Pharmaceutical composition

Abstract

To provide a pharmaceutical composition containing pemafibrate, a salt thereof or a solvate thereof and having excellent homogeneity.SOLUTION: Provided is a pharmaceutical composition that contains the following components (A) and (B): (A) pemafibrate, a salt thereof or a solvate thereof; and (B) one or more selected from the group consisting of the following components (B-1) to (B-7): (B-1) cellulose ethers; (B-2) starches; (B-3) polyvinylpyrrolidones; (B-4) silicate compounds; (B-5) polyhydric alcohols; (B-6) alkyl sulfate esters; (B-7) (meth)acrylic acid-based polymers.SELECTED DRAWING: None

Description

Technical Field

[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 the formula (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, 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 and 2), and is also known to be useful for the prevention and treatment of NAFLD (non-alcoholic fatty liver disease) (Patent Document 2).

[0005] By the way, a compound useful as an active ingredient of a pharmaceutical is usually formulated and supplied as some kind of pharmaceutical composition. From the viewpoint of reliably exhibiting the expected medicinal effects and avoiding unexpected side effects, it is extremely important to ensure a constant quality without variation among lots and the like for the supplied pharmaceutical composition.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

[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. [Summary of the Invention] [Problems to be Solved by the Invention]

[0008] However, the manufacturability of pharmaceutical compositions, including homogeneity, is greatly influenced by the physical and chemical properties of the formulation components. These properties are often not predictable in advance from their chemical structures, etc., and problems are often not discovered until the pharmaceutical composition is actually manufactured. Therefore, it usually requires a great deal of trial and error to establish a technique for ensuring the homogeneity of pharmaceutical compositions. Regarding pemafibrate or its salts or their solvates, only reports have been made that they exhibit the above-described pharmacological effects, and no specific studies have been conducted so far on their use as pharmaceutical compositions. There have been no reports at all on the manufacturability, such as the homogeneity of pharmaceutical compositions. Under such circumstances, in order to develop a pharmaceutical composition containing pemafibrate or its salts or their solvates, the present inventors first actually manufactured a pharmaceutical composition. However, it was found that there was variation in the content of pemafibrate for each pharmaceutical composition, and problems occurred with the homogeneity (content uniformity) of the content of pemafibrate in the pharmaceutical composition. If the content of pemafibrate varies significantly for each pharmaceutical composition, there may also be variation in efficacy and safety among pharmaceutical compositions. Accordingly, an object of the present invention is to provide a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof and having excellent homogeneity.

Means for Solving the Problems

[0009] Therefore, the present inventors further intensively studied to solve the problem of content uniformity of pemafibrate or a salt thereof or a solvate thereof in a pharmaceutical composition. As a result, a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof (hereinafter, sometimes simply referred to as "component (A)" in the present specification) is further added with any one of the following components 1 to 7 (hereinafter, in the present specification, components 1 to 7 are referred to as "component (B-1)", "component (B-2)", "component (B-3)", "component (B-4)", "component (B-5)", "component (B-6)", and "component (B-7)", respectively, and "one or more selected from the group consisting of components (B-1) to (B-7)" may also be referred to as "component (B)").):

[0010] 1. Cellulose ethers typified by croscarmellose, carmellose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and ethylcellulose; 2. Starches typified by pregelatinized starch, corn starch, and sodium carboxymethyl starch; 3. Povidones typified by crospovidone and polyvinylpyrrolidone; 4. Silicic acid compounds typified by magnesium silicate hydrate, silicon dioxide hydrate, and light anhydrous silicic acid; 5. Polyhydric alcohols typified by macrogol and mannitol; 6. Alkyl sulfates typified by sodium lauryl sulfate; 7. (Meth)acrylic acid polymers typified by aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, and methacrylic acid copolymer L; By including it, it was found that the content uniformity of pemafibrate in the pharmaceutical composition was improved, and the present invention was completed.

[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-7); (B-1) Cellulose ethers (B-2) Starches (B-3) Povidones (B-4) Silicic acid compounds (B-5) Polyhydric alcohols (B-6) Alkyl sulfates (B-7) (Meth)acrylic acid polymers And provides a pharmaceutical composition containing the same.

[0012] The present invention also provides a method for improving the content uniformity of pemafibrate or a salt thereof or a solvate thereof in a pharmaceutical composition, which includes a step of including one or more selected from the group consisting of components (B-1) to (B-7) in a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof.

Effects of the Invention

[0013] According to the present invention, it is possible to provide a pharmaceutical composition in which the content uniformity of pemafibrate in the pharmaceutical composition is improved and which is excellent in homogeneity.

Modes for Carrying Out the Invention

[0014] <Pemafibrate or a salt thereof or a solvate thereof (component (A))> As used herein, "pemafibrate or a salt thereof or a solvate thereof" includes pemafibrate (chemical name: (2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid, international nonproprietary name: Pemafibrate) itself, pharmaceutically acceptable salts of pemafibrate, and further solvates of pemafibrate or its pharmaceutically acceptable salts with water, alcohol (e.g., ethanol), etc. Pharmaceutically acceptable salts are not particularly limited, and examples include acid addition salts and base addition salts. Specific examples of acid addition salts include acid addition salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; acid addition salts with organic acids such as benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, and acetate. Specific examples of base addition salts include metal salts such as sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt; salts with amines such as ammonia, trimethylamine, triethylamine, pyridine, collidine, and lutidine; and base addition salts with organic bases such as lysine, arginine, cinchonine, and cinchonidine.

[0015] The shape, size, etc. of pemafibrate or a salt thereof or a solvate thereof are not particularly limited. However, when measuring the average particle diameter of primary particles according to the particle diameter measurement method by laser diffraction in the 17th revised Japanese Pharmacopoeia, it is preferable that d50 and d90 are as follows. d50: Preferably 100 μm or less, more preferably 50 μm or less, even more preferably 20 μm or less, and particularly preferably 1 to 20 μm. It is preferably 200 μm or less, more preferably 135 μm or less, still more preferably 80 μm or less, and particularly preferably 1 to 80 μm.

[0016] Pemafibrate or a salt thereof or a solvate thereof is a known compound and can be produced, for example, by the methods disclosed in Patent Document 1, Non-Patent Document 1, and U.S. Patent No. 7,109,226. In the present invention, it is preferable to use crystals of pemafibrate (preferably having a melting point of 95 to 101°C, particularly preferably 97 to 100°C when measured according to the first method of the melting point measurement method in the seventeenth revised Japanese Pharmacopoeia) that can be produced by the method described in Non-Patent Document 1. The contents of these documents are incorporated herein by reference.

[0017] The content of pemafibrate or a salt thereof or a solvate thereof in the pharmaceutical composition is not particularly limited and can be appropriately determined in consideration of the disease to be applied, the type of formulation, the gender, age, symptoms, etc. of the user. For example, per day, pemafibrate or a salt thereof or a solvate thereof can be contained in an amount such that, in terms of the free form of pemafibrate, 0.05 to 0.8 mg, more preferably 0.075 to 0.6 mg, and particularly preferably 0.1 to 0.4 mg can be administered. The content of pemafibrate or a salt thereof or a solvate thereof in the pharmaceutical composition is preferably 0.01 to 5% by mass, more preferably 0.025 to 1% by mass, and particularly preferably 0.05 to 0.5% by mass in terms of the free form of pemafibrate with respect to the total mass of the pharmaceutical composition. According to the present invention, good content uniformity can be obtained even when pemafibrate or a salt thereof or a solvate thereof is in such a low content.

[0018] <Cellulose ethers (Component (B-1))> As used herein, the term "cellulose ethers" means one or more selected from the group consisting of compounds in which all or part of the hydroxy groups of cellulose form ether bonds and salts thereof. In addition to etherification, the cellulose ethers may be further modified by esterification, crosslinking, etc. as necessary. The salts are not particularly limited, and specific examples include alkali metal salts such as sodium salts and potassium salts; salts with metals of Group 2 elements such as calcium salts and magnesium salts. The average degree of polymerization and properties (crystalline form) of the cellulose ethers are not particularly limited, but the average degree of polymerization is preferably 10 to 10,000. Specific examples of such cellulose ethers include, for example, alkyl celluloses such as methyl cellulose and ethyl cellulose or salts thereof; hydroxyalkyl celluloses such as hydroxyethyl cellulose and hydroxypropyl cellulose or salts thereof; alkyl(hydroxyalkyl) celluloses such as hydroxyethyl methyl cellulose, hypromellose, hypromellose acetate succinate, hypromellose phthalate or derivatives thereof (ester derivatives) or salts thereof; carboxyalkyl celluloses such as carboxymethyl cellulose, carboxymethyl cellulose potassium, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, carboxymethyl ethyl cellulose, croscarmellose sodium or derivatives thereof (crosslinked polymers) or salts thereof, etc. One of these may be used alone or two or more thereof may be used in combination. The alkyl group in the cellulose ethers is not particularly limited, but a linear or branched alkyl group having 1 to 6 carbon atoms is preferred. The degree of substitution of the hydroxyalkoxy group in the hydroxyalkyl cellulose is not particularly limited. For example, hydroxypropyl cellulose includes both non-low-substitution-degree hydroxypropyl cellulose and low-substitution-degree hydroxypropyl cellulose. Here, the low-substitution-degree hydroxypropyl cellulose refers to hydroxypropyl cellulose described in the seventeenth revised Japanese Pharmacopoeia, in which the hydroxypropoxy group is quantified at 5.0 to 16.0% when dried.

[0019] As cellulose ethers, from the viewpoint of improving the content uniformity, one or more selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl(hydroxyalkyl) cellulose, carboxyalkyl cellulose, cross-linked polymers of carboxyalkyl cellulose, and salts thereof are preferable; one or more selected from the group consisting of C1-C6 alkyl cellulose, hydroxy C1-C6 alkyl cellulose, C1-C6 alkyl(hydroxy C1-C6 alkyl) cellulose, carboxy C1-C6 alkyl cellulose, cross-linked polymers of carboxy C1-C6 alkyl cellulose, and salts thereof are more preferable; one or more selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hypromellose, carmellose, and croscarmellose, and salts thereof are even more preferable; one or more selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hypromellose, carmellose, potassium carmellose, calcium carmellose, sodium carmellose, and sodium croscarmellose are even more preferable; one or more selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hypromellose, carmellose, calcium carmellose, sodium carmellose, and sodium croscarmellose are even more preferable; ethyl cellulose is particularly preferable. As hydroxypropyl cellulose, low-substitution-degree hydroxypropyl cellulose is preferable. Further, from the viewpoint of ease of production of pharmaceutical compositions (especially solid preparations), as cellulose ethers, those that are solid at normal temperature (any temperature between 15 and 25 °C) are preferable.

[0020] In addition, the substitution rate of the alkoxy group of alkyl cellulose or its salt is preferably in the range of 20 to 70%, more preferably in the range of 40 to 60%. The quantification of the substitution rate of the alkoxy group of alkyl cellulose or its salt is carried out according to the method for quantifying the methoxy group of methyl cellulose described in the seventeenth revised Japanese Pharmacopoeia. Also, the viscosity of alkyl cellulose or its salt is preferably 0.1 to 5000 mPa·s, more preferably 1 to 200 mPa·s. The viscosity measurement of alkyl cellulose or its salt is carried out according to the viscosity measurement method of methyl cellulose described in the seventeenth revised Japanese Pharmacopoeia. These cellulose ethers are all known components and may be produced by known methods or commercially available products may be used. Examples of such commercially available products include Ethocel (Dow Chemical Japan Co., Ltd.), CMEC (Froint Industry Co., Ltd.), NS-300 (San-Ei Gen F.F.I. Inc.), ECG-505 (San-Ei Gen F.F.I. Inc.), Cellogen (San-Ei Gen F.F.I. Inc.), Ac-Di-Sol (Asahi Kasei Corporation), HEC (Sumitomo Seika Chemicals Co., Ltd.), Hydroxypropylcellulose (Nippon Soda Co., Ltd.), Shin-Etsu AQOAT (Shin-Etsu Chemical Co., Ltd.), METOLOSE90SH-SR (Shin-Etsu Chemical Co., Ltd.), HPMCP (Shin-Etsu Chemical Co., Ltd.), METOLOSE SM (Shin-Etsu Chemical Co., Ltd.), TC-5 (San-Ei Gen F.F.I. Inc.), L-HPC (Shin-Etsu Chemical Co., Ltd.), and the like.

[0021] The content of cellulose ethers in the pharmaceutical composition is not particularly limited and can be appropriately determined according to the type of preparation, the gender, age, symptoms, etc. of the user. However, from the viewpoint of improving the content uniformity, the total amount of cellulose ethers with respect to the total mass of the pharmaceutical composition is preferably 0.5 to 30% by mass, more preferably 1 to 20% by mass, even more preferably 1.5 to 15% by mass, and particularly preferably 2 to 10% by mass.

[0022] When using alkyl cellulose or its salt as the cellulose ethers, from the viewpoint of the effect of improving the content uniformity, the content of the alkyl cellulose or its salt is preferably 0.6 to 22% by mass, more preferably 1.1 to 19% by mass, and particularly preferably 2 to 8% by mass based on the total mass of the pharmaceutical composition.

[0023] When using hydroxyalkyl cellulose or its salt as the cellulose ethers, from the viewpoint of the effect of improving the content uniformity, the content of the hydroxyalkyl cellulose or its salt is preferably 0.7 to 24% by mass, more preferably 1.2 to 18% by mass, and particularly preferably 3 to 8% by mass based on the total mass of the pharmaceutical composition. When using alkyl(hydroxyalkyl)cellulose or its derivative or their salts as the cellulose ethers, from the viewpoint of the effect of improving the content uniformity, the content of the alkyl(hydroxyalkyl)cellulose or its derivative or their salts is preferably 0.8 to 26% by mass, more preferably 1.3 to 17% by mass, and particularly preferably 4 to 9% by mass based on the total mass of the pharmaceutical composition. When using carboxyalkyl cellulose or its derivative or their salts as the cellulose ethers, from the viewpoint of the effect of improving the content uniformity, the content of the carboxyalkyl cellulose or its derivative or their salts is preferably 0.9 to 28% by mass, more preferably 1.4 to 16% by mass, and particularly preferably 1.6 to 9% by mass based on the total mass of the pharmaceutical composition.

[0024] The content mass ratio of pemafibrate or its salt or their solvates and cellulose ethers in the pharmaceutical composition is not particularly limited. However, from the viewpoint of the effect of improving the content uniformity, it is preferable to contain a total of 3 to 200 parts by mass, more preferably 5 to 150 parts by mass, and particularly preferably 10 to 100 parts by mass of cellulose ethers per 1 part by mass of pemafibrate in the free form.

[0025] When alkyl cellulose or its salt is used as the cellulose ethers, the content mass ratio of pemafibrate or its salt or their solvates to alkyl cellulose or its salt in the pharmaceutical composition is not particularly limited. However, from the viewpoint of the effect of improving content uniformity, it is preferably to contain a total of 4 to 160 parts by mass, more preferably 6 to 110 parts by mass, and particularly preferably 20 to 60 parts by mass of alkyl cellulose or its salt per 1 part by mass in terms of the free form of pemafibrate. When hydroxyalkyl cellulose or its salt is used as the cellulose ethers, the content mass ratio of pemafibrate or its salt or their solvates to hydroxyalkyl cellulose or its salt in the pharmaceutical composition is not particularly limited. However, from the viewpoint of the effect of improving content uniformity, it is preferably to contain a total of 4 to 170 parts by mass, more preferably 7 to 120 parts by mass, still more preferably 20 to 100 parts by mass, and particularly preferably 30 to 70 parts by mass of hydroxyalkyl cellulose or its salt per 1 part by mass in terms of the free form of pemafibrate. When alkyl(hydroxyalkyl)cellulose or its derivative or their salt is used as the cellulose ethers, the content mass ratio of pemafibrate or its salt or their solvates to alkyl(hydroxyalkyl)cellulose or its derivative or their salt in the pharmaceutical composition is not particularly limited. However, from the viewpoint of the effect of improving content uniformity, it is preferably to contain a total of 4 to 180 parts by mass, more preferably 8 to 130 parts by mass, still more preferably 20 to 100 parts by mass, and particularly preferably 40 to 80 parts by mass of alkyl(hydroxyalkyl)cellulose or its derivative or their salt per 1 part by mass in terms of the free form of pemafibrate. When carboxyalkyl cellulose, its derivatives, or their salts are used as the cellulose ethers, the content mass ratio of pemafibrate, its salts, or their solvates to carboxyalkyl cellulose, its derivatives, or their salts in the pharmaceutical composition is not particularly limited. However, from the viewpoint of improving content uniformity, it is preferably contained in a total amount of 4 to 190 parts by mass, more preferably 9 to 140 parts by mass, still more preferably 14 to 100 parts by mass, and particularly preferably 19 to 90 parts by mass of carboxyalkyl cellulose, its derivatives, or their salts per 1 part by mass in terms of the free form of pemafibrate.

[0026] <Starches (Component (B-2))> As used herein, the term "starches" means one or more selected from the group consisting of starch itself, those in which all or part of the hydroxy groups of starch form ether bonds, their derivatives, and their salts. Note that starches include those that have been subjected to treatments such as gelatinization and aging. In addition, the above derivatives include those in which starch or its etherified products have been further modified, such as esterification, crosslink formation, and hydrolysis, as necessary. The salts are not particularly limited, and specific examples include alkali metal salts such as sodium salts and potassium salts; salts with metals of Group 2 elements such as calcium salts and magnesium salts. Specific examples of such starches include starches or their salts such as pregelatinized starch, wheat starch, rice starch, corn starch, potato starch, partially pregelatinized starch, wheat flour, rice flour, and dextrin; hydroxyalkyl ethers of starch or their salts such as hydroxypropyl starch; carboxyalkyl ethers of starch or their salts such as sodium carboxymethyl starch, etc. One of these may be used alone or two or more may be used in combination. The alkyl group in the starches is not particularly limited, but a linear or branched alkyl group having 1 to 6 carbon atoms is preferred.

[0027] As starches, from the viewpoint of the action of improving content uniformity, one or more selected from the group consisting of starch, hydroxyalkyl ethers of starch and carboxyalkyl ethers of starch and their salts are preferred, one or more selected from the group consisting of starch, hydroxy C1-C6 alkyl ethers of starch and carboxy C1-C6 alkyl ethers of starch and their salts are more preferred, one or more selected from the group consisting of starch, hydroxypropyl starch and carboxymethyl starch and their salts are even more preferred, and one or more selected from the group consisting of starch and sodium carboxymethyl starch are particularly preferred. Further, from the viewpoint of ease of manufacturing a pharmaceutical composition (especially a solid preparation), as starches, those that are solid at normal temperature (any temperature from 15 to 25°C) are preferred. Incidentally, all of these starches are known components, and they may be produced by known methods, or commercially available products may be used. Examples of such commercially available products include LYCATAB PGS (Rocket Japan Co., Ltd.), GLYCOLYS (Rocket Japan Co., Ltd.), starch (soluble) (Kishida Chemical Co., Ltd.), corn starch (San-Ei Gen F.F.I., Inc.), potato starch (Junsei Chemical Co., Ltd.), HPS-101 (Froint Industry Co., Ltd.), LYCATAB C (Rocket Japan Co., Ltd.), etc.

[0028] The content of starches in the pharmaceutical composition is not particularly limited and can be appropriately considered and determined according to the type of preparation, the gender, age, symptoms, etc. of the user. However, from the viewpoint of the action of improving content uniformity, the total amount of starches relative to the total mass of the pharmaceutical composition is preferably 0.5 to 50% by mass, more preferably 1 to 40% by mass, even more preferably 1.5 to 30% by mass, and particularly preferably 2 to 20% by mass.

[0029] When starch is used as the starch, the content of starch is preferably 0.6 to 47% by mass, more preferably 1.1 to 38% by mass, and particularly preferably 1.6 to 28% by mass relative to the total mass of the pharmaceutical composition from the viewpoint of the action of improving content uniformity. When carboxyalkyl ether of starch or its salt is used as starches, from the viewpoint of the effect of improving content uniformity, the content of carboxyalkyl ether of starch or its salt is preferably 0.8 to 45% by mass, more preferably 1.3 to 36% by mass, and particularly preferably 1.7 to 26% by mass based on the total mass of the pharmaceutical composition.

[0030] The content mass ratio of pemafibrate or its salt or their solvates and starches in the pharmaceutical composition is not particularly limited, but from the viewpoint of the effect of improving content uniformity, it is preferable that the total amount of starches is 5 to 400 parts by mass, more preferably 15 to 300 parts by mass, and particularly preferably 20 to 200 parts by mass with respect to 1 part by mass in terms of the free form of pemafibrate.

[0031] When starch is used as starches, the content mass ratio of pemafibrate or its salt or their solvates and starch in the pharmaceutical composition is not particularly limited, but from the viewpoint of the effect of improving content uniformity, it is preferable that the total amount of starch is 7 to 380 parts by mass, more preferably 16 to 280 parts by mass, and particularly preferably 30 to 190 parts by mass with respect to 1 part by mass in terms of the free form of pemafibrate. When carboxyalkyl ether of starch or its salt is used as starches, the content mass ratio of pemafibrate or its salt or their solvates and carboxyalkyl ether of starch or its salt in the pharmaceutical composition is not particularly limited, but from the viewpoint of the effect of improving content uniformity, it is preferable that the total amount of carboxyalkyl ether of starch or its salt is 9 to 370 parts by mass, more preferably 17 to 270 parts by mass, and particularly preferably 40 to 180 parts by mass with respect to 1 part by mass in terms of the free form of pemafibrate.

[0032] <Povidones (Component (B-3))> As used herein, "povidones" means polymers of 1-vinyl-2-pyrrolidone, and is a concept that includes not only homopolymers of 1-vinyl-2-pyrrolidone but also copolymers of 1-vinyl-2-pyrrolidone and other polymerizable compounds. Further, the polymer may be an uncrosslinked polymer or a crosslinked polymer. Also, in the linear polymer (povidone) of 1-vinyl-2-pyrrolidone, its K value is not particularly limited, but those having a K value of 12 to 90 are preferably used as the indicated K value, and those having a K value of 25 to 90 are particularly preferably used. Specific examples of such povidones include, for example, linear polymers of 1-vinyl-2-pyrrolidone such as povidone (note that the K value of povidone is not particularly limited, and examples of the indicated K value include those having values of 12, 17, 25, 30, and 90); copolymers of 1-vinyl-2-pyrrolidone and vinyl acetate such as copovidone; crosslinked polymers of 1-vinyl-2-pyrrolidone such as crospovidone, etc. Among these, one of them may be used alone or two or more of them may be used in combination. As povidones, from the viewpoint of the effect of improving content uniformity, one or more selected from the group consisting of povidone, copovidone, and crospovidone are preferable, one or more selected from the group consisting of povidone and crospovidone are more preferable, and crospovidone is particularly preferable. Further, from the viewpoint of the ease of manufacturing a pharmaceutical composition (particularly a solid preparation), as povidones, those that are solid at normal temperature (any temperature from 15 to 25 °C) are preferable. In addition, all of these povidones are known components, and they may be produced by known methods, or commercial products may be used. Examples of such commercial products include, for example, Kollidon CL, Kollidon VA64, Kollidon (above, BASF Japan Ltd.), etc.

[0033] The content of povidones in the pharmaceutical composition is not particularly limited and can be appropriately determined in consideration of the type of preparation, the gender, age, symptoms, etc. of the user. However, from the viewpoint of the effect of improving content uniformity, the total amount of povidones with respect to the total mass of the pharmaceutical composition is preferably 0.1 to 20% by mass, more preferably 0.5 to 15% by mass, and particularly preferably 1 to 10% by mass.

[0034] Also, when using a linear polymer of 1-vinyl-2-pyrrolidone as povidones, from the viewpoint of the effect of improving content uniformity, the content of the linear polymer of 1-vinyl-2-pyrrolidone is preferably 0.2 to 16% by mass, more preferably 0.6 to 14% by mass, and particularly preferably 3 to 9% by mass based on the total mass of the pharmaceutical composition. Also, when using a cross-linked polymer of 1-vinyl-2-pyrrolidone as povidones, from the viewpoint of the effect of improving content uniformity, the content of the cross-linked polymer of 1-vinyl-2-pyrrolidone is preferably 0.3 to 17% by mass, more preferably 0.7 to 13% by mass, and particularly preferably 2 to 8% by mass based on the total mass of the pharmaceutical composition.

[0035] The content mass ratio of pemafibrate or its salt or their solvates and povidones in the pharmaceutical composition is not particularly limited, but from the viewpoint of the effect of improving content uniformity, it is preferably to contain a total of 1 to 200 parts by mass, more preferably 3 to 150 parts by mass, and particularly preferably 5 to 100 parts by mass of povidones per 1 part by mass in terms of the free form of pemafibrate.

[0036] Also, when using a linear polymer of 1-vinyl-2-pyrrolidone as povidones, the content mass ratio of pemafibrate or its salt or their solvates and the linear polymer of 1-vinyl-2-pyrrolidone in the pharmaceutical composition is not particularly limited, but from the viewpoint of the effect of improving content uniformity, it is preferably to contain a total of 1.5 to 190 parts by mass, more preferably 3.5 to 140 parts by mass, and particularly preferably 6 to 90 parts by mass of the linear polymer of 1-vinyl-2-pyrrolidone per 1 part by mass in terms of the free form of pemafibrate. When a cross-linked polymer of 1-vinyl-2-pyrrolidone is used as povidones, the mass ratio of pemafibrate or its salt or solvate thereof to the cross-linked polymer of 1-vinyl-2-pyrrolidone in the pharmaceutical composition is not particularly limited. However, from the viewpoint of improving content uniformity, it is preferably 2 to 180 parts by mass, more preferably 4 to 130 parts by mass, and particularly preferably 7 to 80 parts by mass of the cross-linked polymer of 1-vinyl-2-pyrrolidone in total per 1 part by mass in terms of the free form of pemafibrate.

[0037] <Silicic acid compound (component (B-4))> In the present specification, the "silicic acid compound" includes not only the silicic acid compound itself but also salts of the silicic acid compound. Examples of salts of the silicic acid compound include inorganic salts, specifically, for example, alkali metal salts such as sodium salts and potassium salts; salts with metals of Group 2 elements such as magnesium salts and calcium salts, and salts with metals of Group 13 elements such as aluminum salts. Specific examples of such silicic acid compounds include hydrous silicic acid compounds or their salts such as hydrous silicon dioxide, hydrous amorphous silicon oxide, hydrous magnesium silicate, and hydrous magnesium silicate (natural); anhydrous silicic acids or their salts such as light anhydrous silicic acid and heavy anhydrous silicic acid; silicic acids or their salts such as silicon dioxide, natural aluminum silicate, synthetic aluminum silicate, synthetic sodium magnesium silicate, calcium silicate, magnesium silicate, magnesium aluminum silicate, magnesium aluminosilicate, and magnesium metasilicate aluminate, and in addition, diatomaceous earth, bentonite, kaolin, talc, etc. One of these may be used alone or two or more thereof may be used in combination. As the silicic acid compound, from the viewpoint of the action of improving content uniformity, one or more selected from the group consisting of hydrous silicic acid compounds, salts of hydrous silicic acid compounds, anhydrous silicic acids, and salts of anhydrous silicic acids are preferred, and one or more selected from the group consisting of hydrous silicic acid compounds and salts of hydrous silicic acid compounds are particularly preferred. Among the specifically exemplified silicate compounds, from the viewpoint of improving the content uniformity, one or more selected from the group consisting of magnesium silicate hydrate, silicon dioxide hydrate, and light anhydrous silicic acid are preferable, and one or more selected from the group consisting of magnesium silicate hydrate and silicon dioxide hydrate are particularly preferable. Further, from the viewpoint of the ease of manufacturing a pharmaceutical composition (particularly a solid preparation), as the silicate compound, those that are solid at normal temperature (any temperature between 15 and 25 °C) are preferable. In addition, all of these silicate compounds are known components, and they may be produced by known methods or commercially available products may be used. Examples of such commercially available products include Noycillin A (Fuji Chemical Industry Co., Ltd.), Florite (Tomita Pharmaceutical Co., Ltd.), Magnesium Silicate (Tomita Pharmaceutical Co., Ltd.), VEEGUMI Granule (Sanyo Chemical Industries, Ltd.), VEEGUMI HV Granule (Sanyo Chemical Industries, Ltd.), VEEGUMI K Granule (Sanyo Chemical Industries, Ltd.), VEEGUMI F (Sanyo Chemical Industries, Ltd.), Silicia 320 (Fuji Silysia Chemical Ltd.), Silicia 350 (Fuji Silysia Chemical Ltd.), Silicia 320TP (Fuji Silysia Chemical Ltd.), Silicia 320FCP (Fuji Silysia Chemical Ltd.), Mycron FR (Tomita Pharmaceutical Co., Ltd.), Silicon Dioxide (Nippon Aerosil Co., Ltd.), Aerosil 300 (Nippon Aerosil Co., Ltd.), Adsorider 101 (Floyd Industries Co., Ltd.), Adsorider 102 (Floyd Industries Co., Ltd.), Silicia (Fuji Silysia Chemical Ltd.), Silosphere (Fuji Silysia Chemical Ltd.), Hydrous Amorphous Silicon Oxide (Tosoh Silica Co., Ltd.), Noycillin (Fuji Chemical Industry Co., Ltd.), Diatomaceous Earth (Showa Chemical Industry Co., Ltd.), Talc (Sanyo Gosei FFI Co., Ltd.), and the like.

[0038] The content of the silicate compound in the pharmaceutical composition is not particularly limited and can be appropriately determined in consideration of the type of preparation, the gender, age, symptoms, etc. of the user. However, from the viewpoint of the effect of improving the content uniformity, the total amount of the silicate compound with respect to the total mass of the pharmaceutical composition is preferably 0.1 to 20% by mass, more preferably 0.5 to 15% by mass, and particularly preferably 1 to 10% by mass.

[0039] When using one or more selected from the group consisting of hydrous silicic acid compounds and their salts as the silicic acid compound, from the viewpoint of the effect of improving content uniformity, the content of one or more selected from the group consisting of hydrous silicic acid compounds and their salts is preferably 0.2 to 19% by mass, more preferably 0.6 to 14% by mass, and particularly preferably 2 to 6% by mass based on the total mass of the pharmaceutical composition. When using one or more selected from the group consisting of anhydrous silicic acid compounds and their salts as the silicic acid compound, from the viewpoint of the effect of improving content uniformity, the content of one or more selected from the group consisting of anhydrous silicic acid compounds and their salts is preferably 0.4 to 17% by mass, more preferably 0.8 to 12% by mass, and particularly preferably 4 to 8% by mass based on the total mass of the pharmaceutical composition.

[0040] The content mass ratio of pemafibrate or its salt or their solvates and the silicic acid compound in the pharmaceutical composition is not particularly limited, but from the viewpoint of the effect of improving content uniformity, it is preferable to contain a total of 1 to 200 parts by mass, more preferably 3 to 150 parts by mass, and particularly preferably 5 to 100 parts by mass of the silicic acid compound per 1 part by mass in terms of the free form of pemafibrate.

[0041] When using one or more selected from the group consisting of hydrous silicic acid compounds and their salts as the silicic acid compound, the content mass ratio of pemafibrate or its salt or their solvates and one or more selected from the group consisting of hydrous silicic acid compounds and their salts in the pharmaceutical composition is not particularly limited, but from the viewpoint of the effect of improving content uniformity, it is preferable to contain a total of 2 to 160 parts by mass, more preferably 4 to 140 parts by mass, and particularly preferably 10 to 90 parts by mass of one or more selected from the group consisting of hydrous silicic acid compounds and their salts per 1 part by mass in terms of the free form of pemafibrate. In addition, when using one or more selected from the group consisting of silicic anhydride compounds and their salts as the silicic acid compound, the content mass ratio of pemafibrate or its salt or their solvates and one or more selected from the group consisting of silicic anhydride compounds and their salts in the pharmaceutical composition is not particularly limited. However, from the viewpoint of improving content uniformity, it is preferably to contain a total of 2 to 180 parts by mass, more preferably 4 to 120 parts by mass, and particularly preferably 10 to 80 parts by mass of one or more selected from the group consisting of silicic anhydride compounds and their salts per 1 part by mass in terms of the free form of pemafibrate.

[0042] <Polyhydric alcohol (Component (B-5))> In this specification, the "polyhydric alcohol" means a compound having two or more alcoholic hydroxyl groups and not having two or more cyclic ether structures (such as a tetrahydropyran ring, etc.) in the molecule, and it may be a non-polymer or a polymer. Examples of such polyhydric alcohols include sugar alcohols and non-sugar alcohols, and one of these may be used alone or two or more may be used in combination. Further, as the polyhydric alcohol, a polyhydric alcohol not containing a cyclic ether structure (such as a tetrahydropyran ring, etc.) in the molecule or a polyhydric alcohol having only one cyclic ether structure in the molecule is preferred, a polyhydric alcohol not containing a cyclic ether structure in the molecule is more preferred, and a non-cyclic compound among polyhydric alcohols is particularly preferred. In addition, from the viewpoint of ease of manufacturing a pharmaceutical composition (especially a solid preparation), the polyhydric alcohol is preferably solid at normal temperature (any temperature from 15 to 25 °C).

[0043] Specific examples of the sugar alcohol include sugar alcohols having 3 carbon atoms such as glycerin (triitol); sugar alcohols having 4 carbon atoms such as erythritol and threitol (tetritol); sugar alcohols having 5 carbon atoms such as xylitol, arabinitol, ribitol, and adonitol (pentitol); sugar alcohols having 6 carbon atoms such as mannitol, sorbitol, iditol, dulcitol, and galactitol (hexitol); sugar alcohols having 12 carbon atoms such as maltitol and lactitol (dodecitol), etc. Among these, one kind may be used alone or two or more kinds may be used in combination. In addition, although various stereoisomers may exist in these sugar alcohols, the configuration thereof is not particularly limited as the "sugar alcohol", and each kind of stereoisomer alone or any mixture of various stereoisomers in any ratio may be used.

[0044] Among the above sugar alcohols, from the viewpoint of the action of improving content uniformity, one or more selected from the group consisting of erythritol, xylitol, mannitol, sorbitol, maltitol, and lactitol are preferred, one or more selected from the group consisting of mannitol, sorbitol, and maltitol are more preferred, and mannitol is particularly preferred. In addition, all of these sugar alcohols are known components, and they may be produced by known methods or commercially available products may be used. Examples of such commercially available products include erythritol (San-Ei Gen F.F.I., Inc.), xylitt (Towa Kasei Kogyo Co., Ltd.), NEOSORB P (Rocket Japan Co., Ltd.), Reshis (Towa Kasei Kogyo Co., Ltd.), Mannit P (Towa Kasei Kogyo Co., Ltd.), glycerin (NOF Corporation), MALTISORB (Rocket Japan Co., Ltd.), Amalty Syrup (Towa Kasei Kogyo Co., Ltd.), etc.

[0045] Also, as the non-sugar alcohol, an acyclic compound among non-sugar alcohols is preferable. Specifically, for example, alkylene glycols such as ethylene glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, 1,3-butanediol; diethylene glycol, dipropylene glycol, macrogol (for example, macrogol 100, macrogol 200, macrogol 300, macrogol 400, macrogol 600, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, polyethylene glycol 8000, macrogol 20000, macrogol 35000, etc. are exemplified.), polypropylene glycol (for example, polypropylene glycol 2000, etc. are exemplified.), polyoxyethylene polyoxypropylene glycol (for example, polyoxyethylene(3) polyoxypropylene(17) glycol, polyoxyethylene(20) polyoxypropylene(20) glycol, polyoxyethylene(42) polyoxypropylene(67) glycol, polyoxyethylene(54) polyoxypropylene(39) glycol, polyoxyethylene(105) polyoxypropylene(5) glycol, polyoxyethylene(120) polyoxypropylene(40) glycol, polyoxyethylene(124) polyoxypropylene(39) glycol, polyoxyethylene(160) polyoxypropylene(30) glycol, polyoxyethylene(196) polyoxypropylene(67) glycol, polyoxyethylene(200) polyoxypropylene(70) glycol, etc. are exemplified.) and other polyalkylene glycols; polyvinyl alcohol (fully saponified product), polyvinyl alcohol (partially saponified product) and other polyvinyl alcohols; meglumine and the like can be mentioned, and one of these may be used alone or two or more thereof may be used in combination.

[0046] Among the above non-sugar alcohols, from the viewpoint of the effect of improving content uniformity, divalent non-sugar alcohols are preferred, polyalkylene glycols are more preferred, macrogols are even more preferred, and one or more selected from the group consisting of macrogol 100, macrogol 200, macrogol 300, macrogol 400, macrogol 600, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, polyethylene glycol 8000, macrogol 20000 and macrogol 35000 are even more preferred, macrogols having an average molecular weight of 100 to 10000 are even more preferred, those having an average molecular weight of 200 to 8000 are even more preferred, and macrogol 6000 is particularly preferred. The average molecular weight of macrogol can be measured by the "Average Molecular Weight Test" described in the section of "Macrogol 400" in the "Pharmaceutical Articles" of the Seventeenth Revised Japanese Pharmacopoeia. These non-sugar alcohols are all known components, and they may be manufactured by known methods or commercial products may be used. Examples of such commercial products include, for example, Colysorb PG (BASF Japan Ltd.), diethylene glycol (Nippon Shokubai Co., Ltd.), Unisafe DPG-R (Nippon Oil Co., Ltd.), Macrogol 200 (Sanyo Chemical Industries, Ltd.), Colysorb PEG300 (BASF Japan Ltd.), Super Refined PEG400 (Croda Japan Ltd.), CARBOWAX Sentry PEG600 (Dow Chemical Japan Ltd.), Macrogol 1000 (Nippon Oil Co., Ltd.), Macrogol 1500 (Sanyo Chemical Industries, Ltd.), CARBOWAX Sentry PEG1540 (Dow Chemical Japan Ltd.), Macrogol 4000 (Sanyo Chemical Industries, Ltd.), Macrogol 6000 (Sanyo Chemical Industries, Ltd.), Macrogol 20000 (Sanyo Chemical Industries, Ltd.), Newpol PP-2000 (Sanyo Chemical Industries, Ltd.), Pronon 101P (Nippon Oil Co., Ltd.), Colysorb P124 (BASF Japan Ltd.), Pronon 403P (Nippon Oil Co., Ltd.), New Det PE-85 (Sanyo Chemical Industries, Ltd.), PEP-101 (Froint Industries Co., Ltd.), Colyphore P188 (BASF Japan Ltd.), Colyphore P407 Micro (BASF Japan Ltd.), and Unilube DP-950B (Nippon Oil Co., Ltd.), etc.

[0047] The content of polyhydric alcohol in the pharmaceutical composition is not particularly limited and can be appropriately considered and determined according to the type of preparation, the gender, age, symptoms, etc. of the user. However, from the perspective of the effect of improving content uniformity, the total amount of polyhydric alcohol is preferably 0.1 to 99% by mass, more preferably 0.5 to 95% by mass, still more preferably 1 to 90% by mass, and particularly preferably 1.5 to 50% by mass based on the total mass of the pharmaceutical composition.

[0048] When sugar alcohol is used as the polyhydric alcohol, from the perspective of the effect of improving content uniformity, the content of sugar alcohol is preferably 0.2 to 98% by mass, more preferably 0.6 to 94% by mass, and particularly preferably 1.1 to 85% by mass based on the total mass of the pharmaceutical composition. When a non-sugar alcohol is used as the polyhydric alcohol, from the viewpoint of the effect of improving content uniformity, the content of the non-sugar alcohol is preferably 0.3 to 97% by mass, more preferably 0.7 to 93% by mass, and particularly preferably 1.2 to 80% by mass based on the total mass of the pharmaceutical composition. When polyalkylene glycols are used as the polyhydric alcohol, from the viewpoint of the effect of improving content uniformity, the content of the polyalkylene glycols is preferably 0.4 to 96% by mass, more preferably 0.8 to 92% by mass, and particularly preferably 1.3 to 75% by mass based on the total mass of the pharmaceutical composition.

[0049] The content mass ratio of pemafibrate or its salt or their solvates and the polyhydric alcohol in the pharmaceutical composition is not particularly limited. However, from the viewpoint of the effect of improving content uniformity, it is preferable to contain a total of 1 to 2000 parts by mass, more preferably 5 to 1500 parts by mass, still more preferably 10 to 1000 parts by mass, and particularly preferably 15 to 500 parts by mass of the polyhydric alcohol per 1 part by mass of the free form of pemafibrate.

[0050] When a sugar alcohol is used as the polyhydric alcohol, the content mass ratio of pemafibrate or its salt or their solvates and the sugar alcohol in the pharmaceutical composition is not particularly limited. However, from the viewpoint of the effect of improving content uniformity, it is preferable to contain a total of 2 to 1900 parts by mass, more preferably 6 to 1450 parts by mass, and particularly preferably 12 to 950 parts by mass of the sugar alcohol per 1 part by mass of the free form of pemafibrate. When a non-sugar alcohol is used as the polyhydric alcohol, the content mass ratio of pemafibrate or its salt or their solvates and the non-sugar alcohol in the pharmaceutical composition is not particularly limited. However, from the viewpoint of the effect of improving content uniformity, it is preferable to contain a total of 3 to 1850 parts by mass, more preferably 7 to 1400 parts by mass, and particularly preferably 13 to 900 parts by mass of the non-sugar alcohol per 1 part by mass of the free form of pemafibrate. When polyalkylene glycols are used as the polyhydric alcohol, the mass ratio of pemafibrate or its salt or their solvates to polyalkylene glycols in the pharmaceutical composition is not particularly limited. However, from the viewpoint of improving content uniformity, it is preferable to contain a total of 4 to 1800 parts by mass of polyalkylene glycols, more preferably 8 to 1350 parts by mass, and particularly preferably 14 to 850 parts by mass, based on 1 part by mass of the free form of pemafibrate.

[0051] <Alkyl sulfates (Component (B-6))> In the present specification, "alkyl sulfates" refers to the following formula (1): R-O-SO 3 M ···(1) (In the formula, R represents a linear or branched saturated or unsaturated hydrocarbon group having 8 to 22 carbon atoms, and M represents an alkali metal such as sodium or potassium; a metal of Group 2 elements such as magnesium or calcium; an ammonium ion; or a hydroxyalkyl-substituted ammonium having 2 or 3 carbon atoms such as triethanolammonium.) It means an alkyl sulfate salt represented by the formula. Specific examples of such alkyl sulfates include lauryl sulfate salt, tetradecyl sulfate salt, hexadecyl sulfate salt, octadecyl sulfate salt, etc. One of these may be used alone or two or more thereof may be used in combination. As the alkyl sulfates, from the viewpoint of the action of improving content uniformity, one or more selected from the group consisting of lauryl sulfate salt, tetradecyl sulfate salt, hexadecyl sulfate salt and octadecyl sulfate salt are preferable, lauryl sulfate salt is more preferable, and sodium lauryl sulfate is particularly preferable. Further, from the viewpoint of the ease of production of the pharmaceutical composition (particularly solid preparations), the alkyl sulfates are preferably solids at normal temperature (any temperature between 15 and 25 °C). These alkyl sulfates are all known components and may be produced by known methods or commercially available products may be used. Examples of such commercially available products include Coliphor SLS (BASF Japan Ltd.).

[0052] The content of alkyl sulfates in the pharmaceutical composition is not particularly limited and can be appropriately determined according to the type of formulation, the gender, age, symptoms, etc. of the user. However, from the perspective of improving content uniformity, the total amount of alkyl sulfates is preferably 0.1 to 20% by mass, more preferably 0.5 to 15% by mass, and particularly preferably 1 to 10% by mass based on the total mass of the pharmaceutical composition.

[0053] The content mass ratio of pemafibrate or its salt or their solvates and alkyl sulfates in the pharmaceutical composition is not particularly limited. However, from the perspective of improving content uniformity, it is preferably 1 to 200 parts by mass, more preferably 3 to 150 parts by mass, still more preferably 5 to 100 parts by mass, and particularly preferably 5 to 50 parts by mass of alkyl sulfates in total per 1 part by mass in terms of the free form of pemafibrate.

[0054] <(Meth)acrylic acid polymers (Component (B-7))> In this specification, the “(meth)acrylic acid polymers” mean polymers containing one or more structural units (hereinafter also referred to as structural unit X) selected from the group consisting of structural units derived from acrylic acid, structural units derived from methacrylic acid, structural units derived from acrylic esters, and structural units derived from methacrylic esters. Here, examples of the acrylic esters and methacrylic esters include esters of aliphatic alcohols such as methanol, ethanol, propanol, and butanol (preferably linear or branched aliphatic alcohols having 1 to 12 carbon atoms (more preferably 1 to 6 carbon atoms)) and (meth)acrylic acid. In addition, the aliphatic alcohol may further be substituted with an aliphatic amino group (primary to tertiary amino group, or quaternary ammonium group. Here, as the aliphatic group contained in the aliphatic amino group, a linear or branched aliphatic group having 1 to 12 carbon atoms (more preferably 1 to 6 carbon atoms) is preferred.), a hydroxyl group, or a phosphorylcholine group. Specific examples of the monomer that induces the structural unit X include, for example, acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, butyl acrylate, butyl methacrylate, octyl acrylate, octyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, dodecyl acrylate, dodecyl methacrylate, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, trimethylammonium chloride ethyl acrylate, trimethylammonium chloride ethyl methacrylate, 2-acryloyloxyethyl phosphorylcholine, 2-methacryloyloxyethyl phosphorylcholine, and the like. Among these, one kind may be used alone or two or more kinds may be used in combination. In this specification, the (meth)acrylic acid polymers may be polymers (homopolymers) composed of a single kind of monomer or copolymers (copolymers) composed of a plurality of different monomers.

[0055] In addition, as the (meth)acrylic acid polymers, those containing at least one kind of structural unit derived from (meth)acrylic acid esters having one or more substituents selected from primary to tertiary amino groups, quaternary ammonium groups, hydroxyl groups, and phosphorylcholine groups, and one or more structural units selected from structural units derived from (meth)acrylic acid (hereinafter also referred to as structural unit Y) are preferred. As the structural unit Y, a structural unit derived from (meth)acrylic acid di-C1-12 alkylamino C1-12 alkyl, a structural unit derived from (meth)acrylic acid tri-C1-12 alkylammonium C1-12 alkyl, and a structural unit derived from (meth)acrylic acid are preferred. Among the polymers containing the structural unit Y, a polymer containing the structural unit Y and a structural unit derived from (meth)acrylic acid C1-12 alkyl (hereinafter also referred to as structural unit Z) (hereinafter also referred to as polymer P) is preferred.

[0056] In addition, in this specification, the (meth)acrylic acid polymers may contain, in addition to the structural unit X, a structural unit derived from a monomer having a reactive unsaturated group copolymerizable therewith (such as vinyl acetate, vinyl pyrrolidone, 2-methyl-5-vinyl pyridine, etc.). In this case, the content ratio of the structural unit X to the total amount of the structural units constituting the (meth)acrylic acid polymers is not particularly limited. In this specification, the weight average molecular weight of the (meth)acrylic acid polymers is not particularly limited, but is preferably from 1,000 to 1,000,000, more preferably from 10,000 to 500,000, still more preferably from 50,000 to 300,000, and particularly preferably from 100,000 to 200,000. Note that the above weight average molecular weight refers to the value converted to sodium polyacrylate, and can be measured by size exclusion chromatography using a calibration curve prepared with a sodium polyacrylate standard substance manufactured by Polymer Laboratories.

[0057] (Meth)acrylic acid polymers include, for example, acrylic acid / octyl acrylate copolymer, acrylic ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / vinyl pyrrolidone copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer, ethyl acrylate / methyl methacrylate copolymer, silk fibroin / acrylic acid copolymer resin, methyl acrylate / 2-ethylhexyl acrylate copolymer resin, aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer, carboxyvinyl polymer, dimethylaminoethyl methacrylate / methyl methacrylate copolymer, sodium polyacrylate, partially neutralized polyacrylic acid, methacrylic acid / n-butyl acrylate copolymer, methacrylic acid copolymer L, methacrylic acid copolymer LD (including dry methacrylic acid copolymer LD), methacrylic acid copolymer S, methyl acrylate / methacrylic acid copolymer, methyl acrylate / methacrylic acid / methyl methacrylate copolymer, 2-methyl-5-vinylpyridine methyl acrylate / methacrylic acid copolymer, methyl methacrylate / methacrylic acid copolymer, and the like. (Meth)acrylic acid polymers are preferably polymers derived from one or more monomers selected from the group consisting of acrylic acid, methacrylic acid, methyl methacrylate, ethyl acrylate, butyl methacrylate, dimethylaminoethyl methacrylate, and trimethylammonium ethyl methacrylate chloride, from the viewpoint of improving the content uniformity. One or more selected from the group consisting of ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer, carboxyvinyl polymer, methacrylic acid copolymer S, methacrylic acid copolymer L, and methacrylic acid copolymer LD (including dry methacrylic acid copolymer LD) are particularly preferred. As methacrylic acid copolymer LD, dry methacrylic acid copolymer LD is preferred. Incidentally, all of these (meth)acrylic acid polymers are known components, and they may be produced by known methods or commercial products may be used. Examples of such commercial products include Eudragit E100, Eudragit EPO, Eudragit L100, Eudragit L30D-55, Eudragit L100-55, Eudragit S100, Eudragit RL100, Eudragit RLPO, Eudragit RL30D, Eudragit RS100, Eudragit RSPO, Eudragit RS30D, Eudragit NE30D, Eudragit FS30D (all manufactured by Evonik Rohm GmbH), Polyquid PA-30, Polyquid PA-30L, Polyquid PA-30S, Polyquid PA-100, Polyquid LA-100, Polyquid SA-100, Polyquid EA-100, Polyquid EM-30 (all manufactured by Sanyo Chemical Industries, Ltd.), Kollicoat MAE30DP, Kollicoat MAE100-55, Kollicoat Smart Seal 30 D, Kollicoat IR, Kollicoat EMM30D (all manufactured by BASF Japan), Hibiswako 103, Hibiswako 104, Hibiswako 105 (all manufactured by Fujifilm), Carbopol 971PNF, Carbopol 974PNF, Carbopol 71GNF (all manufactured by CBC), and the like.

[0058] The content of (meth)acrylic acid polymers in the pharmaceutical composition is not particularly limited and can be appropriately determined in consideration of the type of formulation, the gender, age, symptoms, etc. of the user. However, from the viewpoint of improving content uniformity, the total amount of (meth)acrylic acid polymers is preferably 0.001 to 30% by mass, more preferably 0.01 to 20% by mass, still more preferably 0.1 to 10% by mass, and particularly preferably 0.5 to 5% by mass based on the total mass of the pharmaceutical composition.

[0059] In the pharmaceutical composition, the mass ratio of pemafibrate or its salt or their solvates to (meth)acrylic acid polymers is not particularly limited. However, from the viewpoint of improving content uniformity, it is preferably 0.001 to 500 parts by mass, more preferably 0.01 to 100 parts by mass, still more preferably 0.5 to 50 parts by mass, and particularly preferably 1 to 25 parts by mass of (meth)acrylic acid polymers in total per 1 part by mass of the free form of pemafibrate.

[0060] In this specification, the dosage form of the "pharmaceutical composition" is not particularly limited and may be any of solid, semi-solid, or liquid preparations, which can be selected according to the intended use and the like. Examples of the dosage form of the pharmaceutical composition include those described in the General Rules of Preparations of the 17th Revised Japanese Pharmacopoeia. Specifically, for example, dosage forms for oral administration include solid preparations such as tablets (including, for example, normal tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, CR tablets, etc.), capsules, granules (including, for example, effervescent granules, etc.), powders, pills, etc.; semi-solid preparations such as oral jellies; and liquid preparations such as oral liquids (including, for example, elixirs, suspensions, emulsions, lemonades, etc.). In addition, dosage forms for parenteral administration include injections, inhalants, eye drops, ear drops, nasal drops, suppositories, external solid preparations, external liquid preparations, sprays, ointments, creams, gels, patches, etc.

[0061] From the viewpoints of ease of administration and ease of manufacture, the pharmaceutical composition is preferably a solid preparation. In particular, when the pharmaceutical composition is a solid preparation, the production is extremely easy. On the other hand, generally, solid preparations are basically manufactured using a large amount of solid components at room temperature (any temperature between 15 and 25 °C), so the mixing and dispersion between components tend to be non-uniform, and the deterioration of content uniformity is particularly likely to be a problem. However, according to the present invention, even in the case of solid preparations, there is an excellent effect that the content uniformity is good. As the solid preparation, an oral solid preparation is preferred, and tablets, capsules, granules, powders, and pills are more preferred, and tablets are particularly preferred. Further, as the solid preparation, a solid preparation containing a mixture containing components (A) and (B) is preferred.

[0062] In the pharmaceutical composition of the present invention, depending on the dosage form, a pharmaceutically acceptable carrier (formulation additive) may be added in addition to the above components. Examples of such formulation additives include, but are not limited to, excipients, disintegrants, binders, lubricants, plasticizers, film-forming agents, antioxidants, flavoring agents, sweetening agents, etc. Specifically, as these formulation additives, those listed in, for example, the Pharmaceutical Additives Dictionary 2016 (published by Yakujutsu Nippo Co., Ltd.), Handbook of Pharmaceutical Excipients, Seventh Edition (published by Pharmaceutical Press), etc. may be used.

[0063] Specific examples of the excipient include inorganic excipients such as sodium sulfate anhydrous, calcium hydrogen phosphate anhydrous, sodium chloride, calcium sulfate, calcium dihydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodium dihydrogen phosphate; organic excipients such as fructose, caramel, agar, paraffin, crystalline cellulose, sucrose, maltose, lactose, lactose hydrate, sucrose, glucose, pullulan, polyoxyethylene hydrogenated castor oil, trehalose, reduced palatinose, maltose, polyvinyl acetal diethylaminoacetate, and calcium citrate. These can be used alone or in combination of two or more. The total content of the excipient is not particularly limited, but is preferably 20 to 99% by mass, more preferably 30 to 97% by mass, based on the total mass of the pharmaceutical composition.

[0064] Specific examples of the disintegrant include gelatin, sodium hydrogen carbonate, dextrin, dehydroacetic acid and its salts, polyoxyethylene hydrogenated castor oil 60, etc. These can be used alone or in combination of two or more.

[0065] Specific examples of the binder include, for example, dextrin, pullulan, gum arabic, agar, gelatin, tragacanth, sodium alginate, polyvinyl acetal diethylaminoacetate, and the like. These can be used alone or in combination of two or more.

[0066] Specific examples of the lubricant include, for example, calcium stearate, magnesium stearate, sodium stearyl fumarate, and the like. These can be used alone or in combination of two or more. The total content of the lubricant is not particularly limited, but is preferably 0.01 to 15% by mass, more preferably 0.1 to 10% by mass, based on the total mass of the pharmaceutical composition. Specific examples of the plasticizer include, for example, sesame oil, castor oil, polysorbate 80 (polyoxyethylene (20) sorbitan oleate), and the like. These can be used alone or in combination of two or more.

[0067] Specific examples of the film-forming agent include, for example, alginic acid such as sodium alginate or its salts, carrageenan, xanthan gum, pullulan, and the like. These can be used alone or in combination of two or more.

[0068] Specific examples of the antioxidant include, for example, ascorbic acid, sodium bisulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopheryl acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, butylhydroxyanisole, and the like. These can be used alone or in combination of two or more.

[0069] As flavoring agents, specifically, for example, terpenes such as limonene, pinene, camphene, cymene, cineole, citronellol, geraniol, nerol, linalool, menthol, terpineol, rosinol, borneol, isoborneol, menthone, camphor, eugenol, and sinzilanol; essential oils containing terpenes such as cedarwood oil, orange oil, peppermint oil, camphor white oil, eucalyptus oil, terpin oil, lemon oil, ginger oil, clove oil, cinnamon oil, lavender oil, perilla oil, chamomile oil, perilla oil, spearmint oil, etc.; acidulants such as ascorbic acid, tartaric acid, citric acid, malic acid, and their salts, etc. may be mentioned. These can be used alone or in combination of two or more.

[0070] As sweetening agents, for example, aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, sodium saccharin, etc. may be mentioned, and one or more of these can be used in combination.

[0071] The pharmaceutical composition of the present invention can be produced by a known method according to its dosage form. For example, when the pharmaceutical composition is a solid preparation, it can be produced by appropriately combining unit operations such as pulverization, mixing, granulation, drying, sizing, classification, filling, tableting, coating, etc. As its production method, a method including a step of mixing component (A) and component (B) is preferable. More specifically, for example, when the dosage form of the pharmaceutical composition is a granular preparation such as granules, powders, pills, etc., in addition to component (A) and component (B), excipients, binders, disintegrants, lubricants, and other formulation additives are used as necessary. After mixing these components, they are granulated by a known granulation method such as extrusion granulation, rolling granulation, stirring granulation, fluidized bed granulation, spray granulation, melt granulation, crushing granulation, etc. to obtain granules, and further classified and sized as necessary to produce them. The obtained granules can also be coated with a coating agent or the like by a known method. When the dosage form of the pharmaceutical composition is a tablet, in addition to components (A) and (B), appropriate pharmaceutical additives such as excipients, binders, disintegrants, lubricants, etc. are used as necessary. These components are mixed to obtain a mixture, which is directly compressed (tableted) (direct powder compression method), or the above granulated product is classified, sized, etc. as necessary and then compressed (tableted) (semi-dry granule compression method, dry granule compression method, wet granule compression method, etc.). The obtained compressed product (tablet) can also be coated with a coating agent or the like by a known method. Furthermore, when the dosage form of the pharmaceutical composition is a capsule, the above granulated product or compressed product may be filled into the capsule.

[0072] The applicable diseases of the pharmaceutical composition of the present invention are not limited at all, and it can be widely used for the prevention or treatment of diseases for which the administration of pemafibrate is considered effective, which are known at present or will be found in the future. For example, pemafibrate or its salt or their solvates have excellent PPARα agonist activity and have effects such as a decrease in plasma triglyceride concentration and an increase in HDL cholesterol. Therefore, the pharmaceutical composition of the present invention can preferably be used as a prophylactic and / or therapeutic agent for dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, etc.), and more preferably as a prophylactic and / or therapeutic agent for hypertriglyceridemia. In addition, pemafibrate or its salt or their solvates are useful for the prevention or treatment of NAFLD (non-alcoholic fatty liver disease). Therefore, the pharmaceutical composition of the present invention can also be used as a prophylactic and / or therapeutic agent for NAFLD (more preferably, NASH (non-alcoholic steatohepatitis)). Furthermore, pemafibrate or its salt or their solvates may be used as a therapeutic agent for primary biliary cirrhosis.

[0073] The administration route of the pharmaceutical composition is not particularly limited and can be appropriately determined according to the disease to be applied, the type of formulation, the gender, age, symptoms, etc. of the user. However, from the perspective of ease of administration, oral administration is preferred. In addition, the pharmaceutical composition can be administered once to four times (preferably once) a day, divided into appropriate intervals, before meals, between meals, after meals, before bedtime, etc.

[0074] Note that this specification is not limited to these, and for example, the following aspects are disclosed. [1-1] 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-7); (B-1) Cellulose ethers (B-2) Starches (B-3) Povidones (B-4) Silicic acid compounds (B-5) Polyhydric alcohols (B-6) Alkyl sulfates (B-7) (Meth)acrylic acid polymers A pharmaceutical composition containing the above. [1-2] The pharmaceutical composition according to [1-1], wherein the component (B-1) is one or more selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl(hydroxyalkyl) cellulose, carboxyalkyl cellulose and cross-linked polymers of carboxyalkyl cellulose and salts thereof. [1-3] The pharmaceutical composition according to [1-1], wherein the component (B-1) is one or more selected from the group consisting of C1-C6 alkyl cellulose, hydroxy C1-C6 alkyl cellulose, C1-C6 alkyl(hydroxy C1-C6 alkyl) cellulose, carboxy C1-C6 alkyl cellulose and cross-linked polymers of carboxy C1-C6 alkyl cellulose and salts thereof. [1-4] The pharmaceutical composition according to [1-1], wherein component (B-1) is at least one selected from the group consisting of methylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, carmellose, carmellose potassium, carmellose calcium, carmellose sodium, and croscarmellose sodium.

[0075] [1-5] The pharmaceutical composition according to any one of [1-1] to [1-4], wherein component (B-2) is at least one selected from the group consisting of starch, hydroxyalkyl ethers of starch, carboxyalkyl ethers of starch, and salts thereof. [1-6] The pharmaceutical composition according to any one of [1-1] to [1-4], wherein component (B-2) is at least one selected from the group consisting of starch, hydroxy C1-C6 alkyl ethers of starch, carboxy C1-C6 alkyl ethers of starch, and salts thereof. [1-7] The pharmaceutical composition according to any one of [1-1] to [1-4], wherein component (B-2) is at least one selected from the group consisting of starch, hydroxypropyl starch, and carboxymethyl starch, and salts thereof.

[0076] [1-8] The pharmaceutical composition according to any one of [1-1] to [1-7], wherein component (B-3) is at least one selected from the group consisting of povidone and crospovidone. [1-9] The pharmaceutical composition according to any one of [1-1] to [1-7], wherein component (B-3) is crospovidone.

[0077] [1-10] The pharmaceutical composition according to any one of [1-1] to [1-9], wherein component (B-4) is at least one selected from the group consisting of hydrous silicate compounds, salts of hydrous silicate compounds, anhydrous silicic acid, and salts of anhydrous silicic acid. [1-11] The pharmaceutical composition according to any one of [1-1] to [1-9], wherein component (B-4) is at least one selected from the group consisting of magnesium hydrous silicate, hydrous silicon dioxide, and light anhydrous silicic acid. The pharmaceutical composition according to any one of [1-1] to [1-9], wherein the component (B-4) is at least one selected from the group consisting of magnesium silicate hydrate and silicon dioxide hydrate.

[0078] The pharmaceutical composition according to any one of [1-1] to [1-12], wherein the component (B-5) is macrogol. The pharmaceutical composition according to any one of [1-1] to [1-12], wherein the component (B-5) is at least one selected from the group consisting of macrogol 100, macrogol 200, macrogol 300, macrogol 400, macrogol 600, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, polyethylene glycol 8000, macrogol 20000, and macrogol 35000. The pharmaceutical composition according to any one of [1-1] to [1-12], wherein the component (B-5) is macrogol having an average molecular weight of 100 to 10000. The pharmaceutical composition according to any one of [1-1] to [1-12], wherein the component (B-5) is macrogol 6000.

[0079] The pharmaceutical composition according to any one of [1-1] to [1-12], wherein the component (B-5) is at least one 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], wherein the component (B-5) is at least one selected from the group consisting of mannitol and sorbitol. The pharmaceutical composition according to any one of [1-1] to [1-12], wherein the component (B-5) is mannitol.

[0080] The pharmaceutical composition according to any one of [1-1] to [1-19], wherein the component (B-6) is at least one selected from the group consisting of lauryl sulfate, tetradecyl sulfate, hexadecyl sulfate, and octadecyl sulfate. [1-21] The pharmaceutical composition according to any one of [1-1] to [1-19], wherein component (B-6) is a lauryl sulfate. [1-22] The pharmaceutical composition according to any one of [1-1] to [1-19], wherein component (B-6) is sodium lauryl sulfate.

[0081] [1-23] The pharmaceutical composition according to any one of [1-1] to [1-22], wherein component (B-7) is a polymer derived from one or more monomers selected from the group consisting of acrylic acid, methacrylic acid, methyl methacrylate, ethyl acrylate, butyl methacrylate, dimethylaminoethyl methacrylate, and trimethylammonium ethyl methacrylate chloride. [1-24] The pharmaceutical composition according to any one of [1-1] to [1-22], wherein component (B-7) is one or more selected from the group consisting of ethyl acrylate-methyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer, carboxyvinyl polymer, methacrylic acid copolymer S, methacrylic acid copolymer L, and methacrylic acid copolymer LD. [1-25] The pharmaceutical composition according to any one of [1-1] to [1-22], wherein component (B-7) is one or more selected from the group consisting of aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer, methacrylic acid copolymer S, methacrylic acid copolymer L, and methacrylic acid copolymer LD.

[0082] [1-26] A prophylactic and / or therapeutic agent for a disease selected from dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, etc.), NAFLD (more preferably, NASH (non-alcoholic steatohepatitis)), and primary biliary cirrhosis, the pharmaceutical composition according to any one of [1-1] to [1-25]. [1-27] The pharmaceutical composition according to any one of [1-1] to [1-26], which is a solid preparation. [1-28] The pharmaceutical composition according to any one of [1-1] to [1-27], wherein the dosage form is tablets, capsules, granules, powders, or pills.

[0083] [2-1] A pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof, comprising at least one selected from the group consisting of the following components (B-1) to (B-7); (B-1) Cellulose ethers (B-2) Starches (B-3) Povidones (B-4) Silicic acid compounds (B-5) Polyhydric alcohols (B-6) Alkyl sulfates (B-7) (Meth)acrylic acid polymers A method for improving the content uniformity of pemafibrate or a salt thereof or a solvate thereof in a pharmaceutical composition, comprising the step of incorporating the same. [2-2] The method according to [2-1], wherein the component (B-1) is at least one selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl(hydroxyalkyl) cellulose, carboxyalkyl cellulose and a cross-linked polymer of carboxyalkyl cellulose and salts thereof. [2-3] The method according to [2-1], wherein the component (B-1) is at least one selected from the group consisting of C1-C6 alkyl cellulose, hydroxy C1-C6 alkyl cellulose, C1-C6 alkyl(hydroxy C1-C6 alkyl) cellulose, carboxy C1-C6 alkyl cellulose and a cross-linked polymer of carboxy C1-C6 alkyl cellulose and salts thereof. [2-4] The method according to [2-1], wherein the component (B-1) is at least one selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hypromellose, carmellose, potassium carmellose, calcium carmellose, sodium carmellose and croscarmellose sodium.

[0084] [2-5] The method according to any one of [2-1] to [2-4], wherein the component (B-2) is at least one selected from the group consisting of starch, hydroxyalkyl ether of starch and carboxyalkyl ether of starch and salts thereof. The method according to any one of [2-1] to [2-4], wherein component (B-2) is at least one selected from the group consisting of starch, hydroxy C1-C6 alkyl ethers of starch, carboxy C1-C6 alkyl ethers of starch, and salts thereof. The method according to any one of [2-1] to [2-4], wherein component (B-2) is at least one selected from the group consisting of starch, hydroxypropyl starch, carboxymethyl starch, and salts thereof.

[0085] The method according to any one of [2-1] to [2-7], wherein component (B-3) is at least one selected from the group consisting of povidone and crospovidone. The method according to any one of [2-1] to [2-7], wherein component (B-3) is crospovidone.

[0086] The method according to any one of [2-1] to [2-9], wherein component (B-4) is at least one selected from the group consisting of hydrous silicate compounds, salts of hydrous silicate compounds, anhydrous silicic acid, and salts of anhydrous silicic acid. The method according to any one of [2-1] to [2-9], wherein component (B-4) is at least one selected from the group consisting of magnesium hydrous silicate, hydrous silicon dioxide, and light anhydrous silicic acid. The method according to any one of [2-1] to [2-9], wherein component (B-4) is at least one selected from the group consisting of magnesium hydrous silicate and hydrous silicon dioxide.

[0087] The method according to any one of [2-1] to [2-12], wherein component (B-5) is macrogol. [2-14] The method according to any one of [2-1] to [2-12], wherein component (B-5) is at least one selected from the group consisting of macrogol 100, macrogol 200, macrogol 300, macrogol 400, macrogol 600, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, polyethylene glycol 8000, macrogol 20000, and macrogol 35000. [2-15] The method according to any one of [2-1] to [2-12], wherein component (B-5) is a macrogol having an average molecular weight of 100 to 10000. [2-16] The method according to any one of [2-1] to [2-12], wherein component (B-5) is macrogol 6000.

[0088] [2-17] The method according to any one of [2-1] to [2-12], wherein component (B-5) is at least one selected from the group consisting of erythritol, xylitol, mannitol, sorbitol, maltitol, and lactitol. [2-18] The method according to any one of [2-1] to [2-12], wherein component (B-5) is at least one selected from the group consisting of mannitol and sorbitol. [2-19] The method according to any one of [2-1] to [2-12], wherein component (B-5) is mannitol.

[0089] [2-20] The method according to any one of [2-1] to [2-19], wherein component (B-6) is at least one selected from the group consisting of lauryl sulfate, tetradecyl sulfate, hexadecyl sulfate, and octadecyl sulfate. [2-21] The method according to any one of [2-1] to [2-19], wherein component (B-6) is lauryl sulfate. [2-22] The method according to any one of [2-1] to [2-19], wherein component (B-6) is sodium lauryl sulfate.

[0090] [2-23] The method according to any one of [2-1] to [2-22], wherein component (B-7) is a polymer derived from one or more monomers selected from the group consisting of acrylic acid, methacrylic acid, methyl methacrylate, ethyl acrylate, butyl methacrylate, dimethylaminoethyl methacrylate, and trimethylammonium ethyl methacrylate chloride. [2-24] The method according to any one of [2-1] to [2-22], wherein component (B-7) is one or more selected from the group consisting of ethyl acrylate-methyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer, carboxyvinyl polymer, methacrylic acid copolymer S, methacrylic acid copolymer L, and methacrylic acid copolymer LD. [2-25] The method according to any one of [2-1] to [2-22], wherein component (B-7) is one or more selected from the group consisting of aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer, methacrylic acid copolymer S, methacrylic acid copolymer L, and methacrylic acid copolymer LD.

[0091] [2-26] The method according to any one of [2-1] to [2-25], wherein the pharmaceutical composition is a prophylactic and / or therapeutic agent for a disease selected from dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, etc.), NAFLD (more preferably, NASH (non-alcoholic steatohepatitis)), and primary biliary cirrhosis. [2-27] The method according to any one of [2-1] to [2-26], wherein the pharmaceutical composition is a solid preparation. [2-28] The method according to any one of [2-1] to [2-27], wherein the dosage form of the pharmaceutical composition is tablets, capsules, granules, powders, or pills.

Examples

[0092] Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto. In the following test examples, the measurement using HPLC was performed using an ODS column as the column and an ultraviolet absorptiometer as the detector, respectively. Regarding the pemafibrate used in the following test examples, as a result of measuring the average particle diameter of the primary particles according to the particle size measurement method by the laser diffraction method in the XVIIth Revised Japanese Pharmacopoeia, d50 was 100 μm or less and d90 was 200 μm or less.

[0093] [Test Example 1] Content Uniformity Evaluation Test - Part 1 In order to evaluate the uniformity of the pemafibrate content in the pharmaceutical composition, the following tests were conducted. That is, tablets were manufactured so that the amount per tablet of each component described in Table 1 would be the amount (mg) described in Table 1. The specific procedure is shown below. (Examples 1 to 6) Pemafibrate and cellulose ethers were mixed for 30 seconds, followed by addition of lactose hydrate and crystalline cellulose and mixing for 30 seconds, and finally magnesium stearate was added and mixed for 30 seconds. Thereafter, the obtained mixture was tabletted using a tabletting machine equipped with a pestle with a diameter of 7 mm to manufacture 1000 tablets with a weight of 120 mg per tablet. (Comparative Example 1) Pemafibrate, lactose hydrate and crystalline cellulose were mixed for 30 seconds, followed by addition of magnesium stearate and mixing for 30 seconds. Thereafter, the obtained mixture was tabletted using a tabletting machine equipped with a pestle with a diameter of 7 mm to manufacture 1000 tablets with a weight of 117.6 mg per tablet.

[0094] Ten tablets were randomly taken out from each of the obtained tablets of the examples or comparative examples, and the pemafibrate content in each tablet was measured by the following method one by one. That is, one tablet was put into water and crushed, and then acetonitrile was added to obtain a sample solution. The obtained sample solution was analyzed with an HPLC apparatus, and the peak area derived from pemafibrate was measured. Then, the content of pemafibrate per tablet was measured by comparing the peak area derived from pemafibrate in the obtained sample solution with the peak area of a standard solution of pemafibrate with a known concentration.

[0095] From the measured values of the content of pemafibrate per tablet obtained, in accordance with the content uniformity test of the 17th revised Japanese Pharmacopoeia, the relative standard deviation (RSD) (%) of the pemafibrate content in the tablets was calculated and used as an index for the variation (degree of uniformity) of the pemafibrate content in the tablets. The results obtained are shown in Table 1.

[0096]

Table 1

[0097] As shown in the results described in Table 1, in Comparative Example 1 that did not contain cellulose ethers, the relative standard deviation was about 140%, and a large variation was observed in the pemafibrate content per tablet. On the other hand, when crosscarmellose sodium, carmellose sodium, low-substituted hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose or ethyl cellulose was contained as cellulose ethers (Examples 1 to 6), the relative standard deviation was small in all cases, and it was revealed that the uniformity of the pemafibrate content per tablet was good. The addition amount of the cellulose ethers was as small as 2.4 mg (2% by mass based on the total mass of the tablets).

[0098] From the above test results, it was revealed that by incorporating cellulose ethers into a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof, the content uniformity of pemafibrate in the pharmaceutical composition was improved.

[0099] [Test Example 2] Content Uniformity Evaluation Test - Part 2 The test was conducted in the same manner as in Test Example 1, except that the composition of the tablets was adjusted to the components and amounts described in Table 2 below. The results are shown in Table 2.

[0100]

Table 2

[0101] As shown in the results in Table 2, even when containing pregelatinized starch, corn starch, or sodium carboxymethyl starch as starches (Examples 7 - 9), the relative standard deviations were all small, similar to the tablets of Examples 1 - 6 containing cellulose ethers in Test Example 1, indicating that the uniformity of the pemafibrate content per tablet was good.

[0102] From the above test results, it was clarified that by incorporating starches into a pharmaceutical composition containing pemafibrate or its salt or their solvates, the content uniformity of pemafibrate in the pharmaceutical composition was improved.

[0103] [Test Example 3] Content Uniformity Evaluation Test - Part 3 The test was conducted in the same manner as in Test Example 1, except that the composition of the tablets was adjusted to the components and amounts described in Table 3 below. The results are shown in Table 3.

[0104]

Table 3

[0105] As shown in the results in Table 3, even when containing crospovidone or polyvinylpyrrolidone as povidones (Examples 10 - 11), the relative standard deviations were all small, similar to the tablets of Examples 1 - 6 containing cellulose ethers in Test Example 1, indicating that the uniformity of the pemafibrate content per tablet was good.

[0106] From the above test results, it was revealed that by including povidones in a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof, the content uniformity of pemafibrate in the pharmaceutical composition was improved.

[0107] [Test Example 4] Content Uniformity Evaluation Test 4 The test was carried out in the same manner as in Test Example 1, except that the composition of the tablets was made to be the components and amounts shown in Table 4 below. The results are shown in Table 4.

[0108]

Table 4

[0109] As shown in the results described in Table 4, even when magnesium silicate hydrate, silicon dioxide hydrate, or light anhydrous silicic acid was included as a silicic acid compound (Examples 12 to 14), similar to the tablets of Examples 1 to 6 containing cellulose ethers in Test Example 1, the relative standard deviations were all small, and it was revealed that the content uniformity of pemafibrate per tablet was good.

[0110] From the above test results, it was revealed that by including a silicic acid compound in a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof, the content uniformity of pemafibrate in the pharmaceutical composition was improved.

[0111] [Test Example 5] Content Uniformity Evaluation Test 5 The test was carried out in the same manner as in Test Example 1, except that the composition of the tablets was made to be the components and amounts shown in Table 5 below. The results are shown in Table 5.

[0112]

Table 5

[0113] As shown in the results described in Table 5, even when macrogoals or mannitol was contained as a polyhydric alcohol (Examples 15 to 16), the relative standard deviations were all small and the uniformity of the pemafibrate content per tablet was good, similar to the tablets of Examples 1 to 6 containing cellulose ethers in Test Example 1.

[0114] From the above test results, it was clarified that by containing a polyhydric alcohol in a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof, the content uniformity of pemafibrate in the pharmaceutical composition was improved.

[0115] [Test Example 6] Content Uniformity Evaluation Test No. 6 The test was carried out in the same manner as in Test Example 1, except that the composition of the tablets was made to be the components and amounts described in Table 6 below. The results are shown in Table 6.

[0116]

Table 6

[0117] As shown in the results described in Table 6, even in Example 17 containing sodium lauryl sulfate as alkyl sulfates, the relative standard deviations were all small and the uniformity of the pemafibrate content per tablet was good, similar to the tablets of Examples 1 to 6 containing cellulose ethers in Test Example 1.

[0118] From the above test results, it was clarified that by containing alkyl sulfates in a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof, the content uniformity of pemafibrate in the pharmaceutical composition was improved.

[0119] [Test Example 7] Content Uniformity Evaluation Test No. 7 The test was carried out in the same manner as in Test Example 1, except that the composition of the tablets was made to be the components and amounts described in Table 7 below. The results are shown in Table 7.

[0120]

Table 7

[0121] As shown in the results described in Table 7, even when ammonioalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, dry methacrylic acid copolymer LD, methacrylic acid copolymer S or methacrylic acid copolymer L was contained as (meth)acrylic acid polymers (Examples 18 to 22), similar to the tablets of Examples 1 to 6 containing cellulose ethers in Test Example 1, it was revealed that the relative standard deviations were all small and the uniformity of the pemafibrate content per tablet was good.

[0122] From the above test results, it was revealed that by containing (meth)acrylic acid polymers in a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof, the content uniformity of pemafibrate in the pharmaceutical composition was improved.

[0123] [Production Examples 1 to 6] Tablets containing the components and amounts (mg) described in Tables 8 to 9 per tablet can be produced by the wet granulation compression method according to a conventional method.

[0124]

Table 8

[0125]

Table 9

[0126] [Production Examples 7 to 12] Tablets containing the components and amounts (mg) described in Tables 10 to 11 per tablet can be produced by the direct powder compression method according to a conventional method.

[0127]

Table 10

[0128]

Table 11

[0129] [Production Examples 13 to 21] Tablets containing the components and amounts (mg) shown in Tables 12 to 14 per tablet can be produced by the direct powder compression method according to a conventional method.

[0130]

Table 12

[0131]

Table 13

[0132]

Table 14

Industrial Applicability

[0133] According to the present invention, since it is possible to provide a pharmaceutical composition containing pemafibrate that exhibits effects such as a decrease in plasma triglyceride concentration and an increase in HDL cholesterol and has excellent homogeneity, it can be used, for example, in the pharmaceutical industry.

Claims

[Claim 1] The invention described in this specification.

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