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：本发明提供含有培马贝特或其盐或者它们的溶剂合物并且均质性优异的医药组合物。该医药组合物含有如下成分(A)和(B)：(A)培马贝特或其盐或者它们的溶剂合物；(B)选自如下成分(B－1)～(B－6)中的1种以上：(B－1)纤维素醚类；(B－2)淀粉类；(B－3)聚维酮类；(B－4)硅酸化合物；(B－5)多元醇；(B－6)烷基硫酸酯类。(The present invention provides a pharmaceutical composition containing pemfibrate, a salt thereof, or a solvate of these compounds and having excellent homogeneity. The pharmaceutical composition comprises the following components (A) and (B): (A) pemabete or a salt thereof or a solvate thereof; (B) 1 or more selected from the following components (B-1) to (B-6): (B-1) cellulose ethers; (B-2) starches; (B-3) Povidones; (B-4) a silicic acid compound; (B-5) a polyol; (B-6) alkyl sulfates.)

1. A pharmaceutical composition, comprising:

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

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

(B) 1 or more selected from the following components (B-1) to (B-6);

(B-1) cellulose ethers such as,

(B-2) starches based on the total amount of the starch,

(B-3) a class of polyvidones,

(B-4) a silicic acid compound,

(B-5) a polyhydric alcohol,

(B-6) alkyl sulfates.

2. The pharmaceutical composition of claim 1, wherein:

the component (B-1) is at least 1 selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, carboxyalkyl cellulose and a crosslinked polymer of carboxyalkyl cellulose and salts thereof.

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

the component (B-1) is at least 1 selected from 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.

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

the component (B-1) is at least 1 selected from methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose and croscarmellose sodium.

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

the component (B-2) is at least 1 selected from starch, hydroxyalkyl ether of starch, carboxyalkyl ether of starch, and salts thereof.

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

the component (B-2) is at least 1 selected from starch, hydroxy C1-C6 alkyl ether of starch, carboxy C1-C6 alkyl ether of starch, and salts thereof.

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

the component (B-2) is at least 1 selected from starch, hydroxypropyl starch, carboxymethyl starch and their salts.

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

the component (B-3) is more than 1 selected from polyvidone and crospovidone.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein:

the component (B-4) is at least 1 selected from the group consisting of hydrous silicic acid compounds, salts of hydrous silicic acid compounds, anhydrous silicic acid and salts of anhydrous silicic acid.

10. The pharmaceutical composition of any one of claims 1-9, wherein:

the component (B-4) is at least 1 selected from hydrous magnesium silicate, hydrous silicon dioxide and light anhydrous silicic acid.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein:

the component (B-5) is more than 1 selected from polyethylene glycol, erythritol, xylitol, mannitol, sorbitol, maltitol and lactitol.

12. The pharmaceutical composition of any one of claims 1-11, wherein:

the component (B-6) is more than 1 selected from lauryl sulfate, myristyl sulfate, cetyl sulfate and stearyl sulfate.

13. The pharmaceutical composition of any one of claims 1-12, wherein:

the component (B-6) is sodium lauryl sulfate.

14. The pharmaceutical composition of any one of claims 1-13, wherein:

it is a solid preparation.

15. The pharmaceutical composition of any one of claims 1-14, wherein:

the preparation is in the form of tablet, capsule, granule, powder or pill.

16. 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:

a step of adding 1 or more selected from the group consisting of components (B-1) to (B-6) to a pharmaceutical composition containing pemabefibrate or a salt thereof or a solvate of the pemabefibrate or the salt,

(B-1) cellulose ethers such as,

(B-2) starches based on the total amount of the starch,

(B-3) a class of polyvidones,

(B-4) a silicic acid compound,

(B-5) a polyhydric alcohol,

(B-6) alkyl sulfates.

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), or a salt thereof or a solvate thereof, which has excellent PPAR α agonist activity, shows effects of lowering plasma triglyceride concentration, increasing HDL cholesterol, and 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), is known.

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

Problems to be solved by the invention

However, the productivity of pharmaceutical compositions represented by homogeneity is greatly affected by the physical and chemical properties of the components to be blended, and as a result, the properties cannot be predicted in advance from the chemical structure thereof, and it is not rare that the problem is found only when the pharmaceutical composition is actually produced. Therefore, in order to establish a technique for ensuring homogeneity of a pharmaceutical composition, a large number of trial and error are generally required.

Further, pemfibrate, a salt thereof or a solvate of the same has been reported to exhibit the above pharmacological effects, but the preparation of a pharmaceutical composition has not been specifically studied so far, and the production of the pharmaceutical composition, such as homogeneity, has not been reported so far.

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 of the same. 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 composition 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 these compounds and having excellent homogeneity.

Means for solving the problems

Accordingly, the present inventors have conducted further intensive studies in order to solve the problem of content uniformity of pemabefibrate, a salt thereof, or a solvate thereof in a pharmaceutical composition, and as a result, have found that a pharmaceutical composition containing pemabefibrate, a salt thereof, or a solvate thereof (hereinafter, sometimes referred to as "component (a)", hereinafter) further contains any component of the following components 1 to 6 (hereinafter, components 1 to 6 are referred to as "component (B-1)", "component (B-2)", "component (B-3)", "component (B-4)", "component (B-5)", and "component (B-6)" respectively, and 1 or more members "selected from the group consisting of components (B-1) to (B-6)" are also referred to as "component (B)"), can improve the content uniformity of pemabefibrate in a pharmaceutical composition, and thus the present invention has been completed.

1. Cellulose ethers represented by crosslinked carboxymethyl cellulose, hydroxypropyl methyl cellulose, and methyl cellulose;

2. starches represented by α -modified starch, corn starch, and sodium carboxymethyl starch;

3. povidone represented by crospovidone and polyvinylpyrrolidone;

4. silicic acid compounds represented by hydrous magnesium silicate, hydrous silicon dioxide, and light anhydrous silicic acid;

5. polyhydric alcohols represented by polyethylene glycol (macrogol) and mannitol;

6. alkyl sulfates represented by sodium lauryl sulfate;

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) 1 or more selected from the following components (B-1) to (B-6);

(B-1) cellulose ethers

(B-2) starches

(B-3) Povidones

(B-4) silicic acid Compound

(B-5) polyol

(B-6) alkyl sulfates.

The present invention also provides a method for improving the content uniformity of pemabefibrate, a salt thereof, or a solvate thereof in a pharmaceutical composition, which comprises a step of adding 1 or more selected from the group consisting of components (B-1) to (B-6) to a pharmaceutical composition containing pemabefibrate, a salt thereof, or a solvate thereof.

ADVANTAGEOUS EFFECTS OF INVENTION

The present invention can provide a pharmaceutical composition having improved content uniformity of pemfibrate and excellent homogeneity.

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 thereof" includes a pharmaceutically acceptable salt of pemfibrate and a solvate of pemfibrate or a pharmaceutically acceptable salt thereof with water or an alcohol (e.g., ethanol) 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 ] butyric acid) itself, international common name: Pemafibrate). 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, hydrobromide, hydroiodide, 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, and lutidine; 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 these are not particularly limited, but when the average particle diameter of primary particles is measured by a particle diameter measurement method according to the seventeenth edition revised japanese pharmacopoeia by laser diffraction, d50 and d90 are preferably as follows, respectively.

d 50: preferably 100 μm or less, more preferably 50 μm or less, still more 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, still more 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 patent document 1, non-patent document 1, and U.S. patent No. 7,109,226, for example. In the present invention, it is preferable to use a crystal capable of producing pemabefibrate by the method described in non-patent document 1 (preferably a crystal having a melting point of 95 to 101 ℃, particularly preferably 97 to 100 ℃ when measured according to the seventeenth revised Japanese pharmacopoeia melting point measurement method 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, symptom 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, 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 0.01 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 free form of pemfibrate, based on the total mass of the pharmaceutical composition. According to the present invention, even in the case where the content of pemfibrate or a salt thereof or a solvate thereof is so low, good content uniformity can be obtained.

< cellulose ethers (component (B-1)) >)

In the present specification, the "cellulose ethers" refers to 1 or more selected from compounds in which all or a part of the hydroxyl groups of cellulose form ether bonds, and salts thereof. The cellulose ethers may be compounds obtained by further modifying cellulose, such as esterification and crosslinking, if necessary, in addition to etherification of cellulose. 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 cellulose ethers are not particularly limited in average degree of polymerization, properties (crystal form), and the like, and the average degree of polymerization is preferably 10 to 10000.

Specific examples of such cellulose ethers include 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 (ester derivatives) thereof, and salts thereof; carboxyalkyl celluloses such as carboxymethyl cellulose, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethylethyl cellulose, and croscarmellose sodium, and derivatives (crosslinked polymers) thereof, or salts thereof may be used alone in 1 kind or in combination with 2 or more kinds. The alkyl group in the cellulose ether is not particularly limited, and a linear or branched alkyl group having 1 to 6 carbon atoms is preferable. The substitution degree of hydroxyalkoxyl groups in hydroxyalkyl cellulose is not particularly limited, and examples of the hydroxyalkyl cellulose include hydroxypropyl cellulose having a non-low substitution degree and hydroxypropyl cellulose having a low substitution degree. Wherein the low-substituted hydroxypropylcellulose is hydroxypropylcellulose having a hydroxypropoxyl group quantified at drying of 5.0 to 16.0% as described in the seventeenth revised Japanese pharmacopoeia.

From the viewpoint of the effect of improving the content uniformity, the cellulose ethers are preferably at least 1 selected from the group consisting of alkylcelluloses, hydroxyalkylcelluloses, alkyl (hydroxyalkyl) celluloses, crosslinked polymers of carboxyalkylcelluloses and carboxyalkylcelluloses, and salts thereof, more preferably at least 1 selected from the group consisting of C1-C6 alkylcelluloses, hydroxyC 1-C6 alkylcelluloses, C1-C6 alkyl (hydroxyC 1-C6 alkyl) celluloses, crosslinked polymers of carboxyC 1-C6 alkylcelluloses and carboxyC 1-C6 alkylcelluloses, and salts thereof, still more preferably at least 1 selected from the group consisting of methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, crosslinked carboxymethylcellulose, and salts thereof, and still more preferably at least 1 selected from the group consisting of methylcellulose, ethylcellulose, hydroxypropylcellulose, and salts thereof, At least one member selected from the group consisting of hydroxypropyl methylcellulose, carboxymethyl cellulose, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose and croscarmellose sodium, and particularly preferably at least one member selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose and croscarmellose sodium. As the hydroxypropyl cellulose, low-substitution hydroxypropyl cellulose is preferable. In addition, from the viewpoint of ease of production of a pharmaceutical composition (particularly a solid preparation), cellulose ethers that are solid at room temperature (any temperature of 15 to 25 ℃) are preferred.

These cellulose ethers 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 ETHOCEL (Toho chemical Japan (trade name)), CMEC (Freund industry (trade name)), NS-300 (Sanrongyuan F.F.I (trade name)), ECG-505 (Sanrongyuan F.F.I (trade name)), CELLOGEN (SanrongyF.F.I (trade name)), Ac-Di-Sol (Asahi chemical industry (trade name)), HEC (Sumitomo refinement (trade name)), hydroxypropyl cellulose (Nipponda (trade name)), shin Cao AQOAT (trade name chemical industry (name)) METOLOSE 90 SH-SR (trade name chemical industry (name)) HPMCP (trade name chemical industry (name) METOLOSE SM (trade name chemical name (name), TC-5 (SanrongyF.F.F.I (trade name), L-HPC (trade name chemical name (name) name, etc.

The content of the cellulose ether in the pharmaceutical composition is not particularly limited, and can be suitably determined by study 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 cellulose ether is preferably 0.5 to 30% by mass, more preferably 1 to 20% by mass, still more preferably 1.5 to 15% by mass, and particularly preferably 2 to 10% by mass, based on the total mass of the pharmaceutical composition.

When alkylcellulose or a salt thereof is used as the cellulose ether, the content of the alkylcellulose or a salt thereof is preferably 0.6 to 22% by mass, more preferably 1.1 to 19% by mass, and particularly preferably 3 to 8% by mass, based on the total mass of the pharmaceutical composition, from the viewpoint of improving the content uniformity.

When hydroxyalkyl cellulose or a salt thereof is used as the cellulose ether, the content of the hydroxyalkyl cellulose or a salt thereof is preferably 0.7 to 24% by mass, more preferably 1.2 to 18% by mass, and particularly preferably 3 to 8% by mass, based on the total mass of the pharmaceutical composition, from the viewpoint of improving the content uniformity.

When alkyl (hydroxyalkyl) cellulose or a derivative thereof or a salt thereof is used as the cellulose ether, the content of the alkyl (hydroxyalkyl) cellulose or a derivative thereof or a salt thereof is preferably 0.8 to 26% by mass, more preferably 1.3 to 17% by mass, and particularly preferably 4 to 9% by mass, based on the total mass of the pharmaceutical composition, from the viewpoint of improving the content uniformity.

When a carboxyalkyl cellulose or a derivative or salt thereof is used as the cellulose ether, the content of the carboxyalkyl cellulose or a derivative or salt thereof is preferably 0.9 to 28 mass%, more preferably 1.4 to 16 mass%, and particularly preferably 1.6 to 9 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 to cellulose ethers in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the content of cellulose ethers is preferably 3 to 200 parts by mass in total, more preferably 5 to 150 parts by mass, and particularly preferably 10 to 100 parts by mass, based on 1 part by mass of pemfibrate free form.

In addition, when an alkylcellulose or a salt thereof is used as the cellulose ether, the content mass ratio of pemabefibrate or a salt thereof or a solvate thereof to the alkylcellulose or a salt thereof in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the total amount of the alkylcellulose or a salt thereof is preferably 4 to 160 parts by mass, more preferably 6 to 110 parts by mass, and particularly preferably 20 to 60 parts by mass, based on 1 part by mass of free pemabefibrate.

In addition, when hydroxyalkyl cellulose or a salt thereof is used as the cellulose ether, the content mass ratio of pemfibrate or a salt thereof or a solvate thereof to hydroxyalkyl cellulose or a salt thereof in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the content of hydroxyalkyl cellulose or a salt thereof is preferably 4 to 170 parts by mass in total, more preferably 7 to 120 parts by mass, still more preferably 20 to 100 parts by mass, and particularly preferably 30 to 70 parts by mass in terms of 1 part by mass of free pemfibrate.

In addition, when an alkyl (hydroxyalkyl) cellulose, a derivative thereof, or a salt thereof is used as the cellulose ether, the content mass ratio of pemfibrate, a salt thereof, or a solvate thereof, and an alkyl (hydroxyalkyl) cellulose, a derivative thereof, or a salt thereof in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the total amount of the alkyl (hydroxyalkyl) cellulose, a derivative thereof, or a salt thereof is preferably 4 to 180 parts by mass, more preferably 8 to 130 parts by mass, still more preferably 20 to 100 parts by mass, and particularly preferably 40 to 80 parts by mass, based on 1 part by mass of the free form of pemfibrate.

In addition, when a carboxyalkyl cellulose or a derivative thereof or a salt thereof is used as the cellulose ether, the content ratio by mass of pemfibrate or a salt thereof or a solvate thereof to the carboxyalkyl cellulose or a derivative thereof or a salt thereof in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the carboxyalkyl cellulose or a derivative thereof or a salt thereof is preferably contained in an amount of 4 to 190 parts by mass in total, more preferably 9 to 140 parts by mass, still more preferably 14 to 100 parts by mass, and particularly preferably 19 to 90 parts by mass based on 1 part by mass of the pemabelate as a free substance.

< starches (component (B-2)) >)

In the present specification, the term "starch" refers to 1 or more species selected from the group consisting of starch itself, a substance in which all or a part of the hydroxyl groups of starch form ether bonds, a derivative thereof, and a salt thereof. The starch includes those subjected to gelatinization, aging, or the like. The derivative includes starch or an etherified product thereof, which is further modified by esterification, crosslinking, hydrolysis, or the like, if necessary. 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.

Specific examples of such starches include α -modified starch, wheat starch, rice starch, corn starch, potato starch, partially α -modified starch, wheat flour, rice flour, and semi-digestible starch, and other starches or salts thereof, hydroxyalkyl ethers of starch such as hydroxypropyl starch, and carboxyalkyl ethers of starch such as sodium carboxymethyl starch, and other salts thereof, and 1 of these may be used alone or 2 or more of these may be used in combination.

The starch is preferably at least 1 selected from the group consisting of starch, hydroxyalkyl ethers of starch, carboxyalkyl ethers of starch, and salts thereof, more preferably at least 1 selected from the group consisting of starch, hydroxyc 1-C6 alkyl ethers of starch, carboxyac 1-C6 alkyl ethers of starch, and salts thereof, still more preferably at least 1 selected from the group consisting of starch, hydroxypropyl starch, carboxymethyl starch, and salts thereof, and particularly preferably at least 1 selected from the group consisting of starch and sodium carboxymethyl starch, from the viewpoint of the effect of improving the content uniformity. In addition, from the viewpoint of ease of manufacturing a pharmaceutical composition (particularly a solid preparation), starches that are solid at room temperature (any temperature of 15 to 25 ℃) are preferred.

These starches 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 LYCATAB PGS (Roquette Japan), GLYCOLYS (Roquette Japan), starch (soluble) (KISHIDA chemical strain), corn starch (sanrong source f.f.i.), (genuine chemical strain)), HPS-101 (free industry strain), and LYCATABC (Roquette Japan strain).

The content of the starch in the pharmaceutical composition is not particularly limited, and can be suitably determined by study 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 starch is preferably 0.5 to 50% by mass, more preferably 1 to 40% by mass, still more preferably 1.5 to 30% by mass, and particularly preferably 2 to 20% by mass, based on the total mass of the pharmaceutical composition.

When starch is used as the starch, the content of starch is preferably 0.6 to 47% by mass, more preferably 1.1 to 38% by mass, and particularly preferably 1.6 to 28% by mass, based on the total mass of the pharmaceutical composition, from the viewpoint of improving the content uniformity.

In addition, when the starch is a carboxyalkyl ether of starch or a salt thereof, the content of the carboxyalkyl ether of starch or a salt thereof is preferably 0.8 to 45 mass%, more preferably 1.3 to 36 mass%, and particularly preferably 1.7 to 26 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 to starch in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the content of starch is preferably 5 to 400 parts by mass in total, more preferably 15 to 300 parts by mass, and particularly preferably 20 to 200 parts by mass in terms of 1 part by mass of pemfibrate free body.

In addition, when starch is used as the starch, the content mass ratio of pemfibrate, a salt thereof, or a solvate thereof to starch in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the pemfibrate or the salt thereof, or the solvate thereof, is preferably contained in an amount of 7 to 380 parts by mass in total, more preferably 16 to 280 parts by mass, and particularly preferably 30 to 190 parts by mass, based on 1 part by mass of the free form of pemfibrate.

In addition, when the carboxyalkyl ether of starch or a salt thereof is used as the starch, the content ratio by mass of pemfibrate or a salt thereof or a solvate thereof to the carboxyalkyl ether of starch or a salt thereof in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the carboxyalkyl ether of starch or a salt thereof is preferably 9 to 370 parts by mass in total, more preferably 17 to 270 parts by mass, and particularly preferably 40 to 180 parts by mass in terms of 1 part by mass of pemfibrate free body.

< Povidones (component (B-3)) >)

In the present specification, "povidone-based" refers to a polymer of 1-vinyl-2-pyrrolidone, and is a concept including not only a homopolymer of 1-vinyl-2-pyrrolidone but also a copolymer of 1-vinyl-2-pyrrolidone and other polymerizable compounds. The polymer may be a non-crosslinked polymer or a crosslinked polymer.

The K value of the linear polymer of 1-vinyl-2-pyrrolidone (povidone) is not particularly limited, and is preferably 12 to 90, and particularly preferably 25 to 90.

As such povidone, specifically, for example, a linear polymer of 1-vinyl-2-pyrrolidone such as povidone (among them, the K value of povidone is not particularly limited, and examples of the K value to be displayed include 12, 17, 25, 30 and 90); copolymers of 1-vinyl-2-pyrrolidone such as copovidone with vinyl acetate; and crosslinked polymers of 1-vinyl-2-pyrrolidone such as crospovidone, and the like, and 1 of these may be used alone or 2 or more may be used in combination.

From the viewpoint of the effect of improving the content uniformity, the povidone type is preferably 1 or more selected from povidone, copovidone, and crospovidone, more preferably 1 or more selected from povidone and crospovidone, and particularly preferably crospovidone. In addition, from the viewpoint of ease of manufacturing a pharmaceutical composition (particularly a solid preparation), povidone is preferably a povidone that is solid at room temperature (any temperature of 15 to 25 ℃).

These povidone-based compounds 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 Kollidon CL, Kollidon VA64, and Kollidon (described above, BASF japan (ltd)).

The content of povidone in the pharmaceutical composition is not particularly limited, and can be determined by appropriate studies according to the type of preparation, sex, age, symptom, and the like of a user, and from the viewpoint of the effect of improving the content uniformity, the total amount of povidone is preferably 0.1 to 20% by mass, more preferably 0.5 to 15% by mass, and particularly preferably 1 to 10% by mass, based on the total mass of the pharmaceutical composition.

In addition, when a linear polymer of 1-vinyl-2-pyrrolidone is used as povidone, the content of the linear polymer of 1-vinyl-2-pyrrolidone is preferably 0.2 to 16% by mass, more preferably 0.6 to 14% by mass, and particularly preferably 3 to 9% by mass, based on the total mass of the pharmaceutical composition, from the viewpoint of improving the content uniformity.

In addition, in the case of using a crosslinked polymer of 1-vinyl-2-pyrrolidone as povidone, the content of the crosslinked polymer of 1-vinyl-2-pyrrolidone is preferably 0.3 to 17 mass%, more preferably 0.7 to 13 mass%, and particularly preferably 2 to 8 mass% with respect to 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 to povidone in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the content of povidone in total is preferably 1 to 200 parts by mass, more preferably 3 to 150 parts by mass, and particularly preferably 5 to 100 parts by mass, based on 1 part by mass of pemfibrate free body.

In addition, when a linear polymer of 1-vinyl-2-pyrrolidone is used as povidone, the content mass ratio of pemfibrate or a salt thereof or a solvate of the same to the linear polymer of 1-vinyl-2-pyrrolidone in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the total amount of 1.5 to 190 parts by mass of the linear polymer of 1-vinyl-2-pyrrolidone is preferably 1 part by mass, more preferably 3.5 to 140 parts by mass, and particularly preferably 6 to 90 parts by mass based on 1 part by mass of the free form of pemfibrate.

In addition, when a crosslinked polymer of 1-vinyl-2-pyrrolidone is used as povidone, the content ratio by mass of pemfibrate or a salt thereof or a solvate of the same and the crosslinked polymer of 1-vinyl-2-pyrrolidone in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the total amount of the crosslinked polymer containing 1-vinyl-2-pyrrolidone is preferably 2 to 180 parts by mass, more preferably 4 to 130 parts by mass, and particularly preferably 7 to 80 parts by mass, based on 1 part by mass of the free form of pemfibrate.

< silicic acid Compound (component (B-4)) >)

In the present specification, the "silicic acid compound" includes a salt of the silicic acid compound in addition to the silicic acid compound itself. Examples of the salt of the silicic acid compound include inorganic salts, and specifically, alkali metal salts such as sodium salt and potassium salt; salts with metals of group 2 elements such as magnesium salts and calcium salts, and salts with metals of group 13 elements such as aluminum salts.

Specific examples of such silicic acid compounds include hydrous silicic acid compounds such as hydrous silicon dioxide, hydrous amorphous silica, hydrous magnesium silicate (natural), and salts thereof; anhydrous silicic acid such as light anhydrous silicic acid and heavy anhydrous silicic acid, or a salt thereof; silica, natural aluminum silicate, synthetic sodium magnesium silicate, calcium silicate, magnesium aluminum silicate, magnesium aluminate metasilicate, etc. silicic acid or its salt, and in addition, diatomaceous earth, bentonite, kaolin, talc, etc. can be used alone in 1, or in combination with 2 or more.

The silicate compound is preferably 1 or more selected from the group consisting of hydrous silicate compounds, salts of hydrous silicate compounds, anhydrous silicic acid and salts of anhydrous silicic acid, and particularly preferably 1 or more selected from the group consisting of hydrous silicate compounds and salts of hydrous silicate compounds, from the viewpoint of improving the content uniformity.

In the specific examples of the silicic acid compound, from the viewpoint of the effect of improving the content uniformity, 1 or more selected from hydrous magnesium silicate, hydrous silicon dioxide and light anhydrous silicic acid is preferable, and 1 or more selected from hydrous magnesium silicate and hydrous silicon dioxide is particularly preferable. In addition, from the viewpoint of ease of production of a pharmaceutical composition (particularly a solid preparation), a silicic acid compound is preferably a solid at room temperature (any temperature of 15 to 25 ℃).

These silicic acid compounds 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 NEUSILIN a (fuji chemical industry strain), FLORITE (fuji pharmaceutical industry strain), magnesium silicate (fuji pharmaceutical industry strain), veegui grain (sanyo chemical industry strain), veegui HV grain (sanyo chemical industry strain), veegui K grain (sanyo chemical industry strain), veegui F (sanyo chemical industry strain), sylisia 320 (fuji sylsia chemical strain), SYLYSIA 350 (fuji siiica chemical strain), sylisia 320TP (fuji sylsia chemical strain), sylisia 320FCP (fuji sylsia chemical strain), MICON FR (fuji pharmaceutical industry strain), silicon dioxide (japanese aesil (strain), AEROSIL 300 (japanese florisil strain), Adsolider 101(Freund chemical industry strain), sysola 102 (solid chemical industry strain), and sysii (sysii chemical strain) Hydrous amorphous Silica (Tosoh Silica, Inc.), Neusilin (Fuji chemical industry, Inc.), diatomaceous earth (Showa chemical industry, Inc.), talc (Sangrong F.F.I., Inc.), and the like.

The content of the silicic acid compound in the pharmaceutical composition is not particularly limited, and can be appropriately determined by study according to the type of the preparation, the sex, age, symptom, and the like of the subject, and from the viewpoint of the effect of improving the content uniformity, the total amount of the silicic acid compound is preferably 0.1 to 20% by mass, more preferably 0.5 to 15% by mass, and particularly preferably 1 to 10% by mass, based on the total mass of the pharmaceutical composition.

In addition, in the silicate compound using selected from the group consisting of silicic acid containing compound and its salt 1 more than, as selected from silicic acid containing compound and its salt 1 more than content, from the content uniformity improvement effect, relative to the total mass of the pharmaceutical composition, preferably 0.2 to 19 mass%, more preferably 0.6 to 14 mass%, especially preferably 2 to 6 mass%.

In addition, in the silicate compound using selected from anhydrous silicate compounds and salts thereof in the case of more than 1, from the content of the anhydrous silicate compounds and salts thereof, from the view point of content uniformity improvement effect, relative to the total mass of the pharmaceutical composition, preferably 0.4 to 17 mass%, more preferably 0.8 to 12 mass%, and particularly preferably 4 to 8 mass%.

The content mass ratio of pemfibrate, a salt thereof, or a solvate of these compounds and a silicic acid compound in the pharmaceutical composition is not particularly limited, and from the viewpoint of improving the content uniformity, the silicic acid compound is preferably contained in an amount of 1 to 200 parts by mass in total, more preferably 3 to 150 parts by mass, and particularly preferably 5 to 100 parts by mass, based on 1 part by mass of the free form of pemfibrate.

In addition, when 1 or more selected from the group consisting of hydrous silicic acid compounds and salts thereof is used as the silicic acid compound, the content by mass ratio of the pemfibrate or the salt thereof or the solvate thereof and 1 or more selected from the group consisting of hydrous silicic acid compounds and salts 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 2 to 160 parts by mass in total of 1 or more selected from the group consisting of hydrous silicic acid compounds and salts thereof, more preferably contains 4 to 140 parts by mass, and particularly preferably contains 10 to 90 parts by mass, based on 1 part by mass of the free form of pemfibrate.

In addition, when 1 or more selected from the group consisting of anhydrous silicic acid compounds and salts thereof is used as the silicic acid compound, the content by mass ratio of pemfibrate, a salt thereof, or a solvate thereof to 1 or more selected from the group consisting of anhydrous silicic acid compounds and salts thereof in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the content is preferably 2 to 180 parts by mass, more preferably 4 to 120 parts by mass, and particularly preferably 10 to 80 parts by mass in total of 1 or more selected from the group consisting of anhydrous silicic acid compounds and salts thereof based on 1 part by mass of the free pemfibrate.

< polyol (component (B-5)) >)

In the present specification, the term "polyol" refers to a compound having 2 or more alcoholic hydroxyl groups and not having 2 or more cyclic ether structures (e.g., tetrahydropyran rings) in the molecule, and may be a non-polymer or a polymer. Examples of such polyols include sugar alcohols and non-sugar alcohols, and 1 of them may be used alone or 2 or more of them may be used in combination. The polyol is preferably a polyol having no cyclic ether structure (e.g., tetrahydropyran ring) in the molecule, or a polyol having only 1 cyclic ether structure in the molecule, more preferably a polyol having no cyclic ether structure in the molecule, and particularly preferably a non-cyclic compound among the polyols.

In addition, from the viewpoint of ease of production of a pharmaceutical composition (particularly a solid preparation), a polyol which is solid at ordinary temperature (any temperature of 15 to 25 ℃) is preferable as the polyol.

Specific examples of the sugar alcohol include sugar alcohols having 3 carbon atoms (trisaccharide alcohols) such as glycerin; a sugar alcohol having 4 carbon atoms (tetrasugar alcohol) such as erythritol and threitol; sugar alcohols having 5 carbon atoms (penta-sugar alcohols) such as xylitol, arabitol, ribitol, and adonitol; sugar alcohols having 6 carbon atoms (hexitol) such as mannitol, sorbitol, iditol, dulcitol, and galactitol; sugar alcohols (lauryl sugar alcohol) having 12 carbon atoms such as maltitol and lactitol may be used alone or in combination of 2 or more. Further, these sugar alcohols may have various stereoisomers, but the "sugar alcohol" is not particularly limited in its stereoconfiguration, and may be each stereoisomer alone or a mixture of each stereoisomer in an arbitrary ratio.

Among the above sugar alcohols, from the viewpoint of the effect of improving the content uniformity, 1 or more selected from erythritol, xylitol, mannitol, sorbitol, maltitol, and lactitol is preferable, 1 or more selected from mannitol, sorbitol, and maltitol is more preferable, and mannitol is particularly preferable.

These sugar alcohols 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 erythritol (sanrong source f.f.i. (strain)), Xilite (eastern harmonization industry (strain)), NEOSORB P (Roquette Japan (strain)), Lesys (eastern harmonization industry (strain)), Mannit P (eastern harmonization industry (strain)), glycerin (solar oil (strain)), maltsorb (Roquette Japan (strain)), and amplitude Syrup (eastern harmonization industry (strain)).

The non-sugar alcohol is preferably a non-cyclic compound among non-sugar alcohols. Specific examples thereof include alkylene glycols such as ethylene glycol, propylene glycol, 1, 3-propanediol, 2-methyl-1, 3-propanediol, and 1, 3-butanediol; diethylene glycol, dipropylene glycol, polyethylene glycol (macrogol, for example, polyethylene glycol 100, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 20000, polyethylene glycol 35000, etc.), polypropylene glycol (for example, polypropylene glycol 2000, etc.), polyoxyethylene polyoxypropylene glycol (for example, polyoxyethylene (3) polyoxypropylene (17) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (124) polyoxypropylene (39) glycol, etc.) Polyoxyethylene (160) polyoxypropylene (30) diol, polyoxyethylene (196) polyoxypropylene (67) diol, polyoxyethylene (200) polyoxypropylene (70) diol, and the like. ) Polyalkylene glycols and the like; polyvinyl alcohols such as polyvinyl alcohol (completely saponified product) and polyvinyl alcohol (partially saponified product); meglumine and the like, and among these, 1 kind may be used alone, or 2 or more kinds may be used in combination.

Among the non-sugar alcohols, from the viewpoint of the effect of improving the content uniformity, a non-sugar alcohol having a valence of 2 is preferable, polyalkylene glycols are more preferable, polyethylene glycol is more preferable, 1 or more selected from the group consisting of polyethylene glycol 100, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 20000, and polyethylene 35000 are more preferable, polyethylene glycol having an average molecular weight of 100 to 10000 is more preferable, polyethylene glycol of 200 to 8000 is more preferable, and polyethylene glycol 6000 is particularly preferable. The average molecular weight of polyethylene glycol can be measured according to the "average molecular weight test" described in the column of "polyethylene glycol 400" in each of japanese pharmacopoeia pharmaceuticals, seventeenth edition.

These non-sugar alcohols are known components, and can be produced by known methods, or commercially available products can be used. Examples of such commercially available products include Kollisolv PG (BASF Japan strain), diethylene glycol ((strain) japanese catalyst), UNISAFE DPG-R (japanese oil strain), polyethylene glycol 200 (sanyo chemical industry strain), Kollisolv PEG300(BASF Japan strain), Super-modified PEG400(Croda Japan strain), CARBOWAX Sentry PEG600 (tao chow chemical Japan strain), polyethylene glycol 1000 (japanese oil strain), polyethylene glycol 1500 (sanyo chemical industry strain), CARBOWAX Sentry PEG1540 (tao chow chemical Japan strain), polyethylene glycol 4000 (sanyo chemical industry strain), polyethylene glycol 6000 (sanyo chemical industry strain), polyethylene glycol 20000 (sanyo chemical industry strain), newwpol PP-2000 (sanyo chemical industry strain), pron 101 (japanese oil strain), and bas strain 124(BASF strain) and the like, PRONON 403P (Nissan oil Co., Ltd.), NEWDET PE-85 (Sanyo chemical industry Co., Ltd.), PEP-101 (Freund industry Co., Ltd.), Kolliphor P188(BASF Japan Co., Ltd.), Kolliphor P407 Micro (BASF Japan Co., Ltd.), UNILUBE-950B (Nissan oil Co., Ltd.), and the like.

The content of the polyhydric alcohol in the pharmaceutical composition is not particularly limited, and can be suitably determined by study 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 polyhydric alcohol is preferably 0.1 to 99% by mass, more preferably 0.5 to 95% by mass, still more preferably 1 to 90% by mass, and particularly preferably 1.5 to 50% by mass, based on the total mass of the pharmaceutical composition.

In addition, when a sugar alcohol is used as the polyol, the content of the sugar alcohol is preferably 0.2 to 98% by mass, more preferably 0.6 to 94% by mass, and particularly preferably 1.1 to 85% by mass, based on the total mass of the pharmaceutical composition, from the viewpoint of improving the content uniformity.

In addition, when a non-sugar alcohol is used as the polyol, the content of the non-sugar alcohol is preferably 0.3 to 97% by mass, more preferably 0.7 to 93% by mass, and particularly preferably 1.2 to 80% by mass, based on the total mass of the pharmaceutical composition, from the viewpoint of improving the content uniformity.

When polyalkylene glycols are used as the polyhydric alcohol, the content of polyalkylene glycols is preferably 0.4 to 96% by mass, more preferably 0.8 to 92% by mass, and particularly preferably 1.3 to 75% 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 of these compounds and a polyol in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the content of the polyol is preferably 1 to 2000 parts by mass in total, more preferably 5 to 1500 parts by mass, still more preferably 10 to 1000 parts by mass, and particularly preferably 15 to 500 parts by mass, based on 1 part by mass of the free form of pemfibrate.

In addition, when a sugar alcohol is used as the polyol, the content mass ratio of pemfibrate, a salt thereof, or a solvate thereof to the sugar alcohol in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the sugar alcohol is preferably contained in an amount of 2 to 1900 parts by mass in total, more preferably 6 to 1450 parts by mass, and particularly preferably 12 to 950 parts by mass in terms of 1 part by mass of pemfibrate free body.

In addition, when a non-sugar alcohol is used as the polyol, the content mass ratio of pemfibrate, a salt thereof, or a solvate thereof to the non-sugar alcohol in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the non-sugar alcohol is contained in an amount of preferably 3 to 1850 parts by mass, more preferably 7 to 1400 parts by mass, and particularly preferably 13 to 900 parts by mass in total based on 1 part by mass of free pemfibrate.

In addition, when polyalkylene glycols are used as the polyhydric alcohol, the content mass ratio of pemfibrate, a salt thereof, or a solvate thereof to polyalkylene glycols in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the polyalkylene glycols are preferably contained in a total amount of 4 to 1800 parts by mass, more preferably 8 to 1350 parts by mass, and particularly preferably 14 to 850 parts by mass, based on 1 part by mass of the free form of pemfibrate.

< alkyl sulfates (component (B-6)) >)

In the present specification, "alkyl sulfate" refers to an alkyl sulfate represented by the following formula (1):

R－O－SO₃M…(1)

(wherein R represents a linear or branched, saturated or unsaturated hydrocarbon group having 8 to 22 carbon atoms, and M represents an alkali metal such as sodium or potassium, a metal of group 2 element such as magnesium or calcium, an ammonium ion, or a hydroxyalkyl-substituted ammonium having 2 or 3 carbon atoms such as triethanolammonium).

Specific examples of the alkyl sulfates include lauryl sulfate, myristyl sulfate, cetyl sulfate, and stearyl sulfate, and 1 of these may be used alone or 2 or more may be used in combination.

The alkyl sulfates are preferably at least 1 selected from lauryl sulfate, myristyl sulfate, cetyl sulfate and stearyl sulfate, more preferably lauryl sulfate, and particularly preferably sodium lauryl sulfate, from the viewpoint of improving the content uniformity. In addition, from the viewpoint of ease of production of a pharmaceutical composition (particularly a solid preparation), the alkyl sulfates are preferably solid at room temperature (any temperature of 15 to 25 ℃).

These alkyl sulfates 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 Kolliphor SLS (BASF JAPAN (ltd)).

The content of the alkyl sulfates in the pharmaceutical composition is not particularly limited, and can be suitably determined by study 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 alkyl sulfates is preferably 0.1 to 20% by mass, more preferably 0.5 to 15% by mass, and particularly preferably 1 to 10% by mass, based on the total mass of the pharmaceutical composition.

The content mass ratio of pemfibrate, a salt thereof, or a solvate thereof and an alkyl sulfate in the pharmaceutical composition is not particularly limited, and from the viewpoint of the effect of improving the content uniformity, the pemfibrate or a salt thereof or a solvate thereof is preferably contained in an amount of 1 to 200 parts by mass, more preferably 3 to 150 parts by mass, still more preferably 5 to 100 parts by mass, and particularly preferably 5 to 50 parts by mass, in total, based on 1 part by mass of pemfibrate free body.

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 (including elixirs, suspensions, emulsions, aqueous lemonades, etc.), etc. 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. 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 ℃), the components are likely to be unevenly mixed and dispersed, and the deterioration of content uniformity is particularly likely to be a problem. However, according to the present invention, even in the case of a solid preparation, there is an excellent effect that content uniformity is good.

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. In addition, as the solid preparation, a solid preparation containing a mixture containing the components (a) and (B) is preferable.

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, poorly water-soluble polymeric substances, antioxidants, flavors, and sweeteners. Specific examples of the Pharmaceutical additives include those contained in a Pharmaceutical additives dictionary 2016 (published by Pharmaceutical Press), a Handbook of Pharmaceutical Excipients, and a Seventh Edition.

Specific examples of the excipient include inorganic excipients such as anhydrous sodium sulfate, anhydrous calcium hydrogen phosphate, sodium chloride, calcium sulfate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodium dihydrogen phosphate; fructose, caramel, agar, paraffin, crystalline cellulose, sucrose, maltose, lactose hydrate, white sugar, glucose, pullulan, polyoxyethylene hydrogenated castor oil, 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 not particularly limited, but is preferably 20 to 99% by mass, more preferably 30 to 97% 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 dextrin, pullulan, gum arabic, agar, gelatin, tragacanth, sodium alginate, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, and the like. These can be used in 1 kind or 2 or more kinds in combination.

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 not particularly limited, but 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 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.

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.

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, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, and saccharin sodium, and 1 kind of these sweeteners or 2 or more kinds of sweeteners can be used in combination.

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, the pharmaceutical composition can be produced by appropriately combining unit operations such as pulverization, mixing, granulation, drying, size control, classification, filling, tableting, and coating, and a method including a step of mixing the component (a) and the component (B) is preferable as a production method thereof.

More specifically, for example, in the case where the pharmaceutical composition is a granular preparation such as granules, powder, and pellets, the pharmaceutical composition can be produced by mixing the components (a) and (B) with, if necessary, other preparation additives such as excipients, binders, disintegrants, and lubricants, 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 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 the components (a) and (B) with appropriate pharmaceutical additives such as an excipient, a binder, a disintegrant, and a lubricant as needed to obtain a mixture, and directly compressing (tableting) the mixture (direct powder compression method), or by classifying, sizing, and the like the granulated product as needed and then compressing (tableting) (semi-dry granulation method, wet granulation method, and the like). The obtained compressed product (tablet) can also 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 is suitably used as a prophylactic and/or therapeutic agent for dyslipidemia (hyperlipidemia, more specifically, for example, primary hyperlipidemia, secondary hyperlipidemia, and the like), and more suitably used 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 suitably determined and studied depending on 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) 1 or more selected from the following components (B-1) to (B-6);

(B-1) cellulose ethers

(B-2) starches

(B-3) Povidones

(B-4) silicic acid Compound

(B-5) polyol

(B-6) alkyl sulfates.

[ 1-2 ] the pharmaceutical composition according to [ 1-1 ], wherein the component (B-1) is at least 1 selected from the group consisting of alkylcelluloses, hydroxyalkylcelluloses, alkyl (hydroxyalkyl) celluloses, crosslinked polymers of carboxyalkylcelluloses and carboxyalkylcelluloses, and salts thereof.

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

[ 1-4 ] the pharmaceutical composition according to [ 1-1 ], wherein the component (B-1) is at least 1 selected from the group consisting of methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose potassium, carboxymethylcellulose calcium, carboxymethylcellulose sodium and croscarmellose sodium.

[ 1-5 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-4 ], wherein the component (B-2) is at least 1 selected from the group consisting of starch, hydroxyalkyl ether of starch, carboxyalkyl ether of starch, and salts thereof.

[ 1-6 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-4 ], wherein the component (B-2) is at least 1 selected from the group consisting of starch, a hydroxy C1-C6 alkyl ether of starch, a carboxy C1-C6 alkyl ether of starch, and a salt thereof.

[ 1-7 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-4 ], wherein the component (B-2) is at least 1 selected from the group consisting of starch, hydroxypropyl starch, carboxymethyl starch, and salts thereof.

[ 1-8 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-7 ], wherein the component (B-3) is at least 1 selected from povidone and crospovidone.

[ 1-9 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-7 ], wherein the component (B-3) is crospovidone.

[ 1-10 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-9 ], wherein the component (B-4) is at least 1 selected from the group consisting of hydrous silicic acid compounds, salts of hydrous silicic acid compounds, anhydrous silicic acid and salts of anhydrous silicic acid.

[ 1-11 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-9 ], wherein the component (B-4) is at least 1 selected from the group consisting of hydrous magnesium silicate, hydrous silicon dioxide and light anhydrous silicic acid.

[ 1-12 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-9 ], wherein the component (B-4) is at least 1 selected from hydrous magnesium silicate and hydrous silicon dioxide.

[ 1-13 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-12 ], wherein the component (B-5) is polyethylene glycol.

[ 1-14 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-12 ], wherein the component (B-5) is at least 1 selected from the group consisting of polyethylene glycol 100, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 20000, and polyethylene glycol 35000.

[ 1-15 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-12 ], wherein the component (B-5) is polyethylene glycol having an average molecular weight of 100 to 10000.

[ 1-16 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-12 ], wherein the component (B-5) is polyethylene glycol 6000.

[ 1-17 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-12 ], wherein the component (B-5) is at least 1 selected from erythritol, xylitol, mannitol, sorbitol, maltitol, and lactitol.

[ 1-18 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-12 ], wherein the component (B-5) is at least 1 selected from mannitol and sorbitol.

[ 1-19 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-12 ], wherein the component (B-5) is mannitol.

[ 1-20 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-19 ], wherein the component (B-6) is at least 1 selected from the group consisting of lauryl sulfate, myristyl sulfate, cetyl sulfate and stearyl sulfate.

[ 1-21 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-19 ], wherein the component (B-6) is lauryl sulfate.

[ 1-22 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-19 ], wherein the component (B-6) is sodium lauryl sulfate.

[ 1-23 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-22 ], 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.

[ 1-24 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-23 ], which is a solid preparation.

[ 1-25 ] the pharmaceutical composition according to any one of [ 1-1 ] to [ 1-24 ], which is in the form of a tablet, capsule, granule, powder or pill.

[ 2-1 ] A method for improving content uniformity of pemabefibrate or a salt thereof or a solvate thereof in a pharmaceutical composition, comprising: the pharmaceutical composition comprising (A) pemabefibrate, a salt thereof or a solvate of the foregoing comprises 1 or more selected from the following components (B-1) to (B-6);

(B-1) cellulose ethers

(B-2) starches

(B-3) Povidones

(B-4) silicic acid Compound

(B-5) polyol

(B-6) alkyl sulfates.

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

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

[ 2-4 ] the method according to [ 2-1 ], wherein the component (B-1) is at least 1 selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose and croscarmellose sodium.

[ 2-5 ] the method according to any one of [ 2-1 ] to [ 2-4 ], wherein the component (B-2) is at least 1 selected from the group consisting of starch, hydroxyalkyl ether of starch, carboxyalkyl ether of starch, and salts thereof.

[ 2-6 ] the method according to any one of [ 2-1 ] to [ 2-4 ], wherein the component (B-2) is at least 1 selected from the group consisting of starch, a hydroxy C1-C6 alkyl ether of starch, a carboxy C1-C6 alkyl ether of starch, and a salt thereof.

[ 2-7 ] the method according to any one of [ 2-1 ] to [ 2-4 ], wherein the component (B-2) is at least 1 selected from the group consisting of starch, hydroxypropyl starch, carboxymethyl starch and salts thereof.

[ 2-8 ] the method according to any one of [ 2-1 ] to [ 2-7 ], wherein the component (B-3) is at least 1 selected from povidone and crospovidone.

[ 2-9 ] the method according to any one of [ 2-1 ] to [ 2-7 ], wherein the component (B-3) is crospovidone.

[ 2-10 ] the method according to any one of [ 2-1 ] to [ 2-9 ], wherein the component (B-4) is at least 1 selected from the group consisting of hydrous silicic acid compounds, salts of hydrous silicic acid compounds, anhydrous silicic acid and salts of anhydrous silicic acid.

[ 2-11 ] the method according to any one of [ 2-1 ] to [ 2-9 ], wherein the component (B-4) is at least 1 selected from the group consisting of hydrous magnesium silicate, hydrous silicon dioxide and light anhydrous silicic acid.

[ 2-12 ] the method according to any one of [ 2-1 ] to [ 2-9 ], wherein the component (B-4) is at least 1 selected from hydrous magnesium silicate and hydrous silicon dioxide.

[ 2-13 ] the method according to any one of [ 2-1 ] to [ 2-12 ], wherein the component (B-5) is polyethylene glycol.

[ 2-14 ] the method according to any one of [ 2-1 ] to [ 2-12 ], wherein the component (B-5) is at least 1 selected from the group consisting of polyethylene glycol 100, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 20000, and polyethylene glycol 35000.

[ 2-15 ] the method according to any one of [ 2-1 ] to [ 2-12 ], wherein the component (B-5) is polyethylene glycol having an average molecular weight of 100 to 10000.

[ 2-16 ] the method according to any one of [ 2-1 ] to [ 2-12 ], wherein the component (B-5) is polyethylene glycol 6000.

[ 2-17 ] the method according to any one of [ 2-1 ] to [ 2-12 ], wherein the component (B-5) is at least 1 selected from erythritol, xylitol, mannitol, sorbitol, maltitol, and lactitol.

[ 2-18 ] the method according to any one of [ 2-1 ] to [ 2-12 ], wherein the component (B-5) is at least 1 selected from mannitol and sorbitol.

[ 2-19 ] the method according to any one of [ 2-1 ] to [ 2-12 ], wherein the component (B-5) is mannitol.

[ 2-20 ] the method according to any one of [ 2-1 ] to [ 2-19 ], wherein the component (B-6) is at least 1 selected from the group consisting of lauryl sulfate, myristyl sulfate, cetyl sulfate and stearyl sulfate.

[ 2-21 ] the method according to any one of [ 2-1 ] to [ 2-19 ], wherein the component (B-6) is a lauryl sulfate.

[ 2-22 ] the method according to any one of [ 2-1 ] to [ 2-19 ], wherein the component (B-6) is sodium lauryl sulfate.

[ 2-23 ] the method according to any one of [ 2-1 ] to [ 2-22 ], 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 preferably NASH (nonalcoholic steatohepatitis)), and primary biliary cirrhosis.

[ 2-24 ] the pharmaceutical composition according to any one of [ 2-1 ] to [ 2-23 ], which is a solid preparation.

[ 2-25 ] the method according to any one of [ 2-1 ] to [ 2-24 ], wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, powder or pill.