JP2009534292A - Pharmaceutical composition of angiotensin II antagonist with pioglitazone hydrochloride - Google Patents

Abstract

（式中、Ｒ^１は置換されていてもよい、脱プロトン化しうる水素原子を有する単環状の含窒素複素環基を示し、Ｒ^２はエステル化されていてもよいカルボキシル基を示し、Ｒ^３は置換されてもよい低級アルキルを示す）
で表される化合物もしくはその塩またはそのプロドラッグと低融点油脂状物質とを含有する核と、
（ｂ）高分子量重合体を含有し当該核を被覆する第一の層と、
（ｃ）塩酸ピオグリタゾンを含有し、当該第一の層を被覆する第二の層と
を含有してなる固形医薬組成物を提供する。
【選択図】なしThe present invention
(A) Formula (I)

(Wherein R ¹ represents an optionally substituted monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated, R ² represents an optionally esterified carboxyl group, and R ³ Represents lower alkyl which may be substituted)
A nucleus containing a compound represented by the formula (1) or a salt thereof or a prodrug thereof and a low melting point oily substance;
(B) a first layer containing a high molecular weight polymer and covering the nucleus;
(C) Provided is a solid pharmaceutical composition comprising pioglitazone hydrochloride and a second layer covering the first layer.
[Selection figure] None

Description

Technical Field It is clinically useful as a prophylactic / therapeutic agent for cardiovascular diseases such as hypertension, heart failure, diabetic nephropathy, arteriosclerosis and metabolic diseases such as diabetes and metabolic syndrome. The present invention relates to a novel solid pharmaceutical composition excellent in pharmacological properties such as being significantly suppressed.

Background of the Invention In recent years, in the field of drug development, development of a combination (a single pharmaceutical preparation containing a plurality of active ingredients) for the purpose of synergistic effects of drugs, reduction of side effects, improvement of patient convenience, etc. Is being actively conducted. For example, JP-A-9-67271 discloses that a combination of a compound having an insulin resistance improving action, a compound having an α-glucosidase inhibitory action, a biguanide compound and the like is useful as a prophylactic / therapeutic agent for diabetes. It is described that there is. JP-A-9-323940 discloses that a combination of a compound having an angiotensin II antagonistic action and a compound having an insulin resistance improving action is useful as a preventive / therapeutic agent for various angiotensin II-mediated diseases. WO 2006/038722 pamphlet describes that a combination of a specific compound having an angiotensin II antagonistic activity and a PPARγ agonist-like substance is useful as a preventive / therapeutic agent for metabolic syndrome. Has been.

Examples of the compound having an angiotensin II antagonistic activity include benzimidazole-7-carboxylic acid derivatives disclosed in JP-A-4-364171 or JP-A-5-271228,
Formula (I)

(Wherein R ¹ represents an optionally substituted monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated, R ² represents an optionally esterified carboxyl group, and R ³ Represents lower alkyl which may be substituted)
It is known that a benzimidazole derivative represented by the formula has an extremely potent angiotensin II antagonistic action and is excellent as an antihypertensive drug. However, although the benzimidazole derivative represented by the formula (I) is stable to temperature, humidity, and light alone in the solid state, the decomposition is accelerated when formed into a solid formulation together with other formulation components, It is known that it can be a problem in quality assurance. In view of this, JP-A-5-194218 discloses that the decomposition of a benzimidazole derivative in a solid preparation is remarkably suppressed by incorporating a low melting point oily substance. Japanese Patent Application Laid-Open No. 7-165580 describes that the decomposition of the benzimidazole derivative in the tablet is remarkably suppressed by adjusting the density of the uncoated tablet to a specific range.

  As a compound having an insulin resistance improving action, pioglitazone hydrochloride is clinically used as an excellent antidiabetic agent, and recently, a combination of pioglitazone hydrochloride and metformin is also clinically used.

  The solid preparation containing pioglitazone hydrochloride and other active ingredients and the preparation method are described in JP-A Nos. 2004-149521, 2004-43478, and 2005-220024. .

  A preparation containing a benzimidazole derivative represented by the formula (I) and pioglitazone hydrochloride is used for metabolizing not only cardiovascular diseases such as hypertension, heart failure, diabetic nephropathy, arteriosclerosis but also diabetes, metabolic syndrome and the like. Since it is effective in the prevention and treatment of sexually transmitted diseases and has extremely high clinical usefulness, the formulation of a combination containing the benzimidazole derivative and pioglitazone hydrochloride was examined. However, the benzimidazole derivative represented by the formula (I) is destabilized by pressure, friction, heat, etc. during formulation, and further, when it coexists with pioglitazone hydrochloride in a solid formulation, the decomposition of the benzimidazole derivative is caused. It was found that it was significantly accelerated. Therefore, in order to prevent physical contact between the benzimidazole derivative represented by the formula (I) and pioglitazone hydrochloride, a granulated powder containing the benzimidazole derivative and a granulated powder containing pioglitazone hydrochloride are produced separately. However, the decomposition of the benzimidazole derivative was not sufficiently suppressed, and practical use was not achieved.

  In addition, since the dissolution rate of a medicinal ingredient from a pharmaceutical preparation can affect the medicinal profile over time after administration, it is necessary to adjust the pharmaceutical composition so that the dissolution rate of the medicinal ingredient is optimized in the practical use of the pharmaceutical preparation. is there. In particular, in the case of a combination, since it is necessary to optimize the dissolution rate for each medicinal ingredient, the difficulty of the preparation is high. For example, a formulation in which a core containing one medicinal ingredient is coated with a layer containing the other medicinal ingredient is also known as the composition of the mixture, but generally the dissolution rate of the medicinal ingredient contained in the nucleus In many cases, the development of the drug product becomes slow and hinders the development of the drug product.

  Therefore, the present inventors have prepared a preparation containing a benzimidazole derivative represented by the formula (I) and pioglitazone hydrochloride, the decomposition of the benzimidazole derivative is sufficiently suppressed, and a medicinal component (benzimidazole). As a result of diligent research to realize a preparation capable of easily adjusting the elution rate of the derivative and pioglitazone hydrochloride), the core containing the benzimidazole derivative and the low melting point oily substance contains a high molecular weight polymer. By covering with a first layer and further covering with a second layer containing pioglitazone hydrochloride, the decomposition of the benzimidazole derivative is unexpectedly significantly suppressed and the dissolution rate of the medicinal component Has been found to be easily adjustable, and the present invention has been completed.

SUMMARY OF THE INVENTION That is, the present invention
(1) Formula (I)

(A) (wherein R ¹ represents an optionally substituted monocyclic nitrogen-containing heterocyclic group having a deprotonable hydrogen atom, and R ² represents an optionally esterified carboxyl group. And R ³ represents an optionally substituted lower alkyl)
A nucleus containing a compound represented by the formula: or a salt thereof or a prodrug thereof (hereinafter simply referred to as compound (I)) and a low melting point oily substance;
(B) a first layer containing a high molecular weight polymer and covering the nucleus;
(C) a solid pharmaceutical composition comprising a second layer containing pioglitazone hydrochloride and covering the first layer (hereinafter sometimes simply referred to as “the pharmaceutical composition of the present invention”);
(2) The compound represented by the formula (I) or a salt thereof or a prodrug thereof is 2-ethoxy-1-{[2 ′-(5-oxo-4,5-dihydro-1,2,4-oxadi (Azol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid (Compound A) according to the above (1);
(3) The compound represented by the formula (I) or a salt thereof or a prodrug thereof is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-{[2 ′-(1H-tetrazol-5-yl) biphenyl] The composition according to the above (1), which is -4-yl] methyl} -1H-benzimidazole-7-carboxylate (Compound B);
(4) The composition according to (1) above, wherein the low melting point oily substance has a melting point of 20 to 90 ° C;
(5) The composition according to (1) above, wherein the low melting point oily substance is an alkylene oxide polymer having a molecular weight of 1000 to 10,000;
(6) The composition according to the above (1), wherein the molecular weight of the high molecular weight polymer is 2500 to 400,000.
(7) The composition according to (1) above, wherein the high molecular weight polymer is hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, or a mixture of two or more of these polymers.

  Below, the solid pharmaceutical composition of this invention is demonstrated in detail.

  The solid pharmaceutical composition of the present invention comprises (a) a core containing compound (I) and a low melting point oily substance, (b) a first layer containing a high molecular weight polymer and covering the core, c) It contains pioglitazone hydrochloride and a second layer covering the first layer.

(A) Core The core used in the present invention contains compound (I) and a low melting point oily substance.
In the formula (I), R ¹ represents an optionally substituted monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated, and may be, for example, an optionally substituted lower (C _1-4). ) Alkyl (eg, methyl, triphenylmethyl, methoxymethyl, acetyloxymethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, pivaloyloxymethyl, etc.), acyl group (eg , A tetrazolyl group or a formula optionally protected by lower (C _2-5 ) alkanoyl, benzoyl, etc.

[Wherein i represents —O— or —S—, and j represents>C═O,> C═S or> S (O) m (wherein m represents 0, 1 or 2). ] (For example, a 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group) etc. are preferably used.

  The 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group has the formula:

There are three tautomers (a ′, b ′ and c ′) represented by the following, and the 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group is the above-mentioned a Includes all of ', b' and c '.

In the formula (I), R ² represents a carboxyl group which may be esterified. For example, the carboxyl group, or a hydroxyl group, amino, halogen, lower (C _2-6 ) alkanoyloxy (eg, acetyloxy, pivaloyloxy) Such),
Lower (C _4-7 ) cycloalkanoyloxy, (lower (C _1-6 ) alkoxy) carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, etc.),
(Lower _{(C 3-7)} cycloalkoxy) carbonyloxy (e.g., such as cyclohexyloxycarbonyloxy) and lower _{(C 1-4)} which may lower substituted with a substituent selected from alkoxy _{(C 1-4)} A carboxyl group esterified with alkyl (for example, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl group) and the like are used.

In the formula (I), R ³ represents a lower alkyl which may be substituted, the R ³ hydroxyl group, an amino group, substituted with a halogen atom and lower (C _1-4) substituents selected from alkoxy groups Preferred is lower (C _1-5 ) alkyl (preferably lower (C _2-3 ) alkyl).

  Examples of the salt of the compound represented by the formula (I) include a pharmaceutically acceptable salt. For example, a salt of the compound represented by the formula (I) with an inorganic base, a salt with an organic base, Examples thereof include salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt and ammonium salt. Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, Examples thereof include salts with p-toluenesulfonic acid. Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like, and preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. Can be mentioned.

  As a prodrug of the compound represented by the formula (I) or a salt thereof, a compound that is converted into a compound represented by the formula (I) or a salt thereof by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, A compound that is enzymatically oxidized, reduced, hydrolyzed, etc. to be converted into a compound represented by formula (I) or a salt thereof, a compound that is hydrolyzed by gastric acid or the like, or a compound represented by formula (I) or its A compound that changes to a salt. As a prodrug of the compound represented by the formula (I) or a salt thereof, a compound in which the amino group of the compound represented by the formula (I) or a salt thereof is acylated, alkylated or phosphorylated (eg, the formula (I The amino group of the compound represented by I) or a salt thereof is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranyl , Pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated compounds); the hydroxyl group of the compound represented by formula (I) or a salt thereof is acylated, alkylated, phosphorylated or borated. The hydroxyl group of the compound represented by the formula (I) or a salt thereof is acetylated, palmitoylated, propanoylated, piva, Ylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated compounds); compounds wherein the carboxyl group of the compound represented by formula (I) or a salt thereof is esterified or amidated (eg, The carboxyl group of the compound represented by formula (I) or a salt thereof is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, 1- (cyclohexyloxycarbonyloxy) ethyl esterification or methylamidation compound, etc.); Can be mentioned. These prodrugs can be produced from the compound represented by the formula (I) or a salt thereof by a method known per se.

  A prodrug of the compound represented by the formula (I) or a salt thereof can be obtained under physiological conditions as described in Hirokawa Shoten 1990, “Development of Pharmaceuticals”, Volume 7, pages 163 to 198, under physiological conditions. It may be a compound represented by I) or a salt thereof.

  Compound (I) may be hydrated or non-hydrated.

  Compound (I) is preferably crystalline and has a melting point of 100 to 250 ° C, particularly 120 to 200 ° C.

  As the compound (I), the compound A or the compound B is preferable. As the crystal of these compounds, the compound A is preferably a crystal having a melting point of 191 ° C., and the compound B is preferably a crystal having a melting point of 163 ° C.

  Compound (I) is contained in the solid pharmaceutical composition of the present invention in a proportion of 0.01 to 50% by weight, preferably 0.05 to 40% by weight, more preferably 0.1 to 30% by weight. .

  As the low melting point oily substance used in the present invention, an oily substance having a melting point of about 20 to 90 ° C., preferably 20 to 60 ° C. is usually used. Any substance that does not adversely affect the active ingredient can be used. In producing the pharmaceutical composition of the present invention, the low melting point oily substance can be blended uniformly with the active ingredient as compared with the high melting point oily substance, and as a result, the decomposition of the active ingredient is suppressed more stably. Pharmaceutical composition can be obtained. Further, the low melting point oily substance may be soluble or insoluble in water. Here, examples of the low-melting point oil-soluble substance soluble in water include a polymer of alkylene oxide described later. Examples of the low melting point oily substance used in the present invention include hydrocarbons, higher fatty acids, higher alcohols, fatty acid esters of polyhydric alcohols, higher alcohol ethers of polyhydric alcohols, and polymers or copolymers of alkylene oxides. Of these, fatty acid esters of polyhydric alcohols, higher alcohol ethers of polyhydric alcohols, alkylene oxide polymers or copolymers, and particularly alkylene oxide polymers are preferably used.

  Examples of the hydrocarbon include n-heptadecane, n-octadecane, n-nonadecane, n-eicosane, n-heneicosan, n-docosan, n-tricosane, n-tetracosane, n-pentacosane, n-triacontane, n- Examples thereof include n-alkanes having 17 to 50 carbon atoms such as pentatriacontane, n-tetracontane, and n-pentacontane, and mixtures thereof (such as petrolatum, paraffin wax, and microcrystalline wax). Examples of the higher fatty acid include capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, serotic acid and mixtures thereof, and higher fatty acids collected from natural fats and oils. .

  Examples of the higher alcohol include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, aralkyl alcohol and mixtures thereof, higher alcohol collected from natural oil, and the like.

  Examples of the fatty acid ester of polyhydric alcohol include alcohols having two or more hydroxyl groups in the molecule (for example, alkylene glycol such as ethylene glycol and propylene glycol, polyalkylene glycol such as polyethylene glycol, polypropylene glycol, and copolymers thereof, Saccharides such as sorbitol and sucrose, intramolecular dehydrated compounds of sorbitol such as 1,5-sorbitan, 1,4-sorbitol and 3,6-sorbitan, glycerin, diethanolamine, pentaerythritol, etc.) and fatty acids (for example, acetic acid, propionic acid) , Butyric acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecanoic acid, undecylenic acid Oleic acid, elaidic acid, sorbic acid, linoleic acid, linolenic acid, arachidonic acid, stearolic acid, etc.), specifically, for example, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan Polyoxyalkylene having a molecular weight of 1000 to 1500 such as sorbitan fatty acid ester having a molecular weight of 400 to 900 such as sesquioleate and sorbitan monopalmitate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monooleate and polyoxyethylene sorbitan tripalmitate Sorbitan fatty acid ester, polyoxyethylene sorbitol hexastearate, polyoxyethylene sorbitol hexaoleate, polyoxyethylene sorbitol tris Polyoxyalkylene sorbitol fatty acid esters such as allate, polyoxyethylene sorbitol tetralaurate, polyoxyalkylene sorbitol beeswax derivatives such as polyoxyethylene sorbitol beeswax derivatives, polyoxyalkylene lanolin derivatives such as polyoxyethylene lanolin derivatives, propylene glycol Monopalmitate, propylene glycol monostearate, propylene glycol dilaurate, propylene glycol dimyristate, propylene glycol dipalmitate, propylene glycol distearate, etc., propylene glycol fatty acid ester having a molecular weight of 200 to 700, ethylene glycol monolaurate, ethylene glycol Palmitate, ethylene glycol margarate, ethylene glycol Cole stearate, ethylene glycol dilaurate, ethylene glycol dimyristate, ethylene glycol dipalmitate, ethylene glycol dimer gallate, etc., alkylene glycol fatty acid esters such as ethylene glycol fatty acid esters of molecular weight 500-1200, polyoxyethylene castor oil derivatives, etc., molecular weight 3500 -4000 polyoxyalkylene castor oil derivatives, polyoxyethylene stearate, polyoxyethylene oleate, polyoxyethylene palmitate, polyoxyethylene linoleate, etc., polyoxyalkylene fatty acid esters of molecular weight 1900-2200, glycerin monoacetate, glycerin Monopropionate, glycerol monostearate, glycerol monooleate, glycerol monopa Glycerol monofatty acid ester having a molecular weight of 300 to 600, such as mitate and glyceryl monolinoleate, sucrose monolaurate, sucrose monomyristate, sucrose monopalmitate, sucrose monostearate, sucrose trimyristate, sucrose tripalmitate, sucrose tristearate Examples thereof include sucrose fatty acid esters having a molecular weight of 400 to 1300 such as a rate.

  Examples of higher alcohol ethers of polyhydric alcohols include polyhydric alcohols (listed as alcohol components of fatty acid esters of the above polyhydric alcohols) and higher fatty acid alcohols (for example, cetyl alcohol, stearyl alcohol, oleyl alcohol, octyl alcohol, decyl alcohol). ), Specifically, for example, polyoxyethylene lauryl alcohol ether, polyoxyethylene cetyl alcohol ether, polyoxyethylene stearyl alcohol ether, polyoxyethylene oleyl alcohol ether, polyoxyethylene octyl alcohol ether, polyoxyethylene Polyoxyethylene higher alcohol ethers such as decyl alcohol ether, polyoxypropylene polyoxyethylene cetyl alcohol Polyoxypropylene polyoxyethylene higher grades such as ether ether, polyoxypropylene polyoxyethylene stearyl alcohol ether, polyoxypropylene polyoxyethylene oleyl alcohol ether, polyoxypropylene polyoxyethylene octyl alcohol ether, polyoxypropylene polyoxyethylene lauryl alcohol ether Alcohol ether is frequently used.

  As the alkylene oxide polymer, those having a molecular weight of 1,000 to 10,000 (eg, polyethylene glycol 6000 (macrogol 6000)) are preferably used. Examples of the alkylene oxide include ethylene oxide, propylene oxide, trimethylene oxide, tetrahydrofuran and the like (preferably ethylene oxide). As the copolymer of alkylene oxide, a copolymer of two or more of the above alkylene oxides having a molecular weight of 1,000 to 10,000 is preferably used.

  These low melting point oily substances may be used alone or in combination of two or more.

  The low melting point oily substance is contained in the pharmaceutical composition of the present invention in a proportion of 0.005 to 40% by weight, preferably 0.02 to 30% by weight, more preferably 0.05 to 15% by weight.

  Further, the content ratio (weight ratio; compound (I) / low melting point oily substance) of compound (I) and low melting point oily substance is about 0.05 to about 50, preferably about 0.1 to about 30. More preferably from about 0.2 to about 20, and even more preferably from about 0.3 to about 15.

  The core may have any shape and size as long as it is a solid that can be covered with a first layer described later. Further, the nucleus may have any internal structure, and the inside may be uniform or non-uniform. As the core, a solid agent (eg, granule, tablet, etc.) produced by molding (granulation, pressure molding, etc.) is preferably used, and among these, a tablet is preferably used.

  The core may further contain an additive conventionally used in the pharmaceutical field, and can be produced according to a known method. Examples of the additive include an excipient, a disintegrant, a binder, a lubricant, a colorant, a pH adjuster, a surfactant, a stabilizer, a sour agent, a fragrance, and a fluidizing agent. These additives are used in amounts conventionally used in the pharmaceutical field.

  Examples of excipients include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; lactose, fructose, glucose, mannitol (eg, D-mannitol) ), Sorbitol (eg, D-sorbitol), erythritol (eg, D-erythritol), sugars or sugar alcohols such as sucrose: anhydrous calcium phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, and the like.

  As the disintegrant, for example, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch and the like are used. The amount of the disintegrant used is preferably 0.5 to 40 parts by weight, more preferably 1 to 30 parts by weight with respect to 100 parts by weight of the pharmaceutical composition of the present invention.

  Examples of the binder include crystalline cellulose (eg, microcrystalline cellulose), hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic powder and the like. The amount of the binder used is preferably 0.1 to 40 parts by weight, more preferably 0.5 to 30 parts by weight with respect to 100 parts by weight of the pharmaceutical composition of the present invention.

  Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate and the like.

  Examples of the colorant include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2, edible lake pigments, and iron sesquioxide.

  Examples of the pH adjuster include citrate, phosphate, carbonate, tartrate, fumarate, acetate, amino acid salt and the like.

  Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol, and the like.

  Examples of the stabilizer include tocopherol, tetrasodium edetate, nicotinamide, and cyclodextrins.

  Examples of sour agents include ascorbic acid, citric acid, tartaric acid, malic acid and the like.

  Examples of the fragrances include menthol, peppermint oil, lemon oil, and vanillin.

  Examples of the fluidizing agent include light anhydrous silicic acid and hydrous silicon dioxide.

  Two or more of the above-described additives may be mixed and used at an appropriate ratio.

  In producing the core, the low melting point oily substance as described above is usually added to the compound (I) and then molded. These blending methods are carried out by blending methods generally used in preparations, for example, mixing, kneading, kneading, sieving, stirring and the like. For example, the low melting point oily substance may be directly added to the active ingredient and mixed (powder addition), or mixed with a solvent, and kneaded, granulated and dried by a conventional method. Alternatively, the low melting point oily substance can be dissolved in an appropriate solvent, and then mixed uniformly with the active ingredient, and kneaded, granulated, dried (liquid addition) and the like by a conventional method. Furthermore, the liquid containing the low melting point oily substance and the liquid containing the compound (I) may be separately sprayed on a powder such as an excipient. As a suitable solvent in the case of liquid addition, for example, a solvent that does not adversely affect an active ingredient such as water, dimethylformamide, acetone, ethanol, propyl alcohol, isopropyl alcohol, butyl alcohol, methylene chloride, trichloroethane is used. After the completion of blending, a tablet containing the active ingredient can be produced by using a known pressure molding means. The pressure molding is to form a desired form by compression under pressure, and most commonly refers to tableting, for example. It is considered that the compounding of the low melting point oily substance reduces the distortion of the crystal of the compound (I) during kneading, granulation and pressure molding. In the method for producing the pharmaceutical composition of the present invention, various additives as described above can be added in an appropriate step.

(B) First layer The first layer used for coating the nucleus in the present invention contains a high molecular weight polymer.

  The high molecular weight polymer used for the first layer in the present invention may be water-soluble or fat-soluble, such as a water-soluble high molecular weight polymer (for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, Polyvinyl alcohol, pullulan or the like, or a mixture of two or more thereof is preferred, and hydroxypropyl methylcellulose is particularly preferred. The molecular weight of the high molecular weight polymer is preferably 2500 to 400000, more preferably 3000 to 150,000, and still more preferably 4000 to 100,000. Here, the molecular weight of the high molecular weight polymer refers to the weight average molecular weight of the high molecular weight polymer, and more specifically refers to the weight average molecular weight measured by gel permeation chromatography (GPC). As the GPC method, for example, the method described in Polymer Journal Vol. 39, No. 4, pp. 293-298 (Kato et al.) Is used. The reference substance used and the detailed measurement conditions are as follows. Reference materials and conditions suitable for the high molecular weight polymer to be used can be appropriately used.

  The high molecular weight polymer is contained in the first layer in an amount of 0.01 to 100% by weight, preferably 0.1 to 100% by weight, more preferably 0.5 to 100% by weight.

  The first layer may further contain a coating additive conventionally used in the pharmaceutical field. Examples of the coating additive include a light-shielding agent and / or a colorant such as titanium oxide, talc, and iron sesquioxide; a plasticizer such as polyethylene glycol, triethyl citrate, castor oil, and polysorbates; citric acid, tartaric acid, apple Acids, organic acids such as ascorbic acid; sugars such as lactose, mannitol (eg, D-mannitol), erythritol (eg, D-erythritol), sucrose; low-substituted hydroxypropylcellulose, carmellose calcium, crospovidone, etc. Disintegrants; binders such as crystalline cellulose (eg, microcrystalline cellulose), hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic powder and the like.

  The first layer to the core is coated according to known methods. For coating, for example, a film coating apparatus is used.

  The coating of the first layer is usually applied at a ratio of 1 to 40 parts by weight, preferably 0.5 to 20 parts by weight, and more preferably 1 to 10 parts by weight with respect to 100 parts by weight of the core.

  When the first layer contains 10 parts by weight or more of saccharides with respect to 1 part by weight of the high molecular weight polymer, the first layer is usually 1 to 100 parts by weight, preferably 100 parts by weight of the core. Is applied in a proportion of 10 to 80 parts by weight, more preferably 50 to 60 parts by weight.

(C) Second layer The second layer contains pioglitazone hydrochloride and covers the first layer.

  The second layer may be formed by any method. For example, the second layer is formed so as to cover the first layer by coating, compression molding, or the like.

  Where the second layer is formed by coating, the second layer may contain coating additives that are conventional in the pharmaceutical arts. Examples of the coating additive include light-shielding agents and / or colorants such as titanium oxide, talc, and iron sesquioxide; plasticizers such as polyethylene glycol, triethyl citrate, castor oil, and polysorbates; citric acid, tartaric acid, malic acid Organic acids such as ascorbic acid; sugars such as lactose, mannitol (eg, D-mannitol), erythritol (eg, D-erythritol), sucrose; disintegration of low-substituted hydroxypropylcellulose, carmellose calcium, crospovidone, etc. Agents; binders such as crystalline cellulose (eg, microcrystalline cellulose), hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic powder and the like.

  The coating of the second layer on the surface of the core (preferably tablet) containing the compound (I) coated with the first layer is performed by a known method (for example, JP-A-2004-43478, For example, a method described in Japanese Unexamined Patent Publication No. 2005-220024. For the coating, for example, a film coating apparatus is used.

  The second layer is usually applied at a ratio of 1 to 80 parts by weight, preferably 1 to 65 parts by weight, and more preferably 5 to 60 parts by weight with respect to 100 parts by weight of the core coated with the first layer. The

  When the second layer is formed by compression molding, the second layer may further contain additives conventionally used in the pharmaceutical field and can be produced according to a known method. As the additive, a conventional additive similar to the additive which may be contained in the core described in the above (a) is used.

  The second layer is usually 1 to 1000 parts by weight, preferably 10 to 500 parts by weight, more preferably 25 to 250 parts by weight with respect to 100 parts by weight of the core coated with the first layer. Formed.

  Furthermore, the coating coated with the second layer may be further coated (top coating) for the purpose of improving the coating strength of the coated formulation or coloring. The coating includes, for example, the high molecular weight polymer described as the high molecular weight polymer used for the first layer, and the coating mentioned as the coating additive that the first layer and / or the second layer may contain. It can carry out in accordance with a well-known method using an additive etc.

  The weight ratio of compound (I) to pioglitazone hydrochloride (pioglitazone hydrochloride / compound (I)) is about 0.0001 to about 6000, preferably about 0.002 to about 500, more preferably about 0.01 to about 100, more preferably about 0.1 to about 50.

  The pharmaceutical composition of the present invention comprises a type and / or amount of a sugar and / or a sugar alcohol, a type and / or amount of a binder, and a type of a disintegrant that are optionally contained in the second layer containing pioglitazone hydrochloride. In addition, there is an advantage in formulation design that the dissolution rate of pioglitazone hydrochloride from the pharmaceutical composition can be controlled by changing the amount and / or the like or by changing the content of pioglitazone hydrochloride.

  The amount of pioglitazone hydrochloride is 0.1 to 40% by weight, preferably 0.5 to 30% by weight, more preferably 1 to 20% by weight in the solid pharmaceutical composition of the present invention.

  Since pioglitazone normalizes the intracellular insulin signal transduction mechanism that is the main cause of insulin resistance, reduces insulin resistance, enhances insulin action, and has glucose tolerance improving action, the pharmaceutical composition of the present invention Is an agent for improving or preventing and / or treating a disease associated with insulin resistance for mammals (eg, humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits, etc.) Used as Such diseases include, for example, insulin resistance and glucose intolerance; non-insulin-dependent diabetes, type II diabetes, type II diabetes with insulin resistance, type II diabetes with impaired glucose tolerance, etc .; high insulin , Hypertension with insulin resistance, hypertension with impaired glucose tolerance, hypertension with diabetes (eg, type II diabetes), hypertension with hyperinsulinemia, insulin resistance associated with hypertension , Glucose intolerance associated with hypertension, diabetes associated with hypertension, hyperinsulinemia associated with hypertension, diabetic complications [eg, microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic Retinopathy, diabetic cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infection (eg, respiratory infection, urinary tract infection, digestive tract infection, skin soft tissue) Etc.), diabetic gangrene, xerostomia, hearing loss, diabetic cerebrovascular disorder, diabetic peripheral blood circulation disorder, diabetic hypertension, etc.], various complications such as diabetic cachexia, etc. Is mentioned. The pharmaceutical composition of the present invention can also be used for the treatment of patients with normal high blood pressure who have developed diabetes.

  Since the compound represented by the formula (I) has a strong angiotensin II antagonism, the pharmaceutical composition of the present invention can be used in mammals (eg, humans, monkeys, cats, pigs, horses, cows, mice, rats, Diseases caused by the contraction and proliferation of blood vessels expressed through the angiotensin II receptor, organ damage, the presence of angiotensin II, or factors induced by the presence of angiotensin II (guinea pigs, dogs, rabbits, etc.) Or, it is useful as a preventive or therapeutic agent for diseases whose onset is accelerated.

  Such diseases include, for example, hypertension, abnormal blood pressure diurnal variation, heart disease (eg, cardiac hypertrophy, acute heart failure, chronic heart failure including congestion, diastolic dysfunction, cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation Motion, arrhythmia, tachycardia, myocardial infarction, etc.), cerebrovascular disorder (eg, asymptomatic cerebrovascular disorder, transient ischemic attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction, etc.), brain Edema, cerebral circulatory disorder, recurrence and sequelae of cerebrovascular disorder (eg, neurological symptoms, psychiatric symptoms, subjective symptoms, impaired daily activities), ischemic peripheral circulatory disorder, myocardial ischemia, venous dysfunction, after myocardial infarction Progression of heart failure, renal disease (eg, nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, complications of dialysis, organ damage including nephropathy due to radiation), arteries including atherosclerosis Sclerosis (eg, aneurysm, coronary atherosclerosis, cerebral arteriosclerosis) Peripheral arteriosclerosis), vascular thickening, intervention (eg, percutaneous coronary angioplasty, stenting, coronary endoscope, intravascular ultrasound, coronary thrombolysis, etc.) vascular thickening or occlusion and organ Disorders, vascular re-occlusion / restenosis after bypass surgery, erythrocytosis / hypertension / organ disorder / vascular thickening after transplantation, rejection after transplantation, eye diseases (eg, glaucoma, ocular hypertension, etc.), thrombosis, Multiple organ failure, endothelial dysfunction, hypertensive tinnitus, other cardiovascular diseases (eg, deep vein thrombosis, obstructive peripheral circulatory disorder, obstructive arteriosclerosis, obstructive thrombotic vasculitis, ischemic cerebral circulation disorder) , Raynaud's disease, Buerger's disease, etc.), metabolic and nutritional disorders (eg obesity, hyperlipidemia, hypercholesterolemia, hyperuricemia, hyperkalemia, hypernatremia), neurodegenerative diseases ( E.g. Alzheimer's disease Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy, etc., central nervous system disorders (eg, disorders such as cerebral hemorrhage and cerebral infarction and its sequelae and complications, head trauma, spinal cord injury, brain edema, sensory dysfunction, Sensory dysfunction, autonomic dysfunction, autonomic dysfunction, multiple sclerosis, etc.), dementia, memory impairment, consciousness disorder, amnesia, anxiety, tension, discomfort, mental illness (eg, depression) , Epilepsy, alcoholism, etc.), inflammatory diseases (eg, rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periosteitis, etc.) inflammation after surgery / trauma; swelling relief; pharyngitis; cystitis Pneumonia; atopic dermatitis; inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; meningitis; inflammatory eye diseases; inflammatory lung diseases such as pneumonia, silicosis, pulmonary sarcoidosis and pulmonary tuberculosis), allergic diseases (Eg, allergic rhinitis, conjunctivitis, gastrointestinal allergy, hay fever, anaphylaxis, etc.), chronic obstructive pulmonary disease, interstitial pneumonia, carini pneumonia, collagen disease (eg, systemic lupus erythematosus, scleroderma, polyarteritis) ), Liver diseases (eg, chronic hepatitis, cirrhosis, etc.), portal hypertension, gastrointestinal diseases (eg, gastritis, gastric ulcer, gastric cancer, post-surgery disorders, dyspepsia, esophageal ulcer, pancreatitis, colon polyps) , Cholelithiasis, hemorrhoid disease, rupture of esophagus and stomach varices, etc., blood and hematopoietic diseases (eg, erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple Myelopathies, etc.), bone diseases (eg fractures, re-fractures, osteoporosis, osteomalacia, Paget's disease of bones, ankylosing myelitis, rheumatoid arthritis, osteoarthritis of the knee and similar diseases, etc.) , Solid tumor, tumor (Eg, malignant melanoma, malignant lymphoma, gastrointestinal (eg, stomach, intestine, etc.) cancer), cancer and associated cachexia, cancer metastasis, endocrine disease (eg, Addison's disease, Cushing syndrome, pheochromocytoma) , Primary aldosteronism), Creutzfeldt-Jakob disease, urological / male genital diseases (eg, cystitis, benign prostatic hyperplasia, prostate cancer, sexually transmitted diseases, etc.), gynecological diseases (eg, menopause, pregnancy toxemia) Endometriosis, uterine fibroids, ovarian diseases, breast diseases, sexually transmitted diseases, etc.), diseases caused by environmental and occupational factors (eg, radiation damage, UV / infrared / laser light damage, altitude sickness, etc.), respiratory diseases (Eg, cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombus / pulmonary embolism, etc.), infection (eg, viral infections such as cytomegalovirus, influenza virus, herpes virus, rickets Infection, bacterial infection, etc.), venomemia (eg, sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxin shock syndrome, etc.), otolaryngology (eg, Menuel syndrome, tinnitus, taste disorder) , Dizziness, balance disorder, dysphagia, etc.), skin diseases (eg, keloids, hemangiomas, psoriasis, etc.), dialysis hypotension, myasthenia gravis, systemic diseases such as chronic fatigue syndrome, and the like.

  The pharmaceutical composition of the present invention can be used for organ damage associated with various diseases (eg, cerebrovascular disorder and accompanying organ damage, organ damage associated with cardiovascular disease, organ damage associated with diabetes, organ damage after intervention, etc.). The pharmaceutical composition of the present invention can be used as a primary and secondary preventive / therapeutic agent, and in particular, the proteinuria inhibitory action of the compound represented by formula (I) is enhanced by the combined use with pioglitazone. It can be used as a protective agent. Therefore, the pharmaceutical composition of the present invention can be advantageously used even when a patient with insulin resistance, impaired glucose tolerance, diabetes, or hyperinsulinemia has the above-mentioned disease or pathological condition.

  Regarding the criteria for determining diabetes, a new criterion was reported in 1999 by the Japan Diabetes Society.

  According to this report, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher. This is a state in which the blood glucose level (glucose concentration in venous plasma) is at least 200 mg / dl as needed. In addition, it does not correspond to the above-mentioned diabetes, and “a fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dl or a 75 g oral glucose tolerance test (75 g OGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl. A state that is not “a state indicating less than dl” (normal type) is called a “boundary type”.

  As for the criteria for determining diabetes, new criteria were reported from ADA (American Diabetes Association) in 1997 and from WHO in 1998.

  According to these reports, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, and a 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is 200 mg / dl. This is a state showing dl or more.

  According to the above report, abnormal glucose tolerance means that fasting blood glucose level (glucose concentration in venous plasma) is less than 126 mg / dl and 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) Is a state showing 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the state where the fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dl or more and less than 126 mg / dl is called IFG (Impaired Fasting Glucose). On the other hand, according to the report of WHO, the IFG (Impaired Fasting Glucose) is a state where the 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dl as IFG (Impaired Fasting Glycemia). Call.

  The pharmaceutical composition of the present invention is an agent for improving or preventing or treating diabetes, borderline diabetes, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above-mentioned new criteria. Furthermore, it is also used as a therapeutic agent for hypertension in hypertensive patients with the above criteria (for example, fasting blood glucose level of 126 mg / dl) or more. Furthermore, the pharmaceutical composition of the present invention can also prevent borderline diabetes, impaired glucose tolerance, IFG or IFG to progress to diabetes.

  The pharmaceutical composition of the present invention comprises a heart disease having diabetes (eg, cardiac hypertrophy, acute heart failure, chronic heart failure including congestion, diastolic failure, cardiomyopathy, angina, myocarditis, atrial fibrillation, arrhythmia, tachycardia. , Myocardial infarction, etc.) It is useful as an agent for lowering cardiac function, progressing cardiac remodeling, suppressing or improving symptom deterioration, or suppressing decrease in survival rate. Diabetic heart disease (eg, cardiac hypertrophy, acute heart failure, chronic heart failure including congestion, diastolic failure, cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, myocardial infarction) and brain It is effective in preventing the onset of vascular disorders (eg, asymptomatic cerebrovascular disorders, transient ischemic attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction, etc.).

  The pharmaceutical composition of the present invention is also useful as a preventive / therapeutic agent for metabolic syndrome. Because patients with metabolic syndrome have a significantly higher rate of developing cardiovascular disease than patients with a single lifestyle-related disease, prevention and treatment of metabolic syndrome prevents cardiovascular disease It is extremely important to do.

  The criteria for determining metabolic syndrome were published by WHO in 1999 and NCEP in 2001. According to WHO criteria, metabolic syndrome is diagnosed when there is at least two of visceral obesity, dyslipidemia (high TG or low HDL), and hypertension based on hyperinsulinemia or impaired glucose tolerance (World Health Organization: Definition, Diagnosis and Classification of 199, Liberals Melitus and Its Completions. Part I: Diagnostics and Qualification.) According to the criteria of Adult Treatment Panel III of the National Cholesterol Education Program, which is a management index of ischemic heart disease in the United States, at least of visceral obesity, hypertriglyceridemia, low HDL cholesterolemia, hypertension, glucose intolerance It is diagnosed as a metabolic syndrome when it has three (National Cholesterol Education Program, Executive Summary of the Third Report of National Chole-Education Program (NCEPD). f High Blood Cholesterol in Adults (Adults Treatment Panel III). The Journal of the American Medical Association, Vol. 285, 2486-2497, 2001).

  The pharmaceutical composition of the present invention can be used for the treatment of hypertensive patients who develop metabolic syndrome.

  The pharmaceutical composition of the present invention can be used as an anti-inflammatory agent as a prophylactic / therapeutic agent for inflammatory diseases. Inflammatory diseases include, for example, arthritis (eg, rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis, synovitis), asthma, allergic diseases, atherosclerosis including atherosclerosis (aneurysm, Coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), digestive diseases such as inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), diabetic complications (diabetic neuropathy, diabetic vascular disorder) ), Atopic dermatitis, chronic obstructive pulmonary disease, systemic lupus erythematosus, visceral inflammatory diseases (nephritis, hepatitis), autoimmune hemolytic anemia, psoriasis, neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, AIDS encephalopathy), central nervous system disorders (eg cerebrovascular disorders such as cerebral hemorrhage and cerebral infarction, head trauma, spinal cord injury, cerebral edema, multiple sclerosis, etc.), meningitis, narrow Heart disease, myocardial infarction Congestive heart failure, vascular thickening or occlusion and organ damage after intervention (percutaneous coronary angioplasty, stenting, coronary endoscopy, intravascular ultrasound, coronary thrombolysis, etc.), blood vessel after bypass surgery Re-occlusion / restenosis, endothelial dysfunction, other cardiovascular diseases (intermittent claudication, obstructive peripheral circulatory disorder, obstructive arteriosclerosis, occlusive thromboangiitis, ischemic cerebral circulatory disorder, Raynaud's disease, barger Disease), inflammatory eye disease, inflammatory lung disease (eg, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis), endometriosis, toxemia (eg, sepsis, septic shock, endotoxic shock, gram) Negative sepsis, toxic shock syndrome), cachexia (eg, cachexia due to infection, cancer cachexia, cachexia due to acquired immune deficiency syndrome), cancer, Addison's disease, Creutzfeldt-Jakob disease Viral infections (eg, cytomegalovirus, influenza virus, viral infections such as herpes viruses), such as inflammatory diseases and the like due to various diseases such as disseminated intravascular coagulation.

  The pharmaceutical composition of the present invention can also be used as an analgesic and as a prophylactic / therapeutic agent for pain. As pain, for example, acute pain due to inflammation, pain associated with chronic inflammation, pain associated with acute inflammation, postoperative pain (incisional pain, deep pain, visceral pain, postoperative chronic pain, etc.), muscle pain (chronic pain) Muscle pain associated with disease, stiff shoulders, etc.), joint pain, toothache, temporomandibular joint pain, headache (migraine, tension headache, fever headache, high blood pressure headache), visceral pain (heart pain, angina pain, abdominal pain, Kidney pain, ureteral pain, bladder pain), gynecological pain (intermediate pain, dysmenorrhea, labor pain), neuralgia (disc herniation, nerve root pain, postherpetic neuralgia, trigeminal neuralgia), cancerous Pain, reflex sympathetic atrophy, complex local pain syndrome and the like. The pharmaceutical composition of the present invention is effective for directly and quickly relieving various pains such as neuropathic pain, cancer pain, inflammatory pain, etc., and patients and pathological conditions (e.g., It exhibits a particularly excellent analgesic effect on hypertension, diabetes, etc., and complications thereof.

  The pharmaceutical composition of the present invention is particularly useful as an analgesic for pain associated with chronic inflammation or headache associated with hypertension, or (1) arteriosclerosis including atherosclerosis, (2) vascular thickening, occlusion or organ damage after intervention. (3) Vascular re-occlusion / restenosis after bypass surgery, endothelial dysfunction, (4) intermittent claudication, (5) obstructive peripheral circulatory disorder or (6) inflammatory disease caused by obstructive arteriosclerosis or It is useful as a prophylactic / therapeutic agent for pain.

  For example, the dose of the compound represented by formula (I) when orally administered to an adult diabetic patient (body weight 60 kg) (when administered as a salt or prodrug of the compound represented by formula (I) (Dose as the compound represented by (I)) varies depending on the administration subject, administration route, target disease, symptom, etc., but the daily dose is about 0.1 to about 600 mg, preferably about 0.5 to About 240 mg, more preferably about 1.0 to about 100 mg, and these amounts may be administered once a day or divided into two or three times.

  The dose of pioglitazone hydrochloride is about 0.1 to about 600 mg, preferably about 0.5 to about 240 mg, more preferably about 1.0 to about 100 mg as a daily dose. It may be administered once a day or divided into two or three times.

  The pharmaceutical composition of the present invention comprises a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antiarteriosclerotic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent and the like. It can be used in combination with one or more selected drugs (hereinafter sometimes abbreviated as concomitant drugs). The pharmaceutical composition of the present invention can also be used in combination with vaccine preparations such as angiotensin vaccine, gene therapy such as peripheral arterial occlusion, or regenerative medicine using embryonic stem cells. When the pharmaceutical composition of the present invention is used in combination with a concomitant drug, the pharmaceutical composition of the present invention and the concomitant drug may be administered in the form of separate drugs, or may be formulated into one combination. Good. When used in combination as separate drugs, the timing of administration of the pharmaceutical composition of the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the administration subject, or may be administered at a time difference. Good. Furthermore, two or more types of concomitant drugs may be used in combination at an appropriate ratio.

  The dose of the concomitant drug can be appropriately determined based on the clinically used dose of each drug. Moreover, the administration ratio of the pharmaceutical composition of the present invention and the concomitant drug can be appropriately determined depending on the administration subject, administration route, target disease, symptom, combination and the like.

  Examples of the therapeutic agent for diabetes include insulin preparations (eg, animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast), α-glucosidase inhibitors ( Eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanide (eg, phenformin, metformin, buformin, etc.), insulin secretagogue [eg, sulfonylurea (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, Acetohexamide, glyclopyramide, glimepiride, glipizide, glybsol, etc.), repaglinide, senaglinide, nateglinide, mitiglinide or its calcium salt hydrate, GLP-1, etc.], amylin agonist (eg, Ramlintide, etc.), phosphotyrosine phosphatase inhibitors (eg, vanadic acid, etc.), dipeptidyl peptidase IV inhibitors (eg, NVP-DPP-278, PT-100, P32 / 98, SYR-322, etc.), β3 agonist ( Examples, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140, etc., gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6--6) Phosphatase inhibitors, glucagon antagonists, etc.), SGLT (sodium-glucose cotransporter) inhibitors (eg, T-1095 etc.) and the like.

  Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CT-112, etc.), neurotrophic factors (eg, , NGF, NT-3, BDNF, etc.), neurotrophic factor production promoter, PKC inhibitor (eg, LY-333531), AGE inhibitor (eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide) (ALT766), EXO-226, etc.), active oxygen scavengers (eg, thioctic acid, etc.), and cerebral vasodilators (eg, thioprid, mexiletine, etc.).

  Antihyperlipidemic agents include, for example, statin compounds that are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, itavastatin, or salts thereof (eg, sodium salt)) Squalene synthase inhibitors (eg, TAK-475 etc.), fibrate compounds having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate etc.) and the like.

  Anti-arteriosclerotic agents include, for example, acyl-coenzyme A cholesterol acyltransferase (ACAT) inhibitors (eg, melinamide, CS-505, etc.), lipid rich plaque regressing agents (eg, WO 02/06264, compounds described in WO 03/069900, and the like.

  Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine etc.), β-inhibitors (eg, metoprolol, Atenolol, propranolol, carvedilol, pindolol, etc.), clonidine and the like.

  Anti-obesity agents include, for example, central anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex, etc.), pancreatic lipase Inhibitors (eg, orlistat, etc.), β3 agonists (eg, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140, etc.), peptide appetite suppression Drugs (eg, leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lynchtrypto, FPL-15849, etc.) and the like.

  Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, Polythiazide, methycrothiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide-based preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, Examples include isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

  Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.) Plant-derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etopoxide and the like. Of these, 5-fluorouracil derivatives such as furtulon and neoflutulon are preferred.

  Examples of immunotherapeutic agents include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques (Eg, interferon, interleukin (IL), etc.), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin, etc.) and the like can be mentioned, among which IL-1, IL-2, IL-12 and the like are preferable.

  In addition, drugs that have been shown to improve cachexia in animal models and clinically, ie, cyclooxygenase inhibitors (eg, indomethacin), progesterone derivatives (eg, megesterol acetate), carbohydrate steroids (eg, dexamethasone) , Metoclopramide drugs, tetrahydrocannabinol drugs (the publication is the same as above), fat metabolism improving agents (eg, eicosapentaenoic acid, etc.), growth hormone, IGF-1, and cachexia Certain TNF-α, LIF, IL-6, antibodies against oncostatin M, and the like can also be used in combination with the agent of the present invention.

  When the pharmaceutical composition of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effects of those agents. Therefore, side effects that may be caused by the combination of these agents can be safely prevented. In addition, the dose of the concomitant drug can be reduced, and as a result, side effects that may be caused by the concomitant drug can be effectively prevented.

  Concomitant drugs used in combination with the pharmaceutical composition of the present invention include biguanides (eg, phenformin, metformin, buformin, etc.), sulfonylureas (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide , Glyclopyramide, glimepiride, glipizide, glybsol, etc.) are preferred.

  Hereinafter, the present invention will be described in more detail with reference to test examples and examples, but the present invention is not limited thereto.

  In addition, in the prescription described as an Example, components (additives) other than the active ingredient may be listed products in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Pharmaceuticals or the Standards for Pharmaceutical Additives, and the like.

Example 1
With the formulation shown in Table 1, tablets containing Compound A (5 mg) and pioglitazone hydrochloride (49.59 mg) per tablet were obtained.

  First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) are dissolved in purified water and bonded. Liquid 1 was obtained. In a fluidized bed granulator / dryer, compound A, lactose (Megure Japan Co., Ltd.) and corn starch (Nihon Corn Starch Co., Ltd.) are mixed uniformly, and the mixture is granulated by spraying the binding liquid 1 in the dryer. Then, the granulated powder was dried in a fluidized bed granulation dryer to obtain a granulated powder.

  The obtained granulated powder was pulverized using a power mill pulverizer, microcrystalline cellulose (PH101, Asahi Kasei Chemicals Corporation), low-substituted hydroxypropyl cellulose (L-HPC-21 Shin-Etsu Chemical Co., Ltd.) Then, magnesium stearate (Taihei Chemical Industry Co., Ltd.) was added and mixed with a tumbler mixer to obtain a granulated powder for tableting. The obtained granulated powder for tableting was tableted with a rotary tableting machine using a 9.5 mmφ punch at a weight of 350 mg to obtain plain tablets containing 5 mg of compound A per tablet. Hydroxypropylmethylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo Co., Ltd.) are dissolved and suspended in purified water to obtain coating solution 1, which is obtained in the coating machine. The obtained nude tablet was sprayed with coating solution 1 until the weight per tablet increased by 15 mg to obtain intermediate coated tablets.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Co., Ltd.) were dissolved and suspended in purified water to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 150 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water using a dispersion apparatus was added to the hydroxypropyl methylcellulose solution 1, and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, spray the coating liquid 3 onto the obtained active drug layer-coated tablets until the weight per tablet increases by 10 mg, and add tablets with the formulation of Table 1 containing 5 mg of Compound A and 49.59 mg of pioglitazone hydrochloride per tablet. Obtained.

Comparative Example 1
With the formulation shown in Table 2, a granulated powder containing 5 mg of Compound A in 90 mg of the granulated powder was produced.

  First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (average molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) are dissolved in purified water, After obtaining the binding liquid 1 and uniformly mixing Compound A, lactose (Megure Japan Co., Ltd.) and corn starch (Nippon Corn Starch Co., Ltd.) in a fluidized bed granulation dryer, the mixture is combined in the drying machine 1 Were sprayed and granulated, and then the granulated powder was dried in a fluidized bed granulating drier to obtain a granulated powder containing 5 mg of Compound A in 90 mg of the granulated powder.

Comparative Example 2
With the formulation shown in Table 3, a granulated powder containing 49.59 mg of pioglitazone hydrochloride in 180 mg of the granulated powder was produced.

  First, hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.) is dissolved in purified water to obtain a binding solution 1, and pioglitazone hydrochloride, lactose (Megure Japan Co., Ltd.) in a fluidized bed granulator / dryer. ) And a half amount of carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) are uniformly mixed, the mixture is granulated by spraying the binding liquid 1 in a dryer, and the granulated powder is then dried in a fluidized bed granulator / dryer. The granulated powder was obtained. The obtained granulated powder was crushed using a power mill grinder, and the remaining carmellose calcium and magnesium stearate (Taihei Chemical Industry Co., Ltd.) were added. The mixture was mixed with a tumbler mixer to obtain a granulated powder containing 49.59 mg of pioglitazone hydrochloride in 180 mg of the granulated powder.

Comparative Example 3
Compound A granulated powder (90 mg) of Comparative Example 1 and pioglitazone hydrochloride granulated powder (180 mg) of Comparative Example 2 were mixed to obtain a mixed granulated powder.

Test example 1
The compound A granulated powder of Comparative Example 1 (90 mg), the mixed granulated powder of Comparative Example 3 (270 mg), and the tablet obtained in Example 1 were stored for 1 month under the conditions of opening at 40 ° C. and 75% RH glass bottle. Then, the increase amount of the ketone body of the acid decomposition product derived from Compound A was measured. The results are shown in Table 4.

  As shown in Table 4, when pioglitazone hydrochloride granulated powder is added to Compound A granulated powder and stored for 1 month under conditions of 40 ° C. and 75% RH glass bottle opening, the ketone body, which is a decomposition product derived from Compound A, Remarkably increased (mixed granulated powder of Comparative Example 3). The solid pharmaceutical composition of the present invention contains pioglitazone hydrochloride together with compound A, but the increase in the ketone body was small, and it was revealed that compound A was stabilized.

Example 2
With the formulation shown in Table 5, tablets containing Compound A (40 mg) and pioglitazone hydrochloride (16.53 mg) per tablet were obtained.

  First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (average molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) are dissolved in purified water, A binding solution 1 was obtained. In a fluidized bed granulator / dryer, compound A, lactose (Megure Japan Co., Ltd.) and corn starch (Nihon Corn Starch Co., Ltd.) are mixed uniformly, and the mixture is granulated by spraying the binding liquid 1 in the dryer. Then, the granulated powder was dried in a fluidized bed granulation dryer to obtain a granulated powder.

  The obtained granulated powder was pulverized using a power mill grinder, microcrystalline cellulose (PH101, Asahi Kasei Chemicals), low-substituted hydroxypropylcellulose (L-HPC-21 Shin-Etsu Chemical Co., Ltd.) and stearic acid. Magnesium (Taihei Chemical Industry Co., Ltd.) was added and mixed with a tumbler mixer to obtain a granulated powder for tableting. The obtained granulated powder for tableting was tableted with a rotary tableting machine using a 9.5 mmφ punch at a weight of 350 mg to obtain plain tablets containing 40 mg of compound A per tablet.

  Hydroxypropylmethylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo Co., Ltd.) are dissolved and suspended in purified water to obtain coating solution 1, which is obtained in the coating machine. The obtained nude tablet was sprayed with coating solution 1 until the weight per tablet increased by 15 mg to obtain intermediate coated tablets.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Co., Ltd.) were dissolved and suspended in purified water to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 150 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water was added to the hydroxypropyl methylcellulose solution 1 and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, spray the coating solution 3 onto the obtained active ingredient layer-coated tablets until the weight per tablet increases by 10 mg, and add tablets with the formulation of Table 5 containing 40 mg of Compound A and 16.53 mg of pioglitazone hydrochloride per tablet. Obtained.

Example 3
With the formulation shown in Table 6, tablets containing Compound A (20 mg) and pioglitazone hydrochloride (33.06 mg) per tablet were obtained.

  First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (average molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) are dissolved in purified water, A binding solution 1 was obtained. In a fluidized bed granulator / dryer, compound A, lactose (Megure Japan Co., Ltd.) and corn starch (Nihon Corn Starch Co., Ltd.) are mixed uniformly, and the mixture is granulated by spraying the binding liquid 1 in the dryer. Then, the granulated powder was dried in a fluidized bed granulation dryer to obtain a granulated powder.

  The obtained granulated powder was pulverized using a power mill pulverizer, microcrystalline cellulose (PH101, Asahi Kasei Chemicals Corporation), low-substituted hydroxypropyl cellulose (L-HPC-21 Shin-Etsu Chemical Co., Ltd.) And magnesium stearate (Taihei Chemical Industry Co., Ltd.) was added and mixed with a tumbler mixer to obtain a granulated powder for tableting. The obtained granulated powder for tableting was tableted with a rotary tableting machine using a 9.5 mmφ punch at a weight of 350 mg to obtain plain tablets containing 20 mg of compound A per tablet.

  Hydroxypropyl methylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.)) and talc (Matsumura Sangyo Co., Ltd.) are dissolved and suspended in purified water to obtain a coating solution 1, and in the coating machine, The obtained bare tablet was sprayed with coating solution 1 until the weight per tablet increased by 15 mg to obtain an intermediate-coated tablet.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Co., Ltd.) were dissolved and suspended in purified water to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 150 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water using a dispersion apparatus was added to the hydroxypropyl methylcellulose solution 1, and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, spray the coating solution 3 onto the obtained active ingredient layer-coated tablets until the weight increases by 10 mg per tablet, and add tablets with the formulation of Table 6 containing 20 mg of Compound A and 33.06 mg of pioglitazone hydrochloride per tablet. Obtained.

Example 4
Tablets containing Compound A (40 mg) and pioglitazone hydrochloride (33.06 mg) per tablet were prepared according to the formulation shown in Table 7.

  First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (average molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) are dissolved in purified water, After obtaining the binding liquid 1 and uniformly mixing Compound A, lactose (Megure Japan Co., Ltd.) and corn starch (Nippon Corn Starch Co., Ltd.) in a fluidized bed granulation dryer, the mixture is combined in the drying machine 1 Was sprayed and granulated, and then the granulated powder was dried in a fluidized bed granulator dryer to obtain a granulated powder.

  The obtained granulated powder was pulverized using a power mill pulverizer, microcrystalline cellulose (PH101, Asahi Kasei Chemicals Corporation), low-substituted hydroxypropyl cellulose (L-HPC-21 Shin-Etsu Chemical Co., Ltd.) Then, magnesium stearate (Taihei Chemical Industry Co., Ltd.) was added and mixed with a tumbler mixer to obtain a granulated powder for tableting. The obtained granulated powder for tableting was tableted with a rotary tableting machine using a 9.5 mmφ punch at a weight of 350 mg to obtain plain tablets containing 40 mg of compound A per tablet.

  Hydroxypropyl methylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.)) and talc (Matsumura Sangyo Co., Ltd.) are dissolved and suspended in purified water to obtain a coating solution 1, and in the coating machine, The obtained bare tablet was sprayed with coating solution 1 until the weight per tablet increased by 15 mg to obtain an intermediate-coated tablet.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Co., Ltd.) were dissolved and suspended in purified water to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 150 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water using a dispersion apparatus was added to the hydroxypropyl methylcellulose solution 1, and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, spray the coating liquid 3 onto the obtained active drug layer-coated tablets until the weight per tablet increases by 10 mg, and add tablets with the formulation of Table 7 containing 40 mg of Compound A and 33.06 mg of pioglitazone hydrochloride per tablet. Obtained.

Example 5
Tablets containing Compound A (20 mg) and pioglitazone hydrochloride (49.59 mg) per tablet were prepared according to the formulation shown in Table 8.

  First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (average molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) are dissolved in purified water, After obtaining the binding liquid 1 and uniformly mixing Compound A, lactose (Megure Japan Co., Ltd.) and corn starch (Nippon Corn Starch Co., Ltd.) in a fluidized bed granulation dryer, the mixture is combined in the drying machine 1 Was sprayed and granulated, and then the granulated powder was dried in a fluidized bed granulator dryer to obtain a granulated powder.

  The obtained granulated powder was pulverized using a power mill pulverizer, microcrystalline cellulose (PH101, Asahi Kasei Chemicals Corporation), low-substituted hydroxypropylcellulose (L-HPC-21, Shin-Etsu Chemical Co., Ltd.) ) And magnesium stearate (Taihei Chemical Industry Co., Ltd.) were added and mixed with a tumbler mixer to obtain a granulated powder for tableting. The obtained granulated powder for tableting was tableted with a rotary tableting machine using a 9.5 mmφ punch at a weight of 350 mg to obtain plain tablets containing 20 mg of compound A per tablet.

  Hydroxypropylmethylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo Co., Ltd.) are dissolved and suspended in purified water to obtain coating solution 1, which is obtained in the coating machine. The obtained nude tablet was sprayed with coating solution 1 until the weight per tablet increased by 15 mg to obtain intermediate coated tablets.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Co., Ltd.) were dissolved and suspended in purified water to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 150 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water using a dispersion apparatus was added to the hydroxypropyl methylcellulose solution 1, and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, spray the coating solution 3 onto the obtained active ingredient layer-coated tablets until the weight per tablet increases by 10 mg, and prepare tablets of the formulation in Table 8 containing 20 mg of Compound A and 49.59 mg of pioglitazone hydrochloride per tablet. Obtained.

Example 6
Tablets containing Compound A (40 mg) and pioglitazone hydrochloride (49.59 mg) per tablet were prepared according to the formulation shown in Table 9.

  First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (average molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) are dissolved in purified water, After obtaining the binding liquid 1 and uniformly mixing Compound A, lactose (Megure Japan Co., Ltd.) and corn starch (Nippon Corn Starch Co., Ltd.) in a fluidized bed granulation dryer, the mixture is combined in the drying machine 1 Was sprayed and granulated, and then the granulated powder was dried in a fluidized bed granulator dryer to obtain a granulated powder.

  The obtained granulated powder was pulverized using a power mill pulverizer, microcrystalline cellulose (PH101, Asahi Kasei Chemicals Corporation), low-substituted hydroxypropyl cellulose (L-HPC-21 Shin-Etsu Chemical Co., Ltd.) Then, magnesium stearate (Taihei Chemical Industry Co., Ltd.) was added and mixed with a tumbler mixer to obtain a granulated powder for tableting. The obtained granulated powder for tableting was tableted with a rotary tableting machine using a 9.5 mmφ punch at a weight of 350 mg to obtain plain tablets containing 40 mg of compound A per tablet.

  Hydroxypropylmethylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo Co., Ltd.) are dissolved and suspended in purified water to obtain coating solution 1, which is obtained in the coating machine. The obtained nude tablet was sprayed with coating solution 1 until the weight per tablet increased by 15 mg to obtain intermediate coated tablets.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Co., Ltd.) were dissolved and suspended in purified water to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 150 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water was added to the hydroxypropyl methylcellulose solution 1 and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, spray the coating solution 3 onto the resulting active drug layer-coated tablets until the weight per tablet increases by 10 mg, and add tablets with the formulation of Table 9 containing 40 mg of Compound A and 49.59 mg of pioglitazone hydrochloride per tablet. Obtained.

Test example 2
The tablets obtained in Examples 2 to 5 and 270 mg of the mixed granulated powder of Comparative Example 3 were packaged in a moisture-proof package and stored for 1 month under conditions of 40 ° C. and 75% RH. The increase was measured. The results are shown in Table 10.

  As shown in Table 10, when pioglitazone hydrochloride was added to Compound A, the ketone body, which was a degradation product derived from Compound A, significantly increased when stored for 1 month under conditions of 40 ° C. and 75% RH (Comparative Example 3). Mixed granulated powder). On the other hand, the solid pharmaceutical composition of the present invention contains pioglitazone hydrochloride together with Compound A, but the increase in the ketone body was small, and it was revealed that Compound A was stabilized.

Example 7
Using the plain tablets obtained in the same manner as in Example 6, tablets containing 49.59 mg of pioglitazone hydrochloride per tablet were prepared according to the formulation shown in Table 11.

  Hydroxypropyl methylcellulose (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo Co., Ltd.) are dissolved and suspended in purified water to obtain coating solution 1, which is obtained in the coating machine. Coating solution 1 was sprayed onto the resulting bare tablets until the weight per tablet increased by 14 mg to obtain intermediate layer-coated tablets.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000-50000 Nippon Soda Co., Ltd.), low-substituted hydroxypropylcellulose (L-HPC-32, Shin-Etsu Chemical Co., Ltd.) and D-mannitol were added to purified water. (Merck Co., Ltd.) was dissolved and suspended to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 150 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water using a dispersion apparatus was added to the hydroxypropyl methylcellulose solution 1, and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, coating liquid 3 was sprayed onto the obtained active ingredient layer-coated tablets until the weight increased by 5 mg per tablet, and tablets with the formulation of Table 11 containing 49.59 mg of pioglitazone hydrochloride per tablet were obtained.

Example 8
Using the plain tablets obtained in the same manner as in Example 6, tablets containing 49.59 mg of pioglitazone hydrochloride per tablet were prepared according to the formulation shown in Table 12.

  Hydroxypropyl methylcellulose (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo Co., Ltd.) are dissolved and suspended in purified water to obtain coating solution 1, which is obtained in the coating machine. Coating solution 1 was sprayed onto the resulting bare tablets until the weight per tablet increased by 14 mg to obtain intermediate layer-coated tablets.

  Next, pioglitazone hydrochloride, low-substituted hydroxypropylcellulose (L-HPC-32, Shin-Etsu Chemical Co., Ltd.), hydroxypropylcellulose (molecular weight 15000-50000 Nippon Soda Co., Ltd.) and erythritol (Niken Kasei) were added to purified water. Co., Ltd.) was dissolved and suspended to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 150 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water using a dispersion apparatus was added to the hydroxypropyl methylcellulose solution 1, and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, coating liquid 3 was sprayed onto the obtained active ingredient layer-coated tablets until the weight increased by 5 mg per tablet, and tablets with the formulation of Table 12 containing 49.59 mg of pioglitazone hydrochloride per tablet were obtained.

Example 9
Tablets containing 49.59 mg of pioglitazone hydrochloride per tablet were prepared using the uncoated tablets similar to the uncoated tablets obtained in the same manner as in Example 6 according to the formulation shown in Table 13.

  Hydroxypropyl methylcellulose (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo Co., Ltd.) are dissolved and suspended in purified water to obtain coating solution 1, which is obtained in the coating machine. Coating solution 1 was sprayed onto the resulting bare tablets until the weight per tablet increased by 14 mg to obtain intermediate layer-coated tablets.

  Next, pioglitazone hydrochloride, low-substituted hydroxypropylcellulose (L-HPC-32 Shin-Etsu Chemical Co., Ltd.), hydroxypropylcellulose (average molecular weight: 15000-50000 Nippon Soda Co., Ltd.) and sucrose (saline) Minato Sugar Co., Ltd.) was dissolved and suspended to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 150 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water using a dispersion apparatus was added to the hydroxypropyl methylcellulose solution 1, and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, coating liquid 3 was sprayed onto the obtained active ingredient layer-coated tablets until the weight increased by 5 mg per tablet, and tablets with the formulation of Table 13 containing 49.59 mg of pioglitazone hydrochloride per tablet were obtained.

Test example 3
About each tablet obtained in Example 7, Example 8 and Example 9, elution of pioglitazone hydrochloride was carried out by paddle method (50 rpm) using 0.3 M hydrochloric acid / potassium chloride buffer (900 mL, 37 ° C., pH 2). Sex was evaluated. The results are shown in Table 14.

  As shown in Table 14, the solid pharmaceutical composition of the present invention was able to change the dissolution rate of pioglitazone hydrochloride by changing the type of sugar.

Test example 4
Elution of pioglitazone hydrochloride by the paddle method (75 rpm) using 0.3 M hydrochloric acid / potassium chloride buffer (900 mL, 37 ° C., pH 2.0) for the tablets obtained in Example 2, Example 4 and Example 6. Sex was evaluated. The results are shown in Table 15.

  As shown in Table 15, the drug dissolution rate could be changed by changing the drug concentration in the preparation.

Example 10
Using the plain tablets obtained in Example 6, tablets containing 49.59 mg of pioglitazone hydrochloride per tablet were prepared according to the formulation shown in Table 16.

  Hydroxypropyl cellulose (average molecular weight: 15000-50000 Nippon Soda Co., Ltd.)), sucrose (saline salt refined sugar) and low-substituted hydroxypropyl cellulose (L-HPC-32, Shin-Etsu Chemical Co., Ltd.) in purified water Dissolved and suspended to obtain coating solution 1, and sprayed coating solution 1 onto the resulting bare tablet in a coating machine until the weight increased by 100 mg per tablet to obtain an intermediate-coated tablet.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Co., Ltd.) were dissolved and suspended in purified water to obtain coating solution 2. In the coating machine, the obtained intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 120 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water was added to the hydroxypropyl methylcellulose solution 1 and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, coating liquid 3 was sprayed onto the obtained active ingredient layer-coated tablets until the weight increased by 5 mg per tablet to obtain tablets having the formulation of Table 16 containing 49.59 mg of pioglitazone hydrochloride per tablet.

Example 11
Using the plain tablets obtained in Example 6, tablets containing 49.59 mg of pioglitazone hydrochloride per tablet were prepared according to the formulation shown in Table 17.

  In purified water, hydroxypropylcellulose (average molecular weight: 15000-50000 Nippon Soda Co., Ltd.), sucrose (Shisui Minato Sugar Co., Ltd.) and low-substituted hydroxypropylcellulose (L-HPC-32, Shin-Etsu Chemical Co., Ltd.) )) Was dissolved and suspended to obtain a coating liquid 1, and the coating liquid 1 was sprayed on the resulting bare tablets in the coating machine until the weight increased by 100 mg per tablet to obtain intermediate coated tablets.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Co., Ltd.) were dissolved and suspended in purified water to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 150 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water was added to the hydroxypropyl methylcellulose solution 1 and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, coating liquid 3 was sprayed onto the obtained active ingredient layer-coated tablets until the weight increased by 5 mg per tablet, and tablets with the formulation of Table 17 containing 49.59 mg of pioglitazone hydrochloride per tablet were obtained.

Test Example 5
About each tablet obtained in Example 10 and Example 11, the dissolution property of pioglitazone hydrochloride was evaluated by the paddle method (50 rpm) using 0.3 M hydrochloric acid / potassium chloride buffer (900 mL, 37 ° C., pH 2). . The results are shown in Table 18.

  As shown in Table 18, the drug dissolution rate could be changed by changing the amount of D-mannitol.

Example 12
Using the plain tablets obtained in Example 6, tablets containing 49.59 mg of pioglitazone hydrochloride per tablet were prepared according to the formulation shown in Table 19.

  In purified water, hydroxypropyl methylcellulose (average molecular weight: 15000-50000 Nippon Soda Co., Ltd.), sucrose (Shisui Minato Sugar Co., Ltd.) and low-substituted hydroxypropylcellulose (L-HPC-32, Shin-Etsu Chemical Co., Ltd.) )) Was dissolved and suspended to obtain a coating liquid 1, and the coating liquid 1 was sprayed on the resulting bare tablets in the coating machine until the weight increased by 100 mg per tablet to obtain intermediate coated tablets.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Co., Ltd.) were dissolved and suspended in purified water to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 150 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water using a dispersion apparatus was added to the hydroxypropyl methylcellulose solution 1, and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, coating liquid 3 was sprayed onto the obtained active drug layer-coated tablets until the weight increased by 5 mg per tablet to obtain tablets having the formulation of Table 19 containing 49.59 mg of pioglitazone hydrochloride per tablet.

Test Example 6
About each tablet obtained in Example 11 and Example 12, the dissolution property of pioglitazone hydrochloride was evaluated by the paddle method (50 rpm) using 0.3 M hydrochloric acid / potassium chloride buffer (900 mL, 37 ° C., pH 2). . The results are shown in Table 20.

  As shown in Table 20, the drug dissolution rate could be changed by changing the amount of the binder in the main drug layer.

Example 13
Using the plain tablets obtained in the same manner as in Example 6, tablets containing 49.59 mg of pioglitazone hydrochloride per tablet were prepared according to the formulations shown in Table 21, Table 22, and Table 23.

  Hydroxypropyl methylcellulose (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo Co., Ltd.) are dissolved and suspended in purified water to obtain coating solution 1, which is obtained in the coating machine. Coating solution 1 was sprayed onto the resulting bare tablets until the weight per tablet increased by 14 mg to obtain intermediate layer-coated tablets.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000-50000 Nippon Soda Co., Ltd.), D-mannitol (Merck Co., Ltd.) and low-substituted hydroxypropylcellulose (L-HPC-32 Shin-Etsu Chemical) were added to purified water. Kogyo Co., Ltd.) was dissolved and suspended to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 150 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water using a dispersion apparatus was added to the hydroxypropyl methylcellulose solution 1, and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, the coating solution 3 was sprayed onto the obtained active ingredient layer-coated tablets until the weight per tablet increased by 5 mg, and the formulations of Table 21, Table 22 and Table 23 containing 49.59 mg of pioglitazone hydrochloride per tablet were used. Tablets were obtained.

Test Example 7
About each tablet obtained in Example 13, the dissolution property of pioglitazone hydrochloride was evaluated by the paddle method (50 rpm) using 0.3 M hydrochloric acid / potassium chloride buffer (900 mL, 37 ° C., pH 2). The results are shown in Table 24.

  As shown in Table 24, the dissolution rate of the drug could be changed by changing the amount of the disintegrant in the main drug layer.

Example 14
Using the plain tablets obtained in the same manner as in Example 6, tablets containing 49.59 mg of pioglitazone hydrochloride per tablet were prepared according to the formulations shown in Table 25, Table 26 and Table 27.

  Hydroxypropyl methylcellulose (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo Co., Ltd.) are dissolved and suspended in purified water to obtain coating solution 1, which is obtained in the coating machine. Coating solution 1 was sprayed onto the resulting bare tablets until the weight per tablet increased by 14 mg to obtain intermediate layer-coated tablets.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000-50000 Nippon Soda Co., Ltd.), erythritol (Nikken Kasei Co., Ltd.) and low-substituted hydroxypropylcellulose (L-HPC-32, Shin-Etsu) were added to purified water. Chemical Industry Co., Ltd.) was dissolved and suspended to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 150 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water using a dispersion apparatus was added to the hydroxypropyl methylcellulose solution 1, and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, spray the coating solution 3 onto the obtained active ingredient layer-coated tablets until the weight per tablet increases by 5 mg, and the formulations of Table 25, Table 26 and Table 27 containing 49.59 mg of pioglitazone hydrochloride per tablet. Tablets were obtained.

Test Example 8
About each tablet obtained in Example 14, the dissolution property of pioglitazone hydrochloride was evaluated by the paddle method (50 rpm) using 0.3 M hydrochloric acid / potassium chloride buffer (900 mL, 37 ° C., pH 2). The results are shown in Table 28.

  As shown in Table 28, the dissolution rate of the drug could be changed by changing the amount of the disintegrant in the main drug layer.

Example 15
Using the plain tablets obtained in the same manner as in Example 6, tablets containing 40 mg of Compound A and 49.59 mg of pioglitazone hydrochloride per tablet were prepared according to the formulation shown in Table 29.

  Hydroxypropylmethylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo Co., Ltd.) are dissolved and suspended in purified water to obtain coating solution 1, which is obtained in the coating machine. The obtained nude tablet was sprayed with coating solution 1 until the weight per tablet increased by 15 mg to obtain intermediate coated tablets.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Co., Ltd.) were dissolved and suspended in purified water to obtain coating solution 2. In the coating machine, the obtained intermediate layer coated tablets were sprayed with coating liquid 2 until the weight per tablet increased by 225 mg to obtain main drug layer coated tablets.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water was added to the hydroxypropyl methylcellulose solution 1 and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, spray the coating solution 3 onto the obtained active ingredient layer-coated tablets until the weight increases by 15 mg per tablet, and add tablets with the formulation of Table 29 containing 40 mg of Compound A and 49.59 mg of pioglitazone hydrochloride per tablet. Obtained.

Example 16
Tablets containing 20 mg of Compound A and 49.59 mg of pioglitazone hydrochloride per tablet were prepared using the plain tablets obtained in the same manner as in Example 5 and the formulation shown in Table 30.

  Hydroxypropyl methylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo) are dissolved and suspended in purified water to obtain a coating solution 1, and the obtained nude is obtained in the coating machine. The tablets were sprayed with coating solution 1 until the weight increased by 15 mg per tablet to obtain intermediate coated tablets.

  Next, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Co., Ltd.) were dissolved and suspended in purified water to obtain coating solution 2. In the coating machine, the resulting intermediate layer coated tablets were sprayed with coating solution 2 until the weight per tablet increased by 225 mg to obtain main drug layer coated tablets.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( A dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd. in purified water was added to the hydroxypropyl methylcellulose solution 1 and the mixture was stirred and mixed with a stirrer to obtain a coating solution 3. In the coating machine, spray the coating liquid 3 onto the obtained active drug layer-coated tablets until the weight increases by 15 mg per tablet, and add tablets with the formulation of Table 30 containing 20 mg of Compound A and 49.59 mg of pioglitazone hydrochloride per tablet. Obtained.

Example 17
Tablets containing 8 mg of Compound B and 33.10 mg of pioglitazone hydrochloride per tablet were obtained with the formulation shown in Table 31.

  First, in purified water, hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.), Macrogol 6000 (average molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) and yellow pigment 5 No. (San-Eigen FFI Co., Ltd.) was dissolved to obtain a binding solution 1. After mixing Compound B, lactose (Megure Japan Co., Ltd.) and corn starch (Nippon Corn Starch Co., Ltd.) uniformly in a fluidized bed granulator / dryer, the mixture is sprayed with the binding liquid 1 in the dryer. Then, the granulated powder was dried in a fluidized bed granulator / dryer to obtain a granulated powder.

  The resulting granulated powder is pulverized using a power mill grinder, and carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) and magnesium stearate (Taihei Chemical Sangyo Co., Ltd.) are added and mixed with a tumbler mixer. A granulated powder for tableting was obtained. The obtained granulated powder for tableting was tableted to a weight of 130 mg using a 7.0 mmφ punch with a rotary tableting machine to obtain a plain tablet containing 8 mg of compound B per tablet.

  D-mannitol (Merck Co., Ltd.) and hydroxypropyl cellulose (average molecular weight: 15000-50000, Nippon Soda Co., Ltd.) are dissolved in purified water to obtain coating solution 1, and the resulting uncoated tablet is coated in the coating machine. The coating liquid 1 was sprayed until the weight increased by 70 mg per tablet to obtain an intermediate layer coated tablet.

  Next, pioglitazone hydrochloride, D-mannitol (Merck Co., Ltd.) and hydroxypropylcellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) were dissolved and suspended in purified water to obtain coating solution 2. In the coating machine, the obtained intermediate layer coated tablets were sprayed with the coating solution 2 until the weight increased by 100 mg per tablet to obtain an active ingredient layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( Dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd.), yellow iron sesquioxide (Univar / Anstead) and iron sesquioxide (BASF Japan KK) in purified water using a dispersing device is a hydroxypropyl methylcellulose solution. In addition to 1, the mixture was stirred and mixed with a stirrer to obtain coating liquid 3. In the coating machine, spray the coating solution 3 onto the obtained active ingredient layer-coated tablets until the weight per tablet increases by 10 mg, and add tablets with the formulation of Table 31 containing 8 mg of Compound B and 33.10 mg of pioglitazone hydrochloride per tablet. Obtained.

Example 18
With the formulation shown in Table 32, tablets containing 4 mg of Compound B and 33.10 mg of pioglitazone hydrochloride per tablet were obtained.

  First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (average molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) are dissolved in purified water, A binding solution 1 was obtained. After mixing Compound B, lactose (Megure Japan Co., Ltd.) and corn starch (Nippon Corn Starch Co., Ltd.) uniformly in a fluidized bed granulator / dryer, the mixture is sprayed with the binding liquid 1 in the dryer. Then, the granulated powder was dried in a fluidized bed granulator / dryer to obtain a granulated powder.

  The resulting granulated powder is pulverized using a power mill grinder, and carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) and magnesium stearate (Taihei Chemical Sangyo Co., Ltd.) are added and mixed with a tumbler mixer. A granulated powder for tableting was obtained. The obtained granulated powder for tableting was tableted to a weight of 130 mg using a 7.0 mmφ punch with a rotary tableting machine to obtain a bare tablet containing 4 mg of compound B per tablet.

  D-mannitol (Merck Co., Ltd.) and hydroxypropyl cellulose (average molecular weight: 15000-50000, Nippon Soda Co., Ltd.) are dissolved in purified water to obtain coating solution 1, and the resulting uncoated tablet is coated in the coating machine. The coating liquid 1 was sprayed until the weight increased by 70 mg per tablet to obtain an intermediate layer coated tablet.

  Next, pioglitazone hydrochloride, D-mannitol (Merck Co., Ltd.) and hydroxypropyl cellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) were dissolved in purified water to obtain coating solution 2. In the coating machine, the obtained intermediate layer coated tablets were sprayed with the coating solution 2 until the weight increased by 100 mg per tablet to obtain an active ingredient layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( Dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd.) and yellow ferric oxide (Univar / Anstead) in purified water using a dispersion apparatus is added to hydroxypropylmethylcellulose solution 1, and the mixture is stirred and mixed with a stirrer. Thus, a coating liquid 3 was obtained. In the coating machine, spray the coating solution 3 onto the obtained active ingredient layer-coated tablets until the weight per tablet increases by 10 mg, and add tablets with the formulation of Table 32 containing 4 mg of Compound B and 33.10 mg of pioglitazone hydrochloride per tablet. Obtained.

Example 19
With the formulation shown in Table 33, tablets containing 8 mg of Compound B and 16.55 mg of pioglitazone hydrochloride per tablet were obtained.

  First, in purified water, hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) and yellow pigment No. 5 (San-Eigen FFI Co., Ltd.) was dissolved to obtain a binding solution 1. After mixing Compound B, lactose (Megure Japan Co., Ltd.) and corn starch (Nippon Corn Starch Co., Ltd.) uniformly in a fluidized bed granulator / dryer, the mixture is sprayed with the binding liquid 1 in the dryer. Then, the granulated powder was dried in a fluidized bed granulator / dryer to obtain a granulated powder.

  The resulting granulated powder is pulverized using a power mill grinder, and carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) and magnesium stearate (Taihei Chemical Sangyo Co., Ltd.) are added and mixed with a tumbler mixer. A granulated powder for tableting was obtained. The obtained granulated powder for tableting was tableted to a weight of 130 mg using a 7.0 mmφ punch with a rotary tableting machine to obtain a plain tablet containing 8 mg of compound B per tablet.

  D-mannitol (Merck Co., Ltd.) and hydroxypropyl cellulose (average molecular weight: 15000-50000, Nippon Soda Co., Ltd.) are dissolved in purified water to obtain coating solution 1, and the resulting uncoated tablet is coated in the coating machine. The coating liquid 1 was sprayed until the weight increased by 70 mg per tablet to obtain an intermediate layer coated tablet.

  Next, pioglitazone hydrochloride, D-mannitol (Merck Co., Ltd.) and hydroxypropyl cellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) were dissolved in purified water to obtain coating solution 2. In the coating machine, the obtained intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 50 mg per tablet to obtain a main drug layer coated tablet.

  Furthermore, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separated from titanium oxide ( Dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd.) and yellow ferric oxide (Univar / Anstead) in purified water using a dispersing device is added to hydroxypropyl methylcellulose solution 1, and the mixture is stirred and mixed with a stirrer. Thus, a coating liquid 3 was obtained. In the coating machine, spray the coating solution 3 onto the obtained active ingredient layer-coated tablets until the weight per tablet increases by 10 mg, and add tablets with the formulation of Table 33 containing 8 mg of Compound B and 16.55 mg of pioglitazone hydrochloride per tablet. Obtained.

Example 20
With the formulation shown in Table 34, tablets containing 4 mg of Compound B and 16.55 mg of pioglitazone hydrochloride per tablet were obtained.

  First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) are dissolved in purified water and bonded. Liquid 1 was obtained. Compound B, lactose (Megure Japan Co., Ltd.) and corn starch (Nippon Corn Starch Co., Ltd.) are uniformly mixed in a fluidized bed granulator / dryer, and the mixture is then sprayed with binding liquid 1 in the dryer. Then, the granulated powder was dried in a fluidized bed granulation dryer to obtain a granulated powder.

  The resulting granulated powder is pulverized using a power mill grinder, and carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) and magnesium stearate (Taihei Chemical Sangyo Co., Ltd.) are added and mixed with a tumbler mixer. A granulated powder for tableting was obtained. The obtained granulated powder for tableting was tableted into a weight of 130 mg using a 7.0 mmφ punch with a rotary tableting machine to obtain a bare tablet containing 4 mg of compound B per tablet.

  D-mannitol (Merck Co., Ltd.) and hydroxypropyl cellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) are dissolved in purified water to obtain a coating solution 1, and the resulting uncoated tablet is coated in the coating machine. The coating liquid 1 was sprayed until the weight increased by 70 mg per tablet to obtain an intermediate layer coated tablet.

  Next, pioglitazone hydrochloride, D-mannitol (Merck Co., Ltd.) and hydroxypropyl cellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) were dissolved in purified water to obtain coating solution 2. In the coating machine, the obtained intermediate layer coated tablets were sprayed with coating solution 2 until the weight increased by 50 mg per tablet to obtain a main drug layer coated tablet.

  Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.) are dissolved in purified water to obtain a hydroxypropylmethylcellulose solution 1, which is separately prepared with titanium oxide ( Dispersion 1 obtained by dispersing Freund Sangyo Co., Ltd.) and yellow ferric oxide (Univar / Anstead) in purified water using a dispersing device is added to hydroxypropyl methylcellulose solution 1, and the mixture is stirred and mixed with a stirrer. Thus, a coating liquid 3 was obtained. In the coating machine, spray the coating liquid 3 onto the obtained active drug layer-coated tablets until the weight per tablet increases by 10 mg, and add tablets with the formulation of Table 34 containing 4 mg of Compound B and 16.55 mg of pioglitazone hydrochloride per tablet. Obtained.

Example 21
With the formulation shown in Table 35, tablets containing 8 mg of Compound B and 33.06 mg of pioglitazone hydrochloride per tablet were obtained.

  First, in purified water, hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.), Macrogol 6000 (average molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) and yellow pigment 5 No. (San-Eigen FFI Co., Ltd.) was dissolved to obtain a binding solution 1. After mixing Compound B, lactose (Megure Japan Co., Ltd.) and corn starch (Nippon Corn Starch Co., Ltd.) uniformly in a fluidized bed granulator / dryer, the mixture is sprayed with the binding liquid 1 in the dryer. Then, the granulated powder was dried in a fluidized bed granulator / dryer to obtain a granulated powder.

  The resulting granulated powder is pulverized using a power mill grinder, and carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) and magnesium stearate (Taihei Chemical Sangyo Co., Ltd.) are added and mixed with a tumbler mixer. A granulated powder for tableting was obtained. The obtained granulated powder for tableting was tableted to a weight of 130 mg using a 7.0 mmφ punch with a rotary tableting machine to obtain a plain tablet containing 8 mg of compound B per tablet.

  In purified water, hydroxypropylmethylcellulose 2910 (average molecular weight: 19000, Shin-Etsu Chemical Co., Ltd.), Macrogol 6000 (average molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) and talc (Matsumura) Sangyo Co., Ltd.) was dissolved and suspended to obtain coating solution 1, and sprayed coating solution 1 onto the resulting bare tablet in a coating machine until the weight increased by 5 mg per tablet to obtain intermediate layer coated tablets. .

  Next, hydroxypropylcellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) is dissolved in purified water to obtain hydroxypropylcellulose solution 1, separately, yellow iron sesquioxide (Univar / Anstead) and iron sesquioxide. Dispersion liquid 1 obtained by dispersing (BASF Japan Ltd.) in purified water using a dispersion apparatus was added to hydroxypropylcellulose solution 1, and the mixture was stirred and mixed with a stirrer to obtain binding liquid 2. Pioglitazone hydrochloride, D-mannitol (Merck Co., Ltd.), crystalline cellulose (KG-802, Asahi Kasei Chemicals Co., Ltd.) and carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) are uniformly mixed in a fluidized bed granulator / dryer. Thereafter, the mixture was granulated by spraying the binding liquid 2 in a dryer, and then the granulated powder was dried in a fluidized bed granulator / dryer to obtain a granulated powder.

  The obtained granulated powder is pulverized using a power mill grinder, carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) and magnesium stearate (Taihei Chemical Industry Co., Ltd.) are added, and the mixture is tumbled with a tumbler mixer. This was mixed to obtain a granulated powder for tableting. The obtained granulated powder for tableting was tableted to a weight of 395 mg using a 10.0 mmφ punch with an intermediate-layer coated tablet as the core, and 8 mg of compound B and pioglitazone hydrochloride per tablet. A dry-coated tablet with the formulation of Table 35 containing 06 mg was obtained.

Example 22
With the formulation shown in Table 36, tablets containing 8 mg of Compound B and 16.53 mg of pioglitazone hydrochloride per tablet were obtained.

  First, in purified water, hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.), Macrogol 6000 (molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) and yellow pigment No. 5 (San-Eigen FFI Co., Ltd.) was dissolved to obtain a binding solution 1. After mixing Compound B, lactose (Megure Japan Co., Ltd.) and corn starch (Nippon Corn Starch Co., Ltd.) uniformly in a fluidized bed granulator / dryer, the mixture is sprayed with the binding liquid 1 in the dryer. Then, the granulated powder was dried in a fluidized bed granulator / dryer to obtain a granulated powder.

  The resulting granulated powder is pulverized using a power mill grinder, and carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) and magnesium stearate (Taihei Chemical Sangyo Co., Ltd.) are added and mixed with a tumbler mixer. A granulated powder for tableting was obtained. The obtained granulated powder for tableting was tableted to a weight of 130 mg using a 7.0 mmφ punch with a rotary tableting machine to obtain a plain tablet containing 8 mg of compound B per tablet.

  In purified water, hydroxypropylmethylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.), Macrogol 6000 (average molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) Dissolve and suspend talc (Matsumura Sangyo Co., Ltd.) to obtain coating solution 1, and spray the coating solution 1 onto the resulting bare tablet in the coating machine until the weight increases by 5 mg per tablet. I got a tablet.

  Next, hydroxypropyl cellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) was dissolved in purified water to obtain a binding solution 2. Pioglitazone hydrochloride, D-mannitol (Merck Co., Ltd.), crystalline cellulose (KG-802, Asahi Kasei Chemicals Co., Ltd.) and carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) are uniformly mixed in a fluidized bed granulator / dryer. Thereafter, the mixture was granulated by spraying the binding liquid 2 in a dryer, and then the granulated powder was dried in a fluidized bed granulator / dryer to obtain a granulated powder.

  The obtained granulated powder is crushed using a power mill grinder, carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) and magnesium stearate (Taihei Chemical Industry Co., Ltd.) are added, and the mixture is tumbled with a tumbler mixer. By mixing, a granulated powder for tableting was obtained. The obtained granulated powder for tableting was tableted to a weight of 395 mg using a 10.0 mmφ punch with an intermediate layer coated tablet as the inner core and a weight of 395 mg, and 8 mg of compound B and pioglitazone hydrochloride per tablet. A dry-coated tablet with the formulation of Table 36 containing 53 mg was obtained.

Example 23
With the formulation shown in Table 37, tablets containing 4 mg of Compound B and 16.53 mg of pioglitazone hydrochloride per tablet were obtained.

  First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (average molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) are dissolved in purified water, A binding solution 1 was obtained. After mixing Compound B, lactose (Megure Japan Co., Ltd.) and corn starch (Nippon Corn Starch Co., Ltd.) uniformly in a fluidized bed granulator / dryer, the mixture is sprayed with the binding liquid 1 in the dryer. Then, the granulated powder was dried in a fluidized bed granulator / dryer to obtain a granulated powder.

  The resulting granulated powder is pulverized using a power mill grinder, and carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) and magnesium stearate (Taihei Chemical Sangyo Co., Ltd.) are added and mixed with a tumbler mixer. A granulated powder for tableting was obtained. The obtained granulated powder for tableting was tableted into a weight of 130 mg using a 7.0 mmφ punch with a rotary tableting machine to obtain a bare tablet containing 4 mg of compound B per tablet.

  In purified water, hydroxypropylmethylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.), Macrogol 6000 (average molecular weight: 7300-9300, melting point: 56-61 ° C., Sanyo Chemical Industries, Ltd.) Dissolve and suspend talc (Matsumura Sangyo Co., Ltd.) to obtain coating solution 1, and spray the coating solution 1 onto the resulting bare tablet in the coating machine until the weight increases by 5 mg per tablet. I got a tablet.

  Next, hydroxypropyl cellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) was dissolved in purified water to obtain a binding solution 2. Pioglitazone hydrochloride, D-mannitol (Merck Co., Ltd.), crystalline cellulose (KG-802, Asahi Kasei Chemicals Co., Ltd.) and carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) are uniformly mixed in a fluidized bed granulator / dryer. Thereafter, the mixture was granulated by spraying the binding liquid 2 in a dryer, and then the granulated powder was dried in a fluidized bed granulator / dryer to obtain a granulated powder.

  The obtained granulated powder is crushed using a power mill grinder, carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) and magnesium stearate (Taihei Chemical Industry Co., Ltd.) are added, and the mixture is tumbled with a tumbler mixer. This was mixed to obtain a granulated powder for tableting. The obtained granulated powder for tableting was tableted to a weight of 395 mg using a 10.0 mmφ punch with an intermediate layer coated tablet as the inner core, and 4 mg of compound B and pioglitazone hydrochloride 16 per tablet. A dry-coated tablet with the formulation of Table 37 containing .53 mg was obtained.

Industrial Applicability The solid pharmaceutical composition of the present invention is used as a prophylactic / therapeutic agent for cardiovascular diseases such as hypertension, heart failure, diabetic nephropathy, arteriosclerosis, and metabolic diseases such as diabetes and metabolic syndrome. It is clinically useful.

This application is based on US Provisional Application No. 60 / 795,179, filed in the United States of America, the contents of which are incorporated in full herein. Further, the patents, patent applications, and publications cited in the present specification are all incorporated in the present specification by being cited.

Claims (7)

(A) Formula (I)

(Wherein R ¹ represents an optionally substituted monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated, R ² represents an optionally esterified carboxyl group, and R ³ Represents lower alkyl which may be substituted)
A nucleus containing a compound represented by the formula:
(B) a first layer containing a high molecular weight polymer and covering the nucleus;
(C) A solid pharmaceutical composition comprising pioglitazone hydrochloride and a second layer covering the first layer.   The compound represented by the formula (I) or a salt thereof or a prodrug thereof is 2-ethoxy-1-{[2 ′-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 The composition of claim 1 which is -yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid.   The compound represented by the formula (I) or a salt thereof or a prodrug thereof is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4- A composition according to claim 1, which is yl] methyl} -1H-benzimidazole-7-carboxylate.   The composition according to claim 1, wherein the low melting point oily substance has a melting point of 20 to 90 ° C.   The composition according to claim 1, wherein the low melting point oily substance is an alkylene oxide polymer having a molecular weight of 1,000 to 10,000.   The composition according to claim 1, wherein the high molecular weight polymer has a molecular weight of 2500 to 400,000.   The composition according to claim 1, wherein the high molecular weight polymer is hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone or polyvinyl alcohol, or a mixture of two or more of these polymers.