Pharmaceutical composition

Abstract

To provide a pharmaceutical composition containing pemafibrate or its salts or solvates thereof, exhibiting excellent homogeneity. [Solution] The following components (A) and (B-1): (A) Pemafibrates or salts thereof, or solvates thereof; (B-1) Hydroxypropylcellulose: 0.5 to 30% by mass relative to the total mass of the pharmaceutical composition; It contains and is a solid dosage form. The mass ratio of component (B-1) per 1 part by mass of pemafibrate-free form is 3 to 200 parts by mass. A pharmaceutical composition containing an amount of ingredient (A) that allows for a daily dose of 0.1 to 0.4 mg of pemafibrate in free form.

Description

Technical Field

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[0001] The present invention relates to pharmaceutical compositions and the like.

Background Art

[0002] The following structural formula:

[0003]

Chemical Formula

[0004] Pemafibrate represented by (chemical name: (2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid ((2R)-2-[3-([1,3-Benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino]methyl)phenoxy]butanoic acid), international common name: Pemafibrate), or a salt thereof or a solvate thereof has excellent PPARα agonist activity and exhibits effects such as a decrease in plasma triglyceride concentration and an increase in HDL cholesterol, and is useful for the prevention and treatment of dyslipidemia (hyperlipidemia) (Patent Document 1, Non-Patent Documents 1, 2), and is also known to be useful for the prevention and treatment of NAFLD (non-alcoholic fatty liver disease) (Patent Document 2). zol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid)、国際一般名:Pemafibrate)若しくはその塩又はそれ らの溶媒和物は、優れたPPARαアゴニスト活性を有し、血漿トリグリセライド濃度の 低下やHDLコレステロールの増加等の作用を示し、脂質異常症(高脂血症)の予防や治 療に有用であること(特許文献1、非特許文献1、2)や、NAFLD(非アルコール性 脂肪性肝疾患)の予防や治療に有用であること(特許文献2)が知られている。

[0005] 脂肪性肝疾患)の予防や治療に有用であること(特許文献2)が知られている。

[0005] However, a compound useful as an active ingredient of a pharmaceutical product is usually formulated and supplied as some kind of pharmaceutical composition. From the viewpoint of reliably exerting the expected medicinal effects and avoiding unexpected side effects, it is extremely important to ensure a constant quality without variation among batches and the like for the supplied pharmaceutical composition. を回避する観点から、供給される医薬組成物について、ロット間等でばらつきなく一定の 品質を確保させることは極めて重要となる。

Prior Art Documents

[0006] [Patent Document 1] International Publication No. 2005 / 023777 Pamphlet [Patent Document 2] International Publication No. 2015 / 005365 Brochure [Non-patent literature]

[0007] [Non-Patent Document 1] Yukiyoshi Yamazaki, et al., Synthesis, 2008(7), 1017-1022. [Non-Patent Document 2] Fruchart JC., Cardiovasc Diabetol., 2013; 12: 82. [Overview of the project] [Problems that the invention aims to solve]

[0008] However, the manufacturability of pharmaceutical compositions, including homogeneity, depends on the physical and chemical properties of the constituent ingredients. This is largely dependent on the specific properties, and these properties cannot be predicted in advance from their chemical structure, etc. In many cases, problems only become apparent after the pharmaceutical composition has actually been manufactured. Establishing techniques to ensure the homogeneity of pharmaceutical compositions typically requires a great deal of trial and error. . Furthermore, with respect to pemafibrates or their salts or solvates, as described above... It has only been reported that it exhibits pharmacological effects, and it is not yet considered a pharmaceutical composition. This has not been specifically considered to date, and the manufacturability, such as the homogeneity of the pharmaceutical composition, is not yet being considered. This had never been reported before. Against this backdrop, pemafibrate or its salts or solvates thereof are contained In order to develop a pharmaceutical composition, the inventors first actually manufactured the pharmaceutical composition. However, it was found that the content of pemafibrate varied among the pharmaceutical compositions, resulting in a problem with the homogeneity (content uniformity) of the pemafibrate content in the pharmaceutical compositions. If the pemafibrate content varies significantly among the pharmaceutical compositions, it may lead to variations in efficacy and safety among the pharmaceutical compositions. Therefore, the problem of the present invention is to provide a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof, which has excellent homogeneity.

Means for Solving the Problems

[0009] Therefore, the inventors further intensively studied to solve the problem of content uniformity of pemafibrate or a salt thereof or a solvate thereof (hereinafter, sometimes simply referred to as "component (A)" in this specification) in the pharmaceutical composition. As a result, in the pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof (hereinafter, sometimes simply referred to as "component (A)" in this specification), any one of the following components 1 to 6 (hereinafter, in this specification, components 1 to 6 are respectively referred to as "component (B-1)", "component (B-2)", "component (B-3)", "component (B-4)", "component (B-5)", "component (B-6)", and "one or more selected from the group consisting of components (B-1) to (B-6)" may also be referred to as "component (B)").):

[0010] [[ID=​​​​​​​​​​​​ Starches; 3. Povidones represented by crospovidone and polyvinylpyrrolidone; 4. Silicate compounds represented by magnesium silicate hydrate, silicon dioxide hydrate, and light anhydrous silicic acid; Compound; 5. Polyhydric alcohols represented by macrogol and mannitol; 6. Alkyl sulfates represented by sodium lauryl sulfate; By containing these, the content uniformity of pemafibrate in the pharmaceutical composition is improved. The inventors have found this and completed the present invention.

[0011] That is, the present invention provides the following components (A) and (B): (A) Pemafibrate or a salt thereof or a solvate thereof; (B) One or more selected from the group consisting of the following components (B-1) to (B-6); (B-1) Cellulose ethers (B-2) Starches (B-3) Povidones (B-4) Silicate compounds (B-5) Polyhydric alcohols (B-6) Alkyl sulfates It provides a pharmaceutical composition containing these. (B-4) Silicate compounds

[0012] Further, the present invention provides a method for improving the content uniformity of pemafibrate or a salt thereof or a solvate thereof in a pharmaceutical composition, which comprises a step of adding one or more selected from the group consisting of components (B-1) to (B-6) to a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof.

Advantages of the Invention

[0013] According to the present invention, the content uniformity of pemafibrate in the pharmaceutical composition is improved, and the homogeneity is This allows us to provide superior pharmaceutical compositions. [Modes for carrying out the invention]

[0014] <Pemafibrate or its salt or solvate thereof (Component (A))> In this specification, "pemafibrate or its salt or solvate thereof" means Mafibrate (Chemical name: (2R)-2-[3-({1,3-benzoxazole-2- Il[3-(4-methoxyphenoxy)propyl]aminomethyl)phenoxy]butane Acid ((2R)-2-[3-([1,3-Benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino]methyl)phen In addition to pemafibrate itself (oxy-butanoic acid, international common name: pemafibrate), pemafibrate is also used. Pharmaceutically acceptable salts, as well as pemafibrate and its pharmaceutically acceptable salts, and water and alcohol This also includes solvates with coal (e.g., ethanol). Pharmaceutically acceptable salts include Examples of acid addition salts include acid addition salts and base addition salts. Specifically, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate. Acid addition salts with inorganic acids; benzoates, methanesulfonates, ethanesulfonates, benzates Zensulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, Examples include acid addition salts with organic acids such as citrates and acetates. Also, as for base addition salts, Specifically, sodium salts, potassium salts, lithium salts, calcium salts, magnesium salts, etc. Metal salts of ammonia, trimethylamine, triethylamine, pyridine, coridine, ru Salts of amines such as thidine; organic bases such as lysine, arginine, cinconine, and cinconidine. Examples include base addition salts.

[0015] The shape, size, etc. of pemafibrates or their salts or solvates are not particularly limited. However, according to the particle size measurement method by laser diffraction in the 17th edition of the Japanese Pharmacopoeia, primary particles When the average particle size is measured, it is preferable that d50 and d90 are as follows, respectively. . d50: Preferably 100 μm or less, more preferably 50 μm or less, 2 A thickness of 0 μm or less is even more preferable, and a thickness of 1 to 20 μm is particularly preferable. d90: Preferably 200 μm or less, more preferably 135 μm or less. It is more preferable that the particle size is 80 μm or less, and particularly preferable that it is between 1 and 80 μm.

[0016] Pemafibrates or their salts or solvates are known compounds, for example. According to the methods disclosed in Patent Document 1, Non-Patent Document 1, and U.S. Patent No. 7,109,226 It can be manufactured by the method described in Non-Patent Document 1. Pemafibrate crystals (preferably according to the Melting Point Measurement Method No. 1 of the 17th Edition of the Japanese Pharmacopoeia) When measured, crystals having a melting point of 95-101°C, particularly preferably 97-100°C, are used. It is preferable that they be included. Furthermore, the contents of these documents are incorporated herein by reference.

[0017] The content of pemafibrate or its salt or solvate in the pharmaceutical composition is There are no particular limitations, and the appropriate approach is taken depending on the disease to which the preparation is applied, the gender and age of the user, symptoms, etc. It can be considered and decided. For example, per day, pemafibrate or its salt Alternatively, 0.05 to 0.8 mg of their solvates, converted to the free form of pemafibrate. More preferably, an amount that can be taken at a dose of 0.075 to 0.6 mg, and especially preferably, 0.1 to 0.4 mg. It can be made to contain. The content of pemafibrate or its salt or solvate thereof in a pharmaceutical composition and Therefore, relative to the total mass of the pharmaceutical composition, the amount of pemafibrate in free form is 0.01 to 5 Preferably it is in mass%, more preferably 0.025 to 1 mass%, and 0.05 to It is particularly preferable that it be 0.5% by mass. According to the present invention, pemafibrate or the Even when the salt or its solvate is present in such low concentrations, good content uniformity can be obtained. It can be done.

[0018] <Cellulose ethers (component (B-1))> In this specification, "cellulose ethers" means all or all of the hydroxyl groups of cellulose. This refers to one or more compounds selected from the group consisting of compounds in which a portion forms an ether bond and salts thereof. It has a taste. In addition to etherification, these cellulose ethers can be esterified as needed. Further modifications such as chemical formation and crosslinking may be applied to the cellulose. Here, the salt is particularly Not limited to these, but specifically, for example, alkali metal salts such as sodium salts and potassium salts; Examples include salts of group 2 elements such as sium salts and magnesium salts. Also, cellulose The average degree of polymerization and properties (crystalline form) of ethers are not particularly limited, but the average degree of polymerization is preferred. Or, it is between 10 and 10,000. Examples of such cellulose ethers include, specifically, methylcellulose and ethylcellulose. Alkylcellulose such as hydrocellulose or its salts; hydroxyethylcellulose, hydro Hydroxyalkylcellulose such as xypropylcellulose or its salts; hydroxyethyl Methylcellulose, hypromellose, hypromellose acetate succinate, Alkyl (hydroxyalkyl) cellulose such as hypromellose phthalate This includes its derivatives (ester derivatives) or salts thereof; carmellose, carmellose potassium Carmellose calcium, carmellose sodium, carboxymethylethylcellulose Carboxyalkylcellulose such as croscarmellose sodium or its derivatives. Examples include cross-linked polymers or salts thereof, and even if one of these is used alone, 2 A combination of more than two species may be used. Note that alkyl groups in the cellulose ethers may also be used. The group is not particularly limited, but linear or branched alkyl groups having 1 to 6 carbon atoms are preferred. Furthermore, the degree of substitution of hydroxyalkoxy groups in hydroxyalkylcellulose is particularly important. It is not limited to this, but for example, hydroxypropyl cellulose has a low degree of substitution. Both hydroxypropylcellulose and low-substituted hydroxypropylcellulose It is included. Here, low-substituted hydroxypropyl cellulose refers to the 17th edition of the Japanese Pharmacopoeia. As described in the method, when dried, 5.0-16.0% of hydroxypropoxy groups are quantified. This refers to hydroxypropyl cellulose.

[0019] As for cellulose ethers, alkylcellulose is used from the viewpoint of improving content uniformity. S, hydroxyalkylcellulose, alkyl(hydroxyalkyl)cellulose, CAL Crosslinked polymers of carboxyalkylcellulose and carboxyalkylcellulose and the Preferably, one or more selected from the group consisting of salts of C1-C6 alkylcellulose, hydr Roxy C1-C6 alkylcellulose, C1-C6 alkyl (hydroxy C1-C6 alkyl (Kil)cellulose, carboxyC1-C6 alkylcellulose and carboxyC1-C6 One or more selected from the group consisting of cross-linked alkylcellulose polymers and salts thereof Preferably, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, Selected from the group consisting of promellose, carmellose, croscarmellose, and their salts. One or more of the following are more preferably methylcellulose, ethylcellulose, hydroxypropylcellulose, etc. Propylcellulose, hypromellose, carmellose, carmellose potassium, carmellose A group consisting of calcium carbonate, carmellose sodium, and croscarmellose sodium. One or more of these are more preferably selected, such as methylcellulose and hydroxypropylcellulose. Sodium, hypromellose, carmellose, carmellose calcium, carmellose sodium One or more selected from the group consisting of and croscarmellose sodium are particularly preferred. As for hydroxypropylcellulose, low-substituted hydroxypropylcellulose is preferred. Furthermore, from the viewpoint of ease of manufacture of pharmaceutical compositions (especially solid dosage forms), cellulose ether Preferably, the material is solid at room temperature (any temperature between 15 and 25°C). Furthermore, these cellulose ethers are all known components and can be processed by known methods. You may manufacture it yourself, or you may use a commercially available product. Examples of such commercially available products include... Etocell (Dow Chemical Japan Ltd.), CMEC (Freund Industrial Co., Ltd.), NS-3 00 (Sanei Gen F.F.I. Co., Ltd.), ECG-505 (Sanei Gen F.F.I. Co., Ltd.) )), Selogen (Sanei Gen F.F.I. Co., Ltd.), Ac-Di-Sol (Asahi Kasei Corporation) ), HEC (Sumitomo Seika Co., Ltd.), Hydroxypropylcellulose (Nippon Soda Co., Ltd.), Shin Shin-Etsu Chemical Co., Ltd. (AQOAT), METOLOSE90SH-SR (Shin-Etsu Chemical Co., Ltd.) (Co., Ltd.), HPMCP (Shin-Etsu Chemical Co., Ltd.), METOLOSE SM (Shin-Etsu Chemical Co., Ltd.) (Co., Ltd.), TC-5 (Sanei Gen F.F.I. Co., Ltd.), L-HPC (Shin-Etsu Chemical Co., Ltd.) Examples include:

[0020] The content of cellulose ethers in a pharmaceutical composition is not particularly limited, and the type of formulation and the amount of cellulose ethers used are not particularly limited. The amount can be determined by considering the user's gender, age, symptoms, etc., as appropriate, but the uniformity of content From the perspective of improvement, the total amount of cellulose ethers relative to the total mass of the pharmaceutical composition is: Preferably, it is 0.5 to 30% by mass, more preferably 1 to 20% by mass, and 1. It is more preferably 5 to 15% by mass, and particularly preferably 2 to 10% by mass.

[0021] Furthermore, when alkylcellulose or its salts are used as cellulose ethers, Regarding the content of cellulose or its salt, from the viewpoint of improving content uniformity, Preferably, the amount is 0.6 to 22% by mass, and more preferably 1.1 to 19% by mass, relative to the total mass of the composition. Furthermore, 3 to 8% by mass is particularly preferred.

[0022] Furthermore, hydroxyalkylcellulose or its salts are used as cellulose ethers. In this case, the content of hydroxyalkylcellulose or its salts is such that it improves the uniformity of the content. From the viewpoint of action, the amount is preferably 0.7 to 24% by mass, and 1.2% by mass, relative to the total mass of the pharmaceutical composition. 18% by mass is more preferable, and 3 to 8% by mass is particularly preferable. Furthermore, as cellulose ethers, alkyl(hydroxyalkyl)cellulose or When using its derivatives or salts, alkyl(hydroxyalkyl)cellulose Regarding the content of s or its derivatives or salts thereof, from the viewpoint of improving content uniformity... Furthermore, the amount is preferably 0.8 to 26% by mass, and 1.3 to 17% by mass, relative to the total mass of the pharmaceutical composition. More preferably, 4 to 9% by mass is particularly preferred. Furthermore, cellulose ethers include carboxyalkylcellulose or its derivatives. Or, when using salts thereof, carboxyalkylcellulose or its derivatives or Regarding the content of these salts, from the viewpoint of improving content uniformity, the amount of salts relative to the total mass of the pharmaceutical composition is considered to be... Preferably, 0.9 to 28% by mass, more preferably 1.4 to 16% by mass, and 1.6 to 9% by mass. Mass percent is particularly preferred.

[0023] In pharmaceutical compositions, pemafibrate or its salt or its solvate and cellulose - The mass ratio of ethers is not particularly limited, but from the viewpoint of improving content uniformity... Then, for every 1 part by mass of pemafibrate in free form, the total amount of cellulose ethers is Preferably, it contains 3 to 200 parts by mass, and more preferably, 5 to 150 parts by mass. It is particularly preferable to contain 10 to 100 parts by mass.

[0024] Furthermore, when using alkylcellulose or its salts as cellulose ethers, In a pharmaceutical composition, pemafibrate or its salt or its solvate and alkyl The mass ratio of lurose or its salt is not particularly limited, but the effect of improving content uniformity is observed. From this point, 1 part by mass of pemafibrate (in terms of free form) contains alkylcellulose or so It is preferable to contain a total of 4 to 160 parts by mass of salt, and preferably 6 to 110 parts by mass. It is preferable to contain 20 to 60 parts by mass. Furthermore, hydroxyalkylcellulose or its salts are used as cellulose ethers. In such cases, the pharmaceutical composition contains pemafibrate or its salt or its solvate. The mass ratio of hydroxyalkylcellulose or its salts is not particularly limited, but the content From the viewpoint of improving uniformity, 1 part by mass of pemafibrate (in terms of free form) contains hydr It is preferable that the total amount of roxyalkylcellulose or its salts be 4 to 170 parts by mass. It is more preferable to contain 7 to 120 parts by mass, and even more preferable to contain 20 to 100 parts by mass. It is particularly preferable that it contains 30 to 70 parts by mass. Furthermore, as cellulose ethers, alkyl(hydroxyalkyl)cellulose or When using its derivatives or salts thereof, pemafibrate in the pharmaceutical composition or its salt or solvates and alkyl(hydroxyalkyl)cellulose or The mass ratio of its derivatives or salts is not particularly limited, but the improvement of content uniformity From the perspective of action, 1 part by mass of pemafibrate (in terms of free form) contains alkyl(hydro A total of 4 to 180 parts by mass of xyalkyl cellulose or its derivatives or salts thereof. It is preferable to contain it, more preferably 8 to 130 parts by mass, and 20 to 100 parts by mass. It is even more preferable to contain parts, and particularly preferable to contain 40 to 80 parts by mass. Furthermore, cellulose ethers include carboxyalkylcellulose or its derivatives. Or, when using their salts, pemafibrate or its salt in the pharmaceutical composition or their solvates and carboxyalkylcellulose or its derivatives or their The mass ratio of salt is not particularly limited, but from the viewpoint of improving content uniformity, pemafi Per 1 part by mass of Braht (on a free form basis), carboxyalkylcellulose or the same Preferably, the mixture contains a total of 4 to 190 parts by mass of derivatives or salts thereof, and 9 to 140 parts by mass. It is more preferable to contain parts, even more preferable to contain 14 to 100 parts by mass, and 19 to 9 It is particularly preferable to contain 0 parts by mass.

[0025] <Starches (Component (B-2))> In this specification, "starchs" refers to starch itself, or the hydroxyl groups of starch. Those which are formed in whole or in part by ether bonding, and their derivatives, and their salts. This means one or more species selected from the group. Note that starches undergo processes such as gelatinization and retrogradation. This also includes those that have undergone the following process. Furthermore, the above derivatives include starch and its etherified products. This includes substances that have undergone further modifications such as esterification, crosslinking, and hydrolysis as needed. Here, the term "salt" is not particularly limited; specifically, it could refer to sodium salts, potassium salts, etc. Alkali metal salts; examples include salts with metals of Group 2 elements such as calcium salts and magnesium salts. It can be done. Examples of these starches include pregelatinized starch and wheat starch. Rice starch, corn starch, potato starch, partially pregelatinized starch Starches such as wheat flour, rice flour, and semi-digested starch, or their salts; hydroxypropyl starch Hydroxyalkyl ethers of starch or their salts; carboxymethyl starch Examples include carboxyalkyl ethers of starch such as sodium thinose or their salts. These may be used individually or in combination of two or more. The alkyl group in the punctum is not particularly limited, but it is a linear or fractional alkyl group having 1 to 6 carbon atoms. Branched alkyl groups are preferred.

[0026] As for starches, from the viewpoint of improving content uniformity, starch and hydrochloride of starch are used. From xyalkyl ethers and carboxyalkyl ethers of starch and salts thereof Preferably, one or more selected from the group, including starch, and hydroxy C1-C6 of starch. Carboxylate ethers and starch carboxyl C1-C6 alkyl ethers, and their salts One or more are more preferably selected from the following group, including starch, hydroxypropyl starch. One or more selected from the group consisting of thio and carboxymethyl starch and their salts More preferably, selected from the group consisting of starch and carboxymethyl starch sodium. One or more of these are particularly preferred. Also, from the viewpoint of ease of manufacture of the pharmaceutical composition (especially solid dosage forms) Furthermore, starches are those that are solid at room temperature (any temperature between 15 and 25°C). preferable. Furthermore, these starches are all known components and can be manufactured using known methods. Good, and you can also use commercially available products. For example, LYCA TAB PGS (Rocket Japan Co., Ltd.), GLYCOLYS (Rocket Japan Co., Ltd.) )), starch (soluble) (Kishida Chemical Co., Ltd.), corn starch (Sanei Gen F.E.) F.I. Co., Ltd., Potato Starch (Pure Chemical Co., Ltd.), HPS-101 (Freon) Examples include To Sangyo Co., Ltd. and LYCATABC (Rocket Japan Co., Ltd.).

[0027] The starch content in the pharmaceutical composition is not particularly limited, and the type of preparation and the gender of the user may affect the content. The appropriate treatment can be determined by considering age, symptoms, etc., but the effect of improving content uniformity is From this perspective, the total amount of starches relative to the total mass of the pharmaceutical composition should be 0.5 to 50% by mass. It is preferable to have it, more preferably 1 to 40% by mass, and 1.5 to 30% by mass. It is even more preferable that the amount is 2 to 20% by mass.

[0028] Furthermore, when using starch as a type of starch, the average starch content is as follows: From the viewpoint of improving uniformity, a concentration of 0.6 to 47% by mass of the total mass of the pharmaceutical composition is preferable. 1.1 to 38% by mass is more preferred, and 1.6 to 28% by mass is particularly preferred. Furthermore, starch carboxyalkyl ethers or salts thereof are used as starches. In this case, the content of carboxyalkyl ether or salt thereof of starch is as follows: From the viewpoint of improving the effect, 0.8 to 45% by mass is preferred based on the total mass of the pharmaceutical composition, 0.3 to 36% by mass is more preferred, and 1.7 to 26% by mass is particularly preferred.

[0029] In pharmaceutical compositions, pemafibrate or its salt or its solvate and starch The mass ratio of the content with other compounds is not particularly limited, but from the viewpoint of improving content uniformity, Pemaf For every 1 part by mass of free dibrate, it contains a total of 5 to 400 parts by mass of starches. It is preferable to include 15 to 300 parts by mass, more preferably 20 to 200 parts by mass. It is particularly preferable to include it.

[0030] Furthermore, when starch is used as a starch, pemafibros in the pharmaceutical composition The mass ratio of starch to starch, its salts, or their solvates is not particularly limited. However, from the viewpoint of improving content uniformity, in terms of free form of pemafibrate, 1 part by mass In contrast, it is preferable to contain a total of 7 to 380 parts by mass of starch, and 16 to 280 parts by mass. It is more preferable to have it, and particularly preferable to contain 30 to 190 parts by mass. Furthermore, starch carboxyalkyl ethers or salts thereof are used as starches. In this case, the pharmaceutical composition contains pemafibrate or its salt or its solvate and The mass ratio of the carboxyalkyl ether or salt thereof to the punctum is not particularly limited. From the viewpoint of improving content uniformity, per 1 part by mass of pemafibrate in terms of free form It contains a total of 9 to 370 parts by mass of starch carboxyalkyl ether or a salt thereof. Preferably, it contains 17 to 270 parts by mass, and more preferably 40 to 180 parts by mass. It is especially preferable to do so.

[0031] <Povidone-based drugs (component (B-3))> In this specification, "povidones" means polymers of 1-vinyl-2-pyrrolidone. Not only homopolymers of 1-vinyl-2-pyrrolidone, but also 1-vinyl-2-pyrrolidone This concept encompasses copolymers with other polymerizable compounds. Furthermore, polymers are non-crosslinked polymers. However, cross-linked polymers are also acceptable. Furthermore, in the linear polymer of 1-vinyl-2-pyrrolidone (povidone), its K value is particularly While not limited to these, a K value of 12 to 90 is preferred, and a K value of 25 to 90 is preferred. Particularly preferable. Examples of such povidones include, specifically, 1-vinyl-2-pyro Linear polymer of lidon (Note: For povidone, its K value is not particularly limited, and the K value shown is...) Examples include those with values ​​of 12, 17, 25, 30, and 90); copolividone Copolymers of 1-vinyl-2-pyrrolidone and vinyl acetate, such as crospovidone; Examples include cross-linked polymers of yl-2-pyrrolidone, and even if one of these is used alone, 2 You may use a combination of more than one species. As for povidones, from the viewpoint of improving content uniformity, povidone, copolividone and Preferably, one or more species selected from the group consisting of crospovidone, including povidone and crospovidone It is more preferable to select one or more from the group consisting of [a certain group], and crospovidone is particularly preferred. Furthermore, from the viewpoint of ease of manufacture of pharmaceutical compositions (especially solid dosage forms), povidone compounds are suitable for use at room temperature It is preferable that the material be solid at any temperature between 15 and 25°C. Furthermore, these povidone compounds are all known ingredients and can be manufactured using known methods. It is fine, and you can also use commercially available products. For example, such commercially available products include Corydon. Examples include CL, Coridon VA64, and Coridon (all from BASF Japan Ltd.).

[0032] The amount of povidone in the pharmaceutical composition is not particularly limited, and the type of formulation and the gender of the user may also be a factor. The appropriate treatment can be determined by considering age, symptoms, etc., but the effect of improving content uniformity is From this perspective, the total amount of povidones relative to the total mass of the pharmaceutical composition should be 0.1 to 20% by mass. It is preferable to have it, more preferably 0.5 to 15% by mass, and 1 to 10% by mass. That is particularly preferable.

[0033] Furthermore, when using a linear polymer of 1-vinyl-2-pyrrolidone as a povidone, Regarding the content of the linear polymer of vinyl-2-pyrrolidone, from the perspective of improving content uniformity. Therefore, 0.2 to 16% by mass is preferred, and 0.6 to 14% by mass is preferred, relative to the total mass of the pharmaceutical composition. More preferably, and 3 to 9% by mass is particularly preferred. Furthermore, when using a cross-linked polymer of 1-vinyl-2-pyrrolidone as a povidone, Regarding the content of the cross-linked polymer of vinyl-2-pyrrolidone, from the perspective of improving content uniformity. Therefore, 0.3 to 17% by mass is preferred, and 0.7 to 13% by mass is preferred, relative to the total mass of the pharmaceutical composition. More preferably, and particularly preferably 2 to 8% by mass.

[0034] In pharmaceutical compositions, pemafibrate or its salt or its solvate and povid The mass ratio of the content with other compounds is not particularly limited, but from the viewpoint of improving content uniformity, Pemaf For every 1 part by mass of free dibrate, it contains a total of 1 to 200 parts by mass of povidone compounds. It is preferable to contain 3 to 150 parts by mass, and more preferably 5 to 100 parts by mass. It is especially preferable to do so.

[0035] Furthermore, when using a linear polymer of 1-vinyl-2-pyrrolidone as a povidone, In a pharmaceutical composition, pemafibrate or its salt or its solvate and 1-vinyl The mass ratio of -2-pyrrolidone to linear polymers is not particularly limited, but improving the uniformity of content From the perspective of beneficial effects, 1 part by mass of pemafibrate (in terms of free form) is equivalent to 1-vinyl-2 - Preferably contains a total of 1.5 to 190 parts by mass of linear polymers of pyrrolidone, and 3.5 It is more preferable to contain approximately 140 parts by mass, and particularly preferable to contain 6 to 90 parts by mass. Furthermore, when using a cross-linked polymer of 1-vinyl-2-pyrrolidone as a povidone, In a pharmaceutical composition, pemafibrate or its salt or its solvate and 1-vinyl The mass ratio of -2-pyrrolidone to the crosslinked polymer is not particularly limited, but improving the uniformity of the content From the perspective of beneficial effects, 1 part by mass of pemafibrate (in terms of free form) is equivalent to 1-vinyl-2 - Preferably contains a total of 2 to 180 parts by mass of cross-linked pyrrolidone polymers, and 4 to 130 It is more preferable to contain parts by mass, and particularly preferable to contain 7 to 80 parts by mass.

[0036] <Silicate compound (component (B-4))> In this specification, "silicic acid compound" refers not only to the silicate compound itself, but also to silicic acid This also includes salts of compound compounds. Examples of salts of silicate compounds include inorganic salts, specifically For example, alkali metal salts such as sodium salts and potassium salts; magnesium salts, calcium salts Examples include salts with metals of Group 2 elements, and salts with metals of Group 13 elements such as aluminum salts. It can be done. Examples of such silicate compounds include, specifically, hydrated silicon dioxide, hydrated amorphous form. Hydrated silica such as silicon dioxide, hydrated magnesium silicate, and hydrated magnesium silicate (natural). Compounds or salts thereof; anhydrous silicic acid such as light anhydrous silicic acid and heavy anhydrous silicic acid, or salts thereof; carbon dioxide Silicon, natural aluminum silicate, synthetic aluminum silicate, synthetic magnesium silicate Thorium, calcium silicate, magnesium silicate, aluminum magnesium silicate, Silicic acid such as magnesium aluminosilicate, magnesium aluminometasilicate, or In addition to salt, other examples include diatomaceous earth, bentonite, kaolin, talc, etc., and of these 1 You may use a single species or a combination of two or more species. As for silicate compounds, from the viewpoint of improving content uniformity, hydrated silicate compounds and hydrated silicate compounds are used. One or more substances selected from the group consisting of salts of silicic acid compounds, anhydrous silicic acid, and salts of anhydrous silicic acid are preferred. Furthermore, one or more selected from the group consisting of hydrated silicate compounds and salts of hydrated silicate compounds are particularly It is preferable. Furthermore, among the silicate compounds specifically mentioned, from the viewpoint of improving content uniformity, Selected from the group consisting of magnesium hydroxide, hydrated silicon dioxide, and light anhydrous silicic acid Preferably, one or more species are selected from the group consisting of hydrated magnesium silicate and hydrated silicon dioxide. One or more of these are particularly preferred. Also, from the viewpoint of ease of manufacture of the pharmaceutical composition (especially solid dosage forms) Furthermore, as silicate compounds, those that are solid at room temperature (any temperature between 15 and 25°C) It is preferable. Furthermore, all of these silicate compounds are known components and can be manufactured by known methods. You can also use commercially available products. For example, Noisi Phosphorus A (Fuji Chemical Industry Co., Ltd.), Fluorite (Tomita Pharmaceutical Co., Ltd.), Magnesium Silicate (Tomita Pharmaceutical Co., Ltd.), VEEGUMI Granules (Sanyo Chemical Industries, Ltd.), VEEGU MI HV Granules (Sanyo Chemical Industries, Ltd.), VEEGUMI K Granules (Sanyo Sanyo Chemical Industries, Ltd., VEEGUMI F, Cylysia 320 (Fuji Silysia Chemical Co., Ltd.), Silysia 350 (Fuji Silysia Chemical Co., Ltd.), Silysia Shea 320TP (Fuji Silysia Chemical Co., Ltd.), Silysia 320FCP (Fuji Silysia A Chemical Co., Ltd., Microcomputer FR (Tomita Pharmaceutical Co., Ltd.), Silicon Dioxide (Nippon Aerosil Co., Ltd.) )), Aerosil 300 (Nippon Aerosil Co., Ltd.), Adsolider 101 (Freund) (Freund Industrial Co., Ltd.), Adsolider 102 (Freund Industrial Co., Ltd.), Silicea (Fuji Silicea) Chemical Co., Ltd.), silospheres (Fuji Silicia Chemical Co., Ltd.), hydrated amorphous silicon dioxide (East So Silica Co., Ltd., Noisilin (Fuji Chemical Industry Co., Ltd.), Diatomaceous earth (Showa Chemical Co., Ltd.) Examples include talc (Sanei Gen F.F.I. Co., Ltd.).

[0037] The content of silicate compounds in a pharmaceutical composition is not particularly limited, and depends on the type of formulation and the gender of the user. The appropriate treatment can be determined by considering factors such as age, symptoms, etc., but it also has an effect on improving the uniformity of content. From this perspective, the total amount of silicate compounds relative to the total mass of the pharmaceutical composition should be 0.1 to 20 mass. Preferably it is %, more preferably 0.5 to 15 mass%, and 1 to 10 mass%. Having it is especially preferable.

[0038] Furthermore, one or more silicic acid compounds selected from the group consisting of hydrated silicic acid compounds and their salts. When using the above, it contains one or more selected from the group consisting of hydrated silicate compounds and their salts. In terms of quantity, from the viewpoint of improving content uniformity, 0.2 to 1% of the total mass of the pharmaceutical composition is appropriate. 9% by mass is preferred, 0.6 to 14% by mass is more preferred, and 2 to 6% by mass is particularly preferred. . Furthermore, one or more silicic acid compounds selected from the group consisting of anhydrous silicic acid compounds and their salts. When using the above, it contains one or more selected from the group consisting of anhydrous silicic acid compounds and their salts. In terms of quantity, from the viewpoint of improving content uniformity, 0.4 to 1% of the total mass of the pharmaceutical composition is appropriate. 7% by mass is preferred, 0.8 to 12% by mass is more preferred, and 4 to 8% by mass is particularly preferred. .

[0039] In pharmaceutical compositions, pemafibrate or its salt or solvates thereof and silicic acid The mass ratio of the compound is not particularly limited, but from the viewpoint of improving content uniformity, Pema For every 1 part by mass of fibrate (in terms of free form), add a total of 1 to 200 parts by mass of silicate compounds. It is preferable to contain it, more preferably 3 to 150 parts by mass, and 5 to 100 parts by mass. It is particularly preferable to include it.

[0040] Furthermore, one or more silicic acid compounds selected from the group consisting of hydrated silicic acid compounds and their salts. When using the above, the pharmaceutical composition contains pemafibrate or its salts or their The mass ratio of the solvate to one or more selected from the group consisting of hydrated silicate compounds and their salts. The rate is not particularly limited, but from the viewpoint of improving content uniformity, pemafibrate free For every 1 part by mass (on a volume basis), one or more selected from the group consisting of hydrated silicate compounds and their salts. Preferably, the total amount is 2 to 160 parts by mass, and more preferably 4 to 140 parts by mass. It is particularly preferable that it contains 10 to 90 parts by mass. Furthermore, one or more silicic acid compounds selected from the group consisting of anhydrous silicic acid compounds and their salts. When using the above, the pharmaceutical composition contains pemafibrate or its salts or their Mass ratio of solvates to one or more selected from the group consisting of anhydrous silicic acid compounds and their salts The rate is not particularly limited, but from the viewpoint of improving content uniformity, pemafibrate free For every 1 part by mass (on a volume basis), one or more selected from the group consisting of anhydrous silicic acid compounds and their salts. Preferably, the total amount is 2 to 180 parts by mass, and more preferably 4 to 120 parts by mass. It is particularly preferable that it contains 10 to 80 parts by mass.

[0041] <Polyhydric alcohol (component (B-5))> In this specification, "polyhydric alcohol" refers to a cyclic ether structure (e.g., tetrahydrop Compounds that do not have two or more ornate rings (such as ornate rings) in their molecule, but have two or more alcoholic hydroxyl groups. This means that it can be either a nonpolymer or a polymer. Examples of such polyhydric alcohols include sugars. Examples include sugar alcohols and non-sugar alcohols, and these can be used individually or in combination of two or more. They may be used in combination. Also, as polyhydric alcohols, cyclic ether structures (e.g., tetra) can be used. Polyhydric alcohols that do not contain a hydropyran ring (or similar) in their molecule, and cyclic ether structures that contain 1 in their molecule. A polyhydric alcohol having only one such element is preferred, and a polyhydric alcohol that does not contain a cyclic ether structure in its molecule is preferred. Coal is more preferred, and among polyhydric alcohols, acyclic compounds are particularly preferred. Furthermore, from the viewpoint of ease of manufacture of pharmaceutical compositions (especially solid dosage forms), polyhydric alcohols are used. It is preferable that the material be solid at room temperature (any temperature between 15 and 25°C).

[0042] The above sugar alcohols specifically include, for example, glycerol and other sugar alcohols with 3 carbon atoms. Calcium (tritol); erythritol, treitol, and other sugar alcohols with 4 carbon atoms (tetrachloride). Thol; a 5-carbon sugar such as xylitol, arabinitol, ribitol, and adonitol. Alcohol (pentitol); mannitol, sorbitol, iditol, dulcitol , galactitol and other 6-carbon sugar alcohols (hexitol); maltitol, lactitol Examples include 12-carbon sugar alcohols such as tor (dodecitol), and among these 1 The seeds may be used individually or in combination of two or more. Furthermore, these sugar alcohols Various stereoisomers can exist, but as a "sugar alcohol," its stereoconfiguration is not particularly limited. It is not fixed, and it may be any stereoisomer individually, or any mixture of any proportions of stereoisomers. .

[0043] Among the sugar alcohols mentioned above, erythritol and xylitol are considered to improve content uniformity. From the group consisting of litol, mannitol, sorbitol, maltitol, and lactitol Preferably, one or more of the selected substances are from the group consisting of mannitol, sorbitol, and maltitol. One or more of these are more preferable, and mannitol is particularly preferable. Furthermore, these sugar alcohols are all known components and can be manufactured by known methods. You can use homemade products, or you can use commercially available products. For example, Ellis Litol (Sanei Gen F.F.I. Co., Ltd.), Xylitol (Towa Kasei Kogyo Co., Ltd.), NE OSORB P (Rocket Japan Co., Ltd.), Resis (Towa Chemical Industries Co., Ltd.), Mannit P (Towa Chemical Industries, Ltd.), Glycerin (NOF Co., Ltd.), MALTISORB (Rocket) Examples include Japan Co., Ltd., and Amalty Syrup (Towa Chemical Industries Co., Ltd.).

[0044] Furthermore, among the non-sugar alcohols mentioned above, those that are acyclic compounds are included. Preferred. Specifically, for example, ethylene glycol, propylene glycol, 1,3-propylene glycol. Ropanediol, 2-methyl-1,3-propanediol, 1,3-butanediol, etc. Alkylene glycols; diethylene glycol, dipropylene glycol, macroglycol (For example, Macrogol 100, Macrogol 200, Macrogol 300, Macrogol) Macrogol 400, Macrogol 600, Macrogol 1000, Macrogol 1500, Macro Logol 1540, Macrogol 4000, Macrogol 6000, Polyethylene Glyco Examples include macrogol 8000, macrogol 20000, macrogol 35000, etc. Polypropylene glycol (for example, polypropylene glycol 2000 is an example) . ), polyoxyethylene polyoxypropylene glycol (for example, polyoxyethylene (3) Polyoxypropylene (17) Glycol, Polyoxyethylene (20) Poly Xypropylene (20) glycol, polyoxyethylene (42) polyoxypropylene (67) Glycol, polyoxyethylene (54) Polyoxypropylene (39) Glyco Polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxy Polyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene ( 124) Polyoxypropylene (39) glycol, polyoxyethylene (160) Oxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene Polyethylene (67) glycol, polyoxyethylene (200), polyoxypropylene (70) Examples include polyalkylene glycols such as glycols; polyvinyl alcohol. Polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), etc. Examples include Meglumine, and these can be used individually or in combination of two or more. It's okay to be there.

[0045] Among the non-sugar alcohols mentioned above, divalent non-sugar alcohols are considered to improve content uniformity. Polyalkylene glycols are preferred, polyalkylene glycols are more preferred, and macrogol is even more preferred. Macrogol 100, Macrogol 200, Macrogol 300, Macrogol 4 00, Macrogol 600, Macrogol 1000, Macrogol 1500, Macrogol Lu 1540, Macrogol 4000, Macrogol 6000, Polyethylene glycol 8 1 selected from the group consisting of 000, macrogol 20000, and macrogol 35000 More than one species is more preferable, and macrogol with an average molecular weight of 100 to 10000 is even more preferable. Furthermore, values ​​between 200 and 8000 are more preferred, and macrogol 6000 is particularly preferred. The average molecular weight of macrogol is as stated in the "Macrogol" section of the 17th edition of the Japanese Pharmacopoeia, under the individual articles of the Pharmaceuticals section. It can be measured by the "average molecular weight test" described in section "L400". Furthermore, these non-sugar alcohols are all known components and can be manufactured by known methods. You may do this yourself, or you may use a commercially available product. For example, such a commercially available product is... Solve PG (BASF Japan Ltd.), Diethylene Glycol (Nippon Shokubai Co., Ltd.), Yu Nisafe DPG-R (NOF Co., Ltd.), Macrogol 200 (Sanyo Chemical Industries, Ltd.), Corydoras Solve PEG300 (BASF Japan Ltd.), Super Refined PEG400 ( Croda Japan Co., Ltd., CARBOWAX Sentry PEG600 (Dow-Ke Mikal Japan Co., Ltd.), Macrogol 1000 (NOF Corporation), Macrogol 1500 (San Yohka Kogyo Co., Ltd., CARBOWAX Sentry PEG1540 (Dow Chemical Co., Ltd.) (Japan Co., Ltd.), Macrogol 4000 (Sanyo Chemical Industries, Ltd.), Macrogol 6000 (Sanyo Chemical Industries, Ltd.), Macrogol 20000 (Sanyo Chemical Industries, Ltd.), Newport Lu PP-2000 (Sanyo Chemical Industries, Ltd.), Pronon 101P (NOF Co., Ltd.), Corisoll B P124 (BASF Japan Ltd.), Pronon 403P (NOF Co., Ltd.), New Det PEP-85 (Sanyo Chemical Industries, Ltd.), PEP-101 (Freund Industrial Co., Ltd.), Fall P188 (BASF Japan Ltd.), Corifol P407 Micro (BASF Examples include F Japan Co., Ltd., and Unilube DP-950B (NOF Corporation).

[0046] The polyhydric alcohol content in a pharmaceutical composition is not particularly limited, and depends on the type of formulation and the user. The method can be appropriately considered and decided upon depending on gender, age, symptoms, etc., but improvements in content uniformity are possible. From a practical standpoint, the total amount of polyhydric alcohols relative to the total mass of the pharmaceutical composition should be between 0.1 and 99%. Preferably, it is in mass%, more preferably 0.5 to 95 mass%, and 1 to 90 mass It is even more preferable that it be %, and particularly preferable that it be 1.5 to 50% by mass.

[0047] Furthermore, when using sugar alcohols as polyhydric alcohols, the sugar alcohol content is... Therefore, from the viewpoint of improving content uniformity, 0.2 to 98 mass of the total mass of the pharmaceutical composition is used. % is preferred, 0.6 to 94% by mass is more preferred, and 1.1 to 85% by mass is particularly preferred. . Furthermore, when using non-sugar alcohols as polyhydric alcohols, the content of non-sugar alcohols From the viewpoint of improving content uniformity, the amount should be 0.3 to 97% of the total mass of the pharmaceutical composition. A mass% is preferred, 0.7 to 93% by mass is more preferred, and 1.2 to 80% by mass is particularly preferred. It's nice. Furthermore, when polyalkylene glycols are used as polyhydric alcohols, Regarding the content of lenglycols, from the viewpoint of improving the uniformity of content, the total content of the pharmaceutical composition With respect to the amount, 0.4 to 96% by mass is preferred, and 0.8 to 92% by mass is more preferred. A concentration of 3 to 75% by mass is particularly preferred.

[0048] In pharmaceutical compositions, pemafibrate or its salt or solvates thereof and polyvalent The mass ratio of alcohol content is not particularly limited, but from the viewpoint of improving content uniformity, For every 1 part by mass of mafibrate (in free form), add a total of 1 to 2000 polyhydric alcohols. It is preferable to contain parts by mass, more preferably 5 to 1500 parts by mass, and 10 to 1 It is even more preferable to contain 000 parts by mass, and particularly preferable to contain 15 to 500 parts by mass.

[0049] Furthermore, when using sugar alcohols as polyhydric alcohols, the pema in the pharmaceutical composition The mass ratio of fibrates or their salts or solvates to sugar alcohols is particularly important. While not limited to this, from the viewpoint of improving content uniformity, pemafibrate free form equivalent Preferably, the mixture contains a total of 2 to 1900 parts by mass of sugar alcohol per 1 part by mass, 6 It is more preferable to contain ~1450 parts by mass, and particularly preferable to contain 12 to 950 parts by mass. It's nice. Furthermore, when using a non-sugar alcohol as a polyhydric alcohol, the pharmaceutical composition contains The mass ratio of mafibrate or its salt or solvate thereof to non-sugar alcohols. While not particularly limited, from the viewpoint of improving content uniformity, the free form of pemafibrate It is preferable that the total amount of non-sugar alcohols be between 3 and 1850 parts by mass per 1 part by mass. It is more preferable to contain 7 to 1400 parts by mass, and more preferably 13 to 900 parts by mass. It is preferable. Furthermore, when polyalkylene glycols are used as polyhydric alcohols, the pharmaceutical composition In the case of pemafibrate or its salt or solvates thereof and polyalkylene compounds The mass ratio of cellulose is not particularly limited, but from the viewpoint of improving content uniformity, For 1 part by mass of mafibrate (in terms of free form), the total amount of polyalkylene glycols is Preferably, it contains 4 to 1800 parts by mass, and more preferably, 8 to 1350 parts by mass. It is particularly preferable that it contains 14 to 850 parts by mass.

[0050] <Alkyl sulfate esters (component (B-6))> In this specification, "alkyl sulfate esters" refers to the following formula (1): RO-SO3M ···(1) (In the formula, R represents a linear or branched saturated or unsaturated hydrocarbon group having 8 to 22 carbon atoms, M These are alkali metals such as sodium and potassium; and Group 2 elements such as magnesium and calcium. Metals; ammonium ions; or triethanolammonium with 2 or 3 carbon atoms (This represents a hydroxyalkyl-substituted ammonium compound.) This refers to alkyl sulfate ester salts represented by [the formula shown]. Examples of such alkyl sulfate esters include, for instance, lauryl sulfate. Salt, tetradecyl sulfate salt, hexadecyl sulfate salt, octadecyl sulfate Examples include ter salts, and these can be used individually or in combination of two or more. That's good too. Among alkyl sulfate esters, lauryl sulfate is used from the viewpoint of improving content uniformity. Sterl salts, tetradecyl sulfate salts, hexadecyl sulfate salts and octadecyl Preferably, one or more selected from the group consisting of sulfate ester salts, and lauryl sulfate ester salt is More preferably, sodium lauryl sulfate is particularly preferred. Also, pharmaceutical compositions (especially solid) From the viewpoint of ease of manufacture (of the agent), alkyl sulfate esters are suitable for use at room temperature (15-25°C). It is preferable that the material be solid at any of the following temperatures. Furthermore, these alkyl sulfate esters are all known components and can be processed by known methods. You may manufacture it yourself, or you may use a commercially available product. For example, such a commercially available product is Examples include Corifor SLS (BASF Japan Ltd.).

[0051] The content of alkyl sulfate esters in the pharmaceutical composition is not particularly limited, and the type of formulation, The dosage can be determined by considering the gender, age, symptoms, etc. of the user, but the uniformity of the content is important. From the viewpoint of improving the effect, the total amount of alkyl sulfate esters is set relative to the total mass of the pharmaceutical composition. Preferably, it is 0.1 to 20% by mass, and more preferably 0.5 to 15% by mass. It is particularly preferable that the amount is 1 to 10% by mass.

[0052] In pharmaceutical compositions, pemafibrate or its salt or its solvate and alkyl The mass ratio of sulfuric acid esters is not particularly limited, but from the viewpoint of improving content uniformity. Therefore, for every 1 part by mass of pemafibrate (on a free form basis), alkyl sulfate esters are added. Preferably, it contains 1 to 200 parts by mass in total, and more preferably, 3 to 150 parts by mass. It is more preferable to contain 5 to 100 parts by mass, and particularly preferable to contain 5 to 50 parts by mass. It seems so.

[0053] In this specification, the dosage form of "pharmaceutical composition" is not particularly limited and may be solid, semi-solid, or liquid. Any form of formulation is acceptable, and the choice can be made according to the intended use, etc. Examples of dosage forms for the product include those listed in the General Provisions for Preparations of the 17th Revised Japanese Pharmacopoeia, etc. Specifically, for example, as a dosage form for oral administration, there are tablets (e.g., regular tablets, orally disintegrating tablets). (including broken tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolvable tablets, etc.), capsules, granules (for example) Solid preparations such as powders and pills (including effervescent granules), and semi-solid preparations such as oral jelly. ; Liquid oral preparations (including, for example, elixirs, suspensions, emulsions, and lemonades) Examples include formulations, etc. Furthermore, parenteral administration forms include injections, inhalants, eye drops, and eye drops. Ear drops, nasal drops, suppositories, topical solid preparations, topical liquid preparations, sprays, ointments, creams, gels Examples include adhesive patches and the like.

[0054] From the viewpoint of ease of administration and ease of manufacture, a solid dosage form is preferred for the pharmaceutical composition. Preferred. In particular, when the pharmaceutical composition is a solid dosage form, it is extremely easy to manufacture, Generally, solid dosage forms contain solid components that are stored at room temperature (any temperature between 15 and 25°C). Because it is used in large quantities during manufacturing, the mixing and dispersion of the components tend to be uneven, resulting in uneven content. The deterioration of this is particularly likely to become a problem. However, according to the present invention, in the case of a solid dosage form, Furthermore, it has the excellent effect of having good uniformity of content. As for solid dosage forms, oral solid dosage forms are preferred, such as tablets, capsules, granules, and powders. Pills are more preferred, and tablets are particularly preferred. Furthermore, as for solid dosage forms, components (A) and A solid formulation containing a mixture including (B) is preferred.

[0055] The pharmaceutical composition of the present invention may contain, depending on its dosage form, a pharmaceutically acceptable carrier in addition to the above-mentioned components ( Pharmaceutical additives may be added. Examples of such pharmaceutical additives include excipients, disintegrants, Binders, lubricants, plasticizers, film-forming agents, poorly water-soluble polymers, antioxidants, flavoring agents, sweeteners Examples include, but are not limited to, flavorings and other additives. Specifically, for example, see the Dictionary of Pharmaceutical Additives 2016 (published by Yakuji Nippo Co., Ltd.), Ha ndbook of Pharmaceutical Excipients, Seventh Edition (Published by Pharmaceutical Press) You can use the materials listed in (or similar publications).

[0056] Examples of excipients include anhydrous sodium sulfate and anhydrous calcium hydrogen phosphate. , sodium chloride, calcium sulfate, monocalcium phosphate, calcium hydrogen phosphate, Sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, dihydrogen phosphate Inorganic excipients such as sodium; fructose, caramel, agar, paraffin, crystalline cellulose Sucrose, maltose, lactose, lactose monohydrate, sucrose, glucose, pullulan, polyoxyethylene Hydrogenated castor oil, trehalose, reduced palatinose, maltose, aminoalkyl methacrylate Rate copolymer E, polyvinyl acetal diethylaminoacetate, calcium citrate Examples include organic excipients such as um. These are used individually or in combination of two or more. It is possible. The total content of excipients is not particularly limited, but preferably 2% of the total mass of the pharmaceutical composition. The mass is 0 to 99%, more preferably 30 to 97%.

[0057] Examples of disintegrants include gelatin, sodium bicarbonate, dextrin, Examples include dehydroacetic acid and its salts, polyoxyethylene hydrogenated castor oil 60, etc. These can be used individually or in combination of two or more types.

[0058] Examples of binders include dextrin, pullulan, gum arabic, and kante. Ingredients: gelatin, tragacanth, sodium alginate, aminoalkyl methacrylate copolymer Examples include Limer E, polyvinyl acetal diethylaminoacetate, etc. These are, One type or a combination of two or more types can be used.

[0059] Examples of lubricants include calcium stearate and magnesium stearate. Examples include sodium stearate and sodium stearyl fumarate. These are used in combinations of one or more types. They can be used together. The total content of the lubricant is not particularly limited, but preferably 0% of the total mass of the pharmaceutical composition. The amount is 0.01 to 15% by mass, more preferably 0.1 to 10% by mass. Examples of plasticizers include sesame oil, castor oil, and polysorbate 80 (polio Examples include xyethylene(20)sorbitan oleate ester. These are type 1 Alternatively, two or more types can be used in combination.

[0060] Specifically, examples of film-forming agents include alginic acid such as sodium alginate or Examples include salt, carrageenan, xanthan gum, pullulan, etc. These are one type or Two or more types can be used in combination.

[0061] Examples of poorly water-soluble polymers include carboxyvinyl polymers and amino acids. Examples include alkyl methacrylate copolymers. These are used in combination of one or more types. They can be used together. Examples of antioxidants include ascorbic acid, sodium bisulfite, and sulfur dioxide. Sodium edetate, sodium erythorbic acid, tocopherol acetate, dibutyl hydroxypropyl alcohol Droxytoluene, natural vitamin E, tocopherol, butylhydroxyanisole, etc. These can be listed. They can be used individually or in combination of two or more types.

[0062] Examples of flavoring agents include limonene, pinene, camphene, cymene, and cine. ol, citronellol, geraniol, nerol, linalool, menthol, terpine Ole, rhozinol, borneol, isoborneol, menthone, camphor, eugenol Terpenes such as lichen, synzeylanol; spruce oil, orange oil, peppermint oil, camphor oil, yu Potassium oil, turpentine oil, lemon oil, ginger oil, clove oil, cinnamon oil, lavender Oils, essential oils containing terpenes such as fennel oil, chamomile oil, perilla oil, and spearmint oil; Examples of acidulants include ascorbic acid, tartaric acid, citric acid, malic acid, and their salts. These can be used individually or in combination of two or more types.

[0063] Examples of sweeteners include aspartame, stevia, sucralose, and glycyrrhizin. Examples include acids, thaumatin, acesulfame potassium, saccharin, and sodium saccharin. These can be used in combination of one or more types.

[0064] The pharmaceutical composition of the present invention can be manufactured by known methods depending on its dosage form. For example, if the pharmaceutical composition is a solid dosage form, the processes may include crushing, mixing, granulation, drying, sizing, and classification. It can be manufactured by appropriately combining unit operations such as filling, tableting, and coating. It is possible, but the manufacturing method involves a step of mixing component (A) and component (B). It is preferable. More specifically, for example, in the case where the dosage form of the pharmaceutical composition is a granular preparation such as granules, powders, or pills. In addition to components (A) and (B), excipients, binders, disintegrants, lubricants, etc. may be added as needed. After mixing these components with additives, extrusion granulation, rolling granulation, stirring granulation, and fluid bed granulation are performed. Granulated material is obtained by granulation using known granulation methods such as particle granulation, spray granulation, melt granulation, and crushing granulation, and further The granules can be manufactured by classifying, sizing, etc., as needed. Alternatively, the coating can be applied using a known method with a coating agent or the like. Furthermore, if the dosage form of the pharmaceutical composition is a tablet, in addition to component (A) and component (B), as needed Using appropriate pharmaceutical additives such as excipients, binders, disintegrants, and lubricants, and mixing these components The mixture is obtained and then directly compressed (tableted) (direct powder compression method), or the above granules are used After classification, granulation, etc. as needed, the granules are compressed (tabletized) (semi-dry granule compression method, dry granule compression method). It can be manufactured by methods such as compression, wet granule compression, etc. The resulting compressed product (tablets) ) can also be coated with a coating agent or the like by known methods. Furthermore, if the dosage form of the pharmaceutical composition is a capsule, the above-mentioned granules or compressed material is placed inside the capsule. Just fill it in.

[0065] The diseases to which the pharmaceutical composition of the present invention can be applied are not limited in any way, but may include those currently known or to be discovered in the future. It is widely used for the prevention or treatment of diseases in which the administration of pemafibrate is considered effective. It is possible. For example, pemafibrates or their salts or solvates are excellent PPARα It possesses gonist activity, leading to a decrease in plasma triglyceride concentration and an increase in HDL cholesterol, etc. It has the effect of [this]. Therefore, the pharmaceutical composition of the present invention is preferably used for dyslipidemia (hyperlipidemia, etc.). More specifically, for example, as a preventive and / or therapeutic agent for primary hyperlipidemia, secondary hyperlipidemia, etc. Furthermore, it can preferably be used as a preventive and / or therapeutic agent for hypertriglyceridemia. Furthermore, pemafibrates or their salts or solvates thereof are NAFLD (non-alkaline). It is useful for the prevention or treatment of fatty liver disease. Therefore, the pharmaceutical composition of the present invention is Prevention of NAFLD (more preferably NASH (non-alcoholic steatohepatitis)) and / or It can also be used as a therapeutic agent. Furthermore, pemafibrates or their salts or solvates are used to treat primary biliary cirrhosis. It may also be used as a treatment for malformations, etc.

[0066] The route of administration of the pharmaceutical composition is not particularly limited, and depends on the disease to which it is applied, the type of formulation, the gender of the person taking the medicine, etc. The appropriate dosage can be determined based on age, symptoms, etc., but from the perspective of ease of administration, Oral administration is preferred. The pharmaceutical composition should be taken in 1 to 4 divided doses per day, before meals and after meals. It can be taken between meals, after meals, before bedtime, etc.

[0067] This specification is not limited to these, but discloses, for example, the following embodiments. do. [1-1] The following components (A) and (B): (A) Pemafibrates or salts thereof, or solvates thereof; (B) One or more selected from the group consisting of the following components (B-1) to (B-6); (B-1) Cellulose ethers (B-2) Starches (B-3) Povidone (B-4) Silicate compounds (B-5) Polyhydric alcohols (B-6) Alkyl sulfates A pharmaceutical composition containing [the specified ingredient]. [1-2] Component (B-1) is alkylcellulose, hydroxyalkylcellulose , alkyl(hydroxyalkyl)cellulose, carboxyalkylcellulose and carboxycellulose One selected from the group consisting of cross-linked polymers of carboxyalkylcellulose and salts thereof. The pharmaceutical composition described in [1-1] above. [1-3] Component (B-1) is C1-C6 alkylcellulose, hydroxy C1-C 6-alkylcellulose, C1-C6 alkyl (hydroxy C1-C6 alkyl) cellulose S, carboxyC1-C6 alkylcellulose and carboxyC1-C6 alkylcellulose [1-1] One or more selected from the group consisting of cross-linked polymers of - and salts thereof. The pharmaceutical composition described. [1-4] Component (B-1) is methylcellulose, ethylcellulose, hydroxypropylcellulose Propylcellulose, hypromellose, carmellose, carmellose potassium, carmellose A group consisting of calcium carbonate, carmellose sodium, and croscarmellose sodium. A pharmaceutical composition according to [1-1], which is one or more selected from the above.

[0068] [1-5] Component (B-2) is starch, hydroxyalkyl ether of starch and One selected from the group consisting of starch carboxyalkyl ethers and their salts. The above is a pharmaceutical composition as described in any of [1-1] to [1-4]. [1-6] Component (B-2) is starch, hydroxy C1-C6 alkyl of starch Ethers and starch carboxyl C1-C6 alkyl ethers and their salts A pharmaceutical composition described in any of [1-1] to [1-4], which is one or more selected from the group. . [1-7] Ingredient (B-2) is starch, hydroxypropyl starch and carboxymethyl ammonium compounds. [1-1] One or more selected from the group consisting of methyl starch and salts thereof. A pharmaceutical composition described in any of the following [1-4].

[0069] [1-8] Component (B-3) is selected from the group consisting of povidone and crospovidone. A pharmaceutical composition comprising one or more types, as described in any of [1-1] to [1-7]. [1-9] The component (B-3) is crospovidone, as in [1-1]~[1-7]. Any of the listed pharmaceutical compositions.

[0070] [1-10] Components (B-4) are hydrated silicate compounds, salts of hydrated silicate compounds, and anhydrous saturates. [1-1]~[1-9 A pharmaceutical composition as described in any of the following: [1-11] Components (B-4) are hydrated magnesium silicate, hydrated silicon dioxide and light One or more types selected from the group consisting of pure anhydrous silicic acid, any of [1-1] to [1-9] The pharmaceutical composition described above. [1-12] Component (B-4) is derived from hydrated magnesium silicate and hydrated silicon dioxide. One or more pharmaceutical compositions selected from the group, as described in any of [1-1] to [1-9]. thing.

[0071] [1-13] Component (B-5) is macrogol, [1-1]~[1-12] Any of the pharmaceutical compositions described above. [1-14] Components (B-5) are macrogol 100, macrogol 200, macro Goal 300, Macro Goal 400, Macro Goal 600, Macro Goal 1000, Mac Logol 1500, Macrogol 1540, Macrogol 4000, Macrogol 600 0, polyethylene glycol 8000, macrogol 20000, and macrogol 350 One or more selected from the group consisting of 00, any one of [1-1] to [1-12] The pharmaceutical composition of. [1-15] Component (B-5) is macrogol with an average molecular weight of 100 to 10000 The pharmaceutical composition according to any one of [1-1] to [1-12]. [1-16] Component (B-5) is macrogol 6000, any one of [1-1] to 12] The pharmaceutical composition according to any one of the above.

[0072] [1-17] Component (B-5) is one or more selected from the group consisting of erythritol, xylitol, mannitol, sorbitol, maltitol, and lactitol. The pharmaceutical composition according to any one of [1-1] to [1-12]. 1-1] to [1-12] The pharmaceutical composition according to any one of the above. [1-18] Component (B-5) is one or more selected from the group consisting of mannitol and sorbitol. The pharmaceutical composition according to any one of [1-1] to [1-12]. [1-19] Component (B-5) is mannitol, any one of [1-1] to [1-12] The pharmaceutical composition according to any one of the above.

[0073] [1-20] Component (B-6) is one or more selected from the group consisting of lauryl sulfate salts, tetradecyl sulfate salts, hexadecyl sulfate salts, and octadecyl sulfate salts. Selected from the group consisting of salts, the pharmaceutical composition according to any one of [1-1] to [1-19]. The pharmaceutical composition according to any one of [1-1] to [1-19]. [1-21] Component (B-6) is lauryl sulfate salt, any one of [1-1] to [1 -19] The pharmaceutical composition according to any one of the above. [1-22] Component (B-6) is sodium lauryl sulfate, any one of [1-1] to [1 -19] The pharmaceutical composition according to any one of the above.

[0074] [1-23] Dyslipidemia (hyperlipidemia, more specifically, primary hyperlipidemia, secondary hyperlipidemia) Hyperlipidemia, etc., NAFLD (more preferably NASH (non-alcoholic steatohepatitis)), and It is a preventive and / or therapeutic agent for diseases selected from primary biliary cirrhosis, [1-1]~[ A pharmaceutical composition as described in any of [1-22]. [1-24] A solid dosage form, with a pharmaceutical composition as described in any of [1-1] to [1-23]. thing. [1-25] The dosage form is a tablet, capsule, granule, powder or pill. [1-1] A pharmaceutical composition as described in any of the following [1-24].

[0075] [2-1] (A) Contains pemafibrate or a salt thereof or a solvate thereof The pharmaceutical composition contains one or more components selected from the group consisting of the following components (B-1) to (B-6); (B-1) Cellulose ethers (B-2) Starches (B-3) Povidone (B-4) Silicate compounds (B-5) Polyhydric alcohols (B-6) Alkyl sulfates A step of including pemafibrate or its salts or the same in a pharmaceutical composition. A method for improving the uniformity of the content of the solvate. [2-2] Component (B-1) is alkylcellulose, hydroxyalkylcellulose , alkyl(hydroxyalkyl)cellulose, carboxyalkylcellulose and carboxycellulose One selected from the group consisting of cross-linked polymers of carboxyalkylcellulose and salts thereof. The method described in [2-1] above. [2-3] Component (B-1) is C1-C6 alkylcellulose, hydroxy C1-C 6-alkyl cellulose, C1-C6 alkyl (hydroxy C1-C6 alkyl) cellulose s, carboxy C1-C6 alkyl cellulose and carboxy C1-C6 alkyl cellulose cross polymers thereof, and one or more selected from the group consisting of salts thereof, [2-1] The method according to the description. [2-4] Component (B-1) is methylcellulose, ethylcellulose, hydroxypropyl cellulose, hypromellose, carmellose, carmellose potassium, carmellose calcium, carmellose sodium and croscarmellose sodium, and one or more selected from the group consisting of The method according to [2-1].

[0076] [2-5] Component (B-2) is starch, hydroxyalkyl ether of starch and carboxyalkyl ether of starch and salts thereof, and one or more selected from the group consisting of The method according to any one of [2-1] to [2-4]. [2-6] Component (B-2) is starch, hydroxy C1-C6 alkyl ether of starch and carboxy C1-C6 alkyl ether of starch and salts thereof, and one or more selected from the group consisting of The method according to any one of [2-1] to [2-4]. [2-7] Component (B-2) is starch, hydroxypropyl starch and carboxy methyl starch and salts thereof, and one or more selected from the group consisting of [2-1] The method according to any one of [2-1] to [2-4].

[0077] [2-8] Component (B-3) is one or more selected from the group consisting of povidone and crospovidone The method according to any one of [2-1] to [2-7]. [2-9] Component (B-3) is crospovidone, [2-1] to [2-7] any one of The method of notation.

[0078] [2-10] Component (B-4) is a hydrated silicate compound, a salt of a hydrated silicate compound, an anhydrous carboxymethyl phosphate. [2-1]~[2-9] One of the methods described in [ ]. [2-11] Components (B-4) are hydrated magnesium silicate, hydrated silicon dioxide and light One or more types selected from the group consisting of pure anhydrous silicic acid, any of [2-1] to [2-9] Or the method of description. [2-12] Component (B-4) is derived from hydrated magnesium silicate and hydrated silicon dioxide. One or more species are selected from the group, as described in one of the methods [2-1] to [2-9].

[0079] [2-13] Component (B-5) is macrogol, [2-1]~[2-12] Either method described above. [2-14] Component (B-5) is macrogol 100, macrogol 200, macro Goal 300, Macro Goal 400, Macro Goal 600, Macro Goal 1000, Mac Logol 1500, Macrogol 1540, Macrogol 4000, Macrogol 600 0, polyethylene glycol 8000, macrogol 20000 and macrogol 350 One or more items selected from the group consisting of 00, described in one of the following [2-1] to [2-12]. The method. [2-15] Component (B-5) is macrogol with an average molecular weight of 100 to 10000. One of the methods described in [2-1] to [2-12]. [2-16] The component (B-5) is macrogol 6000, [2-1]~[2- One of the methods described in

[12] .

[0080] [2-17] Ingredients (B-5) are erythritol, xylitol, mannitol, and It is one or more substances selected from the group consisting of rubitol, maltitol, and lactitol. One of the methods described in [2-1] to [2-12]. [2-18] The component (B-5) is selected from the group consisting of mannitol and sorbitol. One or more types, as described in any of the methods [2-1] to [2-12]. [2-19] The component (B-5) is mannitol, as in [2-1]~[2-12]. Either method described above.

[0081] [2-20] Ingredient (B-6) is lauryl sulfate ester salt, tetradecyl sulfate ester salt Selected from the group consisting of sulfate, hexadecyl sulfate, and octadecyl sulfate. One or more types, as described in any of the methods [2-1] to [2-19]. [2-21] The component (B-6) is a lauryl sulfate salt, [2-1]~[2 -19] One of the methods described below. [2-22] The component (B-6) is sodium lauryl sulfate, [2-1]~[2 -19] One of the methods described below.

[0082] [2-23] Pharmaceutical compositions that cause dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia) Lipidemia, secondary hyperlipidemia, etc.), NAFLD (more preferably NASH (non-alcoholic steatohepatitis) It is a preventive and / or therapeutic agent for diseases selected from fatty liver disease and primary biliary cirrhosis. Use one of the methods described in [2-1] to [2-22]. [2-24] A solid dosage form, with a pharmaceutical composition as described in any of [2-1] to [2-23]. thing. [2-25] The dosage form of the pharmaceutical composition is a tablet, capsule, granule, powder, or pill. One of the methods described in [2-1] to [2-24]. [Examples]

[0083] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way by these examples. It is not something that should be done. In the following test examples, measurements using HPLC were performed using an ODS column. The measurements were performed using an ultraviolet spectrophotometer as the detector. Furthermore, regarding the pemafibrate used in the following test examples, see the 17th edition of the Japanese Pharmacopoeia. According to the particle size measurement method using laser diffraction, the average particle size of the primary particles was measured, d50 was 100 μm or less, and d90 was 200 μm or less.

[0084] [Test Example 1] Content Uniformity Evaluation Test Part 1 The following tests were conducted to evaluate the uniformity of the pemafibrate content in the pharmaceutical composition. . In other words, the amount of each ingredient listed in Table 1 per tablet is equal to the amount (mg) listed in Table 1. The tablets were manufactured. The specific procedure is as follows. (Examples 1-5) Pemafibrate and cellulose ethers are mixed for 30 seconds, followed by lactose monohydrate and cellulose. Add crystalline cellulose and mix for 30 seconds, then finally add magnesium stearate and mix for 30 seconds. The mixture was then mixed. The resulting mixture was then pressed using a tablet press fitted with a 7mm diameter punch. The drug was processed into tablets, and 1000 tablets were manufactured, each containing 120 mg. (Comparative Example 1) Pemafibrate, lactose monohydrate, and crystalline cellulose are mixed for 30 seconds, followed by steating. Magnesium phosphate was added and mixed for 30 seconds. Then, the resulting mixture was cut into 7 mm diameter pieces. Tablets are compressed using a tablet press equipped with a punch, producing 1000 tablets, each containing 117.6 mg. did.

[0085] From each of the obtained examples or comparative examples, 10 tablets were randomly selected and 1 The pemafibrate content in each tablet was measured using the following method. Specifically, one tablet is crushed in water, and then acetonitrile is added to obtain the sample solution. The obtained sample solution was analyzed using an HPLC instrument, and the peak area derived from pemafibrate was determined. The measurement was performed. Then, the peak area derived from pemafibrate in the obtained sample solution was calculated based on the concentration. By comparing the peak area of ​​each tablet with that of a standard solution of pemafibrate, the peak area of ​​each tablet can be determined. The mafibrate content was measured.

[0086] From the measured pemafibrate content of each tablet obtained, the 17th edition of the Japanese Pharmacopoeia In accordance with the content uniformity test, the relative standard deviation (RSD) (%) of the pemafibrate content in the tablets was determined. The following was calculated and used as an indicator of the variability (degree of uniformity) of the pemafibrate content in the tablets: The results obtained are shown in Table 1.

[0087] [Table 1]

[0088] As shown in Table 1, in Comparative Example 1, which does not contain cellulose ethers, the relative The standard deviation was around 140%, indicating a large variation in the pemafibrate content per tablet. It was approved. In contrast, croscarmellose sodium, carmellose sodium, and low-substituted hyphae Roxypropylcellulose, methylcellulose, or hydroxypropylmethylcellulose When it is included as cellulose ethers (Examples 1-5), the relative standard deviation is The deviation was small, and it was clear that the uniformity of the pemafibrate content per tablet was good. The amount of cellulose ethers added is 2.4 mg (2% by mass of the total tablet mass). ) was in very small amounts.

[0089] Based on the above test results, pemafibrate or its salt or solvate is found to be present in By incorporating cellulose ethers into the pharmaceutical composition, the pemanate in the pharmaceutical composition is increased. It was found that the uniformity of fibrate content was improved.

[0090] [Test Example 2] Test for Evaluation of Content Uniformity, Part 2 The tablet composition was the same as in Test Example 1, except that the ingredients and quantities were as listed in Table 2 below. The test was conducted according to the specified method. The results are shown in Table 2.

[0091] [Table 2]

[0092] As shown in Table 2, pregelatinized starch, corn starch, or carboxymethyl saturates Even when sodium tarch was included as a starch (Examples 6-8), the trial Similar to the tablets of Examples 1-5 containing cellulose ethers in Example 1, relative standards The deviations were all small, indicating good uniformity of pemafibrate content per tablet. It became clear.

[0093] Based on the above test results, pemafibrate or its salt or solvate is found to be present in By including starches in the pharmaceutical composition, the pemafibros in the pharmaceutical composition are reduced. It was found that the uniformity of the content of the substance was improved.

[0094] [Test Example 3] Test for Evaluation of Content Uniformity, Part 3 The tablet composition was the same as in Test Example 1, except that the ingredients and quantities were as listed in Table 3 below. The test was conducted according to the specified method. The results are shown in Table 3.

[0095] [Table 3]

[0096] As shown in Table 3, crospovidone or polyvinylpyrrolidone are classified as povidones. Even when included (Examples 9-10), the cellulose ether in Test Example 1 was still present. Similar to the tablets of Examples 1-5 containing the same type, the relative standard deviation is small in all cases, and per tablet It was revealed that the uniformity of the pemafibrate content was good.

[0097] Based on the above test results, pemafibrate or its salt or solvate is found to be present in By including povidones in the pharmaceutical composition, the pemafibros in the pharmaceutical composition It was found that the uniformity of the content of the substance was improved.

[0098] [Test Example 4] Test for Evaluation of Content Uniformity, Part 4 The tablet composition was the same as in Test Example 1, except that the ingredients and quantities were as listed in Table 4 below. The test was conducted according to the specified method. The results are shown in Table 4.

[0099] [Table 4]

[0100] As shown in Table 4, hydrated magnesium silicate, hydrated silicon dioxide, or light anhydrous silica Even when the acid was included as a silicate compound (Examples 11-13), the results in Test Example 1 were the same. Similar to the tablets of Examples 1-5 containing cellulose ethers, the relative standard deviation is The deviation was small, and it was clear that the uniformity of the pemafibrate content per tablet was good. .

[0101] Based on the above test results, pemafibrate or its salt or solvate is found to be present in By including a silicate compound in the pharmaceutical composition, the pemafibros in the pharmaceutical composition are reduced. It was found that the uniformity of the content of the compound was improved.

[0102] [Test Example 5] Test for Evaluation of Content Uniformity, Part 5 The tablet composition was the same as in Test Example 1, except that the ingredients and quantities were as listed in Table 5 below. The test was conducted according to the specified method. The results are shown in Table 5.

[0103] [Table 5]

[0104] As shown in Table 5, macrogol or mannitol is contained as a polyhydric alcohol. Even in the case where the cells were closed (Examples 14-15), the cellulose ethers in Test Example 1 were Similar to the tablets of Examples 1-5, the relative standard deviation is small in all cases, and the peman value per tablet is low. The uniformity of the fibrate content was found to be excellent.

[0105] Based on the above test results, pemafibrate or its salt or solvate is found to be present in By including a polyhydric alcohol in the pharmaceutical composition, the pemafib in the pharmaceutical composition is reduced. It was found that the uniformity of the content of the gluten was improved.

[0106] [Test Example 6] Test for Evaluation of Content Uniformity, Part 6 The tablet composition was the same as in Test Example 1, except that the ingredients and quantities were as listed in Table 6 below. The test was conducted according to the specified method. The results are shown in Table 6.

[0107] [Table 6]

[0108] As shown in Table 6, the alkyl sulfate esters include sodium lauryl sulfate. In Example 16, the cellulose ethers in Test Example 1 are also included. Similar to tablets ~5, the relative standard deviation is small in all cases, and the pemafibrate content per tablet is It was revealed that the uniformity was good.

[0109] Based on the above test results, pemafibrate or its salt or solvate is found to be present in By including alkyl sulfate esters in the pharmaceutical composition, the pe in the pharmaceutical composition is increased. It was found that the uniformity of mafibrate content was improved.

[0110] [Manufacturing Examples 1-6] Tablets containing the ingredients and quantities (mg) listed in Tables 7-8 per tablet are manufactured by a conventional wet process. It can be manufactured by granular compression.

[0111] [Table 7]

[0112] [Table 8]

[0113] [Manufacturing Examples 7-12] Tablets containing the ingredients and quantities (mg) listed in Tables 9-10 per tablet are prepared by conventional methods. It can be manufactured by the contact powder compression method.

[0114] [Table 9]

[0115] [Table 10] [Industrial applicability]

[0116] According to the present invention, a decrease in plasma triglyceride concentration and an increase in HDL cholesterol, etc. Because it can provide a pharmaceutical composition containing pemafibrate that exhibits action and has excellent homogeneity, for example For example, it can be used in the pharmaceutical industry, etc.

Claims

[Claim 1] The following components (A) and (B-1): (A) Pemafibrates or salts thereof or solvates thereof; (B-1) Hydroxypropylcellulose: 0.5 to 30% by mass of the total mass of the pharmaceutical composition; It contains and is a solid dosage form. The mass ratio of component (B-1) per 1 part by mass of pemafibrate-free form is 3 to 200 parts by mass. A pharmaceutical composition containing an amount of ingredient (A) that allows for a daily dose of 0.1 to 0.4 mg of pemafibrate in free form.

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