Pharmaceutical composition

Abstract

To provide a pharmaceutical composition that contains pemafibrate or a salt thereof or their solvates, and at least one selected from the group consisting of metal oxides, bivalent alcohols, esters and silicate compounds, and has excellent storage stability.SOLUTION: A pharmaceutical composition contains following components (A) and (B): (A) pemafibrate or a salt thereof or their solvates; and (B) yellow ferric oxide, so that the component (A) and component (B) are not substantially in contact with each other.SELECTED DRAWING: None

Description

Technical Field

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

Background Art

[0002] The following structural formula:

[0003]

Chemical Formula

[0004] Pemafibrate represented by the formula (chemical name: (2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid, international common name: Pemafibrate), or a salt or solvate thereof has excellent PPARα agonist activity, exhibits effects such as a decrease in plasma triglyceride concentration and an increase in HDL cholesterol, and is useful for the prevention and treatment of dyslipidemia (hyperlipidemia) (Patent Document 1, Non-Patent Documents 1, 2), and is known to be useful for the prevention and treatment of NAFLD (non-alcoholic fatty liver disease) (Patent Document 2).

[0005] By the way, a compound useful as an active ingredient of a pharmaceutical is usually formulated and administered as some kind of pharmaceutical composition, and it is not uncommon for a long period of time to elapse from the production of the pharmaceutical composition to its administration. Therefore, from the viewpoints of exerting the expected medicinal effects and avoiding unexpected side effects, it is extremely important to ensure the storage stability of the active ingredient in the pharmaceutical composition.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

[0007] [Non-Patent Document 1] Yukiyoshi Yamazaki, et al., Synthesis, 2008(7), 1017-1022. [Non-Patent Document 2] Fruchart JC., Cardiovasc Diabetol., 2013; 12: 82. [Summary of the Invention] [Problems to be Solved by the Invention]

[0008] However, the storage stability of an active ingredient is greatly influenced by its physical and chemical properties, and these properties are often not predictable in advance from its chemical structure or the like. In many cases, problems are not discovered until the pharmaceutical composition is actually manufactured. Therefore, it usually requires a great deal of trial and error to establish a technique for ensuring the storage stability of the active ingredient in the pharmaceutical composition. And regarding pemafibrate or its salt or their solvates, only reports have been made that they exhibit the above-described pharmacological effects, and there has been no specific examination so far regarding making them into a pharmaceutical composition, and no reports have been made so far regarding the storage stability in the pharmaceutical composition. However, when the inventor studied the formulation using various formulation additives to develop a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof, it was found that when a pharmaceutical composition prepared by mixing pemafibrate or a salt thereof or a solvate thereof (hereinafter, sometimes simply referred to as "component (A)" in this specification) with any one of the following components 1 to 4 (hereinafter, in this specification, components 1 to 4 are referred to as "component (B-1)", "component (B-2)", "component (B-3)", and "component (B-4)", respectively, and "one or more selected from the group consisting of component (B-1), component (B-2), component (B-3), and component (B-4)" may also be referred to as "component (B)"): 1. Metal oxides typified by titanium oxide, yellow ferric oxide, and ferric oxide 2. Dihydric alcohols typified by macrogol 3. Esters typified by triethyl citrate 4. Silicate compounds typified by light anhydrous silicic acid

[0009] When the pharmaceutical composition thus prepared was stored, unexpectedly, an interaction occurred between component (A) and component (B), and it was found that there was a problem with storage stability in that the decomposition products (analogous substances) of pemafibrate increased. Therefore, an object of the present invention is to provide a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof and one or more selected from the group consisting of metal oxides, dihydric alcohols, esters, and silicate compounds and having excellent storage stability.

Means for Solving the Problems

[0010] Therefore, the present inventors further intensively studied to solve the problem of storage stability due to the interaction between pemafibrate or its salt or their solvates and the above-described components 1 to 4. As a result, it was found that physical contact between pemafibrate or its salt or their solvates and the above-described components 1 to 4 was the cause of the interaction, and by including both components in a pharmaceutical composition so that pemafibrate or its salt or their solvates and the above-described components 1 to 4 hardly came into direct contact with each other, an increase in the degradation products of pemafibrate was suppressed and excellent storage stability was obtained, and the present invention was completed.

[0011] That is, the present invention provides the following components (A) and (B): (A) Pemafibrate or its salt or their solvates; (B) One or more selected from the group consisting of the following components (B-1) to (B-4); (B-1) Metal oxides (B-2) Dihydric alcohols (B-3) Esters (B-4) Silicate compounds and provides a pharmaceutical composition containing the components (A) and (B) such that the components (A) and (B) are not substantially in contact with each other.

[0012] Further, the present invention provides the following components (A) and (B): (A) Pemafibrate or its salt or their solvates; (B) One or more selected from the group consisting of the following components (B-1) to (B-4); (B-1) Metal oxides (B-2) Dihydric alcohols (B-3) Esters (B-4) Silicate compounds and provides a method for stabilizing pemafibrate or its salt or their solvates in a pharmaceutical composition, which method includes a step of containing the components (A) and (B) such that the components (A) and (B) are not substantially in contact with each other. [[Effect of the Invention]]

[0013] According to the present invention, it is possible to provide a pharmaceutical composition in which an increase in the degradation product of pemafibrate is suppressed and which has excellent storage stability.

Embodiments for Carrying Out the Invention

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

[0015] Pemafibrate or a salt thereof or a solvate thereof is a known compound and can be produced, for example, by the method disclosed in Patent Document 1, Non-Patent Document 1, or U.S. Patent No. 7,109,226. In the present invention, it is preferable to use crystals of pemafibrate (preferably crystals having a melting point of 95 to 101°C, particularly preferably 97 to 100°C when measured according to the first method of the melting point measurement method in the Japanese Pharmacopoeia, 17th Edition) which can be produced 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 is not particularly limited and can be appropriately determined in consideration of the type of the preparation, the sex, age, symptoms, etc. of the user. For example, it can contain an amount such that 0.05 to 0.8 mg, more preferably 0.075 to 0.6 mg, particularly preferably 0.1 to 0.4 mg of pemafibrate or a salt thereof or a solvate thereof is taken per day in terms of the free form of pemafibrate.

[0017] The content of pemafibrate or a salt thereof or a solvate thereof in the pharmaceutical composition is preferably 0.001 to 60% by mass, more preferably 0.005 to 25% by mass, still more preferably 0.01 to 10% by mass, still more preferably 0.05 to 5% by mass, particularly preferably 0.05 to 0.5% by mass in terms of the free form of pemafibrate with respect to the total mass of the pharmaceutical composition.

[0018] <Metal oxide (Component (B-1))> In the present specification, the "metal oxide" means an oxide of a metal such as a representative metal or a transition metal, and the type of the metal is not particularly limited. Examples of such a metal include metals of Group 2 elements (such as magnesium and calcium), transition metals (such as titanium and iron), metals of Group 12 elements (such as zinc), and metals of Group 13 elements (such as aluminum). Among these, oxides of metals selected from metals of Group 2 elements and transition metals are preferable, and oxides of metals selected from magnesium, titanium, and iron are more preferable. Examples of such metal oxides include, specifically, iron oxides such as yellow iron oxide, iron(III) oxide, yellow iron(III) oxide, brown iron oxide, and black iron oxide; synthetic hydrotalcite; zinc oxide; aluminum oxide; calcium oxide; titanium oxide; magnesium oxide, etc. One of these may be used alone or two or more thereof may be used in combination. Among these, yellow iron oxide, iron(III) oxide, yellow iron(III) oxide, brown iron oxide, black iron oxide, synthetic hydrotalcite, titanium oxide, and magnesium oxide are preferred, yellow iron oxide, iron(III) oxide, yellow iron(III) oxide, brown iron oxide, black iron oxide, titanium oxide, and magnesium oxide are more preferred, and iron(III) oxide, yellow iron(III) oxide, and titanium oxide are particularly preferred. All of these metal oxides are known components and may be produced by known methods or commercially available products may be used. Examples of such commercially available products include, for example, apatite (Fuji Chemical Industry Co., Ltd.), alkamac (Kyowa Chemical Industry Co., Ltd.), synthetic hydrotalcite (Tomita Pharmaceutical Co., Ltd.), magnesium oxide (Tomita Pharmaceutical Co., Ltd.), yellow iron(III) oxide (San-Ei Gen F.F.I., Inc.), black iron oxide (San-Ei Gen F.F.I., Inc.), titanium oxide (Toho Titanium Co., Ltd.), iron(III) oxide (San-Ei Gen F.F.I., Inc.), etc.

[0019] The content of the metal oxide in the pharmaceutical composition is not particularly limited and can be appropriately determined in consideration of the type of formulation, the gender, age, symptoms, etc. of the user. However, the total amount of the metal oxide relative to the total mass of the pharmaceutical composition is preferably 0.0001 to 95% by mass, more preferably 0.001 to 60% by mass, still more preferably 0.005 to 3% by mass, still more preferably 0.01 to 2% by mass, and particularly preferably 0.1 to 1% by mass.

[0020] The content mass ratio of pemafibrate or its salt or their solvates and the metal oxide in the pharmaceutical composition is not particularly limited, but it is preferably that the total amount of the metal oxide is 0.01 to 30 parts by mass, more preferably 0.05 to 20 parts by mass, and particularly preferably 0.1 to 10 parts by mass with respect to 1 part by mass in terms of the free form of pemafibrate.

[0021] <Dihydric alcohol (Component (B-2))> As used herein, the term "dihydric alcohol" means a compound having two alcoholic hydroxyl groups, which may be either a non-polymer or a polymer. Specific examples of such dihydric alcohols include alkylene glycols such as ethylene glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, 1,3-butanediol; diethylene glycol, dipropylene glycol, macrogol (for example, macrogol 100, macrogol 200, macrogol 300, macrogol 400, macrogol 600, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, polyethylene glycol 8000, macrogol 20000, macrogol 35000, etc. are exemplified), polypropylene glycol (for example, polypropylene glycol 2000, etc. are exemplified), polyoxyethylene polyoxypropylene glycol (for example, polyoxyethylene(3) polyoxypropylene(17) glycol, polyoxyethylene(20) polyoxypropylene(20) glycol, polyoxyethylene(42) polyoxypropylene(67) glycol, polyoxyethylene(54) polyoxypropylene(39) glycol, polyoxyethylene(105) polyoxypropylene(5) glycol, polyoxyethylene(120) polyoxypropylene(40) glycol, polyoxyethylene(124) polyoxypropylene(39) glycol, polyoxyethylene(160) polyoxypropylene(30) glycol, polyoxyethylene(196) polyoxypropylene(67) glycol, polyoxyethylene(200) polyoxypropylene(70) glycol, etc. are exemplified). Such polyalkylene glycols are included, and one of these may be used alone or two or more thereof may be used in combination.

[0022] As the dihydric alcohol, polyalkylene glycols are preferred, macrogols are more preferred, and one or more selected from 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, and macrogol 6000 is particularly preferred. Further, macrogols having an average molecular weight of 100 to 20000 are preferred, macrogols having an average molecular weight of 200 to 10000 are more preferred, and macrogols having an average molecular weight of 300 to 8000 are particularly preferred. The average molecular weight of macrogol can be measured by the "average molecular weight test" described in the section of "Macrogol 400" in the "Japanese Pharmacopoeia, Seventeenth Revision, Articles on Pharmaceuticals". In addition, all of these dihydric alcohols are known components and may be produced by known methods or commercial products may be used. Examples of such commercial products include Colysorb PG (BASF Japan Ltd.), diethylene glycol (Nippon Shokubai Co., Ltd.), Unisafe DPG-R (Nippon Oil Co., Ltd.), Macrogol 200 (Sanyo Chemical Industries, Ltd.), Colysorb PEG300 (BASF Japan Ltd.), Super Refined PEG400 (Croda Japan Ltd.), Carbowax Sentry PEG600 (Dow Chemical Japan Ltd.), Macrogol 1000 (Nippon Oil Co., Ltd.), Macrogol 1500 (Sanyo Chemical Industries, Ltd.), Carbowax Sentry PEG1540 (Dow Chemical Japan Ltd.), Macrogol 4000 (Sanyo Chemical Industries, Ltd.), Macrogol 6000 (Sanyo Chemical Industries, Ltd.), Macrogol 20000 (Sanyo Chemical Industries, Ltd.), Newpol PP-2000 (Sanyo Chemical Industries, Ltd.), Pronon 101P (Nippon Oil Co., Ltd.), Colysorb P124 (BASF Japan Ltd.), Pronon 403P (Nippon Oil Co., Ltd.), Newdet PE-85 (Sanyo Chemical Industries, Ltd.), PEP-101 (Floyd Industries Co., Ltd.), Colyphore P188 (BASF Japan Ltd.), Colyphore P407 Micro (BASF Japan Ltd.), Unilube DP-950B (Nippon Oil Co., Ltd.), and the like.

[0023] The content of the dihydric alcohol in the pharmaceutical composition is not particularly limited and can be appropriately determined in consideration of the type of preparation, the gender, age, symptoms, etc. of the user. However, as the total amount of the dihydric alcohol relative to the total mass of the pharmaceutical composition, it is preferably 0.005 to 95% by mass, more preferably 0.01 to 60% by mass, still more preferably 0.01 to 5% by mass, even more preferably 0.05 to 3% by mass, and particularly preferably 0.1 to 1% by mass.

[0024] The content mass ratio of pemafibrate or its salt or their solvates and the dihydric alcohol in the pharmaceutical composition is not particularly limited. However, it is preferably that the total amount of the dihydric alcohol is 0.1 to 30 parts by mass, more preferably 0.5 to 20 parts by mass, and particularly preferably 1 to 10 parts by mass with respect to 1 part by mass in terms of the free form of pemafibrate.

[0025] <Esters (Component (B-3))> In this specification, "esters" means a compound having one or more (preferably 1 to 4, more preferably 2 to 4, particularly preferably 3 to 4) ester bonds in the molecule. Further, the carboxylic acid and alcohol forming the ester bond are not particularly limited, and examples of the esters include esters of monocarboxylic acids such as acetic acid, butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, sesquioleic acid, and polycarboxylic acids such as citric acid and phthalic acid, and monohydric alcohols such as ethanol, butanol, and tocopherol, and polyhydric alcohols such as glycerin, polyglycerin, propylene glycol, sorbitol, sorbitan, and sucrose. Examples of esters specifically include, for example, sorbitan fatty acid esters, sorbitan sesquioleate, glycerin fatty acid esters, medium-chain fatty acid triglycerides, diethyl phthalate, dibutyl phthalate, butyl phthalyl butyl glycolate, sucrose fatty acid esters, propylene glycol fatty acid esters, dioctyl sodium sulfosuccinate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, tributyl citrate, triacetin, tocopherol acetate, polyoxyethylene hydrogenated castor oil (such as polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, etc.), polyoxyethylene sorbitan fatty acid esters (such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, etc.), aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, polyvinyl acetal diethylaminoacetate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, sodium stearyl fumarate, etc. One of these may be used alone or two or more thereof may be used in combination.

[0026] As esters, compounds having 2 to 4 ester bonds in the molecule are preferred. Diesters or triesters of polycarboxylic acids selected from citric acid and phthalic acid and alcohols (preferably monohydric alcohols), tetraesters having citric acid residues (citric acid alkanoyl trialkyls), triesters of glycerin and carboxylic acids (preferably monocarboxylic acids) are more preferred. Triesters of citric acid and alcohols, tetraesters having citric acid residues, triesters of glycerin and carboxylic acids are even more preferred. Acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, tributyl citrate, triacetin are even more preferred. Triethyl citrate and triacetin are particularly preferred.

[0027] Incidentally, all of these esters are known components, and they may be produced by known methods or commercially available products may be used.Examples of such commercially available products include Food Additive Nonion PP-40R (Nippon Oil Co., Ltd.), Food Additive Nonion SP-60R (Nippon Oil Co., Ltd.), Food Additive Nonion SP-60RP (Nippon Oil Co., Ltd.), Food Additive Nonion OP-80R (Nippon Oil Co., Ltd.), Food Additive Nonion CP-08R (Nippon Oil Co., Ltd.), NIKKOL AO-5MV (Nikko Chemicals Co., Ltd.), POEM B-100 (Riken Vitamin Co., Ltd.), POEM HB (Riken Vitamin Co., Ltd.), POEM J-0381V (Riken Vitamin Co., Ltd.), POEM J-2081 (Riken Vitamin Co., Ltd.), POEM TR-FB (Riken Vitamin Co., Ltd.), POEM W-10 (Riken Vitamin Co., Ltd.), POEM W-60 (Riken Vitamin Co., Ltd.), Pharmaceutical Additive Kosei Panacet 800 (Nippon Oil Co., Ltd.), Pharmaceutical Additive Kosei Panacet 810 (Nippon Oil Co., Ltd.), Pharmaceutical Additive Kosei Panacet 810S (Nippon Oil Co., Ltd.), DK Ester F-160 (Daiichi Kogyo Seiyaku Co., Ltd.), DK Ester F-140 (Daiichi Kogyo Seiyaku Co., Ltd.), DK Ester F-110 (Daiichi Kogyo Seiyaku Co., Ltd.), DK Ester F-90 (Daiichi Kogyo Seiyaku Co., Ltd.), DK Ester F-70 (Daiichi Kogyo Seiyaku Co., Ltd.), DK Ester F-50 (Daiichi Kogyo Seiyaku Co., Ltd.), DK Ester F-20W (Daiichi Kogyo Seiyaku Co., Ltd.), DK Ester F-10 (Daiichi Kogyo Seiyaku Co., Ltd.), DK Ester FA-10E (Daiichi Kogyo Seiyaku Co., Ltd.), NIKKOL Sefsol-218 (Nikko Chemicals Co., Ltd.), NIKKOL Sefsol-228 (Nikko Chemicals Co., Ltd.), Citroflec 2 (SC-60) (San-Ei Gen F.F.I., Inc.), Triacetin (Yuki Gosei Yakuhin Kogyo Co., Ltd.), Rapisol (Nippon Oil Co., Ltd.), NIKKOL HCO-40 (Nikko Chemicals Co., Ltd.), NIKKOL HCO-60 (Nikko Chemicals Co., Ltd.), NIKKOL TL-10 (Nikko Chemicals Co., Ltd.), NIKKOL TP-10EX (Nikko Chemicals Co., Ltd.), NIKKOL TS-10MV (Nikko Chemicals Co., Ltd.), NIKKOL TO-10MV (Nikko Chemicals Co., Ltd.), Eudragit E100 (Higuchi Shokai Co., Ltd.), Eudragit RL100 (Higuchi Shokai Co., Ltd.), AEA "Sankyo" (Sankyo Lifetech Co., Ltd.), HPMCP (Shin-Etsu Chemical Co., Ltd.), Shin-Etsu AQOAT (Shin-Etsu Chemical Co., Ltd.), Pluuv (Kimura Sangyo Co., Ltd.), etc.

[0028] The content of esters in the pharmaceutical composition is not particularly limited and can be appropriately determined in consideration of the type of preparation, the gender, age, symptoms, etc. of the user. However, as the total amount of esters relative to the total mass of the pharmaceutical composition, it is preferably 0.005 to 60% by mass, more preferably 0.01 to 5% by mass, still more preferably 0.05 to 3% by mass, and particularly preferably 0.1 to 1% by mass.

[0029] The content mass ratio of pemafibrate or its salt or their solvates and esters in the pharmaceutical composition is not particularly limited. However, it is preferably that the total amount of esters is 0.01 to 30 parts by mass, more preferably 0.05 to 20 parts by mass, and particularly preferably 0.1 to 10 parts by mass with respect to 1 part by mass in terms of the free form of pemafibrate.

[0030] <Silicic acid compound (Component (B-4))> In this specification, the "silicic acid compound" includes not only the silicic acid compound itself but also salts of the silicic acid compound. Examples of salts of the silicic acid compound include inorganic salts. Specifically, for example, alkali metal salts such as sodium salts and potassium salts; salts with metals of Group 2 elements such as magnesium salts and calcium salts; salts with metals of Group 13 elements such as aluminum salts, etc. Specific examples of such silicic acid compounds include hydrous silicic acid compounds or their salts such as hydrous silicon dioxide, hydrous amorphous silicon oxide, hydrous magnesium silicate, hydrous magnesium silicate (natural), etc.; anhydrous silicic acids or their salts such as light anhydrous silicic acid and heavy anhydrous silicic acid; silicic acids or their salts such as silicon dioxide, natural aluminum silicate, synthetic aluminum silicate, synthetic sodium magnesium silicate, calcium silicate, magnesium silicate, magnesium aluminum silicate, magnesium aluminosilicate metasilicate, etc. In addition, diatomaceous earth, bentonite, kaolin, talc, etc. may be mentioned. One of these may be used alone or two or more of them may be used in combination. As the silicic acid compound, anhydrous silicic acid or its salt is preferred, and light anhydrous silicic acid is particularly preferred. Incidentally, all of these silicate compounds are known components, and they may be produced by known methods or commercial products may be used. Examples of such commercial products include Noshirin A (Fuji Chemical Industry Co., Ltd.), Florite (Tomita Pharmaceutical Co., Ltd.), Magnesium Silicate (Tomita Pharmaceutical Co., Ltd.), VEEGUMI Granule (Sanyo Chemical Industries, Ltd.), VEEGUMI HV Granule (Sanyo Chemical Industries, Ltd.), VEEGUMI K Granule (Sanyo Chemical Industries, Ltd.), VEEGUMI F (Sanyo Chemical Industries, Ltd.), Silicia 320 (Fuji Silysia Chemical Ltd.), Silicia 350 (Fuji Silysia Chemical Ltd.), Silicia 320TP (Fuji Silysia Chemical Ltd.), Silicia 320FCP (Fuji Silysia Chemical Ltd.), Mycon FR (Tomita Pharmaceutical Co., Ltd.), Silicon Dioxide (Nippon Aerosil Co., Ltd.), Adsorider 101 (Floyd Industries Co., Ltd.), Adsorider 102 (Floyd Industries Co., Ltd.), Silicia (Fuji Silysia Chemical Ltd.), Silosphere (Fuji Silysia Chemical Ltd.), Hydrous Amorphous Silicon Oxide (Tosoh Silica Corporation), Noshirin (Fuji Chemical Industry Co., Ltd.), Diatomaceous Earth (Showa Chemical Industry Co., Ltd.), Talc (Mitsubishi Chemical Foods Co., Ltd.), and the like.

[0031] The content of the silicate compound in the pharmaceutical composition is not particularly limited and can be appropriately determined in consideration of the type of formulation, the gender, age, symptoms, etc. of the user. However, the total amount of the silicate compound is preferably 0.001 to 95% by mass, more preferably 0.005 to 60% by mass, still more preferably 0.01 to 5% by mass, even more preferably 0.05 to 3% by mass, and particularly preferably 0.1 to 1% by mass, based on the total mass of the pharmaceutical composition.

[0032] The content mass ratio of pemafibrate or its salt or their solvates and the silicate compound in the pharmaceutical composition is not particularly limited. However, it is preferably that the total amount of the silicate compound is 0.01 to 30 parts by mass, more preferably 0.05 to 20 parts by mass, and particularly preferably 0.1 to 10 parts by mass, per 1 part by mass of the free form of pemafibrate.

[0033] In addition, the total content of component (B) in the pharmaceutical composition is not particularly limited and can be appropriately determined according to the type of preparation, the gender, age, symptoms, etc. of the user. However, it is preferably 0.01 to 95% by mass, more preferably 0.05 to 60% by mass, still more preferably 0.1 to 10% by mass, and particularly preferably 0.5 to 5% by mass based on the total mass of the pharmaceutical composition.

[0034] The content mass ratio of pemafibrate or its salt or their solvates to the whole of component (B) in the pharmaceutical composition is not particularly limited, but it is preferably that the total of component (B) is contained in an amount of 0.005 to 15 parts by mass, more preferably 0.01 to 10 parts by mass, still more preferably 0.05 to 5 parts by mass, and particularly preferably 0.1 to 2 parts by mass per 1 part by mass in terms of the free form of pemafibrate.

[0035] In the present specification, "containing so as not to substantially contact each other" for component (A) and component (B) means a mode in which component (A) and component (B) are contained in the same pharmaceutical composition while avoiding or suppressing contact to such an extent that the interaction is not substantially a problem. Therefore, as long as the interaction is not substantially a problem, a mode in which pemafibrate and component (B) are in contact or in the vicinity is also allowed. Here, specific modes for "containing so as not to substantially contact each other" include, for example, in addition to component (A) and component (B) in the pharmaceutical composition, further allowing other components (such as pharmaceutical additives) to coexist, and by the presence of such other components, preventing the contact between component (A) and component (B) to such an extent that the interaction is not substantially a problem (for example, by arranging the other component on the surface of component (A) and / or component (B) to prevent the contact between component (A) and component (B) to such an extent that the interaction is not substantially a problem, etc.).

[0036] In addition, in the pharmaceutical composition of the present invention, any one of the components selected from component (B-1), component (B-2), component (B-3) and component (B-4) may be contained as component (B) so as not to substantially contact component (A). However, from the viewpoint of suppressing the increase in the degradation products of pemafibrate, an embodiment in which all types of component (B) formulated in the pharmaceutical composition are contained so as not to substantially contact component (A) is particularly preferred. Further, as shown in the test examples described later, in particular, in view of the significant increase in the degradation products of pemafibrate when mixed with component (B-1), component (B-2), and component (B-3), from the viewpoint of suppressing the increase in the degradation products of pemafibrate, an embodiment in which component (A) and one or more selected from component (B-1), component (B-2), and component (B-3) are contained so as not to substantially contact each other is preferred. In particular, among these embodiments, an embodiment in which all of one or more selected from component (B-1), component (B-2), and component (B-3) contained in the pharmaceutical composition are contained so as not to substantially contact component (A) is preferred.

[0037] In this specification, the dosage form of the "pharmaceutical composition" is not particularly limited and may be any of solid, semi-solid, or liquid preparations, which can be selected according to the purpose of use and the like. Examples of the dosage form of the pharmaceutical composition include those described in the General Rules of Preparations of the Japanese Pharmacopoeia, 17th Edition. Specifically, for example, dosage forms for oral administration include solid preparations such as tablets (including, for example, ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, etc.), capsules, granules (including, for example, effervescent granules, etc.), powders, pills, etc.; semi-solid preparations such as oral jellies; and liquid preparations such as oral liquids (including, for example, elixirs, suspensions, emulsions, lemonade preparations, etc.). In addition, dosage forms for parenteral administration include injections, inhalants, eye drops, ear drops, nasal drops, suppositories, external solid preparations, external liquid preparations, sprays, ointments, creams, gels, patches, etc.

[0038] As the dosage form of the pharmaceutical composition, from the viewpoints of ease of administration and ease of production, a solid preparation is preferably used, and solid preparations selected from tablets (including, for example, ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, etc.), capsules, granules (including, for example, effervescent granules, etc.), powders and pills are particularly preferred. When the pharmaceutical composition is a solid preparation, since the movement (flow) of component (A) and component (B) in the pharmaceutical composition is restricted, it becomes easier to contain both components "so as not to substantially contact each other".

[0039] Specific examples of the above solid preparations include, for example, (I) Component (A) itself or a solid composition containing component (A) (hereinafter, such a solid composition will be referred to as the "solid composition of (I)"). and (II) component (B) itself or a solid composition containing component (B) (hereinafter, such a solid composition will be referred to as the "solid composition of (II)"), and a solid preparation in which component (A) and component (B) are arranged so as not to substantially contact each other (however, excluding the case where (I) is component (A) itself and (II) is component (B) itself). That is, it is preferable that either one or both of component (A) and component (B) are in the form of a solid composition, and component (A) and component (B) are arranged so as not to substantially contact each other.

[0040] In such an embodiment, the contact between component (A) and component (B) is prevented by the components (other components (formulation additives, etc.) other than component (A) and component (B)) constituting the solid composition of (I) and / or (II). In such an embodiment, the form of the solid composition is not particularly limited, and examples thereof include powdery (for example, those obtained by coating other components on crushed component (A) or component (B)); granular (for example, those obtained by granulating component (A) or component (B) together with other components); tablet-like (for example, those obtained by tableting component (A) or component (B) together with other components), etc. The size of the solid composition is not particularly limited.

[0041] Here, the content of the solid composition (I) is not particularly limited, but is preferably 15 to 99% by mass, more preferably 90 to 99% by mass, and particularly preferably 94 to 98% by mass based on the total mass of the solid preparation. In the solid composition (I), the total content of component (A) is not particularly limited, but is preferably 0.001 to 10% by mass, more preferably 0.01 to 7% by mass, and particularly preferably 0.05 to 5% by mass based on the total mass of the solid composition (I). Also, the content of the solid composition (II) is not particularly limited, but is preferably 1 to 85% by mass, more preferably 1 to 10% by mass, and particularly preferably 2 to 6% by mass based on the total mass of the solid preparation. In the solid composition (II), the total content of component (B) is not particularly limited, but is preferably 0.1 to 70% by mass, more preferably 1 to 60% by mass, and particularly preferably 5 to 50% by mass based on the total mass of the solid composition (II). When the solid composition (II) contains component (B-1), the total content of component (B-1) is not particularly limited, but is preferably 0.05 to 60% by mass, more preferably 0.5 to 50% by mass, and particularly preferably 5 to 40% by mass based on the total mass of the solid composition (II). When the solid composition (II) contains component (B-2), the total content of component (B-2) is not particularly limited, but is preferably 0.1 to 30% by mass, more preferably 0.5 to 20% by mass, and particularly preferably 1 to 15% by mass based on the total mass of the solid composition (II). When the solid composition (II) contains component (B-3), the total content of component (B-3) is not particularly limited, but is preferably 0.1 to 40% by mass, more preferably 1 to 30% by mass, and particularly preferably 2 to 20% by mass based on the total mass of the solid composition (II). When the solid composition (II) contains component (B-4), the total content of component (B-4) is not particularly limited, but is preferably 0.1 to 50% by mass, more preferably 1 to 40% by mass, and particularly preferably 3 to 35% by mass based on the total mass of the solid composition (II).

[0042] As specific forms of the solid preparation in the above-described mode, for example, the following modes <1> to <8> etc. can be exemplified, and these can be produced and formulated using formulation additives etc. as appropriate by known methods, for example, the known methods described in the General Rules of Preparations of the Seventeenth Revised Japanese Pharmacopoeia.

[0043] <1> Either one of component (A) and component (B) is granulated with an appropriate component by an appropriate method to form a powder or granule, and the other is blended without granulation to produce a powder, granule, etc., and a solid preparation obtained by further coating these agents by an appropriate method. <2> Component (A) and component (B) are each granulated separately with an appropriate component by an appropriate method to form a powder or granule, and these are blended to produce a powder, granule, etc., and a solid preparation obtained by further coating these agents by an appropriate method. <3> A powder, granule, etc. produced by the method of <1> to <2> above and a solid preparation obtained by further coating these agents by an appropriate method are filled into a capsule to form a capsule agent. <4> A tablet obtained by tableting a powder or granule produced by the method of <1> above and the other non-granulated material by an appropriate method, and a solid preparation obtained by further coating the tablet by an appropriate method (such as a sugar-coated tablet or a film-coated tablet), or a tablet obtained by tableting a powder or granule produced by the method of <2> above by an appropriate method, and a solid preparation obtained by further coating the tablet by an appropriate method (such as a sugar-coated tablet or a film-coated tablet). Note that tableting can also be achieved by forming into a certain shape by an appropriate method in addition to the compression method. <5> A multilayer tablet produced by positioning component (A) and component (B) in mutually different layers so that component (A) and component (B) do not substantially contact each other, and a solid preparation obtained by further coating the multilayer tablet by an appropriate method (such as a sugar-coated tablet or a film-coated tablet). As the multilayer tablet, a multilayer tablet of three or more layers is preferred, in which a layer containing component (A) and a layer containing component (B) are positioned so as not to contact each other. Note that as component (A) and component (B), powders, granules, etc. produced by <1> to <2> above can be used. <6> A nucleated tablet in which either component (A) or component (B) is disposed in a core tablet (also referred to as a core tablet or a nucleus tablet), and the components (A) and (B) are included so as not to substantially contact each other, and a solid preparation (such as a sugar-coated tablet or a film-coated tablet) obtained by further coating the nucleated tablet by an appropriate method. Note that, as the components (A) and (B), the powdery substances, granular substances, etc. produced by the above <1> to <2> can be used. <7> Instead of the powdery substances, granular substances, etc. produced by the methods of the above <1> to <2>, a solid preparation produced by the method described in <1> to <4> or <6> using an inclusion compound in which either one or both of the components (A) and (B) are included with cyclodextrins such as α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. <8> A solid preparation in which either component (A) or component (B) is contained in a preparation produced by a normal method, and a sugar-coated layer or a film-coated layer is provided, and the other is contained in the sugar-coated layer or the coating layer so that the components (A) and (B) do not substantially contact each other (when the dosage form is a tablet, it is a sugar-coated tablet, a film-coated tablet, etc.).

[0044] The powdery substances and granular substances in the above <1> and <2> etc. may be appropriately produced using pharmaceutical additives by known dry or wet granulation methods such as extrusion granulation, tumbling granulation, stirring granulation, fluidized bed granulation, spray drying granulation, grinding granulation, and melt granulation. Note that the powdery substances and granular substances containing component (A) and the powdery substances and granular substances containing component (B) may both be produced by the same granulation method or may be produced by different granulation methods.

[0045] From the viewpoints of suppressing interaction and ease of production, as the pharmaceutical composition, the solid preparation of the above aspect <8> is preferable. It contains pemafibrate or its salt or their solvates in a preparation produced by a conventional method, and is a solid preparation provided with a layer (sugar coating layer or film coating layer) on its surface, and a solid preparation containing component (B) in the layer is more preferable. A film-coated tablet containing pemafibrate or its salt or their solvates in the core tablet and containing component (B) in the film coating layer is particularly preferable.

[0046] The pharmaceutical composition of the present invention can be produced by a known method according to its dosage form. For example, when the pharmaceutical composition is a solid preparation, it can be produced by appropriately combining unit operations such as pulverization, mixing, granulation, drying, sizing, classification, filling, tableting, and coating. More specifically, for example, when the dosage form of the pharmaceutical composition is a granular preparation such as granules, powders, or pills, pharmaceutical additives such as excipients, binders, disintegrants, and lubricants are used as necessary, and these components are mixed. After that, granulation is carried out by a known granulation method such as extrusion granulation, rolling granulation, stirring granulation, fluidized bed granulation, spray granulation, melt granulation, or crushing granulation to obtain a granulated product, and further classification, sizing, etc. are carried out as necessary to produce it. The obtained granulated product can also be coated with a coating agent or the like by a known method. In addition, when the dosage form of the pharmaceutical composition is a tablet, appropriate pharmaceutical additives such as excipients, binders, disintegrants, and lubricants are used as necessary, and these components are mixed to obtain a mixture, which is directly compressed (tableted) (direct powder compression method), or the above granulated product is classified, sized, etc. as necessary and then compressed (tableted) (semi-dry granule compression method, dry granule compression method, wet granule compression method, etc.) to produce it. The obtained compressed product (tablet) can also be coated with a coating agent or the like by a known method. Furthermore, when the dosage form of the pharmaceutical composition is a capsule, the above granulated product or compressed product may be filled into the capsule.

[0047] For the pharmaceutical composition, pharmaceutically acceptable carriers (formulation additives) may be added according to the dosage form. Such formulation additives include, for example, excipients, disintegrants, binders, lubricants, plasticizers, film-forming agents, poorly water-soluble polymers, antioxidants, flavoring agents, sweetening agents, etc., but are not limited thereto. Specifically, as these formulation additives, those listed in, for example, the Pharmaceutical Additives Dictionary 2016 (published by Yakujutsu Nippo Co., Ltd.), Handbook of Pharmaceutical Excipients, Seventh Edition (published by Pharmaceutical Press), etc. may be used.

[0048] Specific examples of excipients include inorganic excipients such as anhydrous sodium sulfate, anhydrous calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium dihydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, etc.; organic excipients such as starch syrup, starch (wheat starch, corn starch, tapioca starch, pregelatinized starch, etc.), fructose, caramel, agar, xylitol, paraffin, crystalline cellulose, powdered cellulose, sucrose, maltose, lactose, lactose hydrate, granulated sugar, glucose, pullulan, maltitol, reduced maltose syrup, powdered reduced maltose syrup, erythritol, sorbitol, mannitol, lactitol, trehalose, reduced palatinose, maltose, polyvinyl acetal diethylaminoacetate, calcium citrate, etc. These can be used alone or in combination of two or more. The total content of the excipient is not particularly limited, but is preferably 20 to 99% by mass, more preferably 30 to 95% by mass, based on the total mass of the pharmaceutical composition. Also, when the solid composition of (I) and / or (II) contains an excipient, the total content of the excipient is not particularly limited, but is preferably 20 to 99% by mass, more preferably 30 to 95% by mass, based on the total mass of the solid composition.

[0049] Examples of disintegrants specifically include super disintegrants such as sodium carboxymethyl starch, croscarmellose sodium, and crospovidone, as well as carmellose, calcium carmellose, starch, gelatin, sodium hydrogen carbonate, dextrin, dehydroacetic acid and its salts, povidone, and the like. These can be used alone or in combination of two or more. The total content of the disintegrant is not particularly limited, but is preferably 1 to 30% by mass, more preferably 2 to 20% by mass, based on the total mass of the pharmaceutical composition. When the solid composition of (I) and / or (II) contains a disintegrant, the total content of the disintegrant is not particularly limited, but is preferably 1 to 30% by mass, more preferably 2 to 20% by mass, based on the total mass of the solid composition.

[0050] Examples of binders specifically include methylcellulose, hydroxypropylcellulose, hypromellose, sodium carmellose, starch (such as wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), dextrin, pullulan, gum arabic, agar, gelatin, tragacanth, sodium alginate, povidone, polyvinyl alcohol, and the like. These can be used alone or in combination of two or more. The total content of the binder is not particularly limited, but is preferably 1 to 30% by mass, more preferably 2 to 20% by mass, based on the total mass of the pharmaceutical composition. When the solid composition of (I) and / or (II) contains a binder, the total content of the binder is not particularly limited, but is preferably 1 to 30% by mass, more preferably 2 to 20% by mass, based on the total mass of the solid composition.

[0051] Examples of lubricants specifically include calcium stearate, magnesium stearate, and the like. These can be used alone or in combination of two or more. The total content of the lubricant is not particularly limited, but is preferably 0.01 to 15% by mass, more preferably 0.1 to 10% by mass, based on the total mass of the pharmaceutical composition. Also, when the solid composition of (I) and / or (II) contains a lubricant, 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 solid composition.

[0052] Specific examples of the plasticizer include, for example, glycerin, sorbitol, etc. These can be used alone or in combination of two or more.

[0053] Specific examples of the film-forming agent include, for example, alkyl celluloses such as methyl cellulose and ethyl cellulose; alginic acid or its salts such as sodium alginate; carrageenan; carboxyalkyl celluloses such as sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, potassium carboxymethyl cellulose, carboxymethyl cellulose, and carboxymethyl ethyl cellulose; xanthan gum; hydroxyalkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hypromellose (hydroxypropyl methyl cellulose); pullulan; polyvinyl pyrrolidone, etc. A combination of one or more selected from these is preferred. The total content of the film-forming agent is preferably 1 to 10% by mass, more preferably 3 to 5% by mass based on the total mass of the pharmaceutical composition. Also, when the solid composition of (I) and / or (II) contains a film-forming agent, the total content of the film-forming agent is preferably 1 to 10% by mass, more preferably 3 to 5% by mass based on the total mass of the solid composition.

[0054] Specific examples of the poorly water-soluble polymer substance include, for example, carboxyvinyl polymer, etc. These can be used alone or in combination of two or more. As antioxidants, specifically, for example, ascorbic acid, sodium bisulfite, sodium sulfite, sodium edetate, erythorbic acid, dibutylhydroxytoluene, natural vitamin E, tocopherol, butylhydroxyanisole, etc. may be mentioned. These can be used alone or in combination of two or more.

[0055] As flavoring agents, specifically, for example, terpenes such as limonene, pinene, camphene, cymene, cineole, citronellol, geraniol, nerol, linalool, menthol, terpineol, rhodinol, borneol, isoborneol, menthone, camphor, eugenol, cinnzeylanol, etc.; essential oils containing terpenes such as cedarwood oil, orange oil, peppermint oil, camphor white oil, eucalyptus oil, terpin oil, lemon oil, ginger oil, clove oil, cinnamon oil, lavender oil, perilla oil, spearmint oil, etc.; acidulants such as ascorbic acid, tartaric acid, citric acid, malic acid and their salts, etc. may be mentioned. These can be used alone or in combination of two or more.

[0056] As sweetening agents, for example, aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, sodium saccharin, etc. may be mentioned, and one or more of these can be used in combination.

[0057] The diseases to which the pharmaceutical composition of the present invention is applicable are not limited at all, and it can be widely used for the prevention or treatment of diseases for which the administration of pemafibrate is considered effective, which are known at present or will be found in the future. For example, pemafibrate or its salt or their solvates have excellent PPARα agonist activity and have effects such as a decrease in plasma triglyceride concentration and an increase in HDL cholesterol. Therefore, the pharmaceutical composition of the present invention can preferably be used as a preventive and / or therapeutic agent for dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, etc.), and more preferably as a preventive and / or therapeutic agent for hypertriglyceridemia, etc. In addition, pemafibrate or a salt thereof or a solvate thereof is useful for the prevention or treatment of NAFLD (non-alcoholic fatty liver disease). Therefore, the pharmaceutical composition of the present invention can also be used as a preventive and / or therapeutic agent for 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.

[0058] The administration route of the pharmaceutical composition is not particularly limited and can be appropriately determined according to the disease to be applied, the type of formulation, the sex, age, symptoms, etc. of the recipient. However, from the viewpoint of ease of administration, oral administration is preferred. In addition, the pharmaceutical composition can be administered 1 to 4 times a day, before meals, between meals, after meals, before bedtime, etc.

[0059] Note that this specification discloses, but is not limited to, for example, the following aspects. [1-1] The following components (A) and (B): (A) Pemafibrate or a salt thereof or a solvate thereof; (B) One or more selected from the group consisting of the following components (B-1) to (B-4); (B-1) Metal oxide (B-2) Dihydric alcohol (B-3) Esters (B-4) Silicic acid compound A pharmaceutical composition containing the components and containing the component (A) and the component (B) so as not to be substantially in contact with each other. [1-2] The pharmaceutical composition according to [1-1], wherein in addition to the components (A) and (B) in the pharmaceutical composition, other components coexist, and the other components prevent the component (A) and (B) from being substantially in contact with each other. [1-3] The pharmaceutical composition according to [1-1] or [1-2], which is a solid preparation. [1-4] The following (I) and (II): (I) Component (A) itself or a solid composition containing component (A); (II) Component (B) itself, or a solid composition containing component (B); A solid preparation containing the same, in which component (A) and (B) are arranged so as not to be substantially in contact with each other (however, excluding the case where (I) is component (A) itself and (II) is component (B) itself). The pharmaceutical composition according to any one of [1-1] to [1-3].

[0060] [1-5] The pharmaceutical composition according to any one of [1-1] to [1-4], which is in the form of a solid preparation selected from the above aspects <1> to <8>.

[0061] [1-6] A film-coated tablet containing pemafibrate or a salt thereof or a solvate thereof in a core tablet and containing at least one selected from the group consisting of a metal oxide (component (B-1)), a dihydric alcohol (component (B-2)), esters (component (B-3)), and a silicate compound (component (B-4)) in a film coating layer. [1-7] The pharmaceutical composition according to any one of [1-1] to [1-6], wherein component (B-1) is at least one selected from the group consisting of iron oxide yellow, iron sesquioxide, yellow iron sesquioxide, iron oxide brown, iron oxide black, synthetic hydrotalcite, zinc oxide, aluminum oxide, calcium oxide, titanium oxide, and magnesium oxide. [1-8] The pharmaceutical composition according to any one of [1-1] to [1-7], wherein component (B-2) is at least one selected from the group consisting of ethylene glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, 1,3-butanediol, diethylene glycol, dipropylene glycol, macrogol (polyethylene glycol), polypropylene glycol, and polyoxyethylene polyoxypropylene glycol. [1-9] The pharmaceutical composition according to any one of [1-1] to [1-8], wherein component (B-3) is at least one selected from the group consisting of acetyltriethyl citrate, acetyltributyl citrate, triethyl citrate, tributyl citrate, and triacetin. [1-10] The pharmaceutical composition according to any one of [1-1] to [1-9], wherein the component (B-4) is at least one selected from the group consisting of magnesium aluminum silicate, calcium silicate, magnesium silicate, magnesium aluminum silicate, light anhydrous silicic acid and heavy anhydrous silicic acid. [1-11] The pharmaceutical composition according to any one of [1-1] to [1-10], wherein the dosage form is tablets, capsules, granules, powders or pills. [1-12] The pharmaceutical composition according to any one of [1-1] to [1-11], which is a prophylactic and / or therapeutic agent for diseases selected from dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, etc.), NAFLD (more preferably, NASH (non-alcoholic steatohepatitis)), and primary biliary cirrhosis.

[0062] [2-1] The following components (A) and (B-1): (A) Pemafibrate or a salt thereof or a solvate thereof; (B-1) Metal oxide; A pharmaceutical composition containing them and containing component (A) and component (B-1) so as not to be substantially in contact with each other. [2-2] The pharmaceutical composition according to [2-1], wherein in addition to components (A) and (B-1) in the pharmaceutical composition, other components coexist, and these other components prevent components (A) and (B-1) from being substantially in contact with each other. [2-3] The pharmaceutical composition according to [2-1] or [2-2], which is a solid preparation. [2-4] The following (I) and (II): (I) Component (A) itself or a solid composition containing component (A); (II) Component (B-1) itself or a solid composition containing component (B-1); A solid preparation containing them and arranged so that component (A) and (B-1) are not substantially in contact with each other (however, excluding the case where (I) is component (A) itself and (II) is component (B-1) itself). The pharmaceutical composition according to any one of [2-1] to [2-3].

[0063] The pharmaceutical composition according to any one of [2-1] to [2-4], which is in the form of a solid preparation selected from the above-described embodiments <1> to <8> (wherein, "component (B)" is read as "component (B-1)"). [2-6] A film-coated tablet containing pemafibrate or a salt thereof or a solvate thereof in a core tablet and containing a metal oxide (component (B-1)) in a film coating layer.

[0064] [2-7] The pharmaceutical composition according to any one of [2-1] to [2-6], wherein component (B-1) is at least one selected from the group consisting of iron oxide yellow, ferric oxide, yellow ferric oxide, iron oxide brown, iron oxide black, synthetic hydrotalcite, zinc oxide, aluminum oxide, calcium oxide, titanium oxide, and magnesium oxide. [2-8] The pharmaceutical composition according to any one of [2-1] to [2-7], wherein component (B-1) is at least one selected from the group consisting of iron oxide yellow, ferric oxide, yellow ferric oxide, iron oxide brown, iron oxide black, synthetic hydrotalcite, titanium oxide, and magnesium oxide. [2-9] The pharmaceutical composition according to any one of [2-1] to [2-8], wherein component (B-1) is at least one selected from the group consisting of ferric oxide, yellow ferric oxide, and titanium oxide. [2-10] The pharmaceutical composition according to any one of [2-1] to [2-9], wherein the dosage form is a tablet, capsule, granule, powder, or pill. [2-11] A prophylactic and / or therapeutic agent for a disease selected from dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, etc.), NAFLD (more preferably, NASH (non-alcoholic steatohepatitis)), and primary biliary cirrhosis, according to any one of [2-1] to [2-10].

[0065] [3-1] The following components (A) and (B-2): (A) Pemafibrate or a salt thereof or a solvate thereof; (B-2) A dihydric alcohol; A pharmaceutical composition containing the above and containing component (A) and component (B-2) so as not to be substantially in contact with each other. [3-2] The pharmaceutical composition according to [3-1], wherein, in addition to components (A) and (B-2), other components coexist, and these other components prevent components (A) and (B-2) from substantially contacting each other. [3-3] The pharmaceutical composition according to [3-1] or [3-2], which is a solid preparation. [3-4] The following (I) and (II): (I) Component (A) itself or a solid composition containing component (A); (II) Component (B-2) itself or a solid composition containing component (B-2); A solid preparation containing them, in which components (A) and (B-2) are arranged so as not to substantially contact each other (however, the case where (I) is component (A) itself and (II) is component (B-2) itself is excluded). The pharmaceutical composition according to any one of [3-1] to [3-3].

[0066] [3-5] The pharmaceutical composition according to any one of [3-1] to [3-4], which is in the form of a solid preparation selected from the above aspects <1> to <8> (however, "component (B)" is read as "component (B-2)"). [3-6] A film-coated tablet containing pemafibrate or a salt thereof or a solvate thereof in the core tablet and containing a dihydric alcohol (component (B-2)) in the film coating layer.

[0067] [3-7] The pharmaceutical composition according to any one of [3-1] to [3-6], wherein component (B-2) is at least one selected from the group consisting of ethylene glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, 1,3-butanediol, diethylene glycol, dipropylene glycol, macrogol (polyethylene glycol), polypropylene glycol, and polyoxyethylene polyoxypropylene glycol. [3-8] The pharmaceutical composition according to any one of [3-1] to [3-7], wherein component (B-2) is one or more selected from macrogol 100, macrogol 200, macrogol 300, macrogol 400, macrogol 600, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 20000, and macrogol 35000. [3-9] The pharmaceutical composition according to any one of [3-1] to [3-8], wherein component (B-2) is macrogol 6000. [3-10] The pharmaceutical composition according to any one of [3-1] to [3-9], wherein the dosage form is tablets, capsules, granules, powders, or pills. [3-11] The pharmaceutical composition according to any one of [3-1] to [3-10], which is a prophylactic and / or therapeutic agent for diseases selected from dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, etc.), NAFLD (more preferably, NASH (non-alcoholic steatohepatitis)), and primary biliary cirrhosis.

[0068] [4-1] The following components (A) and (B-3): (A) Pemafibrate or a salt thereof or a solvate thereof; (B-3) Esters; A pharmaceutical composition containing them and containing component (A) and component (B-3) so as not to be in substantial contact with each other. [4-2] The pharmaceutical composition according to [4-1], wherein in addition to components (A) and (B-3) in the pharmaceutical composition, other components coexist, and by means of the other components, components (A) and (B-3) are not in substantial contact with each other. [4-3] The pharmaceutical composition according to [4-1] or [4-2], which is a solid preparation. [4-4] The following (I) and (II): (I) Component (A) itself or a solid composition containing component (A); (II) Component (B-3) itself or a solid composition containing component (B-3); A solid preparation containing them, wherein component (A) and component (B-3) are arranged so as not to substantially contact each other (however, the case where (I) is component (A) itself and (II) is component (B-3) itself is excluded). The pharmaceutical composition according to any one of [4-1] to [4-3].

[0069] [4-5] A solid preparation in the form selected from the above aspects <1> to <8> (however, "component (B)" is read as "component (B-3)"). The pharmaceutical composition according to any one of [4-1] to [4-4]. [4-6] A film-coated tablet containing pemafibrate or a salt thereof or a solvate thereof in the core tablet and containing esters (component (B-3)) in the film coating layer.

[0070] [4-7] Component (B-3) is one or more selected from the group consisting of triethyl acetyl citrate, tributyl acetyl citrate, triethyl citrate, tributyl citrate, and triacetin. The pharmaceutical composition according to any one of [4-1] to [4-6]. [4-8] Component (B-3) is one or more selected from the group consisting of triethyl citrate and triacetin. The pharmaceutical composition according to any one of [4-1] to [4-7]. [4-9] Component (B-3) is triethyl citrate. The pharmaceutical composition according to any one of [4-1] to [4-8]. [4-10] The dosage form is a tablet, capsule, granule, powder or pill. The pharmaceutical composition according to any one of [4-1] to [4-9]. [4-11] A prophylactic and / or therapeutic agent for diseases selected from dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, etc.), NAFLD (more preferably, NASH (non-alcoholic steatohepatitis)), and primary biliary cirrhosis. The pharmaceutical composition according to any one of [4-1] to [4-10].

[0071] [5-1] The following components (A) and (B-4): (A) Pemafibrate or a salt thereof or a solvate thereof; (B-4) Silicic acid compound; A pharmaceutical composition containing the same and containing component (A) and component (B-4) so as not to be substantially in contact with each other. [5-2] The pharmaceutical composition according to [5-1], wherein in addition to components (A) and (B-4), other components coexist in the pharmaceutical composition, and the other components prevent components (A) and (B-4) from being substantially in contact with each other. [5-3] The pharmaceutical composition according to [5-1] or [5-2], which is a solid preparation. [5-4] The following (I) and (II): (I) Component (A) itself or a solid composition containing component (A); (II) Component (B-4) itself or a solid composition containing component (B-4); A solid preparation containing the same and arranged so that component (A) and (B-4) are not substantially in contact with each other (however, excluding the case where (I) is component (A) itself and (II) is component (B-4) itself). The pharmaceutical composition according to any one of [5-1] to [5-3].

[0072] [5-5] The pharmaceutical composition according to any one of [5-1] to [5-4], which is in the form of a solid preparation selected from the above aspects <1> to <8> (however, "component (B)" is read as "component (B-4)"). [5-6] A film-coated tablet containing pemafibrate or a salt thereof or a solvate thereof in a core tablet and containing a silicic acid compound (component (B-4)) in a film coating layer.

[0073] [5-7] The pharmaceutical composition according to any one of [5-1] to [5-6], wherein component (B-4) is at least one selected from the group consisting of magnesium aluminosilicate, calcium silicate, magnesium silicate, magnesium aluminum silicate, light anhydrous silicic acid, and heavy anhydrous silicic acid. [5-8] The pharmaceutical composition according to any one of [5-1] to [5-7], wherein component (B-4) is at least one selected from the group consisting of light anhydrous silicic acid and heavy anhydrous silicic acid. The pharmaceutical composition according to any one of [5-1] to [5-8], wherein the component (B-4) is light anhydrous silicic acid. The pharmaceutical composition according to any one of [5-1] to [5-9], wherein the dosage form is tablets, capsules, granules, powders or pills. The pharmaceutical composition according to any one of [5-1] to [5-10], which is a preventive and / or therapeutic agent for diseases selected from dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, etc.), NAFLD (more preferably, NASH (non-alcoholic steatohepatitis)) and primary biliary cirrhosis.

[0074] [6-1] The following components (A) and (B): (A) Pemafibrate or a salt thereof or a solvate thereof; (B) One or more selected from the following components (B-1) to (B-4); (B-1) Metal oxide (B-2) Dihydric alcohol (B-3) Esters (B-4) Silicic acid compound A method for producing a pharmaceutical composition, comprising a step of containing component (A) and component (B) so that they are not substantially in contact with each other. [6-2] The production method according to [6-1], wherein in addition to components (A) and (B) in the pharmaceutical composition, other components coexist, and the other components prevent components (A) and (B) from being substantially in contact with each other. [6-3] The production method according to [6-1] or [6-2], wherein the pharmaceutical composition is a solid preparation. [6-4] The pharmaceutical composition is the following (I) and (II): (I) Component (A) itself or a solid composition containing component (A); (II) Component (B) itself or a solid composition containing component (B); A solid preparation containing them and arranged so that components (A) and (B) are not substantially in contact with each other (however, excluding the case where (I) is component (A) itself and (II) is component (B) itself). The production method according to any one of [6-1] to [6-3].

[0075] [6-5] The manufacturing method according to any one of [6-1] to [6-4], wherein the pharmaceutical composition is in the form of a solid preparation selected from the above-described aspects <1> to <8>. [6-6] The manufacturing method according to any one of [6-1] to [6-5], wherein the pharmaceutical composition contains pemafibrate or a salt thereof or a solvate thereof in a core tablet, and contains at least one selected from the group consisting of a metal oxide (component (B-1)), a dihydric alcohol (component (B-2)), esters (component (B-3)), and a silicic acid compound (component (B-4)) in a film coating layer, and is in the form of a film-coated tablet. [6-7] The manufacturing method according to any one of [6-1] to [6-6], wherein component (B-1) is at least one selected from the group consisting of iron oxide yellow, ferric oxide, yellow ferric oxide, iron oxide brown, iron oxide black, synthetic hydrotalcite, zinc oxide, aluminum oxide, calcium oxide, titanium oxide, and magnesium oxide. [6-8] The manufacturing method according to any one of [6-1] to [6-7], wherein component (B-2) is at least one selected from the group consisting of ethylene glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, 1,3-butanediol, diethylene glycol, dipropylene glycol, macrogol (polyethylene glycol), polypropylene glycol, and polyoxyethylene polyoxypropylene glycol. [6-9] The manufacturing method according to any one of [6-1] to [6-8], wherein component (B-3) is at least one selected from the group consisting of acetyltriethyl citrate, acetyltributyl citrate, triethyl citrate, tributyl citrate, and triacetin. [6-10] The manufacturing method according to any one of [6-1] to [6-9], wherein component (B-4) is at least one selected from the group consisting of magnesium aluminum silicate, calcium silicate, magnesium silicate, magnesium aluminum silicate, light anhydrous silicic acid, and heavy anhydrous silicic acid. [6-11] The manufacturing method according to any one of [6-1] to [6-10], wherein the dosage form of the pharmaceutical composition is a tablet, capsule, granule, powder or pill. [6-12] The manufacturing method according to any one of [6-1] to [6-11], wherein the pharmaceutical composition is a prophylactic and / or therapeutic agent for diseases selected from dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, etc.), NAFLD (more preferably, NASH (non-alcoholic steatohepatitis)) and primary biliary cirrhosis.

[0076] [7-1] The following components (A) and (B): (A) Pemafibrate or a salt thereof or a solvate thereof; (B) One or more selected from the group consisting of the following components (B-1) to (B-4); (B-1) Metal oxide (B-2) Dihydric alcohol (B-3) Esters (B-4) Silicate compounds A method for stabilizing pemafibrate, comprising a step of containing components (A) and (B) so that they do not substantially contact each other. [7-2] The method according to [7-1], wherein in addition to components (A) and (B) in the pharmaceutical composition, other components coexist, and the other components prevent components (A) and (B) from substantially contacting each other. [7-3] The method according to [7-1] or [7-2], wherein the pharmaceutical composition is a solid preparation. [7-4] The pharmaceutical composition is the following (I) and (II): (I) Component (A) itself or a solid composition containing component (A); (II) Component (B) itself or a solid composition containing component (B); A solid preparation containing them and arranged so that components (A) and (B) do not substantially contact each other (however, excluding the case where (I) is component (A) itself and (II) is component (B) itself). The method according to any one of [7-1] to [7-3].

[0077] [7-5] The method according to any one of [7-1] to [7-4], wherein the pharmaceutical composition is in the form of a solid preparation selected from the above-described aspects <1> to <8>. [7-6] The method according to any one of [7-1] to [7-5], wherein the pharmaceutical composition is in the form of a film-coated tablet containing pemafibrate or a salt thereof or a solvate thereof in the core tablet and containing at least one selected from the group consisting of a metal oxide (component (B-1)), a dihydric alcohol (component (B-2)), esters (component (B-3)), and a silicic acid compound (component (B-4)) in the film-coating layer. [7-7] The method according to any one of [7-1] to [7-6], wherein component (B-1) is at least one selected from the group consisting of iron oxide yellow, iron sesquioxide, yellow iron sesquioxide, iron oxide brown, iron oxide black, synthetic hydrotalcite, zinc oxide, aluminum oxide, calcium oxide, titanium oxide, and magnesium oxide. [7-8] The method according to any one of [7-1] to [7-7], wherein component (B-2) is at least one selected from the group consisting of ethylene glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, 1,3-butanediol, diethylene glycol, dipropylene glycol, macrogol (polyethylene glycol), polypropylene glycol, and polyoxyethylene polyoxypropylene glycol. [7-9] The method according to any one of [7-1] to [7-8], wherein component (B-3) is at least one selected from the group consisting of triethyl acetyl citrate, tributyl acetyl citrate, triethyl citrate, tributyl citrate, and triacetin. [7-10] The method according to any one of [7-1] to [7-9], wherein component (B-4) is at least one selected from the group consisting of magnesium aluminum silicate, calcium silicate, magnesium silicate, magnesium aluminum silicate, light anhydrous silicic acid, and heavy anhydrous silicic acid. [7-11] The method according to any one of [7-1] to [7-10], wherein the dosage form of the pharmaceutical composition is a tablet, a capsule, a granule, a powder, or a pill. [7-12] The method according to any one of [7-1] to [7-11], wherein the pharmaceutical composition is a prophylactic and / or therapeutic agent for a disease selected from dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, etc.), NAFLD (more preferably, NASH (non-alcoholic steatohepatitis)), and primary biliary cirrhosis.

Example

[0078] Hereinafter, the present invention will be described more specifically by way of examples, but the present invention is not limited thereto. In the following test examples, the measurement using HPLC was performed using an ODS column as the column and an ultraviolet absorptiometer as the detector, respectively.

[0079] [Test Example 1] Confirmation of the storage stability of pemafibrate 250 mg of pemafibrate was placed in a polypropylene container (an airtight container defined in the General Rules of the Japanese Pharmacopoeia, Seventeenth Revision) and sealed, and stored in the dark at a temperature of 60°C for 1 month. Before the start of storage and after storage at 60°C for 1 month, the amount of degradation products (related substances) derived from pemafibrate was evaluated by the following method. That is, using an HPLC apparatus, the total area of the peaks derived from related substances was evaluated as the ratio (%) to the area of the peak derived from pemafibrate, and this ratio was defined as the "total amount of related substances (%)". The results are shown in Table 1.

[0080]

Table 1

[0081] As shown in Table 1, pemafibrate alone was stable, and no substantial increase in related substances was observed even after storage at 60°C for 1 month.

[0082] [Test Example 2] Examination of interaction 250 mg of each of the samples of Reference Examples 1 to 4 shown below was placed in a polypropylene container (an airtight container as defined in the General Rules of the Japanese Pharmacopoeia, Seventeenth Revision), sealed, and stored in the dark at 60 °C for 1 month.

[0083] <Reference Example 1> 1 part by mass of titanium oxide (Titanium Oxide NA-65: Toho Titanium Co., Ltd.) was mixed with 1 part by mass of pemafibrate to obtain the sample of Reference Example 1. <Reference Example 2> 1 part by mass of macrogol 6000 (Macrogol 6000: NOF Corporation) was mixed with 1 part by mass of pemafibrate to obtain the sample of Reference Example 2. <Reference Example 3> 1 part by mass of triethyl citrate (CitrofleX 2: Morimura & Co., Ltd.) was mixed with 1 part by mass of pemafibrate to obtain the sample of Reference Example 3. <Reference Example 4> 10 parts by mass of light anhydrous silicic acid (Aerosil 300: Nippon Aerosil Co., Ltd.) was mixed with 1 part by mass of pemafibrate to obtain the sample of Reference Example 4.

[0084] Regarding each of the above various samples, the confirmation of the degradation products (related substances) derived from pemafibrate was carried out as follows. That is, regarding Reference Examples 1 to 4, the total amount (%) of related substances derived from pemafibrate before the start of storage and after storage at 60 °C for 1 month was evaluated using an HPLC apparatus by the same method as in Test Example 1. And, from the total amount (%) of related substances derived from pemafibrate before the start of storage and after storage at 60 °C for 1 month obtained for each of Reference Examples 1 to 4, the increase amount (%) of related substances was calculated according to the following formula.

[0085] Increase amount (%) of related substances = (Total amount (%) of related substances derived from pemafibrate after storage at 60 °C for 1 month) - (Total amount (%) of related substances derived from pemafibrate before the start of storage) The results are shown in Table 2.

[0086]

Table 2

[0087] As shown in Table 2, when pemafibrate was mixed with titanium oxide (Reference Example 1), macrogol 6000 (Reference Example 2), triethyl citrate (Reference Example 3), or light anhydrous silicic acid (Reference Example 4) and stored at 60°C for 1 month, an increase in the degradation products (related substances) derived from pemafibrate was confirmed after storage. In particular, in Reference Examples 1 to 3, the degradation products increased significantly. On the other hand, as confirmed in Test Example 1, when pemafibrate was stored alone, no substantial increase in related substances was observed even after storage at 60°C for 1 month. From these results, it was found that contact between pemafibrate or its salt or solvate and one or more selected from metal oxides represented by titanium oxide, dihydric alcohols represented by macrogol 6000, esters represented by triethyl citrate, and silicate compounds represented by light anhydrous silicic acid causes an interaction, resulting in an increase in the degradation products derived from pemafibrate, and when these are formulated into a pharmaceutical composition, problems with storage stability occur.

[0088] [Test Example 3] Examination of Interaction 250 mg of each of the samples of Comparative Example 1 and Reference Examples 5 to 7 shown below were placed in polypropylene containers (hermetic containers defined in the General Rules of the Japanese Pharmacopoeia, Seventeenth Revision) and sealed, and stored in the dark at a temperature of 60°C for 2 weeks. [Comparative Example 1] Pemafibrate was used as the sample of Comparative Example 1. [Reference Example 5] 1 part by mass of macrogol 6000 (Macrogol 6000: NOF Corporation) was mixed with 1 part by mass of pemafibrate to prepare the sample of Reference Example 5. [Reference Example 6] 10 parts by mass of macrogol 400 (Macrogol 400: NOF Corporation) was mixed with 1 part by mass of pemafibrate to prepare the sample of Reference Example 6. [Reference Example 7] Propylene glycol was mixed with 1 part by mass of pemafibrate at a ratio of 10 parts by mass to obtain the sample of Reference Example 7.

[0089] For each of the above various samples, the properties (presence or absence of discoloration) before the start of storage and after storage at 60 °C for 2 weeks were visually confirmed. The results are shown in Table 3.

[0090]

Table 3

[0091] As shown in Table 3, when pemafibrate was stored alone at 60 °C for 2 weeks, no discoloration occurred. In contrast, when mixed with macrogol 6000 (Reference Example 5), macrogol 400 (Reference Example 6), or propylene glycol (Reference Example 7) and stored at 60 °C for 2 weeks, all changed to light yellow or yellow. From this, it was suggested that even when macrogol 6000 was replaced with a dihydric alcohol other than macrogol 6000 such as macrogol 400 or propylene glycol and mixed with pemafibrate, a formulation change occurred in the same manner as when macrogol 6000 was used.

[0092] [Test Example 4] Examination of Interaction Inhibiting Means Based on the results of Test Example 2 and Test Example 3 above, which showed that an interaction occurred upon contact between pemafibrate or a salt thereof or a solvate thereof and one or more selected from metal oxides, dihydric alcohols, esters, and silicate compounds, the present inventor prepared a pharmaceutical composition containing both components so as not to be in substantial contact with each other in order to prevent contact between pemafibrate or a salt thereof or a solvate thereof and one or more selected from metal oxides, dihydric alcohols, esters, and silicate compounds, and conducted the following examinations.

[0093] That is, a solid preparation (film-coated tablet: Example 1) containing pemafibrate in a solid preparation (core tablet) and having a layer (film coating layer) containing titanium oxide, triethyl citrate, and light anhydrous silicic acid on the surface of the solid preparation was manufactured according to the method described below, packaged in a PTP (airtight container defined in the General Rules of the Japanese Pharmacopoeia, 17th Edition), and further packaged in an aluminum bag (airtight container defined in the General Rules of the Japanese Pharmacopoeia, 17th Edition) and stored in a dark place at 60°C for one month.

[0094] <Example 1> 50 parts by mass of pemafibrate, 874 parts by mass of lactose hydrate, 24 parts by mass of croscarmellose sodium, 240 parts by mass of crystalline cellulose, and 12 parts by mass of magnesium stearate were mixed and then compressed into tablets to obtain core tablets containing 5 mg of pemafibrate per tablet (120 mg). Next, 6 parts by mass of titanium oxide (Toho Titanium), 12 parts by mass of triethyl citrate (Morimura Shoji), 46 parts by mass of hypromellose, and 6 parts by mass of light anhydrous silicic acid (Nippon Aerosil) were dissolved and dispersed in purified water to obtain a film coating solution. The film coating solution was coated onto the above core tablets using a ventilated coating machine, and 0.06 parts by mass of carnauba wax was added for polishing to obtain film-coated tablets weighing 127 mg per tablet.

[0095] The film-coated tablets obtained by the above method were examined for the presence of decomposition products (related substances) derived from pemafibrate as described below. That is, the increase (%) in the amount of related substances derived from pemafibrate after storage at 60° C. for one month was evaluated using an HPLC device in the same manner as in Test Example 2. The results are shown in Table 4.

[0096] [Table 4]

[0097] As is clear from Table 4, by incorporating titanium oxide, triethyl citrate, and light anhydrous silicic acid into the film coating layer to prevent contact between these components and pemafibrate (formulated in the core tablets), the interaction was suppressed, and it was confirmed that the increase in related substances was suppressed (Example 1).

[0098] From the results of Test Examples 1 to 4 above, it became clear that a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof and at least one selected from metal oxides, dihydric alcohols, esters, and silicate compounds, substantially without contacting each other, can stabilize pemafibrate.

[0099] [Test Example 5] Examination of Interaction 250 mg of each of the following Comparative Example 2 and Samples of Reference Examples 8 and 9 were placed in polypropylene containers (airtight containers defined in the General Rules of the Japanese Pharmacopoeia, Seventeenth Revision) and sealed, and stored in the dark at a temperature of 80 °C for 17 days. <Comparative Example 2> Pemafibrate was used as the sample of Comparative Example 2. <Reference Example 8> 1 part by mass of pemafibrate was mixed with 10 parts by mass of yellow ferric oxide (yellow ferric oxide: Kisuika Kasei Co., Ltd.) to obtain the sample of Reference Example 8. <Reference Example 9> 1 part by mass of pemafibrate was mixed with 10 parts by mass of ferric oxide (ferric oxide: Kisuika Kasei Co., Ltd.) to obtain the sample of Reference Example 9.

[0100] Regarding the above various samples, the confirmation of decomposition products (related substances) derived from pemafibrate was carried out as follows. That is, for Comparative Example 2, Reference Examples 8 and 9, the total amount (%) of related substances derived from pemafibrate before the start of storage and after storage at 80 °C for 17 days was evaluated using an HPLC apparatus by the same method as in Test Example 1. Then, for each of Comparative Example 2, Reference Examples 8 and 9, the increase amount (%) of related substances was calculated according to the following formula from the total amount (%) of related substances derived from pemafibrate before the start of storage and after storage at 80°C for 17 days.

[0101] Increase amount (%) of related substances = (Total amount (%) of related substances derived from pemafibrate after storage at 80°C for 17 days) - (Total amount (%) of related substances derived from pemafibrate before the start of storage) The results are shown in Table 5.

[0102]

Table 5

[0103] As shown in Table 5, when pemafibrate was mixed with yellow ferric oxide (Reference Example 8) or ferric oxide (Reference Example 9) and stored at 80°C for 17 days, an increase in degradation products (related substances) derived from pemafibrate was confirmed after storage. On the other hand, when pemafibrate was stored alone (Comparative Example 2), no substantial increase in related substances was observed even after storage at 80°C for 17 days. From these results, it was confirmed that when iron oxide was brought into contact with pemafibrate or its salt or their solvates, an interaction occurred in the same manner as when titanium oxide used in Test Example 2 was brought into contact, resulting in an increase in degradation products derived from pemafibrate, and problems with storage stability occurred when these were formulated into a pharmaceutical composition.

[0104] [Test Example 6] Examination of means for suppressing interaction Similar to Test Example 4, in order to prevent contact between pemafibrate or its salt or their solvates and one or more selected from metal oxides, dihydric alcohols, esters, and silicic acid compounds, a pharmaceutical composition containing both components so as not to be substantially in contact with each other was prepared, and the following examinations were conducted.

[0105] That is, a solid preparation (film-coated tablet: Example 2) containing pemafibrate in a solid preparation (core tablet) and having a layer (film coating layer) containing yellow ferric oxide, titanium oxide, triethyl citrate and light anhydrous silicic acid on the surface of the solid preparation was manufactured according to the method described below, packaged in a PTP (airtight container defined in the General Rules of the Japanese Pharmacopoeia, 17th Edition), and further packaged in an aluminum bag (airtight container defined in the General Rules of the Japanese Pharmacopoeia, 17th Edition) and stored in a dark place at a temperature of 50°C for one month.

[0106] <Example 2> Pemafibrate, lactose hydrate, croscarmellose sodium, crystalline cellulose and magnesium stearate were mixed and then compressed into tablets to obtain core tablets each containing 0.2 mg of pemafibrate (120 mg). Next, yellow ferric oxide (Kishi Chemicals), titanium oxide (Toho Titanium), triethyl citrate (Morimura Shoji), hypromellose and light anhydrous silicic acid (Nippon Aerosil) were dissolved and dispersed in purified water to obtain a film coating solution. The film coating solution was coated onto the above core tablets using a ventilated coating machine, and carnauba wax was added for polishing to obtain film-coated tablets weighing 127 mg each.

[0107] The film-coated tablets obtained by the above method were examined for the presence of decomposition products (related substances) derived from pemafibrate as described below. That is, the increase (%) in the amount of related substances derived from pemafibrate after storage at 50° C. for one month was evaluated using an HPLC device in the same manner as in Test Example 2. The results are shown in Table 6.

[0108] [Table 6]

[0109] As is clear from Table 6, by incorporating yellow ferric oxide, titanium oxide, triethyl citrate, and light anhydrous silicic acid into the film coating layer to prevent contact between these components and pemafibrate (incorporated into the core tablets), it was confirmed that the interaction was suppressed and the increase in related substances was suppressed (Example 2).

[0110] From the results of Test Examples 5 and 6 above, it was confirmed that pemafibrate or its salt or their solvates can be stabilized by using a pharmaceutical composition containing pemafibrate or its salt or their solvates and at least one selected from metal oxides, dihydric alcohols, esters, and silicic acid compounds so as not to be in substantial contact with each other.

[0111] [Production Examples 1 to 12] Film-coated tablets of Production Examples 1 to 12 can be produced by laminating a film coating layer containing the components and amounts (mg) shown in Tables 7 to 8 per tablet on the surface of the core tablets produced in Example 1 above by a conventional method.

[0112] [Table 7]

[0113] [Table 8]

[0114] [Production Examples 13 to 18] Orally disintegrating tablets containing the components and amounts (mg) shown in Table 9 per tablet can be produced by a conventional method. That is, in Table 9, components from pemafibrate to aminoalkyl methacrylate copolymer E are used to produce granules by a wet granulation method. The obtained granules and components below titanium oxide in Table 9 are mixed and tabletted to produce orally disintegrating tablets.

[0115] [Table 9]

Industrial Applicability

[0116] According to the present invention, it is possible to provide a pharmaceutical composition containing pemafibrate which exhibits actions such as a decrease in plasma triglyceride concentration and an increase in HDL cholesterol, and which is excellent in storage stability, and thus it can be used, for example, in the pharmaceutical industry and the like.

Claims

1. The following components (A) and (B): (A) pemafibrate or a salt thereof, or a solvate thereof; (B) Yellow ferric oxide and wherein component (A) and component (B) are not substantially in contact with each other.

2. The pharmaceutical composition according to claim 1, which is in the form of tablets, capsules, granules, powders, or pills and contains 0.1 to 20 parts by mass of yellow ferric oxide per 1 part by mass of component (A) calculated as a free form.

3. 3. The pharmaceutical composition according to claim 1, wherein the dosage form is a film-coated tablet.

4. A film-coated tablet containing pemafibrate or a salt thereof or a solvate thereof in the core tablet and yellow ferric oxide in the film coating layer.

5. The following components (A) and (B): (A) pemafibrate or a salt thereof, or a solvate thereof; (B) Yellow ferric oxide A method for stabilizing pemafibrate or a salt thereof, or a solvate thereof in a pharmaceutical composition, comprising the step of incorporating component (A) and component (B) so that they are not substantially in contact with each other, wherein the pharmaceutical composition is a solid formulation.