Pharmaceuticals

Abstract

This invention provides a technology to suppress changes in the formulation between pemafibrate or its salts or solvates and alkylcelluloses. [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) alkylcelluloses; 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]

Chemical Formula

[0004] Pemafibrate represented by (chemical name: (2R)-2-[3-({1,3-benzoxa zol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)pheno xy]butanoic acid ((2R)-2-[3-([1,3-Benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino methyl)phenoxy]butanoic acid), international common name: Pemafibrate), or a salt thereof or a solvate thereof has excellent PPARα agonist activity 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, 2), and for the prevention and treatment of NAFLD (non-alcoholic fatty liver disease) (Patent Document 2). It is known that a compound useful as an active ingredient of a pharmaceutical is usually formulated as a pharmaceutical composition and administered.

[0005] However, 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. becomes.​​ [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. For the development of a pharmaceutical composition containing a Wajimono, the storage stability when using various formulation additives was examined. However, although pemafibrate itself is extremely stable, when alkyl celluloses typified by ethyl cellulose coexist, a formulation change occurs, and a problem of storage stability such as solidification of the mixture over time has been found. Nevertheless, even though pemafibrate itself is extremely stable, when alkyl celluloses typified by ethyl cellulose coexist, a formulation change occurs, and a problem of storage stability such as solidification of the mixture over time has been found. Nevertheless, even though pemafibrate itself is extremely stable, when alkyl celluloses typified by ethyl cellulose coexist, a formulation change occurs, and a problem of storage stability such as solidification of the mixture over time has been found. has been found. Therefore, an object of the present invention is to provide a technique for suppressing a formulation change between pemafibrate or its salt or their solvates and alkyl celluloses. Therefore, an object of the present invention is to provide a technique for suppressing a formulation change between pemafibrate or its salt or their solvates and alkyl celluloses.

Means for Solving the Problems

[0009] Therefore, as a result of further examination in view of the above situation, the present inventor found that a pharmaceutical composition containing pemafibrate or its salt or their solvates and alkyl celluloses can suppress a formulation change by being housed in an airtight package such as a bottle package or a PTP package, and completed the present invention. That is, the present invention provides a pharmaceutical product in which a pharmaceutical composition containing the following components (A) and (B): is housed in an airtight package. has been found and the present invention has been completed.

[0010] That is, the present invention provides a pharmaceutical product in which a pharmaceutical composition containing the following components (A) and (B): (A) Pemafibrate or its salt or their solvates; (B) Alkyl celluloses; is housed in an airtight package.

[0011] Further, the present invention provides a method for stabilizing a pharmaceutical composition, which includes a step of housing a pharmaceutical composition containing the following components (A) and (B): (A) Pemafibrate or its salt or their solvates; (B) Alkyl celluloses; in an airtight package. is provided.

Effects of the Invention

[0012] According to the present invention, changes in the composition of pemafibrate and alkylcelluloses are suppressed. This allows us to provide pharmaceuticals with 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] <Alkylcellulose> In this specification, "alkylcelluloses" means all of the hydroxyl groups of cellulose. or one or more compounds selected from the group consisting of compounds in which a portion is substituted with an alkoxy group and salts thereof. This means that the above alkoxy group has 1 to 6 carbon atoms (more preferably 1 to 3 carbon atoms). A linear or branched alkoxy group (e.g., a methoxy group, an ethoxy group, etc.) is preferred. Here, the term "salt" is not particularly limited; specifically, it could refer to sodium salts, potassium salts, etc. Alkali metal salts; examples include salts with metals of Group 2 elements such as calcium salts and magnesium salts. Furthermore, the substitution rate of alkoxy groups in alkylcelluloses is preferably in the range of 20-70%. More preferably, the range is 40-60%. The determination of the group substitution rate is based on the determination of the methoxy group of methylcellulose as described in the 17th edition of the Japanese Pharmacopoeia. The method should be carried out according to the specified method. Furthermore, the viscosity of alkylcelluloses should be between 0.1 and 5000 mPa. s is preferred, and 1 to 200 mPa·s is more preferred. Note that the viscosity of alkylcelluloses The viscosity measurement shall be performed in accordance with the method for measuring the viscosity of methylcellulose described in the 17th edition of the Japanese Pharmacopoeia. Examples of such alkylcelluloses include methylcellulose and ethylcellulose. Examples include cellulose, and these can be used individually or in combination of two or more. It may be used. Furthermore, the alkyl group in the alkylcellulose is not particularly limited. However, linear or branched alkyl groups with 1 to 6 carbon atoms (more preferably 1 to 3 carbon atoms) are not available. A lu group is preferred. As for alkylcelluloses, ethylcellulose is used from the viewpoint of suppressing changes in formulation. preferable. Furthermore, these alkylcelluloses are all known components and can be processed by known methods. You may manufacture and use it yourself, or you may use a commercially available product. Examples of such commercially available products include... For example, METOLOSE SM (Shin-Etsu Chemical Co., Ltd.), Metrose (San-Ei Gen F.F.I.) ), Methocel A (Dow Chemical Japan), Etocel (Dow Chemical Japan Ltd.), Aquaco Examples include Asahi Kasei Chemicals.

[0017] The content of alkylcelluloses in a pharmaceutical composition is not particularly limited, and the type of formulation and the amount of alcohol used are not limited. The formula can be determined by considering the user's gender, age, symptoms, etc., as appropriate, but the formula must be carefully formulated to minimize changes in composition. From a production standpoint, the total amount of alkylcelluloses relative to the total mass of the pharmaceutical composition is 0 Preferably, it is 0.001 to 55% by mass, and more preferably 0.005 to 30% by mass. More preferably 0.01 to 20% by mass, and particularly 0.3 to 5% by mass. Preferably, especially when ethylcellulose is used as the alkylcellulose. From the viewpoint of suppressing changes in formulation, the amount should be 0.05 to 55% by mass relative to the total mass of the pharmaceutical composition. It is preferable that the amount be 0.075 to 15% by mass, and more preferably 0.1 to 10% by mass. It is even more preferable that it is 0.5 to 3% by mass.

[0018] In pharmaceutical compositions, pemafibrate or its salt or its solvate and alkyl The mass ratio of cellulose is not particularly limited, but from the perspective of suppressing changes in formulation For every 1 part by mass of pemafibrate (in terms of free form), alkylcelluloses total 0 Preferably, it contains 0.001 to 500 parts by mass, and preferably 0.01 to 100 parts by mass. Preferably, it contains 0.5 to 50 parts by mass. In particular, alkylcellulose When using ethylcellulose as a compound, from the viewpoint of suppressing changes in formulation, For every 1 part by mass of mafibrate (in terms of free form), add 0.005 to 30 parts ethylcellulose. Preferably, it contains 0 parts by mass, more preferably 0.01 to 75 parts by mass, and 1 to It is particularly preferable to contain 20 parts by mass.

[0019] 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.

[0020] 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.

[0021] 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, poorly water-soluble polymers, antioxidants These include, but are not limited to, flavoring agents and sweeteners. Examples of pharmaceutical additives include, for instance, the Pharmaceutical Additives Dictionary 2016 (Yakuji Nippo Co., Ltd.). (Published by the company), Handbook of Pharmaceutical Excipients, Seventh Edition (Pharmaceutical You can use materials included in publications such as those published by Press.

[0022] 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, Aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate Examples include organic excipients such as tate and calcium citrate. These are either one or two types. The above can be used in combination. 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.

[0023] 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.

[0024] 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 Polyvinyl alcohol, aminoalkyl methacrylate copolymer E, polyvinyl alcohol Examples include cetal diethylaminoacetate. These are used in combination of one or more types. They can be used together. 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] Examples of poorly water-soluble polymers include carboxyvinyl polymers and amino acids. Examples include alkyl methacrylate copolymers. These are used in combination of one or more types. They can be used together. 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.

[0030] 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.

[0031] 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.

[0032] 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. In addition to pemafibrates or their salts or solvates thereof, alkylcelluloses Then, as necessary, excipients, binders, disintegrants, lubricants, and other formulation additives are used, and these components After mixing, extrusion granulation, rolling granulation, agitation granulation, fluid bed granulation, spray granulation, melt granulation, crushing granulation Granulation is performed using known granulation methods to obtain granulated material, and further classification, sizing, etc., are carried out as necessary. It can be manufactured by this method. The obtained granules can then be coated by a known method. It can also be covered with an agent or similar substance. Furthermore, if the dosage form of the pharmaceutical composition is a tablet, pemafibrate or its salt or the same In addition to solvates and alkylcelluloses, excipients, binders, disintegrants, and lubricants may be added as needed. Using appropriate pharmaceutical additives such as these, these components are mixed to obtain a mixture, which is then directly compressed (by impact). This involves (direct powder compression method) or, if necessary, classifying and sizing the above granules. By compression (tableting) (semi-dry granular compression method, dry granular compression method, wet granular compression method, etc.) It can be manufactured by [method]. The resulting compressed material (tablet) can be coated by a known method. It can also be coated with a coating agent or similar. 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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 the A-series (manufactured by Kasei Kogyo Co., Ltd.) and the A-series (manufactured by Isoya Glass Industry Co., Ltd.). Also, SP packaging and PT packaging are used. For packaging materials used in P packaging, pillow packaging, and stick packaging, we have Sumilight VSS and Sumilight. Ito VSL, Sumilight NS, Sumilight FCL (all manufactured by Sumitomo Bakelite Co., Ltd.), TA S Series (manufactured by Taisei Chemical Co., Ltd.), PTP vinyl foil, PTP Super Foil (all three (Manufactured by Hishi Resin Co., Ltd.), Nippaku Aluminum Foil (Manufactured by Nippon Foil Co., Ltd.), Plain Silver Aluminum Foil (Manufactured by Yamato Chemical Industry Co., Ltd.) Examples include:

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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) Alkylcelluloses; A pharmaceutical product comprising a pharmaceutical composition containing the above, contained in an airtight package. [1-2] Component (B) is a cellulose hydroxyl group having 1 to 6 carbon atoms, in whole or in part. A selection from the group consisting of compounds substituted with linear or branched alkoxy groups and salts thereof. One or more of the pharmaceutical products listed in [1-1]. [1-3] Component (B) is selected from the group consisting of methylcellulose and ethylcellulose. One or more of the drugs listed in [1-1] that are detectable. [1-4] The pharmaceutical composition is a solid dosage form, as described in any of [1-1] to [1-3]. Pharmaceuticals. [1-5] The pharmaceutical composition is a tablet, capsule, granule, powder or pill, [1- A medicine listed in any of the following categories: [1] to [1-4]. [1-6] 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 [1-5]. Listed medicines. [1-7] 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 -6].

[0043] [2-1] The following components (A) and (B): (A) Pemafibrates or salts thereof, or solvates thereof; (B) Alkylcelluloses; 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 a cellulose hydroxyl group having 1 to 6 carbon atoms, in whole or in part A selection from the group consisting of compounds substituted with linear or branched alkoxy groups and salts thereof. The method described in [2-1], wherein one or more types are included. [2-3] Component (B) is selected from the group consisting of methylcellulose and ethylcellulose. The method described in [2-1], which involves one or more types of detection. [2-4] The pharmaceutical composition is a solid dosage form, as described in any of [2-1] to [2-3]. The method. [2-5] The pharmaceutical composition is in the form of tablets, capsules, granules, powders or pills, [2- One of the methods described in [1] to [2-4]. [2-6] 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 [2-5]. Method of loading. [2-7] 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 -6] One of the methods described below.

[0044] [3-1] The following components (A) and (B) for containment in an airtight package: (A) Pemafibrates or salts thereof, or solvates thereof; (B) Alkylcelluloses; A pharmaceutical composition containing the following: [3-2] Component (B) is a cellulose hydroxyl group having 1 to 6 carbon atoms, in whole or in part. A selection from the group consisting of compounds substituted with linear or branched alkoxy groups and salts thereof. A pharmaceutical composition according to [3-1], comprising one or more of the following types. [3-3] Component (B) is selected from the group consisting of methylcellulose and ethylcellulose. A pharmaceutical composition described in [3-1] that is one or more of the following: [3-4] A solid dosage form of pharmaceutical composition as described in any of [3-1] to [3-3]. [3-5] Tablets, capsules, granules, powders, or pills, [3-1]~[3-4 A pharmaceutical composition as described in any of the following: [3-6] 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 [3-5]. A listed pharmaceutical composition. [3-7] 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 -6]. [Examples]

[0045] 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.

[0046] [Test Example 1] Stability Test After preparing samples 1-1 to 1-4 shown below, set them at 60°C and 80% relative humidity (RH) The samples were stored for 21 days under the following conditions, and the changes in the state of the samples were observed immediately after the start of storage and after 21 days. 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.

[0047] [Sample 1-1] Place the pemafibrate in an open glass container and use it as is for sample 1-1. Ta. [Sample 1-2] Ethyl cellulose (Etocell 10FP: Nisshin Kasei Co., Ltd.) in an open glass container. It was placed in a container and designated as Sample 1-2. [Sample 1-3] To 1 part by mass of pemafibrate, add ethylcellulose (Ethocell 10FP: Nisshin Kasei ( Mix the ingredients in a ratio of 1 part by mass to obtain a mixture, and put this into an open glass container. Therefore, we designated these as samples 1-3. [Sample 1-4] To 1 part by mass of pemafibrate, add ethylcellulose (Ethocell 10FP: Nisshin Kasei ( A mixture was obtained by mixing ()) in a ratio of 1 part by mass. Of the obtained mixture, 0.25 g was used The samples were placed in glass bottles (2K standard bottles: Isoya Glass Industry) and sealed, and these were designated as Samples 1-4.

[0048] [Table 1]

[0049] From the test results shown in Table 1, sample 1-1 contained only pemafibrate, and ethylcellulose. In samples 1-2, the white powdery state remained the same as immediately after storage, even after 21 days. While the properties are maintained, samples 1-3, which are a mixture of pemafibrate and ethylcellulose, In this case, a change in composition occurred, and the mixture solidified. On the other hand, pemafibrate and ethylcellulose were mixed and contained in an airtight package. In samples 1-4, the white powdery state was maintained even after 21 days of storage, just as it was immediately after storage began. It was found to drip.

[0050] Based on the above test results, pemafibrate and alkylcellulose represented by ethylcellulose Changes in the formulation with luroses can be suppressed by housing them in airtight packaging. It became clear.

[0051] [Manufacturing Examples 1-6] Tablets (Examples 1-6) containing the ingredients and quantities (mg) listed in Table 2 per tablet are manufactured by conventional methods. They are manufactured and then housed in high-density polyethylene bottles, as shown in each of the manufacturing examples 1 to 6. Obtain pharmaceuticals.

[0052] [Table 2]

[0053] [Manufacturing Examples 7-12] Tablets (Examples 1-6) containing the ingredients and quantities (mg) listed in Table 2 per tablet are manufactured by conventional methods. A resin sheet (manufactured by Sumitomo Bakelite Co., Ltd.: product name S) is manufactured and the pocket portion is pre-formed. Place it in the pocket of the Miraito VSS-1202, then put it in aluminum foil for PTP packaging (Yamato Chemical Co., Ltd.) The product is sealed with aluminum foil (plain silver) manufactured by Kogyosha and then packaged in PTP packaging. Three sheets (each sheet containing 10 tablets) are further packaged in aluminum pillow packaging, and each This allows us to obtain pharmaceuticals as shown in manufacturing examples 7-12.

[0054] [Manufacturing Examples 13-18] Tablets (Examples 1-6) containing the ingredients and quantities (mg) listed in Table 2 per tablet are manufactured by conventional methods. A resin sheet (manufactured by Sumitomo Bakelite Co., Ltd.: product name S) is manufactured and the pocket portion is pre-formed. Place it in the pocket of the Miraito VSS-1104, then put in aluminum foil for PTP (Yamato Chemical). The product is sealed with aluminum foil (plain silver) manufactured by Kogyosha and then packaged in PTP packaging. Two sheets (each sheet containing 12 tablets) are packaged in aluminum pillow packaging, and each is manufactured separately. Examples 13-18 of pharmaceuticals can be obtained.

[0055] [Manufacturing Examples 19-24] Tablets (Examples 1-6) containing the ingredients and quantities (mg) listed in Table 2 per tablet are manufactured by conventional methods. A resin sheet (manufactured by Sumitomo Bakelite Co., Ltd.: product name S) is manufactured and the pocket portion is pre-formed. Place it in the pocket of the Miraito VSL-4501, then put in aluminum foil for PTP packaging (Yamato Chemical). The product is sealed with aluminum foil (plain silver) manufactured by Kogyosha and then packaged in PTP packaging. Three sheets (each sheet containing 10 tablets) are further packaged in aluminum pillow packaging, and each This allows us to obtain pharmaceuticals as shown in manufacturing examples 19-24.

[0056] [Manufacturing Examples 25-30] Tablets (Examples 1-6) containing the ingredients and quantities (mg) listed in Table 2 per tablet are manufactured by conventional methods. By manufacturing and housing the products in glass bottles, you can obtain pharmaceuticals of production examples 25-30. .

[0057] [Manufacturing Examples 31-36] Tablets (Examples 1-6) containing the ingredients and quantities (mg) listed in Table 2 per tablet are manufactured by conventional methods. The products are manufactured and then SP-packaged using aluminum foil for strip packaging (manufactured by Nissan Chemical Co., Ltd.), and each is a manufacturing example. You can obtain 31 to 36 pharmaceuticals. [Industrial applicability]

[0058] 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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