TWI438201B - Solid preparation - Google Patents

Description

solid preparations

The present invention relates to a solid formulation which exhibits improved solubility properties of the drug from the formulation.

Hypertension is one of the most common diseases in adults. According to the basic research of 2000 kinds of circulating diseases made by the Ministry of Health, Labor and Welfare of Japan, the number of hypertensive patients in Japan (with a systolic blood pressure of not less than 140 mmHg or a diastolic blood pressure of not less than 90 mmHg, or taking antihypertensive agents) has reached about 3 Thousands of million to 38 million. Hypertension is a high risk factor for all circulatory diseases, including cerebrovascular disease and myocardial infarction. Therefore, proper control of blood pressure is important to improve the prognosis of patients and reduce the burden on individuals and society.

A variety of drugs have been developed (eg, decompressive diuretics, alpha blockers, beta blockers, angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, angiotensin II receptor antagonists) Etc.) As a therapeutic drug for hypertension, and many patients diagnosed with hypertension are treated with such antihypertensive agents. For example, a compound represented by the following formula (I) or a salt thereof:

(wherein R ¹ is a monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom, R ² is a carboxyl group which is optionally esterified, and a lower alkyl group which is optionally substituted by R ³ ) is known. Angiotensin II receptor antagonist, which exhibits excellent antihypertensive effects and organ protection. JP-B-2514282 discloses 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid 1 - (Cyclohexyloxycarbonyloxy)ethyl ester (candesartan cilexetil) as an example of a representative agent.

According to J-HOME's study (Japanese family-to-office blood pressure measurement assessment study), about 40% of hypertensive patients receiving drug therapy have reached the required blood pressure (the random blood pressure of outpatients is less than 140/90mmHg), which means Even with existing medications, some patients are unable to adequately control their blood pressure. In order to increase the proportion of blood pressure required, more effective antihypertensive treatment is needed.

For the treatment of drugs that exert a stronger antihypertensive effect, a combination therapy using a plurality of drugs can be mentioned. For example, WO 01/15674 discloses the combined use of a renin-angiotensin inhibitor and other antihypertensive agents, cholesterol lowering drugs, diuretics and the like. WO 02/43807 discloses the combined use of angiotensin II receptor antagonists and other antihypertensive agents or statins. However, the combined use of multiple agents at different times may have an adverse effect on the patient's drug compliance, and may cause fear of inadvertent blood pressure control failure. For clinical practice, in order to more appropriately control blood pressure, it is strongly required to contain a combination preparation of various antihypertensive agents in a single agent because it is an ideal agent that exhibits a strong decompression effect and maintains patient compliance with medication.

A combined preparation containing an angiotensin II receptor antagonist and a calcium antagonist is recommended as the combined preparation. WO 92/10097 discloses a combination preparation comprising an angiotensin II receptor antagonist and other agents (e.g., diuretics, calcium antagonists, etc.). JP-A-2006-290899 discloses a combination preparation containing an imidazole carboxylate type angiotensin II receptor antagonist (for example, olmesartan medoxomil, etc.) and a calcium antagonist. U.S. Patent No. 6,240,281 discloses valsartan (an angiotensin II receptor antagonist) and a 1,4-dihydropyridine compound (for example, amlodipine, etc. as a calcium antagonist). Combination preparation. JP-B-2930252 discloses 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid Or a combination of pharmaceutically acceptable salts thereof, each of which is an angiotensin II receptor antagonist, and diltiazem (a calcium antagonist). Further, JP-B-3057471 discloses a combined preparation containing a benzimidazole derivative (which is an angiotensin receptor antagonist) and a diuretic or calcium antagonist.

In clinical practice, it is expected that a preparation containing a benzimidazole derivative (which is an angiotensin II receptor antagonist) and a calcium antagonist can simultaneously exhibit a benzimidazole derivative (which is a highly organ protective effect of angiotensin II). The efficacy of a body antagonist and the effect of a calcium antagonist (with a strong decompression effect). In addition, because of its combined manner, its action can be enhanced and side effects are reduced, so its clinical utility is extremely high.

However, in order to stabilize the effectiveness and safety of the pharmaceutical product, not only the effectiveness and safety of the active ingredient itself are important, but also the nature of the pharmaceutical preparation such as the dissolution property of the drug in the body is extremely important. For example, when the drug dissolves too slowly from the pharmaceutical preparation, the blood concentration of the drug cannot reach an effective level and may not fully demonstrate its intended efficacy. On the other hand, when the drug is dissolved too quickly from the pharmaceutical preparation, the blood concentration of the drug will rise rapidly, causing a high risk of side effects.

In other words, in addition to effectiveness and safety, pharmaceutical products need to ensure a specific level of drug dissolution. The combination preparation should be compatible with the various conditions required for the various additives and the respective active ingredients. Therefore, the development of formulations that meet all of these conditions is often difficult compared to formulations containing a single active ingredient. In particular, since the benzimidazole derivative (which is an angiotensin II receptor antagonist) is a poorly soluble compound, the solubility properties of the preparation may be lowered by the nature of the additive to be combined and the active ingredient. When the drug is released from the delayed release of the combined preparation, it results in a decrease in drug absorption, a decrease in bioavailability (i.e., a decrease in the efficacy of the active ingredient), and a decrease in the value of the combination agent. Therefore, for a pharmaceutical preparation to be practically applied, it is necessary to adjust the composition of the preparation to optimize the dissolution rate of the active ingredient in the gastrointestinal tract.

Accordingly, it is an object of the present invention to provide a solid preparation containing a benzimidazole derivative (with angiotensin II receptor antagonist action) and a calcium antagonist which is controlled to cause such drugs in the gastrointestinal tract. The solubility properties of the formulation are optimized.

The inventors of the present invention conducted intensive studies in an attempt to solve the above problems, and thus found a preparation comprising (i) a compound represented by the formula (I) or a salt thereof, (ii) a sugar alcohol, and (iii) a calcium antagonist, The formulation exhibits suitably controlled solubility properties in the human gastrointestinal tract. Specifically, they have paid particular attention to excipients, and found that the solubility properties of the drug from the solid preparation can be improved by using a highly water-soluble sugar alcohol, and thus the present invention has been completed.

Accordingly, the present invention relates to [1] a solid preparation comprising (i) a compound of the formula (I) or a salt thereof: (wherein R ¹ is a monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom, R ² is a carboxyl group which is optionally esterified, and R ³ is a lower alkyl group which may be optionally substituted), (ii) a sugar The solid preparation of the above [1], wherein R ² is a lower alkyl group having a carbon number of 1 to 4 as needed (which is optionally selected from the following 1 to Substituted by three substituents: a hydroxyl group, an amine group, a halogen atom, a lower alkyl alkoxy group having a carbon number of 2 to 6, a lower cycloalkyloxy group having a carbon number of 4 to 7, and having a carbon number of 1 to a carbonyloxy group of a lower alkoxy group of 6, a carbonyloxy group having a lower cycloalkoxy group having 3 to 7 carbon atoms, and a carboxyl group esterified with a lower alkoxy group having 1 to 4 carbon atoms; [1B The solid preparation of the above [1], wherein R ² is a 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl group or a carboxyl group; [2] the solid preparation of the above [1], [1A] or [1B] Wherein the compound of the formula (I) or a salt thereof is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzo Imidazole-7-carboxylic acid 1-(cyclohexyloxycarbonyloxy)ethyl ester, 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- Azoxa-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof; [3] above [1], [2], [1A] or [1B A solid preparation wherein the compound of the formula (I) or a salt thereof is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]- 1-(cyclohexyloxycarbonyloxy)ethyl ester of benzimidazole-7-carboxylic acid or a salt thereof; [4] The solid preparation of the above [1], [2], [1A] or [1B], Wherein the compound of the formula (I) or a salt thereof is 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4- Azoxa-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof; [5] above [1], [2], [3], [4] The solid preparation of [1A] or [1B], wherein the sugar alcohol is mannitol, sorbitol or erythritol; [6] the above [1], [2], [3], [4] The solid preparation of [5], [1A] or [1B], wherein the sugar alcohol is mannitol; [7] the above [1], [2], [3], [4], [5], [ 6) The solid preparation of [1A] or [1B], wherein the calcium antagonist is azelnidipine, amlodipine, aranidipine, efonidipine, sini Lidnidipine, nicardipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, barnidipine, felodipine (felodipine), benidipine, manidipine or its salt; [8] above [1], [2], [3], [4], [5], [6], [ 7] The solid preparation of [1A] or [1B], wherein the calcium antagonist is amlodipine or a salt thereof; [9] the above [1], [2], [3], [4], [5] , [6], [7], [8], [1A] or [1B] solid system [10] The solid preparation of the above [9], wherein the polyethylene glycol has a molecular weight of 1,000 to 10,000; [11] a solid preparation comprising (i) 2-ethoxy- 1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid 1-(cyclohexyloxycarbonyloxy)ethyl ester or a solid preparation of the above [11], which comprises a polyethylene glycol; [11B] a solid preparation of the above [11A], wherein The polyethylene glycol has a molecular weight of 1,000 to 10,000 (preferably 3,000 to 10,000); [11C] The solid preparation of the above [11B], wherein the content of the polyethylene glycol is from 1 to 5% by weight; [11D] above [ a solid preparation of 11B], wherein the content of the polyethylene glycol is 1 to 3% by weight; [12] a solid preparation comprising (i) 2-ethoxy-1-[[2'-(4,5- Dihydro-5-oxo-1,2,4- Azoxa-3-yl)biphenyl-4-yl]methyl]-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 [12], which comprises a polyethylene glycol; [12B] The solid preparation of the above [12A], wherein the polyethylene glycol has a molecular weight of 1,000 to 10,000 (preferably 3,000 to 10,000);

[12] The solid preparation of the above [12B], wherein the content of the polyethylene glycol is from 1 to 5% by weight;

[12D] The solid preparation of the above [12B], wherein the content of the polyethylene glycol is from 1 to 3% by weight;

[13] above [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12 a solid preparation of [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D] is a tablet;

[14] above [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12 a solid preparation of [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D] is a single layer tablet;

[15] above [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12 ], [13], [14], [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D] The solid preparation is a prophylactic or therapeutic drug for hypertension, heart failure, diabetic nephropathy or arteriosclerosis;

[16] above [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12 ], [13], [14], [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D] The solid preparation is a prophylactic or therapeutic drug for hypertension or the like; and the like.

According to the present invention, a solid preparation can be obtained, wherein the compound of the above formula (I) (or a salt thereof) and the calcium antagonist are appropriately controlled in the gastrointestinal tract from the dissolution of the preparation, and are finely maintained in the preparation. Stability. That is, the solid preparation of the present invention is excellent in the properties of the compound represented by the above formula (I) or a salt thereof and a calcium antagonist dissolved from the preparation and its stability.

The solid preparation of the present invention will be described in detail below.

The solid preparation of the present invention is a solid preparation including the following:

(i) a compound represented by the following formula (I) or a salt thereof:

Wherein R ¹ is a monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom, R ² is a carboxyl group which is optionally esterified, and R ³ is a lower alkyl group which is optionally substituted; (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), the monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom as R ¹ may, for example, be a tetrazolyl group or a group represented by the following formula:

Where i is -O- or -S-, j is >C=O, >C=S or >S(O) _m

Where m is 0, 1, or 2. Preferred groups may be tetrazolyl, 4,5-dihydro-5-sideoxy-1,2,4- Diazol-3-yl and the like.

4,5-dihydro-5-sideoxy-1,2,4- The oxazol-3-yl group contains three tautomers (a', b' and c') as shown in the following formula:

And the 4,5-dihydro-5-sideoxy-1,2,4- The oxazol-3-yl group includes all of the above a', b' and c'.

In the above formula (I), examples of the carboxyl group which is required to be esterified by R ² include a carboxyl group which is esterified with a lower alkyl group having a carbon number of 1 to 4 as necessary. The above lower alkyl group may be optionally substituted with 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of a hydroxyl group, an amine group, a halogen atom, and a carbon number of 2 to 6 a lower alkyl alkoxy group (for example, acetyloxy group, pivaloyloxy group, etc.), a lower cycloalkyloxy group having a carbon number of 4 to 7, and having a carbon number a carbonyloxy group of a lower alkoxy group of 1 to 6 (for example, a methoxycarbonyloxy group, an ethoxycarbonyloxy group, etc.), a carbonyloxy group having a lower cycloalkyloxy group having a carbon number of 3 to 7 ( For example, a cyclohexyloxycarbonyloxy group or the like) and a lower alkoxy group having a carbon number of 1 to 4. Preferred groups may be 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, carboxy and the like.

In the above formula (I), the lower alkyl group which is required to be substituted as R ³ may be a lower alkyl group having a carbon number of 1 to 5, which may optionally be one to five selected from the group consisting of the following: The substituent (preferably 1 to 3) is substituted with a hydroxyl group, an amine group, a halogen atom, and a lower alkoxy group having 1 to 4 carbon atoms. It is preferably a lower alkyl group having 2 to 3 carbon atoms, more preferably an ethyl group.

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

The compound represented by the above formula (I) or a salt thereof may be a hydrate or a non-hydrate, and may be a solvate or an unsolvate.

Further, the compound represented by the above formula (I) or a salt thereof is preferably in a crystalline form and has a melting point of from 100 ° C to 250 ° C, preferably from 120 ° C to 200 ° C, especially from 130 ° C to 180 ° C. point.

As the solid preparation of the present invention, a compound represented by the above formula (I) or a salt thereof is used. Preferable examples of the compound or a salt thereof include: 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7- 1-(Cyclohexyloxycarbonyloxy)ethyl carboxylate, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]- 1H-benzimidazole-7-carboxylic acid, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole -7-carboxylic acid trimethylacetoxymethyl ester, 2-ethoxy-1-[[2'-(4,5-dihydro-5-pentaoxy-1,2,4- Azoxa-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid and salts thereof. Among them, particularly preferred is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid 1-(cyclo) Hexyloxycarbonyloxy)ethyl ester and its salt, 2-ethoxy-1-[[2'-(4,5-dihydro-5-o-oxy-1,2,4- Azoxa-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid and salts thereof.

In the present invention, the compound represented by the above formula (I) or a salt thereof is used in a ratio of 0.1 to 60% by weight, preferably 1 to 40% by weight, more preferably 3 to 30% by weight (based on the free form) It is included in the solid preparation of the present invention.

As the sugar alcohol to be used in the present invention, any kind of sugar alcohol can be used as long as the sugar alcohol can simultaneously establish the stability of the compound represented by the above formula (I) or a salt thereof in the preparation and the dissolution property thereof from the preparation, And can be used in pharmaceutical products. Examples of the sugar alcohol to be used in the present invention include: monosaccharide sugar alcohols such as butanol (for example, erythritol, D-threitol, L-threitol, etc.), penta-5 Alcohols (eg, D-arabitol, xylitol, etc.), hexitols (eg, D-iditol, galactitol (sweet alcohol), D-glucitol (sorbitol), mannitol , a cyclic sugar alcohol (for example, cyclohexanol, etc.), etc.; a disaccharide sugar alcohol such as hydrogenated maltose, lactitol, reduced paratinose (isomalt), etc.; Sugar sugar alcohols, such as neopentyl alcohol, hydrogenated maltose starch syrup, etc.; among them, monosaccharide sugar alcohols are preferred. More preferably mannitol, sorbitol and erythritol, especially nectar Sugar alcohol is preferred, and D-mannitol is particularly preferred. A sugar alcohol can be used alone, or two or more sugar alcohols can be used in combination. In addition, the sugar alcohol can simultaneously achieve the stability of the calcium antagonist in the preparation. Sex and its self-formulation solubility properties.

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

Examples of calcium antagonists for use in the present invention include: dihydropyridine compounds, for example, adipine, amlodipine, adipine, efavidipine, cilnidipine, nicardipine, nisoldipine, nitrendipine , nifedipine, nilvadipine, bainidipine, felodipine, benidipine, mandipine; benzodiazepine compounds, for example, diltiazem, etc.; Calcium antagonists for use in the present invention also include the aforementioned salts as calcium antagonists.

As the calcium antagonist used in the present invention, a dihydropyridine compound, particularly amlodipine or a salt thereof, is preferred. Among them, a salt of amlodipine is more preferred, and amlodipine besylate is particularly preferred.

In the present invention, the calcium antagonist is included in the present invention in a ratio of usually from 0.05 to 60% by weight, preferably from 0.1 to 40% by weight, more preferably from 0.5 to 20% by weight, based on the free form. In solid preparations. Specifically, for example, the content ratio of amlodipine (based on the free form) is usually from 0.05 to 60% by weight, preferably from 0.1 to 40% by weight, more preferably from 0.5 to 20% by weight.

The solid preparation of the present invention may further comprise an alkylene oxide polymer. Examples of the alkylene oxide polymer include a stretched ethyl oxide polymer, a propylated oxide polymer, a trimethylene oxide polymer or tetrahydrofuran or the like (preferably an ethylidene group). Oxide polymer). The molecular weight of the alkylene oxide polymer is preferably from 1,000 to 10,000, more preferably from 3,000 to 10,000. The alkylene oxide polymer may be an alkylene oxide copolymer, and examples of the alkylene oxide copolymer include copolymers of two or more of the foregoing alkylene oxides, which have from 1,000 to 10,000 (more) A molecular weight of preferably 3,000 to 10,000).

An alkylene oxide polymer may be used alone or in combination of two or more alkylene oxide polymers.

As the alkylene oxide polymer used in the present invention, polyethylene glycol is preferred, polyethylene glycol having a molecular weight of 1,000 to 10,000 is more preferred, and polyethylene glycol having a molecular weight of 3,000 to 10,000 is particularly preferred. For example, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 10000).

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

A preferred embodiment of the solid preparation of the present invention comprises: a solid preparation wherein the compound represented by the above formula (I) or a salt thereof is 2-ethoxy-1-[[2'-(1H-tetrazole- 1-(cyclohexyl-4-yl)methyl]benzimidazole-7-carboxylic acid 1-(cyclohexyloxycarbonyloxy)ethyl ester (hereinafter sometimes referred to as "Compound A") or a salt thereof And the calcium antagonist is amlodipine besylate; a solid preparation, wherein the compound represented by the above formula (I) or a salt thereof is 2-ethoxy-1-[[2'-(4,5-di) Hydrogen-5-sideoxy-1,2,4- Azoxa-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (hereinafter sometimes referred to as "Compound B") or a salt thereof, and the calcium antagonist is benzene Amlodipine sulfonate; and so on.

The solid preparation of the present invention may, for example, be a solid preparation suitable for oral administration such as a tablet, a granule, a fine granule, a capsule, a pill or the like, preferably It is a tablet, more preferably a single layer tablet. When the solid preparation of the present invention is a tablet, it may be in the form of a circle, an ellipse, a rectangle or the like. The size of the lozenge can vary depending on the tablet form (round, oval, caplet, rectangle, etc.) and any size is possible as long as the patient is easy to take. When the solid preparation of the present invention is a single-layer tablet, it is easy to take because of its small size.

Specific examples of the solid preparation of the present invention include:

(1) A set of granulated preparations

The solid preparation comprises a compound represented by the 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 a polyethylene a mixture of diols granulated and obtained by compression molding the obtained granulated material (for example, a set of granulated single-layer tablets);

(2) Two-component granulation preparation

(a) a solid preparation obtained by mixing and compression molding the following individual granulation to obtain the first part and the second part (for example, a two-component granulated tablet);

(b) a solid preparation obtained by compression molding (without mixing) of the following individual granulation to obtain the first part and the second part (for example, a multilayer tablet);

(c) a solid preparation obtained by coating one of the first part and the second part obtained by granulating the following separately (for example, a dry coated tablet);

The first part: a part comprising a compound represented by the formula (I) or a salt thereof (preferably: a compound represented by the formula (I) or a salt thereof, and a polyethylene glycol)

Part II: Parts containing sugar alcohols and calcium antagonists

and many more.

A preferred embodiment of the solid formulation of the present invention is a set of granulated formulations (e.g., a set of granulated monolayer tablets).

The solid preparation of the present invention may contain an additive conventionally used in the field of medicine. Examples of the additive include an excipient, a disintegrator, a binder, a lubricant, a pH adjuster, a colorant, a surfactant, a stabilizer, an acidifier, a flavoring agent, a glidant, and the like. These additives are used in the amounts used in the field of conventional medicine. Further, these additives may be used in a mixture of two or more kinds in an appropriate ratio.

Examples of excipients include starch (eg, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, porous starch, etc.); sugars (eg, lactose, fructose, glucose, sucrose, etc.) Anhydrous calcium phosphate, crystalline cellulose, microcrystalline cellulose, licorice (Glycyrrhiza uralensis), sodium hydrogencarbonate, calcium phosphate, calcium sulfate, calcium carbonate, precipitated calcium carbonate, calcium citrate, and the like.

Examples of the disintegrant include amino acid, starch, corn starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, sodium carboxellose sodium, carboxymethyl cellulose. Carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropyl starch, and the like.

In the present invention, the disintegrating agent is contained in the solid preparation of the present invention in a proportion of preferably from 0.1 to 30% by weight, more preferably from 1 to 10% by weight.

Examples of the binder include crystalline cellulose (for example, microcrystalline cellulose), hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, gelatin, starch, gum arabic powder, and jaundice. Gum, carboxymethyl cellulose, sodium alginate, pullulan, glycerin, and the like.

In the present invention, the binder is contained in the solid preparation of the present invention in a proportion of preferably from 0.1 to 40% by weight, more preferably from 1 to 10% by weight.

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

Examples of the lubricant include citric acid and salts thereof, phosphoric acid and salts thereof, carbonic acid and salts thereof, tartaric acid and salts thereof, fumaric acid and salts thereof, acetic acid and salts thereof, amino acids and salts thereof and the like.

Examples of the coloring agent include food coloring agents such as food coloring yellow No. 5, food coloring red No. 2, food coloring blue No. 2, etc.; food lake color, for example, food coloring yellow No. 4 aluminum lake; Iron oxide pigments, for example, red iron oxide (colcothar), yellow iron oxide, triiron tetroxide (black iron oxide), and the like; and the like.

Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, polyoxyethylene ethyl (160) polyoxypropyl propylene (30) diol, and the like.

Examples of stabilizers include tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin, and the like.

Examples of the acidifying agent include ascorbic acid, citric acid, tartaric acid, malic acid, and the like.

Examples of the flavoring agent include menthol, peppermint oil, lemon oil, vanillin, and the like.

Examples of the glidant include light anhydrous citric acid, hydrated cerium oxide, and the like.

The solid preparation of the present invention can be processed into a film-coated preparation by using a film coating (for example, a coating base, a coating additive, or the like). Examples of the film coating preparation include a sugar coating preparation, a sustained release type film coating preparation, an enteric preparation, and the like.

Preferred examples of the coating base include a sugar-based base, a water-soluble film-coating agent, an enteric film-coating agent, a sustained-release film-coating agent, and the like.

As for the sugar-coated base, sucrose is used. Further, one or more selected from the group consisting of talc, precipitated calcium carbonate, gelatin, gum arabic, polytriglucose, palm wax and the like may also be used in combination.

Examples of the water-soluble film coating base include: a cellulose polymer such as hydroxypropyl cellulose [for example, NISSO HPC (grade: L, SL, SL-T, SSL) (trade name); Nippon Soda Ltd.], hydroxypropyl methylcellulose [eg, TC-5 (grade: MW, E, EW, R, RW) (trade name); Shin-Etsu Chemical Co., Ltd.]], hydroxyethyl cellulose, Methyl hydroxyethyl cellulose, etc.; synthetic polymer, such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Etech E ( Eudragit E, trade name); manufactured by Rohm and Haas Japan, polyvinylpyrrolidone, etc.; polysaccharides such as polytriglucose, etc.;

Examples of enteric film-coating agents include: cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose , cellulose acetate phthalate, etc.; acrylic polymer, such as methacrylic acid copolymer L [Utech L (trade name)], methacrylic acid copolymer LD [Yutz L-30D55 (commodity Name); manufactured by Rohm and Haas Japan], methacrylic acid copolymer S [Utech S (trade name); manufactured by Rohm and Haas Japan], etc.; naturally occurring polymers such as shellac, etc.;

Examples of the sustained release type film coating base include: a cellulose polymer such as ethyl cellulose or the like; an acrylic polymer such as an aminoalkyl methacrylate copolymer RS [Utchi RS (trade name); Solomon Manufactured by Haas Japan Co., Ltd., ethyl acrylate-methyl methacrylate copolymer suspension [Utchi NE (trade name); manufactured by Rohm and Haas Japan], etc.;

Preferable examples of the coating additive include: a light protective agent such as titanium oxide or the like; a glidant such as talc; a coloring agent such as red iron oxide, yellow iron oxide, etc.; a plasticizer such as polyethylene glycol [For example, polyethylene glycol 6000 (macrogol 6000) (trade name); manufactured by Sanyo Chemical Industry Co., Ltd.], triethyl citrate, castor oil, polysorbate, etc.; organic acids such as citric acid, tartaric acid, malic acid , ascorbic acid, etc.;

The solid preparation of the present invention can be produced by a known method (for example, the method described in Japanese Pharmacopoeia 15th Edition, General Principles).

Examples of methods include operations such as mixing, tanning, granulating, compression molding, film coating, and the like, and suitable combinations of such operations.

For example, mixing is carried out using, for example, a mixer (such as a horizontal cylindrical mixer, a V-type mixer, a tumbler mixer, etc.); and using a rotary vessel type tanning machine (for example, a ball mill, etc.), fixing A container type tanning machine (for example, a screw type tanning machine, a Henschel mixer, etc.), a tanning machine, a rolling tanning machine (for example, a rolling mill, a push-rolling machine, etc.); Granulation is carried out by the following method: stirring granulation method using a high-speed stirring granulator, use of a container (pot container, cone-shaped container, multi-stage cone-shaped container (multi Rolling granulation method, fluidized bed granulation and drying method, spray drying granulation method, extrusion granules for -stage conical drum type), roll container with agitating plate, vibrating container, etc. a method, a method using a granulator (for example, a Roller-compactor), and the like.

For example, compression molding is carried out by molding (using an extrusion molding machine) or by ingot (using a single punch tableting machine, a rotary tableting machine, etc.).

When compression grinding is performed using a single stroke tableting machine, a rotary tableting machine, etc., it is generally preferred to use 1 to 35 kilonewtons per square centimeter (kN/cm ² ) (more preferably 5 to 5). 35 kN/cm ² ) tableting pressure. Further, in order to prevent capping, a taper cutting die is preferably used.

For example, the film coating is performed by using a pan coating machine such as a horizontal type or a tilt type; a fluid coating machine such as a horizontal rotary type or a swash plate type; Fluidized bed machines, fluidized bed type, tumbling fluidized bed type, etc.; and the like.

For example, the solid preparation of the present invention can be produced by the following production steps:

(1) If the solid preparation of the present invention is a group of granulation preparations

A compound represented by the 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 a polyethylene glycol) are contained. The mixture was granulated, and the obtained granulated material was subjected to compression molding to obtain a solid preparation of the present invention (a set of granulated single-layer tablets).

Specifically, a compound represented by the above formula (I) or a salt thereof, a calcium antagonist and an additive (for example, an excipient, a sugar alcohol (such as D-mannitol), etc.) are mixed, the mixture is granulated, and sprayed with a solvent. (eg, water) A liquid obtained by dispersing or dissolving polyethylene glycol and an additive such as a binder.

An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material, and after mixing, the mixture is compression molded to obtain a tablet. The tablet is coated with a film solution containing a coating base or the like to prepare a solid preparation of the present invention (a set of granulated single-layer tablets).

(2) If the solid preparation of the present invention is a two-component preparation

(a) a two-part granulated monolayer preparation;

Mixing the compound of the above formula (I) or a salt thereof, an additive (such as an excipient, etc.), granulating the mixture, and spraying a liquid (which is obtained by dispersing or dissolving polyethylene glycol) and dissolving in a solvent (for example, water) Additives (such as binders).

In another aspect, a calcium antagonist and an additive (such as an excipient, a sugar alcohol (such as D-mannitol), etc.) are mixed, the mixture is granulated, and the polyethylene glycol and the additive are sprayed with a solvent (eg, water) ( The resulting liquid is dispersed or dissolved, such as a binder.

An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material containing the compound represented by the above formula (I) or a salt thereof, and added to the obtained granulated material containing the calcium antagonist, and after mixing, the compression mold This mixture was prepared to obtain a solid preparation (two-component granulated tablet) of the present invention.

(b) a multilayer tablet;

Mixing the compound of the above formula (I) or a salt thereof, an additive (such as an excipient, etc.), granulating the mixture, and spraying the solvent (for example, water) to disperse the polyethylene glycol and the additive (such as a binder). Or dissolve the resulting liquid. An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material to obtain a mixed granule.

In another aspect, a calcium antagonist and an additive (such as an excipient, a sugar alcohol (such as D-mannitol), etc.) are mixed, the mixture is granulated, and the polyethylene glycol and the additive are sprayed with a solvent (eg, water) ( The resulting liquid is dispersed or dissolved, such as a binder. An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material to obtain a mixed granule.

The resulting mixed granules containing the compound of the above formula (I) or a salt thereof, and the resulting mixed granules containing a calcium antagonist are stacked one on another and compression-molded to obtain a solid preparation (multilayer tablet) of the present invention.

(c) a dry coated tablet;

Mixing calcium antagonists and additives (such as excipients, sugar alcohols (such as D-mannitol), etc.), granulating the mixture, and spraying or dissolving or dissolving additives (such as binders) in a solvent (eg, water). Liquid. An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material, and after mixing, the mixture is compression molded to obtain a tablet. The tablet is coated with a film solution containing a coating base or the like to prepare a core tablet.

On the other hand, a compound represented by the above formula (I) or a salt thereof, an additive (such as an excipient, etc.) is mixed, the mixture is granulated, and a polyethylene glycol and an additive (such as a binder) are sprayed with a solvent (for example, water). The agent, etc.) disperses or dissolves the resulting liquid. An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material to obtain a mixed granule.

A mixed granule is added as an outer layer to the core tablet described above, and compression-molded to obtain a solid preparation of the present invention (dry coated tablet)

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

When the solid preparation of the present invention is a capsule, it can be obtained by filling the above granules or fine granules into capsules containing gelatin, hydroxypropylmethylcellulose or the like. Further, the hard capsule can be filled into a capsule containing gelatin, hydroxypropylmethylcellulose or the like by the compound represented by the above formula (I) or a salt thereof, a calcium antagonist, together with a sugar alcohol and other excipients and the like. Made in the middle. Further, the soft capsule can be obtained by encapsulating the compound represented by the above formula (I) or a salt thereof and a calcium antagonist into a predetermined shape with a base containing gelatin and a plasticizer (e.g., glycerin or the like).

The solid preparation of the present invention may have an embossed or printed typeface for identification on its surface. Further, it may have a scribe line for division.

The solid preparation of the present invention is low in toxicity and can be safely administered as a mammal by oral or parenteral administration (for example, human, monkey, cat, pig, horse, cow, mouse, rat, guinea pig, dog) , rabbits, etc.).

Since the compound represented by the formula (I) or a salt thereof has strong angiotensin II antagonist activity, the solid preparation of the present invention is suitable for use as a prophylactic or therapeutic drug as follows: (1) development due to stenosis or growth of blood vessels (or promote its development) diseases or organ abnormalities expressed by angiotensin II receptors, (2) diseases that develop (or promote their development) due to the presence of angiotensin II or (3) due to the above-mentioned mammals A disease in which a factor caused by angiotensin II is developed (or promotes its development).

Examples of the diseases (1) to (3) above include: hypertension, blood pressure circadian rhythm abnormality, heart disease (for example, cardiac hypertrophy, acute heart failure, chronic heart failure (including heart failure), Impaired expansion, cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, myocardial infarction, etc., cerebrovascular disease (eg, asymptomatic cerebrovascular disease, transient cerebral ischemia, stroke, brain Vascular dementia, hypertensive brain lesions, cerebral embolism, etc.), cerebral edema, cerebral circulation disorders, recurrence and sequelae of cerebrovascular diseases (eg, neurological symptoms, mental symptoms, subjective symptoms, abnormal activities of daily living, etc.), Ischemic peripheral circulatory disorders, myocardial ischemia, varicose veins, progression of cardiac insufficiency after myocardial infarction, renal disease (eg, nephritis, glomerulonephritis, renal glomerulosclerosis, renal failure, thrombotic angiopathy, Diabetic nephropathy, complications of dialysis, organ damage (including nephropathy caused by radiation exposure), arteriosclerosis (including atherosclerosis) For example, aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular hypertrophy, interventional therapy (eg, percutaneous coronary angioplasty, stent placement, coronary endoscopy, intravascular ultrasound) Vascular hypertrophy or occlusion and organ damage after sonication, dounce thrombolytic therapy, etc., revascularization or restenosis after bypass surgery, erythrocytosis, hypertension, organ damage after transplantation or vascular hypertrophy, post-transplant rejection, eye Diseases (eg, glaucoma, high intraocular pressure, etc.), thrombosis, multiple organ disorders, vascular endothelial cell dysfunction, hypertensive tinnitus, other cardiovascular diseases (eg, deep vein thrombosis, obstructive peripheral circulation disorders, arteries) Sclerosing occlusion, thromboembolic occlusion, ischemic cerebral circulation disorder, Raynaud's disease, Berger disease, etc., metabolic and/or nutritional disorders (eg, obesity, hyperlipemia) Disease, hypercholesterolemia, hyperuricemia, hyperkalemia, hypernatremia, etc.), neurodegenerative diseases (eg, Alzheimer's dis Ease), Parkinson's syndrome, amyotrophic lateral sclerosis, AIDS brain lesions, etc., central nervous system disorders (eg, injuries such as cerebral hemorrhage and cerebral infarction and their sequelae and complications, head Injury, spinal cord injury, cerebral edema, senile dementia, sensory abnormalities, sensory dysfunction, autonomic nervous system disorders, autonomic nervous system dysfunction, multiple sclerosis, etc., dementia, memory impairment, disturbance of consciousness, amnesia , anxiety, nervousness, mental state of discomfort, mental illness (eg, depression, epilepsy, alcoholism, etc.), inflammatory diseases (eg, arthritis, such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periosteum Inflammation, etc.; inflammation after surgery or injury; relief of swelling; pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory bowel disease, such as Crohn's disease, ulcerative colitis, etc. Inflammatory eye disease; inflammatory lung disease such as pneumonia, silicosis, pulmonary sarcoidosis, tuberculosis, etc., allergic diseases (eg , allergic rhinitis, conjunctivitis, digestive tract allergy, hay fever, systemic allergic reaction (anaphylaxis), chronic obstructive pulmonary disease, interstitial pneumonia, pneumocytis carinni pneumonia, collagen disease ( Collagen diseases) (eg, systemic lupus erythematosus, scleroderma, polyarteritis, etc.), liver diseases (eg, hepatitis (including chronic hepatitis), cirrhosis, etc.), portal hypertension, digestive disorders ( For example, gastritis, gastric ulcer, stomach cancer, postoperative gastric disease, dyspepsia, esophageal ulcer, pancreatitis, colon polyps, gallstones, acne disease, rupture of the esophagus and stomach, etc.), blood and/or hematopoietic diseases ( For example, erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple spinal cord disease, etc., bone disease (eg, fracture, refracture) , osteoporosis, osteomalacia, bone Paget's disease, sclerosing myelitis, rheumatoid arthritis a dysfunction of joint tissue caused by osteoarthrosis of the knee and a similar condition), a solid tumor, a tumor (for example, a malignant melanoma, a malignant lymphoma, a cancer of a digestive organ (for example, a stomach, an intestine, etc.), Cancer and malignant diseases with cancer, metastasis cancer, endocrine diseases (eg, Addison's disease, Cushing's syndrome, pheochromocytoma, aldosterone) Hyperactivity, primary corticosterone, etc.), Kuzd's disease, urinary organs and/or male genital diseases (eg, cystitis, prostate enlargement, prostate cancer, sexually transmitted diseases, etc.), Gynecological disorders (eg, menopausal disorders, gestational toxicity, endometriosis, uterine fibroids, ovarian disease, breast disease, sexually transmitted diseases, etc.), diseases associated with environmental or occupational factors (eg, radiation hazards; UV hazards) , the danger of far-infrared or laser beam; alpine disease, etc.), respiratory diseases (for example, cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis and pulmonary embolism) ), infectious diseases (for example, viral infectious diseases such as cytomegalovirus, influenza virus, herpes virus, etc.; rickettsiosis; bacterial infectious diseases, etc.), toxemias (for example, Sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock, etc., otolaryngology (eg, Meniere's syndrome, tinnitus, taste disorder, halo Dizziness, imbalance, difficulty swallowing, etc.), skin diseases (eg, keloid, hemangioma, dryness, etc.), intradialytic hypotension, myasthenia gravis, systemic diseases (eg chronic Fatigue syndrome, etc.) and so on.

The solid preparation of the present invention comprises a compound of the formula (I) or a salt thereof, a combination of a calcium antagonist, and is suitable for use as a prophylactic or therapeutic drug for the above diseases (preferably, hypertension, heart failure, diabetic nephropathy or arteries). A prophylactic or therapeutic drug for sclerosis). Further, the solid preparation of the present invention can reduce the dose of the compound of the formula (I) or a salt thereof, a calcium antagonist, compared to the compound of the formula (I) or a salt thereof or a calcium antagonist.

The dose of the compound of the formula (I) or a salt thereof varies depending on the administration target, the administration route, the target disease, the symptoms, and the like, and the daily dose of the human adult (weight: 60 kg (kg)) (free The form is from about 0.05 to 500 milligrams (mg), preferably from 0.1 to 100 mg, more preferably from 1 to 100 mg, and especially preferably from 2 to 40 mg. For example, the daily dose of Compound A human adult (body weight 60 kg) is about 1 to 80 mg, preferably 2 to 32 mg, and the daily dose of Compound B human adult (body weight 60 kg) is about 1 to 50 mg, preferably 10 to 40 mg.

The dose of the calcium antagonist varies depending on the administration of the target, the route of administration, the target disease, the symptoms, etc., for example, amlodipine or a salt thereof (based on the free form) of a human adult (body weight 60 kg) The daily dose is about 1 to 50 mg, preferably 2.5 to 10 mg.

The solid preparation of the present invention preferably has a frequency of administration to the above mammals of from 1 to 3 times per day, more preferably once a day.

Specific examples of particularly preferred solid preparations of the present invention include "a single layer tablet containing 8 mg of Compound A per bene and 6.93 mg of amlodipine besylate (5 mg of amlodipine)"; "8 mg per ingot" Compound A and 3.47 mg of amlodipine besylate (2.5 mg of amlodipine) in a single-layer tablet"; "4 mg of Compound A per bene and 6.93 mg of amlodipine besylate (amlodipine is 5 mg) of a single-layer tablet"; "a single-layer tablet containing 4 mg of Compound A per serving and 3.47 mg of amlodipine besylate (2.5 mg of amlodipine)"; "40 mg of compound per ingot" B and 6.93 mg of amlodipine besylate (5 mg of amlodipine) in a single-layer tablet"; "40 mg of Compound B per ingot and 3.47 mg of amlodipine besylate (amlodipine is 2.5) a single layer tablet of "mg"; "a single-layer tablet containing 20 mg of Compound B per bene and 6.93 mg of amlodipine besylate (5 mg of amlodipine)"; "20 mg of Compound B per ingot" And 3.47 mg of amlodipine besylate (2.5 mg of amlodipine) in a single-layer tablet"; "10 mg per spindle" Compound B and 6.93 mg of amlodipine besylate (5 mg of amlodipine) in a single layer"; and "10 mg of Compound B per ingot and 3.47 mg of amlodipine besylate (amlodipine) Then it is 2.5 mg) of a single-layer tablet."

The solid preparation of the present invention can be used in combination with one or more different pharmaceutical agents (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, a slimming agent, a diuretic, and the like.

Here, for example, as a therapeutic agent for diabetes, there are: an insulin preparation (for example, an animal insulin preparation extracted from a pancreas of a cow or a pig; a human insulin preparation synthesized by a genetically engineered method from a coliform or a yeast; zinc insulin) a protamine zinc insulin, a fragment or derivative of insulin (for example, INS-1), an insulin oral preparation), an insulin sensitizer (for example, pioglitazone or a salt thereof (preferably a hydrochloride), Rosiglitazone or its salt (maleate), metaglidasen, AMG-131, balaglintazone, MBX-2044, reminate (Rivoglitazone), Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT-505, HR-092l, and WO2007/013694, a compound described in WO2007/018314, WO2008/093639 or WO2008/099794), an α-glycosidase inhibitor (for example, voglibose, acarbose, miglitol) ), emiglitate, biguanides (eg metformin, N-butyl) Buformin or a salt thereof (eg, hydrochloride, fumarate, succinate), insulin secretagogue (eg, sulfonylurea (eg, tolbutamide, glibenclamide) Glubenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glycopyramide, glimepiride ), glipizide, glybuzole, repaglinide, nateglinide, miteglinide or its calcium salt hydrate, A fourth type of dipeptidyl 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-pyridyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-4-fluorobenzyl Nitrile or a salt thereof), a β3 agonist (eg N-5984), a GPR40 agonist (eg WO2004/041266, WO2004/106276, WO2005/063729, WO2005/063725, WO2005/087710, WO2005/095338, WO2007/013689 or WO2008/001931), GLP-1 receptor agonists (eg GLP-1) , GLP-1MR agent, Liraglutide, Exenatide, AVE-0010, BIM-51077, Aib (8,35) hGLP-1 (7,37) NH ₂ , CJC-1131 , Albiglutide, amyloid agonist (eg pramlintide), phosphorylated tyrosine phosphatase inhibitor (eg sodium vanadate), inhibitor of gluconeogenesis (eg glycophosphoric acid) Inhibitors of enzymes, glucose-6-phosphatase inhibitors, blood glucose hormone antagonists, FBPase inhibitors, SGULT2 (sodium-glucose co-transporter 2) inhibitors (eg, paclifraflozin) ), AVE2268, TS-033, YM543, TA-7284, Remogliflozin, ASP1941), SGLT1 inhibitor, 11β-hydroxysteroid dehydrogenase inhibitor (eg BVT-3498, INCB-13739) ), Adiponectin or its agonist, IKK inhibitor (eg AS-2868), leptin resistance enhancing drug, somatostatin An agonist, Glucokinase Activator (eg, Piragliatin, AZD1656, AZD6370, TTP-355, and WO2006/112549, WO2007/028135, WO2008/047821, WO2008/050821, WO2008/ 136428 or a compound described in WO2008/156757), GIP (glucose-dependent insulinotropic peptide), GPR119 agonist, FGF21, FGF analog, and the like.

Agents that can be used as a remedy for diabetes are: aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat) , CT-112, ranirestat (AS-3201), lidorestat, neurotrophic factors and their enhancers (eg, NGF, NT-3, BDNF, described in WO 01/14372) Neurotrophin manufacturing/secretion promoter (for example, 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propane base] Oxazole), described in WO2004/039365), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, N-benzhydrylmethylthiazolium bromide (ALT766) ), EXO-226, pyridorin, pyridoxamine, GABA receptor agonists (eg, gabapentin, pregabalin), serotonin, and adrenal gland Reuptake inhibitors (eg, duloxetine), sodium channel inhibitors (eg, lacosamide), reactive oxygen scavengers (eg, lipoic acid), cerebral vasodilators (eg, Tiapuride, mexiletine, a somatostatin receptor agonist (eg, BIM23190), an apoptotic signal-regulated kinase-1 (ASK-1) inhibitor, and the like.

Among the therapeutic agents for hyperlipidemia are: HMG-CoA reductase inhibitors (for example, pravastatin, simvastatin, lovastatin, atorvastatin) ), fluvastatin, rosuvastatin, pitavastatin, or a salt thereof (eg, sodium salt, calcium salt), squalene synthetase inhibitor (eg, WO97) a compound described in /10224, for example, N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3- Dimethoxyphenyl)-2-keto-1,2,3,5-tetrahydro-4,1-benzo Indomethacin-3-yl]ethinyl]piperidine-4-acetic acid), fibrate compound (for example, bezafibrate, clofibrate, octane fiber) Sodium (simfibrate), clinofibrate, anion exchange resin (eg, colestyramine), probucol, nicotinic acid (eg, nicocamine) Nicomol), niceritrol, niaspan, ethyl icosapentate, phytosterols (eg, soy sterol, γ-glutenol), cholesterol Absorption inhibitors (eg, zechia), CETP inhibitors (eg, dalcetrapib, anacetrapib), omega-3 fatty acid preparations (eg, omega-3 acid ethyl ester 90) )Wait.

Can be used as antihypertensive agents: angiotensin converting enzyme inhibitors (for example, captopril, enalapril, deLapril, etc.), angiotensin II antagonist Agents (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, wasa Valsartan, telmisartan, irbesartan, tasosartan, olmesart, olmesartan medoxomil, azilsartan Azilsartan), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efenidipine, nicardipine, amlodipine, Cilendipine, etc., beta blockers (eg, metoprolol, atenolol, propranolol, carvedilol, guanidine) Pilodol, etc., clonidine, and the like.

Can be used as a weight loss agent: monoamine absorption inhibitors (eg, phentermine, sibutramine, mazindol, fluoxetine, barrelsofen) Tesofensine, serotonin 2C receptor agonist (eg, lorcaserin), serotonin 6 receptor agonist, histamine H3 receptor, GABA-regulating drug (eg, topiramate), Neuropeptide Y antagonists (eg, velneperit), cannabinoid receptor antagonists (eg, rimonabant, taranabant), ghrelinant agonists , ghrelin receptor antagonist, ghrelin acy1ation enzyme inhibitor, opioid receptor antagonist (eg, GSK-1521498), orexin receptor antagonist, melanocortin (melanocortin) 4 receptor agonist, 11β-hydroxysteroid dehydrogenase inhibitor (eg, AZD-4017), pancreatic lipase inhibitor (eg, orlistat, cetialat), β3 Agonist (eg, N-5984), diglyceride thiol transferase 1 (diacylglycerol acylt) Ransferase 1, DGAT1) inhibitor, acetaminophen coenzyme A carboxylase (ACC) inhibitor, acetaminophen coenzyme A desaturase inhibitor, acid glyceride conversion protein inhibitor (eg, R-256918), Na-glucose Transport inhibitors (eg, JNJ-28431754, remogliflozin), NFκB inhibitors (eg, HE-3286), PPAR agonists (eg, GFT-505, DRF-11605), phosphonate Ammonium phosphate inhibitor (eg, sodium vanadate, trodusquemin), GPR119 agonist (eg, PSN-821), glucokinase activator (eg, AZD-1656), leptin, Leptin derivatives (eg, metrepeptin), CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonist, pancreatic hyperglycemia a peptide-like peptide-1 (GLP-1) preparation (for example, an animal GLP-1 preparation derived from cattle or pigs; a human GLP-1 preparation synthesized by coliform bacteria or yeast by genetic engineering methods; a GLP-1 fragment or derivative (eg, exenatide, liraglutide), amyloid agonists (eg, pramlintide, AC-2307), neuropeptide Y agonists (for example, PYY3-36, PYY3-36 derivative, obinepitide, TM-30339, TM-30335), a modulating agent preparation; FGF21 preparation (for example, an animal FGF21 preparation derived from cattle or pigs; Genetic engineering methods are human FGF21 preparations synthesized by Escherichia coli or yeast; FGF21 fragments or derivatives), anti-feeding factors (for example, P-57) and the like.

It can be used as a diuretic, for example, xanthine derivatives (for example, theobromine sodium, salicylate, theobromine calcium salicylate, etc.), thiophene Thiazide preparation (eg, ethyl thiazide) Hexathiophene Compound, trichloromethylthio Compound, hydrochlorothiazide Hydrofluorothiazide Benzyldihydrochlorothiazide Hexafluorothiazide Compound, polythiazide Compound, methyl chloride Compounds, etc., anti-aldosterone preparations (for example, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (for example, acetazolamide, etc.), chlorobenzenesulfonate Indoleamine preparations (for example, chlortalidone, mefruside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid , pitetanide, bumetanide, furosemide, and the like.

It can be used as an antithrombotic agent, for example, heparin (for example, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarins (for example, killing) Mouse spirit potassium), antithrombin drugs (eg, aragatroban, dabigatran), Fxa inhibitors (eg, rivaroxaban, apixaban (apixaban) ), edoxaban, YM150, and WO02/06234, WO2004/048363, WO2005/030740, WO2005/058823, or WO2005/113504), thrombolytic agents (eg, urokinase, esoteric) Kinase (tisokinase), alteplase, nateplase, monteplase, pamiteplase, platelet aggregation inhibitors (eg, tetainin) Ticlopidine) hydrochloride, cilostazol, clopidogrel, prasugrel, E5555, SHC530348, ceroxazole, ethyl hexacarboxylate, berapprost sodium (beraprost sodium), sarpogrelate hydrochloride, and the like.

When the solid preparation of the present invention is used in combination with a concomitant drug, their administration time is not limited, and they may be administered to the subject at the same time or administered in a staggered manner.

Further, the solid preparation of the present invention and the concomitant drug may be administered in a separate preparation; and administered in a single preparation containing the solid preparation of the present invention and a concomitant drug.

The dose of the combined drug can be appropriately determined according to the clinical use dose of each drug. The mixing ratio of the solid preparation of the present invention and the concomitant drug can be appropriately determined depending on the administration target, the administration route, the target disease, the symptom, the composition, and the like. For example, when the target is administered to a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the solid preparation of the present invention.

The combination of drugs used in this way provides the following superior effects:

1) an effect of promoting the action of the solid preparation or the concomitant drug of the present invention (the synergistic effect of the action of the agent);

2) the effect of reducing the dose of the solid preparation or the combined medicine of the present invention (the effect of reducing the dose of the medicine compared to the single administration);

3) the effect of alleviating the secondary action of the solid preparation or the combined use of the present invention; and the like.

The present invention also provides a method for promoting the solubility properties of the following compounds: a compound of the formula (I) or a salt thereof and/or a calcium antagonist, which is contained in a solid preparation containing an added sugar alcohol. According to the present invention, the solubility property of the compound of the formula (I) or a salt thereof in the solid preparation is remarkably improved.

Example

The invention will be described in more detail hereinafter with reference to the examples and the experimental examples, which are not to be construed as limiting.

In the following examples and test examples, the composition (additive) which is not an active ingredient can be used with the Japanese Pharmacopoeia 15th Edition, the Japanese Pharmacopoeia Japanese Pharmaceutical Codex, or Japan. Pharmaceutical Excipients 2003 (Japanese Pharmaceutical Excipients 2003) compatible products.

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

Example 1

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9000 g) to obtain a binder I. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (720.0 g) to obtain the binder II. Amlodipine besylate (1253 g), Compound A (1449 g), D-mannitol (14880 g) and microcrystals in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, ShowaKagakukikai Co., Ltd.) to prepare a ground granule.

(2) Add croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) to the obtained milled granules (40760 g (2 batches)) in a roller mixer (TM20-0) -0, Suehiro Kakoki Co., Ltd.) was mixed to obtain a mixed granule.

(3) The mixed granules obtained as above were subjected to a spindle punching diameter of 7.0 mm in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) (ingoting pressure: 10 kN, weight per spindle: 130 mg) to obtain The tablet tablet of the composition shown in Table 1.

Example 2

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9900 g) to obtain a binder I. Red iron oxide (11.70 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (540.0 g) to obtain the binder II. Amlodipine besylate (1253 g), Compound A (1449 g), D-mannitol (14870 g) and microcrystals in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2) Add croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) to the obtained milled granules (40760 g (2 batches)) in a roller mixer (TM20-0) -0, Suehiro Kakoki Co., Ltd.) was mixed to obtain a mixed granule.

(3) The mixed granules obtained above were punched in a rotary ingot machine (AQUARIUS-36K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 8 kN, each ingot) Weight: 130 mg) A flavonoid having the composition shown in Table 2 was obtained.

Example 3

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9900 g) to obtain a binder I. Red iron oxide (11.70 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (540.0 g) to obtain the binder II. Amlodipine besylate (627.7 g), Compound A (1449 g), D-mannitol (15550 g) and microcrystals in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2) Add croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) to the obtained milled granules (40760 g (2 batches)) in a roller mixer (TM20-0) -0, Suehiro Kakoki Co., Ltd.) was mixed to obtain a mixed granule.

(3) The mixed granules obtained above were punched in a rotary ingot machine (AQUARIUS-36K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 8 kN, each ingot) Weight: 130 mg) A tablet tablet having the composition shown in Table 3 was obtained.

Example 4

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9900 g) to obtain a binder I. Red iron oxide (11.70 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (540.0 g) to obtain the binder II. Amlodipine besylate (1253 g), Compound A (724.3 g), D-mannitol (15600 g) and microcrystals in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2) Add croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) to the obtained milled granules (40760 g (2 batches)) in a roller mixer (TM20-0) -0, Suehiro Kakoki Co., Ltd.) was mixed to obtain a mixed granule.

(3) The mixed granules obtained as above were punched in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) at a diameter of 7 mm (ingot pressure: 10 kN, weight per spindle: 130 mg) to obtain A tablet of the composition shown in Table 4.

Example 5

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9900 g) to obtain a binder I. Yellow iron oxide (11, 70 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (540.0 g) to obtain the binder II. Amlodipine besylate (627.7 g), Compound A (724.3 g), D-mannitol (16200 g) and microcrystals in a fluidized bed granulator (FD-52, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2) Add croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) to the obtained milled granules (40760 g (2 batches)) in a roller mixer (TM20-0) -0, Suehiro Kakoki Co., Ltd.) was mixed to obtain a mixed granule.

(3) The mixed granules obtained as above were punched in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) at a diameter of 7 mm (ingot pressure: 10 kN, weight per spindle: 130 mg) to obtain A tablet of the composition shown in Table 5.

Example 6 Table 6

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9900 g) to obtain a binder I. Red iron oxide (18.72 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (540.0 g) to obtain the binder II. Amlodipine besylate (1248 g), Compound A (1446 g), D-mannitol (14870 g) and microcrystals in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2) Add croscarmellose sodium (924.0 g) and magnesium stearate (148.5 g) to the obtained milled granules (20380 g) in a roller mixer (TM20-0-0, Suehiro) Kakoki Co., Ltd.) was mixed to obtain a mixed granule.

(3) The mixed granules obtained as above were punched in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 8 kN, per Ingot weight: 130 mg) A tablet tablet having the composition shown in Table 6 was obtained.

Example 7

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9900 g) to obtain a binder I. Yellow iron oxide (18.72 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (540.0 g) to obtain the binder II. Amlodipine besylate (625.2 g), Compound A (1446 g), D-mannitol (15500 g) and microcrystals in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2) Add croscarmellose sodium (924.0 g) and magnesium stearate (148.5 g) to the obtained milled granules (20380 g) in a roller mixer (TM20-0-0, Suehiro) Kakoki Co., Ltd.) was mixed to obtain a mixed granule.

(3) The mixed granules obtained above were punched in a rotary ingot machine (AQUARIUS-36K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 8 kN, each ingot) Weight: 130 mg) A flavonoid having the composition shown in Table 7 was obtained.

Example 8

(1) Hydroxypropylcellulose (144.0 g) was dissolved in pure water (1980 g) to obtain a binder I. Yellow iron oxide (3.744 g) was dispersed in pure water (360.0 g) to obtain a dispersion I. The binder I, the dispersion I and the pure water (108.0 g) were mixed to obtain a binder II. Macrogol 6000 (4.680 g) was dissolved in the binder II (259.6 g) to obtain a binder III. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (299.4 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder III was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) Add croscarmellose sodium (16.80 g) and magnesium stearate (2.700 g) to the obtained milled granules (370.5 g), and mix in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3) The mixed granules obtained as above were punched in a rotary tableting machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 7.5 kN, per Ingot weight: 130 mg) A tablet tablet having the composition shown in Table 8 was obtained.

Example 9

(1) Hydroxypropylcellulose (144.0 g) was dissolved in pure water (1980 g) to obtain a binder I. Red iron oxide (3.744 g) was dispersed in pure water (360.0 g) to obtain a dispersion I. The binder I, the dispersion I and the pure water (108.0 g) were mixed to obtain a binder II. Macrogol 6000 (14.04 g) was dissolved in the binder II (259.6 g) to obtain a binder III. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (290.0 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder III was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) Add croscarmellose sodium (16.80 g) and magnesium stearate (2.700 g) to the obtained milled granules (370.5 g), and mix in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3) The mixed granules obtained as above were punched in a rotary tableting machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 7.5 kN, per Ingot weight: 130 mg) A tablet tablet having the composition shown in Table 9 was obtained.

Example 10

(1) Hydroxypropylcellulose (144.0 g) was dissolved in pure water (1980 g) to obtain a binder I. Red iron oxide (3.744 g) was dispersed in pure water (360.0 g) to obtain a dispersion I. The binder I, the dispersion I and the pure water (108.0 g) were mixed to obtain a binder II. Macrogol 6000 (23.40 g) was dissolved in the binder II (259.6 g) to obtain a binder III. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (280.7 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder III was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) Add croscarmellose sodium (16.80 g) and magnesium stearate (2.700 g) to the obtained milled granules (370.5 g), and mix in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3) The mixed granules obtained as above were punched in a rotary tableting machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 7.5 kN, per Ingot weight: 130 mg) A tablet tablet having the composition shown in Table 10 was obtained.

Example 11

(1) Hydroxypropylcellulose (144.0 g) was dissolved in pure water (1980 g) to obtain a binder I. Red iron oxide (3.744 g) was dispersed in pure water (360.0 g) to obtain a dispersion I. The binder I, the dispersion I and the pure water (108.0 g) were mixed to obtain a binder II. Macrogol 6000 (37.44 g) was dissolved in the binder II (259.6 g) to obtain a binder III. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (266.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder III was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) Add croscarmellose sodium (16.80 g) and magnesium stearate (2.700 g) to the obtained milled granules (370.5 g), and mix in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3) The mixed granules obtained as above were punched in a rotary tableting machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 7.5 kN, per Ingot weight: 130 mg) A tablet tablet having the composition shown in Table 11 was obtained.

Example 12

(1) Hydroxypropylcellulose (208.0 g) and macrogol 6000 (160.0 g) were dissolved in pure water (2392.0 g) to obtain a binder. Amlodipine besylate (277.2 g), Compound B (1605.0 g), D-mannitol (1599.0 g) and microcrystals in a fluidized bed granulator (FD-5S, POWREX Co., Ltd.) The cellulose (388.8 g) was uniformly mixed, the mixture was granulated and a binder was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2) crospovidone (331.5 g), microcrystalline cellulose (442.0 g) and magnesium stearate (44.201 g) were added to the obtained milled granules (3602.0 g) in a roller mixer (TM) -15, Suehiro Kakokico., Ltd.) was mixed to obtain a mixed granule.

(3) The mixed granules obtained as above were punched in a rotary tableting machine (Correct 12HUK, Kikusui Seisakusho) at a diameter of 7.0 mm (ingot pressure: 4 kN, weight per spindle: 130 mg) to obtain a core ingot Agent.

(4) Premix I (240.4 g) was dissolved in pure water (2160.0 g) to obtain a film coating solution. In a film coater (DRC-500, POWREX Co., Ltd.), a film coating solution was uniformly sprayed on a core tablet (3120.0 g) to form a film coat to obtain a film ingot having the composition shown in Table 12 (weight per plate: 135 mg). Here, the premix I is a premixed powder. The composition of Premix I is shown in Table 12a.

Example 13 Table 13

(1) Hydroxypropylcellulose (20.80 g) and macrogol 6000 (16.00 g) were dissolved in pure water (239.2 g) to obtain a binder. Amlodipine besylate (27.72 g), Compound B (80.00 g), D-mannitol (240.4 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (38.88 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) crospovidone (34.13 g), microcrystalline cellulose (45.50 g) and magnesium stearate (4.550 g) were added to the obtained milled granules (370.8 g) in a polyethylene bag (4.9 Mix in L) to obtain a mixed granule.

(3) The mixed granules obtained as above were punched in a rotary tableting machine (VEL-5, Kikusui Seisakusho) at a diameter of 7.0 mm (ingot pressure: 4 kN, weight per spindle: 130 mg) to obtain a core. Lozenges.

(4) Premix I (40.00 g) was dissolved in pure water (360.0 g) to obtain a film coating solution. In a film coater (DRC-200, POWREX Co., Ltd.), a film coating solution was uniformly sprayed on a core tablet (200.0 g) to form a film coat to obtain a film ingot having the composition shown in Table 13 (weight per plate: 135 mg). Here, the premix I is a premixed powder. The composition of Premix I is shown in Table 13a.

Example 14

(1) Hydroxypropylcellulose (20.80 g) and macrogol 6000 (16.00 g) were dissolved in pure water (239.2 g) to obtain a binder. Amlodipine besylate (13.88 g), compound B (80.00 g), D-mannitol (254.2 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (38.88 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) crospovidone (34.13 g), microcrystalline cellulose (45.50 g) and magnesium stearate (4.550 g) were added to the obtained milled granules (370.8 g) in a polyethylene bag (4.9 Mix in L) to obtain a mixed granule.

(3) The mixed granules obtained as above were punched in a rotary tableting machine (VEL-5, Kikusui Seisakusho) at a diameter of 7.0 mm (ingot pressure: 4 kN, weight per spindle: 130 mg) to obtain a core. Lozenges.

(4) Premix I (40.00 g) was dissolved in pure water (360.0 g) to obtain a film coating solution. In a film coater (DRC-200, POWREX Co., Ltd.), a film coating solution was uniformly sprayed on a core tablet (200.0 g) to form a film coat to obtain a film ingot having the composition shown in Table 14. (weight per tablet: 135mg).

Example 15

(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (10.40 g), compound B (30.00 g), D-mannitol (250.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained milled granules (289.3 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3) The mixed granules obtained as above were punched in a 6.5 mm diameter in a rotary tableting machine (VEL-5, Kikusui Seisakusho) (ingot pressure: 5 kN, weight per spindle: 130 mg) to obtain a core Lozenges.

(4) The crospovidone (57.44 g) and macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g), red iron oxide (0.1650 g) and yellow iron oxide (0.5100 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, POWREX Co., Ltd.), the film coat solution II was uniformly sprayed on the core tablet (120.0 g) to form a film coat to obtain a film coat having the composition shown in Table 15. Ingot (weight per spindle: 135.154 mg).

Example 16

(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (20.79 g), Compound B (30.00 g), D-mannitol (240.2 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained milled granules (289.3 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3) The mixed granules obtained as above were punched in a 6.5 mm diameter in a rotary tableting machine (VEL-5, Kikusui Seisakusho) (ingot pressure: 5 kN, weight per spindle: 130 mg) to obtain a core Lozenges.

(4) The crospovidone (57.44 g) and macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g), red iron oxide (0.1650 g) and yellow iron oxide (0.5100 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, POWREX Co., Ltd.), the film coat solution II was uniformly sprayed on the core tablet (120.0 g) to form a film coat to obtain a film coat having the composition shown in Table 16. Ingot (weight per spindle: 135.154 mg).

Example 17

(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (10.40 g), Compound B (60.00 g), D-mannitol (220.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained milled granules (289.3 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3) The mixed granules obtained as above were punched in a 6.5 mm diameter in a rotary tableting machine (VEL-5, Kikusui Seisakusho) (ingot pressure: 5 kN, weight per spindle: 130 mg) to obtain a core Lozenges.

(4) The crospovidone (57.44 g) and macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g) and red iron oxide (0.1500 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, POWREX Co., Ltd.), the film coating solution II was uniformly sprayed on the core tablet (120.0 g) to form a film coat to obtain a film coat having the composition shown in Table 17. Ingot (weight per spindle: 135.119 mg).

Example 18

(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (20.79 g), compound B (60.00 g), D-mannitol (210.2 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained milled granules (289.3 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3) The mixed granules obtained as above were punched in a 6.5 mm diameter in a rotary tableting machine (VEL-5, Kikusui Seisakusho) (ingot pressure: 5 kN, weight per spindle: 130 mg) to obtain a core Lozenges.

(4) The crospovidone (57.44 g) and macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g) and red iron oxide (0.1500 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, POWREX Co., Ltd.), the film coat solution II was uniformly sprayed on the core tablet (120.0 g) to form a film coat to obtain a film coat having the composition shown in Table 18. Ingot (weight per spindle: 135.119 mg).

Example 19

(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (10.40 g), Compound B (120.0 g), D-mannitol (160.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained milled granules (289.3 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3) The mixed granules obtained as above were punched in a 6.5 mm diameter in a rotary tableting machine (VEL-5, Kikusui Seisakusho) (ingot pressure: 5 kN, weight per spindle: 130 mg) to obtain a core Lozenges.

(4) The crospovidone (57.44 g) and macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g) and yellow iron oxide (0.6900 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, POWREX Co., Ltd.), the film coat solution II was uniformly sprayed on the core tablet (120.0 g) to form a film coat to obtain a film coat having the composition shown in Table 19. Ingot (weight per spindle: 135.155 mg).

Example 20

(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (20.79 g), compound B (120.0 g), D-mannitol (150.2 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained milled granules (289.3 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3) The mixed granules obtained above were punched in a rotary tableting machine (VEL-5, Kikusui Seisakusho) at a diameter of 7.0 mm (ingot pressure: 5 kN, weight per spindle: 130 mg) to obtain a core. Lozenges.

(4) The crospovidone (57.44 g) and macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g) and yellow iron oxide (0.6900 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, POWREX Co., Ltd.), the film coating solution II was uniformly sprayed on the core tablet (120.0 g) to form a film coat to obtain a film coat having the composition shown in Table 20. Ingot (weight per spindle: 135.155 mg).

Example 21 Table 21 Composition of each preparation (260 mg)

(1) The crospovidone (720.0 g) was dissolved in pure water (9000 g) to obtain a binder I. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion I. Dispersion I and pure water (720.0 g) were mixed in the binder I to obtain a binder II. Uniform amlodipine besylate (1249 g), D-mannitol (16660 g) and microcrystalline cellulose (3600 g) in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The mixture is mixed, the mixture is granulated and the binder II is sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieve mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule I.

(2) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (468.0 g) were dissolved in pure water (9000 g) to obtain a binder III. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion II. Dispersion II and pure water (720.0 g) were mixed in the binder III to obtain a binder IV. Compound A (1436 g), lactose hydrate (16090 g) and corn starch (3600 g) were uniformly mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated and The binder IV is sprayed and then dried to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieve mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule II. .

(3) croscarmellose sodium (1848 g) and magnesium stearate (214.5 g) were added to the obtained milled granule I (20380 g) and ground granule II (20460 g). It was mixed in a tumble mixer (TM20-0-0, Suehiro Kakoki Co., Ltd.) to obtain a mixed granule.

(4) The mixed granules obtained as above were punched in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) at a diameter of 8.5 mm (ingot pressure: 10 kN, weight per spindle: 260 mg) to obtain A tablet of the composition shown in Table 21.

Example 22

(1) The crospovidone (720.0 g) was dissolved in pure water (9000 g) to obtain a binder I. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (720.0 g) to obtain the binder II. Uniform amlodipine besylate (1249 g), D-mannitol (16660 g) and microcrystalline cellulose (3600 g) in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The mixture is mixed, the mixture is granulated and the binder II is sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieve mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule I.

(2) Add croscarmellose sodium (924.0 g) and magnesium stearate (148.5 g) to the obtained ground granule I (20380 g) in a roller mixer (TM-60, Showa Kagakukikai) Co., Ltd.) was mixed to obtain a mixed granule I.

(3) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (468.0 g) were dissolved in pure water (9000 g) to obtain a binder III. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion II. Dispersion II and pure water (720.0 g) were mixed in the binder III to obtain a binder IV. Compound A (1436 g), lactose hydrate (16090 g) and corn starch (3600 g) were uniformly mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated and The binder IV is sprayed and then dried to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieve mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule II.

(4) Carboxymethylcellulose calcium (924.0 g) and magnesium stearate (66.00 g) were added to the obtained ground granule II (20460 g) in a tumble mixer (TM-60, Showa Kagakukikai Co. , Ltd.) mixed to obtain mixed granules II.

(5) The mixed granule I (130 mg) and the mixed granule II (130 mg) obtained as above were used in a rotary tableting machine (HT-CVX54LS-UW/C&3L, HATA IRON WORKS Co., Ltd.) A 8.5 mm diameter punching tablet (pressing pressure: 9 kN, weight per spindle: 260 mg) to obtain a multilayer tablet of the composition shown in Table 22.

Example 23 Table 23 Composition of each preparation (239 mg)

(1) Hydroxypropylcellulose (155.0 g) was dissolved in pure water (1395.0 g) to obtain a binder I. Uniform amlodipine besylate (346.7 g), D-mannitol (2447.0 g) and microcrystalline cellulose (766.7 g) in a fluidized bed granulator (FD-5S, POWREX Co., Ltd.) The mixture is granulated, the mixture is granulated and the binder I is sprayed, followed by drying to obtain a granule having a layer of amlodipine besylate. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to obtain a ground granule of amlodipine besylate.

(2) Hydroxypropylcellulose (280.1 g) and macrogol 6000 (280.0 g) were dissolved in pure water (2520.2 g) to obtain a binder II. 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, POWREX Co., Ltd.) The mixture was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain a granule of the compound B layer. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to obtain a ground granule of the compound B layer.

(3) Carboxymethylcellulose calcium (200.0 g) and magnesium stearate (28.000 g) were added to the obtained amlodipine besylate layer of ground granules (3772.0 g) in a roller mixer (TM- 15, Suehiro Kakoki co., Ltd.) was mixed to obtain a mixed granule of amlodipine besylate.

(4) A low-substituted hydroxypropylcellulose (455.0 g), microcrystalline cellulose (455.1 g), and magnesium stearate (24.53 g) were added to the obtained compound B layer of the ground granule (3616.1 g). It was mixed in a tumble mixer (TM-15, Suehiro Kakoki co., Ltd.) to obtain a mixed granule of the compound B layer.

(5) The mixed granule of the amlodipine besylate layer obtained as described above and the mixed granule of the compound B layer are used in a rotary tableting machine (HT-X12SS-UW & 2L, HATA IRON WORKS Co., Ltd.) 8.0 mm diameter punched ingot (ingoting pressure: 7 kN, weight per spindle: 230 mg (amlodipine besylate: 100 mg; compound B layer: 130 mg)) to obtain a multilayer core tablet.

(6) Premix I (252.0 g) was dissolved in pure water (2268.0 g) to obtain a film coating solution. In a film coater (DRC-500, POWREX Co., Ltd.), a film coating solution was uniformly sprayed on a core tablet (3120.0 g) to form a film coat to obtain a film ingot having the composition shown in Table 23 (weight per tablet: 239 mg). Here, the premix I is a premixed powder. The composition of Premix I is shown in Table 23a.

Example 24

(1) Hydroxypropylcellulose (80.00 g) and macrogol 4000 (36.00 g) were dissolved in pure water (1100 g) to obtain a binder I. Red iron oxide (2.080 g) was dispersed in pure water (200.1 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (60.00 g) to obtain the binder II. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (297.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) Cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder II (266.1 g) was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) croscarmellose sodium (16.81 g) and magnesium stearate (2.700 g) were added to the obtained ground granules (370.5 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3) The mixed granules obtained above were punched in a rotary ingot machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 8.5 kN, each ingot) Weight: 130 mg) A flavonoid having the composition shown in Table 24 was obtained.

Example 25

(1) Hydroxypropylcellulose (80.00 g) and macrogol 10000 (36.00 g) were dissolved in pure water (1100 g) to obtain a binder I. Red iron oxide (2.080 g) was dispersed in pure water (200.1 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (60.10 g) to obtain the binder II. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (297.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) Cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder II (266.1 g) was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2) croscarmellose sodium (16.80 g) and magnesium stearate (2.710 g) were added to the obtained ground granules (370.5 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3) The mixed granules obtained above were punched in a rotary ingot machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 8.5 kN, each ingot) Weight: 130 mg) A flavonoid having the composition shown in Table 25 was obtained.

Comparative Example 1

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (468.0 g) were dissolved in pure water (9000 g) to obtain a binder I. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (720.0 g) to obtain the binder II. Amlodipine besylate (1253 g), Compound A (1449 g), lactose hydrate (14830 g) and corn starch in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) 3600 g) Evenly mixed, granulated the mixture and sprayed the binder II, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2) Calcium carboxymethylcellulose (1848 g) and magnesium stearate (132.0 g) were added to the obtained milled granules (40920 g (2 batches)) in a roller mixer (TM20-0-0) , Suehiro Kakoki co., Ltd.) was mixed to obtain a mixed granule.

(3) The mixed granules obtained as above were punched in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) at a diameter of 7.0 mm (ingot pressure: 9 kN, weight per spindle: 130 mg) to obtain The lozenge of the composition shown in Table 26.

Test Example 1 Dissolution test 1

The solubility properties of the active ingredient (Compound A) from the flavonoids obtained in Examples 1 to 11, 24, 25 and Comparative Example 1 were determined by dissolution test (1.0 (w/w)% polysorbate 20 solution, 900 mL, 37 ° C, Paddle Method, rotation number 50 rpm). The dissolution test was carried out in accordance with Japanese Pharmacopoeia, 15th Edition, Dissolution Test, Apparatus 2 (Paddle Method). The results are shown in Table 27. Table 27 shows the average value, maximum value, and minimum value of the dissolution rate 15 minutes after the start of dissolution. In Examples 1, 4, 5, 8 to 11, 24, 25 and Comparative Example 1, the average, maximum and minimum values of the dissolution rates of the six tablets were serialized, while Examples 2, 3, 6 and 7 were carried out. The average, maximum and minimum values of the dissolution rates of the 12 tablets are listed.

As shown in Table 27, the all-flavored tablets of Examples 1 to 11, 24, and 25 containing a sugar alcohol as an excipient showed superiority of Compound A as compared with the sugar alcohol-free tablet of Comparative Example 1. Solubility properties.

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 the dissolution test (the Japanese Pharmacopoeia, 15th Edition, 2nd fluid for dissolution test, 900 mL, 37 ° C, slurry type, rotation number 50). Rpm) evaluation. The dissolution test was carried out according to the Japanese Pharmacopoeia, 15th Edition, Dissolution Test, Apparatus 2 (Paddle Method). The results are shown in Table 28. Table 28 shows the average value, maximum value, and minimum value of the dissolution rates of 6 tablets at each time point 5 to 60 minutes after the start of the dissolution.

As shown in Table 28, the film ingot of Example 20 showed the excellent solubility properties of Compound B.

Test Example 3 Stability test

The lozenges of Examples 1, 4 and 5 were stored in a sealed glass bottle at 25 ° C / 60% RH for 12 months. The mass of the analog derived from Compound A or amlodipine besylate was measured, and the preservation stability was evaluated based on this. The results are shown in Table 29. The values shown in Table 29 are the ratios (%) of all analogs derived from Compound A or amlodipine besylate when Compound A or amlodipine besylate is 100% (Compound A; 8) Mg or 4 mg / amlodipine besylate; 6.93 mg or 3.47 mg).

As shown in Table 29, the tablet tablets of Examples 1, 4 and 5 showed excellent preservation stability.

Industrial utilization

The present invention provides a solid preparation comprising a compound represented by the formula (I) or a salt thereof, a sugar alcohol, and a calcium antagonist, which suitably controls a compound represented by the formula (I) or a salt thereof, a calcium antagonist in the gastrointestinal tract The solubility properties of the solid preparations are maintained and their good stability in solid preparations is maintained.

The present application is based on Japanese Patent Application Nos. 2009-111381 and 2010-68625, the entire contents of each of which are incorporated herein by reference.

There is no schema in this case.

Claims (4)

A solid preparation comprising: (i) selected from the group consisting of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7 -carboxylic acid 1-(cyclohexyloxycarbonyloxy)ethyl ester and 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxooxy-1,2,4- a compound of oxazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof, (ii) mannitol, (iii) amlodipine or a salt thereof And (iv) polyethylene glycol having a molecular weight of 3,000 to 10,000. The solid preparation according to claim 1, wherein the compound or a salt thereof is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl ]Methyl]benzimidazole-7-carboxylic acid 1-(cyclohexyloxycarbonyloxy)ethyl ester or a salt thereof. The solid preparation according to claim 1, wherein the compound or a salt thereof is 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxy-1). 2,4- Azoxa-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof. The solid preparation according to claim 1, wherein the amlodipine or a salt thereof is amlodipine besylate.