KR101797776B1 - Solid preparation - Google Patents

Abstract

(상기 식 중, 각 기호는 명세서에서 정의한 바와 같다).The present invention provides solid preparations which are excellent in dissolution and stability, comprising (i) a compound represented by the formula (I) or a salt thereof, (ii) a sugar alcohol, and (iii) a calcium antagonist.

(Wherein each symbol is as defined in the specification).

Description

SOLID PREPARATION [0002]

The present invention relates to solid preparations having improved elution properties from pharmaceutical preparations.

Hypertension is one of the most frequently diagnosed diseases in adults. According to the Basic Survey of Circulatory Diseases in 2000 by the Ministry of Health, Labor and Welfare, the number of hypertension patients in Japan (systolic blood pressure of 140 mmHg or more or diastolic blood pressure of 90 mmHg or more or blood pressure lowering drug users) reaches about 31 million to 38 million . Hypertension is a potent risk factor for any cardiovascular disease, including cerebrovascular disease and myocardial infarction. Therefore, proper management of blood pressure is important both in improving the prognosis of the patient and alleviating the personal and social burden.

A variety of drugs have been developed as hypertension medications, including blood pressure lowering diuretics, alpha blockers, beta blockers, angiotensin converting enzyme (ACE) inhibitors, calcium antagonists and angiotensin II receptor antagonists. It is being treated by blood pressure lowering agent. For example, compounds of formula (I):

(Wherein R ¹ is a monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom, R ² is a carboxyl group optionally esterified, and R ³ is an optionally substituted lower alkyl group) Or a salt thereof is known as an angiotensin II receptor antagonist exhibiting excellent blood pressure lowering effect and long-term protective action. JP-B-2514282 discloses, as an example of representative agents, 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) -Yl] methyl] benzimidazole-7-carboxylate (candesartan cilexetil).

According to the J-HOME study, about 40% of hypertensive patients undergoing drug therapy achieved target blood pressure (blood pressure <140/90 mmHg at the time of outpatient visit) This means that some patients have not managed enough blood pressure with conventional medications. In order to improve the target blood pressure achievement rate, a more powerful treatment for lowering blood pressure is required.

As a drug therapy that exhibits a strong blood pressure lowering effect, a combination therapy using a plurality of drugs can be mentioned. For example, WO 01/15674 discloses the combination of a renin-angiotensin inhibitor and other hypotensive agents, cholesterol-lowering drugs, diuretics, and the like. WO 02/43807 discloses the combination of an angiotensin II receptor antagonist and other hypotensive agents or statins. However, combining a plurality of drugs having different dosing timings with each other may adversely affect the patient's compliance with the medication, and thus, there is a fear that the blood pressure management failure due to the negligence may occur. In order to more appropriately manage the blood pressure, a combination preparation containing various hypotensive agents in one medicament exhibits a strong blood pressure lowering effect and is an ideal medicament for maintaining the patient's compliance with the medicines, and thus is strongly required in the clinical field.

As such a combination preparation, there has been proposed a combination preparation containing an angiotensin II receptor antagonist and a calcium antagonist. WO 92/10097 discloses combination formulations containing angiotensin II receptor antagonists and other agents such as diuretics, calcium antagonists, and the like. JP-A-2006-290899 discloses a formulation containing an imidazole carboxylate-type angiotensin II receptor antagonist such as olmesartan medoxomil and the like and a calcium antagonist. US Pat. No. 6,204,281 discloses a combination formulation containing 1,4-dihydropyridine compounds such as valsartan, an angiotensin II receptor antagonist, and amlodipine, a calcium antagonist, and the like. JP-B-2930252 discloses an angiotensin II receptor antagonist, 2-butyl-4-chloro-l - [(2 '- (lH-tetrazol-5-yl) biphenyl- A combination formulation containing a carboxylic acid or a pharmaceutically acceptable salt thereof, and a calcium antagonist, diltiazem, is disclosed. JP-B-3057471 discloses a formulation containing a benzimidazole derivative, which is an angiotensin receptor antagonist, and a diuretic or calcium antagonist.

The preparation containing an angiotensin II receptor antagonist benzimidazole derivative and a calcium antagonist is effective in the efficacy of a benzimidazole derivative, which is an angiotensin II receptor antagonist with long-term protective effect, and a potent antihypertensive effect of calcium antagonist It is expected to exert at the same time. In addition, since the action can be enhanced according to the combination method and side effects can be reduced, its clinical usefulness is extremely high.

However, in order to ensure the efficacy and safety of pharmaceuticals, not only the efficacy and safety of the active ingredient itself are important, but also the properties of pharmaceutical preparations such as drug elution in vivo are extremely important. For example, if drug elution from a pharmaceutical preparation is too slow, the drug concentration in the blood can not reach an effective level, and the expected efficacy can not be fully exerted. On the other hand, if the drug elution from the pharmaceutical preparation is too fast, the drug concentration in the blood rises sharply and the risk of side effects increases.

That is, in addition to efficacy and safety, medicines are required to have a certain level of drug elution. The compounding agent is required to satisfy compatibility with various additives and different conditions required by each active ingredient. Thus, the development of formulations with all of these conditions is often more difficult than with 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 elution property of the preparation may be deteriorated due to the characteristics of the additive and the active ingredient to be compounded. Delayed release of the drug from the administered combination formulation results in decreased absorption of the drug, decreased bioavailability, decreased efficacy of the active ingredient, and decreased value of the formulation. Therefore, in order to put the pharmaceutical preparation into practical use, it is necessary to control the composition of the preparation so that the dissolution rate of the active ingredient in the digestive tract becomes optimum.

Therefore, it is an object of the present invention to provide a solid preparation which stably contains a benzimidazole derivative and angiotensergic agent having an angiotensin II receptor antagonistic action, and which is adjusted so that the elution from these drugs in the gastrointestinal tract becomes optimal .

The inventors of the present invention have conducted intensive studies to solve the above problems and found solid formulations containing (i) a compound represented by the formula (I) or a salt thereof, (ii) a sugar alcohol, and (iii) a calcium antagonist , The formulation exhibits a suitably controlled elution in the human digestive tract. Specifically, the present inventors paid attention to excipients and discovered that the use of sugar alcohols having high water solubility can improve the elution properties of the drug from the solid preparation, thereby completing the present invention.

That is,

(I) a solid preparation containing a compound represented by the following formula (I) or a salt thereof, (ii) a sugar alcohol, and (iii) a calcium antagonist:

(Wherein R ¹ is a monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom, R ² is a carboxyl group optionally esterified, and R ³ is an optionally substituted lower alkyl group);

[1] A process for producing a compound represented by the above-mentioned [1], wherein R ² is a hydroxyl group, an amino group, a halogen atom, a lower alkanoyloxy group having 2 to 6 carbon atoms, a lower cycloalkanoyloxy group having 4 to 7 carbon atoms, Having 1 to 4 carbon atoms optionally substituted with 1 to 3 substituents selected from the group consisting of a carbonyloxy group having a lower alkoxy group, a carbonyloxy group having a lower cycloalkoxy group having 3 to 7 carbon atoms, and a lower alkoxy group having 1 to 4 carbon atoms; Solid formulations that are carboxyl groups that are optionally esterified with an alkyl group;

[1B] A solid preparation as described in [1], wherein R ² is 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl group or carboxyl group;

[2] The method according to [1] above, wherein the compound represented by the formula (I) or a salt thereof is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1- [ Yl] methyl] benzimidazole-7-carboxylate, 2-ethoxy-1 - [[2 '- (1 H -tetrazole- Yl] methyl] -1H-benzimidazole-7-carboxylic acid, 2-ethoxy-1 - [[2 '- (4,5- dihydro- Yl) methyl] -1H-benzimidazole-7-carboxylic acid or a salt thereof;

[3] The method according to [1] above, wherein the compound represented by the formula (I) or a salt thereof is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy -1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a salt thereof;

[4] The method according to [1] above, wherein the compound represented by the formula (I) or a salt thereof is 2-ethoxy-1 - [[2 '- 4-yl] methyl] -1H-benzimidazole-7-carboxylic acid or a salt thereof;

[5] The solid preparation as described in [1], [2], [3], [4], [1] or [1B], wherein the sugar alcohol is mannitol, sorbitol or erythritol;

[6] The solid preparation as described in [1], [2], [3], [4], [5], [1A] or [1B], wherein the sugar alcohol is mannitol;

[7] The method according to any one of [1] to [2], wherein the calcium antagonist is azelnidipine, amlodipine, , A solid preparation which is an ephonidipine, a sildenafil, a nicardipine, a nisol dipine, a nitrenedipine, a nifedipine, a nil bodypin, a barnidipine, a felodipine, a benzydipine, a manidipine or a salt thereof;

[8] The method according to any one of [1] to [2], wherein the calcium antagonist is amlodipine or a salt thereof Formulation;

[9] In the above-mentioned [1], [2], [3], [4], [5], [6], [7], [8] &Lt; / RTI &gt;

[10] The solid preparation according to the above [9], wherein the polyethylene glycol has a molecular weight of 1,000 to 10,000;

[11] (i) Synthesis of 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl- Imidazole-7-carboxylate or a salt thereof, (ii) mannitol, and (iii) amlodipine or a salt thereof;

[11A] A solid preparation according to [11], further comprising polyethylene glycol;

[11B] The solid preparation according to the above [11A], wherein the polyethylene glycol has a molecular weight of 1,000 to 10,000 (preferably 3,000 to 10,000);

[11C] A solid preparation according to the above [11B], wherein the content of polyethylene glycol is 1 to 5% by weight;

[11D] A solid preparation according to the above [11B], wherein the content of polyethylene glycol is 1 to 3% by weight;

[12] (i) 2-Ethoxy-1 - [[2 '- (4,5-dihydro- ] Methyl] -1H-benzimidazole-7-carboxylic acid or a salt thereof, (ii) mannitol, and (iii) amlodipine or a salt thereof;

[12A] A solid preparation according to the above [12], further comprising polyethylene glycol;

[12B] A solid preparation according to the above [12A], wherein the molecular weight of the polyethylene glycol is 1,000 to 10,000 (preferably 3,000 to 10,000);

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

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

[13] The method as described in [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11] A solid preparation which is a tablet in [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D].

[14] The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 A solid preparation which is a single-layer tablet in [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D].

[15] The method as described in [1], [2], [3], [4], [5], [6], [7], [8], [9], [10] 12B], [12C] or [12D], [13C], [12D], [12A], [12B], [12C] or [12D] A solid preparation for preventing or treating hypertension, heart failure, diabetic nephropathy or arteriosclerosis;

[16] The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 12B], [12C] or [12D], [13C], [12D], [12A], [12B], [12C] or [12D] A solid preparation for preventing or treating hypertension;

And the like.

According to the present invention, it is possible to obtain a solid preparation in which the compound represented by the above-mentioned formula (I) or a salt thereof and the calcium antagonist are appropriately controlled in elution from the preparation in the digestive tract and their stability in these preparations is maintained satisfactorily . That is, the solid preparation of the present invention is excellent in the elution properties and stability of the compound represented by the above formula (I) or its salt and calcium antagonist preparation.

Hereinafter, the solid preparation of the present invention will be described in detail.

The solid preparation of the present invention is a solid preparation containing (i) a compound represented by the following formula (I) or a salt thereof, (ii) a sugar alcohol, and (iii) a calcium antagonist (hereinafter also referred to as a solid preparation of the present invention ):

Wherein R ¹ is a monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom, R ² is a carboxyl group optionally esterified, and R ³ is an optionally substituted lower alkyl group.

In the above formula (I), examples of the monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom as R ¹ include a tetrazolyl group and a group represented by the following formula

(Wherein, i is -O- or -S- and j is> C = 0,> C = S or> S (O) _{m wherein} m is 0, 1 or 2)

May be mentioned. Preferable groups include tetrazolyl group, 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group and the like.

The 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group contains three tautomers (a ', b' and c '

The 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group includes all of a ', b' and c 'above.

In the above formula (I), examples of the optionally esterified carboxyl group of R ² include a carboxyl group which is optionally esterified with a lower alkyl group having 1 to 4 carbon atoms. Examples of the lower alkyl group include a hydroxyl group, an amino group, a halogen atom, a lower alkanoyloxy group having 2 to 6 carbon atoms (e.g., an acetyloxy group and a pivaloyloxy group), a lower cycloalkanoyloxy group having 4 to 7 carbon atoms, A carbonyloxy group having 1 to 6 lower alkoxy groups (e.g., a methoxycarbonyloxy group, an ethoxycarbonyloxy group, etc.), a carbonyloxy group having 3 to 7 carbon atoms and a lower cycloalkoxy group (e.g., (Preferably 1 to 3) substituent (s) selected from the group consisting of a lower alkoxy group having 1 to 4 carbon atoms and a lower alkoxy group having 1 to 4 carbon atoms. As preferred groups, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl group, carboxyl group and the like can be mentioned.

In the above formula (I), the optionally substituted lower alkyl group for R ³ is preferably a lower alkyl group of 1 to 5 (preferably 1 to 3 (preferably 1 to 3) substituents selected from the group consisting of a hydroxyl group, an amino group, a halogen atom and a lower alkoxy group having 1 to 4 carbon atoms ) Lower alkyl group optionally substituted by 1 to 5 substituent (s). Preferred is a lower alkyl group having 2 to 3 carbon atoms, particularly preferably an ethyl group.

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

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

In the solid preparation of the present invention, the compound represented by the above formula (I) or a salt thereof is used. Preferable examples of the compound or a salt thereof include 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) ] Benzimidazole-7-carboxylate, 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl- Yl] methyl] -1H-benzimidazole-7-carboxylic acid, pivaloyloxymethyl 2-ethoxy-1 - [[ Carboxylate, 2-ethoxy-1 - [[2 '- (4,5-dihydro-5-oxo-1,2,4-oxadiazol- ] -1H-benzimidazole-7-carboxylic acid and salts thereof. Among them, 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1 H-tetrazol-5-yl) biphenyl- 4- yl] methyl] benzimidazole- 7-carboxylate and salts thereof, 2-ethoxy-1 - [[2 '- (4,5-dihydro- 4-yl] methyl] -1H-benzimidazole-7-carboxylic acid and its salt are particularly preferred.

In the present invention, the compound represented by the above-mentioned formula (I) or a salt thereof is used in a proportion of 0.1 to 60% by weight, preferably 1 to 40% by weight, more preferably 3 to 30% It is contained in the solid preparation of the invention.

As the sugar alcohol used in the present invention, any sugar alcohol can be used as long as it is compatible with the stability of the compound represented by the above formula (I) or its salt in the preparation and the elution from the preparation, and is applicable to pharmaceuticals. Examples of sugar alcohols used in the present invention include tetritol (e.g., erythritol, D-traceol, L-trautol, etc.), pentitol (e.g., D-arabinitol, xylitol, etc.), hexitol Monosaccharide sugar alcohols such as D-iditol, galactitol (dulcitol), D-glucitol (sorbitol), mannitol and the like), cyclitol (e.g., inositol and the like) and the like; Disaccharide sugar alcohols such as maltitol, lactitol, reduced paratinose (isomalt) and the like; Pentaerythritol, hydrogenated maltose starch syrup, and the like. Of these, monosaccharide sugar alcohols are preferred. More preferred are mannitol, sorbitol and erythritol. In particular, mannitol is preferred, and D-mannitol is particularly preferred. The sugar alcohol may be used alone, or two or more thereof may be used in combination. In addition, the sugar alcohol makes both the stability of the calcium antagonist in the preparation and the elution from the preparation compatible.

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 used in the present invention include azelnidipine, amlodipine, aranidipine, ephonidipine, cynidipine, nicardipine, nisoludine, nitrenedipine, nifedipine, neilbodipine, Dihydropyridine compounds such as benzydipine, manidipine, and the like; Benzothiazepine compounds such as diltiazem, and the like. Calcium antagonists for use in the present invention also include salts of the compounds referred to as the calcium antagonists.

As the calcium antagonist to be used in the present invention, a dihydropyridine compound, particularly amlodipine or a salt thereof, is preferable. Of these, salts of amlodipine are more preferred, and amlodipine besylate is particularly preferred.

In the present invention, the calcium antagonist is contained in the solid preparation of the present invention in a proportion of usually 0.05 to 60% by weight, preferably 0.1 to 40% by weight, more preferably 0.5 to 20% by weight in terms of the vitreous body. Specifically, for example, amlodipine is contained in an amount of usually 0.05 to 60% by weight, preferably 0.1 to 40% by weight, more preferably 0.5 to 20% by weight in terms of the glassy body.

The solid formulation of the present invention may further contain an alkylene oxide polymer. Examples of alkylene oxide polymers include polymers of ethylene oxide, propylene oxide, trimethylene oxide, tetrahydrofuran, and the like (preferably ethylene oxide). The molecular weight of the alkylene oxide polymer is preferably 1,000 to 10,000, more preferably 3,000 to 10,000. The alkylene oxide polymer may be a copolymer of an alkylene oxide, and examples of the copolymer of an alkylene oxide include a copolymer of two or more of the above alkylene oxides having a molecular weight of 1,000 to 10,000 (preferably, 3,000 to 10,000) do.

The alkylene oxide polymer may be used alone, or two or more kinds thereof may be used in combination.

As the alkylene oxide polymer used in the present invention, polyethylene glycol is preferable, and polyethylene glycol having a molecular weight of 1,000 to 10,000 is more preferable, and polyethylene glycol having a molecular weight of 3,000 to 10,000 (e.g., polyethylene glycol 4000, polyethylene glycol 6000, polyethylene Glycol 10000) is particularly preferable.

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

A preferred embodiment of the solid preparation of the present invention is that the compound represented by the above formula (I) or a salt thereof is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 ' (Hereinafter occasionally referred to as "Compound A") or a salt thereof, and the calcium antagonist is amlodipine besylate, wherein the calcium antagonist is amlodipine besylate ; Wherein the compound represented by the above formula (I) or a salt thereof is 2-ethoxy-1 - [[2 '- (4,5- ) Biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylic acid (hereinafter occasionally referred to as "Compound B") or a salt thereof and the calcium antagonist is amlodipine besylate do.

As the solid preparation of the present invention, for example, solid preparations suitable for oral administration such as tablets, granules, fine granules, capsules, pills and the like can be mentioned, and tablets are preferable, and single-layer tablets are more preferable. When the solid preparation of the present invention is a tablet, the tablet may have any shape such as a circle, an ellipse, and a rectangle. The size of the tablet varies depending on the shape of the tablet (circular, elliptical, rectangular, etc.), but any size is possible as long as the patient can easily take tablets. When the solid preparation of the present invention is a single-layer tablet, the tablets are small in size and easy to take.

An embodiment of the solid formulation of the present invention is

(1) Group 1 granulation formulation

A mixture containing 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) A solid preparation (for example, a first group granulation monolayer) obtained by granulating and compression-molding the obtained granulation material;

(2) Group 2 granulating agent

(a) solid formulations obtained by mixing and compressing the following first and second portions obtained by individual granulation (e.g., a two-group granulation monolayer);

(b) solid formulations (e. g., multi-layered tablets) obtained by compression molding (without mixing) of the first and second portions described below obtained by individual granulation;

(c) solid formulations (e. g., dry coated tablets) obtained by coating portions of one of the first and second portions below with the other portions obtained by individual granulation;

Part 1: Part containing a compound represented by the formula (I) or a salt thereof (preferably a compound represented by the formula (I) or a salt thereof, and polyethylene glycol)

Part 2: Part containing sugar alcohol and calcium antagonist

And the like.

A preferred embodiment of the solid preparation of the present invention is a first group granulating agent (e.g., a first group granulating monolayer).

The solid preparation of the present invention may contain additives conventionally used in the pharmaceutical field. Examples of such additives include excipients, disintegrants, binders, lubricants, pH adjusters, colorants, surfactants, stabilizers, acidifiers, flavorings, fluidizers and the like. These additives are used in amounts conventionally used in the pharmaceutical field. In addition, these additives may be used as a mixture of two or more appropriate ratios.

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

Examples of disintegrators include, but are not limited to, amino acids, starch, corn starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, Propylcellulose, hydroxypropyl starch, and the like.

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

Examples of binders include, but are not limited to, crystalline cellulose (e.g., microcrystalline cellulose), hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, gelatin, starch, gum arabic powder, tragacanth, carboxymethylcellulose, sodium alginate, Lauryl, glycerol, and the like.

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

Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, talc (refined talc), sucrose esters of fatty acids, sodium stearyl fumarate and the like.

Examples of pH adjusting agents include citric acid and its salts, phosphoric acid and its salts, carbonic acid and its salts, tartaric acid and its salts, fumaric acid and its salts, acetic acid and its salts, amino acids and its salts and the like.

Examples of the coloring agent include an edible lake pigment such as an edible coloring matter such as an edible yellow color No. 5, an edible red color No. 2, an edible blue color No. 2, and an edible yellow color No. 4 aluminum lake, red diatomaceous iron (iron stele), yellow diatomaceous iron oxide, Iron oxide pigments such as iron oxide pigments and the like.

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

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

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

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

Examples of the fluidizing agent include light anhydrous silicic acid, hydrated silicon dioxide and the like.

The solid preparation of the present invention can also be processed into a film coating formulation by applying a film coating agent such as a coating agent, a coating additive and the like. Examples of film coating preparations include sugar preparations, sustained release preparations, enteric preparations and the like.

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

As a sugar base, sucrose is used. Further, one or two or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like can be used in combination.

Examples of water-soluble film coating agents include hydroxypropyl cellulose (e.g., NISSO HPC (products: L, SL, SL-T, SSL) (trade name); Nippon Soda Co., Ltd.], heptromelose [e.g., TC-5 (products: MW, E, EW, R, RW) (trade name); Shin-Etsu Chemical Co., Ltd.], cellulose polymers such as hydroxyethylcellulose, methylhydroxyethylcellulose and the like, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name); ROHM AND HAAS JAPAN K.K.], synthetic polymers such as polyvinylpyrrolidone, polysaccharides such as pullulan, and the like.

Examples of an enteric film coating base include a cellulose polymer such as a hydromellose phthalate ester, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, etc., methacrylic acid copolymer L [Eudragit L (trade name)], Methacrylic acid copolymer LD [Eudragit L-30D55 (trade name); ROHM AND HAAS JAPAN K.K.], methacrylic acid copolymer S [Eudragit S (trade name); ROHM AND HAAS JAPAN K.K.], natural polymers such as shellac, and the like.

Examples of the sustained-release film coating base include cellulose polymers such as ethylcellulose, aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name); ROHM AND HAAS JAPAN K.K.], an ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name); ROHM AND HAAS JAPAN K.K.] and the like.

Preferred examples of the coating additive include a light shielding agent such as titanium dioxide, a fluidizing agent such as talc, a coloring agent such as red ferric oxide, yellow ferric oxide and the like, polyethylene glycol [e.g., macrogol 6000 (trade name); Sanyo Chemical Industries, Ltd.], plasticizers such as triethyl citrate, castor oil, polysorbate and the like, organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid and the like.

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

Examples of such methods include operations such as mixing, kneading, granulating, compression molding, film coating and the like, and appropriate combinations of these operations.

Mixing is carried out using a mixer such as a horizontal cylindrical mixer, a V-mixer, a tumbler mixer, etc., and kneading is carried out using a fixed vessel type kneading such as a rotary container type kneader such as a ball mill, a screw type kneader, A roll mill, a tapered roll mill, or the like. Granulation can be carried out by a granulation method using a high-speed agitating granulator, an electric granulation method using a pan, a conical drum type, a multi-step conical drum type, a drum type with a stirring blade, a vibrating type container, a fluidized bed granulation drying method, , An extrusion granulation method, a method using a granulator such as a roller compactor, or the like.

The compression molding is performed, for example, by molding with an extrusion molding machine, or by a tabletting using a single-edged tablet press, a rotary tablet press, or the like.

In the case of performing compression molding using a single-punch tableting machine, a rotary tabletting machine or the like, it is preferable to employ a tabletting pressure of usually 1 to 35 kN / cm 2 (preferably 5 to 35 kN / cm 2) It is preferable to use a taper cutting die.

The film coating is carried out using, for example, a flow coater such as a pan coater, a horizontal rotator, an inclined plate or the like, a fluid coater such as a fluidized bed type, a divided bed type, a motorized fluidized bed type or the like.

The solid preparation of the present invention can be produced, for example, by the following production process.

(1) When the solid preparation of the present invention is a granular preparation of Group 1

A mixture containing a compound represented by the above-mentioned 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) Is granulated, and the resulting granulated material is compression molded to prepare the solid preparation (Group 1 granulated monolayer preparation) of the present invention.

Concretely, additives such as a compound represented by the above-mentioned formula (I) or a salt thereof, a calcium antagonist and an excipient, a sugar alcohol (e.g., D-mannitol) and the like are mixed and additives such as polyethylene glycol and a binder are dissolved in a solvent (E.g., water), and the obtained liquid is granulated while spraying.

After adding the additives such as a disintegrator, lubricant and the like to the thus obtained granular material and mixing, the mixture is compression molded to prepare tablets. The solid preparation (Group 1 granulated monolayer preparation) of the present invention is prepared by coating a film solution containing a coating agent or the like on the tablet.

(2) When the solid preparation of the present invention is a granular preparation of Group 2

(a) Group 2 granulation monolayer;

The liquid obtained by mixing or dispersing the additive such as polyethylene glycol and a binder in a solvent (e.g., water) or the like is mixed with the additive such as the compound represented by the formula (I) or its salt and excipient, .

On the other hand, a liquid obtained by mixing an additive such as a calcium antagonist and an excipient, sugar alcohol (e.g., D-mannitol) and the like, and dispersing or dissolving an additive such as a binder in a solvent (e.g., water) .

A granulating material containing the compound represented by the above formula (I) or a salt thereof obtained as described above and an additive such as a disintegrant, a lubricant and the like are added to the granulating material containing the calcium antagonist thus obtained, , And the mixture is compression molded to prepare the solid preparation (Group 2 granulated monolayer preparation) of the present invention.

(b) multi-layered tablets;

The liquid obtained by mixing or dispersing the additive such as polyethylene glycol and a binder in a solvent (e.g., water) or the like is mixed with the additive such as the compound represented by the formula (I) or its salt and excipient, . Additives such as disintegrants, lubricants and the like are added to the thus obtained granulated material to prepare mixed granules.

On the other hand, a liquid obtained by mixing an additive such as a calcium antagonist and an excipient, sugar alcohol (e.g., D-mannitol) and the like, and dispersing or dissolving an additive such as a binder in a solvent (e.g., water) . Additives such as disintegrants, lubricants and the like are added to the thus obtained granulated material to prepare mixed granules.

The thus obtained mixed granules containing the compound represented by the above formula (I) or a salt thereof and the mixed granules containing the calcium antagonist thus obtained are layered and compression molded to prepare the solid preparation of the present invention ).

(c) dry coating formulation;

Calcium antagonist and excipient, sugar alcohol (e.g., D-mannitol), and the like. The liquid obtained by dispersing or dissolving an additive such as a binder in a solvent (e.g., water) into the mixture is granulated while spraying. Additives such as a disintegrant, a lubricant and the like are added to the obtained granulated material, and after mixing, the mixture is compression molded to prepare tablets. This tablet is coated with a film solution containing a coating agent or the like to prepare an inner core.

On the other hand, a liquid obtained by mixing additives such as the compound represented by the formula (I) or a salt thereof and an excipient and dispersing or dissolving additives such as polyethylene glycol and a binder in a solvent (e.g., water) Lt; / RTI &gt; Additives such as disintegrants, lubricants and the like are added to the obtained granulated material to prepare mixed granules.

The mixed granules are added to the inner core as an outer layer, and they are compression molded to prepare the solid preparation (dry coating tablet) of the present invention.

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

When the solid preparation of the present invention is a capsule, it can be prepared by charging the granule or the fine granule into capsules containing gelatin, hypromellose and the like. The hard capsule can be prepared by charging the compound represented by the formula (I) or a salt thereof and a calcium antagonist together with a sugar alcohol and other excipients, etc. into capsules containing gelatin, hypromellose and the like. The soft capsule can also be produced by encapsulating the compound represented by the formula (I) or its salt and a calcium antagonist in a predetermined shape by a base containing a plasticizer such as gelatin and glycerol.

The solid preparation of the present invention may have a mark for identification or print characters on the surface. Further, it may have a dividing line for dividing.

The solid preparation of the present invention is low toxic and can be administered orally or parenterally safely as a medicament of a mammal (for example, a human, a monkey, a cat, a pig, a horse, a cow, a mouse, a guinea pig, a dog, .

Since the compound of formula (I) or a salt thereof has potent angiotensin II receptor antagonism, the solid preparation of the present invention is useful for (1) contraction or proliferation of blood vessels expressed through angiotensin II receptor, (Or a disease in which the disease is promoted), (2) a disease caused by the presence of angiotensin II (or a disease in which the disease is promoted), or (3) a factor caused by the presence of angiotensin II Is useful as a preventive or remedy for an onset disease (or a disease in which an onset is promoted).

Examples of diseases of the above (1) to (3) include hypertension, hypertension with a blood pressure of 24 hours or more, heart disease (e.g., cardiomyopathy, acute heart failure, chronic heart failure including congestive heart failure, diastolic dysfunction, cardiomyopathy, angina pectoris, myocarditis, (Cerebral angiopathy, stroke, cerebrovascular dementia, hypertensive brain disease, cerebral infarction, etc.), cerebral edema, cerebral circulation disorder, cerebrovascular disorder Myocardial ischemia, venous insufficiency, progression of heart failure after myocardial infarction, renal disease (eg, nephritis, glomerulonephritis, glomerulonephritis, glomerulonephritis, Or atherosclerosis including atherosclerosis (e.g., aneurysm, coronary artery disease, or atherosclerosis), including atherosclerosis, atherosclerosis, Hypertrophy or obstruction of the blood vessel after hypertrophy, interventional procedures (eg, percutaneous coronary angioplasty, stenting, coronary endoscopy, intravascular ultrasound, and fusional thrombolytic therapy) (Such as glaucoma and ocular hypertension), thrombosis, multiorgan failure, endothelium, and the like, as well as post-operative vascular remodeling and restenosis after transplantation, post-transplant erythropoiesis, hypertension, (Eg, deep vein thrombosis, occlusive peripheral circulation disorder, obstructive atherosclerosis, obstructive thrombotic vasculitis, ischemic cerebral circulation disorder, Raynaud's disease, Burgers disease, etc.), metabolic and metabolic diseases (Eg, obesity, hyperlipemia, hypercholesterolemia, hyperuricemia, hyperkalemia, hypernatremia), neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, A IDS encephalopathy, etc.), central nervous system disorders (e.g., disorders such as cerebral hemorrhage and cerebral infarction, and sequelae and complications thereof, head trauma, spinal cord injury, cerebral edema, senile dementia, perceptual dysfunction, (Eg, neurological dysfunction, multiple sclerosis, etc.), dementia, memory impairment, conscious disorder, forgetfulness, anxiety symptoms, tension symptoms, unpleasant mental state, mental illness Arthritis such as arthritis, osteoarthritis, rheumatoid myelitis, and periostitis; Inflammation after surgery or trauma; Relief of swelling; pharyngitis; cystitis; Pneumonia; Atopic dermatitis; Inflammatory bowel disease such as Crohn's disease, ulcerative colitis and the like; meningitis; Inflammatory eye disease; Inflammatory diseases such as inflammatory lung diseases such as pneumonia, pulmonary silicosis, pulmonary sarcoidosis and pulmonary tuberculosis), allergic diseases (such as allergic rhinitis, conjunctivitis, alimentary allergies, pollen allergies, anaphylaxis), chronic obstructive pulmonary disease, interstitial pneumonia, (Eg, hepatitis including chronic hepatitis, cirrhosis), portal hypertension, gastrointestinal diseases (eg gastritis, gastric ulcer, gastric cancer, postoperative gastrointestinal disorders) , Hemorrhagic disease (eg, erythropoiesis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation), hemorrhagic fever, hemorrhagic fever, (Eg, fracture, fracture, osteoporosis, osteomalacia, bone jets, stiff myelitis, rheumatoid arthritis, osteoarthritis of the knee, and similar diseases) Malignant melanoma, malignant lymphoma, gastrointestinal (eg stomach, bowel) cancer), cachexia accompanied by cancer and cancer, cancer metastasis, endocrine diseases (eg, (Eg, cystitis, cushing's syndrome, pheochromocytoma, high aldosteronism, primary aldosteronism, etc.), Creutzfeldt-Jakob disease, urinary and / (Eg, a disease caused by radiation, ultraviolet rays, infrared rays or laser beams, a disease caused by a high altitude disease (eg, ocular disease, Etc.), respiratory diseases (e.g., cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis and obstruction), infectious diseases (e.g., viral infections such as cytomegalovirus, influenza virus, herpes virus, (E. G., Meniere's syndrome, tinnitus, taste disorder, vertigo, equilibrium disorder), toxic shock syndrome, , Dysphagia, etc.), skin diseases (eg, keloids, hemangiomas, psoriasis, etc.), dialysis hypotension, myasthenia gravis, chronic fatigue syndrome and the like.

A solid preparation of the present invention comprising a combination of a compound represented by the formula (I) or a salt thereof and a calcium antagonist may be used for the prophylactic or therapeutic treatment of the above diseases (preferably for preventing or treating hypertension, heart failure, diabetic nephropathy or arteriosclerosis , More preferably, a preventive or therapeutic agent for hypertension). In addition, the solid preparation of the present invention can be reduced in comparison with the case where the dose of the compound represented by the formula (I) or its salt and the calcium antagonist is used alone.

The dose of the compound represented by the formula (I) or its salt varies depending on the subject to be administered, route of administration, target disease, symptoms, etc., but the daily dose for human adult (body weight 60 kg) Mg, preferably 0.1 to 100 mg, more preferably 1 to 100 mg, still more preferably 2 to 40 mg. For example, a daily dose of Compound A for 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 for a human adult (body weight 60 kg) The dose is about 1 to 50 mg, preferably 10 to 40 mg.

For example, the daily dose of amlodipine or a salt thereof for a human adult (body weight: 60 kg) is about 1 to 50 mg per day in terms of a vitreous body, although the dosage of the calcium antagonist varies depending on the subject to be administered, route of administration, Mg, preferably 2.5 to 10 mg.

The number of administrations of the solid preparation of the present invention to the mammal is preferably 1 to 3 times per day, more preferably once per day.

Particularly preferred embodiments of solid formulations of the present invention include:

"A monolayer containing 8 mg of Compound A per one unit and 6.93 mg of amlodipine besylate (5 mg as amlodipine)";

"Monoglyceride containing 8 mg of Compound A per 1 part and 3.47 mg of amlodipine besylate (2.5 mg as amlodipine) ";

"Monomer containing 4 mg of compound A per unit and 6.93 mg of amlodipine besylate (5 mg as amlodipine) ";

"Monoglyceride containing 4 mg of Compound A per 1 unit and 3.47 mg of amlodipine besylate (2.5 mg as amlodipine) ";

"Monolayer containing 40 mg of compound B per day and 6.93 mg of amlodipine besylate (5 mg as amlodipine) ";

"Monoglyceride containing 40 mg of compound B per day and 3.47 mg of amlodipine besylate (2.5 mg as amlodipine) ";

"Monolayer containing 20 mg of compound B per day and 6.93 mg of amlodipine besylate (5 mg as amlodipine) ";

"Monoclonal formulation containing 20 mg of compound B per day and 3.47 mg of amlodipine besylate (2.5 mg as amlodipine) ";

"Monoglyceride containing 10 mg of compound B per day and 6.93 mg of amlodipine besylate (5 mg as amlodipine) "; And

"Monoclonal formulation containing 10 mg of compound B per tablet and 3.47 mg of amlodipine besylate (2.5 mg as amlodipine).

The solid preparation of the present invention may be used in combination with one or more different kinds of drugs (hereinafter occasionally abbreviated as "combination drugs"). Examples of the "concomitant drug" include a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, a therapeutic agent for hypertension, an anti-obesity agent, a diuretic agent,

Examples of the antidiabetic agent include insulin preparations such as animal insulin preparations extracted from pancreas of cattle or pigs, human insulin preparations synthesized genetically using E. coli or yeast, insulin zinc, protamine insulin zinc, insulin fragments Or a salt thereof (preferably maleate), metaglidascene, or a derivative thereof (e.g., INS-1), an oral insulin preparation), an insulin resistance improving agent (e.g., pioglitazone or its salt (preferably, hydrochloride), rosiglitazone or its salt PLX-204, PN-2034, GFT-505, THR-0921, WO 2007 &lt; RTI ID = 0.0 &gt; Glucosidase inhibitors (for example, boglibose, acarbose, miglitol, emiglitate), an acetylglucosidase inhibitor (e.g., a compound described in WO07 / 013694, WO 2007/018314, WO 2008/093639 or WO200899794) , Metformin, Or a salt thereof (e.g., hydrochloride, fumarate, succinate)), an insulin secretagogue (e.g., sulfonylurea (e.g., tolbutamide, glibenclamide, glyclazide, chlorpropamide, tolazamide, (E.g., acetohexamide, glycopyrimide, glimepiride, glipizide, glybuzole), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate), dipeptidyl peptidase IV inhibitor (e.g., allogliptin or its salt (Preferably benzoate), valdagliptin, citagliptin, saxagliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA- , KRP-104, 2 - [[6 - [(3R) -3-amino-1-piperidinyl] -3,4-dihydro- (E. G., N-5984), GPR40 agonists (e. G., WO 2004/041266, WO 2004/106276, WO 2005/063729, WO 2005/063725, WO 2005/087710, WO 2005/095 1 receptor agonists such as GLP-1, GLP-1 MR, lira glutide, exenatide, AVE-0010, BIM-51077, (E.g., Aib (8,35) hGLP-1 (7,37) NH2, CJC-1131, albiglutide), an amylin agonist (e.g., plumbinide), a phosphotyrosine phosphatase inhibitor ), Your biological inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, FBPase inhibitors), SGLT2 (sodium- glucose co- (E.g. BVT-3498, INCB-13739), adiponectin or its active agent (such as &lt; RTI ID = 0.0 & , An IKK inhibitor (e.g., AS-2868), a leptin resistance improving drug, a somatostatin receptor agonist, a glucokinase activator (e.g. pyragliatine, AZD16 56, AZD6370, TTP-355, WO 2006/112549, WO 2007/028135, WO 2008/047821, WO 2008/050821, WO 2008/136428 or WO 2008/156757), GIP (a glucose-dependent insulin stimulating peptide ), GPR119 agonists (e.g., PSN821), FGF21, FGF analogs, and the like.

Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors such as tolestat, epalrestat, copolestat, fidarestat, CT-112, ranicestat (AS-3201), lidoresist, (For example, NGF, NT-3, BDNF, the neurotrophic factor / secretagogue described in WO 01/14372 (for example, 4- (4- chlorophenyl) -2- (2-methyl-1-imidazolyl) -5 (Eg, compounds described in WO 2004/039365), PKC inhibitors (eg, ruboxystaurin mesylate), AGE inhibitors (eg, ALT946, N-phenacyl GABA receptor agonists (eg, gabapentin, pregabalin), serotonin and norepinephrine reuptake inhibitors (eg, duloxetine), sodium channel inhibitors (eg, thiazolium bromide (ALT766), EXO-226, pyridolines, (Eg, racosamide), active oxygen scavengers (eg, thioctic acid), cerebral vasodilators (eg, thiapuride, mexylin), somatostatin receptors Dongyak (e.g., BIM23190), and the like can be mentioned apoptosis signal regulated kinase -1 (ASK-1) inhibitors.

Examples of the therapeutic agent for hyperlipidemia include HMG-CoA reductase inhibitors such as pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or its salts (e.g. sodium salt, calcium salt), squalene synthetase inhibitors (E.g., a compound described in WO 97/10224 such as N - [[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7- 3-yl] acetyl] piperidine-4-acetic acid), a fibrate compound (e.g., (E.g., benoxaphyreate, clofibrate, simfibrate, clinopibrate), anion exchange resins (e.g., cholestyramine), probucol, nicotinic acid drugs (e.g., nicomol, nisiertrol, niaspann), ethylisocyanate , Plant sterols (e.g., cortisol, gamma oruzanol (gamma-orizanol)), cholesterol absorption inhibitors (e.g., zeitin), CETP inhibitors Saab, Ana set Rafi probe), and the like can be mentioned ω-3 fatty acid preparations (e.g., ω-3- acid ethyl ester 90).

Examples of the therapeutic agent for hypertension include an angiotensin converting enzyme inhibitor (e.g., captopofil, enalapril, delapril, etc.), angiotensin II antagonist (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, (For example, mannitipine, nifedipine, amlodipine, ephonidipine, omega-3 fatty acids, and the like), anticholinergic agents such as valsartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, Beta-blockers (e.g., methoprolol, atenolol, propranolol, carvedilol, pinolol, etc.), clonidine, and the like may be mentioned.

Examples of anti-obesity agents include, but are not limited to, monoamine absorption inhibitors (e.g., pent- eramine, sibutramine, marginal stones, fluoxetine and isoprencine), serotonin 2C receptor agonists (eg, loracercin), serotonin 6 receptor antagonists, histamine H3 receptors, Ghrelin receptor antagonists, ghrelin acylase inhibitors, ghrelin receptor antagonists (e. G., Rimonabant, taranabant), neuropeptide Y antagonists (Eg, GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (eg, AZD-4017), pancreatic lipase inhibitors (eg, Acetyl CoA carboxylase (ACC) inhibitor, stearoyl-CoA de-saturating enzyme (e.g., cetylstart), β3 agonist (eg, N-5984), diacylglycerol acyltransferase 1 (DGAT1) (Eg, R-256918), Na-glucose co-carrier inhibitors (eg JNJ-28431754, lemogliffjin), NFκB inhibitors (eg HE-3286), PPAR agonists (E.g., GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, tromethosamine), GPR119 agonists (e.g., PSN- 821), glucokinase activators 1656), leptin, leptin derivatives (e.g., methoreptin), CNTF (cyclic neurotrophic factor), BDNF (brain derived neurotrophic factor), cholestystinin agonist, glucagon type peptide- Human GLP-1 preparations genetically synthesized using E. coli or yeast; fragments or derivatives of GLP-1 (e.g., exenatide, lira glutide)); Amylin (eg, pleurinide, AC-2307), neuropeptide Y agonists (eg, PYY3-36, PYY3-36 Body, Oviedo Nyepi lactide, TM-30339, TM-30335), auxin Tomo Doolin formulation; (Eg, an animal FGF21 preparation extracted from a pancreas of a cow or a pig; a human FGF21 preparation synthesized genetically using E. coli or yeast; a fragment or a derivative of FGF21)), a suppressive agent (eg, P-57) Can be mentioned.

Examples of diuretics include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate and the like), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide (E.g., spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (e.g., benzoin hydrochloride, benzylhydrochlorothiazide, phenflutiazide, polythiazide and methiclothiazide) (For example, chlorothalidone, mefluxide, indapamide and the like), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, Furosemide, and the like may be mentioned.

Examples of the antithrombotic agent include heparin (e.g., heparin sodium, heparin calcium, sodium enoxaparin, dalteparin sodium), warfarin (e.g., warfarin potassium), antithrombin drugs (e.g., aragatroban, ), A FXa inhibitor (e.g., a compound described in Ribaquivan, apixaban, edoxil class, YM150, WO 02/06234, WO 2004/048363, WO 2005/030740, WO 2005/058823 or WO 2005/113504) (Eg, ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol), thrombolytic agents (eg, thrombin inhibitors such as urokinase, tiokinase, altephea, natepase, montefractase, , Ethyl icosapentate, veraprost sodium, sarpogrelate hydrochloride) and the like can be mentioned.

When the solid preparation of the present invention and a concomitant drug are used in combination, the administration time thereof is not limited, and they can be administered to the administration subject at the same time or at a time difference.

In addition, the solid preparation of the present invention and the concomitant drug may be administered as separate preparations, or as a single preparation containing the solid preparation and the concomitant drug of the present invention.

The dose of the concomitant drug can be appropriately determined based on the clinically used dose of each drug. The compounding ratio of the solid preparation of the present invention and the concomitant drug can be appropriately determined depending on the administration subject, administration route, target disease, symptoms, combination, and the like. For example, when the subject to be administered is a human, the combined drug may be used in an amount of 0.01 to 100 parts by weight based on 1 part by weight of the solid preparation of the present invention.

By using the concomitant drug in this way,

1) the enhancing effect of the action of the solid preparation or the combined medicine of the present invention (synergistic effect of the pharmaceutical action);

2) the effect of reducing the dose of the solid preparation or the concomitant medicament of the present invention (the effect of reducing the dose of the medicament when compared with the single administration);

3) Reduction effect of the secondary action of the solid preparation or the combined medicine of the present invention

And the like can be obtained.

Further, the present invention provides a method for improving the elution property and a method of stabilizing the compound represented by the formula (I) or a salt thereof and / or a calcium antagonist contained in the solid preparation, which comprises adding sugar alcohol. According to the present invention, the solubility of the compound represented by the formula (I) or a salt thereof in the solid preparation is significantly improved.

Example

Hereinafter, the present invention will be described in more detail by way of examples and experimental examples, but the present invention is not limited thereto.

In the following Examples and Experimental Examples, as a component (additive) other than the active ingredient, the Japanese Pharmacopoeia 15th edition, the Japanese Pharmacopoeia and other pharmaceutical specifications or the pharmaceutical additive specifications 2003 compliant product were used.

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

Example 1

The composition per formulation (130 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 82.754 mg Microcrystalline cellulose 20 mg Hydroxypropylcellulose 4 mg macrogol 6000 1.8 mg Sodium croscarmellose sodium 5.6 mg Magnesium stearate 0.9 mg Red ferric oxide 0.016 mg Sum 130 mg

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in purified water (9000 g) to prepare binding solution I. Dispersion I was prepared by dispersing red ferric iron oxide (2.880 g) in purified water (2880 g). Binding Solution I was mixed with Dispersion I and purified water (720.0 g) to prepare Binding Solution II. Amlodipine besylate (1253 g), Compound A (1449 g), D-mannitol (14880 g) and microcrystalline cellulose (3600 g) were uniformly mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding solution II, and then dried to prepare granules. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare pulverized granules.

(2) Croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) were added to the obtained pulverized granules (40760 g (2 batches)) and these were added to a tumbler mixer (TM20-0-0, Suehiro Kakoki Co Ltd., Ltd.) to prepare mixed granules.

(3) The mixed granules thus obtained were tableted (punch pressure 10 kN, weight per tablet: 130 mg) using a punch having a diameter of 7.0 mm with a rotary tablet press (AQUARIUS-36K, Kikusui Seisakusho) Were prepared.

Example 2

The composition per formulation (130 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 82.705 mg Microcrystalline cellulose 20 mg Hydroxypropylcellulose 4 mg macrogol 6000 1.8 mg Sodium croscarmellose sodium 5.6 mg Magnesium stearate 0.9 mg Red ferric oxide 0.065 mg Sum 130 mg

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in purified water (9900 g) to prepare binding solution I. Dispersion I was prepared by dispersing red ferric iron oxide (11.70 g) in purified water (1800 g). Binding Solution I was mixed with Dispersion I and purified water (540.0 g) to prepare Binding Solution II. Amlodipine besylate (1253 g), Compound A (1449 g), D-mannitol (14870 g) and microcrystalline cellulose (3600 g) were homogeneously mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding solution II, and then dried to prepare granules. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare pulverized granules.

(2) Croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) were added to the obtained pulverized granules (40760 g (2 batches)) and these were added to a tumbler mixer (TM20-0-0, Suehiro Kakoki Co Ltd., Ltd.) to prepare mixed granules.

(3) The mixed granules obtained above were tableted (punch pressure 8 kN, weight per tablet: 130 mg) using a punch having a diameter of 8.5 mm and a diameter of 5.0 mm using a rotary tablet press (AQUARIUS-36K, Kikusui Seisakusho) , And nuts having the compositions shown in Table 2 were prepared.

Example 3

The composition per formulation (130 mg) Compound A 8 mg Amlodipine besylate 3.47 mg (2.5 mg as amlodipine) D-mannitol 86.165 mg Microcrystalline cellulose 20 mg Hydroxypropylcellulose 4 mg macrogol 6000 1.8 mg Sodium croscarmellose sodium 5.6 mg Magnesium stearate 0.9 mg Yellow ferric oxide 0.065 mg Sum 130 mg

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in purified water (9900 g) to prepare binding solution I. Dispersion I was prepared by dispersing yellow ferric iron oxide (11.70 g) in purified water (1800 g). Binding Solution I was mixed with Dispersion I and purified water (540.0 g) to prepare Binding Solution II. Amlodipine besylate (627.7 g), Compound A (1449 g), D-mannitol (15550 g) and microcrystalline cellulose (3600 g) were homogeneously mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding solution II, and then dried to prepare granules. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare pulverized granules.

(2) Croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) were added to the obtained pulverized granules (40760 g (2 batches)) and these were added to a tumbler mixer (TM20-0-0, Suehiro Kakoki Co Ltd., Ltd.) to prepare mixed granules.

(3) The mixed granules obtained above were tableted (punch pressure 8 kN, weight per tablet: 130 mg) using a punch having a diameter of 8.5 mm and a diameter of 5.0 mm using a rotary tablet press (AQUARIUS-36K, Kikusui Seisakusho) , And the nose of the composition shown in Table 3 was prepared.

Example 4

The composition per formulation (130 mg) Compound A 4 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 86.705 mg Microcrystalline cellulose 20 mg Hydroxypropylcellulose 4 mg macrogol 6000 1.8 mg Sodium croscarmellose sodium 5.6 mg Magnesium stearate 0.9 mg Red ferric oxide 0.065 mg Sum 130 mg

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in purified water (9900 g) to prepare binding solution I. Dispersion I was prepared by dispersing red ferric iron oxide (11.70 g) in purified water (1800 g). Binding Solution I was mixed with Dispersion I and purified water (540.0 g) to prepare Binding Solution II. Amlodipine besylate (1253 g), Compound A (724.3 g), D-mannitol (15600 g) and microcrystalline cellulose (3600 g) were homogeneously mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding solution II, and then dried to prepare granules. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare pulverized granules.

(2) Croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) were added to the obtained pulverized granules (40760 g (2 batches)) and these were added to a tumbler mixer (TM20-0-0, Suehiro Kakoki Co Ltd., Ltd.) to prepare mixed granules.

(3) The mixed granules thus obtained were tableted (punch pressure 10 kN, weight per tablet: 130 mg) using a punch having a diameter of 7 mm with a rotary tablet press (AQUARIUS-36K, Kikusui Seisakusho) Were prepared.

Example 5

The composition per formulation (130 mg) Compound A 4 mg Amlodipine besylate 3.47 mg (2.5 mg as amlodipine) D-mannitol 90.165 mg Microcrystalline cellulose 20 mg Hydroxypropylcellulose 4 mg macrogol 6000 1.8 mg Sodium croscarmellose sodium 5.6 mg Magnesium stearate 0.9 mg Yellow ferric oxide 0.065 mg Sum 130 mg

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in purified water (9900 g) to prepare binding solution I. Dispersion I was prepared by dispersing yellow ferric iron oxide (11.70 g) in purified water (1800 g). Binding Solution I was mixed with Dispersion I and purified water (540.0 g) to prepare Binding Solution II. Amlodipine besylate (627.7 g), Compound A (724.3 g), D-mannitol (16220 g) and microcrystalline cellulose (3600 g) were uniformly mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding solution II, and then dried to prepare granules. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare pulverized granules.

(2) Croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) were added to the obtained pulverized granules (40760 g (2 batches)) and these were added to a tumbler mixer (TM20-0-0, Suehiro Kakoki Co Ltd., Ltd.) to prepare mixed granules.

(3) The mixed granules thus obtained were tableted (punch pressure 10 kN, weight per tablet: 130 mg) using a punch having a diameter of 7 mm with a rotary tablet press (AQUARIUS-36K, Kikusui Seisakusho) Were prepared.

Example 6

The composition per formulation (130 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 82.666 mg Microcrystalline cellulose 20 mg Hydroxypropylcellulose 4 mg macrogol 6000 1.8 mg Sodium croscarmellose sodium 5.6 mg Magnesium stearate 0.9 mg Red ferric oxide 0.104 mg Sum 130 mg

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in purified water (9900 g) to prepare binding solution I. Dispersion I was prepared by dispersing 18.72 g of red ferric iron oxide in purified water (1800 g). Binding Solution I was mixed with Dispersion I and purified water (540.0 g) to prepare Binding Solution II. Amlodipine besylate (1248 g), Compound A (1446 g), D-mannitol (14870 g) and microcrystalline cellulose (3600 g) were homogeneously mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding solution II, and then dried to prepare granules. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare pulverized granules.

(2) Croscarmellose sodium (924.0 g) and magnesium stearate (148.5 g) were added to the obtained pulverized granules (20380 g), and these were mixed in a tumbler mixer (TM20-0-0, Suehiro Kakoki Co., Ltd.). ) To prepare mixed granules.

(3) The mixed granules obtained above were tableted (punch pressure 8 kN, weight per tablet: 130 mg) using a punch having a diameter of 8.5 mm and a diameter of 5.0 mm using a rotary tablet press (AQUARIUS-36K, Kikusui Seisakusho) , And nuts having the compositions shown in Table 6 were produced.

Example 7

The composition per formulation (130 mg) Compound A 8 mg Amlodipine besylate 3.47 mg (2.5 mg as amlodipine) D-mannitol 86.126 mg Microcrystalline cellulose 20 mg Hydroxypropylcellulose 4 mg macrogol 6000 1.8 mg Sodium croscarmellose sodium 5.6 mg Magnesium stearate 0.9 mg Yellow ferric oxide 0.104 mg Sum 130 mg

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in purified water (9900 g) to prepare binding solution I. Dispersion I was prepared by dispersing yellow iron oxide (18.72 g) in purified water (1800 g). Binding Solution I was mixed with Dispersion I and purified water (540.0 g) to prepare Binding Solution II. Amlodipine besylate (625.2 g), Compound A (1446 g), D-mannitol (15500 g) and microcrystalline cellulose (3600 g) were homogeneously mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding solution II, and then dried to prepare granules. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare pulverized granules.

(2) Croscarmellose sodium (924.0 g) and magnesium stearate (148.5 g) were added to the obtained pulverized granules (20380 g), and these were mixed in a tumbler mixer (TM20-0-0, Suehiro Kakoki Co., Ltd.). ) To prepare mixed granules.

(3) The mixed granules obtained above were tableted (punch pressure 8 kN, weight per tablet: 130 mg) using a punch having a diameter of 8.5 mm and a diameter of 5.0 mm using a rotary tablet press (AQUARIUS-36K, Kikusui Seisakusho) , And nuts having the compositions shown in Table 7 were produced.

Example 8

The composition per formulation (130 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 83.166 mg Microcrystalline cellulose 20 mg Hydroxypropylcellulose 4 mg macrogol 6000 1.3 mg Sodium croscarmellose sodium 5.6 mg Magnesium stearate 0.9 mg Red ferric oxide 0.104 mg Sum 130 mg

(1) Hydroxypropylcellulose (144.0 g) was dissolved in purified water (1980 g) to prepare binding solution I. Dispersion I was prepared by dispersing yellow ferric iron oxide (3.744 g) in purified water (360.0 g). Binding solution I was prepared by mixing dispersion I and purified water (108.0 g). Macrogol 6000 (4.680 g) was dissolved in binding solution II (259.6 g) to prepare binding solution III. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (299.4 g) and microcrystalline cellulose (72.00 g) were homogeneously mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding solution III, and then dried to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

(2) Croscarmellose sodium (16.80 g) and magnesium stearate (2.700 g) were added to the obtained pulverized granules (370.5 g), and they were mixed in a polyethylene bag (4.9 L) to prepare mixed granules.

(3) The mixed granules thus obtained were tableted (Correct 19K, Kikusui Seisakusho) using a punch having a long diameter of 8.5 mm and a short diameter of 5.0 mm (tableting pressure 7.5 kN, weight per tablet: 130 mg) Table 9 shows the results.

Example 9

The composition per formulation (130 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 80.566 mg Microcrystalline cellulose 20 mg Hydroxypropylcellulose 4 mg macrogol 6000 3.9 mg Sodium croscarmellose sodium 5.6 mg Magnesium stearate 0.9 mg Red ferric oxide 0.104 mg Sum 130 mg

(1) Hydroxypropylcellulose (144.0 g) was dissolved in purified water (1980 g) to prepare binding solution I. Dispersion I was prepared by dispersing red ferric iron oxide (3.744 g) in purified water (360.0 g). Binding solution I was prepared by mixing dispersion I and purified water (108.0 g). Macrogol 6000 (14.04 g) was dissolved in binding solution II (259.6 g) to prepare binding solution III. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (290.0 g) and microcrystalline cellulose (72.00 g) were homogeneously mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding solution III, and then dried to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

(2) Croscarmellose sodium (16.80 g) and magnesium stearate (2.700 g) were added to the obtained pulverized granules (370.5 g), and they were mixed in a polyethylene bag (4.9 L) to prepare mixed granules.

(3) The mixed granules thus obtained were tableted (Correct 19K, Kikusui Seisakusho) using a punch having a long diameter of 8.5 mm and a short diameter of 5.0 mm (tableting pressure 7.5 kN, weight per tablet: 130 mg) Table 9 &lt; tb &gt; &lt; tb &gt;

Example 10

The composition per formulation (130 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 77.966 mg Microcrystalline cellulose 20 mg Hydroxypropylcellulose 4 mg macrogol 6000 6.5 mg Sodium croscarmellose sodium 5.6 mg Magnesium stearate 0.9 mg Red ferric oxide 0.104 mg Sum 130 mg

(1) Hydroxypropylcellulose (144.0 g) was dissolved in purified water (1980 g) to prepare binding solution I. Dispersion I was prepared by dispersing red ferric iron oxide (3.744 g) in purified water (360.0 g). Binding solution I was prepared by mixing dispersion I and purified water (108.0 g). Macrogol 6000 (23.40 g) was dissolved in binding solution II (259.6 g) to prepare binding solution III. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (280.7 g) and microcrystalline cellulose (72.00 g) were homogeneously mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding solution III, and then dried to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

(2) Croscarmellose sodium (16.80 g) and magnesium stearate (2.700 g) were added to the obtained pulverized granules (370.5 g), and they were mixed in a polyethylene bag (4.9 L) to prepare mixed granules.

(3) The mixed granules thus obtained were tableted (Correct 19K, Kikusui Seisakusho) using a punch having a long diameter of 8.5 mm and a short diameter of 5.0 mm (tableting pressure 7.5 kN, weight per tablet: 130 mg) Table 9 shows the results.

Example 11

The composition per formulation (130 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 74.066 mg Microcrystalline cellulose 20 mg Hydroxypropylcellulose 4 mg macrogol 6000 10.4 mg Sodium croscarmellose sodium 5.6 mg Magnesium stearate 0.9 mg Red ferric oxide 0.104 mg Sum 130 mg

(1) Hydroxypropylcellulose (144.0 g) was dissolved in purified water (1980 g) to prepare binding solution I. Dispersion I was prepared by dispersing red ferric iron oxide (3.744 g) in purified water (360.0 g). Binding solution I was prepared by mixing dispersion I and purified water (108.0 g). Macrogol 6000 (37.44 g) was dissolved in binding solution II (259.6 g) to prepare binding solution III. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (266.6 g) and microcrystalline cellulose (72.00 g) were homogeneously mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding solution III, and then dried to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

(2) Croscarmellose sodium (16.80 g) and magnesium stearate (2.700 g) were added to the obtained pulverized granules (370.5 g), and they were mixed in a polyethylene bag (4.9 L) to prepare mixed granules.

(3) The mixed granules thus obtained were tableted (Correct 19K, Kikusui Seisakusho) using a punch having a long diameter of 8.5 mm and a short diameter of 5.0 mm (tableting pressure 7.5 kN, weight per tablet: 130 mg) Table 9 shows the results.

Example 12

The composition per formulation (135 mg) Compound B 40 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 40.1 mg Microcrystalline cellulose 9.72 mg Hydroxypropylcellulose 5.2 mg macrogol 6000 4 mg Crospovidone 9.75 mg Microcrystalline cellulose 13 mg Magnesium stearate 1.3 mg Preliminary mixture I 5 mg Sum 135 mg

(1) Hydroxypropylcellulose (208.0 g) and macrogol 6000 (160.0 g) were dissolved in purified water (2392.0 g) to prepare a binding solution. Amlodipine besylate (277.2 g), Compound B (1605.0 g), D-mannitol (1599.0 g) and microcrystalline cellulose (388.8 g) were homogeneously mixed in a fluidized bed granulator (FD-5S, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding liquid, and then dried to prepare granules. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare pulverized granules.

(2) 331.5 g of crospovidone (331.5 g), microcrystalline cellulose (442.0 g) and magnesium stearate (44.201 g) were added to the obtained pulverized granules (3602.0 g), and these were mixed in a tumbler mixer (TM- 15, Suehiro Kakoki co. Ltd.) to prepare mixed granules.

(3) The mixed granules thus obtained were compressed into tablets (Correct 12HUK, Kikusui Seisakusho) using a punch having a diameter of 7.0 mm (tablet pressure 4 kN, weight per tablet: 130 mg) to prepare a tablet.

(4) A preliminary mixture I (240.0 g) was dissolved in purified water (2160.0 g) to prepare a film coating solution. Film coating tablets of the composition shown in Table 12 (weight per tablet: 135 mg) were prepared by uniformly spraying the film coating liquid onto a core (3120.0 g) from a film coater (DRC-500, POWREX Co., Ltd.) ). Here, the preliminary mixture I is a premix powder. The composition of the preliminary mixture I is shown in Table 12a.

[Table 12a]

Example 13

The composition per formulation (135 mg) Compound B 20 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 60.1 mg Microcrystalline cellulose 9.72 mg Hydroxypropylcellulose 5.2 mg macrogol 6000 4 mg Crospovidone 9.75 mg Microcrystalline cellulose 13 mg Magnesium stearate 1.3 mg Preliminary mixture I 5 mg Sum 135 mg

(1) Hydroxypropylcellulose (20.80 g) and macrogol 6000 (16.00 g) were dissolved in purified water (239.2 g) to prepare a binding solution. Amlodipine besylate (27.72 g), Compound B (80.00 g), D-mannitol (240.4 g) and microcrystalline cellulose (38.88 g) were homogeneously mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding liquid, and then dried to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

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

(3) The mixed granules obtained above were compressed into tablets using a rotary tabletting machine (VEL-5, Kikusui Seisakusho) using a punch having a diameter of 7.0 mm (tablet pressure 4 kN, weight per tablet: 130 mg).

(4) A preliminary mixture I (40.00 g) was dissolved in purified water (360.0 g) to prepare a film coating solution. A film-coated tablet having the composition shown in Table 13 (weight per tablet: 135 mg) was obtained by uniformly spraying a film coating liquid onto a core (200.0 g) from a film coater (DRC-200, POWREX Co., Ltd.) ). Here, the preliminary mixture I is a premix powder. The composition of the preliminary mixture I is shown in Table 13a.

[Table 13a]

Example 14

The composition per formulation (135 mg) Compound B 20 mg Amlodipine besylate 3.47 mg (2.5 mg as amlodipine) D-mannitol 63.56 mg Microcrystalline cellulose 9.72 mg Hydroxypropylcellulose 5.2 mg macrogol 6000 4 mg Crospovidone 9.75 mg Microcrystalline cellulose 13 mg Magnesium stearate 1.3 mg Preliminary mixture I 5 mg Sum 135 mg

(1) Hydroxypropylcellulose (20.80 g) and macrogol 6000 (16.00 g) were dissolved in purified water (239.2 g) to prepare a binding solution. Amlodipine besylate (13.88 g), Compound B (80.00 g), D-mannitol (254.2 g) and microcrystalline cellulose (38.88 g) were homogeneously mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding liquid, and then dried to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

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

(3) The mixed granules obtained above were compressed into tablets using a rotary tabletting machine (VEL-5, Kikusui Seisakusho) using a punch having a diameter of 7.0 mm (tablet pressure 4 kN, weight per tablet: 130 mg).

(4) A preliminary mixture I (40.00 g) was dissolved in purified water (360.0 g) to prepare a film coating solution. Film coating tablets of the composition shown in Table 14 (weight per tablet: 135 mg) were prepared by uniformly spraying the film coating liquid onto a core (200.0 g) from a film coater (DRC-200, POWREX Co., Ltd.) ). Here, the preliminary mixture I is a premix powder. The composition of the preliminary mixture I is shown in Table 14a.

[Table 14a]

Example 15

Formulation (135.154 mg) Compound B 10 mg Amlodipine besylate 3.465 mg (2.5 mg as amlodipine) D-mannitol 83.535 mg Microcrystalline cellulose 13 mg Hydroxypropylcellulose 3.9 mg macrogol 6000 1.8 mg Low-substituted hydroxypropylcellulose 13 mg Magnesium stearate 1.3 mg Hypromellose 3.829 mg Titanium dioxide 0.512 mg macrogol 6000 0.768 mg Red ferric oxide 0.011 mg Yellow ferric oxide 0.034 mg Sum 135.154 mg

(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to prepare a binding solution. Amlodipine besylate (10.40 g), Compound B (30.00 g), D-mannitol (250.6 g) and microcrystalline cellulose (39.00 g) were homogeneously mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding liquid, and then dried to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

(2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained ground granules (289.3 g) and mixed in polyethylene bag (4.9 L) to prepare mixed granules .

(3) The mixed granules thus obtained were compressed into tablets (5 kN tablet pressure, 130 mg per tablet) using a rotary tablet press (VEL-5, Kikusui Seisakusho) using a punch having a diameter of 6.5 mm.

(4) Hipromellose (57.44 g) and macrogol 6000 (11.52 g) were dissolved in purified water (375.0 g) to prepare Film Coating Solution I. Dispersion I was prepared by dispersing titanium dioxide (7.680 g), red ferric oxide (0.1650 g) and yellow ferric oxide (0.5100 g) in purified water (330.0 g). Film Coating Solution I, Dispersion I and purified water (68.25 g) were mixed to prepare Film Coating Solution II. The film coating solution II (135.154 g / cm &lt; 2 &gt;) of the composition shown in Table 15 was obtained by uniformly spraying the film coating solution II onto the core (120.0 g) from a film coater (DRC-200, POWREX Co., Mg).

Example 16

Formulation (135.154 mg) Compound B 10 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 80.07 mg Microcrystalline cellulose 13 mg Hydroxypropylcellulose 3.9 mg macrogol 6000 1.8 mg Low-substituted hydroxypropylcellulose 13 mg Magnesium stearate 1.3 mg Hypromellose 3.829 mg Titanium dioxide 0.512 mg macrogol 6000 0.768 mg Red ferric oxide 0.011 mg Yellow ferric oxide 0.034 mg Sum 135.154 mg

(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to prepare a binding solution. Amlodipine besylate (20.79 g), Compound B (30.00 g), D-mannitol (240.2 g) and microcrystalline cellulose (39.00 g) were homogeneously mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding liquid, and then dried to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

(2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained ground granules (289.3 g) and mixed in polyethylene bag (4.9 L) to prepare mixed granules .

(3) The mixed granules thus obtained were compressed into tablets (5 kN tablet pressure, 130 mg per tablet) using a rotary tablet press (VEL-5, Kikusui Seisakusho) using a punch having a diameter of 6.5 mm.

(4) Hipromellose (57.44 g) and macrogol 6000 (11.52 g) were dissolved in purified water (375.0 g) to prepare Film Coating Solution I. Dispersion I was prepared by dispersing titanium dioxide (7.680 g), red ferric oxide (0.1650 g) and yellow ferric oxide (0.5100 g) in purified water (330.0 g). Film Coating Solution I, Dispersion I and purified water (68.25 g) were mixed to prepare Film Coating Solution II. The film coating solution II (135.154 g / cm &lt; 2 &gt;) of the composition shown in Table 16 was obtained by uniformly spraying the film coating solution II onto the core (120.0 g) in a film coating machine (DRC-200, POWREX Co., Mg).

Example 17

The composition (135.119 mg) per composition Compound B 20 mg Amlodipine besylate 3.465 mg (2.5 mg as amlodipine) D-mannitol 73.535 mg Microcrystalline cellulose 13 mg Hydroxypropylcellulose 3.9 mg macrogol 6000 1.8 mg Low-substituted hydroxypropylcellulose 13 mg Magnesium stearate 1.3 mg Hypromellose 3.829 mg Titanium dioxide 0.512 mg macrogol 6000 0.768 mg Red ferric oxide 0.01 mg Sum 135.119 mg

(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to prepare a binding solution. Amlodipine besylate (10.40 g), Compound B (60.00 g), D-mannitol (220.6 g) and microcrystalline cellulose (39.00 g) were uniformly mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding liquid, and then dried to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

(2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained ground granules (289.3 g) and mixed in polyethylene bag (4.9 L) to prepare mixed granules .

(3) The mixed granules thus obtained were compressed into tablets (5 kN tablet pressure, 130 mg per tablet) using a rotary tablet press (VEL-5, Kikusui Seisakusho) using a punch having a diameter of 6.5 mm.

(4) Hipromellose (57.44 g) and macrogol 6000 (11.52 g) were dissolved in purified water (375.0 g) to prepare Film Coating Solution I. Dispersion I was prepared by dispersing titanium dioxide (7.680 g) and red ferric oxide (0.1500 g) in purified water (330.0 g). Film Coating Solution I, Dispersion I and purified water (68.25 g) were mixed to prepare Film Coating Solution II. A film-coated tablet having the composition shown in Table 17 (weight per tablet: 135.119 (by weight) was obtained by uniformly spraying the film coating solution II onto the core (120.0 g) from a film coater (DRC-200, POWREX Co., Ltd.) Mg).

Example 18

The composition (135.119 mg) per composition Compound B 20 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 70.07 mg Microcrystalline cellulose 13 mg Hydroxypropylcellulose 3.9 mg macrogol 6000 1.8 mg Low-substituted hydroxypropylcellulose 13 mg Magnesium stearate 1.3 mg Hypromellose 3.829 mg Titanium dioxide 0.512 mg macrogol 6000 0.768 mg Red ferric oxide 0.01 mg Sum 135.119 mg

(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to prepare a binding solution. Amlodipine besylate (20.79 g), Compound B (60.00 g), D-mannitol (210.2 g) and microcrystalline cellulose (39.00 g) were homogeneously mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding liquid, and then dried to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

(2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained ground granules (289.3 g) and mixed in polyethylene bag (4.9 L) to prepare mixed granules .

(3) The mixed granules thus obtained were compressed into tablets (5 kN tablet pressure, 130 mg per tablet) using a rotary tablet press (VEL-5, Kikusui Seisakusho) using a punch having a diameter of 6.5 mm.

(4) Hipromellose (57.44 g) and macrogol 6000 (11.52 g) were dissolved in purified water (375.0 g) to prepare Film Coating Solution I. Dispersion I was prepared by dispersing titanium dioxide (7.680 g) and red ferric oxide (0.1500 g) in purified water (330.0 g). Film Coating Solution I, Dispersion I and purified water (68.25 g) were mixed to prepare Film Coating Solution II. The film coating solution II (weight per tablet: 135.119 (weight per tablet) shown in Table 18 was obtained by uniformly spraying the film coating solution II onto the core (120.0 g) of the film coating machine (DRC-200, POWREX Co., Ltd.) Mg).

Example 19

The composition per formulation (135.155 mg) Compound B 40 mg Amlodipine besylate 3.465 mg (2.5 mg as amlodipine) D-mannitol 53.535 mg Microcrystalline cellulose 13 mg Hydroxypropylcellulose 3.9 mg macrogol 6000 1.8 mg Low-substituted hydroxypropylcellulose 13 mg Magnesium stearate 1.3 mg Hypromellose 3.829 mg Titanium dioxide 0.512 mg macrogol 6000 0.768 mg Yellow ferric oxide 0.046 mg Sum 135.155 mg

(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to prepare a binding solution. Amlodipine besylate (10.40 g), Compound B (120.0 g), D-mannitol (160.6 g) and microcrystalline cellulose (39.00 g) were uniformly mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding liquid, and then dried to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

(2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained ground granules (289.3 g) and mixed in polyethylene bag (4.9 L) to prepare mixed granules .

(3) The mixed granules thus obtained were compressed into tablets (5 kN tablet pressure, 130 mg per tablet) using a rotary tablet press (VEL-5, Kikusui Seisakusho) using a punch having a diameter of 6.5 mm.

(4) Hipromellose (57.44 g) and macrogol 6000 (11.52 g) were dissolved in purified water (375.0 g) to prepare Film Coating Solution I. Dispersion I was prepared by dispersing titanium dioxide (7.680 g) and yellow ferric oxide (0.6900 g) in purified water (330.0 g). Film Coating Solution I, Dispersion I and purified water (68.25 g) were mixed to prepare Film Coating Solution II. The film coating solution II (135.155 g / cm &lt; 2 &gt;) of the composition shown in Table 19 was obtained by uniformly spraying the film coating solution II onto the core (120.0 g) from a film coater (DRC-200, POWREX Co., Mg).

Example 20

The composition per formulation (135.155 mg) Compound B 40 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 50.07 mg Microcrystalline cellulose 13 mg Hydroxypropylcellulose 3.9 mg macrogol 6000 1.8 mg Low-substituted hydroxypropylcellulose 13 mg Magnesium stearate 1.3 mg Hypromellose 3.829 mg Titanium dioxide 0.512 mg macrogol 6000 0.768 mg Yellow ferric oxide 0.046 mg Sum 135.155 mg

(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to prepare a binding solution. Amlodipine besylate (20.79 g), Compound B (120.0 g), D-mannitol (150.2 g) and microcrystalline cellulose (39.00 g) were uniformly mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , The mixture was granulated while spraying the binding liquid, and then dried to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

(2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained ground granules (289.3 g) and mixed in polyethylene bag (4.9 L) to prepare mixed granules .

(3) The mixed granules thus obtained were compressed into tablets (5 kN of tablet pressure, 130 mg per tablet) using a punch having a diameter of 7.0 mm with a rotary tablet press (VEL-5, Kikusui Seisakusho) to prepare a tablet.

(4) Hipromellose (57.44 g) and macrogol 6000 (11.52 g) were dissolved in purified water (375.0 g) to prepare Film Coating Solution I. Dispersion I was prepared by dispersing titanium dioxide (7.680 g) and yellow ferric oxide (0.6900 g) in purified water (330.0 g). Film Coating Solution I, Dispersion I and purified water (68.25 g) were mixed to prepare Film Coating Solution II. The film coating solution II (135.155 g / cm &lt; 2 &gt; in the composition shown in Table 20) was prepared by uniformly spraying the film coating solution II onto the core (120.0 g) of the film coating machine (DRC-200, POWREX Co., Ltd.) Mg).

Example 21

Formulation (260 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 92.554 mg Microcrystalline cellulose 20 mg Lactose hydrate 89.384 mg Corn starch 20 mg Hypromellose 4 mg Hydroxypropylcellulose 4 mg macrogol 6000 2.6 mg Sodium croscarmellose sodium 11.2 mg Magnesium stearate 1.3 mg Red ferric oxide 0.032 mg Sum 260 mg

(1) Hypromellose (720.0 g) was dissolved in purified water (9000 g) to prepare binding solution I. Dispersion I was prepared by dispersing red ferric iron oxide (2.880 g) in purified water (2880 g). Dispersion I and purified water (720.0 g) were mixed with binding solution I to prepare binding solution II. Amlodipine besylate (1249 g), D-mannitol (16660 g) and microcrystalline cellulose (3600 g) were homogeneously mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) Granulated while spraying, and then dried to prepare granules. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare Grinding Granules I.

(2) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (468.0 g) were dissolved in purified water (9000 g) to prepare binding solution III. Dispersion II was prepared by dispersing red ferric oxide (2.880 g) in purified water (2880 g). Dispersion II and purified water (720.0 g) were mixed with binding solution III to prepare binding solution IV. Compound A (1436 g), lactose hydrate (16090 g) and corn starch (3600 g) were homogeneously mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) Granulated, and then dried to prepare granules. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare Grind granules II.

(3) Croscarmellose sodium (1848 g) and magnesium stearate (214.5 g) were added to the obtained crushed granules I (20380 g) and crushed granules II (20460 g), and these were added to a tumbler mixer 0, Suehiro Kakoki co., Ltd.) to prepare mixed granules.

(4) The mixed granules thus obtained were tableted (punch pressure 10 kN, weight per tablet: 260 mg) using a punch having a diameter of 8.5 mm with a rotary tablet press (AQUARIUS-36K, Kikusui Seisakusho) Were prepared.

Example 22

Formulation (260 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 92.554 mg Microcrystalline cellulose 20 mg Lactose hydrate 89.384 mg Corn starch 20 mg Hypromellose 4 mg Hydroxypropylcellulose 4 mg macrogol 6000 2.6 mg Sodium croscarmellose sodium 5.6 mg Carmellose calcium 5.6 mg Magnesium stearate 1.3 mg Red ferric oxide 0.032 mg Sum 260 mg

(1) Hypromellose (720.0 g) was dissolved in purified water (9000 g) to prepare binding solution I. Dispersion I was prepared by dispersing red ferric iron oxide (2.880 g) in purified water (2880 g). Binding Solution I was mixed with Dispersion I and purified water (720.0 g) to prepare Binding Solution II. Amlodipine besylate (1249 g), D-mannitol (16660 g) and microcrystalline cellulose (3600 g) were homogeneously mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) Granulated while spraying, and then dried to prepare granules. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare Grinding Granules I.

(2) Croscarmellose sodium (924.0 g) and magnesium stearate (148.5 g) were added to the pulverized granule I obtained (20380 g), and these were mixed in a tumbler mixer (TM-60, Showa Kagakukikai Co., Ltd.) To prepare a mixed granule I.

(3) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (468.0 g) were dissolved in purified water (9000 g) to prepare binding solution III. Dispersion II was prepared by dispersing red ferric oxide (2.880 g) in purified water (2880 g). Dispersion II and purified water (720.0 g) were mixed with binding solution III to prepare binding solution IV. Compound A (1436 g), lactose hydrate (16090 g) and corn starch (3600 g) were homogeneously mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) Granulated, and then dried to prepare granules. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare Grind granules II.

(4) Carmellose calcium (924.0 g) and magnesium stearate (66.00 g) were added to the obtained crushed granule II (20460 g) and they were suspended in a tumbler mixer (TM-60, Showa Kagakukikai Co., Ltd.) Mixed granules II were prepared.

(5) The mixed granules I (130 mg) and the mixed granules II (130 mg) obtained above were punched by a rotary tablet press (HT-CVX54LS-UW / C & 3L, HATA IRON WORKS Co., Ltd.) (Net pressure of 9 kN, weight per tablet: 260 mg) to prepare a multilayer tablet having the composition shown in Table 22.

Example 23

The formulation (239 mg) Compound B 40 mg Lactose hydrate 29.3 mg Corn starch 13 mg Microcrystalline cellulose 13 mg Hydroxypropylcellulose 4 mg macrogol 6000 4 mg Low-substituted hydroxypropylcellulose 13 mg Microcrystalline cellulose 13 mg Magnesium stearate 0.7 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 68.94 mg Microcrystalline cellulose 15.33 mg Hydroxypropylcellulose 3.1 mg Carmellose calcium 5 mg Magnesium stearate 0.7 mg Preliminary mixture I 9 mg Sum 239 mg

(1) Hydroxypropylcellulose (155.0 g) was dissolved in purified water (1395.0 g) to prepare binding solution I. Amlodipine besylate (346.7 g), D-mannitol (2447.0 g) and microcrystalline cellulose (766.7 g) were homogeneously mixed in a fluidized bed granulator (FD-5S, POWREX Co., Ltd.) Granulated while spraying, and dried to prepare granules of the amlodipine besylate layer. A part of the granules thus obtained was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare pulverized granules of amlodipine besylate layer.

(2) Hydroxypropylcellulose (280.1 g) and macrogol 6000 (280.0 g) were dissolved in purified water (2520.2 g) to prepare binding solution II. (2808.4 g), lactose hydrate (2043.5 g), corn starch (910.3 g) and microcrystalline cellulose (910.2 g) were homogeneously mixed in a fluidized bed granulator (FD-5S, POWREX Co., Ltd.) Was granulated while spraying the binding solution II, and dried to prepare granules of the compound B layer. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare a crushed granule of the compound B layer.

(3) To the pulverized granules (3772.0 g) of the obtained amlodipine besylate layer, carmellose calcium (200.0 g) and magnesium stearate (28.000 g) were added and they were placed in a tumbler mixer (TM-15, Suehiro Kakoki co. Ltd.) to prepare mixed granules of amlodipine besylate layer.

(4) 455.0 g of low-substituted hydroxypropylcellulose, 455.1 g of microcrystalline cellulose and 24.53 g of magnesium stearate were added to the pulverized granules (3616.1 g) of the obtained Compound B layer, and these were mixed in a tumbler mixer TM-15, Suehiro Kakoki co., Ltd.) to prepare mixed granules of compound B layer.

(5) The mixed granules of the amlodipine besylate layer and the mixed granules of the compound B layer obtained above were tableted using a punch having a diameter of 8.0 mm with a rotary tablet press (HT-X12SS-UW & 2L, HATA IRON WORKS Co., Ltd.) (7 kN of static pressure, 230 mg of amlodipine besylate layer: 100 mg, compound B layer: 130 mg).

(6) A premixture I (252.0 g) was dissolved in purified water (2268.0 g) to prepare a film coating solution. A film-coated tablet of the composition shown in Table 23 (weight per tablet: 239 mg) was obtained by uniformly spraying a film coating liquid onto a core (3120.0 g) from a film coater (DRC-500, POWREX Co., Ltd.) ). Here, the preliminary mixture I is a premix powder. The composition of the preliminary mixture I is shown in Table 23a.

[Table 23a]

Example 24

The composition per formulation (130 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 82.666 mg Microcrystalline cellulose 20 mg Hydroxypropylcellulose 4 mg macrogol 4000 1.8 mg Sodium croscarmellose sodium 5.6 mg Magnesium stearate 0.9 mg Red ferric oxide 0.104 mg Sum 130 mg

(1) Hydroxypropylcellulose (80.00 g) and macrogol 4000 (36.00 g) were dissolved in purified water (1100 g) to prepare binding solution I. Dispersion I was prepared by dispersing red ferric pyrophosphate (2.080 g) in purified water (200.1 g). Binding Solution I was mixed with Dispersion I and purified water (60.00 g) to prepare Binding Solution II. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (297.6 g) and microcrystalline cellulose (72.00 g) were homogeneously mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , And the mixture was granulated while spraying the binding solution II (266.1 g), followed by drying to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

(2) Croscarmellose sodium (16.81 g) and magnesium stearate (2.700 g) were added to the obtained pulverized granules (370.5 g), and they were mixed in a polyethylene bag (4.9 L) to prepare mixed granules.

(3) The mixed granules thus obtained were tableted (Correct 19K, Kikusui Seisakusho) using a punch having a long diameter of 8.5 mm and a short diameter of 5.0 mm (tablet pressure 8.5 kN, weight per tablet: 130 mg) [0251] An annealing having the composition shown in Table 24 was prepared.

Example 25

The composition per formulation (130 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) D-mannitol 82.666 mg Microcrystalline cellulose 20 mg Hydroxypropylcellulose 4 mg macrogol 10000 1.8 mg Sodium croscarmellose sodium 5.6 mg Magnesium stearate 0.9 mg Red ferric oxide 0.104 mg Sum 130 mg

(1) Hydroxypropylcellulose (80.00 g) and macrogol 10000 (36.00 g) were dissolved in purified water (1100 g) to prepare binding solution I. Dispersion I was prepared by dispersing red ferric pyrophosphate (2.080 g) in purified water (200.1 g). The binding solution I was mixed with the dispersion solution I and purified water (60.10 g) to prepare binding solution II. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (297.6 g) and microcrystalline cellulose (72.00 g) were homogeneously mixed in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) , And the mixture was granulated while spraying the binding solution II (266.1 g), followed by drying to prepare granules. A part of the obtained granules was sieved with a sieve (16 mesh) to prepare crushed granules.

(2) Croscarmellose sodium (16.80 g) and magnesium stearate (2.710 g) were added to the obtained pulverized granules (370.5 g), and they were mixed in a polyethylene bag (4.9 L) to prepare mixed granules.

(3) The mixed granules thus obtained were tableted (Correct 19K, Kikusui Seisakusho) using a punch having a long diameter of 8.5 mm and a short diameter of 5.0 mm (tablet pressure 8.5 kN, weight per tablet: 130 mg) [0253] An untreated composition having the composition shown in Table 25 was prepared.

Comparative Example 1

The composition per formulation (130 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (5 mg as amlodipine) Lactose hydrate 82.454 mg Corn starch 20 mg Hydroxypropylcellulose 4 mg macrogol 6000 2.6 mg Carmellose calcium 5.6 mg Magnesium stearate 0.4 mg Red ferric oxide 0.016 mg Sum 130 mg

(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (468.0 g) were dissolved in purified water (9000 g) to prepare binding solution I. Dispersion I was prepared by dispersing red ferric iron oxide (2.880 g) in purified water (2880 g). Binding Solution I was mixed with Dispersion I and purified water (720.0 g) to prepare Binding Solution II. Amlodipine besylate (1253 g), Compound A (1449 g), lactose hydrate (14830 g) and corn starch (3600 g) were uniformly mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The mixture was granulated while spraying the binding solution II, and then dried to prepare granules. A part of the obtained granules was pulverized with a screening mill (P-3, Showa Kagakukikai Co., Ltd.) with a 1.5 mm? Punching screen to prepare pulverized granules.

(2) To the resulting pulverized granules (40920 g (2 batches)) were added carmellose calcium (1848 g) and magnesium stearate (132.0 g) and these were added to a tumbler mixer (TM20-0-0, Suehiro Kakoku co. , Ltd.) to prepare mixed granules.

(3) The mixed granules thus obtained were tableted (punch pressure 9 kN, weight per tablet: 130 mg) using a punch having a diameter of 7.0 mm with a rotary tablet press (AQUARIUS-36K, Kikusui Seisakusho) Were prepared.

Experimental Example 1

Dissolution test 1

The dissolution properties of the active ingredient (Compound A) from the nuts obtained in Examples 1 to 11, 24 and 25 and Comparative Example 1 were evaluated by dissolution test (1.0 (w / w)% polysorbate 20 solution, , Paddle method, revolution speed 50 rpm). The elution test was carried out according to the 15th Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method). The results are shown in Table 27. Table 27 shows the mean value, the maximum value and the minimum value of the dissolution rate after 15 minutes from the start of dissolution. Examples 2, 3, 6, and 7 show the average value, the maximum value, and the minimum value of the dissolution rates of six tablets in Examples 1, 4, 5, 8 to 11, 24, 25 and Comparative Example 1, , The maximum value and the minimum value.

sample After 15 minutes, the dissolution rate (%) medium Maximum value Minimum value Comparative Example 1 43 47 39 Example 1 56 60 51 Example 2 78 84 64 Example 3 75 81 70 Example 4 68 75 61 Example 5 67 72 64 Example 6 74 82 65 Example 7 74 79 69 Example 8 75 80 71 Example 9 74 78 71 Example 10 62 65 57 Example 11 49 56 39 Example 24 75 83 68 Example 25 82 85 75

As shown in Table 27, all of the tabs of Examples 1 to 11, 24, and 25 containing sugar alcohol as an excipient exhibited a good elution property of Compound A as compared to the tabs of Comparative Example 1 which did not contain sugar alcohol.

Experimental Example 2

Dissolution test 2

The elution of the active ingredient (Compound B) from the film-coated tablet obtained in Example 20 was measured by a dissolution test (15th Japanese Pharmacopoeia dissolution test second solution, 900 mL, 37 캜, paddle method, rotation number 50 rpm) Respectively. The elution test was carried out according to the 15th Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method). The results are shown in Table 28. Table 28 shows the average value, the maximum value and the minimum value of the dissolution rates of six tablets at each time point after 5 to 60 minutes from the start of elution.

Measurement time (minute) Dissolution rate (%) medium Maximum value Minimum value 5 34 30 37 10 77 74 81 15 90 88 92 20 92 90 95 25 94 92 96 30 95 93 96 45 96 94 99 60 97 95 101

As shown in Table 28, the film-coated tablets of Example 20 exhibited good elution properties of Compound B.

Experimental Example 3

Stability test

The noodles of Examples 1, 4 and 5 were stored for 12 months under the conditions of a sealed glass bottle and 25 DEG C / 60% RH, and the amount of the analogous substances derived from the compound A or amlodipine besylate was measured to evaluate storage stability. The results are shown in Table 29. The values in Table 29 indicate that the total amount of Compound A or amlodipine besylate in the case where the content of Compound A or amlodipine besylate (Compound A; 8 mg or 4 mg / amlodipine besylate; 6.93 mg or 3.47 mg) (%) Of similar substances.

sample Condition Total analogous material from Compound A All analogues from amlodipine besylate Example 1 At the start of the experiment 0.21% 0.12% 25 ℃ / 60% RH 12 months preservation product 0.86% 0.18% Example 4 At the start of the experiment 0.49% 0.12% 25 ℃ / 60% RH 12 months preservation product 1.21% 0.21% Example 5 At the start of the experiment 0.48% 0.18% 25 ℃ / 60% RH 12 months preservation product 1.12% 0.29%

As shown in Table 29, the loaves of Examples 1, 4 and 5 exhibited good storage stability.

Industrial availability

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, wherein the preparation comprises a compound represented by the formula (I) or a salt thereof and a calcium antagonist , And maintains good stability in these solid preparations.

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

Claims (12)

(i) a compound of formula (I):

1 - [[2 '- (4,5-dihydro-5-oxo-1,2,4-oxadiazol-3- yl) ] Methyl] -1H-benzimidazole-7-carboxylic acid or a salt thereof, (ii) 25 to 75 wt% of a sugar alcohol, (iii) amlodipine or a salt thereof, (iv) a crystalline cellulose, lactose and corn starch (V) a binder selected from the group consisting of crystalline cellulose, hydroxypropylcellulose and hypromellose, (vi) polyethylene glycol having a molecular weight of from 3,000 to 10,000, (vii) an antioxidant selected from the group consisting of croscarmellose sodium , Carmellose calcium and low-substituted hydroxypropylcellulose, and (viii) a solid preparation containing a lubricant. delete delete delete The solid preparation according to claim 1, wherein the sugar alcohol is mannitol, sorbitol or erythritol. The solid preparation according to claim 1, wherein the sugar alcohol is mannitol. delete delete delete delete delete delete