Pharmaceuticals

Abstract

This invention provides a technology to suppress changes in the formulation between pemafibrate or its salts or solvates thereof and (meth)acrylic acid polymers. [Solution] The present invention provides a pharmaceutical product comprising a pharmaceutical composition containing the following components (A) and (B): (A) pemafibrate or a salt thereof or a solvate thereof; (B) (meth)acrylic acid polymers; contained in an airtight package.

Description

Technical Field

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

Background Art

[0002] The following structural formula:

[0003]

Chem.

[0004] Pemafibrate (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 thereof or a solvate thereof has excellent PPARα agonist activity and exhibits effects such as a decrease in plasma triglyceride concentration and an increase in HDL cholesterol, and is useful for the prevention and treatment of dyslipidemia (hyperlipidemia) (Patent Document 1, Non-Patent Documents 1 and 2), and is known to be useful for the prevention and treatment of NAFLD (non-alcoholic fatty liver disease) (Patent Document 2). zol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid)、国際一般名:Pemafibrate)若しくはその塩又はそれ らの溶媒和物は、優れたPPARαアゴニスト活性を有し、血漿トリグリセライド濃度の methyl)phenoxy]butanoic acid), international common name: Pemafibrate), or a salt thereof or a solvate thereof has excellent PPARα agonist activity and shows effects such as a decrease in plasma triglyceride concentration and an increase in HDL cholesterol, and is useful for the prevention and treatment of dyslipidemia (hyperlipidemia) (Patent Document 1, Non-Patent Documents 1 and 2), and is known to be useful for the prevention and treatment of NAFLD (non-alcoholic fatty liver disease) (Patent Document 2). 脂肪性肝疾患)の予防や治療に有用であること(特許文献2)が知られている。 It is known to be useful for the prevention and treatment of fatty liver disease) (Patent Document 2).

[0005] By the way, a compound useful as an active ingredient of a pharmaceutical is usually formulated as a pharmaceutical composition and administered, but 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 viewpoint 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. 化されて投与されることとなるが、医薬組成物が製造されてから投与されるまでに長期間 経過することも珍しいことではない。そのため、期待する薬効の発揮の観点や予期せぬ副 作用の回避の観点から、医薬組成物中での有効成分の保存安定性の確保が極めて重要とな る。 [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. [Overview of the project] [Problems that the invention aims to solve]

[0008] However, the storage stability of the active ingredient is largely dependent on its physical and chemical properties. In many cases, these properties cannot be predicted in advance from the chemical structure, etc., and the actual pharmaceutical composition is not determined. Problems often only become apparent after the product has been manufactured. Furthermore, with respect to pemafibrates or their salts or solvates, as described above... It has only been reported that it exhibits pharmacological effects, and it is not yet considered a pharmaceutical composition. This has not been specifically considered to date, and the storage stability in pharmaceutical compositions is... This had never been reported before. Furthermore, pharmaceutical compositions typically contain, in addition to the active ingredient, Various pharmaceutical additives are included. Against this backdrop, the present inventors have discovered a pemafibrate or its salt or its solvent. In order to develop a pharmaceutical composition containing a waxy substance, the storage stability when using various formulation additives was examined. However, although pemafibrate itself is extremely stable, even when (meth)acrylic acid-based polymers typified by aminoalkyl methacrylate copolymer E coexist, a formulation change occurs, and it has been found that a problem of storage stability occurs where the mixture melts over time. Therefore, an object of the present invention is to provide a technique for suppressing a formulation change between pemafibrate or a salt thereof or a solvate thereof and (meth)acrylic acid-based polymers.

Means for Solving the Problems

[0009] Therefore, as a result of further examination in view of the above situation, the present inventor has found that a formulation change can be suppressed by accommodating a pharmaceutical composition containing pemafibrate or a salt thereof or a solvate thereof and (meth)acrylic acid-based polymers in an airtight package such as a vial package or a PTP package, and has completed the present invention.

[0010] That is, the present invention provides a pharmaceutical product in which a pharmaceutical composition containing the following components (A) and (B):

[0011] (A) Pemafibrate or a salt thereof or a solvate thereof; (B) (meth)acrylic acid-based polymers; is contained in an airtight package. Also, the present invention provides a method for stabilizing a pharmaceutical composition, which includes a step of accommodating a pharmaceutical composition containing the following components (A) and (B): (A) Pemafibrate or a salt thereof or a solvate thereof;

[0012] (B) (meth)acrylic acid-based polymers; in an airtight package. It is something that is provided. [Effects of the Invention]

[0012] According to the present invention, changes in the formulation between pemafibrate and (meth)acrylic acid polymers are suppressed. This allows us to provide pharmaceuticals that are controlled and have excellent storage stability. [Modes for carrying out the invention]

[0013] <Pemafibrates or their salts or solvates thereof> In this specification, "pemafibrate or its salt or solvate thereof" means Mafibrate (Chemical name: (2R)-2-[3-({1,3-benzoxazole-2- Il[3-(4-methoxyphenoxy)propyl]aminomethyl)phenoxy]butane Acid ((2R)-2-[3-([1,3-Benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino]methyl)phen In addition to pemafibrate itself (oxy-butanoic acid, international common name: pemafibrate), pemafibrate is also used. Pharmaceutically acceptable salts, as well as pemafibrate and its pharmaceutically acceptable salts, and water and alcohol This also includes solvates with coal (e.g., ethanol). Pharmaceutically acceptable salts include Examples of acid addition salts include acid addition salts and base addition salts. Specifically, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate. Acid addition salts with inorganic acids; benzoates, methanesulfonates, ethanesulfonates, benzates Zensulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, Examples include acid addition salts with organic acids such as citrates and acetates. Also, as for base addition salts, Specifically, sodium salts, potassium salts, lithium salts, calcium salts, magnesium salts, etc. Metal salts of ammonia, trimethylamine, triethylamine, pyridine, coridine, ru Salts of amines such as thidine; organic bases such as lysine, arginine, cinconine, and cinconidine. Examples include base addition salts.

[0014] Pemafibrates or their salts or solvates are known compounds, for example , by the method disclosed in Patent Document 1, Non-Patent Document 1, and U.S. Patent No. 7,109,226 It can be manufactured by the method described in Non-Patent Document 1. Pemafibrate crystals (preferably according to the Melting Point Measurement Method No. 1 of the 17th Edition of the Japanese Pharmacopoeia) When measured, use a crystal that exhibits a melting point of 95-101°C, particularly preferably 97-100°C. It is preferable to do so. Furthermore, the contents of these documents are incorporated herein by reference.

[0015] The content of pemafibrate or its salt or solvate in the pharmaceutical composition is There are no particular limitations; the appropriate method will be determined based on the type of preparation, the gender and age of the user, symptoms, etc. It is possible to take pemafibrate or its salt or its soluble form per day. The amount of the fordextrin, converted to the free form of pemafibrate, is 0.05 to 0.8 mg, more preferably It contains an amount that allows for administration of 0.075 to 0.6 mg, and more preferably 0.1 to 0.4 mg. It is possible. The content of pemafibrate or its salt or solvate thereof in a pharmaceutical composition and Therefore, the amount of pemafibrate in free form is 0.001 to 6 per unit of total mass of the pharmaceutical composition. Preferably, it is 0% by mass, more preferably 0.0025 to 25% by mass, and 0. It is more preferably 0.005 to 10% by mass, and even more preferably 0.0075 to 5% by mass. It is more preferably 0.01 to 1 mass%, and more preferably 0.05 to 0.5 mass%. That is particularly preferable.

[0016] <(meth)acrylic acid polymers> In this specification, "(meth)acrylic acid polymers" refers to structural units derived from acrylic acid. Position, structural unit derived from methacrylic acid, structural unit derived from acrylic acid esters and methacrylic One or more structural units selected from the group consisting of structural units derived from acid esters (hereinafter referred to as structural units) This refers to polymers containing (also called position X). Here, acrylic acid esters and methacrylic acid Examples of esters include methanol, ethanol, propanol, and butanol. Aliphatic alcohols (preferably linear or carbon-1 to carbon-12 (more preferably carbon-1 to carbon-6)) Examples include esters of branched-chain aliphatic alcohols and (meth)acrylic acid. The aliphatic alcohol may also contain a dimethylamino group, a trimethylammonium group, etc. aliphatic amino groups (primary to tertiary amino groups, or quaternary ammonium groups). The aliphatic group included in the mino group has 1 to 12 carbon atoms (more preferably 1 to 6 carbon atoms). Linear or branched aliphatic groups are preferred. ) and hydroxyl groups, phosphorylcholine groups are substituted. That's good too. Furthermore, specific examples of monomers that induce structural unit X include acrylic acid, methacris, etc. lylic acid, methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate Lu, butyl acrylate, butyl methacrylate, octyl acrylate, octyl methacrylate 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, 2-ethylhexyl acrylate Syl, dodecyl methacrylate, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate Roxyethyl acrylate, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, Ethyl trimethylammonium acrylate, trimethylammonium methacrylate Muethyl, 2-acryloyloxyethyl phosphorylcholine, 2-methacryloyloxy Examples include ethyl phosphorylcholine. Even if one of these is used alone, two or more of them are used. They may be used in combination. In this specification, (meth)acrylic acid polymers are composed of a single monomer. Even among polymers (homopolymers), copolymers (copolymers) are composed of multiple different monomers. -) is also acceptable.

[0017] Furthermore, (meth)acrylic acid polymers include primary to tertiary amino groups and quaternary ammonia. (Meta) having one or more substituents selected from a um group, a hydroxyl group, and a phosphorylcholine group. Selected from structural units derived from acrylic acid esters and structural units derived from (meth)acrylic acid. It is preferable to include at least one type of structural unit (hereinafter also referred to as structural unit Y). i. As structural unit Y, (meth)acrylate diC1~12alkylaminoC1~12 Structural units derived from lukyl, (meth)acrylate triC1-12alkylammoniumC1- Structural units derived from 12 alkyl groups and structural units derived from (meth)acrylic acid are preferred. In polymers containing Y, the structural unit Y and (meth)acrylate C1-12 alkyl are derived from each other. A polymer containing a structural unit (hereinafter also referred to as structural unit Z) (hereinafter also referred to as polymer P) It is preferable.

[0018] Furthermore, in this specification, (meth)acrylic acid polymers are defined as having structural units other than X. monomers having reactive unsaturated groups that can copolymerize with this (vinyl acetate, vinylpyrrolidone, 2- It may contain structural units derived from methyl-5-vinylpyridine, etc. In this specification, the weight-average molecular weight of (meth)acrylic acid polymers is not particularly limited. However, 1,000 to 1,000,000 is preferable, and 10,000 to 500,000 is more preferable. 50,000 to 300,000 is more preferable, and 100,000 to 200,000 is particularly preferred. It's nice. Note that the above weight-average molecular weight refers to the value converted to sodium polyacrylate, and polymer Using a calibration curve prepared with sodium polyacrylate standard material manufactured by - Laboratory Co., Ltd., It can be measured using isz exclusion chromatography.

[0019] Examples of (meth)acrylic acid polymers include, for example, acrylic acid, acrylic acid Octyl ester copolymer, acrylic acid ester / vinyl acetate copolymer, acrylic acid 2 -Ethylhexyl vinylpyrrolidone copolymer, 2-ethylhexyl acrylate / methac 2-ethylhexyl methacrylate copolymer, ethyl acrylate / methac Methyl acrylate copolymer, silk fibroin acrylate copolymer resin, methyl acrylate • 2-ethylhexyl acrylate copolymer resin, aminoalkyl methacrylate copolymer E, ammoniaalkyl methacrylate copolymer, carboxyvinyl polymer, dimethyl L-aminoethyl methacrylate / methyl methacrylate copolymer, polyacrylic acid Sodium, partially neutralized polyacrylic acid, methacrylic acid / n-butyl acrylate copolymer - Methacrylic acid copolymer L, methacrylic acid copolymer LD (dried methacrylic acid copolymer Contains M-LD, methacrylate copolymer S, methyl acrylate / methacrylate copolymer Polymers, methyl acrylate / methacrylic acid / methyl methacrylate copolymer, 2-Methyl-5-vinylpyridinemethyl acrylate / methacrylate copolymer, methyl Examples include methacrylate-methacrylic acid copolymers. (Meth)acrylic acid polymers are selected from the viewpoint of content uniformity, using acrylic acid and methac Lylic acid, methyl methacrylate, ethyl acrylate, butyl methacrylate, di methacrylate From the group consisting of methylaminoethyl and trimethylammonium ethyl methacrylate It is preferable that the polymer is derived from one or more selected monomers, and ethyl acrylate / methac Methyl lylate copolymer, aminoalkyl methacrylate copolymer E, ammoniacal Kill methacrylate copolymer, carboxyvinyl polymer, methacrylate copolymer S , methacrylic acid copolymer L and methacrylic acid copolymer LD (dried methacrylic acid copolymer One or more selected from the group consisting of (including ) methacrylate copolymer As the rimer LD, dried methacrylate copolymer LD is preferred. Furthermore, these (meth)acrylic acid polymers are all known components, and are known It is permissible to manufacture it by law, or to use a commercially available product. For example, Eudragit E100, Eudragit EPO, Eudragit L100, Oidragit L30D-55, Oidragit L100-55, Oidragit S10 0, Eudragit RL100, Eudragit RLPO, Eudragit RL30D, Oidragit RS100, Oidragit RSPO, Oidragit RS30D, Oi Dragitt NE30D, Oidragitt FS30D (both manufactured by Evonik Rohm GmbH), Poly Kid PA-30, Polykid PA-30L, Polykid PA-30S, Polykid PA -100, Polyliquid LA-100, Polyliquid SA-100, Polyliquid EA-100 Polyliquid EM-30 (all manufactured by Sanyo Chemical Industries), Coricoat MAE30DP, Coricoat MAE100-55, Coricoat Smart Seal 30 D, Coricoat IR, Corico EMM30D (all manufactured by BASF Japan), Hibiscus Wako 103, Hibiscus Wako -104, Hibiscus Wako 105 (both manufactured by Fujifilm), Carbopol 971P NF, Carbopol974PNF, Carbopol71GNF (all manufactured by CBC) These are some examples.

[0020] The content of (meth)acrylic acid polymers in the pharmaceutical composition is not particularly limited, and the formulation The type, gender, age, symptoms, etc. can be appropriately considered and determined, but the content From the viewpoint of uniformity and storage stability, (meth)acrylic acid polymerization is carried out with respect to the total mass of the pharmaceutical composition. The total amount of body components is preferably 0.001 to 50% by mass, and preferably 0.005 to 30% by mass. It is more preferably a percentage by amount, even more preferably 0.01 to 20% by mass, and 0.1 It is more preferably ~10% by mass, and particularly preferably 0.5 to 5% by mass.

[0021] In a pharmaceutical composition, pemafibrate or its salt or solvates thereof and (meth The mass ratio of acrylic acid polymers is not particularly limited, but the uniformity of content and storage stability are important. From a qualitative standpoint, per 1 part by mass of pemafibrate in free form, (meth)acrylic Preferably, the mixture contains a total of 0.001 to 500 parts by mass of acid polymers, and more preferably 0.01 to 10 It is more preferable to contain 0 parts by mass, and even more preferable to contain 0.5 to 50 parts by mass. It is particularly preferable to contain 1 to 20 parts by mass.

[0022] In this specification, the dosage form of "pharmaceutical composition" is not particularly limited and may be solid, semi-solid, or liquid. Any form of formulation is acceptable, and the choice can be made according to the intended use, etc. Examples of dosage forms for the product include those listed in the General Provisions for Preparations of the 17th Revised Japanese Pharmacopoeia, etc. Specifically, for example, as a dosage form for oral administration, there are tablets (e.g., regular tablets, orally disintegrating tablets). (Including broken tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolvable tablets, CR tablets, etc.), capsules, granules Solid preparations such as powders, pills, and other solid preparations (including effervescent granules, etc.); semi-solid preparations such as oral jelly preparations. Formulations; oral liquid preparations (including, for example, elixirs, suspensions, emulsions, and lemonades) Examples of liquid formulations include those listed above. Furthermore, parenteral administration forms include injections, inhalants, and injections. Eye drops, ear drops, nasal drops, suppositories, topical solid preparations, topical liquid preparations, sprays, ointments, creams Examples include gels, patches, and the like.

[0023] From the viewpoint of ease of administration and ease of manufacture, a solid dosage form is preferred for the pharmaceutical composition. preferable. As for solid dosage forms, oral solid dosage forms are preferred, such as tablets, capsules, granules, and powders. Pills are more preferred, and tablets are particularly preferred.

[0024] The pharmaceutical composition used in this invention may contain, depending on its dosage form, other pharmaceutically acceptable components in addition to the above-mentioned components. A carrier (formulation additive) may be added. Examples of such formulation additives include excipients and disintegrants. Destructors, binders, lubricants, plasticizers, film-forming agents, powders, antioxidants, flavoring agents, sweeteners, etc. These are some examples, but are not limited to them. Furthermore, these pharmaceutical additives include: Specifically, for example, the Dictionary of Pharmaceutical Additives 2016 (published by Yakuji Nippo Co., Ltd.), Handbook o f Pharmaceutical Excipients, Seventh Edition (published by Pharmaceutical Press), etc. You can use the ones that are listed.

[0025] Examples of excipients include aluminum silicate, anhydrous sodium sulfate, and anhydrous sodium sulfate. Calcium hydrogen phosphate, sodium chloride, calcium silicate, light anhydrous silicic acid, heavy anhydrous silicic acid Silicic acid, calcium sulfate, monocalcium phosphate, calcium hydrogen phosphate, hydrogen phosphate Sodium, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate Inorganic excipients such as: syrup powder, caramel, agar, paraffin, sucrose, fructose, maltose, Lactose, lactose monohydrate, sucrose, glucose, pullulan, polyoxyethylene hydrogenated castor oil, reduction Maltose syrup, powdered reduced maltose syrup, trehalose, reduced palatinose, maltose, Organic excipients such as polyvinyl acetal diethylaminoacetate and calcium citrate. These are some examples. These can be used individually or in combination of two or more types. The total content of excipients is preferably 20 to 99% by mass of the total mass of the pharmaceutical composition. Preferably, it is 30 to 95% by mass.

[0026] Examples of disintegrants include gelatin, sodium bicarbonate, dextrin, Examples include dehydroacetic acid and its salts, polyoxyethylene hydrogenated castor oil 60, etc. These can be used individually or in combination of two or more types.

[0027] Examples of binders include, specifically, hardened beef tallow, hardened oil, hydrogenated vegetable oil, and hardened soybean oil. In addition to oils and fats such as keratinized oils, carnauba wax, bleached beeswax, beeswax, and Japanese wax, dextrose Phosphorus, pullulan, acacia gum, agar, gelatin, tragacanth, sodium alginate Examples include polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, etc. These can be used individually or in combination of two or more types. The total content of the binder is preferably 0.001 to 30% by mass relative to the total mass of the pharmaceutical composition. The percentage is %, more preferably 1 to 25% by mass, and particularly preferably 2 to 20% by mass.

[0028] Examples of lubricants include calcium stearate and magnesium stearate. Examples include sodium stearate and sodium stearyl fumarate. These are used in combinations of one or more types. They can be used together. The total content of the lubricant is preferably 0.01 to 15% by mass relative to the total mass of the pharmaceutical composition. More preferably, it is 0.1 to 10% by mass.

[0029] Examples of plasticizers include triethyl citrate, sesame oil, castor oil, and polysorbate. Examples include Rubate 80 (polyoxyethylene (20) sorbitan oleate ester). These can be used individually or in combination of two or more types. The total content of plasticizers is preferably 0.01 to 5% by mass, relative to the total mass of the pharmaceutical composition. More preferably, it is 0.1 to 1% by mass.

[0030] Specifically, examples of film-forming agents include alginic acid such as sodium alginate or Examples include salt, carrageenan, xanthan gum, pullulan, etc. These are one type or Two or more types can be used in combination.

[0031] The powders include talc, titanium dioxide, yellow iron(III) oxide, iron(III) oxide, and organic dyes such as legally approved dyes. Examples include powders or inorganic powders. These can be used individually or in combination of two or more types. It is possible. The total powder content is preferably 0.005 to 3% by mass relative to the total mass of the pharmaceutical composition. More preferably, it is 0.01 to 2% by mass.

[0032] Examples of antioxidants include ascorbic acid, sodium bisulfite, and sulfur dioxide. Sodium edetate, sodium erythorbic acid, tocopherol acetate, dibutyl hydroxypropyl alcohol Droxytoluene, natural vitamin E, tocopherol, butylhydroxyanisole, etc. These can be listed. They can be used individually or in combination of two or more types.

[0033] Examples of flavoring agents include limonene, pinene, camphene, cymene, and cine. ol, citronellol, geraniol, nerol, linalool, menthol, terpine Ole, rhozinol, borneol, isoborneol, menthone, camphor, eugenol Terpenes such as lichen, synzeylanol; spruce oil, orange oil, peppermint oil, camphor oil, yu Potassium oil, turpentine oil, lemon oil, ginger oil, clove oil, cinnamon oil, lavender Oils, essential oils containing terpenes such as fennel oil, chamomile oil, perilla oil, and spearmint oil; Examples of acidulants include ascorbic acid, tartaric acid, citric acid, malic acid, and their salts. These can be used individually or in combination of two or more types.

[0034] Examples of sweeteners include aspartame, stevia, sucralose, and glycyrrhizin. Examples include acids, thaumatin, acesulfame potassium, saccharin, and sodium saccharin. These can be used in combination of one or more types.

[0035] The pharmaceutical compositions used in this invention can be manufactured by known methods depending on their dosage form. ru. For example, if the pharmaceutical composition is a solid dosage form, the processes may include crushing, mixing, granulation, drying, sizing, and classification. It can be manufactured by appropriately combining unit operations such as filling, tableting, and coating. can. More specifically, for example, in the case where the dosage form of the pharmaceutical composition is a granular preparation such as granules, powders, or pills. pemafibrates or their salts or solvates thereof, (meth)acrylic acid polymers In addition to these, excipients, binders, disintegrants, lubricants, and other formulation additives are used as needed. After mixing the components, extrusion granulation, rolling granulation, agitation granulation, fluid bed granulation, spray granulation, and melt granulation are performed. Granulation is performed using known granulation methods such as crushing and granulation to obtain granulated material, and then classification and processing are performed as necessary. It can be manufactured by forming granules, etc. The obtained granules can be coated by known methods. It can also be coated with a coating agent or similar. Furthermore, if the dosage form of the pharmaceutical composition is a tablet, pemafibrate or its salt or the same In addition to solvates and (meth)acrylic acid polymers, excipients, binders, and disintegrants may be used as needed. Using appropriate pharmaceutical additives such as lubricants, these components are mixed to obtain a mixture, and this mixture is directly Compression (tableting) (direct powder compression method), and classification and sizing of the above granules as needed. After that, the material is compressed (tabletized) (semi-dry granular compression method, dry granular compression method, wet granular compression method, etc.) It can be manufactured by ( ). The resulting compressed material (tablet) can be manufactured by known methods It can also be covered with a coating agent or similar material. Furthermore, if the dosage form of the pharmaceutical composition is a capsule, the above-mentioned granules or compressed material is placed inside the capsule. Just fill it in.

[0036] In this specification, "airtight packaging" means that under normal handling, transportation, or storage conditions... This refers to packaging that can prevent the entry of solid or liquid foreign matter, as defined in the General Rules of the 17th Revised Japanese Pharmacopoeia. This concept encompasses the definitions of "airtight containers" and "sealed containers." As for airtight packaging, Both standard and irregular shapes can be used, specifically for example, bottle packaging, SP (Strip Package) packaging, PTP (Press Through Pack) Examples include age) packaging, pillow packaging, stick packaging, etc. As for airtight packaging, this It may also be a combination of multiple such components. Specifically, for example, the pharmaceutical composition may first be prepared using PTP (Press-Through Packaging). One possible method is to package the product in packaging and then further package it in pillow packaging.

[0037] As a packaging material (material) for airtight packaging, it is possible to suppress the intrusion of solid or liquid foreign matter. If so, it is not particularly limited, and for example, in fields such as pharmaceuticals and food products, moisture protection for contents that are sensitive to moisture. Materials used for purposes such as these can be used as appropriate. Examples of materials used for the bottle body in bottle packaging include glass, plastic (polyester). Polyethylene (low density (LDPE), medium density (MDPE), high density (HDPE)) (including), polycarbonate, polystyrene, polypropylene, etc.), metal (aluminum) Examples include the following. When packaging in bottles, for example, the pharmaceutical composition can be placed inside a commercially available bottle. Store an appropriate quantity in the container, and then seal it with a suitable stopper or lid. Note that the bottle is used for storage. The appropriate size should be selected according to the quantity of the pharmaceutical composition, etc., and the bottle capacity is as follows: For example, it is about 10-500 mL, preferably 14-400 mL, and 24-350 mL. More preferable. Glass, polyethylene, and polypropylene are preferred materials for bottle packaging. Glass, low-density polyethylene (LDPE), and high-density polyethylene (HDPE) are good options. Glass and high-density polyethylene (HDPE) are particularly preferred.

[0038] Furthermore, packaging materials used in SP packaging, PTP packaging, pillow packaging, stick packaging, etc. For example, biaxially oriented polypropylene (OPP), biaxially oriented polyester (PET), Glycol-modified PET (PET-G), biaxially oriented nylon (ONy, PA), cellophane, Paper, low-density polyethylene (LDPE), linear low-density polyethylene (L-LDPE), E Thiene-vinyl acetate copolymer (EVA), unoriented polypropylene (CPP, IPP), A Ionomer resin (IO), ethylene-methacrylic acid copolymer (EMAA), polyacrylo Nitrile (PAN), biaxially oriented polyvinylidene chloride (PVDC), ethylene-vinyl aluminum Coal copolymer resin (EVOH), polyvinyl chloride (PVC), cyclic polyolefin (CO C) Unstretched nylon (CNy), polycarbonate (PC), polystyrene (PS), Examples include resins such as rigid polyvinyl chloride (VSC) and metal foils such as aluminum foil (AL). These may be combined in any way to form a multilayer structure. Structurally, for example, it is made by laminating PVC and PVDC (PVC / PVDC; the same applies hereafter). Abbreviated notation is used. ), PVC / PVDC / PE / PVC, PVC / PVDC / PE / PVDC / PVC, CPP / COC / CPP, PVC / AL, CPP / AL, CPP / C Examples include PP / CPP. Methods for forming such a multilayer structure include extrusion lamination. Lamination methods include dry lamination, co-extrusion lamination, thermal lamination, and wet lamination. Examples include known lamination methods such as non-solvent lamination and heat lamination. Packaging materials used in SP packaging, PTP packaging, pillow packaging, stick packaging, etc. Polyvinyl chloride and aluminum foil are preferred.

[0039] The form of PTP packaging is such that a desired number of pockets are formed in a resin sheet or the like using a known method. The pharmaceutical composition is stored one unit or one dose unit at a time, and then metal foil such as aluminum foil is used as a constituent material. One method is to use the sheet material as a lid to cover it. Furthermore, a pocket can be formed. The sheet used is a sheet with aluminum foil as a constituent material, a so-called double-sided aluminum sheet. It may also be packaged in PTP packaging. In the present invention, from the viewpoint of storage stability, PTP packaging is used. Furthermore, it is preferable to package them in pillow packaging (for example, aluminum pillow packaging). As for the form of SP packaging, pillow packaging, and stick packaging, resin sheets and A are used by known methods. Using sheets or the like that made of aluminum foil as a constituent material, the pharmaceutical composition is divided into one unit or one dose unit. One example is packaging. In the present invention, from the viewpoint of storage stability, aluminum foil It is preferable to use a sheet made of the following material.

[0040] In this specification, the occupancy rate (volume ratio) of the pharmaceutical composition within the packaging of a pharmaceutical product is defined as the occupancy rate (volume ratio). ) When the packaging is in glass bottles, the percentage is usually 25-90%, preferably 28-75%. 30-50% is more preferable. Also, the packaging is SP packaging, PTP packaging, pillow packaging, ste For bulk packaging, the humidity is typically 30-98%, preferably 40-95%, and 45-93%. More preferably, and 50-90% is particularly preferred. In this case, the occupancy rate is: This refers to the percentage of the total volume inside the packaging that is occupied by the pharmaceutical composition. When calculating the space occupancy rate, packing materials and stoppers used to prevent damage to the delivered pharmaceutical composition should be considered. It is not something that should be considered.

[0041] As for the airtight packaging, commercially available packaging can be used as is, or commercially available packaging materials can be added. It may be modified for use. Examples of commercially available bottle packaging include the Z-series (Hanshin Examples include those manufactured by Kasei Kogyo Co., Ltd., and the A-series (manufactured by Isoya Glass Industry Co., Ltd.). Also, SP packaging, P For TP packaging, pillow packaging, and stick packaging, Sumilight VSS and Sumilight are used as packaging materials. Light VSL, Sumilight NS, Sumilight FCL (all manufactured by Sumitomo Bakelite Co., Ltd.), T AS series (manufactured by Taisei Chemical Co., Ltd.), PTP vinyl foil, PTP super foil (all of the above, Mitsubishi Plastics Ltd., Nippaku Aluminum Foil (Nippon Foil Co., Ltd.), Plain Silver Aluminum Foil (Yamato Chemical Industry Co., Ltd.) Examples include (manufactured by...).

[0042] The method of enclosing the pharmaceutical composition in an airtight package is not particularly limited, and the contents of the package This can be achieved by placing the pharmaceutical composition inside the packaging by appropriate means such as adding the pharmaceutical composition. In this case, a desiccant (for example, cylindrical tablets) is placed inside the packaging along with the pharmaceutical composition. A method for introducing molded or sheet-like materials may also be used.

[0043] The diseases to which the pharmaceutical product of this invention may be applied are not limited in any way, but may include those currently known or to be discovered in the future. Furthermore, it is widely used for the prevention or treatment of diseases in which pemafibrate administration is considered effective. It is possible. For example, pemafibrates or their salts or solvates are excellent PPARα It possesses gonist activity, leading to a decrease in plasma triglyceride concentration and an increase in HDL cholesterol, etc. It has the effect of [details omitted]. Therefore, the pharmaceutical product of the present invention is preferably used for dyslipidemia (hyperlipidemia, more detailed For example, it is used as a preventive and / or therapeutic agent for primary hyperlipidemia, secondary hyperlipidemia, etc. Furthermore, it can be preferably used as a preventive and / or therapeutic agent for hypertriglyceridemia. Furthermore, pemafibrates or their salts or solvates thereof are NAFLD (non-alkaline). It is useful for the prevention or treatment of cholesterol-related fatty liver disease. Therefore, the pharmaceutical product of the present invention is NA Prevention and / or treatment of FLD (more preferably NASH (non-alcoholic steatohepatitis)) It can also be used as a pharmaceutical agent. Furthermore, pemafibrates or their salts or solvates are used to treat primary biliary cirrhosis. It may also be used as a treatment for malformations, etc.

[0044] The route of administration of the pharmaceutical composition used in this invention is not particularly limited, and depends on the disease to which it is applied, the type of formulation, etc. The dosage can be determined by considering the gender, age, symptoms, etc. of the person taking the medication, but ease of administration From a sexual standpoint, oral administration is preferred. Furthermore, the pharmaceutical composition should be administered 1 to 4 times per day (preferably...). It can be taken in divided doses (approximately once a day) before meals, between meals, after meals, before bedtime, etc.

[0045] This specification is not limited to these, but discloses, for example, the following embodiments. do. [1-1] The following components (A) and (B): (A) Pemafibrates or salts thereof, or solvates thereof; (B)(meth)acrylic acid polymers; A pharmaceutical product comprising a pharmaceutical composition containing the above, contained in an airtight package. [1-2] Component (B) is acrylic acid, methacrylic acid, methyl methacrylate, acrylic acid Ethyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate, and methacrylic acid Polymerization derived from one or more monomers selected from the group consisting of trimethylammonium ethyl chloride. The drug in question is the one described in [1-1]. [1-3] Component (B) is ethyl acrylate / methyl methacrylate copolymer, amine Noalkyl methacrylate copolymer E, ammoniaalkyl methacrylate copolymer , carboxyvinyl polymer, methacrylic acid copolymer S, methacrylic acid copolymer L and One or more selected from the group consisting of methacrylate copolymer LD, as described in [1-1]. Pharmaceuticals. [1-4] Component (B) is aminoalkyl methacrylate copolymer E, ammonia Alkyl methacrylate copolymer, methacrylate copolymer S, methacrylate copolymer - One or more selected from the group consisting of L and methacrylic acid copolymer LD, [1-1 The listed pharmaceuticals. [1-5] The pharmaceutical composition is a solid dosage form, as described in any of [1-1] to [1-4]. Pharmaceuticals. [1-6] The pharmaceutical composition is a tablet, capsule, granule, powder or pill, [1- A medicine listed in any of the following categories: [1] to [1-5]. [1-7] Airtight packaging includes bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging. One or more types selected from the group consisting of [1-1] to [1-6]. Listed medicines. [1-8] Dyslipidemia (hyperlipidemia, more specifically, primary hyperlipidemia, secondary hyperlipidemia) Lipidemia, etc.), NAFLD (more preferably NASH (non-alcoholic steatohepatitis)), and It is a preventive and / or therapeutic agent for diseases selected from primary biliary cirrhosis, [1-1]~[1 A medicine listed in any of the following -7].

[0046] [2-1] The following components (A) and (B): (A) Pemafibrates or salts thereof, or solvates thereof; (B)(meth)acrylic acid polymers; A method for stabilizing a pharmaceutical composition, comprising the step of housing the pharmaceutical composition containing in an airtight package. [2-2] Component (B) is acrylic acid, methacrylic acid, methyl methacrylate, acrylic acid Ethyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate, and methacrylic acid Polymerization derived from one or more monomers selected from the group consisting of trimethylammonium ethyl chloride. The method described in [2-1] is a body. [2-3] Component (B) is ethyl acrylate / methyl methacrylate copolymer, amine Noalkyl methacrylate copolymer E, ammoniaalkyl methacrylate copolymer , carboxyvinyl polymer, methacrylic acid copolymer S, methacrylic acid copolymer L and One or more selected from the group consisting of methacrylate copolymer LD, as described in [2-1]. The method. [2-4] Component (B) is aminoalkyl methacrylate copolymer E, ammonia Alkyl methacrylate copolymer, methacrylate copolymer S, methacrylate copolymer - One or more selected from the group consisting of L and methacrylic acid copolymer LD, [2-1 The method described. [2-5] The pharmaceutical composition is a solid dosage form, as described in any of [2-1] to [2-4]. The method. [2-6] The pharmaceutical composition is a tablet, capsule, granule, powder or pill, [2- One of the methods described in [1] to [2-5]. [2-7] Airtight packaging includes bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging. One or more types selected from the group consisting of [2-1] to [2-6]. Method of loading. [2-8] Dyslipidemia (hyperlipidemia, more specifically, primary hyperlipidemia, secondary hyperlipidemia) Lipidemia, etc.), NAFLD (more preferably NASH (non-alcoholic steatohepatitis)), and It is a preventive and / or therapeutic agent for diseases selected from primary biliary cirrhosis, [2-1]~[2 -7] One of the methods described below.

[0047] [3-1] The following components (A) and (B) for containment in an airtight package: (A) Pemafibrates or salts thereof, or solvates thereof; (B)(meth)acrylic acid polymers; A pharmaceutical composition containing the following: [3-2] Component (B) is acrylic acid, methacrylic acid, methyl methacrylate, acrylic acid Ethyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate, and methacrylic acid Polymerization derived from one or more monomers selected from the group consisting of trimethylammonium ethyl chloride. The pharmaceutical composition described in [3-1]. [3-3] Component (B) is ethyl acrylate / methyl methacrylate copolymer, amine Noalkyl methacrylate copolymer E, ammoniaalkyl methacrylate copolymer , carboxyvinyl polymer, methacrylic acid copolymer S, methacrylic acid copolymer L and One or more selected from the group consisting of methacrylate copolymer LD, as described in [3-1]. A pharmaceutical composition. [3-4] Component (B) is aminoalkyl methacrylate copolymer E, ammonia Alkyl methacrylate copolymer, methacrylate copolymer S, methacrylate copolymer - One or more selected from the group consisting of L and methacrylic acid copolymer LD, [3-1 The pharmaceutical composition described in [ ]. [3-5] A pharmaceutical composition described in any of [3-1] to [3-4], which is a solid dosage form. [3-6] Tablets, capsules, granules, powders, or pills, [3-1]~[3-5 A pharmaceutical composition as described in any of the following: [3-7] Airtight packaging includes bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging. One or more types selected from the group consisting of [3-1] to [3-6]. A listed pharmaceutical composition. [3-8] Dyslipidemia (hyperlipidemia, more specifically, primary hyperlipidemia, secondary hyperlipidemia) Lipidemia, etc.), NAFLD (more preferably NASH (non-alcoholic steatohepatitis)), and It is a preventive and / or therapeutic agent for diseases selected from primary biliary cirrhosis, [3-1]~[3 A pharmaceutical composition as described in any of the following -7]. [Examples]

[0048] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way by these examples. It is not something that should be done.

[0049] [Test Example 1] Stability Test After preparing samples 1-1 to 1-4 shown below, set them at 40°C and 75% relative humidity (RH) The samples were stored for one month under the following conditions, and the changes in the state of the samples immediately after the start of storage and after one month were observed. We evaluated whether or not there was a change in the formulation and confirmed whether or not there was a change in the composition. The results are shown in Table 1.

[0050] [Sample 1-1] Place the pemafibrate in an open glass container and use it as is for sample 1-1. Ta. [Sample 1-2] Aminoalkyl methacrylate copolymer E (Eudragit EPO: Evonik Rohm GmbH) The sample was placed in an open glass container and designated as Sample 1-2. [Sample 1-3] Per 1 part by mass of pemafibrate, aminoalkyl methacrylate copolymer E (Oil A mixture is obtained by mixing Dragit EPO (Evonik Rohm GmbH) at a ratio of 1 part by mass, and this is then used. The samples were placed in open glass containers and designated as Samples 1-3. [Sample 1-4] Per 1 part by mass of pemafibrate, aminoalkyl methacrylate copolymer E (Oil A mixture was obtained by mixing Dragit EPO (Evonik Rohm GmbH) at a ratio of 1 part by mass. Place 0.25g of the mixture into a glass bottle (2K standard bottle: Isoya Glass Industry) and close the lid. These were designated as Samples 1-4.

[0051] [Table 1]

[0052] From the test results shown in Table 1, in sample 1-1, which used only pemafibrate, for 1 month... Even after storage, the white powder state is maintained, just as it was immediately after storage began. In samples 1-2 containing only rate copolymer E, a slight discoloration from white to a faint yellow was observed. While it is only compressed and remains in a state that is almost unchanged as a powder, pemafibros In samples 1-3, which were a mixture of t and aminoalkyl methacrylate copolymer E, A change in composition occurred, causing the mixture to melt and transform significantly from a powder to a candy-like consistency. On the other hand, pemafibrate and aminoalkyl methacrylate copolymer E are mixed, In samples 1-4, which were contained in airtight packaging, the results after one month of storage were the same as immediately after storage began. Similarly, it was found that the white powdery state was maintained.

[0053] Based on the above test results, pemafibrate and aminoalkyl methacrylate copolymer The compound changes between (meth)acrylic acid polymers, such as E, are contained in airtight packaging. It became clear that this would suppress the effect.

[0054] [Manufacturing Examples 1-9] Tablets (Examples 1-9) containing the ingredients and quantities (mg) listed in Tables 2-4 per tablet are manufactured by conventional methods. Manufactured by [method], and housed in high-density polyethylene bottles, each as shown in Production Example 1~ Obtain 9 medicines.

[0055] [Table 2]

[0056] [Table 3]

[0057] [Table 4]

[0058] [Manufacturing Examples 10-18] Tablets (Examples 1-9) containing the ingredients and quantities (mg) listed in Tables 2-4 per tablet are manufactured by conventional methods. Manufactured using a resin sheet with pre-formed pocket sections (Sumitomo Bakelite Co., Ltd.: product name). Place it in the pocket of the Sumilight VSS-1202, then put in aluminum foil for PTP (Yamato The product is sealed with aluminum foil (plain silver) manufactured by Chemical Industry Co., Ltd. and packaged in PTP packaging. The packaging consists of three sheets (each sheet containing 10 tablets), which are then further packaged in aluminum pillow packaging. Each of the 10 to 18 pharmaceutical products can be obtained through manufacturing.

[0059] [Manufacturing Examples 19-27] Tablets (Examples 1-9) containing the ingredients and quantities (mg) listed in Tables 2-4 per tablet are manufactured by conventional methods. Manufactured using a resin sheet with pre-formed pocket sections (Sumitomo Bakelite Co., Ltd.: product name). Place it in the pocket of the Sumilight VSS-1104, then put in aluminum foil for PTP (Yamato The product is sealed with aluminum foil (plain silver) manufactured by Chemical Industry Co., Ltd. and packaged in PTP packaging. Two packs (each containing 12 tablets) are packaged in aluminum pillow packaging, and each Pharmaceuticals can be obtained as shown in manufacturing examples 19-27.

[0060] [Manufacturing Examples 28-36] Tablets (Examples 1-9) containing the ingredients and quantities (mg) listed in Tables 2-4 per tablet are manufactured by conventional methods. Manufactured using a resin sheet with pre-formed pocket sections (Sumitomo Bakelite Co., Ltd.: product name). Place it in the pocket of the Sumilight VSL-4501, then put in aluminum foil for PTP (Yamato The product is sealed with aluminum foil (plain silver) manufactured by Chemical Industry Co., Ltd. and packaged in PTP packaging. The packaging consists of three sheets (each sheet containing 10 tablets), which are then further packaged in aluminum pillow packaging. Each of the manufacturing examples 28-36 can be obtained.

[0061] [Manufacturing Examples 37-45] Tablets (Examples 1-9) containing the ingredients and quantities (mg) listed in Tables 2-4 per tablet are manufactured by conventional methods. By manufacturing and housing the products in glass bottles, pharmaceuticals can be obtained as shown in manufacturing examples 37-45. Cut.

[0062] [Manufacturing Examples 46-54] Tablets (Examples 1-9) containing the ingredients and quantities (mg) listed in Tables 2-4 per tablet are manufactured by conventional methods. Manufactured by [company name], and SP-packaged in strip packaging aluminum foil (manufactured by Nissan Chemical Co., Ltd.), and each product is manufactured by [company name]. Pharmaceuticals can be obtained as shown in examples 46-54. [Industrial applicability]

[0063] According to the present invention, a decrease in plasma triglyceride concentration and an increase in HDL cholesterol, etc. This provides a pharmaceutical composition containing pemafibrate that exhibits efficacy and has excellent storage stability. For example, it can be used in the pharmaceutical industry, etc.

Claims

[Claim 1] The invention described in the specification.

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