阅读说明：本技术 医药品 (Pharmaceutical products ) 是由 杉本信 南园明人 于 2018-06-29 设计创作，主要内容包括：本发明提供一种改善含有培马贝特或其盐或者它们的溶剂合物和纤维素类的医药组合物的保存稳定性的新技术。一种医药品,其是通过将医药组合物收纳在气密包装体中而得到的,上述医药组合物含有以下的成分(A)和(B)：(A)培马贝特或其盐或者它们的溶剂合物；(B)纤维素类。(The present invention provides a novel technique for improving the storage stability of a pharmaceutical composition containing pemfibrate or a salt thereof or a solvate thereof and cellulose. A pharmaceutical product obtained by containing a pharmaceutical composition in an airtight package, the pharmaceutical composition comprising the following components (A) and (B): (A) pemabete or a salt thereof or a solvate thereof; (B) cellulose.)

1. A pharmaceutical product characterized by:

which is obtained by containing a pharmaceutical composition in an airtight package,

the pharmaceutical composition contains the following components (A) and (B):

(A) pemabete or a salt thereof or a solvate thereof;

(B) cellulose.

2. The pharmaceutical according to claim 1, wherein:

the component (B) is at least 1 selected from cellulose, C1-C6 alkyl cellulose, hydroxy C1-C6 alkyl cellulose, C1-C6 alkyl (hydroxy C1-C6 alkyl) cellulose, cross-linked polymer of carboxy C1-C6 alkyl cellulose and carboxy C1-C6 alkyl cellulose, and salt thereof.

3. The pharmaceutical according to claim 1 or 2, wherein:

the component (B) is at least 1 selected from the group consisting of cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, crosslinked carboxymethyl cellulose, and salts thereof.

4. The pharmaceutical according to any one of claims 1 to 3, wherein:

the pharmaceutical composition is a solid preparation.

5. The pharmaceutical according to any one of claims 1 to 4, wherein:

the pharmaceutical composition is a tablet, a capsule, a granule, powder or a pill.

6. The pharmaceutical according to any one of claims 1 to 5, wherein:

the airtight package is at least 1 selected from the group consisting of a bottle package, an SP package, a PTP package, a pillow package, and a stick package.

7. The pharmaceutical according to any one of claims 1 to 6, wherein:

the moisture content of the pharmaceutical composition is 3.4 mass% or less.

8. A method for stabilizing pemabefibrate or a salt thereof or a solvate of the same in a pharmaceutical composition, comprising:

comprising a step of storing the pharmaceutical composition in an airtight package,

the pharmaceutical composition contains the following components (A) and (B):

(A) pemabete or a salt thereof or a solvate thereof;

(B) cellulose.

Technical Field

The present invention relates to a pharmaceutical product and the like.

Background

Pemabete (chemical name: (2R) -2- [3- ({1, 3-Benzoxazol-2-yl [3- (4-methoxyphenoxy) propyl ] amino } methyl) phenoxy ] butanoic acid ((2R) -2- [3- ([1,3-Benzoxazol-2-yl [3- (4-methoxyphenoxy) propyl ] amino ] methyl) phenoxy ] butanoic acid), international common name: Pemafibrate), a salt thereof, or a solvate thereof, which has excellent PPAR α agonistic activity, shows an effect of lowering plasma triglyceride concentration, increasing HDL cholesterol, or the like, is useful for the prevention and treatment of dyslipidemia (hyperlipidemia) (patent document 1, non-patent documents 1, 2), and is useful for the prevention and treatment of NAFLD (non-alcoholic fatty liver disease) (patent document 2).

In addition, a compound useful as an active ingredient of a pharmaceutical is generally provided as a pharmaceutical composition formulated into a certain form, but the pharmaceutical composition usually takes a long time from the production to the administration. Therefore, from the viewpoint of achieving the desired medicinal effect and from the viewpoint of avoiding undesirable side effects, it is extremely important to ensure the storage stability of the active ingredient in the pharmaceutical composition.

Disclosure of Invention

Technical problem to be solved by the invention

However, the storage stability of the active ingredient is greatly affected by its physical and chemical properties, and as a result, the properties are often not predicted in advance from its chemical structure or the like, and it is not rare that problems can be clarified only when a pharmaceutical composition is actually produced.

In addition, only the pemfibrate or a salt thereof or a solvate of the pemfibrate or the salt thereof has been reported to exhibit the above-mentioned pharmacological effects, and there has been no specific study on the preparation of a pharmaceutical composition and no report on the storage stability of the pharmaceutical composition. In addition, pharmaceutical compositions are usually blended with various pharmaceutical additives in addition to the active ingredients.

Under such a background, the present inventors have studied the storage stability when various formulation additives are used in order to develop a pharmaceutical composition containing pemofibrate or a salt thereof or a solvate of the same. However, it was found that, even though pemfibrate itself is extremely stable under high humidity conditions, when pemfibrate itself coexists with cellulose such as hydroxypropyl cellulose, interaction occurs under high humidity conditions, decomposition products (analogous substances) of pemfibrate increase, and there is a problem in storage stability.

Accordingly, an object of the present invention is to provide a novel technique for improving the storage stability of a pharmaceutical composition containing pemabefibrate or a salt thereof or a solvate thereof and cellulose.

Means for solving the technical problem

In view of the above-mentioned situation, the present inventors have further studied and found that the interaction is caused by the invasion and contact of moisture in order to solve the problem of storage stability due to the interaction between pemofibrate or a salt thereof or a solvate thereof and cellulose. And found that: the present inventors have completed the present invention by storing a pharmaceutical composition containing pemfibrate, a salt thereof, or a solvate thereof and cellulose in an airtight package capable of suppressing substantial invasion of moisture, whereby the increase of decomposition products of pemfibrate can be suppressed and excellent storage stability can be obtained.

That is, the present invention provides a pharmaceutical product obtained by containing a pharmaceutical composition in an airtight package, the pharmaceutical composition containing the following components (a) and (B):

(A) pemabete or a salt thereof or a solvate thereof;

(B) cellulose.

Further, the present invention provides a method for stabilizing pemabefibrate, a salt thereof, or a solvate of the foregoing in a pharmaceutical composition, which comprises a step of storing the pharmaceutical composition in an airtight package, wherein the pharmaceutical composition comprises the following components (a) and (B):

(A) pemabete or a salt thereof or a solvate thereof;

(B) cellulose.

ADVANTAGEOUS EFFECTS OF INVENTION

The present invention can provide a pharmaceutical composition which is inhibited from increasing in the amount of decomposition products of pemabefibrate and has excellent storage stability.

Drawings

FIG. 1 is a graph showing the powder X-ray diffraction pattern of the crystals of Pemafibrate obtained in test example 6.

Detailed Description

Pesimofibrate or salt thereof or solvate of the same

In the present specification, "pemfibrate or a salt thereof or a solvate of the same" includes a pharmaceutically acceptable salt of pemfibrate, further a solvate of pemfibrate, a pharmaceutically acceptable salt thereof with water, an alcohol (e.g., ethanol), or the like, in addition to pemfibrate (chemical name: (2R) -2- [3- ({1, 3-Benzoxazol-2-yl [3- (4-methoxyphenoxy) propyl ] amino } methyl) phenoxy ] butyric acid ((2R) -2- [3- ([1,3-Benzoxazol-2-yl [3- (4-methoxyphenoxy) propyl ] amino ] methyl) phenoxy ] butanoic acid), international common name: Pemafibrate) itself. The pharmaceutically acceptable salt is not particularly limited, and examples thereof include acid addition salts and base addition salts. Specific examples of the acid addition salts include acid addition salts with inorganic acids such as hydrochloride, hydrogen bromide, hydrogen iodide, sulfate, nitrate and phosphate; acid addition salts with organic acids such as benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, acetate, and the like. Specific examples of the base addition salts include metal salts such as sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt; salts with amines such as ammonia, trimethylamine, triethylamine, pyridine, collidine, lutidine, etc.; and base addition salts with organic bases such as lysine, arginine, cinchonine, and cinchonidine.

Pemfibrate, a salt thereof, or a solvate of the same is a known compound, and can be produced by a method disclosed in, for example, patent document 1, non-patent document 1, and U.S. patent No. 7,109,226. In the present invention, it is preferable to use a crystal of pemabefibrate (preferably a crystal showing a melting point of 95 to 101 ℃ and particularly preferably 97 to 100 ℃ when measured according to the seventeenth revised Japanese pharmacopoeia melting point measurement method 1) which can be produced by the method described in non-patent document 1. As shown in the following test examples, since the crystals of pemfibrate which can be produced by the method described in non-patent document 1 do not have hygroscopicity, the use of such crystals of pemfibrate can suppress the invasion and contact of moisture from the outside even before the pharmaceutical composition is stored in an airtight package. The contents of these documents are also incorporated by reference into the present specification.

The content of pemfibrate, a salt thereof, or a solvate of the same in the pharmaceutical composition is not particularly limited, and can be determined by appropriate examination according to the type of preparation, the nature of the user, age, symptoms, and the like. For example, the pemabelate or its salt or solvate thereof can be contained in an amount of 0.05 to 0.8mg, more preferably 0.075 to 0.6mg, and particularly preferably 0.1 to 0.4mg, per day, as a pemabelate free body.

The content of pemfibrate, a salt thereof, or a solvate of these compounds in the pharmaceutical composition is preferably 0.001 to 60% by mass, more preferably 0.0025 to 25% by mass, even more preferably 0.005 to 10% by mass, even more preferably 0.0075 to 5% by mass, even more preferably 0.01 to 1% by mass, and particularly preferably 0.05 to 0.5% by mass, in terms of an amount of pemabebrate free form, relative to the total mass of the pharmaceutical composition.

< celluloses >

In the present specification, "cellulose-based" refers to 1 or more species selected from cellulose itself, ether derivatives of cellulose (hereinafter, referred to as "cellulose ethers" in the present specification), and salts thereof. Here, the "cellulose ethers" are compounds selected from cellulose in which all or a part of the hydroxyl groups form ether bonds. The cellulose itself or cellulose ethers may be modified as necessary by esterification, crosslinking, hydrolysis, and the like.

In the cellulose-based material, the kind of the salt is not particularly limited, and specific examples thereof include alkali metal salts such as sodium salt and potassium salt; salts with metals of group 2 elements such as calcium salts and magnesium salts. The average degree of polymerization and the properties (crystal form) of the cellulose are not particularly limited, and the average degree of polymerization is preferably 50 to 10000.

Specific examples of such celluloses include Cellulose such as crystalline Cellulose, crystalline Cellulose (fine particles), crystalline Cellulose (particles), powdered Cellulose (average degree of polymerization: 800 to 1100), Cellulose acetate phthalate (Cellulose acetate phthalate), derivatives (esters) thereof, and salts thereof; alkyl celluloses such as methyl cellulose and ethyl cellulose and salts thereof; hydroxyalkyl cellulose such as hydroxyethyl cellulose and hydroxypropyl cellulose or a salt thereof; alkyl (hydroxyalkyl) celluloses such as hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, and hydroxypropyl methylcellulose phthalate, derivatives (esters) thereof, and salts thereof; carboxyalkyl celluloses such as carboxymethyl cellulose, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethylethyl cellulose, and croscarmellose sodium, derivatives thereof (crosslinked polymers), salts thereof, and the like may be used alone in 1 or in combination of 2 or more. The alkyl group in the cellulose ether group is not particularly limited, and a linear or branched alkyl group having 1 to 6 carbon atoms is preferable.

The cellulose is preferably at least 1 selected from the group consisting of cellulose, alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, crosslinked polymers of carboxyalkyl cellulose and carboxyalkyl cellulose, and salts thereof, more preferably at least 1 selected from the group consisting of cellulose, C1-C6 alkyl cellulose, hydroxy C1-C6 alkyl cellulose, C1-C6 alkyl (hydroxy C1-C6 alkyl) cellulose, crosslinked polymers of carboxy C1-C6 alkyl cellulose and carboxy C1-C6 alkyl cellulose, and salts thereof, further preferably at least 1 selected from the group consisting of cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and crosslinked carboxymethyl cellulose, and salts thereof, further preferably at least 1 selected from the group consisting of crystalline cellulose, methyl cellulose, (non-low-substituted) hydroxypropyl cellulose, and salts thereof, More than 1 of low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose and croscarmellose sodium, and especially preferred are (non-low-substituted) hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose.

These celluloses may be known components, and may be produced by known methods or commercially available products may be used. Examples of such commercially available products include CEOLUS PH-101 (Asahi Kasei Co., Ltd.), Tableting aid K (Merck Co., Ltd.), CAP (Wako pure chemical industries, Ltd.), ETHOCEL (Dow chemical Japan K.K.), CMEC (Freund industries, Ltd.), NS-300 (Sanboon FFI Co., Ltd.), ECG-505 (Sanboon FFI Co., Ltd.), CELLOGEN (Sanboon FFI Co., Ltd.), Ac-Di-Sol (Asahi Kasei Co., Ltd.), HEC (Sumitomo Seiki Co., Ltd.), hydroxypropyl cellulose (Nippon Cao Kasei Co., Ltd.), Kyowa AQOAT (shin chemical industries, Ltd.), METOLOSE90 SH-SR (shin chemical industries, Ltd.), HPP (Xinyu chemical industries, Ltd.), MCP chemical industries, MCP Co., Ltd.), METO chemical industries, Mitsukui Katsukui Kaishi, Mitsukui Kaishi, Mitsukui Kaishi, Kaishi Kaish, CELPHERE (Sanrongyo FFI Co., Ltd.), ARBOCEL (Kimura industries, Ltd.), and the like.

The content of the cellulose in the pharmaceutical composition is not particularly limited, and can be determined by appropriate studies according to the type of the preparation, the nature, age, symptom, and the like of the user, and from the viewpoint of storage stability, the content is preferably 0.5 to 90% by mass, more preferably 1 to 70% by mass, further preferably 1.5 to 50% by mass, and particularly preferably 2 to 30% by mass, based on the total amount of the cellulose, relative to the total mass of the pharmaceutical composition.

The content of pemfibrate, a salt thereof, or a solvate of these substances and cellulose in the pharmaceutical composition is not particularly limited, and from the viewpoint of storage stability, the content of cellulose is preferably 0.5 to 800 parts by mass, more preferably 1 to 600 parts by mass, further preferably 3 to 400 parts by mass, further preferably 5 to 300 parts by mass, and particularly preferably 10 to 200 parts by mass in total, based on 1 part by mass of the free body in terms of pemabefibrate.

In the present specification, the dosage form of the "pharmaceutical composition" is not particularly limited, and may be any dosage form of solid, semisolid or liquid preparation, and may be selected according to the purpose of use thereof or the like. Examples of the dosage form of the pharmaceutical composition include those described in the seventeenth revised general rules of the japanese pharmacopoeia and the like. Specifically, examples of the dosage form for oral administration include solid preparations such as tablets (including normal tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, and the like), capsules, granules (including effervescent granules, and the like), powders, pills, and the like; semi-solid preparations such as oral jelly; liquid preparations such as oral liquid (e.g., elixirs, suspensions, emulsions, aqueous lemonades, etc.), and the like. Examples of the dosage form for parenteral administration include injections, inhalants, eye drops, ear drops, nasal drops, suppositories, external solid preparations, external liquids, sprays, ointments, creams, gels, patches, and the like.

The pharmaceutical composition is preferably a solid preparation from the viewpoint of easy administration and easy production.

The solid preparation is preferably a solid preparation for oral administration, more preferably a tablet, capsule, granule, powder or pill, and particularly preferably a tablet.

The pharmaceutical composition used in the present invention may contain a pharmaceutically acceptable carrier (formulation additive) in addition to the above-mentioned components, depending on the dosage form. Examples of such pharmaceutical additives include, but are not limited to, excipients, disintegrants, binders, lubricants, plasticizers, film-forming agents, powders, poorly water-soluble polymeric substances, antioxidants, flavors, and sweeteners. Further, as these Pharmaceutical additives, for example, those contained in the Pharmaceutical additives dictionary 2016 (manufactured by Nissan Kagaku K.K.), Handbook of Pharmaceutical Excipients, Seventh edition (manufactured by Pharmaceutical Press), and the like can be specifically used.

Specific examples of the excipient include inorganic excipients such as aluminum silicate, anhydrous sodium sulfate, anhydrous calcium hydrogen phosphate, sodium chloride, calcium silicate, light anhydrous silicic acid, heavy anhydrous silicic acid, calcium sulfate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodium dihydrogen phosphate; maltose powder, caramel, agar, paraffin, sucrose, fructose, maltose, lactose hydrate, white sugar, glucose, pullulan, polyoxyethylene hydrogenated castor oil, reduced maltose syrup, powdered reduced maltose syrup, trehalose, reduced palatinose, maltose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, calcium citrate, and other organic excipients. These can be used in 1 kind or 2 or more kinds in combination.

The total content of the excipients is preferably 20 to 99% by mass, more preferably 30 to 95% by mass, based on the total mass of the pharmaceutical composition.

Specific examples of the disintegrant include gelatin, sodium bicarbonate, dextrin, dehydroacetic acid and its salt, polyoxyethylene hydrogenated castor oil 60, and the like. These can be used in 1 kind or 2 or more kinds in combination.

Specific examples of the binder include oils and fats such as hydrogenated tallow, hydrogenated oil, hydrogenated vegetable oil, hydrogenated soybean oil, carnauba wax, white beeswax, yellow beeswax, and wood wax, and dextrin, pullulan, gum arabic, agar, gelatin, tragacanth, sodium alginate, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, and polyvinyl acetal diethylaminoacetate. These can be used in 1 kind or 2 or more kinds in combination.

The total content of the binding agent is preferably 0.001 to 30% by mass, more preferably 1 to 25% by mass, and particularly preferably 2 to 20% by mass, based on the total mass of the pharmaceutical composition.

Specific examples of the lubricant include calcium stearate, magnesium stearate, and sodium stearyl fumarate. These can be used in 1 kind or 2 or more kinds in combination.

The total content of the lubricant is preferably 0.01 to 15% by mass, more preferably 0.1 to 10% by mass, based on the total mass of the pharmaceutical composition.

Specific examples of the plasticizer include triethyl citrate, sesame oil, castor oil, and polysorbate 80 (polyoxyethylene (20) sorbitan oleate). These can be used in 1 kind or 2 or more kinds in combination.

The total content of the plasticizer is preferably 0.01 to 5% by mass, more preferably 0.1 to 1% by mass, based on the total mass of the pharmaceutical composition.

Specific examples of the film-forming agent include alginic acid such as sodium alginate or a salt thereof, carrageenan, xanthan gum, pullulan, and the like. These can be used in 1 kind or 2 or more kinds in combination.

Examples of the powder include organic or inorganic powders such as talc, titanium oxide, yellow iron oxide, ferric oxide, and legal pigments. These can be used in 1 kind or 2 or more kinds in combination.

The total content of the powder is preferably 0.005 to 3% by mass, more preferably 0.01 to 2% by mass, based on the total mass of the pharmaceutical composition.

Specific examples of the sparingly water-soluble polymer substance include carboxyvinyl polymers and aminoalkyl methacrylate copolymers. These can be used in 1 kind or 2 or more kinds in combination.

Specific examples of the antioxidant include ascorbic acid, sodium hydrogen sulfite, sodium ethylenediaminetetraacetate, isoascorbic acid, tocopheryl acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, and butylhydroxyanisole. These can be used in 1 kind or 2 or more kinds in combination.

Specific examples of the taste-modifying agent include terpenes such as limonene, pinene, camphene, cymene, cineole, citronellol, geraniol, nerol, linalool, menthol, terpineol, rhodol (rhodinol), borneol, isoborneol, menthone, camphor, eugenol, and cineole (Cinnzeylanol); essential oil containing terpene such as orange oil, oleum Menthae Dementholatum, Camphora white oil, oleum Eucalypti, oleum Terebinthinae, lemon oil, rhizoma Zingiberis recens oil, oleum Caryophylli, oleum Cinnamomi, oleum Lavandula Angustifolia, oleum Foeniculi, flos Matricariae Chamomillae oil, Perilla oil, and spearmint oil; sour agents such as ascorbic acid, tartaric acid, citric acid, malic acid and salts thereof, and the like. These can be used in 1 kind or 2 or more kinds in combination.

Examples of the sweetener include aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, and saccharin sodium, and 1 of these or 2 or more of these can be used in combination.

The pharmaceutical composition used in the present invention can be produced by a known method depending on the dosage form thereof.

For example, when the pharmaceutical composition is a solid preparation, it can be produced by appropriately combining unit operations such as pulverization, mixing, granulation, drying, size adjustment, classification, filling, tableting, and coating.

More specifically, for example, when the pharmaceutical composition is in the form of a granular preparation such as granules, powder, or pellets, the pharmaceutical composition can be produced by mixing these components with a pharmaceutical additive such as an excipient, a binder, a disintegrant, or a lubricant, if necessary, in addition to pemabefibrate or a salt thereof or a solvate thereof or a cellulose, granulating the mixture by a known granulation method such as extrusion granulation, tumbling granulation, stirring granulation, fluidized bed granulation, spray granulation, melt granulation, or crushing granulation to obtain a granulated product, and further classifying and sizing the granulated product as necessary. The obtained granulated product can be coated with a coating agent or the like by a known method.

In addition, when the pharmaceutical composition is in the form of a tablet, it can be produced by mixing these components together with pemfibrate or a salt thereof or a solvate thereof or a cellulose, if necessary, using appropriate pharmaceutical additives such as an excipient, a binder, a disintegrant, and a lubricant to obtain a mixture, and directly compressing (tableting) the mixture (direct powder compression method), or by classifying, granulating, and compressing (tableting) the granulated substance after granulating, if necessary (semi-dry granulation method, wet granulation method, and the like). The obtained compressed product (tablet) may be coated with a coating agent or the like by a known method.

When the dosage form of the pharmaceutical composition is a capsule, the granulated substance or the compressed substance may be filled in the capsule.

The moisture content of the pharmaceutical composition is not particularly limited, and from the viewpoint of suppressing an increase in the decomposition product of pemabefibrate, the moisture content is preferably about 3.4% by mass or less, more preferably about 2.4% by mass or less, even more preferably about 2.1% by mass or less, even more preferably about 1.9% by mass or less, even more preferably about 1.7% by mass or less, even more preferably about 1.5% by mass or less, and particularly preferably about 1.3% by mass or less. Further, it is preferably about 0.3% by mass or more, more preferably about 0.5% by mass or more, still more preferably about 0.8% by mass or more, still more preferably about 1.0% by mass or more, and particularly preferably about 1.2% by mass or more. As will be apparent from the description of test examples below, the increase in the decomposition product of pemabefibrate can be further suppressed by adjusting the moisture content of the pharmaceutical composition in the airtight package to the above range.

Here, the "moisture content of the pharmaceutical composition" can be measured by a dry weight loss test method. Specifically, the drying loss value (mass%) is measured according to the seventeenth edition modified japanese pharmacopoeia drying loss test method. Here, the measurement conditions (drying temperature and drying time) are as follows. That is, the drying temperature may be set so that the amount of adhering water can be measured depending on the components blended in the pharmaceutical composition during heating. For example, when a formulation additive having crystal water is blended, the temperature is set to a low level at which the crystal water is not lost. Specifically, the temperature may be, for example, about 60 to 80 ℃ when drying at normal pressure. The drying time is a time that can be regarded as a time when the moisture content reaches approximately a constant amount. Specifically, for example, the amount of change per 1 hour until the measured value of the loss on drying is 0.1 mass% or less.

In addition, when the moisture content of the pharmaceutical composition which has been packaged in the airtight package is measured, it is preferable to perform the measurement immediately after taking out the airtight package from the viewpoint of accurately evaluating the moisture content in the airtight package.

The method for adjusting the water content of the pharmaceutical composition includes a humidifying method and a drying method, and these methods may be appropriately selected and combined according to the dosage form of the pharmaceutical composition and the like.

As a humidifying method, for example, a method of using a water-containing solvent as a kneading liquid in a wet granulation operation, and the like can be cited.

Examples of the drying method include a method using a drying device and a method using a drying agent. Here, as the drying device, a device commonly used in the field of pharmaceuticals and foods can be used, and specific examples thereof include a box dryer, a fluidized bed dryer, a spray dryer, a freeze dryer, a vacuum dryer, and a high-frequency dryer. As the desiccant, one commonly used in the fields of pharmaceuticals and foods can be used, and specific examples thereof include 1 or more kinds selected from silica gel, silica alumina gel (e.g., allophane), natural zeolite, synthetic zeolite (e.g., molecular sieve), quick lime (calcium oxide), bentonite (e.g., montmorillonite), calcium chloride, magnesium chloride, and magnesium oxide, and these may be mixed with activated carbon. As the drying method, a method using a drying apparatus is preferred from the viewpoint of ease of adjusting the moisture content of the pharmaceutical composition.

The humidification method and the drying method may be performed during the production of the pharmaceutical composition, or may be performed after the production of the pharmaceutical composition.

In the present specification, the term "airtight package" refers to a package capable of suppressing substantial intrusion of moisture from the outside of the package in a state of ordinary handling, transportation, storage, or the like, and is a concept including an "airtight container" and a "sealed container" defined in the seventeenth revised japanese pharmacopoeia general rules. As the airtight package, any of a set shape and an indeterminate shape can be used, and specific examples thereof include a bottle package, an sp (strip package) package, a ptp (press Through package), a pillow package, a stick package, and the like. As the airtight package, these various combinations can be used, and specifically, for example, a mode in which the pharmaceutical composition is first packaged in PTP package and then further packaged in pillow package, and the like can be mentioned.

The packaging material (material) of the airtight package is not particularly limited as long as it is a material capable of exhibiting moisture-proof properties, and materials used for the purpose of moisture-proof of contents which are easily affected by moisture in the fields of pharmaceuticals, foods and the like can be suitably used.

Examples of the material of the bottle main body used for bottle packaging include glass, plastic (polyester, polyethylene (including Low Density (LDPE), Medium Density (MDPE), and High Density (HDPE)), polycarbonate, polystyrene, and polypropylene), and metal (aluminum). In the case of bottle packaging, for example, the pharmaceutical composition may be contained in a suitable amount in a commercially available bottle and then sealed with a suitable cap or stopper. The size of the bottle may be appropriately selected depending on the amount of the pharmaceutical composition to be contained, and the capacity of the bottle is, for example, about 10 to 500mL, preferably 14 to 400mL, and more preferably 24 to 350 mL. The material for bottle packaging is preferably polyethylene or polypropylene, more preferably Low Density Polyethylene (LDPE) or High Density Polyethylene (HDPE), and particularly preferably High Density Polyethylene (HDPE).

Examples of the packaging material used for SP packaging, PTP packaging, pillow packaging, rod packaging, and the like include resins such as biaxially stretched polypropylene (OPP), biaxially stretched Polyester (PET), glycol-modified PET (PET-G), biaxially stretched nylon (ONy, PA), cellophane, paper, Low Density Polyethylene (LDPE), linear low density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), unstretched polypropylene (CPP, IPP), ionomer resin (IO), ethylene-methacrylate copolymer (EMAA), Polyacrylonitrile (PAN), biaxially stretched polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC), cyclic polyolefin (COC), unstretched nylon (CNy), Polycarbonate (PC), Polystyrene (PS), and hard vinyl chloride (VSC), A metal foil such as aluminum foil (AL) may be formed into a multilayer structure in which 1 or 2 or more of these are appropriately combined. Examples of such multilayer structures include a multilayer structure obtained by laminating PVC and PVDC (hereinafter, abbreviated as PVC/PVDC), PVC/PVDC/PE/PVC, PVC/PVDC/PE/PVDC/PVC, CPP/COC/CPP, PVC/AL, CPP/CPP, and the like. Examples of the method for forming such a multilayer structure include known lamination methods such as extrusion lamination, dry lamination, coextrusion lamination, thermal (thermal) lamination, wet lamination, solventless lamination, and heat (heat) lamination. As a packaging material used for SP packaging, PTP packaging, pillow packaging, bar packaging, and the like, polyvinyl chloride and aluminum foil are preferable.

The PTP package may be formed by filling a desired number of pouches (pockets) formed of a resin sheet or the like by a known method with the pharmaceutical composition one by one or each administration unit, and then covering the pouches with a sheet made of a metal foil such as an aluminum foil as a cover material. Further, as the sheet forming the bag, a sheet using an aluminum foil as a constituent material, that is, a double-sided aluminum foil PTP package may be used. In the present invention, from the viewpoint of improving moisture resistance, it is preferable that the PTP package is further packaged by a pillow package (for example, an aluminum pillow package).

Examples of the form of the SP package, pillow package, and stick package include a sheet comprising a resin sheet or aluminum foil as a constituent material by a known method, and the pharmaceutical composition is packaged one by one or each administration unit. In the present invention, from the viewpoint of improving moisture resistance, it is preferable to use a sheet comprising an aluminum foil as a constituent material.

In the present specification, the content (volume fraction) of the pharmaceutical composition in the package is usually 25 to 90%, preferably 28 to 75%, and more preferably 30 to 50% when the package is a bottle package. In addition, when the package is SP package, PTP package, pillow package, or stick package, the content is usually 30 to 98%, preferably 40 to 95%, more preferably 45 to 93%, and particularly preferably 50 to 90%. In this case, the occupancy ratio is an occupancy ratio of the pharmaceutical composition with respect to the total volume inside the package, and the filler, the inner plug, and the like for preventing the breakage of the pharmaceutical composition, which are incorporated in the package, are not considered in calculating the space occupancy ratio.

As the airtight package, a commercially available package may be used as it is, or a commercially available packaging material may be processed and used. Examples of the package of a commercially available bottle package include a Z-series (manufactured by sakazakichen chemical industry co., ltd.). Further, examples of the packaging material for SP packages, PTP packages, pillow packages, and stick packages include SumiliteVSS, Sumilite VSL, Sumilite NS, Sumilite FCL (manufactured by Sumitomo Corp.), TAS series (manufactured by Dainichi chemical Co., Ltd.), VINYFOIL for PTP, SUPERFOIL for PTP (manufactured by Mitsubishi resin Co., Ltd.), NIPAK Aluminum Foil (manufactured by Nippon Foil Co., Ltd.), and Aluminum Foil Silver Base (manufactured by Dainichi chemical Co., Ltd.).

The method for housing the pharmaceutical composition in the airtight package is not particularly limited, and the pharmaceutical composition can be disposed in the package by an appropriate method such as feeding the pharmaceutical composition into the package. In this case, a method of introducing the pharmaceutical composition and a desiccant (for example, a cylindrical (tablet) desiccant or a sheet desiccant) into the package can be used.

The applicable diseases of the pharmaceutical composition of the present invention are not limited at all, and can be widely used for the prevention or treatment of diseases known at present or discovered in the future in which the administration of pemfibrate is effective.

Accordingly, the pharmaceutical composition of the present invention can be suitably used as a prophylactic and/or therapeutic agent for dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, and the like), and further as a prophylactic and/or therapeutic agent for hypertriglyceridemia, and the like.

In addition, pemofibrate or a salt thereof or a solvate of the same is useful for the prevention or treatment of NAFLD (non-alcoholic fatty liver disease). Therefore, the pharmaceutical composition of the present invention can also be used as a prophylactic and/or therapeutic agent for NAFLD (more preferably NASH (nonalcoholic steatohepatitis)).

In addition, pemabefibrate, a salt thereof or a solvate of the same can be used as a therapeutic agent for primary biliary cirrhosis or the like.

The route of administration of the pharmaceutical composition used in the present invention is not particularly limited, and can be determined by appropriate studies according to the disease to be applied, the type of the preparation, the sex, age, symptom and the like of the subject, and oral administration is preferable from the viewpoint of ease of administration. The pharmaceutical composition can be administered before, during, after, or before bedtime, for example, 1 to 4 times per day.

The present specification is not limited to these examples, and the following examples are disclosed.

[ 1-1 ] A pharmaceutical product obtained by containing a pharmaceutical composition in an airtight package, the pharmaceutical composition comprising the following components (A) and (B):

(A) pemabete or a salt thereof or a solvate thereof;

(B) cellulose.

[ 1-2 ] the pharmaceutical agent according to [ 1-1 ], wherein the cellulose is at least 1 selected from the group consisting of cellulose, alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, crosslinked polymers of carboxyalkyl cellulose and carboxyalkyl cellulose, and salts thereof.

[ 1-3 ] the pharmaceutical agent according to [ 1-1 ] or [ 1-2 ], wherein the cellulose is at least 1 selected from the group consisting of cellulose, C1-C6 alkylcellulose, hydroxy C1-C6 alkylcellulose, C1-C6 alkyl (hydroxy C1-C6 alkyl) cellulose, carboxy C1-C6 alkylcellulose, and a crosslinked polymer of carboxy C1-C6 alkylcellulose, and a salt thereof.

[ 1-4 ] the pharmaceutical product according to any one of [ 1-1 ] to [ 1-3 ], wherein the cellulose is at least 1 selected from the group consisting of cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, crosslinked carboxymethyl cellulose, and salts thereof.

[ 1-5 ] the pharmaceutical product according to any one of [ 1-1 ] to [ 1-4 ], wherein the cellulose is at least 1 selected from the group consisting of crystalline cellulose, methylcellulose, (non-low-substituted) hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose potassium, carboxymethylcellulose calcium, carboxymethylcellulose sodium, and croscarmellose sodium.

[ 1-6 ] the pharmaceutical product according to any one of [ 1-1 ] to [ 1-5 ], wherein the pharmaceutical composition is a solid preparation.

[ 1-7 ] the pharmaceutical product according to any one of [ 1-1 ] to [ 1-6 ], wherein the pharmaceutical composition is a tablet, capsule, granule, powder or pill.

[ 1-8 ] the pharmaceutical product according to any one of [ 1-1 ] to [ 1-7 ], wherein the airtight package is at least 1 selected from the group consisting of a bottle package, an SP package, a PTP package, a pillow package, and a stick package.

[ 1-9 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-8 ], wherein the moisture content of the pharmaceutical composition is 3.4% by mass or less (preferably 0.3 to 3.4% by mass, more preferably 0.5 to 3.4% by mass, even more preferably 0.8 to 3.4% by mass, even more preferably 1.0 to 3.4% by mass, and particularly preferably 1.2 to 3.4% by mass).

[ 1-10 ] the pharmaceutical product according to any one of [ 1-1 ] to [ 1-8 ], wherein the pharmaceutical composition has a water content of 2.4% by mass or less (preferably 0.3 to 2.4% by mass, more preferably 0.5 to 2.4% by mass, even more preferably 0.8 to 2.4% by mass, even more preferably 1.0 to 2.4% by mass, and particularly preferably 1.2 to 2.4% by mass).

[ 1-11 ] the pharmaceutical product according to any one of [ 1-1 ] to [ 1-8 ], wherein the pharmaceutical composition has a water content of 2.1% by mass or less (preferably 0.3 to 2.1% by mass, more preferably 0.5 to 2.1% by mass, even more preferably 0.8 to 2.1% by mass, even more preferably 1.0 to 2.1% by mass, and particularly preferably 1.2 to 2.1% by mass).

[ 1-12 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-8 ], wherein the moisture content of the pharmaceutical composition is 1.9% by mass or less (preferably 0.3 to 1.9% by mass, more preferably 0.5 to 1.9% by mass, even more preferably 0.8 to 1.9% by mass, even more preferably 1.0 to 1.9% by mass, and particularly preferably 1.2 to 1.9% by mass).

[ 1-13 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-8 ], wherein the moisture content of the pharmaceutical composition is 1.7% by mass or less (preferably 0.3 to 1.7% by mass, more preferably 0.5 to 1.7% by mass, even more preferably 0.8 to 1.7% by mass, even more preferably 1.0 to 1.7% by mass, and particularly preferably 1.2 to 1.7% by mass).

[ 1-14 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-8 ], wherein the moisture content of the pharmaceutical composition is 1.5% by mass or less (preferably 0.3 to 1.5% by mass, more preferably 0.5 to 1.5% by mass, even more preferably 0.8 to 1.5% by mass, even more preferably 1.0 to 1.5% by mass, and particularly preferably 1.2 to 1.5% by mass).

[ 1-15 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-8 ], wherein the moisture content of the pharmaceutical composition is 1.3% by mass or less (preferably 0.3 to 1.3% by mass, more preferably 0.5 to 1.3% by mass, even more preferably 0.8 to 1.3% by mass, even more preferably 1.0 to 1.3% by mass, and particularly preferably 1.2 to 1.3% by mass).

[ 1-16 ] the pharmaceutical product according to any one of [ 1-1 ] to [ 1-15 ], wherein the pemfibrate or a salt thereof or a solvate thereof is a crystal of pemfibrate.

[ 1-17 ] the pharmaceutical product according to [ 1-16 ], wherein the crystal of pemabefibrate is a crystal having a melting point of 95 to 101 ℃ (preferably 97 to 100 ℃).

[ 1-18 ] the pharmaceutical product according to [ 1-16 ] or [ 1-17 ], wherein the crystal of pemabefibrate has a peak at 1 or more diffraction angles (2 θ) selected from the group consisting of near 7.3 ± 0.2 °, near 14.6 ± 0.2 °, near 15.3 ± 0.2 °, near 16.2 ± 0.2 °, near 18.2 ± 0.2 °, near 18.9 ± 0.2 °, near 20.6 ± 0.2 °, near 21.5 ± 0.2 °, near 22.5 ± 0.2 ° and near 24.1 ± 0.2 ° in a powder X-ray diffraction pattern obtained by irradiation of copper K α radiation.

[ 1-19 ] the pharmaceutical according to [ 1-16 ] or [ 1-17 ], wherein the crystal of pemabefibrate has peaks at diffraction angles (2 θ) of around 14.6 ± 0.2 °, around 15.3 ± 0.2 °, around 20.6 ± 0.2 ° and around 22.5 ± 0.2 ° in a powder X-ray diffraction pattern obtained by irradiation of copper K α rays.

[ 1-20 ] the pharmaceutical product according to [ 1-16 ] or [ 1-17 ], wherein the crystal of pemabefibrate has peaks at diffraction angles (2. theta.) of around 7.3 + -0.2 °, around 14.6 + -0.2 °, around 15.3 + -0.2 °, around 16.2 + -0.2 °, around 18.2 + -0.2 °, around 18.9 + -0.2 °, around 20.6 + -0.2 °, around 21.5 + -0.2 °, around 22.5 + -0.2 ° and around 24.1 + -0.2 ° in a powder X-ray diffraction pattern obtained by irradiation of copper K α radiation.

[ 1-21 ] the pharmaceutical product according to any one of [ 1-1 ] to [ 1-20 ], which is a prophylactic and/or therapeutic agent for a disease selected from dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, and the like), NAFLD (more preferably NASH (nonalcoholic steatohepatitis)), and primary biliary cirrhosis.

[ 2-1 ] A method for stabilizing pemfibrate, a salt thereof or a solvate of pemfibrate or a salt thereof in a pharmaceutical composition (preferably, a method for suppressing an increase in decomposition products of pemfibrate), which comprises a step of storing the pharmaceutical composition in an airtight package,

the pharmaceutical composition contains the following components (A) and (B):

(A) pemabete or a salt thereof or a solvate thereof;

(B) cellulose.

[ 2-2 ] the method according to [ 2-1 ], wherein the cellulose is at least 1 selected from the group consisting of cellulose, alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, crosslinked polymers of carboxyalkyl cellulose and carboxyalkyl cellulose, and salts thereof.

[ 2-3 ] the method according to [ 2-1 ] or [ 2-2 ], wherein the cellulose is at least 1 selected from the group consisting of cellulose, C1-C6 alkylcellulose, hydroxyC 1-C6 alkylcellulose, C1-C6 alkyl (hydroxyC 1-C6 alkyl) cellulose, carboxyC 1-C6 alkylcellulose, and carboxyC 1-C6 alkylcellulose, and salts thereof.

[ 2-4 ] the method according to any one of [ 2-1 ] to [ 2-3 ], wherein the cellulose is at least 1 selected from the group consisting of cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, crosslinked carboxymethyl cellulose, and salts thereof.

[ 2-5 ] the method according to any one of [ 2-1 ] to [ 2-4 ], wherein the cellulose is at least 1 selected from the group consisting of crystalline cellulose, methylcellulose, (non-low-substituted) hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose potassium, carboxymethylcellulose calcium, carboxymethylcellulose sodium, and croscarmellose sodium.

[ 2-6 ] the method according to any one of [ 2-1 ] to [ 2-5 ], wherein the pharmaceutical composition is a solid preparation.

[ 2-7 ] the method according to any one of [ 2-1 ] to [ 2-6 ], wherein the pharmaceutical composition is a tablet, capsule, granule, powder or pill.

[ 2-8 ] the method according to any one of [ 2-1 ] to [ 2-7 ], wherein the airtight package is at least 1 kind selected from the group consisting of a bottle package, an SP package, a PTP package, a pillow package, and a stick package.

[ 2-9 ] the method according to any one of [ 2-1 ] to [ 2-8 ], wherein the pharmaceutical composition has a water content of 3.4% by mass or less (preferably 0.3 to 3.4% by mass, more preferably 0.5 to 3.4% by mass, still more preferably 0.8 to 3.4% by mass, yet still more preferably 1.0 to 3.4% by mass, particularly preferably 1.2 to 3.4% by mass).

[ 2-10 ] the method according to any one of [ 2-1 ] to [ 2-8 ], wherein the pharmaceutical composition has a water content of 2.4% by mass or less (preferably 0.3 to 2.4% by mass, more preferably 0.5 to 2.4% by mass, still more preferably 0.8 to 2.4% by mass, yet still more preferably 1.0 to 2.4% by mass, particularly preferably 1.2 to 2.4% by mass).

[ 2-11 ] the method according to any one of [ 2-1 ] to [ 2-8 ], wherein the pharmaceutical composition has a water content of 2.1% by mass or less (preferably 0.3 to 2.1% by mass, more preferably 0.5 to 2.1% by mass, still more preferably 0.8 to 2.1% by mass, yet still more preferably 1.0 to 2.1% by mass, particularly preferably 1.2 to 2.1% by mass).

[ 2-12 ] the method according to any one of [ 2-1 ] to [ 2-8 ], wherein the pharmaceutical composition has a water content of 1.9% by mass or less (preferably 0.3 to 1.9% by mass, more preferably 0.5 to 1.9% by mass, still more preferably 0.8 to 1.9% by mass, yet still more preferably 1.0 to 1.9% by mass, particularly preferably 1.2 to 1.9% by mass).

[ 2-13 ] the method according to any one of [ 2-1 ] to [ 2-8 ], wherein the pharmaceutical composition has a water content of 1.7% by mass or less (preferably 0.3 to 1.7% by mass, more preferably 0.5 to 1.7% by mass, still more preferably 0.8 to 1.7% by mass, yet still more preferably 1.0 to 1.7% by mass, particularly preferably 1.2 to 1.7% by mass).

[ 2-14 ] the method according to any one of [ 2-1 ] to [ 2-8 ], wherein the pharmaceutical composition has a water content of 1.5% by mass or less (preferably 0.3 to 1.5% by mass, more preferably 0.5 to 1.5% by mass, still more preferably 0.8 to 1.5% by mass, yet still more preferably 1.0 to 1.5% by mass, particularly preferably 1.2 to 1.5% by mass).

[ 2-15 ] the method according to any one of [ 2-1 ] to [ 2-8 ], wherein the pharmaceutical composition has a water content of 1.3% by mass or less (preferably 0.3 to 1.3% by mass, more preferably 0.5 to 1.3% by mass, still more preferably 0.8 to 1.3% by mass, yet still more preferably 1.0 to 1.3% by mass, particularly preferably 1.2 to 1.3% by mass).

[ 2-16 ] the method according to any one of [ 2-1 ] to [ 2-15 ], wherein the pemfibrate or a salt thereof or a solvate thereof is a crystal of pemfibrate.

[ 2-17 ] the process according to [ 2-16 ], wherein the crystal of pemabefibrate is a crystal showing a melting point of 95 to 101 ℃ (preferably 97 to 100 ℃).

[ 2-18 ] the method according to [ 2-16 ] or [ 2-17 ], wherein the crystal of pemabefibrate has a peak at 1 or more diffraction angles (2 θ) selected from the group consisting of near 7.3 ± 0.2 °, near 14.6 ± 0.2 °, near 15.3 ± 0.2 °, near 16.2 ± 0.2 °, near 18.2 ± 0.2 °, near 18.9 ± 0.2 °, near 20.6 ± 0.2 °, near 21.5 ± 0.2 °, near 22.5 ± 0.2 ° and near 24.1 ± 0.2 ° in a powder X-ray diffraction pattern obtained by irradiation of copper K α radiation.

[ 2-19 ] the method according to [ 2-16 ] or [ 2-17 ], wherein the crystal of pemabefibrate has peaks at diffraction angles (2 θ) of around 14.6 ± 0.2 °, around 15.3 ± 0.2 °, around 20.6 ± 0.2 ° and around 22.5 ± 0.2 ° in a powder X-ray diffraction pattern obtained by irradiation of copper K α rays.

[ 2-20 ] the method according to [ 2-16 ] or [ 2-17 ], wherein the crystal of pemabefibrate has peaks at diffraction angles (2. theta.) of around 7.3 + -0.2 °, around 14.6 + -0.2 °, around 15.3 + -0.2 °, around 16.2 + -0.2 °, around 18.2 + -0.2 °, around 18.9 + -0.2 °, around 20.6 + -0.2 °, around 21.5 + -0.2 °, around 22.5 + -0.2 ° and around 24.1 + -0.2 ° in a powder X-ray diffraction pattern obtained by irradiation of copper K α radiation.

[ 2-21 ] the method according to any one of [ 2-1 ] to [ 2-20 ], which is a prophylactic and/or therapeutic agent for a disease selected from dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, etc.), NAFLD (more suitable for NASH (nonalcoholic steatohepatitis)), and primary biliary cirrhosis.

[ 3-1 ] A pharmaceutical composition for storage in an airtight package, comprising the following components (A) and (B):

(A) pemabete or a salt thereof or a solvate thereof;

(B) cellulose.

[ 3-2 ] the pharmaceutical composition according to [ 3-1 ], wherein the cellulose is at least 1 selected from the group consisting of cellulose, alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, crosslinked polymers of carboxyalkyl cellulose and carboxyalkyl cellulose, and salts thereof.

[ 3-3 ] the pharmaceutical composition according to [ 3-1 ] or [ 3-2 ], wherein the cellulose is at least 1 selected from the group consisting of cellulose, C1-C6 alkylcellulose, hydroxy C1-C6 alkylcellulose, C1-C6 alkyl (hydroxy C1-C6 alkyl) cellulose, carboxy C1-C6 alkylcellulose, and a crosslinked polymer of carboxy C1-C6 alkylcellulose, and a salt thereof.

[ 3-4 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-3 ], wherein the cellulose is at least 1 selected from the group consisting of cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, crosslinked carboxymethyl cellulose, and salts thereof.

[ 3-5 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-4 ], wherein the cellulose is at least 1 selected from the group consisting of crystalline cellulose, methylcellulose, (non-low-substituted) hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose potassium, carboxymethylcellulose calcium, carboxymethylcellulose sodium, and croscarmellose sodium.

[ 3-6 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-5 ], which is a solid preparation.

[ 3-7 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-6 ], which is a tablet, capsule, granule, powder or pill.

[ 3-8 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-7 ], wherein the airtight package contains 1 or more kinds selected from the group consisting of a bottle package, an SP package, a PTP package, a pillow package and a stick package.

[ 3-9 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-8 ], wherein the water content is 3.4% by mass or less (preferably 0.3 to 3.4% by mass, more preferably 0.5 to 3.4% by mass, still more preferably 0.8 to 3.4% by mass, yet still more preferably 1.0 to 3.4% by mass, particularly preferably 1.2 to 3.4% by mass).

[ 3-10 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-8 ], wherein the water content is 2.4% by mass or less (preferably 0.3 to 2.4% by mass, more preferably 0.5 to 2.4% by mass, still more preferably 0.8 to 2.4% by mass, yet still more preferably 1.0 to 2.4% by mass, particularly preferably 1.2 to 2.4% by mass).

[ 3-11 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-8 ], wherein the water content is 2.1% by mass or less (preferably 0.3 to 2.1% by mass, more preferably 0.5 to 2.1% by mass, still more preferably 0.8 to 2.1% by mass, yet still more preferably 1.0 to 2.1% by mass, particularly preferably 1.2 to 2.1% by mass).

[ 3-12 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-8 ], wherein the water content is 1.9% by mass or less (preferably 0.3 to 1.9% by mass, more preferably 0.5 to 1.9% by mass, still more preferably 0.8 to 1.9% by mass, yet still more preferably 1.0 to 1.9% by mass, particularly preferably 1.2 to 1.9% by mass).

[ 3-13 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-8 ], wherein the water content is 1.7% by mass or less (preferably 0.3 to 1.7% by mass, more preferably 0.5 to 1.7% by mass, still more preferably 0.8 to 1.7% by mass, yet still more preferably 1.0 to 1.7% by mass, particularly preferably 1.2 to 1.7% by mass).

[ 3-14 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-8 ], wherein the water content is 1.5% by mass or less (preferably 0.3 to 1.5% by mass, more preferably 0.5 to 1.5% by mass, still more preferably 0.8 to 1.5% by mass, yet still more preferably 1.0 to 1.5% by mass, particularly preferably 1.2 to 1.5% by mass).

[ 3-15 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-8 ], wherein the water content is 1.3% by mass or less (preferably 0.3 to 1.3% by mass, more preferably 0.5 to 1.3% by mass, still more preferably 0.8 to 1.3% by mass, yet still more preferably 1.0 to 1.3% by mass, particularly preferably 1.2 to 1.3% by mass).

[ 3-16 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-15 ], wherein the pemfibrate or a salt thereof or a solvate thereof is a crystal of pemfibrate.

[ 3-17 ] the pharmaceutical composition according to [ 3-16 ], wherein the crystal of pemabefibrate is a crystal showing a melting point of 95 to 101 ℃ (preferably 97 to 100 ℃).

[ 3-18 ] the pharmaceutical composition according to [ 3-16 ] or [ 3-17 ], wherein the crystal of pemabefibrate has a peak at 1 or more diffraction angles (2 θ) selected from the group consisting of near 7.3 ± 0.2 °, near 14.6 ± 0.2 °, near 15.3 ± 0.2 °, near 16.2 ± 0.2 °, near 18.2 ± 0.2 °, near 18.9 ± 0.2 °, near 20.6 ± 0.2 °, near 21.5 ± 0.2 °, near 22.5 ± 0.2 ° and near 24.1 ± 0.2 ° in a powder X-ray diffraction pattern obtained by irradiation of copper K α radiation.

[ 3-19 ] the pharmaceutical composition according to [ 3-16 ] or [ 3-17 ], wherein the crystal of pemabefibrate has peaks at diffraction angles (2 θ) of around 14.6 ± 0.2 °, around 15.3 ± 0.2 °, around 20.6 ± 0.2 ° and around 22.5 ± 0.2 ° in a powder X-ray diffraction pattern obtained by irradiation of copper K α rays.

[ 3-20 ] the pharmaceutical composition according to [ 3-16 ] or [ 3-17 ], wherein the crystal of pemabefibrate has peaks at diffraction angles (2 θ) of around 7.3 ± 0.2 °, around 14.6 ± 0.2 °, around 15.3 ± 0.2 °, around 16.2 ± 0.2 °, around 18.2 ± 0.2 °, around 18.9 ± 0.2 °, around 20.6 ± 0.2 °, around 21.5 ± 0.2 °, around 22.5 ± 0.2 ° and around 24.1 ± 0.2 ° in a powder X-ray diffraction pattern obtained by irradiation of copper K α radiation.

[ 3-21 ] the pharmaceutical composition according to any one of [ 3-1 ] to [ 3-20 ], which is a prophylactic and/or therapeutic agent for a disease selected from dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, and the like), NAFLD (more suitable for NASH (nonalcoholic steatohepatitis)), and primary biliary cirrhosis.

Further, the crystal of pemfibrate can be produced by recrystallization from an ethyl acetate/heptane mixed solution according to the production method of the crystal of pemfibrate described in non-patent document 1, for example. Specifically, by adding pemfibrate in an amount such that its final concentration becomes about 20 w/v% to ethyl acetate, heating to about 60 ℃ to dissolve the pemfibrate, cooling the mixture, adding heptane having a volume of about 2 to 5 times the volume of the mixture, and standing at about one second evening at room temperature (1 to 30 ℃), crystals of pemfibrate can be obtained.