阅读说明：本技术 医药组合物 (Pharmaceutical composition ) 是由 杉本信 南园明人 于 2018-06-29 设计创作，主要内容包括：本发明提供一种医药组合物，其含有培马贝特或其盐或者它们的溶剂合物，且均质性优异。一种医药组合物，其含有以下的成分(A)和(B)：(A)培马贝特或其盐或者它们的溶剂合物；(B)二糖类。(The present invention provides a pharmaceutical composition which contains pemofibrate, a salt thereof or a solvate of the same and is excellent in homogeneity. A pharmaceutical composition comprising the following components (A) and (B): (A) pemabete or a salt thereof or a solvate thereof; (B) a disaccharide.)

1. A pharmaceutical composition, comprising:

comprises the following components (A) and (B):

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

(B) a disaccharide.

2. The pharmaceutical composition of claim 1, wherein:

the component (B) is at least 1 selected from sucrose, lactulose, lactose, maltose, trehalose, cellobiose, kojibiose, nigerose, isomaltose, neotrehalose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose, gentiobiulose, mannobiose, melibiose, plantabiose, neolactose, galactosucrose, scitalose, glufosinate, rutinose, podobiose, xylobiose, primrose, and sucralose, and solvates thereof.

3. The pharmaceutical composition of claim 1 or 2, wherein:

the component (B) is at least 1 selected from sucrose, lactose, maltose, trehalose, palatinose, sucralose and their solvates.

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

further contains a component (C):

(C) cellulose.

5. The pharmaceutical composition of any one of claims 1-4, wherein:

it is a solid preparation.

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

the dosage form is tablet, capsule, granule, powder or pill.

7. A method for improving content uniformity of pemabefibrate or a salt thereof or a solvate of pemabefibrate or a salt thereof in a pharmaceutical composition, comprising:

and a step of adding a disaccharide to the pharmaceutical composition containing pemabefibrate, a salt thereof or a solvate of the pemabefibrate and the salt.

Technical Field

The present invention relates to a pharmaceutical composition 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, 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 steatohepatitis) (patent document 2).

In addition, although compounds useful as active ingredients of pharmaceuticals are generally provided as pharmaceutical compositions in the form of preparations, it is extremely important to provide pharmaceutical compositions in which a certain quality is ensured without causing variation among batches or the like, from the viewpoint of reliably exerting a desired drug effect and avoiding undesirable side effects.

Disclosure of Invention

Technical problem to be solved by the invention

However, the manufacturability of pharmaceutical compositions represented by homogeneity is greatly influenced by the physical and chemical properties of the components to be blended, and these properties cannot be predicted in advance from the chemical structure thereof in many cases, and it is not rare that problems can be clarified only when pharmaceutical compositions are actually manufactured. Therefore, a large number of trial and error are generally required to establish a technique for ensuring homogeneity of a pharmaceutical composition.

In addition, only the pemfibrate, 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 there has been no report on the productivity of the pharmaceutical composition such as homogeneity.

Under such a background, the present inventors first tried to actually produce a pharmaceutical composition in order to develop a pharmaceutical composition containing pemofibrate or a salt thereof or a solvate thereof. However, it was found that the content of pemfibrate fluctuates in each pharmaceutical composition, and that homogeneity (content uniformity) of the content of pemfibrate in the pharmaceutical composition is problematic. If the content of pemfibrate in each pharmaceutical composition is greatly different, the pharmaceutical compositions may vary in effectiveness and safety.

Accordingly, an object of the present invention is to provide a pharmaceutical composition containing pemabelate, a salt thereof, or a solvate of the foregoing and having excellent homogeneity.

Technical solution for solving technical problem

The present inventors have further studied to solve the problem of content uniformity of pemfibrate, a salt thereof, or a solvate thereof in a pharmaceutical composition, and as a result, have found that the content uniformity of pemfibrate in a pharmaceutical composition can be improved by further containing a disaccharide represented by lactose (hereinafter, also simply referred to as "component (B)" in the present specification) in a pharmaceutical composition containing pemfibrate, a salt thereof, or a solvate thereof (hereinafter, also simply referred to as "component (a)" in the present specification), and have completed the present invention.

That is, the present invention provides a pharmaceutical composition comprising the following components (a) and (B):

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

(B) a disaccharide.

The present invention also provides a method for improving the content uniformity of pemfibrate, a salt thereof, or a solvate thereof in a pharmaceutical composition, comprising a step of adding a disaccharide to a pharmaceutical composition containing pemfibrate, a salt thereof, or a solvate thereof.

ADVANTAGEOUS EFFECTS OF INVENTION

According to the present invention, a pharmaceutical composition having improved content uniformity of pemfibrate in the pharmaceutical composition and excellent homogeneity can be provided.

Detailed Description

< Pesimofibrate or a salt thereof or a solvate thereof (component (A)) >

In the present specification, "pemfibrate or a salt thereof or a solvate of the same" includes 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, a pharmaceutically acceptable salt of pemfibrate, and a solvate of pemfibrate and a pharmaceutically acceptable salt thereof with water, alcohol (e.g., ethanol), and the like. 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.

The shape, size and the like of the pemfibrate or a salt thereof or a solvate of the pemfibrate or a salt thereof are not particularly limited, but when the average particle diameter of the primary particles is measured by a particle diameter measuring method according to the seventeenth edition revised japanese pharmacopoeia by a laser diffraction method, d50 and d90 are preferably as follows, respectively.

d 50: preferably 100 μm or less, more preferably 50 μm or less, further preferably 20 μm or less, and particularly preferably 1 to 20 μm.

d 90: preferably 200 μm or less, more preferably 135 μm or less, further preferably 80 μm or less, and particularly preferably 1 to 80 μm.

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. The contents of these documents are incorporated herein by reference.

The content of pemabefibrate, a salt thereof or a solvate of pemabefibrate or a salt thereof in the pharmaceutical composition 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, symptoms of the subject, 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, particularly preferably 0.1 to 0.4mg per day in terms of the amount of pemabelate free form.

The content of pemfibrate, a salt thereof, or a solvate of these compounds in the pharmaceutical composition is preferably 0.01 to 5% by mass, more preferably 0.025 to 1% by mass, and particularly preferably 0.05 to 0.5% by mass in terms of an episome of pemabefibrate, based on the total mass of the pharmaceutical composition. According to the present invention, even when pemfibrate or a salt thereof or a solvate of them is contained at such a low content, good content uniformity can be obtained.

< disaccharides (component (B)) >)

In the present specification, "disaccharide" means 1 or more selected from the group consisting of disaccharide itself, a substance obtained by substituting all or a part of the hydroxyl groups of disaccharide with a halogen atom such as a chlorine atom, and a solvate thereof. Here, the solvate is not particularly limited, and specifically, for example, a hydrate and the like are exemplified. The type of monosaccharide constituting the disaccharide is not particularly limited, and examples thereof include pentoses such as arabinose and xylose; hexoses such as glucose, galactose, fructose, mannose, altrose, and rhamnose.

Specific examples of such disaccharides include sucrose (sucrose), lactulose, Lactose (Lactose), maltose, trehalose, cellobiose, kojibiose, nigerose, isomaltose, isohydralose, neotrehalose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose, gentiobiose, mannobiose, melibiose, plantabiose, neolactose, galactosucrose, sciobiose, lubutose, rutinose, podobiose, xylobiose, primrose, and sucralose, and 1 of these may be used alone or 2 or more of these may be used in combination.

The disaccharide is preferably 1 or more selected from sucrose, lactose, maltose, trehalose, palatinose, sucralose and solvates thereof, more preferably 1 or more selected from sucrose, lactose, trehalose, sucralose and hydrates thereof, still more preferably 1 or more selected from lactose and hydrates thereof, and particularly preferably 1 or more selected from lactose crystalline cellulose spherical particles, lactose hydrates, lactose granules and anhydrous lactose, from the viewpoint of the effect of improving the content uniformity. In addition, from the viewpoint of ease of production of the pharmaceutical composition (particularly, solid preparation), the disaccharide is preferably a disaccharide which is solid at room temperature (any temperature of 15 to 25 ℃).

These disaccharides are known components, and can be produced by a known method, or commercially available products can be used. Examples of such commercially available products include nonopareil-105 (Freund corporation), lactose hydrate (sanyuan FFI), lactose G (Freund corporation), Lactopress anhydrous (CBC corporation), japanese crystalline maltose (japan food chemical corporation), trehalose P (asahi chemical corporation), sucralose (sanyuan FFI corporation), and Pharmatose 200M (DFE pharma corporation).

The content of the disaccharide in the pharmaceutical composition is not particularly limited, and can be determined by appropriate studies according to the type of the preparation, the sex, age, symptom and the like of the user, and from the viewpoint of the effect of improving the content uniformity, the total amount of the disaccharide is preferably 1 to 99% by mass, more preferably 3 to 95% by mass, further preferably 5 to 90% by mass, and particularly preferably 7 to 85% by mass, based on the total mass of the pharmaceutical composition.

When 1 or more selected from lactose and hydrates thereof are used as the disaccharide, the content thereof is preferably 2 to 98% by mass, more preferably 4 to 93% by mass, and particularly preferably 8 to 80% by mass, based on the total mass of the pharmaceutical composition, from the viewpoint of improving the content uniformity.

The content mass ratio of pemfibrate, a salt thereof, or a solvate thereof and a disaccharide in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the content of the disaccharide in total is preferably 10 to 1750 parts by mass, more preferably 50 to 1500 parts by mass, further preferably 80 to 1200 parts by mass, and particularly preferably 100 to 900 parts by mass, based on 1 part by mass of pemfibrate in terms of free bodies.

In addition, when 1 or more selected from lactose and hydrates thereof is used as the disaccharide, the content mass ratio of pemfibrate or a salt thereof or a solvate thereof to 1 or more selected from lactose and hydrates thereof in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the pharmaceutical composition preferably contains 30 to 1150 parts by mass, more preferably 50 to 1050 parts by mass, further preferably 70 to 950 parts by mass, and particularly preferably 120 to 850 parts by mass of 1 part by mass of pemfibrate in terms of free body.

< cellulose (component (C)) >)

The pharmaceutical composition of the present invention preferably contains cellulose in addition to the components (a) and (B). By combining the inclusion of disaccharides and cellulose, the content uniformity of pemabefibrate becomes better.

In the present specification, "cellulose" means 1 or more selected from cellulose and salts thereof. In the cellulose, 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 polymerization degree and the properties (crystal form) of cellulose are not particularly limited, and the average polymerization degree is preferably 50 to 10000. Here, the average polymerization degree can be confirmed by performing a test according to the confirmation test (3) described in the seventeenth edition revised japanese pharmacopoeia "crystalline cellulose".

Specific examples of such cellulose include crystalline cellulose, crystalline cellulose (fine particles), crystalline cellulose (granules), powdered cellulose, and powdered cellulose (average degree of polymerization: 800 to 1100), and 1 of these may be used alone or 2 or more may be used in combination. Further, these crystalline celluloses and the like are those described in a pharmaceutical additive dictionary 2016 (manufactured by Nissan Kagaku K.K.).

These celluloses are all known components and can be produced by a known method or commercially available products can be used. Examples of such commercially available products include CEOLUS PH-101 (Asahi Kasei Co., Ltd.), CELPHERE (Sangroyuan FFI Co., Ltd.), ARBOCEL (Kimura industries, Ltd.).

The content of cellulose in the pharmaceutical composition is not particularly limited, and can be determined by appropriate studies according to the type of the preparation, the sex, age, symptom, and the like of the user, and from the viewpoint of the effect of improving the content uniformity, the content is preferably 1 to 40% by mass, more preferably 3 to 35% by mass, further preferably 5 to 30% by mass, and particularly preferably 8 to 25% by mass, based on the total amount of cellulose, relative to the total mass of the pharmaceutical composition.

The content mass ratio of pemfibrate, a salt thereof, or a solvate thereof to cellulose in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the content of cellulose is preferably 5 to 5000 parts by mass in total, more preferably 30 to 3500 parts by mass, and particularly preferably 60 to 2000 parts by mass in terms of free body to 1 part by mass of pemfibrate.

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.

From the viewpoint of ease of administration and ease of production, a solid preparation is preferred as the pharmaceutical composition. Particularly, in the case of a pharmaceutical composition which is a solid preparation, the production is extremely easy, but in general, since solid preparations are produced using components which are solid at substantially normal temperature (any temperature of 15 to 25 ℃), mixing and dispersion of the components are likely to become uneven, and the content uniformity tends to become particularly problematic. However, according to the present invention, there is an excellent effect that content uniformity is good even in the case of a solid preparation.

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 solid preparation is preferably a solid preparation containing a mixture of the components (a) and (B), and more preferably a solid preparation containing a mixture of the components (a) to (C).

The pharmaceutical composition of 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 a Pharmaceutical additives dictionary 2016 (manufactured by Nissan Co., Ltd.), 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, sodium chloride, light anhydrous silicic acid, heavy anhydrous silicic acid, calcium sulfate, calcium monohydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodium dihydrogen phosphate, organic excipients such as starch (wheat starch, rice starch, corn starch, partially α -modified starch, and the like), fructose, caramel, agar, xylitol, paraffin, glucose, pullulan, polyoxyethylene hydrogenated castor oil, maltitol, erythritol, sorbitol, mannitol, lactitol, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, and calcium citrate, and these excipients can be used in 1 kind or in combination of 2 or more kinds.

Among these excipients, light anhydrous silicic acid and mannitol are preferable.

Specific examples of the disintegrant include super disintegrants such as sodium carboxymethyl starch, croscarmellose sodium and crospovidone, carboxymethyl cellulose, calcium carboxymethyl cellulose, starch, sucrose fatty acid esters, gelatin, dextrin, dehydroacetic acid and salts thereof, polyvinylpyrrolidone and polyoxyethylene hydrogenated castor oil 60. These can be used in 1 kind or 2 or more kinds in combination.

Among these disintegrants, sodium carboxymethyl starch and croscarmellose sodium are preferable.

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 oils and fats such as methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, starch (wheat starch, rice starch, corn starch, partially α -modified starch, and the like), dextrin, pullulan, gum arabic, agar, gelatin, tragacanth gum, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, and polyvinyl acetal diethylaminoacetate, and these can be used in 1 kind or in combination of 2 or more kinds.

Among these binders, carnauba wax, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer E are preferable.

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

Among these lubricants, calcium stearate, magnesium stearate, and sodium stearyl fumarate are preferable.

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

Among these plasticizers, triethyl citrate, glycerin, and sorbitol are preferable.

Specific examples of the film-forming agent include alkyl celluloses such as methyl cellulose and ethyl cellulose; alginic acid such as sodium alginate or a salt thereof; carrageenan; carboxyalkyl celluloses such as sodium carboxymethylcellulose, calcium carboxymethylcellulose, potassium carboxymethylcellulose, and carboxymethylethylcellulose; xanthan gum; hydroxyalkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose (hydroxypropyl methyl cellulose); hydroxyalkyl cellulose phthalates such as hydroxypropyl methyl cellulose phthalate; pullulan; polyvinyl acetate; polyvinyl acetate phthalate; polyvinylpyrrolidone, and the like. These can be used in 1 kind or 2 or more kinds in combination.

Among these film forming agents, alkyl cellulose and hydroxyalkyl cellulose are preferable.

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.

Among these powders, titanium oxide, yellow iron oxide, ferric oxide, and legal pigments are preferable.

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, borneol, isoborneol, menthone, camphor, eugenol, and cineole (cinnarizanol); essential oils containing terpene such as orange oil, peppermint oil, camphor white oil, eucalyptus oil, turpentine oil, lemon oil, ginger oil, clove oil, cinnamon oil, lavender oil, fennel oil, chamomile oil, perilla oil, spearmint oil, etc.; 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, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, and saccharin sodium, and 1 kind of these or 2 or more kinds of these can be used in combination.

In addition, as the pharmaceutical composition of the present invention, it is preferable that 1 or more selected from croscarmellose sodium, magnesium stearate, titanium oxide, triethyl citrate, hydroxypropylmethylcellulose, hydroxypropylcellulose, light anhydrous silicic acid, and carnauba wax are contained in the above pharmaceutically acceptable carrier.

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

For example, when the pharmaceutical composition is a solid preparation, it can be produced by appropriately combining unit operations such as pulverization, mixing, granulation, drying, size control, classification, filling, tableting, and coating, and as a production method thereof, a method including a step of mixing the component (a) and the component (B) is preferable, and a method including steps of mixing the components (a) to (C) is more preferable.

More specifically, for example, when the dosage form of the pharmaceutical composition is a granular preparation such as granules, powder, and pellets, the pharmaceutical composition can be produced by mixing the component (C) and pharmaceutical additives such as excipients, binders, disintegrants, and lubricants in addition to the component (a) and the component (B) as needed, granulating the mixture by a known granulation method such as extrusion granulation, tumbling granulation, stirring granulation, fluidized bed granulation, spray granulation, melt granulation, and crushing granulation to obtain a granulated product, and further classifying and sizing the granulated product as needed. The obtained granulated product can be coated with a coating agent or the like by a known method.

When the pharmaceutical composition is in the form of a tablet, it can be produced by mixing the component (C) and suitable pharmaceutical additives such as an excipient, a binder, a disintegrant, and a lubricant, if necessary, in addition to the component (a) and the component (B), to obtain a mixture, and directly compressing (tableting) the mixture (direct powder compression method), or by classifying, granulating, and the like the granulated product as necessary and then compressing (tableting) (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 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 (nonalcoholic steatohepatitis). 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 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 technical solutions are disclosed.

[ 1-1 ] A pharmaceutical composition comprising the following components (A) and (B):

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

(B) a disaccharide.

[ 1-2 ] the pharmaceutical composition according to [ 1-1 ], wherein the component (B) is at least 1 selected from sucrose (sucrose), lactulose, Lactose (Lactose), maltose, trehalose, cellobiose, kojibiose, nigerose, isomaltose, isomaltulose, neotrehalose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose, gentiobiulose, mannobiose, melibiose, psyllium disaccharide, neolactose, galactosucrose, raffinose, ludinose, rutinose, podobiose, xylobiose, primrose, and sucralose, and solvates thereof.

[ 1-3 ] the pharmaceutical composition according to [ 1-1 ], wherein the component (B) is at least 1 selected from the group consisting of sucrose, lactose, maltose, trehalose, palatinose and sucralose, and solvates thereof.

[ 1-4 ] the pharmaceutical composition according to [ 1-1 ], wherein the component (B) is at least 1 selected from the group consisting of sucrose, lactose, trehalose, sucralose and hydrates thereof.

[ 1-5 ] the pharmaceutical composition according to [ 1-1 ], wherein the component (B) is at least 1 selected from lactose and hydrates thereof.

[ 1-6 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-5 ], which further comprises a component (C):

(C) cellulose.

[ 1-7 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-6 ], 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.

[ 1-8 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-7 ], which is a solid preparation.

[ 1-9 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-8 ], wherein the dosage form is a tablet, a capsule, a granule, a powder or a pill.

[ 2-1 ] A method for improving content uniformity of pemabefibrate or a salt thereof or a solvate thereof in a pharmaceutical composition, comprising:

a pharmaceutical composition comprising (A) pemabefibrate, a salt thereof or a solvate of the foregoing comprises the following component (B):

(B) a disaccharide.

[ 2-2 ] the method according to [ 2-1 ], wherein the component (B) is 1 or more selected from sucrose (sucrose), lactulose, Lactose (Lactose), maltose, trehalose, cellobiose, kojibiose, nigerose, isomaltose, isomaltulose, neotrehalose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose, gentiobiulose, mannobiose, melibiose, psyllium disaccharide, neolactose, galactosucrose, scitalose, rutinose, podobiose, xylobiose, primrose, and sucralose, and solvates thereof.

[ 2-3 ] the method according to [ 2-1 ], wherein the component (B) is at least 1 selected from the group consisting of sucrose, lactose, maltose, trehalose, palatinose and sucralose, and solvates thereof.

[ 2-4 ] the method according to [ 2-1 ], wherein the component (B) is at least 1 selected from the group consisting of sucrose, lactose, trehalose, and sucralose, and hydrates thereof.

[ 2-5 ] the process according to [ 2-1 ], wherein the component (B) is at least 1 selected from lactose and hydrates thereof.

[ 2-6 ] the method according to any one of [ 2-1 ] to [ 2-5 ], further comprising:

a step of further containing a component (C):

(C) cellulose.

[ 2-7 ] the method according to any one of [ 2-1 ] to [ 2-6 ], wherein the pharmaceutical composition is a prophylactic and/or therapeutic agent for a disease selected from dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, etc.), NAFLD (more suitable for NASH (nonalcoholic steatohepatitis)), and primary biliary cirrhosis.

[ 2-8 ] the method according to any one of [ 2-1 ] to [ 2-7 ], wherein the pharmaceutical composition is a solid preparation.

[ 2-9 ] the method according to any one of [ 2-1 ] to [ 2-8 ], wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, powder or pill.