Process for the preparation of selexipag containing tablets

Abstract

To provide a method for producing highly stable tablets containing Selexipag.SOLUTION: According to one embodiment of the present invention, there is provided a method for producing tablets containing Selexipag, comprising granulating additives to produce a granulated product, mixing the granulated product with Selexipag to obtain a mixture, and tableting the mixture, wherein the granulated product does not substantially contain Selexipag in the method for producing tablets containing Selexipag. The additive in the granulated product may include at least one selected from the group consisting of D-mannitol, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Selexipag (2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide) is a selective prostacyclin receptor (IP receptor) agonist. Selexipag selectively binds to human prostacyclin receptors, concentration-dependently increasing cyclic AMP production and exhibiting agonist activity. Selexipag-containing tablets include, for example, Uptravi® Tablets, which can be used to treat pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension that is unsuitable for surgical treatment or that persists or recurs after surgical treatment.

[0003] In order to improve the stability of selexipag-containing tablets, for example, Patent Document 1 discloses a method for preparing tablets having a specific surface area of ​​1.0 m 2

[0003] Patent Document 2 discloses the use of D-mannitol at a concentration of 0.1g or less. Patent Document 2 also discloses that by using starch and at least one binder selected from the group consisting of hydroxypropyl cellulose and hypromellose in a specific ratio together with selexipag, solid tablets exhibit good disintegration properties while suppressing the degradation of selexipag and stably maintaining selexipag. Patent Document 2 also discloses a process of preparing a powder mixture of selexipag, starch, and excipients, adding a solution containing at least one binder selected from the group consisting of hydroxypropyl cellulose and hypromellose to the powder mixture, and granulating the mixture to obtain a granulated product. Patent Documents 1 and 2 improve the stability of selexipag by using specific additives or by using specific additives to obtain a selexipag-containing granulated product. However, there is a need for a simpler method for improving the stability of selexipag. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 6825574 [Patent Document 2] Patent No. 6989064 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a method for producing selexipag-containing tablets with improved stability. [Means for solving the problem]

[0006] According to one embodiment of the present invention, there is provided a method for producing a selexipag-containing formulation, which comprises granulating additives to produce a granule, mixing the granule with selexipag to obtain a mixture, and compressing the mixture into tablets, wherein the granule does not substantially contain selexipag.

[0007] The additive in the granules may include at least one selected from the group consisting of D-mannitol, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose. [Effects of the Invention]

[0008] According to the present invention, a method for producing a selexipag-containing tablet with improved stability is provided. DETAILED DESCRIPTION OF THE INVENTION

[0009] The method for producing the selexipag-containing tablet of the present invention will be described in detail below. However, the method for producing the selexipag-containing tablet of the present invention should not be construed as being limited to the description of the following embodiments and examples.

[0010] As a result of investigations conducted by the present inventors, it was found that the stability of selexipag deteriorates when selexipag-containing tablets are produced by direct compression. However, when selexipag-containing tablets are produced by producing a granulation product not containing selexipag by wet granulation and then tableting a mixture containing the granulation product and selexipag, the stability of selexipag is improved.

[0011] Selexipag may be contained in an amount of, for example, 0.2 mg or 0.4 mg per selexipag-containing tablet according to the present invention.

[0012] Selexipag may have a particle size D50 of 4.4, 4.51, 5.50, 8.57, 9.07, 8.65, 9.34, 12.6, or 18.2 μm. The use of selexipag with a particle size D50 of 4.4 μm or greater can improve stability and ensure content uniformity in selexipag-containing tablets.

[0013] The selexipag-containing tablet of this embodiment contains additives necessary for forming the tablet. Examples of additives include excipients, binders, disintegrants, lubricants, etc. The additives may be used alone or in combination of two or more. When two or more additives are used, the tablet may contain a so-called premixed additive, which is a mixture of multiple additives and granulated in advance.

[0014] The selexipag-containing tablets of this embodiment are manufactured by first preparing a granulated product substantially free of selexipag by wet granulation, and then tableting a mixture containing the granulated product and selexipag. It is preferable to add a lubricant when preparing the mixture containing the granulated product and selexipag. The selexipag-containing tablets of this embodiment may be manufactured from a mixture containing the granulated product and selexipag. After preparing a granulated product substantially free of selexipag, selexipag and, if necessary, other additives are mixed with the granulated product, and the mixture is tableted, resulting in selexipag-containing tablets with improved stability.

[0015] In this embodiment, examples of additives contained in the granules include excipients, binders, disintegrants, lubricants, and the like.

[0016] Examples of excipients include, but are not limited to, starch, crystalline cellulose, cellulose derivatives and salts thereof, dextrin, lactose hydrate, D-mannitol, sorbitol, xylitol, trehalose, anhydrous calcium hydrogen phosphate, sucrose, talc (natural magnesium silicate dihydrate), precipitated calcium carbonate, corn starch, light anhydrous silicic acid, magnesium aluminometasilicate, etc. Preferred excipients include, for example, D-mannitol and corn starch.

[0017] Examples of binders include, but are not limited to, starch, dextrin, tragacanth, gelatin, povidone, polyvinyl alcohol, hydroxypropyl cellulose (HPC), crystalline cellulose, hypromellose, ethyl cellulose, methacrylic acid copolymer, sucrose, starch syrup, gum arabic, etc. Preferred binders include, for example, hydroxypropyl cellulose and hypromellose.

[0018] Examples of disintegrants include, but are not limited to, starch, crystalline cellulose, carmellose calcium, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), sodium starch glycolate, croscarmellose sodium, carmellose, powdered agar, etc. The disintegrant preferably contains one or more selected from, for example, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and sodium starch glycolate.

[0019] Examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, sodium stearyl fumarate, boric acid, paraffin, cocoa butter, macrogol, leucine, sodium benzoate, etc. A preferred lubricant is, for example, magnesium stearate.

[0020] Preferred examples of additives contained in the granules include D-mannitol, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose.

[0021] In this embodiment, selexipag and additives are added outside the granules. Examples of additives added outside the granules include magnesium stearate.

[0022] (Manufacturing method) The selexipag-containing tablet of the present invention is first produced by preparing granules substantially free of selexipag using a known granulation method, such as wet granulation methods like agitation granulation and fluidized bed granulation, or dry granulation methods like flake granulation, briquette granulation, and melt granulation.

[0023] The resulting granules are then mixed with selexipag, and the resulting mixture is compressed using a commonly used tablet press to produce selexipag-containing tablets. Any shape can be used for the tablets, and they can be molded into, for example, tablet-shaped, oval, spherical, or rod-shaped shapes.

[0024] The method for producing selexipag-containing tablets according to this embodiment involves first producing a granulated product substantially free of selexipag by wet granulation, and then tableting a mixture containing the granulated product and selexipag, thereby suppressing the production of selexipag-related substances during storage and improving the stability of selexipag. [Example]

[0025] An example of a method for producing a selexipag-containing tablet according to the present invention is shown below, but this description is merely an example and is not intended to limit the scope of the present invention.

[0026] Example 1 Per tablet, 30.0 mg of D-mannitol (Pearitol® 100SD, Rocket Japan Co., Ltd.), 7.0 mg of hydroxypropyl cellulose (HPC SSL, Nippon Soda Co., Ltd.), and 90.8 mg of low-substituted hydroxypropyl cellulose (L-HPC® LH-B1, Shin-Etsu Chemical Co., Ltd.) were mixed in a high-speed wet granulator (Fukae Kogyo Co., Ltd., FS-GS-5J) to obtain a mixture. The resulting mixture was subjected to fluidized bed granulation while spraying purified water. The resulting granules were dried and then sized using a power mill (mesh opening: approximately 480 μm) to obtain granules.

[0027] A portion of the resulting granules was mixed with 0.2 mg of selexipag (particle size D50: 4.4 μm), and the remaining granules were added and mixed. 2.0 mg of magnesium stearate (from a plant, Taihei Chemical Industry) was added and mixed thoroughly, and the mixture was compressed using a rotary tablet press (VELA5, Kikusui Seisakusho Co., Ltd.) to obtain 130.0 mg selexipag-containing tablets (semi-direct compression method). The particle size D50 mentioned above is the 50% particle size (mean particle size (μm)) in the cumulative particle size distribution on a volume basis, and was measured dry by the laser diffraction / scattering method using a laser diffraction / scattering particle size distribution analyzer.

[0028] (Comparative Example 1) Selexipag and all of the additives were added in the amounts identical to those used in Example 1 and mixed thoroughly, and then molded using a rotary tableting machine (VELA5, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a selexipag-containing tablet with a mass of 130.0 mg (direct compression method).

[0029] (Stability of selexipag-containing tablets) The selexipag-containing tablets were stored at 60°C under sealed conditions for one week. To evaluate stability, the purity of the selexipag-containing tablets after storage was evaluated using HPLC. Using the area percentage method, the sum of the peak areas of selexipag and selexipag-derived analogs obtained on the chromatogram was set to 100, and the amounts (%) of selexipag-derived hydrolysates and total analogs were calculated from the peak area ratio. The amounts (%) of selexipag-derived hydrolysates and total analogs contained in Example 1 and Comparative Example 1 are shown in Table 1.

[0030] [Table 1]

[0031] Table 1 shows the amounts (%) of selexipag-derived hydrolysates and total related substances after storage in Example 1 and Comparative Example 1. As shown in Table 1, the selexipag-containing tablets of Example 1, which were produced by a semi-direct compression method in which selexipag-free granules were produced by wet granulation and then a mixture containing the granules and selexipag was compressed into tablets, were able to suppress the generation of selexipag-related substances during storage and improve the stability of selexipag compared to the selexipag-containing tablets of Comparative Example 1, which were produced by direct compression.

[0032] Examples 2 to 9 Per tablet, 24.0 mg of D-mannitol (Pearitol® 100SD, Rocket Japan Co., Ltd.), 6.0 mg of hydroxypropyl cellulose (HPC SSL, Nippon Soda Co., Ltd.), 22.8 mg of low-substituted hydroxypropyl cellulose (L-HPC® LH-B1, Shin-Etsu Chemical Co., Ltd.), and 22.8 mg of corn starch (xx16, Nippon Food Chemical Co., Ltd.) were mixed in a high-speed wet granulator (Fukae Kogyo Co., Ltd., FS-GS-5J) to obtain a mixture. The resulting mixture was subjected to fluidized bed granulation while spraying purified water. The resulting granules were dried and then sized using a power mill (mesh opening: approximately 480 μm) to obtain granules.

[0033] A portion of the obtained granules was mixed with 0.2 mg of selexipag having different particle sizes (particle size D50: 4.51, 5.50, 8.57, 9.07, 8.65, 9.34, 12.6, or 18.2 μm), and the remaining granules were added and mixed. 10.0 mg of hydroxypropyl cellulose (HPC SSL-SFP, Nippon Soda Co., Ltd.), 8.0 mg of low-substituted hydroxypropyl cellulose (L-HPC (registered trademark) LH-B1, Shin-Etsu Chemical Co., Ltd.), and 1.0 mg of magnesium stearate (plant-based, Taihei Chemical Industry Co., Ltd.) were added and mixed thoroughly, and the mixture was formed using a rotary tablet press (VELA5, Kikusui Seisakusho Co., Ltd.) to obtain selexipag-containing tablets with a mass of 130.0 mg (semi-direct compression method). The particle size D50 of selexipag is the 50% particle size (average particle size (μm)) in the cumulative particle size distribution on a volume basis, and was measured in a dry state by the laser diffraction / scattering method using a laser diffraction / scattering particle size distribution analyzer.

[0034] (Stability of selexipag-containing tablets) The selexipag-containing tablets were stored at 60°C under sealed conditions for 2 weeks. To evaluate stability, the purity of the selexipag-containing tablets after storage was evaluated using HPLC. Using the area percentage method, the sum of the peak areas of selexipag and selexipag-derived analogs obtained on the chromatogram was set to 100, and the amounts (%) of selexipag-derived hydrolysates and total analogs were calculated from the peak area ratio. The amounts (%) of selexipag-derived hydrolysates and total analogs contained in Examples 2 to 9 are shown in Table 2.

[0035] (Uniformity of selexipag-containing tablets) The uniformity of the selexipag-containing tablets was evaluated according to the content uniformity test of the Dosage Form Uniformity Test Method of the 18th Edition of the Japanese Pharmacopoeia, with the number of samples being n = 10. The selexipag content in the formulation was quantified by high-performance liquid chromatography (HPLC).

[0036] [Table 2]

[0037] Table 2 shows the amounts (%) of selexipag-derived hydrolysates and total related substances before and after storage in Examples 2 to 9. As shown in Table 2, the selexipag-containing tablets of Examples 2 to 9, which were produced by a semi-direct compression method in which selexipag-free granules were produced by wet granulation and then a mixture containing the granules and selexipag was compressed into tablets, were able to suppress the production of selexipag-related substances during storage and improve the stability of selexipag compared to the selexipag-containing tablets of Comparative Example 1 produced by direct compression.

[0038] Furthermore, the selexipag-containing tablets of Examples 2 to 9, which used selexipag with different particle sizes (particle size D50: 4.51, 5.50, 8.57, 9.07, 8.65, 9.34, 12.6, and 18.2 μm), showed that the larger the particle size, the more effectively they could suppress the generation of selexipag-related substances during storage, thereby improving the stability of selexipag.All of the selexipag-containing tablets of Examples 2 to 9, which used selexipag with different particle sizes (particle size D50: 4.51, 5.50, 8.57, 9.07, 8.65, 9.34, 12.6, and 18.2 μm), were able to ensure content uniformity.

[0039] Even if there are other effects and advantages different from those brought about by the aspects of each of the above-mentioned embodiments, those that are clear from the description in this specification or that can be easily predicted by a person skilled in the art are naturally understood to be brought about by the present invention.

Claims

1. granulating the additives to produce a granulated product; The granules are mixed with selexipag to obtain a mixture, and compressing the mixture into tablets, A method for producing a selexipag-containing tablet, wherein the granules do not substantially contain selexipag.

2. 2. The method for producing a selexipag-containing tablet according to claim 1, wherein the additive in the granules comprises at least one selected from the group consisting of D-mannitol, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose.

3. The method for producing a selexipag-containing tablet according to claim 1, wherein the particle size of the selexipag is D50 of 4.4 μm or more.

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