogenated oil, povidone, hydroxypropyl cellulose, hypromellose, red ferric oxide, yellow red ferric oxide, and light anhydrous silicic acid. Lactose hydrate: Tablettose 70 (manufactured by Megre) Crystalline cellulose: Ceolus OD-20P (manufactured by Asahi Kasei Corporation) Partially pregelatinized starch: PCS PC-10 (manufactured by Asahi Kasei Corporation) Low-substituted hydroxypropyl cellulose: NBD-022 (Shin-Etsu Chemical Co., Ltd.) Macrogol: Macrogol 6000P (NOF Corporation) Sodium starch glycolate: EXPLOTAB (manufactured by JRS Pharma) Sodium stearyl fumarate: PRUV (manufactured by JRS Pharma) Carnauba wax: Polishing Wax-105 (manufactured by Freund Corporation) Polyvinyl alcohol: EG-05PW (Mitsubishi Chemical Corporation) Stearic acid: STEARIC ACID 50 (STEARINERIE DUBOIS) Sucrose fatty acid ester: Ryoto Sugar Ester S-370F (Mitsubishi Chemical Foods Corporation) Hardened oil: Rubriwax-101 (manufactured by Freund Corporation) Povidone: Kolidon K30 (BASF) Hydroxypropyl cellulose: HPC-SSL-SFP (Nippon Soda Co., Ltd.) Hypromellose: Metrose NE-4VF (Shin-Etsu Chemical Co., Ltd.) Iron sesquioxide: Iron sesquioxide (manufactured by Kishi Chemical Co., Ltd.) Yellow ferric oxide: Yellow ferric oxide (manufactured by Kishi Chemical Co., Ltd.) Light anhydrous silicic acid: Adsolider-101 (manufactured by Freund Corporation)

[0056] Example 1 Tablets (mass 140 mg, hardness 40 N, thickness 3.3 mm) each containing 0.4 mg of selexipag were obtained by the following steps.

[0057] (1) 0.6 g of selexipag as component (a), 10.5 g of partially pregelatinized starch as a base particle component, 0.6 g of carnauba wax as component (b) (first addition), and 5.4 g of polyvinyl alcohol as component (c) were mixed and granulated using a dry compounding device (Nobilta (registered trademark), manufactured by Hosokawa Micron Corporation). Then, 5.4 g of carnauba wax as component (b) (second addition) was further added and mixed, followed by granulation to form granules (granulation step).

[0058] (2) 7.5 g of the granules obtained in the granulation step were mixed with 2 g of sodium starch glycolate as component (d), 50 g of lactose hydrate as component (e), 10 g of low-substituted hydroxypropyl cellulose as an excipient, and 0.5 g of sodium stearyl fumarate as a lubricant, and then compressed to form a core tablet (tabletting step), producing the core tablets of Example 1. Table 1 shows the content (mg / tablet) of each component per tablet. In Example 1, the content (% by mass) of the components contained inside the granules relative to the total mass of the granules was 2.67% by mass for component (a), 26.7% by mass for component (b), and 24.0% by mass for component (c). In addition, in Example 1, the content (mass %) of the components contained in the tablet relative to the total mass of the tablet is as follows: component (a) 0.286 mass %, component (b) 2.86 mass %, component (c) 2.57 mass %, component (d) 2.86 mass %, and component (e) 71.4 mass %.

[0059] [Table 1]

[0060] (Examples 2 to 18, Comparative Examples 1 to 3) Uncoated tablets containing 0.4 mg or 0.2 mg of selexipag per tablet were produced in the same manner as in Example 1, except that the tablet ingredients, the content of each ingredient per tablet (mg / tablet), and the final tablet mass (mass of the uncoated tablet) were changed as shown in Tables 1 to 4.

[0061] [Table 2]

[0062] [Table 3]

[0063] [Table 4]

[0064] In Examples 2 and 3, macrogol was added as component (c) instead of polyvinyl alcohol in Example 1 during the granulation process. In Examples 4 to 6, povidone, hydroxypropyl cellulose, or hypromellose was added instead of component (c) in Example 1 during the granulation process. In Example 7, ferric oxide and yellow ferric oxide were added as colorants in addition to the components of Example 1 during the tabletting process. In Examples 8 to 14, the amount of carnauba wax added as component (b) and the amount of polyvinyl alcohol added as component (c) were changed from those in Example 1 during the granulation process. In Examples 15 and 16, crystalline cellulose was added as an excipient in addition to the components of Example 1 during the tabletting process. In Examples 17 and 18, crystalline cellulose was added as an excipient, light anhydrous silicic acid was added as a fluidizing agent, and ferric oxide and yellow ferric oxide were added as colorants in addition to the components of Example 1 during the tabletting process.

[0065] In Comparative Examples 1 to 3, stearic acid, sucrose fatty acid ester, or hardened oil was added in place of the carnauba wax of component (b) in Example 1 in the granulation step.

[0066] In each example and each comparative example, the content (mass%) of component (a) contained inside the granule relative to the total mass of the granule is 4.0 mass% for Example 2, 5.0 mass% for Example 3, 2.67 mass% for Example 4, 2.67 mass% for Example 5, 2.67 mass% for Example 6, 2.67 mass% for Example 7, 2.67 mass% for Example 8, 4.76 mass% for Example 9, 4.44 mass% for Example 10, 4.17 mass% for Example 11, 3.64 mass% for Example 12, 3.45 mass% for Example 13, 3.08 mass% for Example 14, 2.94 mass% for Example 15, 2.67 mass% for Example 16, 2.67 mass% for Example 17, 2.67 mass% for Example 18, 2.67 mass% for Comparative Example 1, 2.67 mass% for Comparative Example 2, and 2.67 mass% for Comparative Example 3.

[0067] In each example and each comparative example, the content (% by mass) of component (a) contained in the tablet relative to the total tablet mass was 0.286% by mass for Example 2, 0.286% by mass for Example 3, 0.286% by mass for Example 4, 0.286% by mass for Example 5, 0.286% by mass for Example 6, 0.286% by mass for Example 7, 0.286% by mass for Example 8, 0.286% by mass for Example 9, and 0.286% by mass for Example 10. 6% by mass, Example 11 is 0.286% by mass, Example 12 is 0.286% by mass, Example 13 is 0.286% by mass, Example 14 is 0.286% by mass, Example 15 is 0.286% by mass, Example 16 is 0.286% by mass, Example 17 is 0.286% by mass, Example 18 is 0.286% by mass, Comparative Example 1 is 0.286% by mass, Comparative Example 2 is 0.286% by mass, and Comparative Example 3 is 0.286% by mass.

[0068] In each example and each comparative example, the content (mass%) of component (b) contained inside the granule relative to the total mass of the granule is 10.0 mass% for Example 2, 12.5 mass% for Example 3, 26.7 mass% for Example 4, 26.7 mass% for Example 5, 26.7 mass% for Example 6, 26.7 mass% for Example 7, 9.52 mass% for Example 8, 15.6 mass% for Example 9, 20.8 mass% for Example 10, 12.7 mass% for Example 11, 17.2 mass% for Example 12, 10.8 mass% for Example 13, 14.7 mass% for Example 14, 26.7 mass% for Example 15, 26.7 mass% for Example 16, 26.7 mass% for Example 17, 26.7 mass% for Example 18, 0 mass% for Comparative Example 1, 0 mass% for Comparative Example 2, and 0 mass% for Comparative Example 3.

[0069] In each example and each comparative example, the content (% by mass) of component (b) contained in the tablet relative to the total tablet mass is: Example 2: 0.714% by mass, Example 3: 0.714% by mass, Example 4: 2.86% by mass, Example 5: 2.86% by mass, Example 6: 2.86% by mass, Example 7: 2.86% by mass, Example 8: 0.571% by mass, Example 9: 1.00% by mass, Example 10: 1.43% by mass, Example 11: 1.00% by mass, Example 12: 1.43% by mass, Example 13: 1.00% by mass, Example 14: 1.43% by mass, Example 15: 2.86% by mass, Example 16: 2.86% by mass, Example 17: 2.86% by mass, Example 18: 2.86% by mass, Comparative Example 1: 0% by mass, Comparative Example 2: 0% by mass, Comparative Example 3: 0% by mass.

[0070] In each example and each comparative example, the content (mass%) of component (c) contained inside the granule relative to the total mass of the granule is 4.0 mass% for Example 2, 5.0 mass% for Example 3, 0 mass% for Example 4, 0 mass% for Example 5, 0 mass% for Example 6, 24.0 mass% for Example 7, 0 mass% for Example 8, 0 mass% for Example 9, 0 mass% for Example 10, 18.2 mass% for Example 11, 17.2 mass% for Example 12, 30.8 mass% for Example 13, 29.4 mass% for Example 14, 24.0 mass% for Example 15, 24.0 mass% for Example 16, 24.0 mass% for Example 17, 24.0 mass% for Example 18, 24.0 mass% for Comparative Example 1, 24.0 mass% for Comparative Example 2, and 24.0 mass% for Comparative Example 3.

[0071] In each example and each comparative example, the content (% by mass) of component (c) contained in the tablet relative to the total tablet mass is: Example 2: 0.286% by mass, Example 3: 0.286% by mass, Example 4: 0% by mass, Example 5: 0% by mass, Example 6: 0% by mass, Example 7: 2.57% by mass, Example 8: 0% by mass, Example 9: 0% by mass, Example 10: 0% by mass, Example 11: 1.43% by mass, Example 12: 1.43% by mass, Example 13: 2.86% by mass, Example 14: 2.86% by mass, Example 15: 2.57% by mass, Example 16: 2.57% by mass, Example 17: 2.57% by mass, Example 18: 2.57% by mass, Comparative Example 1: 2.57% by mass, Comparative Example 2: 2.57% by mass, and Comparative Example 3: 2.57% by mass.

[0072] In each example and each comparative example, the content (% by mass) of component (d) contained in the tablet relative to the total tablet mass is 2.86% by mass for Example 2, 3.57% by mass for Example 3, 2.86% by mass for Example 4, 2.86% by mass for Example 5, 2.86% by mass for Example 6, 2.86% by mass for Example 7, 2.86% by mass for Example 8, 3.57% by mass for Example 9, 3.57% by mass for Example 10, 3.57% by mass for Example 11, 3.57% by mass for Example 12, 3.57% by mass for Example 13, 3.57% by mass for Example 14, 3.57% by mass for Example 15, 2.86% by mass for Example 16, 2.86% by mass for Example 17, 3.00% by mass for Example 18, 2.86% by mass for Comparative Example 1, 2.86% by mass for Comparative Example 2, and 2.86% by mass for Comparative Example 3.

[0073] In each example and each comparative example, the content (% by mass) of component (e) contained in the tablet relative to the total tablet mass is 53.6% by mass in Example 2, 55.0% by mass in Example 3, 71.4% by mass in Example 4, 71.4% by mass in Example 5, 71.4% by mass in Example 6, 71.4% by mass in Example 7, 71.4% by mass in Example 8, 67.9% by mass in Example 9, 67.9% by mass in Example 10, 67.9% by mass in Example 11, 67.9% by mass in Example 12, 67.9% by mass in Example 13, 67.9% by mass in Example 14, 67.9% by mass in Example 15, 64.3% by mass in Example 16, 64.3% by mass in Example 17, 35.7% by mass in Example 18, 35.7% by mass in Comparative Example 1, 71.4% by mass in Comparative Example 2, and 71.4% by mass in Comparative Example 3.

[0074] (evaluation) The tablets obtained in Examples 1 to 14, 17 to 18 and Comparative Examples 1 to 3 were subjected to an impurity measurement test, a disintegration test, and a dissolution test as described above. In the impurity measurement test, the amount of impurities before storage and the amount of impurities after storage at 60°C for one month were measured for each tablet, and the increase in impurities after storage at 60°C for one month was calculated using the following formula. In addition, a disintegration test was also conducted for Examples 15 and 16.

[0075]

number

[0076] Tables 5 to 8 show the increase in impurities after storage at 60°C for one month, the disintegration time, and the dissolution rate (%) at 120 minutes in the first dissolution test fluid (pH 1.2) for Examples 1 to 18 and Comparative Examples 1 to 3.

[0077] [Table 5]

[0078] [Table 6]

[0079] [Table 7]

[0080] [Table 8]

[0081] As shown in Tables 5 to 8, Examples 1 to 14, 17, and 18, which contain carnauba wax as component (b), were able to significantly reduce the amount of impurity increase compared to Comparative Examples 1 to 3, which do not contain carnauba wax as component (b). In other words, it was found that the inclusion of carnauba wax as component (b) can improve storage stability.

[0082] Furthermore, as can be seen from a comparison between Examples 1 to 3 and Examples 4 to 6, Examples 1 to 3, which contain polyvinyl alcohol or macrogol as component (c), achieved higher dissolution rates than Examples 4 to 6, which do not contain component (c). Furthermore, Examples 1 to 3 also achieved excellent results in terms of disintegration. In addition, Example 1, which contains polyvinyl alcohol as component (c), was better in terms of storage stability and disintegration. In other words, it was found that the inclusion of component (c) can achieve excellent disintegration and dissolution properties, and that the inclusion of polyvinyl alcohol as component (c) can achieve excellent properties in terms of storage stability, disintegration, and dissolution.

[0083] Although the present invention has been described above by giving embodiments and examples, the present invention is not limited to the above embodiments and examples, and various modifications are possible. [Industrial Applicability]

[0084] According to the present invention, a selexipag-containing tablet having excellent storage stability can be provided.

Claims

1. A selexipag-containing tablet, characterized in that the uncoated tablet contains (a) at least one member selected from the group consisting of selexipag, a salt of selexipag, and a solvate of selexipag, and (b) carnauba wax.

2. 2. The selexipag-containing tablet according to claim 1, wherein the uncoated tablet portion has granules, and the granules contain the component (a) and the component (b).

3. The selexipag-containing tablet according to claim 1 or 2, characterized in that the uncoated tablet contains (c) at least one member selected from the group consisting of polyvinyl alcohol and macrogol.

4. The selexipag-containing tablet according to claim 3, characterized in that the uncoated tablet portion has granules, and the component (c) is contained inside the granules.

5. The selexipag-containing tablet according to claim 1 or 2, characterized in that the uncoated tablet contains (d) sodium starch glycolate.

6. The selexipag-containing tablet according to claim 1 or 2, characterized in that the uncoated tablet contains (e) lactose hydrate.

7. A method for producing a selexipag-containing tablet, comprising a tableting step of tableting a mixture containing (a) at least one selected from the group consisting of selexipag, a salt of selexipag, and a solvate of selexipag, and (b) carnauba wax to form a core tablet.

8. The method for producing a selexipag-containing tablet according to claim 7, further comprising a granulation step of granulating a composition containing the component (a) and the component (b) to form granules prior to the tableting step.

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