WO2007126135A1

WO2007126135A1 - Pharmaceutical composition of angiotensin ii antagonists with pioglitazone hcl

Info

Publication number: WO2007126135A1
Application number: PCT/JP2007/059428
Authority: WO
Inventors: Kenichirou Kiyoshima; Kenji Nakamura; Junya Nomura
Original assignee: Takeda Pharmaceutical Company Limited
Priority date: 2006-04-27
Filing date: 2007-04-26
Publication date: 2007-11-08
Also published as: PE20080696A1; CL2007001195A1; JP2009534292A; TW200800299A; AR060663A1

Abstract

The present invention provides a solid pharmaceutical composition containing (a) a core containing a compound represented by the formula (I) wherein R1 is an optionally substituted, monocyclic nitrogen-containing heterocyclic group having an optionally deprotonated hydrogen atom, R2 is an optionally esterified carboxyl group, and R3 is an optionally substituted lower alkyl, or a salt thereof or a prodrug thereof, and a substance like fat and oil having a low melting point, (b) a first layer containing a high molecular weight polymer, which coats the core, and (c) a second layer containing pioglitazone hydrochloride, which coats the first layer.

Description

DESCRIPTION

PHARMACEUTICAL COMPOSITION OF ANGIOTENSIN II ANTAGONISTS WITH PIOGLITAZONE HCL

Technical Field

The present invention relates to a novel solid pharmaceutical composition clinically useful as a prophylactic or therapeutic drug for circulatory diseases such as hypertension, cardiac failure, diabetic nephropathy, arteriosclerosis and the like, and metabolic diseases such as diabetes, metabolic syndrome and the like, which is superior in pharmaceutical properties such as markedly suppressed decomposition of the active ingredient in the preparation and the like.

Background of the Invention

In recent years, in the pharmaceutical development field, the development of combination drug (single pharmaceutical preparation containing plural active ingredients) has been actively undertaken in an attempt to provide a synergistic action in the drug efficacy, reduction of side effects, improved convenience for patients and the 0 like. For example, JP-A-9-67271 describes that a combination drug of a compound having an activity of improving insulin resistance with a compound having an α-glucosidase inhibitory activity, a biguanide compound or the like is useful as a medicament for the prophylaxis or treatment of diabetes. In 5 addition, JP-A-9-323940 describes that a combination drug of a compound having an angiotensin II antagonistic activity with a compound having an activity of improving insulin resistance is useful as a medicament for the prophylaxis or treatment of various angiotensin II-mediated diseases, and WO2006/038722 0 describes that a combination drug of a particular compound having an angiotensin II antagonistic activity with a PPARγ agonist-like substance is useful as a medicament for the prophylaxis or medicament of metabolic syndrome.

As a compound having an angiotensin II antagonistic 5 activity, benzimidazole-7-carboxylic acid derivatives disclosed in JP-A-4-364171, JP-A-5-271228 and the like, particularly, a benzimidazole derivative represented by the formula (I)

wherein

R¹ is an optionally substituted, monocyclic nitrogen- containing heterocyclic group having an optionally deprotonated hydrogen atom, R² is an optionally esterified carboxyl group, and R³ is an optionally substituted lower alkyl, is known to have an extremely potent angiotensin II antagonistic activity, and to be superior as an antihypertensive. However, while the benzimidazole derivative represented by the formula (I) alone in a solid state is stable to temperature, humidity and light, when it is prepared in a solid dosage form together with other preparation ingredients, its decomposition is accelerated to the extent a quality assurance issue may be provoked. Thus, JP-A-5-194218 discloses that the decomposition of a benzimidazole derivative in a solid dosage form can be remarkably suppressed by the addition of an oily substance having a low melting point. In addition, JP-A-7-165580 describes that the decomposition of a benzimidazole derivative in a tablet can be remarkably suppressed by adjusting the density of plain tablet to fall within a particular range. As a compound having an activity of improving insulin resistance, pioglitazone hydrochloride is clinically used as a superior therapeutic medicament for diabetes, and a combination drug of pioglitazone hydrochloride with metformin is also used clinically in recent years. A solid dosage form containing pioglitazone hydrochloride and other active ingredients and a method for forming a preparation thereof are described in JP-A-2004- 149521, JP-A-2004-43478, JP-A-2005-220024 and the like.

A preparation containing a benzimidazole derivative represented by the formula (I) and pioglitazone hydrochloride is effective for the prophylaxis or treatment of not only circulatory diseases such as hypertension, cardiac failure, diabetic nephropathy, arteriosclerosis and the like, but also metabolic diseases such as diabetes, metabolic syndrome and the like, and is clinically extremely highly useful. Therefore, preparation of a combination drug containing the benzimidazole derivative and pioglitazone hydrochloride was studied. However, it was found that a benzimidazole derivative represented by the formula (I) is unstabilized by the pressure, friction, heat and the like during preparation, and coexistence with pioglitazone hydrochloride in a solid dosage form markedly accelerates decomposition of the benzimidazole derivative. To prevent physical contact between a benzimidazole derivative represented by the formula (I) and pioglitazone hydrochloride, therefore, granules containing the benzimidazole derivative and granules containing pioglitazone hydrochloride were independently produced, and these granules were used for the production of tablets and capsules. However, the decomposition of the benzimidazole derivative could not be suppressed sufficiently and practical use thereof was not attainable.

In addition, since the dissolution rate of the active ingredient from a preparation could affect the time course efficacy profile after administration, the composition of the preparation needs to be adjusted to optimize the dissolution rate of the active ingredient for practical use of the preparation. In the case of a combination drug, since optimization of the dissolution rate of each active ingredient is particularly necessary, formulation of combination drug is highly difficult. For example, as a constitution of combination drugs, a preparation wherein a core containing one active ingredient is coated with a layer containing the other active ingredient is known. In general, the dissolution rate of the active ingredient contained in the core becomes slow, which often prevents development of preparations. Thus, the present inventors have conducted intensive studies in an attempt to realize a preparation containing a benzimidazole derivative represented by the formula (I) and pioglitazone hydrochloride, and to sufficiently suppress decomposition of the benzimidazole derivative, wherein an dissolution rate of the active ingredients (the benzimidazole derivative and pioglitazone hydrochloride) can be controlled easily. As a result, they have found that, by coating a core containing the benzimidazole derivative and a substance like fat and oil having a low melting point with the first layer containing a high molecular weight polymer, and further coating the circumference with the second layer containing pioglitazone hydrochloride, the decomposition of the benzimidazole derivative can be unexpectedly suppressed markedly, and the elution rate of the active ingredients can be controlled easily, which resulted in the completion of the present invention.

Summary of the Invention

Accordingly, the present invention relates to: [1] a solid pharmaceutical composition comprising (a) a core comprising a compound represented by the formula (D

wherein

R¹ is an optionally substituted, monocyclic nitrogen- containing heterocyclic group having an optionally deprotonated hydrogen atom,

R² is an optionally esterified carboxyl group, and R³ is an optionally substituted lower alkyl, or a salt thereof or a prodrug thereof (hereinafter simply referred to as "Compound (I)"), and a substance like fat and oil having a low melting point,

(b) a first layer comprising a high molecular weight polymer, which coats the core, and

(c) a second layer comprising pioglitazone hydrochloride, which coats the first layer (hereinafter simply referred to as "the pharmaceutical composition of the present invention") ;

[2] the composition of the above-mentioned [1], wherein the compound represented by the formula (I) or a salt thereof or a prodrug thereof is 2-ethoxy-l-{ [2' - (5-oxo-4, 5-dihydro-l, 2, 4- oxadiazol-3-yl ) biphenyl-4-yl] methyl } -lH-benzimidazole-7- carboxylic acid (compound A) ;

[3] the composition of the above-mentioned [1], wherein the compound represented by the formula (I) or a salt thereof or a prodrug thereof is 1- (cyclohexyloxycarbonyloxy) ethyl 2- ethoxy-1- { [2' - (lH-tetrazol-5-yl) biphenyl-4-yl]methyl }-IH- benzimidazole-7-carboxylate (compound B) ;

[4] the composition of the above-mentioned [1], wherein the melting point of the substance like fat and oil having a low melting point is from 20°C to 90⁰C;

[5] the composition of the above-mentioned [1], wherein the substance like fat and oil having a low melting point is an alkylene oxide polymer having molecular weight of from 1000 to 10000; [6] the composition of the above-mentioned [1], wherein the molecular weight of the high molecular weight polymer is from 2500 to 400000;

[7] the composition of the above-mentioned [1], wherein the high molecular weight polymer is hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone or polyvinyl alcohol, or a mixture of two or more of these polymers, and the like.

The solid pharmaceutical composition of the present invention is explained in detail in the following. The solid pharmaceutical composition of the present invention comprises (a) a core comprising compound (I) and a substance like fat and oil having a low melting point, (b) a first layer comprising a high molecular weight polymer, which coats the core, and (c) a second layer comprising pioglitazone hydrochloride, which coats the first layer. (a) core

The core to be used in the present invention contains compound (I) and a substance like fat and oil having a low melting point. In the aforementioned formula (I), R¹ is an optionally substituted, monocyclic nitrogen-containing heterocyclic group having an optionally deprotonated hydrogen atom and, for example, a tetrazolyl group or a group represented by the formula

wherein i is -0- or -S-, j is >C=O, >C=S or >S(0)m wherein m is 0, 1 or 2) (e.g., 4, 5-dihydro-5-oxo-l, 2, 4-oxadiazol-3-yl group and the like) and the like, which are optionally protected by optionally substituted lower (Ci_₄) alkyl (e.g., methyl, triphenylmethyl, methoxymethyl, acetyloxymethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, pivaloyloxymethyl and the like), acyl group (e.g., lower (C₂-s) alkanoyl, benzoyl and the like) and the like, are preferably used. The 4, 5-dihydro-5-oxo-l,2, 4-oxadiazol-3-yl group contains three tautomers (a', b' and c' ) of the formulas:

a¹ b¹ c¹ and the 4, 5-dihydro-5-oxo-l, 2, 4-oxadiazol-3-yl group includes all of the above-mentioned a' , b' and c' .

In the aforementioned formula (I), R² is an optionally esterified carboxyl group and, for example, a carboxyl group, or a carboxyl group esterified by lower (Ci_₄)alkyl optionally substituted by substituent selected from a hydroxyl group, amino, halogen, lower (C₂-6) alkanoyloxy (e.g., acetyloxy, pivaloyloxy and the like), lower (C₄-7) cycloalkanoyloxy, (lower (Ci-β) alkoxy) carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy and the like) , (lower (C₃-

7) cycloalkoxy) carbonyloxy (e.g., cyclohexyloxycarbonyloxy and the like) and lower (C1-4) alkoxy, (e.g., 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl group) , and the like are used.

In the aforementioned formula (I), R³ is an optionally substituted lower alkyl and, as R³, lower (Ci_₅)alkyl (preferably, lower (C2-3) alkyl) optionally substituted by substituent selected from a hydroxyl group, an amino group, a halogen atom and a lower (C₁-.4) alkoxy group is preferable.

As salts of the compound represented by the formula (I) , pharmaceutically acceptable salts can be mentioned and, for example, salts of a compound represented by the formula (I) with inorganic base, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid and the like can be mentioned. As preferable examples of the salts with inorganic base, for example, alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the like; aluminum salt, ammonium salt and the like can be mentioned. As preferable examples of salts with the organic base, for example, salts with trimethy1amine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'- dibenzylethylenediamine and the like can be mentioned. As preferable examples of the salts with inorganic acid, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned. As preferable examples of the salts with organic acid, for example, salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. As preferable examples of the salts with basic amino acid, for example, salts with arginine, lysine, ornithine and the like can be mentioned, and as preferable examples of the salts with acidic amino acid, for example, salts with aspartic acid, glutamic acid and the like can be mentioned.

A prodrug of the compound represented by the formula (I) or a salt thereof is a compound that converts to the compound represented by the formula (I) or a salt thereof due to the reaction of enzyme, gastric acid or the like under the physiological conditions in the body. That is, a compound that converts to the compound represented by the formula (I) or a salt thereof by enzymatic oxidation, reduction, hydrolysis or the like, and a compound that converts to the compound represented by the formula (I) or a salt thereof by hydrolysis or the like by gastric acid and the like. A prodrug of the compound represented by the formula (I) or a salt thereof is exemplified by a compound wherein an amino group of the compound represented by the formula (I) or a salt thereof is acylated, alkylated, phosphorylated (e.g., compound where amino group of the compound represented by the formula (I) or a salt thereof is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-l, 3-dioxolen-4- yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated or the like) ; compound wherein a hydroxy group of the compound represented by the formula (I) or a salt thereof is acylated, alkylated, phosphorinated, borated (e.g., compound where hydroxy group of the compound represented by the formula (I) or a salt thereof is acetylated, palmitoylated, propanoylated, pivaloylated, succinilated, fumarinated, alanilated, dimethylaminomethylcarbonylated and the like) ; compound wherein a carboxyl group of the compound represented by the formula (I) or a salt thereof is esterified or amidated (e.g., compound where carboxyl group of the compound represented by the formula (I) or a salt thereof is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethy1 esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5- methyl-2-oxo-l, 3-dioxolen-4-yl) methyl esterified, 1- (cyclohexyloxycarbonyoxy) ethyl esterified, methylamidated or the like) or the like. These compounds 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 may be a compound that converts to the compound represented by the formula (I) or a salt thereof under physiological conditions as described in Development of pharmaceutical products, vol. 7, Molecule Design, 163-198, Hirokawa Shoten (1990) .

The compound (I) may be an anhydride or a hydrate. Compound (I) is preferably crystalline and has a melting point of from 100°C to 250°C, particularly from 120°C to 200°C.

As compound (I), the above-mentioned compound A or compound B is preferable. As a crystal .of these compounds, a crystal of compound A having a melting point of 191°C is preferably used, and a crystal of compound B having a melting point of 163°C is preferably used- Compound (I) is contained in the solid pharmaceutical composition of the present invention in a proportion of from 0.01 to 50 wt%, preferably from 0.05 to 40 wt%, more preferably from 0.1 to 30 wt%.

As the substance like fat and oil having a low melting point to be used in the present invention, a substance like fat and oil generally having a melting point of from about 20°C to 90°C, preferably from 20°C to 60°C, is used. Any substance can be used as long as it does not adversely influence the active ingredient. In the production of the pharmaceutical composition of the present invention, the substance like fat and oil having a low melting point can be added uniformly with the active ingredient as compared to a substances like fat and oil having a high melting point and, as a result, a more stable pharmaceutical composition suppressed decomposition and the like of the active ingredient can be obtained. The substance like fat and oil having a low melting point may be water-soluble or insoluble. As used herein, examples of water- soluble substance like fat and oil having a low melting point include the below-mentioned alkylene oxide polymer. As the substance like fat and oil having a low melting point to be used in the present invention, for example, hydrocarbon, higher fatty acid, higher alcohol, fatty acid ester of polyhydric alcohol, higher alcohol ether of polyhydric alcohol, polymer or copolymer of alkylene oxide or the like can be mentioned, of which fatty acid ester of polyhydric alcohol, higher alcohol ether of polyhydric alcohol, polymer or copolymer of alkylene oxide, particularly, a polymer of alkylene oxide, are preferably used.

As hydrocarbon, for example, n-alkane having 17 to 50 carbon atoms such as n-heptadecane, n-octadecane, n-nonadecane, n-eicosane, n-heneicosane, n-docosane, n-tricosane, n- tetracosane, n-pentacosane, n-triacontane, n-pentatriacontane, n-tetracontane, n-pentacontane and the like and mixtures thereof (petrolatum, paraffin wax, macrocrystalline wax etc.) and the like can be mentioned. As the higher fatty acid, for example, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid and a mixture thereof, higher fatty acid recovered from natural fat and oil and the like can be mentioned.

As the higher alcohol, for example, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, arachyl alcohol and a mixture thereof, higher alcohol recovered from natural oil and the like can be mentioned.

As the fatty acid ester of polyhydric alcohol, esters of alcohol having two or more hydroxyl groups in a molecule (e.g., alkylene glycol such as ethylene glycol, propylene glycol and the like, polyalkylene glycols such as polyethylene glycol, polypropylene glycol or copolymers thereof and the like, saccharides such as sorbitol, saccharose and the like, intramolecular dehydrating compound of sorbitol such as 1,5- sorbitan, 1, 4-sorbitol, 3, 6-sorbitan and the like, glycerol, diethanolamine, pentaerythritol and the like) and a fatty acid (e.g., acetic acid, propionic acid, butyric acid, pelargonic acid, capric acid, undecyl acid, lauric acid, tridecyl acid, myristic acid, pentadecyl acid, palmitic acid, heptadecyl acid, stearic acid, nonadecane acid, undecylene acid, oleic acid, elaidic acid, sorbic acid, linolic acid, linolenic acid, arachidonic acid, stearol acid and the like) , specifically, for example, sorbitan fatty acid ester having a molecular weight of from 400 to 900 such as sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan monopalmitate and the like, polyoxyalkylenesorbitan fatty acid ester having a molecular weight of from 1000 to 1500 such as sorbitan polyoxyethylene tristearate, sorbitan polyoxyethylene monooleate, sorbitan polyoxyethylene tripalmitate and the like, polyoxyalkylenesorbitol fatty acid esters such as polyoxyethylenesorbitol hexastearate, polyoxyethylenesorbitol hexaoleate, polyoxyethylenesorbitol tristearate, polyoxyethylene sorbitol tetralaurate and the like, polyoxyalkylenesorbitol beewax derivatives such as polyoxyethylene sorbitol beewax derivative and the like, polyoxyalkylene lanolin derivatives such as polyoxyethylene lanolin derivative and the like, propylene glycol fatty acid esters having a molecular weight of from 200 to 700 such as propylene glycol monopalmitate, propylene glycol monostearate, propylene glycol dilaurate, propylene glycol dimyristate, propylene glycol dipalmitate, propylene glycol distearate and the like, alkylene glycol fatty acid ester such as ethylene glycol fatty acid esters having a molecular weight of from 500 to 1200 such as ethylene glycol monolaurate, ethylene glycol palmitate, ethylene glycol margarate, ethylene glycol stearate, ethylene glycol dilaurate, ethylene glycol dimyristate, ethylene glycol dipalmitate, ethylene glycol dimargarate and the like, and the like, polyoxyalkylene castor oil derivatives having a molecular weight of from 3500 to 4000 such as polyoxyethylene castor oil derivative and the like, polyoxyalkylene fatty acid esters having a molecular weight of from 1900 to 2200 such as polyoxyethylene stearate, polyoxyethylene oleate, polyoxyethylene palmitate, polyoxyethylene linorate and the like, glycerol monofatty acid esters having a molecular weight of from 300 to 600 such as glycerol monoacetate, glycerol monopropionate, glycerol monostearate, glycerol monooleate, glycerol monopalmitate, glycerol monolinorate and the like, sucrose esters of fatty acids having a molecular weight of from 400 to 1300 such as saccharose monolaurate, saccharose monomyristate, saccharose monopalmitate, saccharose monostearate, saccharose trimyristate, saccharose tripalmitate, saccharose tristearate and the like, and the like can be mentioned.

As the higher alcohol ethers of polyhydric alcohol, ethers of polyhydric alcohol (those recited as the alcohol component of the above-mentioned fatty acid ester of polyhydric alcohol) and higher fatty acid alcohol (e.g., cetyl alcohol, stearyl alcohol, oleyl alcohol, octyl alcohol, decyl alcohol) , specifically, for example, polyoxyethylene higher alcohol ethers such as polyoxyethylene lauryl alcohol ether, polyoxyethylene cetyl alcohol ether, polyoxyethylene stearyl alcohol ether, polyoxyethylene oleyl alcohol ether, polyoxyethylene octyl alcohol ether, polyoxyethylene decyl alcohol ether and the like, polyoxypropylenepolyoxyethylene higher alcohol ethers such as polyoxypropylenepolyoxyethylene cetyl alcohol ether, polyoxypropylenepolyoxyethylene stearyl alcohol ether, polyoxypropylenepolyoxyethylene oleyl alcohol ether, polyoxypropylenepolyoxyethylene octylalcohol ether, polyoxypropylenepolyoxyethylene lauryl alcohol ether and the like, and the like are frequently used.

As the polymers of alkylene oxide, those having a molecular weight of from 1,000 to 10,000 (e.g., polyethylene glycol 6000 (Macrogol 6000) ) is preferably used. As the alkylene oxide, for example, ethylene oxide, propylene oxide, trimethylene oxide, tetrahydrofuran and the like (preferably, ethylene oxide) can be mentioned. As the copolymers of alkylene oxide, a copolymer of two or more from the above- mentioned alkylene oxides and having a molecular weight of from 1,000 to 10,000 is preferably used. These substances like fat and oil having a low melting point may be used alone or two or more thereof may be used in combination.

A substance like fat and oil having a low melting point is contained in the pharmaceutical composition of the present invention in a proportion of from 0.005 to 40 wt%, preferably from 0.02 to 30 wt%, more preferably from 0.05 to 15 wt%.

The content ratio of compound (I) and a substance like fat and oil having a low melting point (weight ratio; compound (I) /substance like fat and oil having a low melting point) is from about 0.05 to about 50, preferably from about 0.1 to about 30, more preferably from about 0.2 to about 20, even more preferably from about 0.3 to about 15.

The above-mentioned core may have any shape and size as long as it is a solid that can be coated with the below- mentioned first layer. The core may have any inner structure, and the inside may be uniform or nonuniform. As the core, a solid dosage form (e.g., granule, tablet and the like) that can be produced by forming (granulation, compression and the like) is preferably used and, of these, tablet is preferably used.

The core may further contain an additive conventionally used in the preparation field, and can be produced by a known method. As the additive, for example, excipient, disintegrant, binder, lubricant, coloring agent, pH adjusting agent, surfactant, stabilizer, acidulant, flavoring, glidant and the like can be mentioned. These additives are used in amounts conventionally employed in the preparation field.

As the excipient, for example, starch such as corn starch, potato starch, wheat starch, rice starch, partly pregelatinized starch, pregelatinized starch, porous starch and the like; sugar or sugar alcohols such as lactose, fructose, glucose, mannitol (e.g., D-mannitol) , sorbitol (e.g., D-sorbitol) , erythritol (e.g., D-erythritol) , sucrose and the like: anhydrous calcium phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate and the like can be mentioned.

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

As the binder, for example, crystalline cellulose (e.g., microcrystalline cellulose) , hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic powder and the like can be mentioned. The amount of the binder to be used is preferably from 0.1 to 40 parts by weight, more preferably from 0.5 to 30 parts by weight, per 100 parts by weight of the pharmaceutical composition of the present invention. As preferable examples of the lubricant, for example, magnesium stearate, calcium stearate, talc, sucrose esters of fatty acids, sodium stearyl fumarate and the like can be mentioned.

As the coloring agent, for example, foodcolors such as Food Yellow No. 5, Food Red No. 2, Food Blue No. 2 and the like, food lake colors, ferric oxide and the like can be mentioned.

As the pH adjusting agent, citrate, phosphate, carbonate, tartrate, fumarate, acetate, amino acid salt and the like can be mentioned.

As the surfactant, sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol and the like can be mentioned.

As the stabilizer, for example, tocopherol, tetrasodium edetate, nicotinic acid amide, cyclodextrins and the like can be mentioned.

As the acidulant, for example, ascorbic acid, citric acid, tartaric acid, malic acid and the like can be mentioned.

As the flavoring agent, for example, menthol, peppermint oil, lemon oil, vanillin and the like can be mentioned.

As the glidant, for example, light anhydrous silicic acid, hydrated silicon dioxide and the like can be mentioned.

Two or more kinds of the above-mentioned additives may be used in a mixture in an appropriate ratio. The above-mentioned core is generally produced by admixing the above-mentioned substance like fat and oil having a low melting point with compound (I) and molding the mixture. For admixing, a method generally used for preparations, such as mixing, massing, kneading, sieving, stirring and the like, is employed. For example, a substance like fat and oil having a low melting point may be directly added to the active ingredient and mixed therewith (powder addition) , or a solvent may be added and mixed therewith, and the mixture may be kneaded, granulated and dried by conventional methods. In addition, the admixing may include dissolving a substance like fat and oil having a low melting point in a suitable solvent, uniformly mixing the solution with the active ingredient and performing kneading, granulation, drying (liquid addition) and the like by conventional methods. Moreover, a liquid containing a substance like fat and oil having a low melting point and a liquid containing compound (I) may be separately sprayed on a powder such as excipient and the like to mix them. As a suitable solvent for liquid addition, for example, solvents that do not adversely influence the active ingredient, such as water, dimethylformamide, acetone, ethanol, propyl alcohol, isopropyl alcohol, butyl alcohol, methylene chloride, trichloroethane and the like are used. After the completion of mixing, a tablet containing the active ingredient can be produced by a known compressing means. The compressing means compression under pressurization to give a desired form, and most generally refers to, for example, tableting and the like. By the addition of a substance like fat and oil having a low melting point, distortion and the like of the crystal of compound (I) during kneading, granulation and compressing is considered to be reduced. In the production method of the pharmaceutical composition of the present invention, moreover, the above-mentioned various additives may be added in a suitable step. (b) the first layer The first layer to coat the above-mentioned core in the present invention contains a high molecular weight polymer.

The high molecular weight polymer to be used for the first layer in the present invention may be water-soluble or lipid-soluble, with preference given to water-soluble high molecular weight polymers (e.g., any of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, pullulan and the like or mixture of two or more of them) . Of these, hydroxypropylmethylcellulose is particularly preferable. The molecular weight of a high molecular weight polymer is preferably from 2500 to 400000, more preferably from 3000 to 150000, more preferably from 4000 to 100000. As used herein, the molecular weight of the high molecular weight polymer is a weight average molecular weight of the high molecular weight polymer, specifically a weight average molecular weight as measured by gel permeation chromatography (GPC) . As the method of GPC, for example, the method described in Kobunshi Ronbunshu Vol. 39, part 4, pp. 293-298 (Kato et al.) is used. As the standard substance and detailed measurement conditions, a standard substance and conditions suitable for a measurement target high molecular weight polymer can be appropriately ^'used. The high molecular weight polymer is contained in the first layer in a proportion of from 0.01 to 100 wt%, preferably from 0.1 to 100 wt%, more preferably from 0.5 to 100 wt%.

The above-mentioned first layer may further contain coating additives conventionally employed in the preparation field. As the coating additive, for example, light shielding agent and/or coloring agent such as titanium oxide, talc, ferric oxide and the like; plasticizers such as polyethylene glycol, triethyl citrate, castor oil, polysorbates and the like; organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid and the like; saccharides such as lactose, mannitol (e.g., D-mannitol) , erythritol (e.g., D-erythritol) , sucrose and the like; disintegrants such as low-substituted hydroxypropylcellulose, carmellose calcium, crospovidone and the like; binders such as crystalline cellulose (e.g., microcrystalline cellulose) , hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic powder and the like, and the like can be mentioned.

The above-mentioned core is coated with the first layer according to a known method. For coating, for example, a film coating apparatus is used.

The first layer is applied in a proportion of generally from 1 to 40 parts by weight, preferably from 0.5 to 20 parts by weight, more preferably from 1 to 10 parts by weight, per 100 parts by weight of the core. When the first layer contains not less than 10 parts by weight of saccharides per 1 part by weight of a high molecular weight polymer, the first layer is applied in a proportion of generally from 1 to 100 parts by weight, preferably from 10 to 80 parts by weight, more preferably from 50 to 60 parts by weight, per 100 parts by weight of the core. (c) the second layer

The second layer contains pioglitazone hydrochloride, and covers the first layer.

The second layer may be formed by any method and, for example, is formed to cover the above-mentioned first layer by coating, compressing and the like.

When the second layer is formed by coating, the second layer may contain coating additives conventionally used in the field of preparations. As the coating additive, for example, light shielding agents and/or coloring agents such as titanium oxide, talc, ferric oxide and the like; plasticizers such as polyethylene glycol, triethyl citrate, castor oil, polysorbates and the like; organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid and the like; saccharides such as lactose, mannitol (e.g., D-mannitol), erythritol (e.g., D-erythritol) , sucrose and the like; disintegrants such as low-substituted hydroxypropylcellulose, carmellose calcium, crospovidone and the like; binders such as crystalline cellulose (e.g., microcrystalline cellulose), hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic powder and the like; and the like can be mentioned.

The surface of the core (preferably, tablet) containing compound (I) , which is coated with the above- mentioned first layer, is coated with the second layer according to a known method (e.g., method described in JP-A- 2004-43478, JP-A-2005-220024 and the like, and the like) . For coating, for example, a film coating apparatus is used. The second layer is applied in a proportion of generally from 1 to 80 parts by weight, preferably from 1 to 65 parts by weight, more preferably from 5 to 60 parts by weight, per 100 parts by weight of the core coated with the first layer.

When the second layer is formed by compression, the second layer may further contain coating additives conventionally employed in the preparation field, and can be produced according to a known method. As the additive, conventional additives such as those that may be contained in the core as explained in the above-mentioned (a) and the like are used.

The second layer is formed to achieve a proportion of generally from 1 to 1000 parts by weight, preferably from 10 to 500 parts by weight, more preferably from 25 to 250 parts by weight, per 100 parts by weight of the core coated with the first layer.

Furthermore, the preparation coated with the second layer may be subjected to a further coating (top coating) aiming at an improved strength, coloring and the like of the coated preparation. The coating can be formed using, for example, high molecular weight polymers explained as the high molecular weight polymers to be used for the aforementioned first layer, the coating additives recited as the coating additives optionally contained in the aforementioned first layer and/or second layer and the like, and according to a known method.

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

The pharmaceutical composition of the present invention is advantageous for the design of preparations in that the dissolution rate of pioglitazone hydrochloride from a pharmaceutical composition can be controlled by changing the kind and/or amount of the sugar and/or sugar alcohol, the kind and/or amount of the binder, the kind and/or amount of the disintegrant and the like, which are contained as necessary in the second layer containing pioglitazone hydrochloride, or by changing the content of pioglitazone hydrochloride.

The amount of pioglitazone hydrochloride to be contained in the solid pharmaceutical composition of the present invention is from 0.1 to 40 wt%, preferably from 0.5 to 30 wt%, more preferably from 1 to 20 wt%. Since pioglitazone normalizes the intracellular insulin signal transduction mechanism, which mainly causes insulin resistance, thereby reducing insulin resistance and enhancing insulin action, and has a glucose tolerance improvement action. Therefore, the pharmaceutical composition of the present invention can be used for mammals (e.g., human, monkey, cat, pig, horse, bovine, mouse, rat, guinea pig, dog, rabbit etc.) as an improving agent or an agent for the prophylaxis and/or treatment of the diseases in which insulin resistance is involved. As such diseases, for example, insulin resistance, impaired glucose tolerance; diabetes such as noninsulin dependent diabetes, type II diabetes, type II diabetes associated with insulin resistance, type II diabetes associated with impaired glucose tolerance etc.; various complications such as hyperinsulinemia, hypertension associated with insulin resistance, hypertension associated with impaired glucose tolerance, hypertension associated with diabetes (e.g., type II diabetes etc.), hypertension occurring in association with hyperinsulinemia, insulin resistance occurring in association with hypertension, impaired glucose tolerance occurring in association with hypertension, diabetes occurring in association with hypertension, hyperinsulinemia occurring in association with hypertension, diabetic complications [e.g., microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cataract, large vessel disease, osteopenia, diabetic hyperosmolar coma, infectious diseases (e.g., respiratory infectious disease, urinary tract infectious disease, digestive infectious disease, infectious disease of dermal soft tissue, infectious disease of inferior limb etc.), diabetic gangrene, dry mouth, lowered sense of hearing, diabetic cerebrovascular disorder, diabetic peripheric hematogenous disorder, diabetic hypertension and the like] , diabetic cachexia and the like; and the like can be mentioned. The pharmaceutical composition of the present invention can also be used for treating patients of high normal blood pressure with diabetes.

Since the compound of the formula (I) has a strong angiotensin II antagonistic activity, the pharmaceutical composition of the present invention is useful as an agent for the prophylaxis or treatment of a disease (or a disease whose onset is promoted) developed by the contraction or growth of blood vessels or organ disorder, which expresses via an angiotensin II receptor, or due to the presence of angiotensin II, or a factor induced by the presence of angiotensin II, in mammals (e.g., human, monkey, cat, pig, horse, bovine, mouse, rat, guinea pig, dog, rabbit etc.). As such diseases, for example, hypertension, blood pressure circadian rhythm abnormality, heart diseases (e.g., cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, impaired vasodilation, cardiac myopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, cardiac infarction etc.), cerebrovascular disorders (e.g., asymptomatic cerebrovascular disorder, transient cerebral ischemia, apoplexy, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction etc.), cerebral edema, cerebral circulatory disorder, recurrence and sequela of cerebrovascular disorders (e.g., neurotic symptom, psychic symptom, subjective symptom, disorder in daily living activities etc.), ischemic peripheral circulation disorder, myocardial ischemia, venous insufficiency, progression of cardiac insufficiency after cardiac infarction, renal diseases (e.g., nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic vasculopathy, complication of dialysis, organ dysfunction including nephropathy by radiation damage etc.), arteriosclerosis including atherosclerosis (e.g., aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis etc.), vascular hypertrophy, vascular hypertrophy or obliteration and organ disorders after intervention (e.g., percutaneous transluminal coronary angioplasty, stenting, coronary angioscopy, intravascular ultrasound, dounce thrombolytic therapy etc.), vascular re- obliteration and restenosis after bypass, polycythemia, hypertension, organ disorder and vascular hypertrophy after transplantation, rejection after transplantation, ocular diseases (e.g., glaucoma, ocular hypertension etc.), thrombosis, multiple organ disorder, endothelial dysfunction, hypertensive tinnitus, other cardiovascular diseases (e.g., deep vein thrombosis, obstructive peripheral circulatory disorder, arteriosclerosis obliterans, obstructive thromboangiitis, ischemic cerebral circulatory disorder, Raynaud's disease, Berger' s disease etc.) , metabolic and/or nutritional disorders (e.g., obesity, hyperlipidemia, hypercholesterolemia, hyperuricacidemia, hyperkalemia, hypernatremia etc.), nerve degeneration diseases (e.g., Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, AIDS encephalopathy etc.), central nervous system disorders (e.g., disorders such as cerebral hemorrhage, cerebral infarction etc., and their sequela and complication, head injury, spinal injury, cerebral edema, sensory malfunction, sensory functional disorder, autonomic nervous system disorder, autonomic nervous system malfunction, multiple sclerosis etc.), dementia, defects of memory, disorder of consciousness, amnesia, anxiety symptom, catatonic symptom, discomfort mental state, psychopathies (e.g., depression, epilepsy, alcoholism etc.), inflammatory diseases (e.g., arthritis such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periostitis etc.; inflammation after operation and injury; remission of swelling; pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory intestinal diseases such as Crohn's disease, ulcerative colitis etc.; meningitis; inflammatory ocular disease; inflammatory pulmonary disease such as pneumonia, pulmonary silicosis, pulmonary sarcoidosis, pulmonary tuberculosis etc.), allergic diseases (e.g., allergic rhinitis, conjunctivitis, gastrointestinal allergy, pollinosis, anaphylaxis etc.), chronic obstructive pulmonary disease, interstitial pneumonia, pneumocytis carinni pneumonia, collagen diseases (e.g., systemic lupus erythematosus, scleroderma, polyarteritis etc.), hepatic diseases (e.g., hepatitis including chronic hepatitis, hepatic cirrhosis etc.), portal hypertension, digestive system disorders (e.g., gastritis, gastric ulcer, gastric cancer, gastric disorder after operation, dyspepsia, esophageal ulcer, pancreatitis, colon polyp, cholelithiasis, hemorrhoidal disease, varices ruptures of esophagus and stomach etc.), blood and/or myelopoietic diseases (e.g., erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple myelopathy etc.)_/ bone diseases (e.g., fracture, refracture, osteoporosis, osteomalacia, bone Paget' s disease, sclerosing myelitis, rheumatoid arthritis, osteoarthritis of the knee and joint tissue dysfunction and the like caused by diseases similar to these etc.), solid tumor, tumors (e.g., malignant melanoma, malignant lymphoma, cancer of digestive organs (e.g., stomach, intestine etc.) etc.), cancer and cachexia following cancer, metastasis cancer, endocrinopathy (e.g., Addison' s disease, Cushing' s syndrome, pheochromocytoma, primary aldosteronism etc.), Creutzfeldt-Jakob disease, urinary organ and/or male genital diseases (e.g., cystitis, prostatic hypertrophy, prostatic cancer, sex infectious disease etc.), female disorders (e.g., climacteric disorder, gestosis, endometriosis, hysteromyoma, ovarian disease, breast disease, sex infectious disease etc.), disease relating to environment and occupational factors (e.g., radiation hazard, hazard by ultraviolet, infrared or laser beam, altitude sickness etc.), respiratory diseases (e.g., cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis and pulmonary embolism etc.), infectious diseases (e.g., viral infectious diseases with cytomegalovirus, influenza virus, herpes virus etc., rickettsiosis, bacterial infectious disease etc.), toxemias (e.g., sepsis, septic shock, endotoxin shock, Gram- negative sepsis, toxic shock syndrome etc.), otorhinolaryngological diseases (e.g., Meniere's syndrome, tinnitus, dysgeusia, vertigo, disequilibrium, dysphagia etc.), skin diseases (e.g., keloid, hemangioma, psoriasis etc.), intradialytic hypotension, myasthenia gravis, systemic diseases such as chronic fatigue syndrome and the like can be mentioned.

The pharmaceutical composition of the present invention can be used as an agent for the primary and secondary prophylaxis or treatment of organ disorders associated with various diseases (e.g., cerebrovascular disorder and organ disorder associated therewith, organ disorder associated with cardiovascular disease, organ disorder associated with diabetes, organ disorder after intervention etc.). In particular, since the compound represented by the formula (I) has an activity of inhibiting proteinuria, the pharmaceutical composition of the present invention can be used as an agent for protecting kidney. Therefore, the pharmaceutical composition of the present invention can be advantageously used when the patients with insulin resistance, impaired glucose tolerance, diabetes or hyperinsulinemia have concurrently developed the above-mentioned diseases or clinical condition.

The new criteria were reported about diabetic criteria in 1999 by the Japan Diabetes Society.

According to this report, diabetes is a condition wherein the fasting blood glucose level (glucose concentration of venous plasma) is not less than 126 mg/dl, the 2-hour value (glucose concentration of venous plasma) of the 75 g oral glucose tolerance test (75 g OGTT) is not less than 200 mg/dl, or the casual blood glucose level (glucose concentration of venous plasma) is not less than 200 mg/dl. In addition, a condition which does not fall under the above-mentioned diabetes, and which is not a "condition where the fasting blood glucose level (glucose concentration of venous plasma) is less than 110 mg/dl or the 2-hour value (glucose concentration of venous plasma) of the 75 g oral glucose tolerance test (75 g OGTT) is less than 140 mg/dl" (normal type), is called a "borderline type". In addition, regarding diagnostic criteria for diabetes, new diagnostic criteria were reported by ADA (The American Diabetes Association) in 1997 and by WHO in 1998.

According to these reports, diabetes is a condition where the fasting blood glucose level (glucose concentration in venous plasma) is not less than 126 mg/dl, and the 2-hour value (glucose concentration in venous plasma) of the 75 g oral glucose tolerance test is not less than 200 mg/dl.

In addition, according to the above reports, impaired glucose tolerance is a condition where the fasting blood glucose level (glucose concentration in venous plasma) is less than 126 mg/dl, and the 2-hour value (glucose concentration in venous plasma) of the 75 g oral glucose tolerance test is not less than 140 mg/dl and less than 200 mg/dl. Furthermore, according to the ADA report, a condition where the fasting blood glucose level (glucose concentration in venous plasma) is not less than 110 mg/dl and less than 126 mg/dl, is called IFG (Impaired Fasting Glucose) . On the other hand, according to the WHO report, of the conditions of IFG (Impaired Fasting Glucose) , a condition where the 2-hour value (glucose concentration in venous plasma) of the 75 g oral glucose tolerance test is less than 140 mg/dl, is called IFG (Impaired Fasting Glycemia) .

The pharmaceutical composition of the present invention can be used as an improving agent or an agent for the prophylaxis or treatment of diabetes, borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) as defined by the above- mentioned new diagnostic criteria. Furthermore, the pharmaceutical composition of the present invention can be also used as a therapeutic agent for hypertension of hypertensive patients showing a level not less than the above- mentioned diagnostic criteria (e.g., fasting blood glucose level of 126 mg/dl) . Moreover, the pharmaceutical composition of the present invention can be also used to prevent the progression of the borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.

The pharmaceutical composition of the present invention is effective as a drug for the suppression or improvement of cardiac hypofunction, progression of cardiac remodeling and aggravation of conditions in, or a drug for the suppression of decreased survival rate of, cardiac patients (e.g., cardiac hypertrophy, acute cardiac failure, chronic cardiac failure including congestive cardiac failure, impaired vasodilation, cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, cardiac infarction and the like) with diabetes. In addition, it is effective for the prevention of the onset of a cardiac disease (e.g., cardiac hypertrophy, acute cardiac failure, chronic cardiac failure including congestive cardiac failure , impaired vasodilation, cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, cardiac infarction and the like) and a cerebrovascular disorder (e.g., asymptomatic cerebrovascular disorder, transient cerebral ischemic attack, cerebral apoplexy, cerebrovascular dementia, hypertensive encephalopathia, cerebral infarction and the like) in diabetic patients .

The pharmaceutical composition of the present invention is useful as an agent for the prophylaxis or treatment of metabolic syndrome. Because patients with metabolic syndrome have an extreme high incidence of cardiovascular diseases as compared to patients with single lifestyle-related disease, the prophylaxis or treatment of metabolic syndrome is quite important to prevent cardiovascular diseases. Criteria for diagnosis of metabolic syndrome are announced by WHO in 1999, and by NCEP in 2001. According to the criterion of WHO, patients with at least two of abdominal obesity, dyslipidemia (high TG or low HDL cholesterol) , hypertension in addition to hyperinsulinemia or impaired glucose tolerance are diagnosed as metabolic syndrome (World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Part I: Diagnosis and Classification of Diabetes Mellitus, World Health Organization, Geneva, 1999) . According to the criterion of Adult Treatment Panel III of National Cholesterol Education Program, that is an indicator for managing ischemic heart diseases in America, patients with at least three of abdominal obesity, high triglycerides, low HDL cholesterol, hypertension and impaired glucose tolerance are diagnosed as metabolic syndrome (National Cholesterol Education Program: Executive Summary of the Third Report of National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of 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 treating patients of high blood pressure with metabolic syndrome.

The pharmaceutical composition of the present invention can be used as an anti-inflammatory agent for preventing or treating inflammatory diseases. Examples of inflammatory diseases include inflammatory diseases due to various diseases such as arthritis (e.g., rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis, synovitis) , asthma, allergic diseases, arteriosclerosis including atherosclerosis (aneurysm, coronary sclerosis, cerebral arterial sclerosis, peripheral arterial sclerosis etc.), digestive tract diseases such as inflammatory intestine diseases (e.g., Crohn's disease, ulcerative colitis) , diabetic complications (diabetic nerves disorder, diabetic vascular disorder) , atopic dermatitis, chronic obstructive pulmonary disease, systemic lupus erythematosus, visceral inflammatory diseases (nephritis, hepatitis) , autoimmune hemolytic anemia, psoriasis, nervous degenerative diseases (e.g., Alzheimer's disease, Parkinson's diseases, amyotrophic lateral sclerosis, AIDS encephalopathy) , central nervous disorders (e.g., cerebrovascular disorder such as cerebral hemorrhage and cerebral infarct, head trauma, spinal damage, cerebral edema, multiple sclerosis) , meningitis, angina, cardiac infarct, congestive cardiac failure, vascular hypertrophy or occlusion and organ disorder after intervention (transdermal coronary plasty, stent indwelling, coronary endoscope, intravascular ultrasound, intracoronary thrombolysis etc) , vascular reocculusion or restenosis after bypass operation, endothelial functional disorder, other circulatory diseases (intermittent claudication, obstructive peripheral circulatory disorder, obstructive arteriosclerosis, obstructive thrombotic angitis, ischemic cerebral circulatory disorder, Raynaud's disease, Berger' s disease), inflammatory ocular disease, inflammatory pulmonary diseases (e.g., chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis), endometritis, toxemia (e.g., sepsis, septic shock, endotoxin shock, gram negative sepsis, toxic shock syndrome), cachexia (e.g., cachexia due to infection, carcinomatous cachexia, cachexia due to acquired immunodeficiency syndrome), cancer, Addison's disease,

Creutzfeldt-Jakob disease, virus infection (e.g., infection of virus such as cytomegalovirus, influenza virus, herpes etc.), disseminated intravascular coagulation and the like.

The pharmaceutical composition of the present invention can be also used as an analgesic agent for preventing or treating pain. Examples of pain diseases include acute pain due to inflammation, pain associated with chronic inflammation, pain associated with acute inflammation, pain after operation (pain of incisional, deep pain, organ pain, chronic pain after operation etc.), muscular pain (muscular pain associated with chronic pain disease, shoulder stiffness etc.), arthralgia, toothache, gnathicarthralgia, headache (migraine, catatonic headache, headache associated with fever, headache associated hypertension) , organ pain (cardiac pain, angina pain, abdominal pain, renal pain, ureterane pain, bladder pain) , pain in obstetrics area (mittelschmerz, dysmenorrheal, labor pain) , neuralgia (disc hernia, nerve root pain, neuralgia after herpes zoster, trigeminal neuralgia) , carcinomatous pain, reflex sympathetic atrophy, complex local pain syndrome, and the like. The pharmaceutical composition of the present invention is effective in alleviate directly and rapidly various pains such as nervous pain, carcinomatous pain and inflammatory pain, and exhibits the particularly excellent analgesic effect to patients and pathologies (e.g., hypertension, diabetes, etc. and their complications and the like) in which a pain sense threshold is lowered.

The pharmaceutical composition of the present invention is particularly useful as an analgesic agent for pain associated with chronic inflammation or headache associated with hypertension, or as an agent for preventing or treating inflammatory disease or pain due to (1) arteriosclerosis including atherosclerosis, (2) vascular hypertrophy, occlusion or organ disorder after intervention, (3) reocclusion, restenosis or endothelial functional disorder after bypass operation, (4) intermittent claudication, (5) occlusive peripheral circulatory disorder, or (6) occlusive arteriosclerosis .

For example, the dose of a compound represented by the formula (I) (when administered as a salt or a prodrug of a compound represented by the formula (I), the dose as a compound represented by the formula (I) ) for oral administration to an adult diabetic patient (body weight 60 kg) varies depending on the subject of administration, administration route, target disease, condition and the like. However, the daily dose is from about 0.1 to about 600 mg, preferably from about 0.5 to about 240 mg, more preferably from about 1.0 to about 100 mg, which may be administered at once per day, or administered in 2 or 3 portions.

The daily dose of pioglitazone hydrochloride is from about 0.1 to about 600 mg, preferably from about 0.5 to about 240 mg, more preferably from about 1.0 to about 100 mg, which may be administered at once per day, or administered in 2 or 3 portions.

The compound of the present invention can be used in combination with pharmaceutical agents such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an anti-hyperlipidemia agent, an anti- arteriosclerotic agent, an anti-hypertensive agent, an anti- obesity agent, a diuretic, a chemotherapeutic agent, an immunotherapeutic agent and the like (hereinafter to be abbreviated as a drug for combined use) . In addition, the pharmaceutical composition of the present invention can be used in combination with vaccine preparation such as angiotensin vaccine and the like, or a gene therapy of peripheral arterial obstruction and the like, or a regenerative medicine using embryonic stem cells, and the like. When the pharmaceutical composition of the present invention is used in combination with a drug for combined use, the pharmaceutical composition of the present invention and the drug for combined use may be administered in the form of separate pharmaceutical agents, or formulated in a single combination drug. When they are used in combination as separate pharmaceutical agents, the administration period of the pharmaceutical composition of the present invention and the drug for combined use is not limited, and they may be simultaneously administered to the subject of administration, or administered in a staggered manner. Moreover, the drug for combined use may contain two or more kinds of drugs in an appropriate ratio. The dose of the drug for combined use can be appropriately determined with the dose clinically employed for each pharmaceutical agent as the standard. In addition, the administration ratio of the pharmaceutical composition of the present invention and the drug for combined use can be appropriately determined depending on the subject of administration, administration route, target disease, condition, combination and the like.

As the therapeutic agent for diabetes, for example, insulin preparations (e.g., animal insulin preparations extracted from the bovine or swine pancreas; human insulin preparations synthesized by a genetic engineering technique using E. coli or a yeast, and the like) , α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate etc.), biguanides (e.g., phenforinin, metformin, buformin etc.), insulin secretagogues [e.g., sulfonylureas (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole etc.), repaglinide, senaglinide, nateglinide, mitiglinide or its calcium salt hydrate, GLP-I etc.], amylin agonists (e.g., pramlintide etc.), phosphotyrosine phosphatase inhibitors (e.g., vanadic acid etc.), dipeptidylpeptidase IV inhibitors (e.g., NVP-DPP-278, PT-IOO, P32/98, SYR-322 etc.), β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 etc.), gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist etc.), SGLT (sodium-glucose cotransporter) inhibitors (e.g., T-1095 etc.) and the like can be mentioned.

As the therapeutic agents for diabetic complications, for example, aldose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CT-112 etc.), neurotrophic factors (e.g., NGF, NT-3, BDNF etc.), agents for accelerating generation of neurotrophic factors, PKC inhibitors (e.g., LY-333531 etc.), AGE inhibitors (e.g., ALT946, pimagedine, pyratoxathine, N-phenacylthiazolium bromide (ALT766) , EXO-226 etc.), active oxygen scavengers (e.g., thioctic acid etc.), cerebral vasodilators (e.g., tiapride, mexiletine etc.) and the like can be mentioned.

As the anti-hyperlipidemia agents, for example, statin compounds which are cholesterol synthesis inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, itavastatin or salts thereof (e.g., sodium salt etc.) etc.), squalene synthetase inhibitors (e.g., TAK-475) , fibrate compounds having a triglyceride lowering effect (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate etc.) and the like can be mentioned.

As the anti-arteriosclerotic agents, for example, an acyl-Coenzyme A cholesterol acyltransferase (ACAT) inhibitor (e.g. melinamide, CS-505 etc.), a lipid rich plaque regressing agent (e.g. compounds described in WO 02/06264, WO 03/059900 etc.) and the like can be mentioned.

As the antihypertensive agents, for example, angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril etc.), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine etc.), β-blocker (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol etc.), clonidine and the like can be mentioned.

As the anti-obesity agents, for example, central acting anti-obesity agent (e.g., dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex etc.), pancreatic lipase inhibitors (e.g., orlistat etc.), β3 agonist (e.g., CL- 316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 etc.), anorectic peptides (e.g., leptin, CNTF (ciliary neurotropic factor) etc.), cholecystokinin agonists (e.g., lintitript, FPL-15849 etc.) and the like can be mentioned. As the diuretics, for example, xanthine derivatives (e.g., theobromine and sodium salicylate, theobromine and calcium salicylate etc.), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide etc.), anti-aldosterone preparations (e.g., spironolactone, triamterene etc.), carbonic anhydrase inhibitors (e.g., acetazolamide etc.), chlorobenzenesulfonamide preparations (e.g., chlortalidone, mefruside, indapamide etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like can be mentioned. As the cheiriotherapeutic agents, for example, alkylating agents (e.g., cyclophosphamide, ifosphamide etc.), metabolic antagonists (e.g., methotrexate, 5-fluorouracil etc.), anticancer antibiotics (e.g., mitomycin, adriamycin etc.), plant-derived anticancer agents (e.g., vincristine, vindesine, taxol etc.), cisplatin, carboplatin, etoposide and the like can be mentioned. Of these, furtulon, neofurtulon etc., which are 5-fluorouracil derivatives, and the like are preferable. As the immunotherapeutic agents, for example, microorganism or bacterial components (e.g., muramyl dipeptide derivative, picibanil etc.), polysaccharides having immunostimulant activity (e.g., lenthinan, schizophyllan, krestin etc.), cytokines obtained by genetic engineering techniques (e.g., interferon, interleukin (IL) etc.), colony stimulating factor (e.g., granulocyte-colony stimulating factor, erythropoietin etc.) and the like can be mentioned, with preference given to IL-I, IL-2, IL-12 and the like. Moreover, pharmaceutical agents having a cachexia improving effect acknowledged in animal models and clinical situations, which include cyclooxygenase inhibitors (e.g., indomethacin etc.), progesterone derivatives (e.g., megestrol acetate), glucosteroid (e.g., dexamethasone etc.), metoclopramide pharmaceutical agents, tetrahydrocannabinol pharmaceutical agent (publications are the same as the above) , fat metabolism improving agent (e.g., eicosapentanoic acid etc.), growth hormone, IGF-I, and antibodies against TNF-α, LIF, IL-6 and oncostatin M, which induce cachexia, and the like, can be also used in combination with the pharmaceutical agent of the present invention. When the pharmaceutical composition of the present invention is used in combination with a drug for combined use, the amount of each drug can be reduced within a safe range in consideration of the opposite effect of these drugs. As a result, the side effects possibly caused by the combination of these agents can be prevented safely. In addition, the dose of the drug for combined use can be reduced and, as a result, the side effects possibly caused by the combination drug can be effectively prevented.

As the drug for combined use to be used in combination with the pharmaceutical composition of the present invention, biguanides (e.g., phenformin, metformin, buformin etc.), sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole etc.) and the like are preferable.

The present invention is explained in more detail in the following by referring to Experimental Examples and Examples, which are not to be construed as limitative. In the formulations described as Examples, as the components (additives) other than the active ingredient, those listed in the Japan Pharmacopoeia, the Japan Pharmacopoeia Japanese Pharmaceutical Codex or Japanese Pharmaceutical Excipients and the like can be used. Example 1 Tablets containing compound A (5 mg) and pioglitazone hydrochloride (49.59 mg) per tablet were obtained according to the formulation shown in Table 1.

First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (molecular weight: 7300 - 9300, melting point: 56

- 61°C/ Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give binder liquid 1. Compound A, lactose (Meggle Japan Co., Ltd.) and corn starch (Nihon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulating drier, and the mixture was granulated while spraying the binder liquid 1 thereon in the drier, and the granules were dried in the fluidized bed granulating drier to give granules.

The obtained granules were milled in a power mill grinder, macrocrystalline cellulose (PHlOl, Asahi Kasei Chemicals Corporation) , low-substituted hydroxypropylcellulose (L-HPC-21 Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were added and mixed in a tumbler mixer to give granules for tableting. The obtained granules for tableting were tableted using a rotary tabletting machine and a 9.5 mmφ punch at a weight of 350 mg to give 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 K. K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 15 mg per tablet to give intermediate layer-coated tablets. Then, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 - 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 150 mg per tablet to give active drug layer-coated tablets.

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 10 mg per tablet to give tablets having the formulation of Table 1, containing 5 mg of compound A and 49.59 mg of pioglitazone hydrochloride per tablet .

[Table 1]

Comparative Example 1

Granules containing 5 mg of compound A in 90 mg of granules were produced according to the formulation shown in Table 2.

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.) were dissolved in purified water to give a binder liquid 1, compound A, lactose (Meggle Japan Co., Ltd.) and corn starch (Nihon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying the binder liquid 1 in the drier, and then dried in the fluidized bed granulating drier to give granules containing 5 mg of compound A in 90 mg of granules. [Table 2]

Comparative Example 2

Granules containing 49.59 mg of pioglitazone hydrochloride in 180 mg of granules were produced according to the formulation shown in Table 3.

First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) was dissolved in purified water to give a binder liquid 1, pioglitazone hydrochloride, lactose (Meggle Japan Co., Ltd.) and the half amount of carmellose calcium (Gotoku

Chemical Company Limited) were uniformly mixed in a fluidized bed granulating drier, and the mixture was granulated while spraying the binder liquid 1 in the drier and then dried in the fluidized bed granulating drier to give granules. The obtained granules were milled in a power mill grinder, and the rest of carmellose calcium and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) was added. The mixture was admixed in a tumbler mixer to give granules containing 49.59 mg of pioglitazone hydrochloride in 180 mg of granules.

[Table 3]

Comparative Example 3

Compound A granules (90 mg) of Comparative Example 1 and pioglitazone hydrochloride granules (180 mg) of

Comparative Example 2 were mixed to give mixed granules.

Experimental Example 1

Compound A granules (90 mg) of Comparative Example 1, mixed granules (270 mg) of Comparative Example 3 and the tablet obtained in Example 1 were stored for one month under the conditions of 40°C 75%RH in an open glass bottle, and the increase amount of the ketone form, which is a compound A- derived acid-decompose, was measured. The results are shown in Table 4.

[Table 4]

As shown in Table 4, during storage of mixture of compound A granules added with pioglitazone hydrochloride granules under the conditions of 40°C 75%RH in an open glass bottle for one month, the ketone form, which is a decompose derived from compound A, increased remarkably (mixed granules of Comparative Example 3) . It has been clarified that the solid pharmaceutical composition of the present invention containing pioglitazone hydrochloride together with compound A shows a small increase of the ketone form, and compound A is stabilized.

Example 2

Tablets containing compound A (40 mg) and pioglitazone hydrochloride (16.53 mg) per tablet were obtained according to the formulation shown in Table 5.

First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (average molecular weight: 7300 - 9300, melting point: 56 - 61⁰C, Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give binder solution 1. Compound A, lactose (Meggle Japan Co., Ltd.) and corn starch (Nihon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying the binder solution 1 thereon in the drier, and the granules were dried in the fluidized bed granulating drier to give granules.

The obtained granules were milled in a power mill grinder, macrocrystalline cellulose (PHlOl, Asahi Kasei Chemicals Corporation) , low-substituted hydroxypropylcellulose (L-HPC-21 Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were added and mixed in a tumbler mixer to give granules for tableting. The obtained granules for tableting were tableted using a rotary tabletting machine and a 9.5 mmφ punch at a weight of 350 mg to give 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 K. K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 15 mg per tablet to give intermediate layer-coated tablets.

Then, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 - 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 150 mg per tablet to give active drug layer-coated tablets. Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 10 mg per tablet to give tablets having the formulation of Table 5, containing 40 mg of compound A and 16.53 mg of pioglitazone hydrochloride per tablet.

[ Table 5 ]

Example 3

Tablets containing compound A (20 mg) and pioglitazone hydrochloride (33.06 mg) per tablet were obtained according to the formulation shown in Table 6.

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.) were dissolved in purified water to give binder liquid 1.

Compound A, lactose (Meggle Japan Co., Ltd.) and corn starch (Nihon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying the binder liquid 1 thereon in the drier, and the granules were dried in the fluidized bed granulating drier to give granules .

The obtained granules were milled in a power mill grinder, microcrystalline cellulose (PHlOl, Asahi Kasei Chemicals Corporation) , low-substituted hydroxypropylcellulose (L-HPC-21 Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were added and mixed in a tumbler mixer to give granules for tableting. The obtained granules for tableting were tableted using a rotary tabletting machine and a 9.5 mmφ punch at a weight of 350 mg to give 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 K.K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 15 mg per tablet to give intermediate layer-coated tablets. Then, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 -

50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 150 mg per tablet to give active drug layer-coated tablets.

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd. ) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 10 mg per tablet to give tablets having the formulation of Table 6, containing 20 mg of compound A and 33.06 mg of pioglitazone hydrochloride per tablet. [ Table 6 ]

Example 4 Tablets containing compound A (40 mg) and pioglitazone hydrochloride (33.06 mg) per tablet were produced 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.) were dissolved in purified water to give binder liquid 1.

Compound A, lactose (Meggle Japan Co., Ltd.) and corn starch

(Nihon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying the binder liquid 1 thereon in the drier, and the granules were dried in the fluidized bed granulating drier to give granules.

The obtained granules were milled in a power mill grinder, microcrystalline cellulose (PHlOl, Asahi Kasei Chemicals Corporation) , low-substituted hydroxypropylcellulose

(L-HPC-21 Shin-Etsu Chemical Co., Ltd.) and magnesium stearate

(Taihei Chemical Industrial Co., Ltd.) were added and mixed in a tumbler mixer to give granules for tableting. The obtained granules for tableting were tableted using a rotary tabletting machine and a 9.5 mmφ punch at a weight of 350 mg to give 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 K.K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 15 mg per tablet to give intermediate layer-coated tablets. Then, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 - 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 150 mg per tablet to give active drug layer-coated tablets.

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 10 mg per tablet to give tablets having the formulation of Table 7, containing 40 mg of compound A and 33.06 mg of pioglitazone hydrochloride per tablet .

[Table 7]

Example 5

Tablets containing compound A (20 mg) and pioglitazone hydrochloride (49.59 mg) per tablet were produced 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.) were dissolved in purified water to give binder liguid 1. Compound A, lactose (Meggle Japan Co., Ltd.) and corn starch (Nihon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulating drier, and the mixture was granulated while spraying the binder liquid 1 thereon in the drier, and the granules were dried in the fluidized bed granulating drier to give granules.

The obtained granules were milled in a power mill grinder, macrocrystalline cellulose (PHlOl, Asahi Kasei Chemicals Corporation) , low-substituted hydroxypropylcellulose (L-HPC-21 Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were added and mixed in a tumbler mixer to give granules for tableting. The obtained granules for tableting were tableted using a rotary tabletting machine and a 9.5 mmφ punch at a weight of 350 mg to give 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 K. K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 15 mg per tablet to give intermediate layer-coated tablets.

Then, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 - 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 150 mg per tablet to give active drug layer-coated tablets.

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo

Chemical Industries, Ltd. ) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 10 mg per tablet to give tablets having the formulation of Table 8, containing 20 iαg of compound A and 49.59 mg of pioglitazone hydrochloride per tablet.

[Table 8]

Example 6

Tablets containing compound A (40 mg) and pioglitazone hydrochloride (49.59 mg) per tablet were produced 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.) were dissolved in purified water to give binder liquid 1. Compound A, lactose (Meggle Japan Co., Ltd.) and corn starch (Ninon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying the binder liquid 1 thereon in the drier, and the granules were dried in the fluidized bed granulating drier to give granules. The obtained granules were milled in a power mill grinder, microcrystalline cellulose (PHlOl, Asahi Kasei Chemicals Corporation) , low-substituted hydroxypropylcellulose (L-HPC-21 Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were added and mixed in a tumbler mixer to give granules for tableting. The obtained granules for tableting were tableted using a rotary tabletting machine and a 9.5 mmφ punch at a weight of 350 mg to give 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 K.K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 15 mg per tablet to give intermediate layer-coated tablets.

Then, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 - 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 150 mg per tablet to give active drug layer-coated tablets. Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 10 mg per tablet to give tablets having the formulation of Table 9, containing 40 mg of compound A and 49.59 mg of pioglitazone hydrochloride per tablet.

[Table 9]

Experimental Example 2

The tablets obtained in Examples 2 to 5 and the mixed granules (270 mg) of Comparative Example 3 were moisture-proof packaged, preserved for one month under the conditions of 40°C 75%RH, and the increase amount of the ketone form of compound A-derived acid decompose was measured. The results are shown in Table 10. [ Table 10 ]

As shown in Table 10, when pioglitazone hydrochloride was added to compound A, the ketone form, which is a decompose derived from compound A, increased remarkably by preservation for one month under the conditions of 40°C 75%RH (mixed granules of Comparative Example 3) . In contrast, it has been clarified that the solid pharmaceutical composition of the present invention containing pioglitazone hydrochloride together with compound A shows a small increase of the ketone form, and compound A is stabilized.

Example 7

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

Hydroxypropylmethylcellulose (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo K. K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 14 mg per tablet to 'give intermediate layer-coated tablets. Then, 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 (Merck Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 150 mg per tablet to give active drug layer-coated tablets.

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 5 mg per tablet to give tablets having the formulation of Table 11, containing 49.59 mg of pioglitazone hydrochloride per tablet.

[Table 11]

Example 8

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

Hydroxypropylmethylcellulose (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo K. K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 14 mg per tablet to give intermediate layer-coated tablets.

Then, pioglitazone hydrochloride, low-substituted hydroxypropylcellulose (L-HPC-32, Shin-Etsu Chemical Co., Ltd.), hydroxypropylcellulose (molecular weight: 15000 - 50000 Nippon Soda Co., Ltd.) and erythritol (Nikken Fine Chemical Co., Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 150 mg per tablet to give active drug layer-coated tablets.

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd. ) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 5 mg per tablet to give tablets having the formulation of Table 12, containing 49.59 mg of pioglitazone hydrochloride per tablet. [ Table 12 ]

Example 9

Using plain tablets similar to those obtained in the same manner as in Example 6 and according to the formulation of Table 13, tablets containing 49.59 mg of pioglitazone hydrochloride per tablet were produced.

Hydroxypropylmethylcellulose (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo K.K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 14 mg per tablet to give intermediate layer-coated tablets. Then, 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 (Ensuiko Sugar Refining Co., Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 150 mg per tablet to give active drug layer-coated tablets. Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 5 mg per tablet to give tablets having the formulation of Table 13, containing 49.59 mg of pioglitazone hydrochloride per tablet.

[Table 13]

Experimental Example 3

For the respective tablets obtained in Example 7, Example 8 and Example 9, the dissolution property of pioglitazone hydrochloride was evaluated by the Paddle Methpd (50 rpm) using 0.3 M hydrochloric acid-potassium chloride buffer (900 mL, 37°C, pH 2) . The results are shown in Table 14 [ Table 14 ]

As shown in Table 14, the solid pharmaceutical composition of the present invention could show altered dissolution rate of pioglitazone hydrochloride by changing the kind of the sugar.

Experimental Example 4

For the respective tablets obtained in Example 2, Example 4 and Example 6, the dissolution property of pioglitazone hydrochloride was evaluated by the Paddle Method (75 rpm) using 0.3 M hydrochloric acid-potassium chloride buffer (900 mL, 37°C, pH 2) . The results are shown in Table 15,

[Table 15]

As shown in Table 15, the dissolution rate of the drug could be altered by changing the drug concentration in the preparation. Example 10

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

Hydroxypropylmethylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.), sucrose (Ensuiko Sugar Refining Co., Ltd.) and low-substituted hydroxypropylcellulose (L-HPC-32, Shin-Etsu Chemical Co., Ltd.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 100 mg per tablet to give intermediate layer- coated tablets.

Then, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 - 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 120 mg per tablet to give active drug layer-coated tablets.

Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 5 mg per tablet to give tablets having the formulation of Table 16, containing 49.59 mg of pioglitazone hydrochloride per tablet.

[Table 16]

Example 11

Using the plain tablets obtained in Example 6 and according to the formulation of Table 17, tablets containing 49.59 mg of pioglitazone hydrochloride per tablet were produced. Hydroxypropylmethylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.), sucrose (Ensuiko Sugar Refining Co., Ltd.) and low-substituted hydroxypropylcellulose (L-HPC-32, Shin-Etsu Chemical Co., Ltd.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 100 mg per tablet to give intermediate layer- coated tablets.

Then, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 -

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo • Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 5 mg per tablet to give tablets having the formulation of Table 17, containing 49.59 mg of pioglitazone hydrochloride per tablet.

[Table 17]

Experimental Example 5 For the respective tablets 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. [Table 18]

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

Example 12

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

Hydroxypropylcellulose (average molecular weight: 15000 to 50000 Nippon Soda Co., Ltd.), sucrose (Ensuiko Sugar Refining Co., Ltd.) and low-substituted hydroxypropylcellulose (L-HPC-32, Shin-Etsu Chemical Co., Ltd.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the plain tablets in a coating machine until the weight gain of the tablets increased by 100 mg per tablet to give intermediate layer-coated tablets. Then, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 - 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 150 mg per tablet to give active drug layer-coated tablets.

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 5 mg per tablet to give tablets having the formulation of Table 19, containing 49.59 mg of pioglitazone hydrochloride per tablet.

[Table 19]

Experimental Example 6 For the respective tablets obtained 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 iriL, 37°C, pH 2) . The results are shown in Table 20. [ Table 20 ]

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

Example 13

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

Hydroxypropylmethylcellulose (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo K. K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the plain tablets in a coating machine until the weight gain of the tablets increased by 14 mg per tablet to give intermediate layer-coated tablets. Then, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 -

50000 Nippon Soda Co., Ltd.), D-mannitol (Merck Ltd.) and low- substituted hydroxypropylcellulose (L-HPC-32 Shin-Etsu Chemical Co., Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 150 mg per tablet to give active drug layer-coated tablets.

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 5 mg per tablet to give tablets having the formulations of Tables 21, 22 and 23, containing 49.59 mg of pioglitazone hydrochloride per tablet.

[Table 21]

[ Table 22 ]

[ Table 23 ]

Experimental Example 7

For the respective tablets obtained 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. [Table 24]

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

Example 14

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

Hydroxypropylmethylcellulose (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo K.K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 14 mg per tablet to give intermediate layer-coated tablets. Then, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 -

50000 Nippon Soda Co., Ltd.), erythritol (Nikken Fine Chemical Co., Ltd.) and low-substituted hydroxypropylcellulose (L-HPC- 32 Shin-Etsu Chemical Co., Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 150 mg per tablet to give active drug layer-coated tablets.

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 5 mg per tablet to give tablets having the formulations of Tables 25, 26 and 27, containing 49.59 mg of pioglitazone hydrochloride per tablet.

[Table 25]

[ Table 26 ]

[ Table 27 ]

Experimental Example 8

For the respective tablets obtained 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 altered by changing the amount of the disintegrant in the active drug layer.

Example 15

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

Hydroxypropylmethylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo K. K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the plain tablets in a coating machine until the weight gain of the tablets increased by 15 mg per tablet to give intermediate layer-coated tablets. Then, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 -

50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 225 mg per tablet to give active drug layer-coated tablets.

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylitiethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 15 mg per tablet to give tablets having the formulation of Table 29, containing 40 mg of compound A and 49.59 mg of pioglitazone hydrochloride per tablet.

[Table 29]

Example 16

Using the plain tablets obtained in the same manner as in Example 5 and according to the formulation of Table 30, tablets containing 20 mg of compound A and 49.59 mg of pioglitazone hydrochloride per tablet were produced. Hydroxypropylmethylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo K.K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the plain tablets in a coating machine until the weight gain of the tablets increased by 15 mg per tablet to give intermediate layer-coated tablets.

Then, pioglitazone hydrochloride, hydroxypropylcellulose (average molecular weight: 15000 - 50000 Nippon Soda Co., Ltd.) and D-mannitol (Merck Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 225 mg per tablet to give active drug layer-coated tablets.

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 15 mg per tablet to give tablets having the formulation of Table 30, containing 20 mg of compound A and 49.59 mg of pioglitazone hydrochloride per tablet.

[ Table 30 ]

Example 17

Tablets containing 8 mg of compound B and 33.10 mg of pioglitazone hydrochloride per tablet were obtained according to the formulation shown in Table 31.

First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.), Macrogol 6000 (average molecular weight: 7300 - 9300, melting point: 56 - 61°C, Sanyo Chemical Industries, Ltd.) and yellow dye No. 5 (San-Ei Gen F.F.I., Inc.) were dissolved in purified water to give binder liquid 1. Compound B, lactose (Meggle Japan Co., Ltd.) and corn starch (Nihon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying the binder liquid 1 thereon in the drier, and the granules were dried in the fluidized bed granulating drier to give granules .

The obtained granules were milled in a power mill grinder, carmellose calcium (Gotoku Chemical Company Limited) and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were added and mixed in a tumbler mixer to give granules for tableting. The obtained granules for tableting were tableted using a rotary tabletting machine and a 7.0 mmφ punch at a weight of 130 mg to give plain tablets containing 8 mg of compound B per tablet.

D-mannitol (Merck Ltd.) and hydroxypropylcellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) were dissolved in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 70 mg per tablet to give intermediate layer-coated tablets.

Then, pioglitazone hydrochloride, D-mannitol (Merck Ltd.) and hydroxypropylmethylcellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) were dissolved and suspended in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 100 mg per tablet to give active drug layer-coated tablets.

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) , yellow ferric oxide (Univar/Anstead) and ferric oxide (BASF Japan Ltd.) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 10 mg per tablet to give tablets having the formulation of Table 31, containing 8 mg of compound B and 33.10 mg of pioglitazone hydrochloride per tablet.

Example 18

Tablets containing 4 mg of compound B and 33.10 mg of pioglitazone hydrochloride per tablet were obtained according to the formulation shown in Table 32.

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.) were dissolved in purified water to give binder liguid 1. Compound B, lactose (Meggle Japan Co., Ltd.) and corn starch (Ninon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying the binder liquid 1 thereon in the drier, and the granules were dried in the fluidized bed granulating drier to give granules.

The obtained granules were milled in a power mill grinder, carmellose calcium (Gotoku Chemical Company Limited) and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were added and mixed in a tumbler mixer to give granules for tableting. The obtained granules for tableting were tableted using a rotary tabletting machine and a 7.0 mmφ punch at a weight of 130 mg to give plain tablets containing 4 mg of compound B per tablet.

Then, pioglitazone hydrochloride, D-mannitol (Merck Ltd.) and hydroxypropylcellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) were dissolved in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 100 mg per tablet to give active drug layer- coated tablets.

Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) and yellow ferric oxide (Univar/Anstead) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 10 mg per tablet to give tablets having the formulation of Table 32, containing 4 mg of compound B and 33.10 mg of pioglitazone hydrochloride per tablet. [ Table 32 ]

Example 19

Tablets containing 8 mg of compound B and 16.55 mg of pioglitazone hydrochloride per tablet were obtained according to the formulation shown in Table 33.

First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.), Macrogol 6000 (average molecular weight: 7300 - 9300, melting point: 56 - 61°C, Sanyo Chemical Industries, Ltd.) and yellow dye No. 5 (San-Ei Gen F.F.I., Inc.) were dissolved in purified water to give binder liquid 1. Compound B, lactose (Meggle Japan Co., Ltd.) and corn starch (Ninon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying the binder liquid 1 thereon in the drier, and the granules were dried in the fluidized bed granulating drier to give granules . The obtained granules were milled in a power mill grinder, carmellose calcium (Gotoku Chemical Company Limited) and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were added and mixed in a tumbler mixer to give granules for tableting. The obtained granules for tableting were tableted using a rotary tabletting machine and a 7.0 mmφ punch at a weight of 130 mg to give plain tablets containing 8 mg of compound B per tablet.

D-mannitol (Merck Ltd.) and hydroxypropylcellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd. ) were dissolved in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 70 mg per tablet to give intermediate layer-coated tablets.

Then, pioglitazone hydrochloride, D-mannitol (Merck Ltd.) and hydroxypropylcellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) were dissolved in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 50 mg per tablet to give active drug layer-coated tablets.

Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium .oxide (Freund Corporation) and yellow ferric oxide (Univar/Anstead) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 10 mg per tablet to give tablets having the formulation of Table 33, containing 8 mg of compound B and 16.55 mg of pioglitazone hydrochloride per tablet.

[Table 33]

Example 20

Tablets containing 4 mg of compound B and 16.55 mg of pioglitazone hydrochloride per tablet were obtained according to the formulation shown in Table 34. First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and Macrogol 6000 (molecular weight: 7300 - 9300, melting point: 56 - 61°C, Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give binder liquid 1. Compound B, lactose (Meggle Japan Co., Ltd.) and corn starch (Nihon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying the binder liquid 1 thereon in the drier, and the granules were dried in the fluidized bed granulating drier to give granules.

The obtained granules were milled in a power mill grinder, carmellose calcium (Gotoku Chemical Company Limited) and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were added and mixed in a tumbler mixer to give granules for tableting. The obtained granules for tableting were tableted using a rotary tabletting machine and a 7.0 mmφ punch at a weight of 130 mg to give plain tablets containing 4 mg of compound B per tablet . D-mannitol (Merck Ltd.) and hydroxypropylcellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) were dissolved in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 70 mg per tablet to give intermediate layer-coated tablets.

Then, pioglitazone hydrochloride, D-mannitol (Merck Ltd.) and hydroxypropylcellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) were dissolved in purified water to give coating liquid 2. In a coating machine, coating liquid 2 was sprayed on the obtained intermediate layer-coated tablets until the weight gain of the tablets increased by 50 mg per tablet to give active drug layer-coated tablets. Moreover, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industries, Ltd.) were dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing titanium oxide (Freund Corporation) and yellow ferric oxide (Univar/Anstead) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was ^■ stirred in a stirrer to give coating liquid 3. In a coating machine, coating liquid 3 was sprayed on the obtained active drug layer-coated tablets until the weight gain of the tablets increased by 10 mg per tablet to give tablets having the formulation of Table 34_/ containing 4 mg of compound B and 16.55 mg of pioglitazone hydrochloride per tablet.

[Table 34]

Example 21

Tablets containing 8 mg of compound B and 33.06 mg of pioglitazone hydrochloride per tablet were obtained according to the formulation shown in Table 35.

Hydroxypropylmethylcellulose 2910 (average molecular weight: 19000, Macrogol 6000 (average molecular weight: 7300 to 9300, melting point: 56 to 61°C, Sanyo Chemical Industries, Ltd.) and talc (Matsumura Sangyo K.K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 5 mg per tablet to give intermediate layer-coated tablets . Then, hydroxypropylmethylcellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) was dissolved in purified water to give hydroxypropylmethylcellulose solution 1, dispersion liquid 1 separately obtained by dispersing yellow ferric oxide (Univar/Anstead) and ferric oxide (BASF Japan Ltd. ) in purified water using a dispersion apparatus was added to hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to give binder liquid 2. Pioglitazone hydrochloride, D-mannitol (Merck Ltd.), microcrystalline cellulose (KG-802, Asahi Kasei Chemicals Corporation) and carmellose calcium (Gotoku Chemical Company Limited) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying binder liquid 2 in the drier, and then dried in the fluidized bed granulating drier to give granules. The obtained granules were milled in a power mill grinder, carmellose calcium (Gotoku Chemical Company Limited) and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were added, and the mixture was admixed in a tumbler mixer to give granules for tableting. The obtained tableting granules were tableted with the intermediate layer-coated tablet as an inner core by a nucleated tablet tabletting machine using a

10.0 mmφ punch to give 395 mg nucleated tablets containing 8 mg of compound B and 33.06 mg of pioglitazone hydrochloride per tablet according to the formulation shown in Table 35.

[Table 35]

Example 22

Tablets containing 8 mg of compound B and 16.53 mg of pioglitazone hydrochloride per tablet were obtained according to the formulation shown in Table 36.

First, hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.), Macrogol 6000 (molecular weight: 7300 - 9300, melting point: 56 - 61°C, Sanyo Chemical Industries, Ltd.) and yellow dye No. 5 (San-Ei Gen F.F.I., Inc.) were dissolved in purified water to give binder liquid 1. Compound B, lactose (Meggle Japan Co., Ltd.) and corn starch (Nihon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying the binder liquid 1 thereon in the drier, and the granules were dried in the fluidized bed granulating drier to give granules.

Hydroxypropylmethylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.), Macrogol 6000 (average molecular weight: 7300 to 9300, melting point: 56 to 61°C, Sanyo Chemical Industries, Ltd.) and talc (Matsumura Sangyo K. K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 5 mg per tablet to give intermediate layer-coated tablets.

Then, hydroxypropylmethylcellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) was dissolved in purified water to give binder liquid 2. Pioglitazone hydrochloride, D-mannitol (Merck Ltd.), macrocrystalline cellulose (KG-802, Asahi Kasei Chemicals Corporation) and carmellose calcium (Gotoku Chemical Company Limited) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying binder liquid 2 in the drier, and then dried in the fluidized bed granulating drier to give granules .

The obtained granules were milled in a power mill grinder, carmellose calcium (Gotoku Chemical Company Limited) and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were added, and the mixture was admixed in a tumbler mixer to give granules for tableting. The obtained tableting granules were tableted with the intermediate layer-coated tablet as an inner core by a nucleated tablet tabletting machine using a 10.0 mmφ punch to give 395 mg nucleated tablets containing 8 mg of compound B and 16.53 mg of pioglitazone hydrochloride per tablet according to the formulation shown in Table 36.

[Table 36]

Example 23

Tablets containing 4 mg of compound B and 16.53 mg of pioglitazone hydrochloride per tablet were obtained according to the formulation shown in Table 37. 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.) were dissolved in purified water to give binder liquid 1. Compound B, lactose (Meggle Japan Co., Ltd.) and corn starch (Nihon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying the binder liquid 1 thereon in the drier, and the granules were dried in the fluidized bed granulating drier to give granules .

Hydroxypropylmethylcellulose 2910 (average molecular weight: 19000, TC-5E, Shin-Etsu Chemical Co., Ltd.), Macrogol 6000 (average molecular weight: 7300 to 9300, melting point:56 to 61⁰C, Sanyo Chemical Industries, Ltd.) and talc (Matsumura Sangyo K. K.) were dissolved and suspended in purified water to give coating liquid 1, and coating liquid 1 was sprayed on the obtained plain tablets in a coating machine until the weight gain of the tablets increased by 5 mg per tablet to give intermediate layer-coated tablets.

Then, hydroxypropylmethylcellulose (average molecular weight: 15000 to 50000, Nippon Soda Co., Ltd.) was dissolved in purified water to give binder liquid 2. Pioglitazone hydrochloride, D-mannitol (Merck Ltd.), macrocrystalline cellulose (KG-802, Asahi Kasei Chemicals Corporation) and carmellose calcium (Gotoku Chemical Company Limited) were uniformly mixed in a fluidized bed granulating drier, the mixture was granulated while spraying binder liquid 2 in the drier, and then dried in the fluidized bed granulating drier to give granules.

The obtained granules were milled in a power mill grinder, carmellose calcium (Gotoku Chemical Company Limited) and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were added, and the mixture was admixed in a tumbler mixer to give granules for tableting. The obtained tableting granules were tableted with the intermediate layer-coated tablet as an inner core by a nucleated tablet tabletting machine using a 10.0 mmφ punch to give 395 mg of nucleated tablets containing 4 mg of compound B and 16.53 mg of pioglitazone hydrochloride per tablet according to the formulation shown in Table 37.

[Table 37]

Industrial Applicability

The solid pharmaceutical composition of the present invention is clinically useful as a drug for the prophylaxis or treatment of circulatory diseases such as hypertension, cardiac failure, diabetic nephropathy, arterial sclerosis and the like and metabolic diseases such as diabetes, metabolic syndrome and the like.

This application is based on U.S. provisional application No. 60/795,179, the contents of which are hereby incorporated by reference. All of the references cited herein, including patents, patent applications and publications, are hereby incorporated in their entireties by reference.

Claims

1. A solid pharmaceutical composition comprising

(a) a core comprising a compound represented by the formula

(D

wherein

R² is an optionally esterified carboxyl group, and R³ is an optionally substituted lower alkyl, or a salt thereof or a prodrug thereof, and a substance like fat and oil having a low melting point,

(c) a second layer comprising pioglitazone hydrochloride, which coats the first layer.

2. The composition of claim 1, wherein the compound represented by the formula (I) or a salt thereof or a prodrug thereof is 2-ethoxy-l-{ [2' - (5-oxo-4, 5-dihydro-l, 2, 4-oxadiazol- 3-yl) biphenyl-4-yl]methyl }-lH-benzimidazole-7-carboxylic acid.

3. The composition of claim 1, wherein the compound represented by the formula (I) or a salt thereof or a prodrug thereof is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-l- { [2' - ( lH-tetrazol-5-yl) biphenyl-4-yl] methyl } -lH-benzimidazole-7- carboxylate.

4. The composition of claim 1, wherein the melting point of the substance like fat and oil having a low melting point is from 20°C to 90°C.

5. The composition of claim 1, wherein the substance like fat and oil having a low melting point is an alkylene oxide polymer having a molecular weight of from 1000 to 10000.

6. The composition of claim 1, wherein the molecular weight of the high molecular weight polymer is from 2500 to 400000.

7. The composition of 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.