Pharmaceutical compositions

Abstract

Provided is a pharmaceutical composition comprising pemafibrate, a salt thereof or a solvate thereof and having excellent homogeneity.SOLUTION: A pharmaceutical composition comprising (A) pemafibrate, a salt thereof or a solvate thereof and (B) one or more disaccharides selected from the group consisting of sucrose, maltose, trehalose, sucralose and a solvate thereof, wherein the pharmaceutical composition is a solid preparation.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-benzoxazolidinyl) 2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)pheno (2R)-2-[3-([1,3-Benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino]butanoate ]methyl)phenoxy]butanoic acid), international nonproprietary name: Pemafibrate) or its salts or These solvates have excellent PPARα agonist activity and suppress the plasma triglyceride concentration. It has the effect of lowering cholesterol and increasing HDL cholesterol, and is effective in preventing and treating dyslipidemia (hyperlipidemia). It is useful for the treatment of NAFLD (non-alcoholic fatty liver disease) (Patent Document 1, Non-Patent Documents 1 and 2). It is known to be useful in the prevention and treatment of fatty liver disease (Patent Document 2).

[0005] Meanwhile, compounds useful as active ingredients of pharmaceuticals are usually formulated as some kind of pharmaceutical composition. The drug will be manufactured and supplied, but it will be necessary to ensure that it exerts the expected efficacy and prevents unexpected side effects. In order to avoid this, the pharmaceutical composition to be supplied must be consistent and free from variations between lots, etc. Ensuring quality is extremely important. [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, depends on the physical and chemical properties of the ingredients. The properties of the material are largely dependent on its chemical structure, and these properties cannot be predicted in advance from the chemical structure, etc. In many cases, problems are only discovered after the pharmaceutical composition is actually manufactured. However, establishing a technique to ensure the homogeneity of pharmaceutical compositions usually requires a great deal of trial and error. . As for pemafibrate or its salts or solvates thereof, It has only been reported that it exhibits such pharmacological effects, and there is no information available about its use as a pharmaceutical composition. Regarding the homogeneity of pharmaceutical compositions, there has been no specific study on the manufacturability of the pharmaceutical composition. had never been reported before. Under these circumstances, the use of a compound containing pemafibrate or its salt or a solvate thereof In order to develop a pharmaceutical composition that can achieve this, the present inventors first tried to actually produce the pharmaceutical composition. However, the content of pemafibrate varies among pharmaceutical compositions, and It was found that there was a problem with the homogeneity of the pemafibrate content in the medicine. If the content of pemafibrate differs significantly between pharmaceutical compositions, the efficacy and safety of each pharmaceutical composition may differ. This could also lead to gender imbalance. Therefore, the object of the present invention is to provide pemafibrate or a salt thereof or a solvate thereof. The present invention aims to provide a pharmaceutical composition containing the above compound and having excellent homogeneity. [Means for solving the problem]

[0009] Therefore, the present inventors have investigated the use of pemafibrate or a salt thereof in a pharmaceutical composition. Further investigations were carried out to resolve the issue of content uniformity of the solvate of Pemafibril. or a salt thereof, or a solvate thereof (hereinafter, in this specification, simply referred to as "component ( A)) and a disaccharide such as lactose. (Note that, hereinafter, in this specification, this may be simply referred to as "component (B)"). It has been found that the content uniformity of pemafibrate in the pharmaceutical composition is improved by adding As a result, the present invention was completed.

[0010] That is, the present invention provides a composition comprising the following components (A) and (B): (A) pemafibrate or a salt thereof or a solvate thereof; (B) disaccharides; The present invention provides a pharmaceutical composition comprising:

[0011] The present invention also relates to a pharmaceutical composition containing pemafibrate or a salt thereof, or a solvate thereof. A method for preparing pemafibrate or a disaccharide in a pharmaceutical composition, comprising the step of incorporating a disaccharide into the pharmaceutical composition. provides a method for improving the content uniformity of the salt or solvate thereof. [Effects of the Invention]

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

[0013] <Pemafibrate or its salt or solvate thereof (ingredient (A))> As used herein, "pemafibrate or a salt thereof, or a solvate thereof" includes pemafibrate. Mafibrate (chemical name: (2R)-2-[3-({1,3-benzoxazole-2- Il[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butane Acid ((2R)-2-[3-([1,3-Benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino]methyl)phen oxy]butanoic acid), international generic name: Pemafibrate) itself, as well as pemafibrate Pharmaceutically acceptable salts, and further, pemafibrate or its pharmaceutically acceptable salts in water or alcohol. Also included are solvates with alcohols (e.g., ethanol), etc. Pharmaceutically acceptable salts include Although not particularly limited, examples thereof include acid addition salts and base addition salts. Specifically, hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, etc. Acid addition salts with inorganic acids such as benzoates, methanesulfonates, ethanesulfonates, benzoates, toluenesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, Examples of the acid addition salt include an organic acid addition salt such as a citrate or acetate. Specifically, sodium salts, potassium salts, lithium salts, calcium salts, magnesium salts, etc. Metal salts of; ammonia, trimethylamine, triethylamine, pyridine, collidine, Salts with amines such as lysine; organic bases such as lysine, arginine, cinchonine, and cinchonidine and base addition salts thereof.

[0014] The shape, size, etc. of pemafibrate or its salt or solvate thereof are not particularly limited. However, the primary particle size is measured according to the particle size measurement method by laser diffraction method in the 17th edition of the Japanese Pharmacopoeia. When the average particle diameter of the above is measured, it is preferable that d50 and d90 are as follows: . d50: preferably 100 μm or less, more preferably 50 μm or less, 2 It is even more preferable that the thickness is 0 μm or less, and particularly preferable that the thickness is 1 to 20 μm. d90: preferably 200 μm or less, more preferably 135 μm or less; It is 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 examples thereof include , Patent Document 1, Non-Patent Document 1, and the method disclosed in U.S. Patent No. 7,109,226. In the present invention, the compound can be produced by the method described in Non-Patent Document 1. Crystals of pemafibrate (preferably according to Melting Point Method 1 of the Japanese Pharmacopoeia, 17th Edition) When measured, crystals having a melting point of 95 to 101°C, particularly preferably 97 to 100°C, are used. The contents of these documents are incorporated herein by reference.

[0016] The content of pemafibrate or its salt or solvate thereof in the pharmaceutical composition is There are no particular limitations, and the dosage may be adjusted as appropriate depending on the disease to be treated, the type of preparation, the gender, age, symptoms, etc. of the recipient. For example, the dose of pemafibrate or its salt per day can be determined by examining the dose. Or their solvates, converted into the free form of pemafibrate, 0.05 to 0.8 mg , more preferably 0.075 to 0.6 mg, and particularly preferably 0.1 to 0.4 mg. can be contained. The content of pemafibrate or its salt or solvate thereof in the pharmaceutical composition The amount of pemafibrate in free form is 0.01 to 5% of the total mass of the pharmaceutical composition. The content is preferably 0.025 to 1 mass%, more preferably 0.05 to 1 mass%, and 0.5% by weight is particularly preferred. Even with such a low content of salts or solvates thereof, good content uniformity can be obtained. can be.

[0017] <Disaccharide (component (B))> As used herein, "disaccharide" refers to a disaccharide itself and to a disaccharide in which all or some of the hydroxy groups of the disaccharide are substituted. The group consisting of those in which the moiety is substituted with a halogen atom such as a chlorine atom, and solvates thereof Here, the solvate is not particularly limited, and specifically includes the following: For example, hydrates and the like can be mentioned. The type of monosaccharide constituting the disaccharide is not particularly limited, and examples thereof include For example, pentoses such as arabinose and xylose; glucose, galactose, fructosyl Examples of suitable sugars include hexoses such as tallow, mannose, altrose, and rhamnose. Specific examples of such disaccharides include sucrose, lactulose, Lactose, maltose, trehalose, cellobiose, kojibiose, Sucrose, isomaltose, isotrehalose, neotrehalose, sophorose, laminari Biose, Gentiobiose, Turanose, Maltulose, Palatinose, Gentiobiu Lactose, mannobiose, melibiose, melibiulose, neolactose, galactose clos, scylabiose, rutinose, rutinulose, vicianose, xylobiose, Primeverose and sucralose are examples of these. The above may be used in combination.

[0018] As disaccharides, sucrose, lactose, maltose, threose, etc. are used from the viewpoint of improving the content uniformity. haloth, palatinose, sucralose, and solvates thereof One or more of the above sugars are preferred, and sucrose, lactose, trehalose, sucralose, and their waters are also preferred. More preferably, one or more selected from the group consisting of lactose and its hydrates are used. More preferably, one or more selected from the group consisting of lactose-crystalline cellulose spherical granules, lactose hydrate, and milk Particularly preferred is one or more selected from the group consisting of sugar granules and anhydrous lactose. From the viewpoint of ease of manufacturing products (especially solid preparations), disaccharides are preferred because they can be stored at room temperature (15 to 25°C). Preferably, the compound is solid at any temperature. These disaccharides are all known compounds and may be produced by known methods. Alternatively, commercially available products may be used. Examples of such commercially available products include Nonpareil 105 (Freund Corporation), lactose hydrate (Sanei Gen F.F.I. Co., Ltd.), lactose G (Freund Corporation), Lactopress anhydrous (CBC Corporation) )), eclipse crystal maltose (Nihon Shokuhin Kako Co., Ltd.), trehalose P (Asahi Kasei Co., Ltd.), Sucralose (Sanei Gen F.F.I. Co., Ltd.), Pharmatose 200M (D FE Pharma, etc.

[0019] The content of disaccharide in the pharmaceutical composition is not particularly limited, and may vary depending on the type of formulation, the gender and age of the recipient, etc. The dosage can be determined based on the patient's age, symptoms, etc., but from the viewpoint of improving content uniformity, Therefore, the total amount of disaccharides is preferably 1 to 99% by mass based on the total mass of the pharmaceutical composition. The content is preferably 3 to 95% by mass, and more preferably 5 to 90% by mass. It is particularly preferable that the content is 7 to 85 mass %.

[0020] In addition, when one or more disaccharides selected from the group consisting of lactose and its hydrates are used, In this case, the content of the compound is, from the viewpoint of improving content uniformity, based on the total mass of the pharmaceutical composition. The content is preferably 2 to 98% by mass, more preferably 4 to 93% by mass, and particularly preferably 8 to 80% by mass. I wish.

[0021] Pemafibrate or its salt or solvate thereof and disaccharide in pharmaceutical composition The mass ratio of the content of pemafib is not particularly limited, but from the viewpoint of improving the content uniformity, It contains 10 to 1750 parts by mass of disaccharides per part by mass of ester in free form. It is preferable that the content is 50 to 1500 parts by mass, more preferably 80 to 1200 parts by mass. It is more preferable that the content is 100 to 900 parts by mass, and particularly preferable that the content is 100 to 900 parts by mass.

[0022] In addition, when one or more disaccharides selected from the group consisting of lactose and its hydrates are used, In this case, pemafibrate or a salt thereof or a solvate thereof and lactose in a pharmaceutical composition The mass ratio of the content of one or more selected from the group consisting of From the viewpoint of improving content uniformity, for 1 part by mass of pemafibrate in free form, and lactose and its hydrates in a total amount of 30 to 1150 parts by mass. It is preferable that the content is 50 to 1050 parts by mass, more preferably 70 to 950 parts by mass. It is more preferable that the content is 120 to 850 parts by mass, and particularly preferable that the content is 120 to 850 parts by mass.

[0023] <Cellulose (component (C))> The pharmaceutical composition of the present invention further contains cellulose in addition to the components (A) and (B). By incorporating a combination of disaccharides and cellulose, The content uniformity of mafibrate is improved. As used herein, "cellulose" refers to a compound selected from the group consisting of cellulose and its salts. In the case of cellulose, the type of salt is not particularly limited, and specific examples include For example, alkali metal salts such as sodium salts and potassium salts; calcium salts and magnesium salts Examples include salts with metals of group 2 elements. In addition, the average degree of polymerization and properties (crystal form) of cellulose ) is not particularly limited, but the average degree of polymerization is preferably 50 to 10,000. The average degree of polymerization is determined by the verification test described in the section on "crystalline cellulose" in the 17th revised Japanese Pharmacopoeia. This can be confirmed by conducting tests in accordance with (3). Specific examples of such cellulose include crystalline cellulose, crystalline cellulose ( Microparticles), crystalline cellulose (granules), powdered cellulose, powdered cellulose (average degree of polymerization: 80 0-1100), and one of these can be used alone or in combination of two or more. These crystalline celluloses and the like can be used as pharmaceutical additives. This refers to crystalline cellulose, etc., as described in the Pharmaceuticals and Medical Devices Agency (published by Yakuji Nipposha). These celluloses are all known components and can be produced by known methods. Alternatively, commercially available products may be used. PH-101 (Asahi Kasei Corporation), Cellphea (Sanei Gen F.F.I. Co., Ltd.), AR Examples include BOCEL (Kimura Sangyo Co., Ltd.).

[0024] The amount of cellulose contained in the pharmaceutical composition is not particularly limited, and may vary depending on the type of formulation and the gender of the recipient. The dosage can be determined based on the patient's age, symptoms, etc., but the dosage may be adjusted based on the effect of improving content uniformity. From this viewpoint, the total amount of cellulose is 1 to 40% by mass relative to the total mass of the pharmaceutical composition. It is preferably 3 to 35% by mass, more preferably 5 to 30% by mass. It is particularly preferable that the content is 8 to 25 mass %.

[0025] Pemafibrate or a salt thereof or a solvate thereof and cellulose in a pharmaceutical composition The mass ratio of the content to the base is not particularly limited, but from the viewpoint of improving the content uniformity, The total amount of cellulose contained is 5 to 5,000 parts by mass per part by mass of the free form of cellulose. It is preferable that the content is 30 to 3500 parts by mass, and more preferable that the content is 60 to 2000 parts by mass. It is particularly preferable that the content is 100 parts by mass.

[0026] In the present specification, the dosage form of the "pharmaceutical composition" is not particularly limited, and may be a solid, semi-solid, or liquid form. The pharmaceutical composition may be any of the above-mentioned preparations, and can be selected depending on the purpose of use. The dosage form of the composition may be, for example, the dosage form described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 17th Edition. Specifically, for example, dosage forms for oral administration include tablets (e.g., regular tablets, orally disintegrating tablets, etc.). tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules (e.g. solid preparations such as effervescent granules, powders, pills, etc.; semi-solid preparations such as oral jellies, etc. Oral liquids (e.g., elixirs, suspensions, emulsions, lemonades, etc.) Dosage forms for parenteral administration include injections, inhalants, eye drops, and topical preparations. Ear drops, nasal drops, suppositories, solid topical preparations, liquid topical preparations, sprays, ointments, creams, gels , patches, etc.

[0027] From the viewpoints of ease of administration and ease of production, a solid preparation is preferred as a pharmaceutical composition. In particular, when the pharmaceutical composition is a solid preparation, it is extremely easy to manufacture, and Generally, solid preparations are basically solid ingredients at room temperature (any temperature between 15 and 25°C). Since a large amount of ingredients are used in the manufacturing process, the ingredients tend to be mixed and dispersed unevenly, resulting in inconsistent content. Therefore, according to the present invention, in the case of a solid preparation, deterioration of the viscosity is particularly likely to become a problem. In addition, it has the excellent effect of providing good content uniformity. As the solid preparation, a solid preparation for oral administration is preferable, and examples thereof include tablets, capsules, granules, and powders. In addition, as a solid preparation, a compound containing component (A) and a hydroxybenzoate is preferably used. A solid preparation containing a mixture including (B) is preferred, and a solid preparation containing a mixture including components (A) to (C) is preferred. A solid preparation containing the compound is more preferred.

[0028] The pharmaceutical composition of the present invention may contain, in addition to the above-mentioned components, a pharmaceutically acceptable carrier ( Formulation additives may be added. Examples of such formulation additives include excipients, disintegrants, Binders, lubricants, plasticizers, film formers, powders, poorly water-soluble polymers, antioxidants, flavor masking agents These additives include, but are not limited to, sweeteners and flavoring agents. Specific examples of additives include those listed in the Pharmaceutical Additives Dictionary 2016 (published by Yakuji Nippo Co., Ltd.). ), Handbook of Pharmaceutical Excipients, Seventh Edition (Pharmaceutical Press It is sufficient to use the information contained in the publications such as the NIMS.

[0029] Specific examples of the excipient include aluminum silicate, anhydrous sodium sulfate, and chloride. Sodium, light anhydrous silicic acid, heavy anhydrous silicic acid, calcium sulfate, calcium hydrogen phosphate Sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, dibasic phosphate Inorganic excipients such as sodium hydrogen carbonate; starch (wheat starch, rice starch, corn starch) starch, partially pregelatinized starch, etc.), fructose, caramel, agar, xylitol ethanol, paraffin, glucose, pullulan, polyoxyethylene hydrogenated castor oil, maltitol , erythritol, sorbitol, mannitol, lactitol, aminoalkylmethacrylate Acrylate copolymer E, polyvinyl acetal diethylaminoacetate, calcium citrate These may be used alone or in combination of two or more. It can be used. Among these excipients, light anhydrous silicic acid and mannitol are preferred.

[0030] Specific examples of disintegrants include sodium carboxymethyl starch and croscarmellose. Super disintegrants such as crospovidone and carmellose Calcium, starch, sucrose fatty acid ester, gelatin, dextrin, dehydroacetic acid acid and its salts, povidone, polyoxyethylene hydrogenated castor oil 60, etc. can be used alone or in combination of two or more. Among these disintegrants, sodium carboxymethyl starch, croscarmellose sodium Thorium is preferred.

[0031] Specific examples of binders include hardened beef tallow oil, hardened oil, hydrogenated vegetable oil, and soybean hardener. In addition to oils and fats such as methylcellulose, carnauba wax, white beeswax, beeswax, and wax, cellulose, hydroxypropyl cellulose, hypromellose, carmellose sodium, Starch (wheat starch, rice starch, corn starch, partially pregelatinized starch) starch, etc.), dextrin, pullulan, gum arabic, agar, gelatin, tragacanth , sodium alginate, povidone, polyvinyl alcohol, aminoalkyl methacrylate Examples of such copolymers include polyvinyl acetal copolymer E and polyvinyl acetal diethylamino acetate. These can be used alone or in combination of two or more. Among these binders are carnauba wax, hydroxypropyl cellulose, hypromellose, Preferred are cetethase, povidone, and aminoalkyl methacrylate copolymer E.

[0032] Specific examples of lubricants include calcium stearate and magnesium stearate. These include cereals containing glutathione, sodium stearyl fumarate, and sucrose fatty acid esters. One or more of these can be used in combination. Among these lubricants, calcium stearate, magnesium stearate, fumarate Sodium stearyl acid is preferred.

[0033] Specific examples of the plasticizer include triethyl citrate, glycerin, sesame oil, and sol Vitol, castor oil, polysorbate 80 (polyoxyethylene (20) sorbitan oleate) These may be used alone or in combination of two or more. It is possible. Of these plasticizers, triethyl citrate, glycerin, and sorbitol are preferred.

[0034] Specific examples of film-forming agents include methyl cellulose, ethyl cellulose, etc. Alkyl cellulose; alginic acid or its salts such as sodium alginate; carrageenan ;Carboxymethylcellulose sodium, carboxymethylcellulose calcium, calcium Potassium carboxymethylcellulose, Carboxymethylcellulose, Carboxymethylester Carboxyalkyl cellulose such as ethyl cellulose; xanthan gum; hydroxymethyl Cellulose, Hydroxyethylcellulose, Hydroxypropylcellulose, Hypromello hydroxyalkyl cellulose such as hydroxypropyl methylcellulose; hydroxyalkyl cellulose phthalate, such as hydroxypropyl methylcellulose phthalate pullulan; polyvinyl acetate; polyvinyl acetate phthalate; polyvinylpyrrolidone, etc. These may be used alone or in combination of two or more. Among these film-forming agents, alkyl cellulose, hydroxyalkyl cellulose, is preferred.

[0035] Powders include talc, titanium oxide, yellow ferric oxide, ferric oxide, and organic pigments such as legal pigments. These may be used alone or in combination of two or more. This can be done. Among these powders, titanium oxide, yellow ferric oxide, ferric oxide, and legal pigments are preferred. .

[0036] Specific examples of poorly water-soluble polymeric substances include carboxyvinyl polymers, amino Alkyl methacrylate copolymers and the like are examples of such copolymers. These may be used alone or in combination of two or more. They can be used in combination. Specific examples of antioxidants include ascorbic acid, sodium hydrogen sulfite, and sulfite. Sodium edetate, sodium edetate, erythorbic acid, tocopheryl acetate, dibutyl hydroxybenzoate Hydroxytoluene, natural vitamin E, tocopherol, butylhydroxyanisole, etc. These may be used alone or in combination of two or more.

[0037] Specific examples of flavoring agents include limonene, pinene, camphene, cymene, and cine ol, citronellol, geraniol, nerol, linalool, menthol, terpine ol, rhodinol, borneol, isoborneol, menthone, camphor, eugenol Terpenes such as cinzeylanol, spruce oil, orange oil, peppermint oil, camphor white oil, Potassium oil, turpentine oil, lemon oil, ginger oil, clove oil, cinnamon oil, lavender essential oils containing terpenes, such as oil, fennel oil, chamomile oil, perilla oil, and spearmint oil; Acidulants such as ascorbic acid, tartaric acid, citric acid, malic acid and salts thereof are included. These may be used alone or in combination of two or more.

[0038] Examples of sweeteners include aspartame, stevia, glycyrrhizin, and thaumatin. , acesulfame potassium, saccharin, saccharin sodium, etc., They can be used alone or in combination of two or more.

[0039] Furthermore, among the above-mentioned pharmaceutically acceptable carriers, the pharmaceutical composition of the present invention may further comprise a croscal Mellose sodium, magnesium stearate, titanium oxide, triethyl citrate, Made from promellose, hydroxypropyl cellulose, light anhydrous silicic acid and carnauba wax It is preferable to contain one or more selected from the group consisting of:

[0040] 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 may be subjected to pulverization, mixing, granulation, drying, sizing, classification, etc. It can be manufactured by appropriately combining unit operations such as filling, tableting, and coating. However, the manufacturing method thereof includes a process of mixing component (A) and component (B). is preferred, and a method including a step of mixing components (A) to (C) is more preferred. More specifically, for example, when the dosage form of the pharmaceutical composition is a granular preparation such as granules, powders, or pills, In addition to component (A) and component (B), component (C) may also be used, as necessary, as well as excipients and binders. After mixing these ingredients with formulation additives such as disintegrants and lubricants, the mixture is extruded and tumbled. Granulation by a known granulation method such as stirring granulation, fluidized bed granulation, spray granulation, melt granulation, or crushing granulation. The granules are then obtained, and further classified, sized, etc., as necessary, to produce the product. The resulting granules can 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, in addition to the component (A) and the component (B), In addition to component (C), appropriate formulation additives such as excipients, binders, disintegrants, lubricants, etc. are used. These ingredients are mixed to obtain a mixture, which is then directly compressed (tableted) (direct powder compression method). The granulated material is classified and sized as necessary before being compressed (tableted) (semi-dry granulation). It can be produced by a method such as granule compression, dry granule compression, or wet granule compression. The obtained compressed product (tablet) can 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 is placed in the capsule. Just fill it up.

[0041] The pharmaceutical composition of the present invention is not limited to any particular disease, and may be used for any disease currently known or discovered in the future. It is widely used in the prevention or treatment of diseases for which administration of pemafibrate is effective. It is possible. For example, pemafibrate or a salt thereof or a solvate thereof is an excellent PPARα antagonist. It has agonist activity, lowering plasma triglyceride levels and increasing HDL cholesterol, etc. Therefore, the pharmaceutical composition of the present invention is preferably used for the treatment of dyslipidemia (hyperlipidemia, More specifically, as an agent for preventing and / or treating primary hyperlipidemia, secondary hyperlipidemia, etc. More preferably, it can be used as an agent for preventing and / or treating hypertriglyceridemia. Pemafibrate or its salts or solvates thereof are also effective in the treatment of non-alcoholic fatty liver disease (NAFLD). Therefore, the pharmaceutical composition of the present invention is useful for the prevention or treatment of cholangiocarcinoma (cholangiocarcinoma-associated fatty liver disease). Prevention of NAFLD (more preferably NASH (non-alcoholic steatohepatitis)) and / or It can also be used as a therapeutic agent. Furthermore, pemafibrate or a salt thereof or a solvate thereof is useful for the treatment of primary biliary cirrhosis. It may also be used as a therapeutic agent for cancer.

[0042] The route of administration of the pharmaceutical composition is not particularly limited, and may vary depending on the disease to which it is applied, the type of formulation, the gender of the recipient, The dosage can be determined based on age, symptoms, etc., but from the perspective of ease of administration, Oral administration is preferred. The pharmaceutical composition may be administered 1 to 4 times a day, before meals, after meals, or after meals. It can be taken between meals, before bed, etc.

[0043] The present specification discloses the following embodiments, for example, but is not limited to these: do. [1-1] The following components (A) and (B): (A) pemafibrate or a salt thereof or a solvate thereof; (B) disaccharides; A pharmaceutical composition comprising: [1-2] Component (B) is sucrose, lactulose, or lactose ), maltose, trehalose, cellobiose, kojibiose, nigerose, isomaltose Trehalose, isotrehalose, neotrehalose, sophorose, laminaribiose, gentian Obios, turanose, maltulose, palatinose, gentiobiulose, mannobi ose, melibiose, melibiulose, neolactose, galactosucrose, Shirabi ose, rutinose, rutinulose, vicianose, xylobiose, primeverose and and sucralose, and solvates thereof, 1] The pharmaceutical composition described above. [1-3] Component (B) is sucrose, lactose, maltose, trehalose, palatinose and sucralose and solvates thereof, [1 -1] The pharmaceutical composition described in the above. [1-4] Ingredient (B) is sucrose, lactose, trehalose, sucralose, and the like. The pharmaceutical composition according to [1-1], wherein the compound is one or more selected from the group consisting of hydrates thereof. [1-5] The component (B) is one or more selected from the group consisting of lactose and its hydrates. The pharmaceutical composition described in [1-1]. [1-6] Furthermore, component (C): (C) cellulose; The pharmaceutical composition according to any one of [1-1] to [1-5],

[0044] [1-7] Dyslipidemia (hyperlipidemia, more specifically, primary hyperlipidemia, secondary hyperlipidemia, etc.) hyperlipidemia, etc.), NAFLD (more preferably, NASH (non-alcoholic steatohepatitis)), and [1-1] to [1-2] are agents for preventing and / or treating diseases selected from primary biliary cirrhosis. -6] The pharmaceutical composition according to any one of the preceding claims. [1-8] The pharmaceutical composition according to any one of [1-1] to [1-7], which is a solid formulation. [1-9] The dosage form is a tablet, capsule, granule, powder or pill, [1-1] to The pharmaceutical composition according to any one of [1-8].

[0045] [2-1] (A) Contains pemafibrate or its salt or a solvate thereof The pharmaceutical composition comprises the following component (B): (B) disaccharides; A pharmaceutical composition comprising pemafibrate or a salt thereof, or A method for improving the content uniformity of solvates. [2-2] Component (B) is sucrose, lactulose, or lactose ), maltose, trehalose, cellobiose, kojibiose, nigerose, isomaltose Trehalose, isotrehalose, neotrehalose, sophorose, laminaribiose, gentian Obios, turanose, maltulose, palatinose, gentiobiulose, mannobi ose, melibiose, melibiulose, neolactose, galactosucrose, Shirabi ose, rutinose, rutinulose, vicianose, xylobiose, primeverose and and sucralose, and solvates thereof, 1] The method described. [2-3] Component (B) is sucrose, lactose, maltose, trehalose, palatinose and sucralose and solvates thereof, [2 -1] The method described. [2-4] Ingredient (B) is sucrose, lactose, trehalose, sucralose, and the like. The method according to [2-1], wherein the hydrate is one or more selected from the group consisting of hydrates thereof. [2-5] The component (B) is one or more selected from the group consisting of lactose and its hydrates. The method described in [2-1]. [2-6] Furthermore, component (C): (C) cellulose; The method according to any one of [2-1] to [2-5], comprising a step of incorporating:

[0046] [2-7] The pharmaceutical composition is for treating dyslipidemia (hyperlipidemia, more specifically, primary hyperlipidemia) hyperlipidemia, secondary hyperlipidemia, etc.), NAFLD (more preferably NASH (non-alcoholic fatty liver disease) a preventive and / or therapeutic agent for a disease selected from the group consisting of hepatitis, primary biliary cirrhosis, and primary biliary cirrhosis; The method according to any one of [2-1] to [2-6]. [2-8] The pharmaceutical composition according to any one of [2-1] to [2-7], wherein the pharmaceutical composition is a solid formulation. method. [2-9] The dosage form of the pharmaceutical composition is a tablet, capsule, granule, powder, or pill; The method described in any one of [2-1] to [2-8]. [Example]

[0047] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. It is not something that is done. In the following test examples, the HPLC measurements were performed using an ODS column. and an ultraviolet spectrophotometer as a detector. In addition, pemafibrate used in the following test examples is The average particle size of primary particles was measured according to the particle size measurement method using laser diffraction. The d50 was less than 100 μm and the d90 was less than 200 μm.

[0048] [Test Example 1] Content uniformity evaluation test To evaluate the uniformity of pemafibrate content in the pharmaceutical composition, the following tests were performed: . In other words, the amount of each ingredient per tablet shown in Table 1 should be the amount (mg) shown in Table 1. The specific procedure is as follows: Example 1 Pemafibrate, lactose monohydrate, croscarmellose sodium and hydroxypropyl After mixing the cellulose for 5 minutes, purified water was added and kneaded for 3 minutes, granulated, dried, and then The granules were mixed with magnesium stearate and then compressed into tablets. Then, 10,000 tablets of 120 mg each were manufactured. Example 2 The same method as in Example 1 was used except that part of the lactose hydrate was replaced with crystalline cellulose. 10,000 tablets of 120 mg each were manufactured. (Comparative Example 1) The same method as in Example 1 was used except that the entire amount of lactose hydrate was replaced with crystalline cellulose. 10,000 tablets of 120 mg each were manufactured.

[0049] Ten tablets were randomly selected from each of the obtained tablets of each Example or Comparative Example. The pemafibrate content in each tablet was measured by the following method. That is, one tablet was crushed in water, and then acetonitrile was added to obtain a sample solution. The obtained sample solution was analyzed by HPLC, and the peak area derived from pemafibrate was The peak area of ​​pemafibrate in the obtained sample solution was measured. By comparing the peak area with that of a known standard solution of pemafibrate, the pemafibrate concentration of each tablet was The content of mafibrate was determined.

[0050] The measured content of pemafibrate in each tablet was calculated according to the 17th edition of the Japanese Pharmacopoeia. According to the content uniformity test, the relative standard deviation (RSD) of the pemafibrate content in the tablets (% ) was calculated and used as an index of the variation (degree of uniformity) of the pemafibrate content in the tablets. The results obtained are shown in Table 1.

[0051] [Table 1]

[0052] As shown in Table 1, when lactose hydrate, a disaccharide, was added (Examples 1 and 2), The relative standard deviations were all smaller than those of Comparative Example 1, which did not contain disaccharides, and It was revealed that the uniformity of the pemafibrate content in the lactose monohydrate was good. In addition, Example 2, which further contains crystalline cellulose, has a smaller relative standard deviation and is more stable than the tablet. The uniformity of the pemafibrate content per tablet was particularly good.

[0053] Based on the above test results, it is possible to confirm that the By incorporating a disaccharide into the pharmaceutical composition, the amount of pemafibrate in the pharmaceutical composition can be reduced. It was found that the content uniformity was improved.

[0054] [Manufacturing Examples 1 to 3] Tablets containing the ingredients and amounts (mg) listed in Table 2 per tablet are prepared by wet granulation in the usual manner. It can be manufactured by compression method.

[0055] [Table 2]

[0056] [Manufacturing Examples 4 to 6] Tablets containing the ingredients and amounts (mg) listed in Table 3 per tablet were directly powdered in the usual way. It can be manufactured by compression method.

[0057] [Table 3] [Industrial Applicability]

[0058] According to the present invention, it is possible to achieve the effects of the present invention such as a decrease in plasma triglyceride concentration and an increase in HDL cholesterol. Since the present invention provides a pharmaceutical composition containing pemafibrate, which exhibits the effect of For example, it can be used in the pharmaceutical industry.

Claims

[Claim 1] The invention described in the application.

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