Pharmaceutical compositions

Abstract

Provided is a pharmaceutical composition comprising pemafibrate, a salt thereof or a solvate thereof and having excellent homogeneity.SOLUTION: Pemafibrate, a salt thereof or a solvate thereof in an amount of 0.017 to 4.2 mass% in terms of a free form of pemafibrate relative to the total mass of the pharmaceutical composition, and one or more selected from the group consisting of cellulose ethers, starches, povidones, silicic acid compounds, polyhydric alcohols, alkyl sulfate esters, disaccharides and cellulose, wherein the pharmaceutical composition is a solid preparation (excluding a tablet). However, the following (1) and (2) are excluded. (1) A pharmaceutical composition for preventing and / or treating dyslipidemia, comprising pemafibrate, a salt thereof or a solvate of any of these and a cholesterol absorption inhibitor, wherein pemafibrate, a salt thereof or a solvate of any of these and the cholesterol absorption inhibitor are formulated into a single preparation. (2) A pharmaceutical composition for preventing and / or treating dyslipidemia for use in a kit together with a pharmaceutical composition for preventing and / or treating dyslipidemia comprising a cholesterol absorption inhibitor, the pharmaceutical composition comprising pemafibrate, a salt thereof or a solvate thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition and the like. [Background technology]

[0002] The following structural formula:

[0003] [ka]

[0004] Pemafibrate (chemical name: (2R)-2-[3-({1,3-Benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid), represented by the formula (Ir), 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 known to be useful in the prevention and treatment of dyslipidemia (hyperlipidemia) (Patent Document 1, Non-Patent Documents 1 and 2) and NAFLD (non-alcoholic fatty liver disease) (Patent Document 2).

[0005] Compounds useful as active ingredients of pharmaceuticals are usually formulated and supplied as some kind of pharmaceutical composition. From the viewpoint of ensuring the expected efficacy and avoiding unexpected side effects, it is extremely important to ensure that the supplied pharmaceutical composition has a consistent quality without variation between lots, etc. [Prior art documents] [Patent documents]

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

[0007] [Non-Patent Document 1] Yukiyoshi Yamazaki, et al., Synthesis, 2008(7), 1017-1022. [Non-patent document 2] Fruchart JC., Cardiovasc Diabetol., 2013; 12: 82. Summary of the Invention [Problem 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 compounded ingredients, and these properties often cannot be predicted in advance from their chemical structures, etc., and problems often become apparent only after the pharmaceutical composition is actually manufactured. For this reason, establishing technology to ensure the homogeneity of pharmaceutical compositions usually requires a great deal of trial and error. It has only been reported that pemafibrate or its salts or solvates thereof exhibit the above-mentioned pharmacological effects, but no specific studies have been conducted to date on their formulation into pharmaceutical compositions, and no reports have been made at all on the manufacturability of pharmaceutical compositions, such as homogeneity. Under these circumstances, the present inventors first attempted to develop a pharmaceutical composition containing pemafibrate, its salt, or a solvate thereof by actually preparing the pharmaceutical composition. However, although the content uniformity of a component in a pharmaceutical composition is generally good when the content of that component is high, it was surprisingly found that the pemafibrate content varied from one pharmaceutical composition to another, even when the pemafibrate content in the pharmaceutical composition was low (below 0.01% by mass) or high (over 5% by mass) relative to the total mass of the pharmaceutical composition, resulting in poor content uniformity (content uniformity) of the pemafibrate content in the pharmaceutical composition. Significant differences in the pemafibrate content between pharmaceutical compositions could lead to variations in efficacy and safety between pharmaceutical compositions. Therefore, an object of the present invention is to provide a pharmaceutical composition containing pemafibrate or a salt thereof, or a solvate thereof, which has excellent homogeneity. [Means for solving the problem]

[0009] Therefore, the inventors further conducted intensive research to solve the problem of content uniformity of pemafibrate or a salt thereof, or a solvate thereof in a pharmaceutical composition, and found that the content uniformity of pemafibrate in a pharmaceutical composition can be improved by adjusting the content of pemafibrate or a salt thereof, or a solvate thereof in the pharmaceutical composition to within the range of 0.017 to 4.2 mass% in terms of the free form of pemafibrate, relative to the total mass of the pharmaceutical composition, and thus completed the present invention.

[0010] That is, the present invention provides a pharmaceutical composition containing pemafibrate or a salt thereof, or a solvate thereof in an amount of 0.017 to 4.2 mass % calculated as the free form of pemafibrate relative to the total mass of the pharmaceutical composition.

[0011] 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 incorporating pemafibrate or a salt thereof, or a solvate thereof, in an amount of 0.017 to 4.2 mass% calculated as the free form of pemafibrate relative to the total mass of the pharmaceutical composition. [Effects of the Invention]

[0012] According to the present invention, the content uniformity of pemafibrate in a pharmaceutical composition is improved, and a pharmaceutical composition with excellent homogeneity can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0013] <Pemafibrate or its salt or solvate> 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, as well as pharmaceutically acceptable salts of pemafibrate and solvates of pemafibrate or pharmaceutically acceptable salts thereof with water or alcohol (e.g., ethanol). 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; and 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.

[0014] The shape, size, etc. of pemafibrate or its salt, or a solvate thereof are not particularly limited. However, when the average particle size of primary particles is measured according to the particle size measurement method using laser diffraction in the Seventeenth Edition of the Japanese Pharmacopoeia, it is preferable that the 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. d90: Preferably 200 μm or less, more preferably 135 μm or less, even more preferably 80 μm or less, and particularly preferably 1 to 80 μm.

[0015] Pemafibrate or a salt thereof, or a solvate thereof is a known compound and can be prepared by the methods disclosed in, for example, Patent Document 1, Non-Patent Document 1, and U.S. Patent No. 7,109,226. In the present invention, it is preferable to use a crystal of pemafibrate (preferably a crystal showing a melting point of 95 to 101°C, particularly preferably 97 to 100°C, when measured according to Melting Point Method 1 of the Japanese Pharmacopoeia, Seventeenth Edition) that can be prepared by the method described in Non-Patent Document 1. The contents of these documents are incorporated herein by reference.

[0016] The content of pemafibrate or a salt thereof, or a solvate thereof in the pharmaceutical composition of the present invention is 0.017 to 4.2% by mass, calculated as the free form of pemafibrate, relative to the total mass of the pharmaceutical composition. By setting the content of pemafibrate or a salt thereof, or a solvate thereof within this range, content uniformity is improved. From the viewpoint of improving content uniformity, the content is preferably 0.042 to 4.2% by mass, more preferably 0.042 to 1.7% by mass, and particularly preferably 0.042 to 0.83% by mass. The content of pemafibrate or a salt thereof, or a solvate thereof per dosage unit of the pharmaceutical composition may be adjusted appropriately depending on the content in the pharmaceutical composition and the dosage form, size, etc. of the pharmaceutical composition, but for example, one dosage unit preferably contains 0.02 to 5 mg, and more preferably 0.05 to 1 mg, of pemafibrate in free form. When the pharmaceutical composition of the present invention is in the form of a tablet, the content of pemafibrate or a salt thereof, or a solvate thereof per tablet is preferably 0.02 to 5 mg, and more preferably 0.05 to 1 mg, of pemafibrate in free form, as described above. The content of pemafibrate or a salt thereof, or a solvate thereof can be quantified, for example, by measuring the pharmaceutical composition by HPLC.

[0017] The pharmaceutical composition of the present invention may further optionally contain one or more components selected from the group consisting of the following components 1 to 8: Component 1. Cellulose ethers Ingredient 2. Starches Ingredient 3. Povidone Component 4. Silicate compounds Ingredient 5. Polyhydric alcohol Ingredient 6. Alkyl sulfate esters Ingredient 7.Disaccharide Component 8. Cellulose By including the above-mentioned ingredients in the pharmaceutical composition, the content uniformity of pemafibrate can be improved.

[0018] <Cellulose ethers> As used herein, the term "cellulose ethers" refers to one or more compounds selected from the group consisting of compounds in which all or some of the hydroxy groups of cellulose have formed ether bonds, and salts thereof. The cellulose ethers may be cellulose that has been further modified, as necessary, by esterification, crosslinking, or the like. The salts are not particularly limited, and specific examples include alkali metal salts such as sodium salts and potassium salts; and 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 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 or derivatives thereof (ester derivatives) or salts thereof, such as hydroxyethyl methyl cellulose, hypromellose, hypromellose acetate succinate, and hypromellose phthalate; and carboxyalkyl celluloses or derivatives thereof (crosslinked polymers) or salts thereof, such as carmellose, carmellose potassium, carmellose calcium, carmellose sodium, carboxymethyl ethyl cellulose, and croscarmellose sodium. These may be used alone or 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-substituted hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose. Here, low-substituted hydroxypropyl cellulose refers to hydroxypropyl cellulose described in the 17th edition of the Japanese Pharmacopoeia, which contains 5.0 to 16.0% hydroxypropoxy groups when dried.

[0019] From the viewpoint of improving content uniformity, the cellulose ether is preferably at least one selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, carboxyalkyl cellulose, crosslinked polymers of carboxyalkyl cellulose, and salts thereof, more preferably 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, crosslinked polymers of carboxy C1-C6 alkyl cellulose, and salts thereof, and more preferably at least one selected from the group consisting of methyl cellulose, ethyl cellulose, More preferably, the cellulose ether is at least one selected from the group consisting of methylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, carmellose, carmellose potassium, carmellose calcium, carmellose sodium, and croscarmellose sodium, and particularly preferably at least one selected from the group consisting of methylcellulose, hydroxypropylcellulose, hypromellose, carmellose, carmellose calcium, carmellose sodium, and croscarmellose sodium. Low-substituted hydroxypropylcellulose is preferred as the hydroxypropyl cellulose. Furthermore, from the viewpoint of ease of production of pharmaceutical compositions (particularly solid formulations), cellulose ethers that are solid at room temperature (any temperature between 15 and 25°C) are preferred. 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 (Freund Corporation), NS-300 (Sanei Gen F.F.I., Inc.), ECG-505 (Sanei Gen F.F.I., Inc.), CELLOGEN (Sanei Gen F.F.I., Inc.), Ac-Di-Sol (Asahi Kasei Corporation), HEC (Sumitomo Seika Chemicals Co., Ltd.), hydroxypropyl cellulose (Nippon Soda Co., Ltd.), Shin-Etsu AQOAT (Shinetsu Chemical Co., Ltd.), METOLOSE 90SH-SR (Shinetsu Chemical Co., Ltd.), HPMCP (Shinetsu Chemical Co., Ltd.), METOLOSE SM (Shinetsu Chemical Co., Ltd.), TC-5 (Sanei Gen F.F.I., Inc.), and L-HPC (Shinetsu Chemical Co., Ltd.).

[0020] When cellulose ethers are used, the content of the cellulose ethers in the pharmaceutical composition is not particularly limited and can be determined appropriately depending on the type of formulation, the gender, age, symptoms, etc. of the recipient. From the viewpoint of improving content uniformity, however, the total amount of cellulose ethers relative 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.

[0021] Furthermore, when alkyl cellulose or a salt thereof is used as the cellulose ether, the content of alkyl cellulose or a salt thereof is preferably 0.6 to 22% by mass, more preferably 1.1 to 19% by mass, and particularly preferably 3 to 8% by mass, relative to the total mass of the pharmaceutical composition, from the viewpoint of improving content uniformity. Furthermore, when hydroxyalkyl cellulose or a salt thereof is used as the cellulose ether, the content of hydroxyalkyl cellulose or a salt thereof is preferably 0.7 to 24% by mass, more preferably 1.2 to 18% by mass, and particularly preferably 3 to 8% by mass, relative to the total mass of the pharmaceutical composition, from the viewpoint of improving content uniformity. Furthermore, when alkyl(hydroxyalkyl)cellulose or its derivatives or salts thereof are used as the cellulose ethers, the content of alkyl(hydroxyalkyl)cellulose or its derivatives or salts thereof is preferably 0.8 to 26% by mass, more preferably 1.3 to 17% by mass, and particularly preferably 4 to 9% by mass, relative to the total mass of the pharmaceutical composition, from the viewpoint of improving content uniformity. Furthermore, when carboxyalkylcellulose or its derivatives or salts thereof are used as the cellulose ethers, the content of carboxyalkylcellulose or its derivatives or salts thereof 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, relative to the total mass of the pharmaceutical composition, from the viewpoint of improving content uniformity.

[0022] When cellulose ethers are used, the mass ratio of pemafibrate or its salts or solvates thereof to the cellulose ethers in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable to contain a total of 3 to 200 mass parts of cellulose ethers per 1 mass part of pemafibrate in free form, more preferably 5 to 150 mass parts, and particularly preferably 10 to 100 mass parts.

[0023] Furthermore, when alkylcellulose or a salt thereof is used as the cellulose ether, the mass ratio of pemafibrate or a salt thereof, or a solvate thereof to alkylcellulose or a salt thereof in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable that the total amount of alkylcellulose or a salt thereof is 4 to 160 parts by mass, more preferably 6 to 110 parts by mass, and particularly preferably 20 to 60 parts by mass, per part by mass of pemafibrate in free form. Furthermore, when hydroxyalkyl cellulose or a salt thereof is used as the cellulose ether, the mass ratio of pemafibrate or a salt thereof, or a solvate thereof to hydroxyalkyl cellulose or a salt thereof in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable that the pharmaceutical composition contains a total of 4 to 170 mass parts of hydroxyalkyl cellulose or a salt thereof per 1 mass part of pemafibrate in free form, more preferably 7 to 120 mass parts, even more preferably 20 to 100 mass parts, and particularly preferably 30 to 70 mass parts. Furthermore, when alkyl(hydroxyalkyl)cellulose or its derivatives or salts thereof are used as cellulose ethers, the mass ratio of pemafibrate or its salts or solvates thereof to alkyl(hydroxyalkyl)cellulose or its derivatives or salts thereof in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable that the total amount of alkyl(hydroxyalkyl)cellulose or its derivatives or salts thereof is 4 to 180 parts by mass, more preferably 8 to 130 parts by mass, even more preferably 20 to 100 parts by mass, and particularly preferably 40 to 80 parts by mass, per part by mass of pemafibrate in free form. Furthermore, when carboxyalkylcellulose or its derivatives or salts thereof are used as cellulose ethers, the mass ratio of pemafibrate or its salts or solvates thereof to carboxyalkylcellulose or its derivatives or salts thereof in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable that the pharmaceutical composition contains a total of 4 to 190 mass parts of carboxyalkylcellulose or its derivatives or salts thereof per 1 mass part of pemafibrate in free form, more preferably 9 to 140 mass parts, even more preferably 14 to 100 mass parts, and particularly preferably 19 to 90 mass parts.

[0024] <Starches> As used herein, "starch" refers to one or more starches selected from the group consisting of starch itself, starch in which all or part of the hydroxyl groups of the starch have formed ether bonds, derivatives thereof, and salts thereof. Starches also include those that have been subjected to treatments such as gelatinization and retrogradation. The derivatives also include starch or its etherified products that have been further modified, as necessary, by esterification, cross-linking, hydrolysis, or the like. The salts used herein are not particularly limited, and specific examples include alkali metal salts such as sodium salts and potassium salts; and salts with metals of Group 2 elements such as calcium salts and magnesium salts. Specific examples of such starches include starches or salts thereof such as pregelatinized starch, wheat starch, rice starch, corn starch, potato starch, partially pregelatinized starch, wheat flour, rice flour, and semi-digested starch; hydroxyalkyl ethers of starch or salts thereof such as hydroxypropyl starch; and carboxyalkyl ethers of starch or salts thereof such as sodium carboxymethyl starch, and any of these may be used alone or in combination of two or more. The alkyl group in the starches is not particularly limited, but is preferably a linear or branched alkyl group having 1 to 6 carbon atoms.

[0025] From the viewpoint of improving content uniformity, the starches are preferably one or more selected from the group consisting of starch, hydroxyalkyl ethers of starch, carboxyalkyl ethers of starch, and salts thereof, more preferably one or more selected from the group consisting of starch, hydroxy C1-C6 alkyl ethers of starch, carboxy C1-C6 alkyl ethers of starch, and salts thereof, even more preferably one or more selected from the group consisting of starch, hydroxypropyl starch, carboxymethyl starch, and salts thereof, and particularly preferably one or more selected from the group consisting of starch and sodium carboxymethyl starch. Furthermore, from the viewpoint of ease of production of pharmaceutical compositions (particularly solid formulations), starches that are solid at room temperature (any temperature between 15 and 25°C) are preferred. These starches are all known ingredients and may be produced by known methods, or commercially available products may be used, such as LYCATAB PGS (Rocket Japan Co., Ltd.), GLYCOLYS (Rocket Japan Co., Ltd.), starch (soluble) (Kishida Chemical Co., Ltd.), corn starch (Sanei Gen F.F.I. Co., Ltd.), potato starch (Junsei Chemical Co., Ltd.), HPS-101 (Freund Corporation), and LYCATABC (Rocket Japan Co., Ltd.).

[0026] When starches are used, the content of starches in the pharmaceutical composition is not particularly limited and can be determined appropriately depending on the type of formulation, the gender, age, symptoms, etc. of the recipient. From the viewpoint of improving content uniformity, however, 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.

[0027] Furthermore, 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 improving content uniformity. Furthermore, when a carboxyalkyl ether of starch or a salt thereof is used as the starch, the content of the carboxyalkyl ether of starch or a salt thereof 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, relative to the total mass of the pharmaceutical composition, from the viewpoint of improving content uniformity.

[0028] When starches are used, the mass ratio of pemafibrate or its salts or solvates thereof to starches in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable to contain a total of 5 to 400 mass parts of starches per 1 mass part of pemafibrate in free form, more preferably 15 to 300 mass parts, and particularly preferably 20 to 200 mass parts.

[0029] Furthermore, when starch is used as the starch, the mass ratio of pemafibrate or its salt or solvate thereof to starch in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable to contain a total of 7 to 380 mass parts of starch per 1 mass part of pemafibrate in free form, more preferably 16 to 280 mass parts, and particularly preferably 30 to 190 mass parts. Furthermore, when a starch carboxyalkyl ether or a salt thereof is used as the starch, the mass ratio of pemafibrate or a salt thereof, or a solvate thereof to the starch carboxyalkyl ether or a salt thereof in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable that the pharmaceutical composition contains a total of 9 to 370 mass parts of starch carboxyalkyl ether or a salt thereof per 1 mass part of pemafibrate in free form, more preferably 17 to 270 mass parts, and particularly preferably 40 to 180 mass parts.

[0030] <Povidone> In this specification, the term "povidone" refers to a polymer of 1-vinyl-2-pyrrolidone, and is a concept that encompasses not only homopolymers of 1-vinyl-2-pyrrolidone but also copolymers of 1-vinyl-2-pyrrolidone with other polymerizable compounds. The polymer may be a non-crosslinked polymer or a crosslinked polymer. Furthermore, in the linear polymer of 1-vinyl-2-pyrrolidone (povidone), the K value is not particularly limited, but a K value of 12 to 90 is preferred, and a K value of 25 to 90 is particularly preferred. Specific examples of such povidones include 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 K value include those of 12, 17, 25, 30, and 90); copolymers of 1-vinyl-2-pyrrolidone and vinyl acetate such as copolyvidone; and crosslinked polymers of 1-vinyl-2-pyrrolidone such as crospovidone, and any of these may be used alone or in combination of two or more. From the viewpoint of improving content uniformity, the povidone is preferably at least one selected from the group consisting of povidone, copolyvidone, and crospovidone, more preferably at least one selected from the group consisting of povidone and crospovidone, and particularly preferably crospovidone. Furthermore, from the viewpoint of ease of production of pharmaceutical compositions (particularly solid preparations), the povidone is preferably solid at room temperature (any temperature between 15 and 25°C). These povidones are all known ingredients and may be produced by known methods, or commercially available products may be used, such as Kollidon CL, Kollidon VA64, and Kollidon (all manufactured by BASF Japan Ltd.).

[0031] When povidones are used, the content of povidones in the pharmaceutical composition is not particularly limited and can be determined appropriately depending on the type of formulation, the gender, age, symptoms, etc. of the user. From the viewpoint of improving content uniformity, however, the total amount of povidones relative 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.

[0032] Furthermore, when a linear polymer of 1-vinyl-2-pyrrolidone is used as the povidone, 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, relative to the total mass of the pharmaceutical composition, from the viewpoint of improving content uniformity. Furthermore, when a crosslinked polymer of 1-vinyl-2-pyrrolidone is used as the povidone, the content of the crosslinked 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, relative to the total mass of the pharmaceutical composition, from the viewpoint of improving content uniformity.

[0033] When povidone analogues are used, the mass ratio of pemafibrate or its salt or solvate thereof to povidone analogues in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable to contain a total of 1 to 200 mass parts of povidone analogues per 1 mass part of pemafibrate in free form, more preferably 3 to 150 mass parts, and particularly preferably 5 to 100 mass parts.

[0034] Furthermore, when a linear polymer of 1-vinyl-2-pyrrolidone is used as the povidone, the mass ratio of pemafibrate or a salt thereof, or a solvate thereof to the linear polymer of 1-vinyl-2-pyrrolidone in the pharmaceutical composition is not particularly limited. However, from the viewpoint of improving content uniformity, it is preferable that the linear polymer of 1-vinyl-2-pyrrolidone is contained in total at 1.5 to 190 mass parts, more preferably 3.5 to 140 mass parts, and particularly preferably 6 to 90 mass parts per mass part of pemafibrate in free form. Furthermore, when a crosslinked polymer of 1-vinyl-2-pyrrolidone is used as the povidone, the mass ratio of pemafibrate or a salt thereof or a solvate thereof to the crosslinked polymer of 1-vinyl-2-pyrrolidone in the pharmaceutical composition is not particularly limited. However, from the viewpoint of improving content uniformity, it is preferable that the crosslinked polymer of 1-vinyl-2-pyrrolidone contains a total of 2 to 180 mass parts, more preferably 4 to 130 mass parts, and particularly preferably 7 to 80 mass parts per mass part of pemafibrate in free form.

[0035] <Silicate compounds> In this specification, the term "silicic acid compound" includes not only the silicic acid compound itself but also salts of the silicic acid compound. Examples of the salts of the silicic acid compound include inorganic salts, specifically 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 hydrated silicic acid compounds or salts thereof, such as hydrated silicon dioxide, hydrated amorphous silicon oxide, hydrated magnesium silicate, and hydrated magnesium silicate (natural); anhydrous silicic acid or salts thereof, such as light anhydrous silicic acid and heavy anhydrous silicic acid; silicic acid or salts thereof, such as silicon dioxide, natural aluminum silicate, synthetic aluminum silicate, synthetic magnesium sodium silicate, calcium silicate, magnesium silicate, magnesium aluminum silicate, magnesium aluminosilicate, and magnesium aluminometasilicate; as well as diatomaceous earth, bentonite, kaolin, talc, and the like, and these may be used alone or in combination of two or more. From the viewpoint of improving content uniformity, the silicic acid compound is preferably at least one selected from the group consisting of hydrous silicic acid compounds, salts of hydrous silicic acid compounds, silicic anhydride and salts of silicic anhydride, and particularly preferably at least one selected from the group consisting of hydrous silicic acid compounds and salts of hydrous silicic acid compounds. Among the silicic acid compounds specifically exemplified, from the viewpoint of improving content uniformity, one or more selected from the group consisting of hydrous magnesium silicate, hydrous silicon dioxide, and light anhydrous silicic acid are preferred, and one or more selected from the group consisting of hydrous magnesium silicate and hydrous silicon dioxide are particularly preferred. Furthermore, from the viewpoint of ease of production of pharmaceutical compositions (particularly solid preparations), silicic acid compounds that are solid at room temperature (any temperature between 15 and 25°C) are preferred. These silicate compounds 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 Neusilin A (Fuji Chemical Industry Co., Ltd.), Fluorite (Tomita Pharmaceutical Co., Ltd.), Magnesium Silicate (Tomita Pharmaceutical Co., Ltd.), VEEGUMI Granules (Sanyo Chemical Industries, Ltd.), VEEGUMI HV Granules (Sanyo Chemical Industries, Ltd.), VEEGUMI K Granules (Sanyo Chemical Industries, Ltd.), VEEGUMI F (Sanyo Chemical Industries, Ltd.), Sylysia 320 (Fuji Silysia Chemical Co., Ltd.), Sylysia 350 (Fuji Silysia Chemical Co., Ltd.), Sylysia 320TP (Fuji Silysia Chemical Co., Ltd.), and Sylysia 350 (Fuji Silysia Chemical Co., Ltd.). 320FCP (Fuji Silysia Chemical Ltd.), Micon FR (Tomita Pharmaceutical Co., Ltd.), silicon dioxide (Nippon Aerosil Co., Ltd.), Aerosil 300 (Nippon Aerosil Co., Ltd.), Adsolider 101 (Freund Corporation), Adsolider 102 (Freund Corporation), Sylysia (Fuji Silysia Chemical Ltd.), Sylosphere (Fuji Silysia Chemical Ltd.), hydrous amorphous silicon oxide (Tosoh Silica Corporation), Neusilin (Fuji Chemical Industry Co., Ltd.), diatomaceous earth (Showa Kako Co., Ltd.), talc (Sanei Gen F.F.I. Co., Ltd.), and the like.

[0036] When a silicic acid compound is used, the content of the silicic acid compound in the pharmaceutical composition is not particularly limited and can be determined appropriately depending on the type of formulation, the gender, age, symptoms, etc. of the recipient. From the viewpoint of improving content uniformity, however, the total amount of the silicic acid compound relative 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.

[0037] Furthermore, when one or more compounds selected from the group consisting of hydrous silicic acid compounds and salts thereof are used as the silicic acid compound, the content of the one or more compounds selected from the group consisting of hydrous silicic acid compounds and salts thereof is preferably 0.2 to 19% by mass, more preferably 0.6 to 14% by mass, and particularly preferably 2 to 6% by mass, relative to the total mass of the pharmaceutical composition, from the viewpoint of improving content uniformity. Furthermore, when one or more compounds selected from the group consisting of anhydrous silicic acid compounds and salts thereof are used as the silicic acid compound, the content of the one or more compounds selected from the group consisting of anhydrous silicic acid compounds and salts thereof is preferably 0.4 to 17% by mass, more preferably 0.8 to 12% by mass, and particularly preferably 4 to 8% by mass, relative to the total mass of the pharmaceutical composition, from the viewpoint of improving content uniformity.

[0038] When a silicate compound is used, the mass ratio of pemafibrate or its salt or solvate thereof to the silicate compound in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable to contain a total of 1 to 200 mass parts of silicate compound per 1 mass part of pemafibrate in free form, more preferably 3 to 150 mass parts, and particularly preferably 5 to 100 mass parts.

[0039] Furthermore, when one or more types selected from the group consisting of hydrous silicate compounds and salts thereof are used as the silicate compound, the mass ratio of pemafibrate or its salts or solvates thereof to one or more types selected from the group consisting of hydrous silicate compounds and salts thereof in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable that the pharmaceutical composition contains a total of 2 to 160 mass parts, more preferably 4 to 140 mass parts, and particularly preferably 10 to 90 mass parts of one or more types selected from the group consisting of hydrous silicate compounds and salts thereof per 1 mass part of pemafibrate in free form. Furthermore, when one or more types selected from the group consisting of anhydrous silicic acid compounds and salts thereof are used as the silicic acid compound, the mass ratio of pemafibrate or its salts or solvates thereof to one or more types selected from the group consisting of anhydrous silicic acid compounds and salts thereof in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable that the pharmaceutical composition contains a total of 2 to 180 mass parts, more preferably 4 to 120 mass parts, and particularly preferably 10 to 80 mass parts of one or more types selected from the group consisting of anhydrous silicic acid compounds and salts thereof per 1 mass part of pemafibrate in free form.

[0040] <Polyhydric alcohol> In this specification, the term "polyhydric alcohol" refers to cellulose ethers having two or more alcoholic hydroxyl groups, excluding disaccharides and cellulose, and refers to compounds other than these having two or more alcoholic hydroxyl groups. The polyhydric alcohol may be either a non-polymer or a polymer. Examples of such polyhydric alcohols include sugar alcohols and non-sugar alcohols, and these may be used alone or in combination of two or more. Preferred polyhydric alcohols are polyhydric alcohols that do not contain a cyclic ether structure (e.g., a tetrahydropyran ring) in the molecule, and polyhydric alcohols that have only one cyclic ether structure in the molecule. Polyhydric alcohols that do not contain a cyclic ether structure in the molecule are more preferred, and acyclic polyhydric alcohols are particularly preferred. Furthermore, from the viewpoint of ease of production of pharmaceutical compositions (particularly solid preparations), polyhydric alcohols that are solid at room temperature (any temperature between 15 and 25° C.) are preferred.

[0041] Specific examples of the sugar alcohols include sugar alcohols with 3 carbon atoms (thritol) such as glycerin; sugar alcohols with 4 carbon atoms (tetritol) such as erythritol and threitol; sugar alcohols with 5 carbon atoms (pentitol) such as xylitol, arabinitol, ribitol, and adonitol; sugar alcohols with 6 carbon atoms (hexitol) such as mannitol, sorbitol, iditol, dulcitol, and galactitol; and sugar alcohols with 12 carbon atoms (dodecitol) such as maltitol and lactitol. These sugar alcohols may be used alone or in combination with two or more. These sugar alcohols may have various stereoisomers, but the stereoconfiguration of the "sugar alcohol" is not particularly limited, and the various stereoisomers may be used alone or in any mixture of the various stereoisomers in any ratio.

[0042] Among the above sugar alcohols, from the viewpoint 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. These sugar alcohols are all known ingredients and may be produced by known methods, or commercially available products may be used, such as erythritol (Sanei Gen F.F.I., Inc.), Xylitol (Towa Chemical Industry Co., Ltd.), NEOSORB P (Rocket Japan Co., Ltd.), Resys (Towa Chemical Industry Co., Ltd.), Mannit P (Towa Chemical Industry Co., Ltd.), glycerin (NOF Corporation), MALTISORB (Rocket Japan Co., Ltd.), and Amalti Syrup (Towa Chemical Industry Co., Ltd.).

[0043] Among the non-sugar alcohols, acyclic compounds are preferred. Specific examples include alkylene glycols such as ethylene glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, and 1,3-butanediol; diethylene glycol, dipropylene glycol, macrogol (e.g., 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), polypropylene glycol (e.g., polypropylene glycol 2000), polyoxyethylene polyoxypropylene glycol (e.g., polyoxyethylene (3) polyoxypropylene (17) glycol, polyoxyethylene (20) polyoxypropylene glycol), and the like. Examples of the alkylene glycols include polyoxyethylene (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, and polyoxyethylene (200) polyoxypropylene (70) glycol; polyvinyl alcohols such as polyvinyl alcohol (completely saponified) and polyvinyl alcohol (partially saponified); meglumine, and the like. These may be used singly or in combination of two or more.

[0044] Among the non-sugar alcohols listed above, from the viewpoint of improving content uniformity, dihydric non-sugar alcohols are preferred, polyalkylene glycols are more preferred, macrogol is 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 10,000 are even more preferred, those having an average molecular weight of 200 to 8,000 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 on "Macrogol 400" in the 17th Edition of the Japanese Pharmacopoeia. These non-sugar alcohols 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 Corisolv PG (BASF Japan Ltd.), diethylene glycol (Nippon Shokubai Co., Ltd.), Unisafe DPG-R (NOF Corporation), Macrogol 200 (Sanyo Chemical Industries, Ltd.), Corisolv PEG 300 (BASF Japan Ltd.), Super Refined PEG 400 (Croda Japan Co., Ltd.), CARBOWAX Sentry PEG 600 (Dow Chemical Japan Co., Ltd.), Macrogol 1000 (NOF Corporation), Macrogol 1500 (Sanyo Chemical Industries, Ltd.), CARBOWAX Sentry Examples of such antifungal agents include PEG1540 (Dow Chemical Japan Co., 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 (NOF Corporation), Corisolv P124 (BASF Japan Ltd.), Pronon 403P (NOF Corporation), Newdet PE-85 (Sanyo Chemical Industries, Ltd.), PEP-101 (Freund Corporation), Corifol P188 (BASF Japan Ltd.), Corifol P407 Micro (BASF Japan Ltd.), and Unilube DP-950B (NOF Corporation).

[0045] When a polyhydric alcohol is used, the content of the polyhydric alcohol in the pharmaceutical composition is not particularly limited and can be determined appropriately depending on the type of formulation, the gender, age, symptoms, etc. of the recipient. From the viewpoint of improving content uniformity, however, the total amount of the polyhydric alcohol relative to the total mass of the pharmaceutical composition is preferably 0.1 to 99% by mass, more preferably 0.5 to 95% by mass, even more preferably 1 to 90% by mass, and particularly preferably 1.5 to 50% by mass.

[0046] Furthermore, when a sugar alcohol is used as the polyhydric alcohol, the content of the 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, relative to the total mass of the pharmaceutical composition, from the viewpoint of improving content uniformity. Furthermore, when a non-sugar alcohol is used as the polyhydric alcohol, 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, relative to the total mass of the pharmaceutical composition, from the viewpoint of improving content uniformity. Furthermore, when polyalkylene glycols are used as the polyhydric alcohol, 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, relative to the total mass of the pharmaceutical composition, from the viewpoint of improving content uniformity.

[0047] When a polyhydric alcohol is used, the mass ratio of pemafibrate or its salt or solvate thereof to the polyhydric alcohol in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable that the polyhydric alcohol is contained in total in an amount of 1 to 2000 mass parts per mass part of pemafibrate in free form, more preferably 5 to 1500 mass parts, even more preferably 10 to 1000 mass parts, and particularly preferably 15 to 500 mass parts.

[0048] Furthermore, when a sugar alcohol is used as the polyhydric alcohol, the mass ratio of pemafibrate or its salt or solvate thereof to the sugar alcohol in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable that the sugar alcohol be contained in total at 2 to 1,900 mass parts, more preferably 6 to 1,450 mass parts, and particularly preferably 12 to 950 mass parts per mass part of pemafibrate in free form. Furthermore, when a non-sugar alcohol is used as the polyhydric alcohol, the mass ratio of pemafibrate or its salt or solvate thereof to the non-sugar alcohol in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable that the non-sugar alcohol is contained in total at 3 to 1850 mass parts, more preferably 7 to 1400 mass parts, and particularly preferably 13 to 900 mass parts per mass part of pemafibrate in free form. Furthermore, when polyalkylene glycols are used as polyhydric alcohols, the mass ratio of pemafibrate or its salts or solvates thereof to polyalkylene glycols in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable to contain a total of 4 to 1800 mass parts of polyalkylene glycols per 1 mass part of pemafibrate in free form, more preferably 8 to 1350 mass parts, and particularly preferably 14 to 850 mass parts.

[0049] <Alkyl sulfate esters> As used herein, the term "alkyl sulfate esters" refers to compounds represented by the following formula (1): RO-SO3M (1) (In the formula, R represents a linear or branched, saturated or unsaturated hydrocarbon group having 8 to 22 carbon atoms, 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.) The alkyl sulfate ester salt is represented by the formula: Specific examples of such alkyl sulfates include lauryl sulfate, tetradecyl sulfate, hexadecyl sulfate, and octadecyl sulfate, and these may be used alone or in combination of two or more. From the viewpoint of improving content uniformity, the alkyl sulfate is preferably one or more selected from the group consisting of lauryl sulfate, tetradecyl sulfate, hexadecyl sulfate, and octadecyl sulfate, more preferably lauryl sulfate, and particularly preferably sodium lauryl sulfate. Furthermore, from the viewpoint of ease of production of pharmaceutical compositions (particularly solid formulations), the alkyl sulfate is preferably solid at room temperature (any temperature between 15 and 25°C). These alkyl sulfates are known compounds and may be produced by known methods, or commercially available products such as Corifol SLS (BASF Japan Ltd.) may be used.

[0050] When alkyl sulfates are used, the content of the alkyl sulfates in the pharmaceutical composition is not particularly limited and can be determined appropriately depending on the type of formulation, the gender, age, symptoms, etc. of the recipient. From the viewpoint of improving content uniformity, however, the total amount of alkyl sulfates relative 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.

[0051] When alkyl sulfates are used, the mass ratio of pemafibrate or its salts or solvates thereof to alkyl sulfates in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable that the total amount of alkyl sulfates is 1 to 200 parts by mass, more preferably 3 to 150 parts by mass, even more preferably 5 to 100 parts by mass, and particularly preferably 5 to 50 parts by mass, per part by mass of pemafibrate in free form.

[0052] <Disaccharides> As used herein, the term "disaccharide" refers to one or more species selected from the group consisting of disaccharides themselves, disaccharides in which all or part of the hydroxy groups have been substituted with halogen atoms such as chlorine atoms, and solvates thereof. The solvates are not particularly limited, and specific examples include hydrates. The monosaccharides constituting the disaccharides are not particularly limited, and examples include pentoses such as arabinose and xylose; and hexoses such as glucose, galactose, fructose, mannose, altrose, and rhamnose. Specific examples of such disaccharides include sucrose, lactulose, milk sugar, maltose, trehalose, cellobiose, kojibiose, nigerose, isomaltose, isotrehalose, neotrehalose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose, gentiobiulose, mannobiose, melibiose, melibiulose, neolactose, galactosucrose, scillabiose, rutinose, rutinulose, vicianose, xylobiose, primeverose, and sucralose, and any of these may be used alone or in combination of two or more.

[0053] From the viewpoint of improving content uniformity, the disaccharide is preferably one or more selected from the group consisting of sucrose, lactose, maltose, trehalose, palatinose, sucralose, and solvates thereof, more preferably one or more selected from the group consisting of sucrose, lactose, trehalose, sucralose, and hydrates thereof, even more preferably one or more selected from the group consisting of lactose and hydrates thereof, and particularly preferably one or more selected from the group consisting of lactose-crystalline cellulose spherical granules, lactose hydrate, lactose granules, and anhydrous lactose. Furthermore, from the viewpoint of ease of production of pharmaceutical compositions (particularly solid formulations), disaccharides that are solid at room temperature (any temperature between 15 and 25°C) are preferred. These disaccharides are all known components and may be produced by known methods, or commercially available products such as Nonpareil-105 (Freund Corporation), lactose hydrate (Sanei Gen F.F.I.), lactose G (Freund Corporation), Lactopress anhydrous (CBC Corporation), Nisshoku Crystalline Maltose (Nihon Shokuhin Kako Co., Ltd.), Trehalose P (Asahi Kasei Corporation), sucralose (Sanei Gen F.F.I.), and Pharmatose 200M (DFE Pharma).

[0054] When disaccharides are used, the content of disaccharides in the pharmaceutical composition is not particularly limited and can be determined appropriately depending on the type of formulation, the gender, age, symptoms, etc. of the recipient. From the viewpoint of improving content uniformity, however, the total amount of disaccharides relative to the total mass of the pharmaceutical composition is preferably 1 to 99% by mass, more preferably 3 to 95% by mass, even more preferably 5 to 90% by mass, and particularly preferably 7 to 85% by mass.

[0055] Furthermore, when one or more disaccharides selected from the group consisting of lactose and its hydrates are used as the disaccharide, the content thereof is preferably 2 to 98% by mass, more preferably 4 to 93% by mass, and particularly preferably 8 to 80% by mass, relative to the total mass of the pharmaceutical composition, from the viewpoint of improving content uniformity.

[0056] When disaccharides are used, the mass ratio of pemafibrate or its salts or solvates thereof to disaccharides in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable that the pharmaceutical composition contains a total of 10 to 1750 mass parts of disaccharides per 1 mass part of pemafibrate in free form, more preferably 50 to 1500 mass parts, even more preferably 80 to 1200 mass parts, and particularly preferably 100 to 900 mass parts.

[0057] Furthermore, when one or more disaccharides selected from the group consisting of lactose and its hydrates are used, the mass ratio of pemafibrate or a salt thereof or a solvate thereof to one or more disaccharides selected from the group consisting of lactose and its hydrates in the pharmaceutical composition is not particularly limited. However, from the viewpoint of improving content uniformity, it is preferable that the pharmaceutical composition contains a total of 30 to 1150 mass parts, more preferably 50 to 1050 mass parts, even more preferably 70 to 950 mass parts, and particularly preferably 120 to 850 mass parts of one or more disaccharides selected from the group consisting of lactose and its hydrates per 1 mass part of pemafibrate in free form.

[0058] <Cellulose> As used herein, "cellulose" refers to one or more types selected from the group consisting of cellulose and its salts. The type of cellulose salt is not particularly limited, and specific examples include alkali metal salts such as sodium salt and potassium salt; and salts with metals of Group 2 elements such as calcium salt and magnesium salt. Furthermore, the average degree of polymerization and properties (crystalline form) of cellulose are not particularly limited, but the average degree of polymerization is preferably 50 to 10,000. The average degree of polymerization can be confirmed by conducting a test in accordance with the verification test (3) described in the section on "crystalline cellulose" in the 17th edition of the Japanese Pharmacopoeia. Specific examples of such cellulose include crystalline cellulose, crystalline cellulose (fine particles), crystalline cellulose (granules), powdered cellulose, and powdered cellulose (average degree of polymerization: 800 to 1100). One of these may be used alone, or two or more may be used in combination. Note that these crystalline celluloses refer to the crystalline celluloses listed in the Pharmaceutical Additives Dictionary 2016 (published by Yakuji Nippo Co., Ltd.). These celluloses are all known components and may be produced by known methods, or commercially available products such as Ceolus PH-101 (Asahi Kasei Corporation), Cellupher (Sanei Gen F.F.I. Co., Ltd.), and ARBOCEL (Kimura Sangyo Co., Ltd.) may be used.

[0059] When cellulose is used, the content of cellulose in the pharmaceutical composition is not particularly limited and can be determined appropriately depending on the type of formulation, the gender, age, symptoms, etc. of the recipient. From the viewpoint of improving content uniformity, however, the total amount of cellulose relative to the total mass of the pharmaceutical composition is preferably 1 to 40% by mass, more preferably 3 to 35% by mass, even more preferably 5 to 30% by mass, and particularly preferably 8 to 25% by mass.

[0060] When cellulose is used, the mass ratio of pemafibrate or its salt or solvate thereof to cellulose in the pharmaceutical composition is not particularly limited, but from the viewpoint of improving content uniformity, it is preferable to contain a total of 5 to 5,000 mass parts of cellulose per 1 mass part of pemafibrate in free form, more preferably 30 to 3,500 mass parts, and particularly preferably 60 to 2,000 mass parts.

[0061] The dosage form of the "pharmaceutical composition" herein is not particularly limited and may be any of solid, semi-solid, or liquid preparations, and can be selected depending on the intended use. Examples of dosage forms of pharmaceutical compositions include those described in the General Provisions for Preparations of the Seventeenth Edition of the Japanese Pharmacopoeia. Specific examples of dosage forms for oral administration include solid preparations such as tablets (e.g., regular tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules (e.g., effervescent granules, etc.), powders, and pills; semi-solid preparations such as oral jellies; and liquid preparations such as oral liquids (e.g., elixirs, suspensions, emulsions, lemonades, etc.). Dosage forms for parenteral administration include injections, inhalants, eye drops, ear drops, nasal drops, suppositories, solid preparations for topical application, liquid preparations for topical application, sprays, ointments, creams, gels, and patches.

[0062] From the viewpoints of ease of administration and ease of manufacture, a pharmaceutical composition is preferably a solid preparation. In particular, while a pharmaceutical composition in the form of a solid preparation is extremely easy to manufacture, solid preparations are generally produced at room temperature (any temperature between 15 and 25°C) using a large amount of solid components, which tends to result in uneven mixing and dispersion of the components, and deterioration of content uniformity is particularly likely to be a problem. However, the present invention has the excellent effect of providing good content uniformity even in the case of a solid preparation. As the solid preparation, a solid preparation for oral administration is preferable, and tablets, capsules, granules, powders and pills are more preferable, and tablets are particularly preferable.

[0063] In addition to the above-mentioned components, the pharmaceutical composition of the present invention may contain pharmaceutically acceptable carriers (formulation additives) depending on the dosage form. Examples of such formulation additives include, but are not limited to, excipients, disintegrants, binders, lubricants, plasticizers, film-forming agents, powders, poorly water-soluble polymeric substances, antioxidants, flavoring agents, and sweeteners. Specific examples of these formulation additives include those listed in the Pharmaceutical Additives Dictionary 2016 (published by Yakuji Nippo Co., Ltd.) and the Handbook of Pharmaceutical Excipients, Seventh Edition (published by Pharmaceutical Press).

[0064] Specific examples of excipients include inorganic excipients such as anhydrous sodium sulfate, anhydrous calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodium dihydrogen phosphate; and organic excipients such as caramel, agar, paraffin, glucose, pullulan, polyoxyethylene hydrogenated castor oil, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, and calcium citrate. These may be used alone or in combination of two or more. The total content of excipients 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.

[0065] Specific examples of disintegrants include gelatin, sodium hydrogen carbonate, dextrin, dehydroacetic acid and its salts, and polyoxyethylene hydrogenated castor oil 60. These can be used alone or in combination of two or more.

[0066] Specific examples of binders include dextrin, pullulan, gum arabic, agar, gelatin, tragacanth, sodium alginate, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, etc. These can be used alone or in combination of two or more.

[0067] Specific examples of lubricants include calcium stearate, magnesium stearate, sodium stearyl fumarate, etc. 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.

[0068] Specific examples of plasticizers include sesame oil, castor oil, polysorbate 80 (polyoxyethylene (20) sorbitan oleate), etc. These can be used alone or in combination of two or more.

[0069] Specific examples of film-forming agents include alginic acid or salts thereof such as sodium alginate, carrageenan, xanthan gum, pullulan, etc. These may be used alone or in combination of two or more.

[0070] Examples of powders include organic or inorganic powders such as talc, titanium oxide, yellow ferric oxide, ferric oxide, legal pigments, etc. These can be used alone or in combination of two or more.

[0071] Specific examples of poorly water-soluble polymeric substances include carboxyvinyl polymers, aminoalkyl methacrylate copolymers, etc. These may be used alone or in combination of two or more.

[0072] Specific examples of antioxidants include ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, butylhydroxyanisole, etc. These can be used alone or in combination of two or more.

[0073] Specific examples of flavoring agents include terpenes such as limonene, pinene, camphene, cymene, cineole, citronellol, geraniol, nerol, linalool, menthol, terpineol, rhodinol, borneol, isoborneol, menthone, camphor, eugenol, and cinzeylanol; terpene-containing essential oils such as spruce oil, orange oil, peppermint oil, camphor oil, eucalyptus oil, turpentine oil, lemon oil, ginger oil, clove oil, cinnamon oil, lavender oil, fennel oil, chamomile oil, perilla oil, and spearmint oil; and acidulants such as ascorbic acid, tartaric acid, citric acid, malic acid, and salts thereof. These may be used alone or in combination of two or more.

[0074] Examples of sweeteners include aspartame, stevia, glycyrrhizinic acid, thaumatin, acesulfame potassium, saccharin, and saccharin sodium, and these can be used alone or in combination of two or more.

[0075] The pharmaceutical composition of the present invention can be prepared by known methods depending on the 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, and coating. More specifically, for example, when the pharmaceutical composition is in the form of a granular preparation such as granules, powders, or pills, the pharmaceutical composition can be produced by mixing the above-mentioned components 1 to 8 and formulation additives such as excipients, binders, disintegrants, and lubricants as needed, and then granulating the mixture by a known granulation method such as extrusion granulation, tumbling granulation, stirring granulation, fluidized bed granulation, spray granulation, melt granulation, or crushing granulation to obtain a granulated product, which can then be further classified, sized, etc., as needed. The obtained granulated product can also be coated with a coating agent or the like by a known method. Furthermore, when the pharmaceutical composition is in the form of a tablet, the above-mentioned components 1 to 8 and appropriate formulation additives such as excipients, binders, disintegrants, lubricants, etc. are used as needed, and these components are mixed to obtain a mixture, which is then directly compressed (tableted) (direct powder compression method), or the above-mentioned granules are classified, sized, etc. as needed, 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-mentioned granulated or compressed product may be filled into the capsule.

[0076] The pharmaceutical composition of the present invention is not limited in any way to the diseases to which it can be applied, and can be widely used for the prevention or treatment of diseases that are known at present or that will be discovered in the future and for which administration of pemafibrate is considered effective. For example, pemafibrate or a salt thereof, or a solvate thereof has excellent PPARα agonist activity and has effects such as lowering plasma triglyceride levels and increasing HDL cholesterol, etc. Therefore, the pharmaceutical composition of the present invention can be preferably 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, etc. Furthermore, pemafibrate or a salt thereof, or a solvate thereof is useful for preventing or treating NAFLD (non-alcoholic fatty liver disease). Therefore, the pharmaceutical composition of the present invention can also be used as an agent for preventing and / or treating NAFLD (more preferably, NASH (non-alcoholic steatohepatitis)). Furthermore, pemafibrate or a salt thereof or a solvate thereof may be used as a therapeutic agent for primary biliary cirrhosis.

[0077] The route of administration of the pharmaceutical composition is not particularly limited and can be determined appropriately depending on the disease to be treated, the type of formulation, the gender, age, symptoms, etc. of the recipient, but oral administration is preferred from the viewpoint of ease of administration. Furthermore, the pharmaceutical composition can be taken in divided doses about 1 to 4 times a day, before meals, between meals, after meals, before bedtime, etc.

[0078] The dose of pemafibrate or a salt thereof, or a solvate thereof in the pharmaceutical composition is not particularly limited and can be determined appropriately depending on the disease to which it is applied, the type of formulation, the gender, age, symptoms, etc. of the recipient. For example, the dose of pemafibrate or a salt thereof, or a solvate thereof, calculated as the free form of pemafibrate, per day is 0.05 to 0.8 mg, more preferably 0.075 to 0.6 mg, and particularly preferably 0.1 to 0.4 mg.

[0079] The present specification discloses the following embodiments, for example, but is not limited to these. [1-1] A pharmaceutical composition containing pemafibrate or a salt thereof, or a solvate thereof, in an amount of 0.017 to 4.2 mass% (preferably 0.042 to 4.2 mass%, more preferably 0.042 to 1.7 mass%, and particularly preferably 0.042 to 0.83 mass%), calculated as the free form of pemafibrate, relative to the total mass of the pharmaceutical composition. [1-2] The pharmaceutical composition according to [1-1], which contains 0.02 to 5 mg (preferably 0.05 to 1 mg) of pemafibrate or a salt thereof, or a solvate thereof, calculated as the free form of pemafibrate per dosage unit of the pharmaceutical composition. [1-3] The pharmaceutical composition according to [1-1] or [1-2], which is a solid formulation. [1-4] The pharmaceutical composition according to any one of [1-1] to [1-3], which is in the form of a tablet, capsule, granule, powder or pill. [1-5] The pharmaceutical composition according to any one of [1-1] to [1-4], which contains 0.02 to 5 mg (preferably 0.05 to 1 mg) of pemafibrate or a salt thereof, or a solvate thereof, calculated as the free form of pemafibrate per tablet.

[0080] [1-6] Furthermore, one or more selected from the group consisting of the following components (1) to (8): (1) Cellulose ethers (2) Starches (3) Povidone (4) Silicate compounds (5) Polyhydric alcohol (6) Alkyl sulfate esters (7) Disaccharides (8) Cellulose The pharmaceutical composition according to any one of [1-1] to [1-5],

[0081] [1-7] The pharmaceutical composition according to [1-6], wherein component (1) is one or more selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, carboxyalkyl cellulose, and crosslinked polymers of carboxyalkyl cellulose, and salts thereof. [1-8] The pharmaceutical composition according to [1-6], wherein component (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 crosslinked polymers of carboxy C1-C6 alkyl cellulose, and salts thereof. [1-9] The pharmaceutical composition according to [1-6], wherein component (1) is one or more selected from the group consisting of methylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, carmellose, carmellose potassium, carmellose calcium, carmellose sodium, and croscarmellose sodium.

[0082] [1-10] The pharmaceutical composition according to any one of [1-6] to [1-9], wherein component (2) is one or more selected from the group consisting of starch, hydroxyalkyl ethers of starch, carboxyalkyl ethers of starch, and salts thereof. [1-11] The pharmaceutical composition according to any one of [1-6] to [1-9], wherein component (2) is one or more selected from the group consisting of starch, hydroxy C1-C6 alkyl ether of starch, carboxy C1-C6 alkyl ether of starch, and salts thereof. [1-12] The pharmaceutical composition according to any one of [1-6] to [1-9], wherein the component (2) is one or more selected from the group consisting of starch, hydroxypropyl starch, carboxymethyl starch, and salts thereof.

[0083] [1-13] The pharmaceutical composition according to any one of [1-6] to [1-12], wherein the component (3) is one or more selected from the group consisting of povidone and crospovidone. [1-14] The pharmaceutical composition according to any one of [1-6] to [1-12], wherein the component (3) is crospovidone.

[0084] [1-15] The pharmaceutical composition according to any one of [1-6] to [1-14], wherein component (4) is one or more selected from the group consisting of hydrous silicic acid compounds, salts of hydrous silicic acid compounds, anhydrous silicic acid, and salts of anhydrous silicic acid. [1-16] The pharmaceutical composition according to any one of [1-6] to [1-14], wherein the component (4) is one or more selected from the group consisting of hydrous magnesium silicate, hydrous silicon dioxide, and light anhydrous silicic acid. [1-17] The pharmaceutical composition according to any one of [1-6] to [1-14], wherein the component (4) is at least one selected from the group consisting of hydrous magnesium silicate and hydrous silicon dioxide.

[0085] [1-18] The pharmaceutical composition according to any one of [1-6] to [1-17], wherein the component (5) is macrogol. [1-19] The pharmaceutical composition according to any one of [1-6] to [1-17], wherein the component (5) is 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. [1-20] The pharmaceutical composition according to any one of [1-6] to [1-17], wherein the component (5) is a macrogol having an average molecular weight of 100 to 10,000. [1-21] The pharmaceutical composition according to any one of [1-6] to [1-17], wherein the component (5) is macrogol 6000.

[0086] [1-22] The pharmaceutical composition according to any one of [1-6] to [1-17], wherein the component (5) is one or more selected from the group consisting of erythritol, xylitol, mannitol, sorbitol, maltitol, and lactitol. [1-23] The pharmaceutical composition according to any one of [1-6] to [1-17], wherein the component (5) is one or more selected from the group consisting of mannitol and sorbitol. [1-24] The pharmaceutical composition according to any one of [1-6] to [1-17], wherein the component (5) is mannitol.

[0087] [1-25] The pharmaceutical composition according to any one of [1-6] to [1-24], wherein the component (6) is one or more selected from the group consisting of lauryl sulfate, tetradecyl sulfate, hexadecyl sulfate, and octadecyl sulfate. [1-26] The pharmaceutical composition according to any one of [1-6] to [1-24], wherein the component (6) is a lauryl sulfate ester salt. [1-27] The pharmaceutical composition according to any one of [1-6] to [1-24], wherein the component (6) is sodium lauryl sulfate.

[0088] [1-28] The pharmaceutical composition according to any one of [1-6] to [1-27], wherein component (7) is one or more selected from the group consisting of sucrose, lactulose, milk sugar, maltose, trehalose, cellobiose, kojibiose, nigerose, isomaltose, isotrehalose, neotrehalose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose, gentiobiulose, mannobiose, melibiose, melibiulose, neolactose, galactosucrose, scillabiose, rutinose, rutinulose, vicianose, xylobiose, primeverose, and sucralose, and solvates thereof. [1-29] The pharmaceutical composition according to any one of [1-6] to [1-27], wherein the component (7) is one or more selected from the group consisting of sucrose, lactose, maltose, trehalose, palatinose, sucralose, and solvates thereof. [1-30] The pharmaceutical composition according to any one of [1-6] to [1-27], wherein the component (7) is one or more selected from the group consisting of sucrose, lactose, trehalose, sucralose, and hydrates thereof. [1-31] ​​The pharmaceutical composition according to any one of [1-6] to [1-27], wherein the component (7) is one or more members selected from the group consisting of lactose and its hydrates.

[0089] [1-32] The pharmaceutical composition according to any one of [1-6] to [1-31], wherein the component (8) is one or more members selected from the group consisting of cellulose and salts thereof.

[0090] [1-33] The pharmaceutical composition according to any one of [1-1] to [1-32], which is an agent for preventing and / or treating 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.

[0091] [2-1] A method for improving the content uniformity of pemafibrate or a salt thereof or a solvate thereof in a pharmaceutical composition, comprising a step of incorporating pemafibrate or a salt thereof or a solvate thereof in an amount of 0.017 to 4.2% by mass (preferably 0.042 to 4.2% by mass, more preferably 0.042 to 1.7% by mass, and particularly preferably 0.042 to 0.83% by mass) calculated as the free form of pemafibrate relative to the total mass of the pharmaceutical composition (preferably a method for improving the content uniformity of pemafibrate or a salt thereof or a solvate thereof in a pharmaceutical composition, characterized in that the content of pemafibrate or a salt thereof or a solvate thereof in the pharmaceutical composition is 0.017 to 4.2% by mass (preferably 0.042 to 4.2% by mass, more preferably 0.042 to 1.7% by mass, and particularly preferably 0.042 to 0.83% by mass) calculated as the free form of pemafibrate relative to the total mass of the pharmaceutical composition). [2-2] The method described in [2-1], wherein the step is a step of containing 0.02 to 5 mg (preferably 0.05 to 1 mg) of pemafibrate or a salt thereof, or a solvate thereof, calculated as the free form of pemafibrate per dosage unit of the pharmaceutical composition. [2-3] The method according to [2-1] or [2-2], wherein the pharmaceutical composition is a solid formulation. [2-4] The method according to any one of [2-1] to [2-3], wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, powder, or pill. [2-5] The method according to any one of [2-1] to [2-4], wherein the step is a step of containing 0.02 to 5 mg (preferably 0.05 to 1 mg) of pemafibrate or a salt thereof, or a solvate thereof, calculated as the free form of pemafibrate, per tablet.

[0092] [2-6] One or more selected from the group consisting of the following components (1) to (8): (1) Cellulose ethers (2) Starches (3) Povidone (4) Silicate compounds (5) Polyhydric alcohol (6) Alkyl sulfate esters (7) Disaccharides (8) Cellulose The method according to any one of [2-1] to [2-5], comprising a step of incorporating the above into a pharmaceutical composition.

[0093] [2-7] The method according to [2-6], wherein component (1) is at least one selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, carboxyalkyl cellulose, and crosslinked polymers of carboxyalkyl cellulose, and salts thereof. [2-8] The method according to [2-6], wherein component (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 crosslinked polymers of carboxy C1-C6 alkyl cellulose, and salts thereof. [2-9] The method described in [2-6], wherein component (1) is one or more selected from the group consisting of methylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, carmellose, carmellose potassium, carmellose calcium, carmellose sodium, and croscarmellose sodium.

[0094] [2-10] The method according to any one of [2-6] to [2-9], wherein the component (2) is at least one selected from the group consisting of starch, hydroxyalkyl ethers of starch, carboxyalkyl ethers of starch, and salts thereof. [2-11] The method according to any one of [2-6] to [2-9], wherein component (2) is one or more selected from the group consisting of starch, hydroxy C1-C6 alkyl ether of starch, carboxy C1-C6 alkyl ether of starch, and salts thereof. [2-12] The method according to any one of [2-6] to [2-9], wherein the component (2) is one or more selected from the group consisting of starch, hydroxypropyl starch, carboxymethyl starch, and salts thereof.

[0095] [2-13] The method according to any one of [2-6] to [2-12], wherein the component (3) is one or more selected from the group consisting of povidone and crospovidone. [2-14] The method according to any one of [2-6] to [2-12], wherein the component (3) is crospovidone.

[0096] [2-15] The method according to any one of [2-6] to [2-14], wherein the component (4) is at least one selected from the group consisting of hydrous silicic acid compounds, salts of hydrous silicic acid compounds, silicic anhydride, and salts of silicic anhydride. [2-16] The method according to any one of [2-6] to [2-14], wherein the component (4) is at least one selected from the group consisting of hydrous magnesium silicate, hydrous silicon dioxide, and light anhydrous silicic acid. [2-17] The method according to any one of [2-6] to [2-14], wherein the component (4) is at least one selected from the group consisting of hydrous magnesium silicate and hydrous silicon dioxide.

[0097] [2-18] The method according to any one of [2-6] to [2-17], wherein the component (5) is macrogol. [2-19] The method according to any one of [2-6] to [2-17], wherein component (5) is 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. [2-20] The method according to any one of [2-6] to [2-17], wherein the component (5) is a macrogol having an average molecular weight of 100 to 10,000. [2-21] The method according to any one of [2-6] to [2-17], wherein the component (5) is macrogol 6000.

[0098] [2-22] The method according to any one of [2-6] to [2-17], wherein the component (5) is one or more selected from the group consisting of erythritol, xylitol, mannitol, sorbitol, maltitol, and lactitol. [2-23] The method according to any one of [2-6] to [2-17], wherein the component (5) is one or more selected from the group consisting of mannitol and sorbitol. [2-24] The method according to any one of [2-6] to [2-17], wherein the component (5) is mannitol.

[0099] [2-25] The method according to any one of [2-6] to [2-24], wherein the component (6) is at least one selected from the group consisting of lauryl sulfate, tetradecyl sulfate, hexadecyl sulfate, and octadecyl sulfate. [2-26] The method according to any one of [2-6] to [2-24], wherein the component (6) is a lauryl sulfate ester salt. [2-27] The method according to any one of [2-6] to [2-24], wherein the component (6) is sodium lauryl sulfate.

[0100] [2-28] The method according to any one of [2-6] to [2-27], wherein component (7) is one or more selected from the group consisting of sucrose, lactulose, milk sugar, maltose, trehalose, cellobiose, kojibiose, nigerose, isomaltose, isotrehalose, neotrehalose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose, gentiobiulose, mannobiose, melibiose, melibiulose, neolactose, galactosucrose, scillabiose, rutinose, rutinulose, vicianose, xylobiose, primeverose, and sucralose, and solvates thereof. [2-29] The method according to any one of [2-6] to [2-27], wherein the component (7) is one or more selected from the group consisting of sucrose, lactose, maltose, trehalose, palatinose, sucralose, and solvates thereof. [2-30] The method according to any one of [2-6] to [2-27], wherein the component (7) is one or more selected from the group consisting of sucrose, lactose, trehalose, sucralose, and hydrates thereof. [2-31] The method according to any one of [2-6] to [2-27], wherein the component (7) is one or more selected from the group consisting of lactose and its hydrates.

[0101] [2-32] The method according to any one of [2-6] to [2-31], wherein the component (8) is at least one member selected from the group consisting of cellulose and salts thereof.

[0102] [2-33] The method according to any one of [2-1] to [2-32], wherein the pharmaceutical composition is an agent for preventing and / or treating 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. [Example]

[0103] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples in any way. In the following test examples, measurements using HPLC were carried out using an ODS column as the column and an ultraviolet absorptiometer as the detector. Furthermore, the average particle size of the primary particles of the pemafibrate used in the following test examples was measured according to the particle size measurement method by laser diffraction in the 17th edition of the Japanese Pharmacopoeia. The results showed that d50 was 100 μm or less and d90 was 200 μm or less.

[0104] [Test Example 1] Content uniformity evaluation test Part 1 To evaluate the uniformity of the pemafibrate content in the pharmaceutical composition, the following test was carried out. That is, the tablets of Examples 1 to 8 were produced so that the amount of each ingredient per tablet shown in Table 1 was the amount (mg) shown in Table 1. Specifically, pemafibrate and croscarmellose sodium were mixed for 30 seconds, followed by the addition of lactose hydrate and microcrystalline cellulose and mixing for 30 seconds, and finally the addition of magnesium stearate and mixing for 30 seconds. The resulting mixture was then compressed into tablets using a tablet press equipped with a 7 mm diameter punch to produce 1,000 tablets, each weighing 120 mg.

[0105] Ten tablets were randomly selected from each of the obtained tablets, and the pemafibrate content in each tablet was measured by the following method. Specifically, one tablet was crushed in water, and then acetonitrile was added to obtain a sample solution. The obtained sample solution was analyzed using an HPLC system to measure the peak area derived from pemafibrate. The peak area derived from pemafibrate in the obtained sample solution was then compared with the peak area of ​​a standard solution of pemafibrate with a known concentration to determine the content of pemafibrate in each tablet.

[0106] The relative standard deviation (RSD) (%) of the pemafibrate content in the tablets was calculated from the measured value of the pemafibrate content in each tablet in accordance with the content uniformity test of the 17th Edition of the Japanese Pharmacopoeia, and used as an index of the variability (degree of uniformity) of the pemafibrate content in the tablets. The results obtained are shown in Table 1.

[0107] [Table 1]

[0108] As shown in the results in Table 1, in Example 1, where the pemafibrate content in the tablet was less than 0.017% by mass, and in Example 8, where the pemafibrate content was more than 4.2% by mass, the relative standard deviation was high, exceeding 8%, and the uniformity of the pemafibrate content per tablet was poor. On the other hand, in Examples 2 to 7, in which the pemafibrate content in the tablets was within the range of 0.017 to 4.2% by mass, the relative standard deviation was below 8%, and the uniformity of the pemafibrate content per tablet was good.

[0109] From the above test results, it was revealed that in a pharmaceutical composition containing pemafibrate or its salt or a solvate thereof, the content uniformity of pemafibrate in the pharmaceutical composition can be improved by setting the content of pemafibrate or its salt or a solvate thereof within the range of 0.017 to 4.2 mass% converted to the free form of pemafibrate relative to the total mass of the pharmaceutical composition.

[0110] [Test Example 2] Content uniformity evaluation test Part 2 To evaluate the uniformity of the pemafibrate content in the pharmaceutical composition, the following test was carried out. That is, the tablets of Examples 9 to 12 were produced so that the amount of each ingredient per tablet shown in Table 2 was the amount (mg) shown in Table 2. Specifically, pemafibrate and cellulose ethers were mixed for 30 seconds, followed by the addition of lactose hydrate and microcrystalline cellulose and mixing for 30 seconds, and finally the addition of magnesium stearate and mixing for 30 seconds. The resulting mixture was then compressed into tablets using a tablet press equipped with a 7 mm diameter punch to produce 1,000 tablets, each weighing 120 mg.

[0111] Ten tablets were randomly selected from each of the obtained tablets, and the pemafibrate content in each tablet was measured in the same manner as in Test Example 1. From the measured value of the pemafibrate content in each obtained tablet, the relative standard deviation (RSD) (%) of the pemafibrate content in the tablet was calculated in accordance with the content uniformity test of the Japanese Pharmacopoeia, 17th Edition, and used as an index of the variation (degree of uniformity) of the pemafibrate content in the tablet. The results obtained are shown in Table 2.

[0112] [Table 2]

[0113] As shown in Table 2, even when carmellose sodium, low-substituted hydroxypropyl cellulose, methylcellulose, or hydroxypropylmethylcellulose was used as the cellulose ether instead of croscarmellose sodium (Examples 9 to 12), the relative standard deviation was small and it was clear that the uniformity of the pemafibrate content per tablet was good. The amount of cellulose ether added was a small amount of 2.4 mg (2% by mass of the total tablet mass).

[0114] The above test results demonstrate that pharmaceutical compositions containing cellulose ethers together with 0.017 to 4.2% by mass of pemafibrate or a salt thereof, or a solvate thereof have good content uniformity.

[0115] [Test Example 3] Content uniformity evaluation test No. 3 The test was carried out in the same manner as in Test Example 2, except that the tablet composition was adjusted to the ingredients and amounts shown in Table 3 below. The results are shown in Table 3.

[0116] [Table 3]

[0117] As shown in the results in Table 3, even when gelatinized starch, corn starch, or sodium carboxymethyl starch was contained as the starch (Examples 13 to 15), the relative standard deviations were small, similar to the tablets of Examples 4 and 9 to 12 containing cellulose ethers in Test Example 2, and it was revealed that the uniformity of the pemafibrate content per tablet was good.

[0118] The above test results demonstrate that pharmaceutical compositions containing 0.017 to 4.2% by mass of pemafibrate or a salt thereof, or a solvate thereof, together with starches, have good content uniformity.

[0119] [Test Example 4] Content uniformity evaluation test No. 4 The test was carried out in the same manner as in Test Example 2, except that the tablet composition was adjusted to the ingredients and amounts shown in Table 4 below. The results are shown in Table 4.

[0120] [Table 4]

[0121] As shown in Table 4, even when crospovidone or polyvinylpyrrolidone was contained as the povidone (Examples 16 and 17), the relative standard deviations were small, similar to the tablets of Examples 4 and 9 to 12 containing cellulose ethers in Test Example 2, and it was revealed that the uniformity of the pemafibrate content per tablet was good.

[0122] The above test results demonstrate that pharmaceutical compositions containing povidones together with 0.017 to 4.2% by mass of pemafibrate or a salt thereof, or a solvate thereof have good content uniformity.

[0123] [Test Example 5] Content uniformity evaluation test No. 5 The test was carried out in the same manner as in Test Example 2, except that the tablet composition was adjusted to the ingredients and amounts shown in Table 5 below. The results are shown in Table 5.

[0124] [Table 5]

[0125] As shown in the results in Table 5, even when hydrous magnesium silicate or hydrous silicon dioxide was contained as the silicate compound (Examples 18 and 19), the relative standard deviations were small, similar to the tablets of Examples 4 and 9 to 12 containing cellulose ethers in Test Example 2, and it was revealed that the uniformity of the pemafibrate content per tablet was good.

[0126] The above test results demonstrate that a pharmaceutical composition containing a silicic acid compound together with 0.017 to 4.2% by mass of pemafibrate or a salt thereof, or a solvate thereof has good content uniformity.

[0127] [Test Example 6] Content uniformity evaluation test No. 6 The test was carried out in the same manner as in Test Example 2, except that the tablet composition was adjusted to the ingredients and amounts shown in Table 6 below. The results are shown in Table 6.

[0128] [Table 6]

[0129] As shown in the results in Table 6, even when macrogol was added as the polyhydric alcohol (Example 20), the relative standard deviations were small, similar to the tablets of Examples 4 and 9 to 12 containing cellulose ethers in Test Example 2, and it was revealed that the uniformity of the pemafibrate content per tablet was good.

[0130] The above test results demonstrate that a pharmaceutical composition containing 0.017 to 4.2% by mass of pemafibrate or a salt thereof, or a solvate thereof together with a polyhydric alcohol has good content uniformity.

[0131] [Test Example 7] Content uniformity evaluation test No. 7 The test was carried out in the same manner as in Test Example 2, except that the tablet composition was adjusted to the ingredients and amounts shown in Table 7 below. The results are shown in Table 7.

[0132] [Table 7]

[0133] As shown in the results in Table 7, even when sodium lauryl sulfate was added as the alkyl sulfate ester (Example 21), the relative standard deviations were small, similar to the tablets of Examples 4 and 9 to 12 containing cellulose ethers in Test Example 2, and it was revealed that the uniformity of the pemafibrate content per tablet was good.

[0134] The above test results demonstrate that pharmaceutical compositions containing 0.017 to 4.2% by mass of pemafibrate or a salt thereof, or a solvate thereof, together with alkyl sulfate esters, have good content uniformity.

[0135] [Test Example 8] Content uniformity evaluation test No. 8 To evaluate the uniformity of the pemafibrate content in the pharmaceutical composition, the following test was carried out. That is, tablets of Examples 22 to 25 were produced so that the amount per tablet of each component shown in Table 8 was the amount (mg) shown in Table 8. The specific procedure is as follows. (Example 22) Pemafibrate, lactose hydrate, croscarmellose sodium, and hydroxypropyl cellulose were mixed for 5 minutes, then purified water was added and the mixture was kneaded for 3 minutes, granulated, dried, and sized to obtain a granule. The resulting granule was mixed with magnesium stearate and compressed into 10,000 tablets, each weighing 120 mg. (Example 23) Ten thousand tablets, each weighing 120 mg, were produced in the same manner as in Example 22, except that part of the lactose hydrate was replaced with crystalline cellulose. (Example 24) Ten thousand tablets, each weighing 120 mg, were produced in the same manner as in Example 23, except that the entire amount of lactose hydrate was replaced with mannitol. (Example 25) Ten thousand tablets, each weighing 120 mg, were produced in the same manner as in Example 22, except that the entire amount of lactose hydrate was replaced with crystalline cellulose.

[0136] Ten tablets were randomly selected from each of the obtained tablets, and the pemafibrate content in each tablet was measured in the same manner as in Test Example 1. From the measured value of the pemafibrate content in each obtained tablet, the relative standard deviation (RSD) (%) of the pemafibrate content in the tablet was calculated in accordance with the content uniformity test of the Japanese Pharmacopoeia, 17th Edition, and used as an index of the variation (degree of uniformity) of the pemafibrate content in the tablet. The results obtained are shown in Table 8.

[0137] [Table 8]

[0138] As shown in the results in Table 8, when lactose hydrate was added as the disaccharide (Examples 22 and 23), when mannitol was added as the polyhydric alcohol (Example 24), and when crystalline cellulose was added as the cellulose (Example 25), the relative standard deviation was small, demonstrating good uniformity of the pemafibrate content per tablet.

[0139] The above test results revealed that a pharmaceutical composition containing 0.017 to 4.2 mass% of pemafibrate or its salt or a solvate thereof, together with at least one species selected from the group consisting of disaccharides, polyhydric alcohols and cellulose, has good content uniformity.

[0140] [Manufacturing Examples 1 to 6] Tablets containing the ingredients and amounts (mg) shown in Table 9 per tablet can be produced by conventional methods.

[0141] [Table 9]

[0142] [Manufacturing Examples 7 to 12] Tablets containing the ingredients and amounts (mg) shown in Tables 10 to 11 per tablet can be produced by a conventional wet granule compression method.

[0143] [Table 10]

[0144] [Table 11]

[0145] [Manufacturing Examples 13 to 18] Tablets containing the ingredients and amounts (mg) shown in Tables 12 and 13 per tablet can be produced by direct powder compression in a conventional manner.

[0146] [Table 12]

[0147] [Table 13]

[0148] [Manufacturing Examples 19-21] Tablets containing the ingredients and amounts (mg) listed in Table 14 per tablet can be produced by a conventional wet granule compression method.

[0149] [Table 14]

[0150] [Manufacturing Examples 22-24] Tablets containing the ingredients and amounts (mg) listed in Table 15 per tablet can be produced by direct powder compression using conventional methods.

[0151] [Table 15]

[0152] [Manufacturing Examples 25-30] Tablets containing the ingredients and amounts (mg) shown in Table 16 per tablet can be produced by conventional methods.

[0153] [Table 16] [Industrial Applicability]

[0154] According to the present invention, a pharmaceutical composition containing pemafibrate, which exhibits effects such as lowering plasma triglyceride levels and increasing HDL cholesterol, and having excellent homogeneity can be provided, and therefore can be used, for example, in the pharmaceutical industry.

Claims

[Claim 1] The invention described in the application.

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