JP2012525323A - Solid preparation - Google Patents

Abstract

(i) Formula (I):

(Wherein each symbol is as described in the description) or a salt thereof, (ii) a sugar alcohol, and (iii) a calcium antagonist. provide.
[Selection figure] None

Description

  The present invention relates to a solid preparation having improved drug dissolution from a preparation.

[Background of the invention]
Hypertension is one of the most common diseases in adults. According to the Cardiovascular Disease Basic Survey conducted by the Ministry of Health, Labor and Welfare in 2000, 3 million people in Japan have hypertensive patients (people with systolic blood pressure of 140 mmHg or more or those with diastolic blood pressure of 90 mmHg or more). , Up to about 8 million people. Hypertension is a powerful risk factor for all cardiovascular diseases including cerebrovascular disease and myocardial infarction. Therefore, appropriate management of blood pressure is important both in terms of improving patient prognosis and reducing personal and social burdens.

  Various types of antihypertensive drugs such as antihypertensive diuretics, alpha blockers, beta blockers, angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, angiotensin II receptor antagonists have been developed. Many patients diagnosed with hypertension are treated with these antihypertensive drugs. For example, the following formula (I):

(In the formula, R ¹ represents a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated, R ² represents a carboxyl group that may be esterified, and R ³ may be substituted. A compound represented by the following formula: or a salt thereof is known as an angiotensin II receptor antagonist that exhibits an excellent antihypertensive effect and organ protective action. In Patent Document 1, as a typical drug, 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benz Imidazole-7-carboxylate (candesartan cilexetil) is disclosed.

  On the other hand, according to the J-HOME study (The Japan Home vs. Office blood pressure Measurement Evaluation study), among patients with hypertension undergoing drug treatment, the target antihypertensive value (less than 140/90 mmHg blood pressure during outpatient treatment) was achieved. Only about 40% of all patients do this, which means that there are patients whose blood pressure management is still insufficient even with existing medications. In order to improve the achievement rate of the antihypertensive target value, more powerful antihypertensive treatment is required.

  A combination therapy using a plurality of drugs is given as a drug therapy that exhibits a strong antihypertensive effect. For example, Patent Document 2 discloses the combined use of a renin-angiotensin system inhibitor with other antihypertensive drugs, cholesterol lowering drugs, diuretics and the like. Patent Document 3 discloses the combined use of an angiotensin II receptor antagonist and other antihypertensive drugs or statins. However, taking a combination of a plurality of medicines having different dosage timings may lead to a decrease in patient compliance, and there is a concern about inadequate blood pressure control due to forgetting to take. Therefore, for more appropriate blood pressure management, a combination of various antihypertensive drugs formulated as a single drug exerts a strong antihypertensive effect and is an ideal drug that maintains patient compliance. Is strongly sought after.

  As such a combination drug, a combination drug of an angiotensin II receptor antagonist and a calcium antagonist has been proposed. Patent Document 4 discloses a combination drug of an angiotensin II receptor antagonist and other drugs such as diuretics and calcium antagonists. Patent Document 5 discloses a combination drug of an imidazole carboxylate-based angiotensin II receptor antagonist such as olmesartan medoxomil and a calcium antagonist. Patent Document 6 discloses a combination of valsartan, which is an angiotensin II receptor antagonist, and 1,4-dihydropyridine compounds such as amlodipine, which is a calcium antagonist. Patent Document 7 discloses 2-butyl-4-chloro-1-[(2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] imidazole-5, which is an angiotensin II receptor antagonist. A combination of carboxylic acid or a pharmaceutically acceptable salt thereof and diltiazem, which is a calcium antagonist, is disclosed. Patent Document 8 discloses a combination drug of a benzimidazole derivative that is an angiotensin receptor antagonist and a diuretic or a calcium antagonist.

  A preparation containing a benzimidazole derivative that is an angiotensin II receptor antagonist and containing a calcium antagonist has a strong effect on the clinical efficacy of the benzimidazole derivative that is an angiotensin II receptor antagonist with a high organ protecting effect. The efficacy of calcium antagonists with antihypertensive effects can be expected at the same time. In addition, the combination leads to enhancement of action and reduction of side effects, and its clinical usefulness is extremely high.

  However, in order to ensure the effectiveness and safety of pharmaceuticals, not only the efficacy and safety of medicinal ingredients themselves are important, but also the characteristics of the drug product, such as drug dissolution in vivo, are extremely important. . For example, if drug elution from the preparation is too slow, the drug in blood does not reach an effective concentration, and the expected drug effect may not be sufficiently exerted. On the other hand, if drug dissolution from the preparation is too fast, the drug concentration in the blood rises rapidly, increasing the risk of side effects.

  In other words, pharmaceutical products are required to have certain drug dissolution properties in addition to efficacy and safety. In the case of a compounding agent, in addition to the compatibility with various additives, the conditions required for each active ingredient are different, so the development of a preparation having all these conditions may be difficult compared to a preparation containing a single active ingredient. Many. In particular, since a benzimidazole derivative that is an angiotensin II receptor antagonist is a poorly soluble compound, the dissolution property from the preparation may be reduced depending on the properties of the additive and the active ingredient to be blended. Delaying the release of the drug from the administered combination leads to a decrease in drug absorbability and a decrease in bioavailability, that is, a decrease in the efficacy of the active ingredient, thereby reducing the value of the combination. Therefore, in order to put the preparation into practical use, it was necessary to adjust the preparation composition so that the dissolution rate of the active ingredient in the digestive tract was optimized.

Japanese Patent No. 2514282 International Publication No. 01/15674 Pamphlet International Publication No. 02/43807 Pamphlet WO92 / 10097 pamphlet JP 2006-290899 A US Pat. No. 6,204,281 Japanese Patent No. 2930252 Japanese Patent No. 3057471

  Therefore, in the present invention, the benzimidazole derivative having an angiotensin II receptor antagonistic action and a calcium antagonist were stably contained, and the dissolution property of these drugs in the digestive tract was adjusted so as to be optimal. The object is to obtain a solid preparation.

  As a result of intensive studies to solve the above problems, the present inventors have appropriately controlled the dissolution property in the human digestive tract, (i) a compound represented by the formula (I) or a salt thereof, We have found a solid preparation containing (ii) a sugar alcohol and (iii) a calcium antagonist. Specifically, the inventors have found that the drug dissolution from a solid preparation can be improved by paying attention to the excipient and using a sugar alcohol with high water solubility, and have completed the present invention.

That is, the present invention
[1] (i) Formula (I):

(In the formula, R ¹ represents a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated, R ² represents a carboxyl group that may be esterified, and R ³ may be substituted. A solid preparation containing a compound represented by the following formula: or a salt thereof, (ii) a sugar alcohol, and (iii) a calcium antagonist;
[1A] Carbonyl having R ² having a hydroxyl group, an amino group, a halogen atom, a lower alkanoyloxy group having 2 to 6 carbon atoms, a lower cycloalkanoyloxy group having 4 to 7 carbon atoms, or a lower alkoxy group having 1 to 6 carbon atoms 1 to 3 carbon atoms optionally substituted with 1 to 3 substituents selected from an oxy group, a carbonyloxy group having a lower cycloalkoxy group having 3 to 7 carbon atoms, and a lower alkoxy group having 1 to 4 carbon atoms The solid preparation of the above-mentioned [1], which is a carboxyl group optionally esterified with 4 lower alkyl groups;
[1B] The solid preparation according to the above [1], wherein R ² is 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl group or carboxyl group;
[2] The compound represented by the formula (I) or a salt thereof is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4- Yl] methyl] benzimidazole-7-carboxylate, 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylic acid 2-ethoxy-1-[[2 ′-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -1H-benzimidazole A solid preparation according to the above [1], [1A] or [1B], which is a -7-carboxylic acid or a salt thereof;
[3] The compound represented by the formula (I) or a salt thereof is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4- [Il] methyl] benzimidazole-7-carboxylate or a salt thereof, the solid preparation according to [1], [2], [1A] or [1B] above;
[4] The compound represented by the formula (I) or a salt thereof is 2-ethoxy-1-[[2 ′-(4,5-dihydro-5-oxo-1,2,4-oxadiazole-3]. -Yl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylic acid or a salt thereof according to the above [1], [2], [1A] or [1B];
[5] The solid preparation according to any one of [1], [2], [3], [4], [1A] or [1B], wherein the sugar alcohol is mannitol, sorbitol, or erythritol;
[6] The solid preparation according to the above [1], [2], [3], [4], [5], [1A] or [1B], wherein the sugar alcohol is mannitol;
[7] The above [1], [2], wherein the calcium antagonist is azelnidipine, amlodipine, alanidipine, efonidipine, cilnidipine, nicardipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, varnidipine, felodipine, benidipine, manidipine or a salt thereof. , [3], [4], [5], [6], [1A] or [1B]
[8] The above [1], [2], [3], [4], [5], [6], [7], [1A] or [1B], wherein the calcium antagonist is amlodipine or a salt thereof The described solid formulation;
[9] The above [1], [2], [3], [4], [5], [6], [7], [8], [1A] or [1B] further containing polyethylene glycol The described solid formulation;
[10] The solid preparation of the above-mentioned [9], wherein the molecular weight of polyethylene glycol is 1,000 to 10,000;
[11] (i) 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate Or a salt thereof, (ii) mannitol, and (iii) amlodipine or a salt thereof;
[11A] The solid preparation of the above-mentioned [11], further comprising polyethylene glycol;
[11B] The solid preparation according to [11A] above, wherein the molecular weight of polyethylene glycol is 1,000 to 10,000 (preferably 3,000 to 10,000);
[11C] The solid preparation according to [11B] above, wherein the content of polyethylene glycol is 1 to 5% by weight;
[11D] The solid preparation according to [11B] above, wherein the content of polyethylene glycol is 1 to 3% by weight;
[12] (i) 2-Ethoxy-1-[[2 ′-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] A solid preparation containing -1H-benzimidazole-7-carboxylic acid or a salt thereof, (ii) mannitol, and (iii) amlodipine or a salt thereof;
[12A] The solid preparation of the above-mentioned [12], further comprising polyethylene glycol;
[12B] The solid preparation according to the above [12A], wherein the polyethylene glycol has a molecular weight of 1,000 to 10,000 (preferably 3,000 to 10,000);
[12C] The solid preparation according to [12B] above, wherein the content of polyethylene glycol is 1 to 5% by weight;
[12D] The solid preparation according to [12B] above, wherein the content of polyethylene glycol is 1 to 3% by weight;
[13] Tablets, the above [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11 ], [12], [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D]
[14] The above [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], which are monolayer tablets [11], [12], [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D] Formulation;
[15] The above [1], [2], [3], [4], [5], [6], [6], which is a preventive or therapeutic agent for hypertension, heart failure, diabetic nephropathy or arteriosclerosis 7], [8], [9], [10], [11], [12], [13], [14], [1A], [1B], [11A], [11B], [11C] , [11D], [12A], [12B], [12C] or [12D]
[16] The above-mentioned [1], [2], [3], [4], [5], [6], [7], [8], [9], which is a prophylactic or therapeutic agent for hypertension, [10], [11], [12], [13], [14], [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B ], [12C] or [12D] described solid formulation;
Etc.

  According to the present invention, the elution of the compound represented by the above formula (I) or a salt thereof and the calcium antagonist in the gastrointestinal tract is appropriately controlled, and the stability in these formulations is also kept good. A solid formulation can be obtained. That is, the solid preparation of the present invention is excellent in dissolution and stability from the respective preparations of the compound represented by the above formula (I) or a salt thereof and a calcium antagonist.

Detailed Description of the Invention
Below, the solid formulation of this invention is demonstrated in detail.
The solid preparation of the present invention comprises (i) the following formula (I):

(In the formula, R ¹ represents a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated, R ² represents a carboxyl group that may be esterified, and R ³ may be substituted. And a salt thereof, (ii) a sugar alcohol, and (iii) a calcium antagonist (hereinafter also referred to as a solid preparation of the present invention).

In the above formula (I), examples of the monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated represented by R ¹ include a tetrazolyl group,

[Wherein i represents —O— or —S—, and j represents>C═O,> C═S or> S (O) _m (wherein m represents 0, 1 or 2). . ]

Group represented by these. Preferred groups include a tetrazolyl group and a 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group.
The 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group has the formula:

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

In the above formula (I), as the carboxyl group which may be esterified shown by R ^2, for example, carboxyl group which may be esterified with a lower alkyl group having 1 to 4 carbon atoms. The lower alkyl group includes a hydroxyl group, an amino group, a halogen atom, a lower alkanoyloxy group having 2 to 6 carbon atoms (for example, acetyloxy group, pivaloyloxy group, etc.), a lower cycloalkanoyloxy group having 4 to 7 carbon atoms, carbon A carbonyloxy group having a lower alkoxy group of 1 to 6 (for example, methoxycarbonyloxy group, ethoxycarbonyloxy group, etc.), a carbonyloxy group having a lower cycloalkoxy group of 3 to 7 carbon atoms (for example, cyclohexyloxycarbonyloxy) Group), and 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of lower alkoxy groups having 1 to 4 carbon atoms. Preferable groups include 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl group, carboxyl group and the like.

In the above formula (I), the optionally substituted lower alkyl group represented by R ³ is 1 to 5 selected from the group consisting of a hydroxyl group, an amino group, a halogen atom, and a lower alkoxy group having 1 to 4 carbon atoms. A lower alkyl group having 1 to 5 carbon atoms which may be substituted with 1 to 3 (preferably 1 to 3) substituents, and a lower alkyl group having 2 to 3 carbon atoms is preferable, and an ethyl group is particularly preferable. .

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

In addition, the compound represented by the above formula (I) or a salt thereof may be either a hydrate or a non-hydrate, and may be a solvate or a non-solvate. Good.
Furthermore, the compound represented by the above formula (I) or a salt thereof is preferably crystalline and has a melting point of 100 to 250 ° C, particularly 120 to 200 ° C, particularly 130 to 180 ° C. preferable.

  In the solid preparation of the present invention, the compound represented by the above formula (I) or a salt thereof is used. Such compounds or salts thereof include 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7- Carboxylate, 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylic acid, pivaloyloxymethyl 2-ethoxy -1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate, 2-ethoxy-1-[[2'-(4 5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -1H-benzimidazole- 7-carboxylic acid or a salt thereof is exemplified as a preferable one. Among them, 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a salt thereof 2-ethoxy-1-[[2 ′-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -1H-benzimidazole -7-carboxylic acid or a salt thereof is particularly preferable.

  In the present invention, the compound represented by the above formula (I) or a salt thereof is 0.1 to 60% by weight, preferably 1 to 40% by weight in terms of the free form in the solid preparation of the present invention. More preferably 3 to 30% by weight is contained.

  As the sugar alcohol used in the present invention, the compound represented by the above formula (I) or a salt thereof has both the stability in the preparation and the dissolution property from the preparation, and can be applied to pharmaceutical products. Any sugar alcohol may be used. Examples of the sugar alcohol used in the present invention include tetritol (eg, erythritol, D-threitol, L-threitol, etc.), pentitol (eg, D-arabinitol, xylitol, etc.), hexitol (eg, D-iditol, galactitol). (Dulcitol), D-glucitol (sorbitol), mannitol, etc.), monosaccharide sugar alcohols such as cyclitol (eg, inositol, etc.); disaccharide sugar alcohols such as maltitol, lactitol, reduced palatinose (isomalt); pentaerythritol , Oligosaccharide sugar alcohols such as reduced maltose starch syrup, and the like. Among these, monosaccharide sugar alcohols are preferable, and mannitol, sorbitol, or erythritol is more preferable. In particular, mannitol is preferable, and D-mannitol is particularly preferable. The sugar alcohols may be used alone or in combination of two or more. The sugar alcohol also achieves both stability in the preparation and dissolution from the preparation for calcium antagonists.

  In the present invention, the sugar alcohol is contained in the solid preparation of the present invention in an amount of 15 to 85% by weight, preferably 20 to 80% by weight, and more preferably 25 to 75% by weight.

  Examples of calcium antagonists used in the present invention include dihydropyridine compounds such as azelnidipine, amlodipine, alanidipine, efonidipine, cilnidipine, nicardipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, varnidipine, felodipine, benidipine, manidipine; System compounds; and the like. The calcium antagonist used in the present invention includes salts of the compounds mentioned as the calcium antagonist.

  The calcium antagonist used in the present invention is preferably a dihydropyridine compound, particularly amlodipine or a salt thereof, and more preferably an amlodipine salt. Particularly preferred is amlodipine besylate.

  In the present invention, the calcium antagonist is usually 0.05 to 60% by weight, preferably 0.1 to 40% by weight, more preferably 0.5 to 20% in terms of the free form in the solid preparation of the present invention. Contains by weight. Specifically, for example, in the case of amlodipine, it is usually contained in an amount of 0.05 to 60% by weight, preferably 0.1 to 40% by weight, and more preferably 0.5 to 20% by weight in terms of free form.

The solid preparation of the present invention may further contain an alkylene oxide polymer. Examples of the alkylene oxide polymer include polymers of ethylene oxide, propylene oxide, trimethylene oxide, tetrahydrofuran and the like (preferably ethylene oxide). The molecular weight of the alkylene oxide polymer is preferably 1,000 to 10,000, and more preferably 3,000 to 10,000. The alkylene oxide polymer may be a copolymer of alkylene oxide, and examples of the alkylene oxide copolymer include a molecular weight of 1,000 to 10,000 (preferably 3,000 to 10,000). And the copolymer of 2 or more types of the said alkylene oxide is mentioned.
The said alkylene oxide polymer may be used independently, or may use 2 or more types together.

  The alkylene oxide polymer used in the present invention is preferably polyethylene glycol, more preferably polyethylene glycol having a molecular weight of 1,000 to 10,000, and polyethylene glycol having a molecular weight of 3,000 to 10,000 (eg, polyethylene glycol 4000, polyethylene). Glycol 6000 and polyethylene glycol 10000) are particularly preferred.

  In the present invention, the alkylene oxide polymer is preferably contained in the solid preparation of the present invention in an amount of 1 to 5% by weight, more preferably 1 to 3% by weight.

As a preferred embodiment of the solid preparation of the present invention,
The compound represented by the above formula (I) or a salt thereof is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl. ] A solid preparation which is benzimidazole-7-carboxylate (hereinafter sometimes referred to as “compound A”) or a salt thereof, and the calcium antagonist is amlodipine besylate;
The compound represented by the above formula (I) or a salt thereof is 2-ethoxy-1-[[2 ′-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl). Biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylic acid (hereinafter sometimes referred to as “compound B”) or a salt thereof, and a solid preparation in which the calcium antagonist is amlodipine besylate;
Etc.

  Examples of the solid preparation of the present invention include solid preparations suitable for oral administration such as tablets, granules, fine granules, capsules, pills, etc. Among them, tablets are preferable, and monolayer tablets are more preferable. When the solid preparation of the present invention is a tablet, the shape of the tablet may be round, oval, oblong or the like. The size of the tablet varies depending on the shape of the tablet (round shape, caplet shape, oblong shape, etc.), but may be any size that can be easily taken by the patient. When the solid preparation of the present invention is a monolayer tablet, the tablet size is small and easy to take.

As an aspect of the solid preparation in the present invention,
(1) One-group granulated preparation: Compound represented by formula (I) or a salt thereof, sugar alcohol, and calcium antagonist (preferably a compound represented by formula (I) or a salt thereof, sugar alcohol, calcium antagonist , And polyethylene glycol), and a solid preparation (eg, one-group granulated monolayer tablet) obtained by compression molding the resulting granulated product;
(2) Two-group granulated preparation (a) Solid preparation obtained by mixing and compression-molding the following first part and second part obtained by granulating individually (eg, two groups) Granulated monolayer tablets);
(B) a solid preparation (eg, laminated tablet) obtained by compression molding without mixing the following first part and second part obtained by granulating each separately;
(C) In the following first part and second part obtained by granulating individually, a solid preparation (eg, dry-coated tablet) obtained by coating one part with the other part;
First part: a part containing a compound represented by the formula (I) or a salt thereof (preferably a part containing a compound represented by the formula (I) or a salt thereof and polyethylene glycol)
Second part: a part containing a sugar alcohol and a calcium antagonist, and the like.
As a preferable embodiment of the solid preparation in the present invention, one group granulated preparation (eg, one group granulated monolayer tablet) is exemplified.

  The solid preparation of the present invention may contain additives commonly used in the pharmaceutical field. Examples of the additive include an excipient, a disintegrant, a binder, a lubricant, a pH adjuster, a colorant, a surfactant, a stabilizer, a sour agent, a fragrance, and a fluidizing agent. These additives are used in amounts conventionally used in the pharmaceutical field. Moreover, you may mix these additives in 2 or more types in a suitable ratio.

  Examples of excipients include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch, sugars such as lactose, fructose, glucose, and sucrose, anhydrous Examples include calcium phosphate, crystalline cellulose, microcrystalline cellulose, licorice powder, sodium hydrogen carbonate, calcium phosphate, calcium sulfate, calcium carbonate, precipitated calcium carbonate, calcium silicate, and the like.

Examples of the disintegrant include amino acids, starch, corn starch, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethyl starch, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxy Propyl starch or the like is used.
In the present invention, the disintegrant is preferably contained in the solid preparation of the present invention in an amount of 0.1 to 30% by weight, more preferably 1 to 10% by weight.

Examples of the binder include crystalline cellulose (eg, microcrystalline cellulose), hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, gelatin, starch, gum arabic powder, tragacanth, carboxymethylcellulose, sodium alginate, pullulan, glycerin and the like.
In the present invention, the binder is preferably contained in the solid preparation of the present invention in an amount of 0.1 to 40% by weight, more preferably 1 to 10% by weight.

  Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, talc (purified talc), sucrose fatty acid ester, sodium stearyl fumarate and the like.

  Examples of the pH adjuster include citric acid or a salt thereof, phosphoric acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, fumaric acid or a salt thereof, acetic acid or a salt thereof, an amino acid or a salt thereof, and the like.

  Examples of the colorant include edible pigments such as edible yellow No. 5, edible red No. 2 and edible blue No. 2, edible lake pigments such as edible yellow No. 4 aluminum lake, ferric oxide, yellow ferric oxide, Examples thereof include iron oxide pigments such as triiron tetroxide (black iron oxide).

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

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

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

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

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

  The solid preparation of the present invention can be film-coated with a coating base, a coating additive or the like to form a film coating preparation. Examples of the film coating preparation include sugar coating, sustained release preparation, enteric preparation and the like.

  Preferable examples of the coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base and the like.

  Sucrose is used as the sugar coating base. Furthermore, one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.

  Examples of the water-soluble film coating base include hydroxypropylcellulose [eg, NISSO HPC (grade: L, SL, SL-T, SSL) (trade name); manufactured by Nippon Soda Co., Ltd.], hypromellose [eg, TC- 5 (grade: MW, E, EW, R, RW) (trade name); manufactured by Shin-Etsu Chemical Co., Ltd.], cellulosic polymers such as hydroxyethyl cellulose and methyl hydroxyethyl cellulose, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [ Eudragit E (trade name); manufactured by Rohm and Haas], synthetic polymers such as polyvinylpyrrolidone, polysaccharides such as pullulan, and the like.

  Examples of enteric film coating bases include cellulosic polymers such as hypromellose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate, methacrylic acid copolymer L [Eudragit L (trade name) )], Acrylic polymer such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name); manufactured by Rohm and Haas], methacrylic acid copolymer S [Eudragit S (trade name); manufactured by Rohm and Haas], And natural polymers such as shellac.

  Examples of the sustained-release film coating base include cellulose polymers such as ethyl cellulose, aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name); manufactured by Rohm and Haas Co., Ltd.], ethyl acrylate / methyl methacrylate copolymer Examples thereof include acrylic polymers such as suspension [Eudragit NE (trade name); manufactured by Rohm and Haas].

  Preferable examples of the coating additive include a light shielding agent such as titanium dioxide, a fluidizing agent such as talc, a colorant such as iron sesquioxide and yellow sesquioxide, polyethylene glycol [eg, Macrogol 6000 (trade name); Sanyo Chemical Industries, Ltd.], plasticizers such as triethyl citrate, castor oil, polysorbates, and organic acids such as citric acid, tartaric acid, malic acid, and ascorbic acid.

  The solid preparation of the present invention can be produced by a method known per se (for example, a method described in the 15th revised Japanese Pharmacopoeia General Rules for Preparations).

  Examples of such a method include operations such as mixing, kneading, granulation, compression molding, and film coating, or an appropriate combination of these operations.

  Mixing is performed using a mixer such as a horizontal cylindrical mixer, V-type mixer, or tumbler mixer, and kneading is performed using a rotating container-type kneader such as a ball mill, a fixed container such as a screw-type kneader or a Henschel mixer. This is carried out using a roll kneading apparatus such as a mold kneading apparatus, a roll mill, or a taper roll mill. In addition, the granulation is performed by agitation granulation using a stirring granulation method using a high speed agitation type granulator, a pan type, a conical drum type, a multistage conical drum type, a drum type with stirring blades, a vibration type, etc. Or a fluidized bed granulation drying method, a spray drying granulation method, an extrusion granulation method, or a method using a granulator such as a roller compactor.

The compression molding is performed by, for example, molding with an extrusion molding machine or tableting with a single-shot tableting machine, a rotary tableting machine, or the like.
In addition, when compression molding is performed using a single-shot tablet machine, a rotary tableting machine, etc., it is usually preferable to employ a tableting pressure of 1 to 35 kN / cm ² (preferably 5 to 35 kN / cm ² ). Furthermore, it is preferable to use a tapered die for the purpose of preventing capping.

  Film coating includes, for example, pan coating apparatuses such as horizontal and inclined types, fluidized coating apparatuses such as horizontal rotating disk types and inclined dish types, and fluidized coating apparatuses such as fluidized bed type, spouted bed type, and fluidized rolling type. It is done using.

The solid preparation of the present invention can be produced, for example, according to the following production steps.
(1) When the solid preparation of the present invention is a one-group granulated preparation;
A compound represented by the above formula (I) or a salt thereof, a sugar alcohol, and a calcium antagonist (preferably a compound represented by the formula (I) or a salt thereof, a sugar alcohol, a calcium antagonist, and polyethylene glycol) The mixture containing is granulated, and the resulting granulated product is compression-molded to obtain a solid preparation (eg, a group of granulated monolayer tablets) of the present invention.
More specifically, the compound represented by the above formula (I) or a salt thereof and a calcium antagonist are mixed with an additive such as an excipient and a sugar alcohol (eg, D-mannitol), and then mixed with polyethylene glycol. And an additive such as a binder in a solvent (e.g., water) dispersed or dissolved, and granulated while spraying.
Additives such as a disintegrant and a lubricant are added to the granulated product thus obtained, and after mixing, compression molding is performed to obtain a tablet. The tablet is coated with a film solution containing a coating base or the like. In this way, the solid preparation (one-group granulated monolayer tablet) of the present invention is produced.

(2) When the solid preparation of the present invention is a two-group granulated preparation;
(A) two-group granulated monolayer tablets;
After mixing the compound represented by the above formula (I) or a salt thereof with additives such as excipients, the mixture was dispersed or dissolved in polyethylene glycol and an additive such as a binder in a solvent (eg, water). Granulate while spraying the liquid.
On the other hand, after mixing a calcium antagonist with an additive such as an excipient and a sugar alcohol (eg, D-mannitol), a liquid in which an additive such as a binder is dispersed or dissolved in a solvent (eg, water) is added to the mixture. Granulate while spraying.
After adding an additive such as a disintegrant and a lubricant to the granulated product containing the compound represented by the above formula (I) or a salt thereof obtained as above and a granulated product containing a calcium antagonist, and after mixing The solid preparation (two-group granulated monolayer tablet) of the present invention is produced by compression molding.
(B) laminated tablets;
After mixing the compound represented by the above formula (I) or a salt thereof with additives such as excipients, the mixture was dispersed or dissolved in polyethylene glycol and an additive such as a binder in a solvent (eg, water). Granulate while spraying the liquid. Add additives such as disintegrants and lubricants to the resulting granulated product to obtain a mixed powder.
On the other hand, after mixing a calcium antagonist with an additive such as an excipient and a sugar alcohol (eg, D-mannitol), a liquid in which an additive such as a binder is dispersed or dissolved in a solvent (eg, water) is added to the mixture. Granulate while spraying. Add additives such as disintegrants and lubricants to the resulting granulated product to obtain a mixed powder.
The solid powder (laminate) of the present invention is obtained by stacking the mixed powder containing the compound represented by the above formula (I) or a salt thereof obtained in this way and the mixed powder containing a calcium antagonist in a layered manner and compression molding. Tablet).
(C) dry-coated tablets;
After mixing the calcium antagonist with an excipient and an additive such as sugar alcohol (eg, D-mannitol), the mixture is sprayed with a solution in which an additive such as a binder is dispersed or dissolved in a solvent (eg, water). While granulating. Additives such as a disintegrant and a lubricant are added to the resulting granulated product, and after mixing, compression molding is performed to obtain a tablet. The tablet is coated with a film solution containing a coating base or the like to obtain an inner core tablet.
On the other hand, after mixing the compound represented by the above formula (I) or a salt thereof with an additive such as an excipient, the mixture is dispersed with an additive such as polyethylene glycol and a binder in a solvent (eg, water) or Granulate while spraying the dissolved liquid. Add additives such as disintegrants and lubricants to the resulting granulated product to obtain a mixed powder.
The mixed powder is blended into the inner core tablet as an outer layer and compression molded to produce the solid preparation (nucleated tablet) of the present invention.

  When the solid preparation of the present invention is a granule or a fine granule, it can be produced by the same method as described above.

  When the solid preparation of the present invention is a capsule, it can be produced by filling the above granules or fine granules into a capsule containing gelatin, hypromellose and the like. Furthermore, a hard capsule is prepared by filling a capsule containing gelatin, hypromellose, etc. together with a sugar alcohol, other excipients, etc., with the compound represented by the above formula (I) or a salt thereof and a calcium antagonist. In addition, a soft capsule is obtained by encapsulating the compound represented by the above formula (I) or a salt thereof and a calcium antagonist in a certain shape with a base obtained by adding a plasticizer such as glycerin to gelatin. Can be manufactured.

  The surface of the solid preparation of the present invention may be marked with a mark for identification and printed with characters. Further, a dividing line for division may be attached.

  The solid preparation of the present invention has low toxicity and can be safely administered orally or parenterally as a pharmaceutical for mammals (eg, humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits, etc.). Can be administered.

  Since the compound represented by the formula (I) or a salt thereof has a strong angiotensin II receptor antagonistic action, the solid preparation of the present invention can be used for (1) angiotensin II receptor via the angiotensin II receptor. Disease that develops due to contraction or proliferation of blood vessels that develop or organ damage (or disease that is accelerated), (2) Disease that develops due to the presence of angiotensin II (or disease whose development is accelerated), or (3) Angiotensin It is useful as a preventive or therapeutic agent for a disease (or a disease whose onset is accelerated) caused by a factor induced by the presence of II.

  Examples of the diseases (1) to (3) include hypertension, abnormal blood pressure diurnal variation, heart disease (eg, cardiac hypertrophy, acute heart failure, chronic heart failure including heart failure, diastolic failure, cardiomyopathy, angina, Myocarditis, atrial fibrillation, arrhythmia, tachycardia, myocardial infarction, etc.), cerebrovascular disorder (eg, asymptomatic cerebrovascular disorder, transient ischemic attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, brain Infarction, etc.), cerebral edema, cerebral circulatory disorder, recurrence and sequelae of cerebrovascular disorder (eg, neurological symptoms, psychiatric symptoms, subjective symptoms, impaired daily activities), ischemic peripheral circulatory disorder, myocardial ischemia, venous dysfunction , Progression of heart failure after myocardial infarction, kidney disease (eg, nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, diabetic nephropathy, complications of dialysis, nephropathy due to radiation) Organ damage), arteriosclerosis including atherosclerosis (eg arteries) , Coronary atherosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular thickening, intervention (eg, percutaneous coronary angioplasty, stent placement, coronary endoscopy, intravascular ultrasound, coronary thrombolysis) Etc.) After vascular thickening or occlusion and organ damage, vascular re-occlusion / restenosis after bypass surgery, erythrocytosis / hypertension / organ damage / vascular thickening after transplantation, rejection after transplantation, eye disease (eg, glaucoma) ), Thrombosis, multiple organ failure, endothelial dysfunction, hypertensive tinnitus, and other cardiovascular diseases (eg, deep vein thrombosis, obstructive peripheral circulatory disorder, obstructive arteriosclerosis, obstructive) Thrombotic vasculitis, ischemic cerebral circulatory disorder, Raynaud's disease, Buerger's disease, etc.), metabolic and / or nutritional disorders (eg obesity, hyperlipidemia, hypercholesterolemia, hyperuricemia, hyperkalemia) Hypernatremia, etc. , Neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy), central nervous system disorders (eg, cerebral hemorrhage and cerebral infarction, etc. Spinal cord injury, brain edema, senile dementia, sensory dysfunction, sensory dysfunction, autonomic dysfunction, autonomic dysfunction, multiple sclerosis, etc.), dementia, memory impairment, consciousness disorder, amnesia, anxiety symptoms , Tension symptoms, uncomfortable mental state, mental illness (eg, depression, epilepsy, alcoholism, etc.), inflammatory diseases (eg, rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periosteitis, etc.) Inflammation after trauma; remission of swelling; sore throat; cystitis; pneumonia; atopic dermatitis; inflammatory bowel disease such as Crohn's disease, ulcerative colitis; meningitis; inflammatory eye disease; pneumonia, silicosis, lung sarcoidosis ), Allergic diseases (eg, allergic rhinitis, conjunctivitis, gastrointestinal allergy, hay fever, anaphylaxis), chronic obstructive pulmonary disease, interstitial pneumonia, carini pneumonia, collagen disease ( Eg, systemic lupus erythematosus, scleroderma, polyarteritis), liver disease (eg, chronic hepatitis, cirrhosis, etc.), portal hypertension, gastrointestinal disease (eg, gastritis, gastric ulcer, gastric cancer, gastric surgery) Post-injury, dyspepsia, esophageal ulcer, pancreatitis, colon polyp, cholelithiasis, hemorrhoid disease, esophageal or gastric varicose rupture, etc., blood and / or hematopoietic disease (eg, erythrocytosis, vascular purpura, self Immune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple myelosis, etc.), bone disease (eg, fracture, re-fracture, osteoporosis, osteomalacia, Paget's disease, ankylosing myelitis, rheumatoid arthritis, deformity) Knee osteoarthritis and Joint tissue destruction in these similar diseases), solid tumors, tumors (eg, malignant melanoma, malignant lymphoma, gastrointestinal (eg, stomach, intestine, etc.) cancer), cancer and associated cachexia, cancer Metastases, endocrine disorders (eg, Addison's disease, Cushing syndrome, pheochromocytoma, hyperaldosteronism, primary aldosteronism, etc.), Creutzfeldt-Jakob disease, urinary and / or male genital diseases (eg, cystitis, benign prostatic hyperplasia) , Prostate cancer, sexually transmitted diseases, etc.), gynecological diseases (eg, menopause, pregnancy poisoning, endometriosis, uterine fibroids, ovarian diseases, breast diseases, sexually transmitted diseases, etc.), diseases caused by environmental and occupational factors ( E.g. radiation damage, UV / infrared / laser beam damage, altitude sickness, etc., respiratory disease (eg, cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombus / pulmonary embolism, etc.), infection (eg, site) Viral infections such as gallovirus, influenza virus, herpes virus, rickettsial infection, bacterial infection, etc.), toxicemia (eg, sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxin shock syndrome, etc.) , ENT disorders (eg, Menuel syndrome, tinnitus, taste disorder, dizziness, balance disorder, dysphagia), skin disorders (eg, keloid, hemangioma, psoriasis), dialysis hypotension, myasthenia gravis, chronic fatigue Examples include systemic diseases such as syndromes.

  The solid preparation of the present invention combines the compound represented by the formula (I) or a salt thereof and a calcium antagonist to prevent or treat the above diseases (preferably hypertension, heart failure, diabetic nephropathy, arteries). It is useful as a preventive or therapeutic agent for sclerosis, more preferably as a prophylactic or therapeutic agent for hypertension). In addition, the solid preparation of the present invention can reduce the dose of the compound represented by the formula (I) or a salt thereof and a calcium antagonist, as compared with the case where it is used alone.

  The dose of the compound represented by the formula (I) or a salt thereof varies depending on the administration subject, administration route, target disease, symptom, etc., but in the case of a human adult (body weight 60 kg), the daily dose is free. In terms of body, it is about 0.05 to 500 mg, preferably 0.1 to 100 mg, more preferably 1 to 100 mg, and still more preferably 2 to 40 mg. For example, Compound A is about 1 to 80 mg, preferably 2 to 32 mg per day for a human adult (weight 60 kg), and Compound B is about 1 to 80 mg for human adult (weight 60 kg). The daily dose is about 1-50 mg, preferably 10-40 mg.

  The dose of calcium antagonist varies depending on the administration subject, administration route, target disease, symptom, and the like. For example, in the case of a human adult (body weight 60 kg), the daily dose is a free substance. It is about 1 to 50 mg, preferably 2.5 to 10 mg in terms of.

  The frequency of administration of the solid preparation of the present invention to the mammal is preferably 1 to 3 times a day, more preferably once a day.

As a particularly preferred specific example of the solid preparation of the present invention,
"A single-layer tablet containing 8 mg of Compound A and 6.93 mg of amlodipine besylate (5 mg as amlodipine) per tablet";
"Monolayer tablet containing 8 mg of compound A and 3.47 mg of amlodipine besylate (2.5 mg as amlodipine) per tablet";
"Monolayer tablet containing 4 mg of compound A and 6.93 mg of amlodipine besylate (5 mg as amlodipine) per tablet";
"A single-layer tablet containing 4 mg of Compound A and 3.47 mg of amlodipine besylate (2.5 mg as amlodipine) per tablet";
"Monolayer tablet containing 40 mg of Compound B and 6.93 mg of amlodipine besylate (5 mg as amlodipine) per tablet";
"Monolayer tablet containing 40 mg of Compound B and 3.47 mg of amlodipine besylate (2.5 mg as amlodipine) per tablet";
"Monolayer tablet containing 20 mg of Compound B and 6.93 mg of amlodipine besylate (5 mg as amlodipine) per tablet";
"Monolayer tablet containing 20 mg of compound B and 3.47 mg of amlodipine besylate (2.5 mg as amlodipine) per tablet";
"Monolayer tablet containing 10 mg of compound B and 6.93 mg of amlodipine besylate (5 mg as amlodipine) per tablet";
"Monolayer tablet containing 10 mg of compound B and 3.47 mg of amlodipine besylate (2.5 mg as amlodipine) per tablet";
Is mentioned.

  The solid preparation of the present invention can be used in combination with one or more other types of drugs (hereinafter sometimes abbreviated as “concomitant drugs”). Examples of the “concomitant drug” include a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an anti-obesity agent, a diuretic, and an antithrombotic agent.

  Here, as a therapeutic agent for diabetes, for example, insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast; insulin zinc; protamine insulin zinc An insulin fragment or derivative (eg, INS-1), an oral insulin preparation), an insulin sensitizer (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof; (Preferably maleate), metaglidasen, AMG-131, balaglitazone, MBX-2044, riboglitazone, aleglitazar, agliglitazar, chiglitazar, lobeglitazone , PLX-204, PN-2034, GFT-505, THR-0921, WO2007 / 013694, WO2007 / 018314 , Compounds described in WO2008 / 093639 or WO2008 / 099794), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate), biguanides (eg, metformin) ), Buformin or a salt thereof (eg, hydrochloride, fumarate, succinate)), insulin secretagogue (eg, sulfonylurea (eg, tolbutamide, glibenclamide), gliclazide ( gliclazide), chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole), repaglinide, Nateglinide, mitiglinide or its calcium salt hydrate), dipipe A peptidyl peptidase IV inhibitor (eg, alogliptin or a salt thereof (preferably benzoate), vildagliptin, sitagliptin, saxagliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, 2-[[6-[(3R) -3-Amino-1-piperidinyl] -3,4- Dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile or a salt thereof), β3 agonist (eg, N-5984), GPR40 agonist (eg, WO2004 / 041266 , WO2004 / 106276, WO2005 / 063729, WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 or WO2008 / 001931), GLP-1 receptor agonist (eg, GLP-1, GLP-1MR agent) , Liraglutide, exenatide, AVE-0010, BIM-51077, Aib (8,35) hGLP-1 (7,37) NH2, CJC-1131, arubygur Albiglutide), amylin agonist (eg, pramlintide), phosphotyrosine phosphatase inhibitor (eg, sodium vanadate), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon) Antagonist, FBPase inhibitor), SGLT2 (sodium-glucose cotransporter 2) inhibitor (eg, depagliflozin, AVE2268, TS-033, YM543, TA-7284, remogliflozin, ASP1941), SGLT1 inhibitor Drugs, 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498, INCB-13739), adiponectin or agonists thereof, IKK inhibitors (eg, AS-2868), leptin resistance improvers, somatostatin receptor agonists, Glucokinase activator (eg, piragliatin, AZD1656, AZD6370, TTP-355, WO2006 / 112549, WO2007 / 028135, WO 2008/047821, WO2008 / 050821, WO2008 / 136428 or WO2008 / 156757), GIP (Glucose-dependent insulinotropic peptide), GPR119 agonist (eg, PSN821), FGF21, FGF analog and the like.

  Diabetes complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201) ), Lidorestat), neurotrophic factor and its increasing drug (eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg, 4- (4-chlorophenyl)- 2- (2-methyl-1-imidazolyl) -5- [3- (2-methylphenoxy) propyl] oxazole), a compound described in WO2004 / 039365), a PKC inhibitor (eg, ruboxistaurin mesylate )), AGE inhibitors (eg, ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridorin, pyridoxamine), GABA receptor agonists (eg, GA) Gabapentin, pregabalin), serotonin / noradrenaline reuptake inhibitors (eg, duloxetine), sodium channel inhibitors (eg, lacosamide), active oxygen scavengers (eg, thioctic acid) And cerebrovascular dilators (eg, tiapuride, mexiletine), somatostatin receptor agonists (eg, BIM23190), apoptosis signal regulating kinase-1 (ASK-1) inhibitors, and the like.

  Antihyperlipidemic agents include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, rosuvastatin, Pitavastatin or a salt thereof (eg, sodium salt, calcium salt)), a squalene synthase inhibitor (eg, a compound described in WO97 / 10224, for example, N-[[(3R, 5S) -1- (3 -Acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3 -Yl] acetyl] piperidine-4-acetic acid), fibrate compounds (eg, bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resin (eg, choles) Tyramine (colestyr amine, probucol, nicotinic acid drugs (eg, nicomol, nicoeritrol, niaspan), ethyl icosapentate, plant sterols (eg, soysterol), gamma oryzanol ( γ-oryzanol)), cholesterol absorption inhibitors (eg, zetia), CETP inhibitors (eg, dalcetrapib, anacetrapib), omega-3 fatty acid preparations (eg, ω-3-acid ethyl esters 90) Etc.

  Antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, candesartan, candesartan, losartan) (losartan), losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan, olmesartan med Sultan (azilsartan), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine, amlodipine, cilnidipine) , Beta blockers (eg, metoprolol (metoprolol), atenolol (atenolol), propranolol (propranolol), carvedilol (carvedilol), such as pindolol (pindolol)), clonidine (clonidine), and the like.

  Anti-obesity agents include monoamine uptake inhibitors (eg, phentermine, sibutramine, mazindol, floxetine, tesofensine), serotonin 2C receptor agonists (eg, lorcaserin) (lorcaserin)), serotonin 6 receptor antagonist, histamine H3 receptor, GABA modulator (eg, topiramate), neuropeptide Y antagonist (eg, velnepeit), cannabinoid receptor antagonist ( Examples, rimonabant, taranabant, ghrelin antagonist, ghrelin receptor antagonist, ghrelin acylase inhibitor, opioid receptor antagonist (eg, GSK-1521498), orexin receptor antagonist, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (eg, AZD-4017), pancreatic lipase inhibitors (eg, Orlistat, cetilistat), β3 agonist (eg, N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitor, acetyl CoA carboxylase (ACC) inhibitor, stearate CoA desaturase inhibitor Drugs, microsomal triglyceride transfer protein inhibitors (eg, R-256918), Na-glucose co-transport carrier inhibitors (eg, JNJ-28431754, remogliflozin), NFκB inhibitors (eg, HE-3286), PPAR agonists (Eg, GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitors (eg, sodium vanadate, trodusquemin), GPR119 agonists (eg, PSN-821), glucokinase activators (eg, AZD- 1656), leptin, leptin derivatives (eg, metreleptin), CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), Resistokinin agonist, glucagon-like peptide-1 (GLP-1) formulation (eg, animal GLP-1 formulation extracted from bovine and porcine pancreas; human GLP-1 formulation genetically engineered using Escherichia coli and yeast Fragments or derivatives of GLP-1 (eg, exenatide, liraglutide), amylin preparations (eg, pramlintide, AC-2307), neuropeptide Y agonists (eg, PYY3-36, Derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oxyntomodulin preparations; FGF21 preparations (eg, animal FGF21 preparations extracted from bovine and porcine pancreas; genetic engineering using Escherichia coli and yeast Synthetically synthesized human FGF21 preparations; FGF21 fragments or derivatives)), antifeedants (eg, P-57) and the like.

  Examples of the diuretic include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethyazide, trichloromethyazide, hydrochlorothiazide) ), Hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, poly5thiazide, poly5thiazide, methyclothiazide, etc., anti-aldosterone formulations (eg, spironolactone, spironolactone) (e.g., triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), chlorobenzenesulfonamides (e.g., chlortalidone, mefruside, i) Dapamido (Indapamide), etc.), azosemide (Azosemide), isosorbide (Isosorbide), ethacrynic acid, piretanide (Piretanide), bumetanide (Bumetanide), and the like furosemide (furosemide).

  Examples of the antithrombotic agents include heparin (eg, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, argatroban (eg, aragatroban), dabigatran), FXa inhibitors (eg, rivaroxaban, apixaban, edoxaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823 or WO2005 / 113504), thrombolytic agents (eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamitepase (pamiteplase)), platelet aggregation inhibitors (eg, Ticlopidine hydrochloride, clopidogrel, prasug Le (prasugrel), E5555, SHC530348, cilostazol (cilostazol), ethyl icosapentate, beraprost sodium (beraprost sodium), and the like sarpogrelate hydrochloride (sarpogrelate hydrochloride)) is.

When the solid preparation of the present invention and a concomitant drug are used in combination, their administration timing is not limited, and they may be administered simultaneously to administration subjects, or may be administered with a time difference.
In addition, the solid preparation of the present invention and the concomitant drug may be administered as separate tablets, or may be administered as a single preparation containing the solid preparation of the present invention and the concomitant drug.

The dose of the concomitant drug can be appropriately selected based on the clinically used dose of each drug. The mixing ratio of the solid preparation of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the solid preparation of the present invention.
Thus, by using a concomitant drug,
1) Effect of enhancing the action of the solid preparation of the present invention or the concomitant drug (synergistic effect of drug action)
2) The effect of reducing the dose of the solid preparation or the concomitant drug of the present invention (the effect of reducing the dose of the drug compared to when administered alone);
3) Reduction effect of secondary action of solid preparation or concomitant drug of the present invention;
Excellent effects such as can be obtained.

  The present invention also provides a method for improving the dissolution and stabilization of a compound represented by the formula (I) or a salt thereof and / or a calcium antagonist in a solid preparation, characterized by containing a sugar alcohol. According to the present invention, the dissolution property of the compound represented by formula (I) or a salt thereof in the solid preparation is significantly improved.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.
In the following Examples and Test Examples, as the components (additives) other than the active ingredient, Japanese Pharmacopoeia 15th revision, Japanese Pharmacopoeia Standards for Pharmaceuticals or Pharmaceutical Additives Standards 2003 compliant products were used.

  In the following Examples, Compound A or Compound B was used as the compound represented by the above formula (I) or a salt thereof.

[Example 1]

Manufacturing method:
(1) A binding liquid I was prepared by dissolving hydroxypropyl cellulose (720.0 g) and macrogol 6000 (324.0 g) in purified water (9000 g). Dispersion I was prepared by dispersing ferric sesquioxide (2.880 g) in purified water (2880 g). Dispersion I and purified water (720.0 g) were mixed with binding liquid I to prepare binding liquid II. After uniformly mixing amlodipine besylate (1253 g), compound A (1449 g), D-mannitol (14880 g) and microcrystalline cellulose (3600 g) in a fluidized bed granulator (FD-S2, Paulec Co., Ltd.) Granulation was carried out while spraying the binding liquid II, followed by drying to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) To the obtained sized powder (40760 g (2 batches)), croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) were added, and a tumbler mixer (TM20-0-0, Suehiro Chemical) By mixing at a manufacturing plant), a mixed powder was obtained.
(3) The mixed powder obtained above is compressed with a rotary tableting machine (AQUAARIUS-36K, Kikusui Seisakusho) using a 7.0 mm diameter punch (tablet pressure 10 kN, weight per tablet: 130 mg) Thus, an uncoated tablet having the composition shown in Table 1 was obtained.

[Example 2]

Manufacturing method:
(1) A binding solution I was prepared by dissolving hydroxypropyl cellulose (720.0 g) and macrogol 6000 (324.0 g) in purified water (9900 g). Dispersion I was prepared by dispersing ferric sesquioxide (11.70 g) in purified water (1800 g). Dispersion I and purified water (540.0 g) were mixed with binding liquid I to prepare binding liquid II. After uniformly mixing amlodipine besylate (1253 g), compound A (1449 g), D-mannitol (14870 g) and microcrystalline cellulose (3600 g) in a fluidized bed granulator (FD-S2, Paulec Co., Ltd.) Granulation was carried out while spraying the binding liquid II, followed by drying to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) To the obtained sized powder (40760 g (2 batches)), croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) were added, and a tumbler mixer (TM20-0-0, Suehiro Chemical) By mixing at a manufacturing plant), a mixed powder was obtained.
(3) The mixed powder obtained above is tableted with a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) using a punch with a major axis of 8.5 mm and a minor axis of 5.0 mm (tablet pressure 8 kN, 1 tablet). Per unit weight: 130 mg), and uncoated tablets having the compositions shown in Table 2 were obtained.

[Example 3]

Manufacturing method:
(1) A binding solution I was prepared by dissolving hydroxypropyl cellulose (720.0 g) and macrogol 6000 (324.0 g) in purified water (9900 g). Dispersion I was prepared by dispersing yellow ferric oxide (11.70 g) in purified water (1800 g). Dispersion I and purified water (540.0 g) were mixed with binding liquid I to prepare binding liquid II. In a fluidized bed granulator (FD-S2, Paulec Co., Ltd.), amlodipine besylate (627.7 g), compound A (1449 g), D-mannitol (15550 g) and microcrystalline cellulose (3600 g) were uniformly mixed. Thereafter, granulation was performed while spraying the binding liquid II, followed by drying to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) To the obtained sized powder (40760 g (2 batches)), croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) were added, and a tumbler mixer (TM20-0-0, Suehiro Chemical) By mixing at a manufacturing plant), a mixed powder was obtained.
(3) The mixed powder obtained above is tableted with a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) using a punch with a major axis of 8.5 mm and a minor axis of 5.0 mm (tablet pressure 8 kN, 1 tablet). Per weight: 130 mg), and uncoated tablets having the compositions shown in Table 3 were obtained.

[Example 4]

Manufacturing method:
(1) A binding solution I was prepared by dissolving hydroxypropyl cellulose (720.0 g) and macrogol 6000 (324.0 g) in purified water (9900 g). Dispersion I was prepared by dispersing ferric sesquioxide (11.70 g) in purified water (1800 g). Dispersion I and purified water (540.0 g) were mixed with binding liquid I to prepare binding liquid II. In a fluidized bed granulator (FD-S2, Paulec Co., Ltd.), amlodipine besylate (1253 g), compound A (724.3 g), D-mannitol (15600 g) and microcrystalline cellulose (3600 g) were uniformly mixed. Thereafter, granulation was performed while spraying the binding liquid II, followed by drying to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) To the obtained sized powder (40760 g (2 batches)), croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) were added, and a tumbler mixer (TM20-0-0, Suehiro Chemical) By mixing at a manufacturing plant), a mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a rotary tableting machine (AQUAARIUS-36K type, Kikusui Seisakusho) using a 7 mm diameter punch (tablet pressure 10 kN, weight per tablet: 130 mg), Uncoated tablets having the compositions shown in Table 4 were obtained.

[Example 5]

Manufacturing method:
(1) A binding solution I was prepared by dissolving hydroxypropyl cellulose (720.0 g) and macrogol 6000 (324.0 g) in purified water (9900 g). Dispersion I was prepared by dispersing yellow ferric oxide (11.70 g) in purified water (1800 g). Dispersion I and purified water (540.0 g) were mixed with binding liquid I to prepare binding liquid II. Uniformly amlodipine besylate (627.7 g), compound A (724.3 g), D-mannitol (16220 g) and microcrystalline cellulose (3600 g) in a fluidized bed granulator (FD-S2, Paulec Co., Ltd.) After mixing, the mixture was granulated while spraying the binding liquid II, and then dried to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) To the obtained sized powder (40760 g (2 batches)), croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) were added, and a tumbler mixer (TM20-0-0, Suehiro Chemical) By mixing at a manufacturing plant), a mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a rotary tableting machine (AQUAARIUS-36K type, Kikusui Seisakusho) using a 7 mm diameter punch (tablet pressure 10 kN, weight per tablet: 130 mg), Uncoated tablets having the compositions shown in Table 5 were obtained.

[Example 6]

Manufacturing method:
(1) A binding solution I was prepared by dissolving hydroxypropyl cellulose (720.0 g) and macrogol 6000 (324.0 g) in purified water (9900 g). Dispersion I was prepared by dispersing ferric sesquioxide (18.72 g) in purified water (1800 g). Dispersion I and purified water (540.0 g) were mixed with binding liquid I to prepare binding liquid II. After uniformly mixing amlodipine besylate (1248 g), compound A (1446 g), D-mannitol (14870 g) and microcrystalline cellulose (3600 g) in a fluidized bed granulator (FD-S2, Paulec Co., Ltd.) Granulation was carried out while spraying the binding liquid II, followed by drying to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) To the obtained sized powder (20380 g), croscarmellose sodium (924.0 g) and magnesium stearate (148.5 g) are added, and a tumbler mixer (TM20-0-0, Suehiro Koki Co., Ltd.) is used. By mixing, a mixed powder was obtained.
(3) The mixed powder obtained above is tableted with a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) using a punch with a major axis of 8.5 mm and a minor axis of 5.0 mm (tablet pressure 8 kN, 1 tablet). Per unit weight: 130 mg), and uncoated tablets having the compositions shown in Table 6 were obtained.

[Example 7]

Manufacturing method:
(1) A binding solution I was prepared by dissolving hydroxypropyl cellulose (720.0 g) and macrogol 6000 (324.0 g) in purified water (9900 g). Dispersion I was prepared by dispersing yellow ferric oxide (18.72 g) in purified water (1800 g). Dispersion I and purified water (540.0 g) were mixed with binding liquid I to prepare binding liquid II. In a fluidized bed granulator (FD-S2, Paulec Co., Ltd.), amlodipine besylate (625.2 g), compound A (1446 g), D-mannitol (15500 g) and microcrystalline cellulose (3600 g) were mixed uniformly. Thereafter, granulation was performed while spraying the binding liquid II, followed by drying to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) To the obtained sized powder (20380 g), croscarmellose sodium (924.0 g) and magnesium stearate (148.5 g) are added, and a tumbler mixer (TM20-0-0, Suehiro Koki Co., Ltd.) is used. By mixing, a mixed powder was obtained.
(3) The mixed powder obtained above is tableted with a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) using a punch with a major axis of 8.5 mm and a minor axis of 5.0 mm (tablet pressure 8 kN, 1 tablet). Per unit weight: 130 mg), and uncoated tablets having the compositions shown in Table 7 were obtained.

[Example 8]

Manufacturing method:
(1) A binding liquid I was prepared by dissolving hydroxypropyl cellulose (144.0 g) in purified water (1980 g). Dispersion I was prepared by dispersing ferric sesquioxide (3.744 g) in purified water (360.0 g). Dispersion I and purified water (108.0 g) were mixed with binding liquid I to prepare binding liquid II. Macrogol 6000 (4.680 g) was dissolved in binding liquid II (259.6 g) to prepare binding liquid III. In a fluidized bed granulator (Lab-1, Paulek, Inc.), amlodipine besylate (24.95 g), compound A (28.80 g), D-mannitol (299.4 g) and microcrystalline cellulose (72.00 g) ) Were mixed uniformly, and then granulated while spraying the binding liquid III, and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) By adding croscarmellose sodium (16.80 g) and magnesium stearate (2.700 g) to the obtained sized powder (370.5 g), mixing in a polyethylene bag (4.9 L), A mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a rotary tableting machine (collect 19K type, Kikusui Seisakusho) using a punch having a major axis of 8.5 mm and a minor axis of 5.0 mm (tablet pressure 7.5 kN, 1 (Weight per tablet: 130 mg), and uncoated tablets having the compositions shown in Table 8 were obtained.

[Example 9]

Manufacturing method:
(1) A binding liquid I was prepared by dissolving hydroxypropyl cellulose (144.0 g) in purified water (1980 g). Dispersion I was prepared by dispersing ferric sesquioxide (3.744 g) in purified water (360.0 g). Dispersion I and purified water (108.0 g) were mixed with binding liquid I to prepare binding liquid II. Macrogol 6000 (14.04 g) was dissolved in binding liquid II (259.6 g) to prepare binding liquid III. In a fluid bed granulator (Lab-1, Paulek, Inc.), amlodipine besylate (24.95 g), compound A (28.80 g), D-mannitol (290.0 g) and microcrystalline cellulose (72.00 g) ) Were mixed uniformly, and then granulated while spraying the binding liquid III, and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) By adding croscarmellose sodium (16.80 g) and magnesium stearate (2.700 g) to the obtained sized powder (370.5 g), mixing in a polyethylene bag (4.9 L), A mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a rotary tableting machine (collect 19K type, Kikusui Seisakusho) using a punch having a major axis of 8.5 mm and a minor axis of 5.0 mm (tablet pressure 7.5 kN, 1 Weight per tablet: 130 mg), and uncoated tablets having the compositions shown in Table 9 were obtained.

[Example 10]

Manufacturing method:
(1) A binding liquid I was prepared by dissolving hydroxypropyl cellulose (144.0 g) in purified water (1980 g). Dispersion I was prepared by dispersing ferric sesquioxide (3.744 g) in purified water (360.0 g). Dispersion I and purified water (108.0 g) were mixed with binding liquid I to prepare binding liquid II. Macrogol 6000 (23.40 g) was dissolved in binding liquid II (259.6 g) to prepare binding liquid III. In a fluid bed granulator (Lab-1, Paulek, Inc.), amlodipine besylate (24.95 g), compound A (28.80 g), D-mannitol (280.7 g) and microcrystalline cellulose (72.00 g) ) Were mixed uniformly, and then granulated while spraying the binding liquid III, and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) By adding croscarmellose sodium (16.80 g) and magnesium stearate (2.700 g) to the obtained sized powder (370.5 g), mixing in a polyethylene bag (4.9 L), A mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a rotary tableting machine (collect 19K type, Kikusui Seisakusho) using a punch having a major axis of 8.5 mm and a minor axis of 5.0 mm (tablet pressure 7.5 kN, 1 (Weight per tablet: 130 mg), and uncoated tablets having the composition shown in Table 10 were obtained.

[Example 11]

Manufacturing method:
(1) A binding liquid I was prepared by dissolving hydroxypropyl cellulose (144.0 g) in purified water (1980 g). Dispersion I was prepared by dispersing ferric sesquioxide (3.744 g) in purified water (360.0 g). Dispersion I and purified water (108.0 g) were mixed with binding liquid I to prepare binding liquid II. Macrogol 6000 (37.44 g) was dissolved in binding liquid II (259.6 g) to prepare binding liquid III. In a fluid bed granulator (Lab-1, Paulek, Inc.), amlodipine besylate (24.95 g), compound A (28.80 g), D-mannitol (266.6 g) and microcrystalline cellulose (72.00 g) ) Were mixed uniformly, and then granulated while spraying the binding liquid III, and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) By adding croscarmellose sodium (16.80 g) and magnesium stearate (2.700 g) to the obtained sized powder (370.5 g), mixing in a polyethylene bag (4.9 L), A mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a rotary tableting machine (collect 19K type, Kikusui Seisakusho) using a punch having a major axis of 8.5 mm and a minor axis of 5.0 mm (tablet pressure 7.5 kN, 1 (Weight per tablet: 130 mg), and uncoated tablets having the composition shown in Table 11 were obtained.

[Example 12]

Manufacturing method:
(1) Hydroxypropyl cellulose (208.0 g) and Macrogol 6000 (160.0 g) were dissolved in purified water (2392.0 g) to prepare a binding solution. In a fluidized bed granulator (FD-5S, Paulek Co., Ltd.), amlodipine besylate (277.2 g), compound B (1605.0 g), D-mannitol (1599.0 g) and microcrystalline cellulose (388.8 g) ) Were mixed uniformly, and then granulated while spraying the binding solution, and then dried to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) Crospovidone (331.5 g), microcrystalline cellulose (442.0 g) and magnesium stearate (44.201 g) are added to the obtained sized powder (3602.0 g), and a tumbler mixer (TM-15 The mixture powder was obtained by mixing with a mold, Suehiro Chemical Industries Co., Ltd.).
(3) The mixed powder obtained above was tableted using a 7.0 mm diameter punch with a rotary tableting machine (Collect 12 HUK, Kikusui Seisakusho) (tablet pressure 4 kN, weight per tablet: 130 mg), I got a bare tablet.
(4) Premix I (240.0 g) was dissolved in purified water (2160.0 g) to prepare a film coating solution. In a film coating machine (DRC-500, POWREC Co., Ltd.), the film coating solution was uniformly sprayed onto the uncoated tablet (3120.0 g) to apply the film coating, and film coating tablets having the compositions shown in Table 12 ( Weight per tablet: 135 mg) was obtained. Here, premix I is a premixed powder. The composition of premix I is shown in Table 12a.

[Example 13]

Manufacturing method:
(1) Hydroxypropyl cellulose (20.80 g) and macrogol 6000 (16.00 g) were dissolved in purified water (239.2 g) to prepare a binding solution. In a fluid bed granulator (Lab-1, Paulek, Inc.), amlodipine besylate (27.72 g), compound B (80.00 g), D-mannitol (240.4 g) and microcrystalline cellulose (38.88 g) ) Were mixed uniformly, and then granulated while spraying the binding solution, and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) Crospovidone (34.13 g), microcrystalline cellulose (45.50 g) and magnesium stearate (4.550 g) were added to the obtained sized powder (370.8 g), and a polyethylene bag (4.9 L) By mixing in, a mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a 7.0 mm diameter punch (tablet pressure 4 kN, weight per tablet: 130 mg) with a rotary tableting machine (VEL-5, Kikusui Seisakusho). Got bare tablets.
(4) Premix I (40.00 g) was dissolved in purified water (360.0 g) to prepare a film coating solution. In a film coating machine (DRC-200, POWREC Co., Ltd.), the film coating solution was uniformly sprayed onto the uncoated tablets (200.0 g) to form a film coating tablet having the composition shown in Table 13 ( Weight per tablet: 135 mg) was obtained. Here, premix I is a premixed powder. The composition of premix I is shown in Table 13a.

[Example 14]

Manufacturing method:
(1) Hydroxypropyl cellulose (20.80 g) and macrogol 6000 (16.00 g) were dissolved in purified water (239.2 g) to prepare a binding solution. In a fluid bed granulator (Lab-1, Paulek, Inc.), amlodipine besylate (13.88 g), compound B (80.00 g), D-mannitol (254.2 g) and microcrystalline cellulose (38.88 g) ) Were mixed uniformly, and then granulated while spraying the binding solution, and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) Crospovidone (34.13 g), microcrystalline cellulose (45.50 g) and magnesium stearate (4.550 g) were added to the obtained sized powder (370.8 g), and a polyethylene bag (4.9 L) By mixing in, a mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a 7.0 mm diameter punch (tablet pressure 4 kN, weight per tablet: 130 mg) with a rotary tableting machine (VEL-5, Kikusui Seisakusho). Got bare tablets.
(4) Premix I (40.00 g) was dissolved in purified water (360.0 g) to prepare a film coating solution. In a film coating machine (DRC-200, POWREC Co., Ltd.), a film coating solution was applied by spraying the film coating solution uniformly onto a bare tablet (200.0 g), and film coating tablets having the compositions shown in Table 14 ( Weight per tablet: 135 mg) was obtained. Here, premix I is a premixed powder. The composition of premix I is shown in Table 14a.

[Example 15]

Manufacturing method:
(1) Hydroxypropyl cellulose (35.10 g) and Macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to prepare a binding solution. In a fluid bed granulator (Lab-1, Paulek, Inc.), amlodipine besylate (10.40 g), compound B (30.00 g), D-mannitol (250.6 g) and microcrystalline cellulose (39.00 g) ) Were mixed uniformly, and then granulated while spraying the binding solution, and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) Add low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) to the resulting sized powder (289.3 g) and mix in a polyethylene bag (4.9 L). Thus, a mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a 6.5 mm diameter punch (tablet pressure 5 kN, weight per tablet: 130 mg) with a rotary tableting machine (VEL-5, Kikusui Seisakusho). Got bare tablets.
(4) A film coating solution I was prepared by dissolving hypromellose (57.44 g) and macrogol 6000 (11.52 g) in purified water (375.0 g). Dispersion I was prepared by dispersing titanium oxide (7.680 g), iron sesquioxide (0.1650 g) and yellow iron sesquioxide (0.5100 g) in purified water (330.0 g). Film coating solution I, dispersion I and purified water (68.25 g) were mixed to prepare film coating solution II. In the film coating machine (DRC-200, Powrec Co., Ltd.), the film coating solution II was uniformly sprayed onto the naked tablet (120.0 g), and the film coating tablet having the composition shown in Table 15 was applied. (Weight per tablet: 135.154 mg) was obtained.

[Example 16]

Manufacturing method:
(1) Hydroxypropyl cellulose (35.10 g) and Macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to prepare a binding solution. In a fluidized bed granulator (Lab-1, Paulek, Inc.), amlodipine besylate (20.79 g), compound B (30.00 g), D-mannitol (240.2 g) and microcrystalline cellulose (39.00 g) ) Were mixed uniformly, and then granulated while spraying the binding solution, and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) Add low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) to the resulting sized powder (289.3 g) and mix in a polyethylene bag (4.9 L). Thus, a mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a 6.5 mm diameter punch (tablet pressure 5 kN, weight per tablet: 130 mg) with a rotary tableting machine (VEL-5, Kikusui Seisakusho). Got bare tablets.
(4) A film coating solution I was prepared by dissolving hypromellose (57.44 g) and macrogol 6000 (11.52 g) in purified water (375.0 g). Dispersion I was prepared by dispersing titanium oxide (7.680 g), iron sesquioxide (0.1650 g) and yellow iron sesquioxide (0.5100 g) in purified water (330.0 g). Film coating solution I, dispersion I and purified water (68.25 g) were mixed to prepare film coating solution II. In a film coating machine (DRC-200, POWREC Co., Ltd.), the film coating solution II was uniformly sprayed onto the bare tablet (120.0 g) to apply the film coating, and the film coated tablets having the compositions shown in Table 16 were obtained. (Weight per tablet: 135.154 mg) was obtained.

[Example 17]

Manufacturing method:
(1) Hydroxypropyl cellulose (35.10 g) and Macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to prepare a binding solution. In a fluidized bed granulator (Lab-1, Paulek, Inc.), amlodipine besylate (10.40 g), compound B (60.00 g), D-mannitol (220.6 g) and microcrystalline cellulose (39.00 g) ) Were mixed uniformly, and then granulated while spraying the binding solution, and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) Add low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) to the resulting sized powder (289.3 g) and mix in a polyethylene bag (4.9 L). Thus, a mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a 6.5 mm diameter punch (tablet pressure 5 kN, weight per tablet: 130 mg) with a rotary tableting machine (VEL-5, Kikusui Seisakusho). Got bare tablets.
(4) A film coating solution I was prepared by dissolving hypromellose (57.44 g) and macrogol 6000 (11.52 g) in purified water (375.0 g). Dispersion I was prepared by dispersing titanium oxide (7.680 g) and iron sesquioxide (0.1500 g) in purified water (330.0 g). Film coating solution I, dispersion I and purified water (68.25 g) were mixed to prepare film coating solution II. In a film coating machine (DRC-200, POWREC Co., Ltd.), the film coating solution II was uniformly sprayed onto the naked tablet (120.0 g) to form a film coating, and film coating tablets having the compositions shown in Table 17 were applied. (Weight per tablet: 135.119 mg) was obtained.

[Example 18]

Manufacturing method:
(1) Hydroxypropyl cellulose (35.10 g) and Macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to prepare a binding solution. In a fluidized bed granulator (Lab-1, Paulek Co., Ltd.), amlodipine besylate (20.79 g), compound B (60.00 g), D-mannitol (210.2 g) and microcrystalline cellulose (39.00 g) ) Were mixed uniformly, and then granulated while spraying the binding solution, and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) Add low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) to the resulting sized powder (289.3 g) and mix in a polyethylene bag (4.9 L). Thus, a mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a 6.5 mm diameter punch (tablet pressure 5 kN, weight per tablet: 130 mg) with a rotary tableting machine (VEL-5, Kikusui Seisakusho). Got bare tablets.
(4) A film coating solution I was prepared by dissolving hypromellose (57.44 g) and macrogol 6000 (11.52 g) in purified water (375.0 g). Dispersion I was prepared by dispersing titanium oxide (7.680 g) and iron sesquioxide (0.1500 g) in purified water (330.0 g). Film coating solution I, dispersion I and purified water (68.25 g) were mixed to prepare film coating solution II. In the film coating machine (DRC-200, Powrec Co., Ltd.), the film coating solution II was uniformly sprayed onto the naked tablet (120.0 g) to apply the film coating, and the film coated tablets having the compositions shown in Table 18 were obtained. (Weight per tablet: 135.119 mg) was obtained.

[Example 19]

Manufacturing method:
(1) Hydroxypropyl cellulose (35.10 g) and Macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to prepare a binding solution. In a fluid bed granulator (Lab-1, Paulek, Inc.), amlodipine besylate (10.40 g), compound B (120.0 g), D-mannitol (160.6 g) and microcrystalline cellulose (39.00 g) ) Were mixed uniformly, and then granulated while spraying the binding solution, and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) Add low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) to the resulting sized powder (289.3 g) and mix in a polyethylene bag (4.9 L). Thus, a mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a 6.5 mm diameter punch (tablet pressure 5 kN, weight per tablet: 130 mg) with a rotary tableting machine (VEL-5, Kikusui Seisakusho). Got bare tablets.
(4) A film coating solution I was prepared by dissolving hypromellose (57.44 g) and macrogol 6000 (11.52 g) in purified water (375.0 g). Dispersion I was prepared by dispersing titanium oxide (7.680 g) and yellow ferric oxide (0.6900 g) in purified water (330.0 g). Film coating solution I, dispersion I and purified water (68.25 g) were mixed to prepare film coating solution II. In a film coating machine (DRC-200, POWREC Co., Ltd.), the film coating solution II was uniformly sprayed onto the naked tablet (120.0 g) to apply the film coating, and the film coated tablets having the compositions shown in Table 19 (Weight per tablet: 135.155 mg) was obtained.

[Example 20]

Manufacturing method:
(1) Hydroxypropyl cellulose (35.10 g) and Macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to prepare a binding solution. In a fluidized bed granulator (Lab-1, Paulek, Inc.), amlodipine besylate (20.79 g), compound B (120.0 g), D-mannitol (150.2 g) and microcrystalline cellulose (39.00 g) ) Were mixed uniformly, and then granulated while spraying the binding solution, and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) Add low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) to the resulting sized powder (289.3 g) and mix in a polyethylene bag (4.9 L). Thus, a mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a 7.0 mm diameter punch using a rotary tableting machine (VEL-5, Kikusui Seisakusho) (tablet pressure 5 kN, weight per tablet: 130 mg). Got bare tablets.
(4) A film coating solution I was prepared by dissolving hypromellose (57.44 g) and macrogol 6000 (11.52 g) in purified water (375.0 g). Dispersion I was prepared by dispersing titanium oxide (7.680 g) and yellow ferric oxide (0.6900 g) in purified water (330.0 g). Film coating solution I, dispersion I and purified water (68.25 g) were mixed to prepare film coating solution II. In a film coating machine (DRC-200, POWREC Co., Ltd.), the film coating solution II was uniformly sprayed onto the naked tablet (120.0 g) to apply the film coating, and film coating tablets having the compositions shown in Table 20 were obtained. (Weight per tablet: 135.155 mg) was obtained.

[Example 21]

Manufacturing method:
(1) Binding liquid I was prepared by dissolving hypromellose (720.0 g) in purified water (9000 g). Dispersion I was prepared by dispersing ferric sesquioxide (2.880 g) in purified water (2880 g). Dispersion I and purified water (720.0 g) were mixed with binding liquid I to prepare binding liquid II. In a fluidized bed granulator (FD-S2, Paulec Co., Ltd.), amlodipine besylate (1249 g), D-mannitol (16660 g) and microcrystalline cellulose (3600 g) were mixed uniformly, and then the binding liquid II was sprayed. Then, it was granulated and then dried to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder I.
(2) Binding liquid III was prepared by dissolving hydroxypropyl cellulose (720.0 g) and macrogol 6000 (468.0 g) in purified water (9000 g). Dispersion II was prepared by dispersing ferric sesquioxide (2.880 g) in purified water (2880 g). Dispersion liquid II and purified water (720.0 g) were mixed with binding liquid III to prepare binding liquid IV. Compound A (1436 g), lactose hydrate (16090 g) and corn starch (3600 g) were uniformly mixed in a fluidized bed granulator (FD-S2, POWREC Co., Ltd.) and then sprayed with binding liquid IV. Granulated and then dried to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill pulverizer (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder II.
(3) Croscarmellose sodium (1848 g) and magnesium stearate (214.5 g) are added to the obtained sized powder I (20380 g) and sized powder II (20460 g), and a tumbler mixer (TM20-0-0) is added. The powder was obtained by mixing at Suehiro Chemical Industries, Ltd.).
(4) The mixed powder obtained above was tableted with a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) using a 8.5 mm diameter punch (tablet pressure 10 kN, weight per tablet: 260 mg) Thus, uncoated tablets having the compositions shown in Table 21 were obtained.

[Example 22]

Manufacturing method:
(1) Binding liquid I was prepared by dissolving hypromellose (720.0 g) in purified water (9000 g). Dispersion I was prepared by dispersing ferric sesquioxide (2.880 g) in purified water (2880 g). Dispersion I and purified water (720.0 g) were mixed with binding liquid I to prepare binding liquid II. In a fluidized bed granulator (FD-S2, Paulec Co., Ltd.), amlodipine besylate (1249 g), D-mannitol (16660 g) and microcrystalline cellulose (3600 g) were mixed uniformly, and then the binding liquid II was sprayed. Then, it was granulated and then dried to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder I.
(2) To the obtained sized powder I (20380 g), croscarmellose sodium (924.0 g) and magnesium stearate (148.5 g) are added, and a tumbler mixer (TM-60, Showa Chemical Machinery Co., Ltd.) is used. By mixing, a mixed powder I was obtained.
(3) Hydroxypropyl cellulose (720.0 g) and macrogol 6000 (468.0 g) were dissolved in purified water (9000 g) to prepare a binding solution III. Dispersion II was prepared by dispersing ferric sesquioxide (2.880 g) in purified water (2880 g). Dispersion liquid II and purified water (720.0 g) were mixed with binding liquid III to prepare binding liquid IV. Compound A (1436 g), lactose hydrate (16090 g) and corn starch (3600 g) were uniformly mixed in a fluidized bed granulator (FD-S2, POWREC Co., Ltd.) and then sprayed with binding liquid IV. Granulated and then dried to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill pulverizer (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder II.
(4) Carmellose calcium (924.0 g) and magnesium stearate (66.00 g) are added to the obtained sized powder II (20460 g) and mixed with a tumbler mixer (TM-60, Showa Chemical Machinery Co., Ltd.). Thus, mixed powder II was obtained.
(5) The mixed powder I (130 mg) and mixed powder II (130 mg) obtained above are laminated with a rotary tableting machine (HT-CVX54LS-UW / C & 3L, Hata Iron Works) using a 8.5 mm diameter punch. Into tablets (tablet pressure 9 kN, weight per tablet: 260 mg), and uncoated tablets with the compositions shown in Table 22 were obtained.

[Example 23]

Manufacturing method:
(1) A binding liquid I was prepared by dissolving hydroxypropyl cellulose (155.0 g) in purified water (1395.0 g). After mixing amlodipine besylate (346.7 g), D-mannitol (2447.0 g) and microcrystalline cellulose (766.7 g) in a fluidized bed granulator (FD-5S, Paulec Co., Ltd.) Granulation was carried out while spraying the binding liquid I, followed by drying to obtain a granulated powder of the amlodipine besylate layer. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder of the amlodipine besylate layer. It was.
(2) A binding solution II was prepared by dissolving hydroxypropyl cellulose (280.1 g) and macrogol 6000 (280.0 g) in purified water (2520.2 g). Compound B (2808.4 g), lactose hydrate (2043.5 g), corn starch (910.3 g) and microcrystalline cellulose (910.2 g) in a fluidized bed granulator (FD-5S, Powrec Co., Ltd.) ) Were uniformly mixed, and then granulated while spraying the binding liquid II, followed by drying to obtain a granulated powder of the compound B layer. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder of the compound B layer. .
(3) Carmellose calcium (200.0 g) and magnesium stearate (28.000 g) are added to the sized powder (3772.0 g) of the obtained amlodipine besylate layer, and a tumbler mixer (TM-15, powder) By mixing at Kako Koki Seisakusho, a powdered amlodipine besylate layer was obtained.
(4) Low-substituted hydroxypropylcellulose (455.0 g), microcrystalline cellulose (455.1 g) and magnesium stearate (24.53 g) were added to the sized powder (3616.1 g) of the obtained compound B layer. The mixed powder of the compound B layer was obtained by mixing with a tumbler mixer (TM-15 type, Suehiro Chemical Industries, Ltd.).
(5) The mixed powder of the amlodipine besylate layer and the mixed powder of the compound B layer obtained above are laminated with a rotary tableting machine (HT-X12SS-UW & 2L, Hata Iron Works) using a punch with a diameter of 8.0 mm. Were tableted (tablet pressure 7 kN, weight per tablet: 230 mg (amlodipine besylate layer: 100 mg, compound B layer: 130 mg)) to obtain a laminated uncoated tablet.
(6) Premix I (252.0 g) was dissolved in purified water (2268.0 g) to prepare a film coating solution. In the film coating machine (DRC-500, POWREC Co., Ltd.), the film coating was applied to the nude tablet while uniformly spraying the film coating solution onto the nude tablet (3120.0 g), and the film coating having the composition shown in Table 23 was performed. Tablets (weight per tablet: 239 mg) were obtained. Here, premix I is a premixed powder. The composition of premix I is shown in Table 23a.

[Example 24]

Manufacturing method:
(1) A binding solution I was prepared by dissolving hydroxypropylcellulose (80.00 g) and macrogol 4000 (36.00 g) in purified water (1100 g). Dispersion I was prepared by dispersing ferric sesquioxide (2.080 g) in purified water (200.1 g). Dispersion I and purified water (60.00 g) were mixed with binding liquid I to prepare binding liquid II. In a fluid bed granulator (Lab-1, Paulek, Inc.), amlodipine besylate (24.95 g), compound A (28.80 g), D-mannitol (297.6 g) and microcrystalline cellulose (72.00 g) ) Were mixed uniformly, and then granulated while spraying the binding liquid II (266.1 g), and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) By adding croscarmellose sodium (16.81 g) and magnesium stearate (2.700 g) to the obtained sized powder (370.5 g), mixing in a polyethylene bag (4.9 L), A mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a rotary tableting machine (collect 19K type, Kikusui Seisakusho) using a punch having a major axis of 8.5 mm and a minor axis of 5.0 mm (tablet pressure 8.5 kN, 1 (Weight per tablet: 130 mg), and uncoated tablets having the composition shown in Table 24 were obtained.

[Example 25]

Manufacturing method:
(1) A binding solution I was prepared by dissolving hydroxypropyl cellulose (80.00 g) and macrogol 10000 (36.00 g) in purified water (1100 g). Dispersion I was prepared by dispersing ferric sesquioxide (2.080 g) in purified water (200.1 g). Dispersion I and purified water (60.10 g) were mixed with binding liquid I to prepare binding liquid II. In a fluid bed granulator (Lab-1, Paulek, Inc.), amlodipine besylate (24.95 g), compound A (28.80 g), D-mannitol (297.6 g) and microcrystalline cellulose (72.00 g) ) Were mixed uniformly, and then granulated while spraying the binding liquid II (266.1 g), and then dried to obtain a granulated powder. Part of the obtained granulated powder was sized using a sieve (16 mesh) to obtain a sized powder.
(2) By adding croscarmellose sodium (16.80 g) and magnesium stearate (2.710 g) to the obtained sized powder (370.5 g), mixing in a polyethylene bag (4.9 L), A mixed powder was obtained.
(3) The mixed powder obtained above was tableted with a rotary tableting machine (collect 19K type, Kikusui Seisakusho) using a punch having a major axis of 8.5 mm and a minor axis of 5.0 mm (tablet pressure 8.5 kN, 1 (Weight per tablet: 130 mg), and uncoated tablets having the compositions shown in Table 25 were obtained.

[Comparative Example 1]

Manufacturing method:
(1) A binding liquid I was prepared by dissolving hydroxypropylcellulose (720.0 g) and macrogol 6000 (468.0 g) in purified water (9000 g). Dispersion I was prepared by dispersing ferric sesquioxide (2.880 g) in purified water (2880 g). Dispersion I and purified water (720.0 g) were mixed with binding liquid I to prepare binding liquid II. In a fluidized bed granulator (FD-S2, Paulec Co., Ltd.), amlodipine besylate (1253 g), compound A (1449 g), lactose hydrate (14830 g) and corn starch (3600 g) were uniformly mixed, Granulation was carried out while spraying the binding liquid II, followed by drying to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a screening mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) Carmellose calcium (1848 g) and magnesium stearate (132.0 g) are added to the obtained sized powder (40920 g (for 2 batches)), and a tumbler mixer (TM20-0-0, Suehiro Chemical Industries, Ltd.) is added. ) To obtain a mixed powder.
(3) The mixed powder obtained above was tableted with a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) using a 7.0 mm diameter punch (tablet pressure 9 kN, weight per tablet: 130 mg) Thus, uncoated tablets having the compositions shown in Table 26 were obtained.

[Test Example 1]
Dissolution test 1
The dissolution properties of the active ingredient (Compound A) from the uncoated tablets obtained in Examples 1 to 11, 24, 25 and Comparative Example 1 were determined using a dissolution test (1.0 (w / w)% polysorbate 20 solution, 900 mL, 37 (C, paddle method, rotation speed 50 rpm). The dissolution test was conducted according to the 15th revised Japanese Pharmacopoeia dissolution test method 2 (paddle method). The results are shown in Table 27. Table 27 shows the average value, maximum value, and minimum value of the elution rate 15 minutes after the start of elution. Examples 1, 4, 5, 8 to 11, 24, 25 and Comparative Example 1 are the average value, maximum value and minimum value of the dissolution rate of 6 tablets, and Examples 2, 3, 6 and 7 are tablets 12 The average value, maximum value, and minimum value of the dissolution rate.

  As shown in Table 27, in any of the uncoated tablets of Examples 1 to 11, 24, and 25 containing sugar alcohol as an excipient, compound A was compared with the uncoated tablet of Comparative Example 1 not containing sugar alcohol. The good elution property of was shown.

[Test Example 2]
Dissolution test 2
The dissolution property of the active ingredient (Compound B) from the film-coated tablet obtained in Example 20 was determined by dissolution test (15th revised Japanese Pharmacopoeia dissolution test 2nd solution, 900 mL, 37 ° C., paddle method, rotation speed 50 rpm). evaluated. The dissolution test was conducted according to the 15th revised Japanese Pharmacopoeia dissolution test method 2 (paddle method). The results are shown in Table 28. Table 28 shows the average value, maximum value, and minimum value of the dissolution rate of 6 tablets at each time point 5 to 60 minutes after the start of dissolution.

  As shown in Table 28, the film-coated tablet of Example 20 showed a good dissolution property of Compound B.

[Test Example 3]
Stability test The uncoated tablets of Examples 1, 4 and 5 were stored at 25 ° C./60% RH for 12 months under the conditions of glass bottle seals, and the amounts of related substances derived from compound A or amlodipine besylate were measured. The storage stability was evaluated. The results are shown in Table 29. The values in Table 29 are derived from compound A or amlodipine besylate when the content of compound A or amlodipine besylate (compound A; 8 mg or 4 mg / amlodipine besylate; 6.93 mg or 3.47 mg) is 100%. The percentage of total related substances is shown.

  As shown in Table 29, the uncoated tablets of Examples 1, 4 and 5 showed good storage stability.

  The present invention provides a solid preparation containing a compound represented by the formula (I) or a salt thereof, a sugar alcohol, and a calcium antagonist, and in the solid preparation, the compound represented by the formula (I) or a compound thereof The elution of the salt and calcium antagonist from the solid preparation in the gastrointestinal tract is appropriately controlled, and the stability in these solid preparations is also good.

  This application is based on patent application Nos. 2009-111181 and 2010-68625 filed in Japan, the contents of which are incorporated in full herein.

Claims (12)

(i) Formula (I):

(In the formula, R ¹ represents a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated, R ² represents a carboxyl group that may be esterified, and R ³ may be substituted. Or a salt thereof, (ii) a sugar alcohol, and (iii) a calcium antagonist.   The compound represented by the formula (I) or a salt thereof is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl. Benzimidazole-7-carboxylate, 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylic acid, 2- Ethoxy-1-[[2 ′-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -1H-benzimidazole-7- The solid preparation according to claim 1, which is a carboxylic acid or a salt thereof.   The compound represented by the formula (I) or a salt thereof is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl. The solid preparation according to claim 1, which is benzimidazole-7-carboxylate or a salt thereof.   The compound represented by the formula (I) or a salt thereof is 2-ethoxy-1-[[2 ′-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl). The solid preparation according to claim 1, which is biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylic acid or a salt thereof.   The solid preparation according to claim 1, wherein the sugar alcohol is mannitol, sorbitol or erythritol.   The solid preparation according to claim 1, wherein the sugar alcohol is mannitol.   The solid preparation according to claim 1, wherein the calcium antagonist is azelnidipine, amlodipine, alanidipine, efonidipine, cilnidipine, nicardipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, varnidipine, felodipine, benidipine, manidipine or a salt thereof.   The solid preparation according to claim 1, wherein the calcium antagonist is amlodipine or a salt thereof.   The solid preparation according to claim 1, further comprising polyethylene glycol.   The solid preparation according to claim 9, wherein the polyethylene glycol has a molecular weight of 1,000 to 10,000.   (i) 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a salt thereof (Ii) A solid preparation containing mannitol and (iii) amlodipine or a salt thereof.   (i) 2-Ethoxy-1-[[2 '-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -1H- A solid preparation containing benzimidazole-7-carboxylic acid or a salt thereof, (ii) mannitol, and (iii) amlodipine or a salt thereof.