CN102481248A

CN102481248A - Solid preparation

Info

Publication number: CN102481248A
Application number: CN2010800289702A
Authority: CN
Inventors: 保科亘; 福田诚人; 丸中成之
Original assignee: Takeda Chemical Industries Ltd
Current assignee: Takeda Pharmaceutical Co Ltd
Priority date: 2009-04-30
Filing date: 2010-04-28
Publication date: 2012-05-30
Anticipated expiration: 2030-04-28
Also published as: TW201041873A; MA33280B1; MX2011011011A; AU2010242308A1; BRPI1014388A2; SG175794A1; EA201171329A1; CL2011002662A1; IL215962A0; ECSP11011494A; WO2010126168A3; MY158158A; DOP2011000329A; ZA201108375B; CO6470841A2; NZ596395A; CA2760073A1; PE20120315A1; JP2012525323A; WO2010126168A2

Abstract

Provided is a solid preparation comprising (i) a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof, (ii) a sugar alcohol, and (iii) a calcium antagonist, which is superior in the dissolution property and stability.

Description

Solid preparation

Technical field of the present invention

The present invention relates to solid preparation, it shows the performance of the medicine stripping from preparation that improves.

Background of invention

Vascular hypertension is modal a kind of disease among the adult.According to Ministry of Health; The basic research of the blood circulation diseases in 2000 of Labour and Welfare; In Japan; Vascular hypertension patient's's (systolic pressure is not less than 140mmHg or diastolic pressure is not less than 90mmHg, or the inhibitor receiver) number is up to 31,000,000 to 38,000,000.Vascular hypertension is any blood circulation diseases strong risk factor of (comprising cerebrovascular disease and myocardial infarction).Thus, for the prognoses that improves the patient, alleviate self and burden on society, suitably controlling blood pressure is important.

Medicine for vascular hypertension; Various medicines have been developed; The for example diuretic of blood pressure lowering, alpha blocker, Beta receptor blockers, angiotensin converting enzyme (ACE) inhibitor, calcium antagonist, angiotensin ii receptor antagonist or the like, and the patient that many diagnosis suffer from vascular hypertension is treating with these inhibitor.For example, the compound or its salt of following formula (I) representative:

R wherein ¹But be monocycle nitrogen heterocyclic ring group with deprotonation hydrogen atom, R ²Be the carboxyl of optionally esterify, R ³Be optional substituted low alkyl group, be called as angiotensin ii receptor antagonist, it has shown excellent blood pressure lowering effect and organ protection.JP-B-2514282 discloses 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 1-(cyclohexyl oxygen base ketonic oxygen base) ethyl ester (Candesartan Cilexetil) is as the example of representative drugs.

According to J-HOME research (The Japan Home vs.Office blood pressure Measurement Evaluation research); The vascular hypertension patient of about 40% Drug therapy has reached target blood pressure (outpatient's blood pressure at random is less than 140/90mmHg), uses existing Drug therapy also to fail controlling blood pressure fully even this means some patients.In order to improve the ratio that reaches the target blood pressure, need more effective abrupt antihypertensive therapy.

For the pharmacotherapy that produces strong blood pressure lowering effect, can use the combined therapy of multiple drug.For example, WO01/15674 discloses the combination that Chymosin-angiotensin inhibitor and other inhibitor, cholesterol reduce medicine, diuretic or the like and has used.WO02/43807 discloses the combination of angiotensin ii receptor antagonist and other inhibitor or department's Statins (statin) and has used.Yet for the different absorption medicine time, the drug compliance that possibly influence the patient is unfriendly used in the combination of multiple drug, in these Drug therapys, worries the patient because forgetful and uncontrollable blood pressure.For controlling blood pressure more suitably, in clinical practice, need in a kind of medicine, comprise the combination preparation of various inhibitor consumingly, this is because it is the ideal medicament that demonstrates strong blood pressure lowering effect, and can keep patient's drug compliance.

For this combination preparation, proposed to comprise the combination preparation of angiotensin ii receptor antagonist and calcium antagonist.WO92/10097 discloses the combination preparation that comprises angiotensin ii receptor antagonist and other medicine (for example diuretic, calcium antagonist or the like).JP-A-2006-290899 discloses the combination preparation that comprises imidazolyl carboxylic acid esters type angiotensin ii receptor antagonist (for example olmesartan medoxomil or the like) and calcium antagonist.U.S. Pat 6204281 discloses and has comprised valsartan (it is an angiotensin ii receptor antagonist) and 1, the combination preparation of 4-dihydropyridine compound (for example amlodipine or the like, it is a calcium antagonist) or the like.JP-B-2930252 discloses combination preparation, and it comprises 2-butyl-4-chloro-1-[(2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl) methyl] imidazole-5-carboxylic acid or its officinal salt (each all is an angiotensin ii receptor antagonist) and diltiazem (it is a calcium antagonist).In addition, JP-B-3057471 discloses combination preparation, and it comprises benzimidizole derivatives (it is an angiotensin receptor antagonist) and diuretic or calcium antagonist.

In clinical practice, the preparation that expectation comprises benzimidizole derivatives (it is an angiotensin ii receptor antagonist) and calcium antagonist shows the effect of the height organ protection that benzimidizole derivatives (it is an angiotensin ii receptor antagonist) is had and the strong blood pressure lowering effect that calcium antagonist is had simultaneously.In addition, its clinical effectiveness is very high, and this is owing to can improve curative effect according to compound mode, and can reduce side effect.

Yet for effectiveness and the safety that guarantees drug products, not only the effectiveness of active component itself and safety are important, and the performance of pharmaceutical preparation also is very important, and for example medicine is at intravital dissolving out capability of body or the like.For example, when medicine when stripping is too late from pharmaceutical preparation, the blood drug level of medicine can not reach effect level, and maybe not can demonstrate desired effects fully.On the other hand, when medicine when stripping is too fast from pharmaceutical preparation, the blood drug level of medicine can improve apace, brings the excessive risk of side effect.

In other words, except effectiveness and safety, also require drug products can guarantee certain medicine stripping level.The requirement combination preparation satisfies the compatibility and the desired various conditions of each active component with various additives.Thus, compare with the preparation that comprises the single-activity component, the preparation that exploitation meets all these conditions usually is very difficult.Especially, because benzimidizole derivatives (it is an angiotensin ii receptor antagonist) is poorly soluble chemical compound, so the solubility property of preparation may reduce owing to the performance of additive that will make up and active component.When medicine delays to discharge from the combination preparation that is given, cause the reduction of drug absorption rate, bioavailability to reduce, that is, the effect of active component reduces and the value of combination preparation reduces.Therefore, more practical in order to make pharmaceutical preparation, need to regulate the combination of preparation, thereby optimize the dissolution rate of active component in gastrointestinal tract.

The present invention's general introduction

The problem that the present invention solves

For this reason, the purpose of this invention is to provide solid preparation, it stably comprises benzimidizole derivatives and the calcium antagonist with angiotensin-ii receptor antagonism, optimize these medicines in gastrointestinal tract from preparation the performance of stripping.

The method of dealing with problems

In order to address the above problem; The inventor furthers investigate, and has found to comprise following solid preparation: (i) compound or its salt of formula (I) representative, (ii) sugar alcohol; (iii) calcium antagonist, said preparation has shown suitable control dissolving out capability in the human gastrointestinal tract.Specifically, they have noted excipient, and find, the performance of medicine stripping from solid preparation can improve through the sugar alcohol that uses highly-water-soluble, and this causes completion of the present invention.

Correspondingly, the present invention relates to

[1] a kind of solid preparation, it comprises: (i) compound or its salt of formula (I) representative,

R wherein ¹But be monocycle nitrogen heterocyclic ring group with deprotonation hydrogen atom (deprotonatable hydrogen atom), R ²Be the carboxyl of optionally esterify, R ³Be optional substituted low alkyl group, (ii) sugar alcohol and (iii) calcium antagonist;

The solid preparation of [1A] above-mentioned [1], wherein R ²It is optional carboxyl with low alkyl group esterification of 1 to 4 carbon number; It is chosen wantonly by 1 to 3 and is selected from following substituent group replacement: hydroxyl, amino, halogen atom; Lower alkanoyloxy with 2 to 6 carbon numbers; Rudimentary cycloalkanes acyloxy with 4 to 7 carbon numbers has the ketonic oxygen base of the lower alkoxy of 1 to 6 carbon number, has the ketonic oxygen base and the lower alkoxy with 1 to 4 carbon number of the rudimentary cycloalkyloxy of 3 to 7 carbon numbers;

The solid preparation of [1B] above-mentioned [1], wherein R ²Be 1-(cyclohexyl oxygen base ketonic oxygen base) carbethoxyl group or carboxyl;

[2] solid preparation of above-mentioned [1], [1A] or [1B]; The compound or its salt of its Chinese style (I) representative is 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 1-(cyclohexyl oxygen base ketonic oxygen base) ethyl ester; 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid; 2-ethyoxyl-1-[[2 '-(4; 5-dihydro-5-oxo-1; 2,4-

diazole-3-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid, or its salt;

[3] solid preparation of above-mentioned [1], [2], [1A] or [1B]; The compound or its salt of its Chinese style (I) representative is 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 1-(cyclohexyl oxygen base ketonic oxygen base) ethyl ester, or its salt;

[4] solid preparation of above-mentioned [1], [2], [1A] or [1B]; The compound or its salt of its Chinese style (I) representative is 2-ethyoxyl-1-[[2 '-(4; 5-dihydro-5-oxo-1; 2,4-

diazole-3-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid or its salt;

[5] solid preparation of above-mentioned [1], [2], [3], [4], [1A] or [1B], wherein said sugar alcohol is mannitol, Sorbitol or erythritol;

[6] solid preparation of above-mentioned [1], [2], [3], [4], [5], [1A] or [1B], wherein said sugar alcohol is a mannitol;

[7] solid preparation of above-mentioned [1], [2], [3], [4], [5], [6], [1A] or [1B], wherein said calcium antagonist is azelnidipine (azelnidipine), amlodipine (amlodipine); Aranidipine (aranidipine), efonidipine (efonidipine), cilnidipine (cilnidipine); Nicardipine (nicardipine), nisoldipine (nisoldipine), nitrendipine (nitrendipine); Nifedipine (nifedipine), nilvadipine (nilvadipine), barnidipine (barnidipine); Felodipine (felodipine), benidipine (benidipine), Manidipine (manidipine) or its salt;

[8] solid preparation of above-mentioned [1], [2], [3], [4], [5], [6], [7], [1A] or [1B], wherein calcium antagonist is amlodipine or its salt;

[9] solid preparation of above-mentioned [1], [2], [3], [4], [5], [6], [7], [8], [1A] or [1B], it further comprises Polyethylene Glycol;

[10] solid preparation of above-mentioned [9], wherein said Polyethylene Glycol has 1000 to 10000 molecular weight;

[11] solid preparation, it comprises: (i) 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 1-(cyclohexyl oxygen base ketonic oxygen base) ethyl ester or its salt, (ii) mannitol and (iii) amlodipine or its salt;

The solid preparation of [11A] above-mentioned [11], it further comprises Polyethylene Glycol;

The solid preparation of [11B] above-mentioned [11A], wherein Polyethylene Glycol has 1000 to 10000 molecular weight (preferred 3000 to 10000);

The solid preparation of [11C] above-mentioned [11B], wherein the content of Polyethylene Glycol is 1 to 5 weight %;

The solid preparation of [11D] above-mentioned [11B], wherein the content of Polyethylene Glycol is 1 to 3 weight %;

[12] solid preparation; It comprises: (i) 2-ethyoxyl-1-[[2 '-(4; 5-dihydro-5-oxo-1,2,4-

diazole-3-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid or its salt; (ii) mannitol and (iii) amlodipine or its salt;

The solid preparation of [12A] above-mentioned [12], it further comprises Polyethylene Glycol;

The solid preparation of [12B] above-mentioned [12A], wherein Polyethylene Glycol has 1000 to 10000 molecular weight (preferred 3000 to 10000);

The solid preparation of [12C] above-mentioned [12B], wherein the content of Polyethylene Glycol is 1 to 5 weight %;

The solid preparation of [12D] above-mentioned [12B], wherein the content of Polyethylene Glycol is 1 to 3 weight %;

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

[14] solid preparation of above-mentioned [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D], it is the monolayer tablet;

[15] solid preparation of above-mentioned [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [1 3], [14], [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D], it is vascular hypertension, heart failure, diabetic nephropathy or arteriosclerotic prevention or medicine;

[16] solid preparation of above-mentioned [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [1 3], [14], [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D], it is the prevention or the medicine of vascular hypertension;

Or the like.

Effect of the present invention

According to the present invention; Can obtain solid preparation; In this solid preparation, can suitably control the stripping from said preparation in gastrointestinal tract of above-mentioned formula (I) representative compound or its salt and calcium antagonist, and can keep its stability in said preparation well.That is to say that solid preparation of the present invention has superiority aspect above-mentioned formula (I) representative compound or its salt and calcium antagonist dissolving out capability and its from preparation is stable.

(detailed description of the present invention)

Specify solid preparation of the present invention below.

Solid preparation of the present invention is to comprise following solid preparation: (i) compound or its salt of following formula (I) representative:

R wherein ¹But be monocycle nitrogen heterocyclic ring group with deprotonation hydrogen atom, R ²Be the carboxyl of optionally esterify, R ³Be optional substituted low alkyl group, (ii) sugar alcohol and (iii) calcium antagonist (also being called solid preparation of the present invention hereinafter).

In above-mentioned formula (I), for R ¹But the monocycle nitrogen heterocyclic ring group with deprotonation hydrogen atom, can mention, for example, the group of tetrazole radical and following formula representative

Wherein i be-O-or-S-, j is＞C=O,＞C=S or＞S (O) _m, wherein m is 0,1 or 2, or the like.For preferred group; Can mention tetrazole radical; 4; 5-dihydro-5-oxo-1,2,4-two

azoles-3-base or the like.

4; 5-dihydro-5-oxo-1; 2,4-

diazole-3-base comprises 3 tautomers (a ', b ' and c ') of following formula representative:

and

4; 5-dihydro-5-oxo-1; 2,4-

diazole-3-base comprises above-mentioned all a ', b ' and c '.

In the above-mentioned formula (I), R ²The example of carboxyl of optionally esterify comprise optional carboxyl with low alkyl group esterification of 1 to 4 carbon number.Above-mentioned low alkyl group is optional to be selected from following substituent group replacement by 1 to 5 (preferred 1 to 3): hydroxyl, amino, halogen atom; Lower alkanoyloxy (for example, acetoxyl group, penta acyloxy or the like) with 2 to 6 carbon numbers; Rudimentary cycloalkanes acyloxy with 4 to 7 carbon numbers; Ketonic oxygen base (for example, methoxycarbonyl oxygen base, ethoxy carbonyl oxygen base or the like) with lower alkoxy of 1 to 6 carbon number; Have the ketonic oxygen base (for example, cyclohexyl oxygen base ketonic oxygen base or the like) of the rudimentary cycloalkyloxy of 3 to 7 carbon numbers and have the lower alkoxy of 1 to 4 carbon number.For preferred group, can mention 1-(cyclohexyl oxygen base ketonic oxygen base) carbethoxyl group, carboxyl or the like.

In the above-mentioned formula (I), for R ³Optional substituted low alkyl group, can mention low alkyl group with 1 to 5 carbon number, it is optional to be selected from following substituent group by 1 to 5 (preferred 1 to 3) and to replace: hydroxyl, amino, halogen atom and the lower alkoxy with 1 to 4 carbon number.The low alkyl group that preferably has 2 to 3 carbon numbers, especially preferred ethyl.

The salt of above-mentioned formula (I) representative chemical compound must be officinal salt, for example, can mention the salt that formula (I) representative chemical compound becomes with inorganic base; The salt that becomes with organic base, the salt that becomes with mineral acid, the salt that becomes with organic acid; The salt that becomes with alkalescence or acidic amino acid, or the like.The preferred example of the salt that becomes with inorganic base comprises: alkali metal salt, sodium salt for example, potassium salt or the like; Alkali salt, calcium salt for example, magnesium salt or the like; Aluminum salt; Ammonium salt or the like.The preferred example of the salt that becomes with organic base comprises and the following salt that becomes: trimethylamine, and triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N '-dibenzyl-ethylenediamin, or the like.The preferred example of the salt that becomes with mineral acid comprises: the salt that becomes with hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid or the like.The preferred example of the salt that becomes with organic acid comprises and the following salt that becomes: 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-methyl benzenesulfonic acid or the like.The preferred example of the salt that becomes with basic amino acid comprises the salt that becomes with following basic amino acid: arginine, lysine, ornithine or the like.The preferred example of the salt that becomes with acidic amino acid comprises the salt that becomes with following acidic amino acid: aspartic acid, glutamic acid or the like.

Above-mentioned formula (I) representative compound or its salt can be hydrate or non-hydrate, solvate or non-solvent compound.

In addition, preferred, above-mentioned formula (I) representative compound or its salt is a crystal, and fusing point is 100 to 250 ℃, preferred 120 to 200 ℃, and especially 130 to 180 ℃.

For solid preparation of the present invention, can use the compound or its salt of above-mentioned formula (I) representative.The preferred example of this compound or its salt comprises: 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 1-(cyclohexyl oxygen base ketonic oxygen base) ethyl ester; 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid; 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid oxy acid methyl neopentyl ester; 2-ethyoxyl-1-[[2 '-(4; 5-dihydro-5-oxo-1; 2; 4-

diazole-3-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid and its salt.Among these; Especially preferred 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 1-(cyclohexyl oxygen base ketonic oxygen base) ethyl ester and its salt; 2-ethyoxyl-1-[[2 '-(4; 5-dihydro-5-oxo-1; 2,4-

diazole-3-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid and its salt.

In the present invention, above-mentioned formula (I) representative compound or its salt is included in the solid preparation of the present invention, and based on free form, its ratio is 0.1 to 60 weight %, preferred 1 to 40 weight %, more preferably 3 to 30 weight %.

Sugar alcohol for using in the present invention can use any sugar alcohol, if it establish simultaneously the stability of above-mentioned formula (I) representative compound or its salt in preparation with its from preparation dissolving out capability and can be used for drug products.The example of the sugar alcohol that uses in the present invention comprises the monosaccharide sugar alcohol, for example tetritol (for example, erythritol, D-threitol; L-threitol or the like), pentitol (for example, D-arabitol (arabinitol), xylitol or the like); Hexitol (for example, D-iditol, dulcitol (galactitol), D-glucitol (Sorbitol); Mannitol or the like), cyclitol (for example, inositol or the like) or the like; The disaccharide sugar alcohol, maltose alcohol for example, lactose, reductive palatinose (hydroxyl isomaltulose (isomalt)) or the like; The oligosaccharide sugar alcohol, tetramethylolmethane for example, hydrogenant maltose starch syrup or the like; Or the like.In the middle of these, preferred monosaccharide sugar alcohol.More preferably mannitol, Sorbitol and erythritol.Especially preferred mannitol, preferred especially D-mannitol.Can use sugar alcohol separately, maybe can make up and use its two kinds or more kinds of.In addition, sugar alcohol can be realized the stability of calcium antagonist in preparation and its dissolving out capability from preparation simultaneously.

In the present invention, sugar alcohol is included in the solid preparation of the present invention, and its ratio is 15 to 85 weight %, preferred 20 to 80 weight %, more preferably 25 to 75 weight %.

The example of the calcium antagonist that uses in the present invention comprises: dihydropyridine compound, azelnidipine for example, amlodipine, aranidipine; Efonidipine, cilnidipine, nicardipine, nisoldipine; Nitrendipine, nifedipine, nilvadipine, barnidipine; Felodipine, benidipine, Manidipine or the like; Benzodiazepine

chemical compound, for example diltiazem or the like; Or the like.The calcium antagonist that uses in the present invention also comprises the salt of the chemical compound that above-mentioned calcium antagonist is cited.

For employed calcium antagonist among the present invention, preferred dihydropyridine compound, especially preferred amlodipine or its salt.In the middle of these, the more preferably salt of amlodipine, especially preferred Amlodipine Besylate Tablet.

In the present invention, calcium antagonist is included in the solid preparation of the present invention, and based on free form, its ratio is generally 0.05 to 60 weight %, preferred 0.1 to 40 weight %, more preferably 0.5 to 20 weight %.Specifically, for example, amlodipine is included in the solid preparation of the present invention, and based on free form, its ratio is generally 0.05 to 60 weight %, preferred 0.1 to 40 weight %, more preferably 0.5 to 20 weight %.

Solid preparation of the present invention can further comprise oxyalkylene polymer.The example of oxyalkylene polymer comprises the polymer of ethylene oxide, propylene oxide, oxetanes, oxolane or the like (preferred, ethylene oxide).The molecular weight of oxyalkylene polymer preferably 1,000 to 10,000, more preferably 3,000 to 10,000.Oxyalkylene polymer can be the copolymer of oxyalkylene, and the example of the copolymer of oxyalkylene comprises the copolymer of two kinds or more kinds of above-mentioned oxyalkylenes, and it has 1,000 to 10,000 molecular weight (preferred 3,000 to 10,000).

Can use oxyalkylene polymer separately, maybe can make up and use its two kinds or more kinds of.

For employed oxyalkylene polymer in the present invention, preferred Polyethylene Glycol more preferably has 1,000 to 10; 000 molecular weight polyethylene glycol (for example especially preferably has 3,000 to 10,000 molecular weight polyethylene glycol; Macrogol 4000, polyethylene glycol 6000, cetomacrogol 1000 0).

In the present invention, oxyalkylene polymer is included in the solid preparation of the present invention, and preferably its ratio is 1 to 5 weight %, more preferably 1 to 3 weight %.

The preferred embodiment of solid preparation of the present invention comprises:

A kind of solid preparation; Wherein above-mentioned formula (I) representative compound or its salt is 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 1-(cyclohexyl oxygen base ketonic oxygen base) ethyl ester (being sometimes referred to as " compd A " hereinafter) or its salt, calcium antagonist is an Amlodipine Besylate Tablet;

A kind of solid preparation; Wherein above-mentioned formula (I) representative compound or its salt is 2-ethyoxyl-1-[[2 '-(4; 5-dihydro-5-oxo-1; 2; 4-

diazole-3-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid (being sometimes referred to as " compd B " hereinafter) or its salt, calcium antagonist is an Amlodipine Besylate Tablet;

Or the like.

For solid preparation of the present invention, can mention, for example, be suitable for the solid preparation of oral administration, tablet for example, granule, microgranule, capsule, pill or the like, preferred tablet, and more preferably monolayer tablet.When solid preparation of the present invention was tablet, the form of tablet can be circle, ellipse, rectangle or the like.Although the size of tablet changes (circle, Caplet, rectangle or the like) according to the form of tablet, can be any size, as long as the patient can easily absorb tablet.When solid preparation of the present invention is the monolayer tablet, because tablet small-sized, so picked-up easily.

The embodiment of solid preparation of the present invention comprises:

(1) single group pelletize preparation (one group granulated preparation)

Through with mixture pelleting and solid preparation that the granulating raw material compression molding that is obtained is obtained; It is (preferred that wherein this mixture comprises compound or its salt, sugar alcohol and the calcium antagonist of formula (I) representative; Compound or its salt, sugar alcohol, calcium antagonist and the Polyethylene Glycol of formula (I) representative) (for example, single group pelletize monolayer tablet);

(2) two groups of pelletize preparations (two group granulated preparation)

(a) through the solid preparation (for example, two groups of pelletize monolayer tablets) that also compression molding obtained is mixed in following first and second portion (utilizing single granulation to obtain);

(b) solid preparation (for example, multilayer tablet) through following first and second portion (utilizing single granulation to obtain) compression molding (need not mix) is obtained;

(c) solid preparation (for example, dry coationg tablet) through being obtained with a kind of coating another kind in following first and the second portion (utilizing single granulation to obtain);

First: the part (preferred, the compound or its salt and the Polyethylene Glycol of formula (I) representative) that comprises formula (I) representative compound or its salt

Second portion: the part that comprises sugar alcohol and calcium antagonist

Or the like.

The preferred embodiment of solid preparation of the present invention is single group pelletize preparation (for example, single group pelletize monolayer tablet).

Solid preparation of the present invention can comprise the normally used additive of drug world.The example of additive comprises excipient, disintegrating agent, binding agent, lubricant, pH value regulator, coloring agent, surfactant, stabilizing agent, acidulant, flavoring agent, fluidizer or the like.The usage quantity of these additives is the normally used quantity of drug world.In addition, these additives can use with its two kinds of proper ratio or more kinds of form of mixtures.

The example of excipient comprises: starch, corn starch for example, potato starch, wheat starch, rice starch, the starch that part is pregelatinized; Pregelatinized starch, porous-starch or the like, sugar, lactose for example, fructose, glucose; Sucrose or the like, anhydrous calcium phosphate, crystalline cellulose, microcrystalline Cellulose, Radix Glycyrrhizae, sodium bicarbonate; Calcium phosphate, calcium sulfate, calcium carbonate, winnofil, calcium silicates or the like.

Examples of disintegrants comprises aminoacid, starch, corn starch, carmellose; Carboxymethylcellulose calcium, carboxymethyl starch sodium, carmethose, carboxymethylcellulose calcium; Cross-linked carboxymethyl cellulose sodium, crospovidone, low substituted hydroxypropyl cellulose, hydroxypropyl starch or the like.

In the present invention, preferred, the comprise ratio of disintegrating agent in solid preparation of the present invention is 0.1 to 30 weight %, more preferably 1 to 10 weight %.

The example of binding agent comprises crystalline cellulose (for example, microcrystalline Cellulose), hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, gelatin, starch, gum arabic powder, Tragacanth, carmellose, sodium alginate, amylopectin, glycerol or the like.

In the present invention, preferred, the comprise ratio of binding agent in solid preparation of the present invention is 0.1 to 40 weight %, more preferably 1 to 10 weight %.

The example of lubricant comprises magnesium stearate, stearic acid, calcium stearate, Pulvis Talci (purification Pulvis Talci), fatty acid cane sugar ester, sodium stearyl fumarate or the like.

The example of pH value regulator comprises citric acid and its salt, phosphoric acid and its salt, carbonic acid and its salt, tartaric acid and its salt, fumaric acid and its salt, acetic acid and its salt, aminoacid and its salt or the like.

The example of coloring agent comprises: food colour, and for example food colour is yellow No. 5, red No. 2 of food colour; Blue No. 2 of food colour or the like, food lake colours, for example yellow No. 4 aluminum lake colours of food or the like; Iron oxide pigment; Red ferric oxide (colcother) for example, yellow ferric oxide, ferroso-ferric oxide (iron oxide black) or the like; Or the like.

The example of surfactant comprises sodium lauryl sulphate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol or the like.

The example of stabilizing agent comprises tocopherol, sequestrene Na4, nicotiamide, cyclodextrin or the like.

The example of acidulant comprises ascorbic acid, citric acid, tartaric acid, malic acid or the like.

The example of flavoring agent comprises menthol, Oleum menthae, Fructus Citri Limoniae oil, vanillin or the like.

The example of fluidizer comprises lightweight anhydride silica, hydrated SiO 2 or the like.

Can also be through using film coating, for example coating base material, coating additive or the like can also be processed as the film coated preparation with solid preparation of the present invention.The example of film coated preparation comprises: sweet tablet preparation, slow releasing preparation, enteric coated preparation or the like.

The preferred example of coating base material comprises: sugar-coat base material, water miscible film coating base material, the film coating base material of enteric solubility, sustained release film coat base material or the like.

For the sugar-coat base material, can use sucrose.In addition, one or more is selected from following material can to make up use: Talcum, winnofil, gelatin, Radix Acaciae senegalis, amylopectin, Carnauba wax or the like.

The example of water miscible film coating base material comprises: cellulosic polymer, for example hydroxypropyl cellulose [for example, NISSO HPC (grade: L, SL, SL-T, SSL) (trade (brand) name); Nippon Soda Co., Ltd.], hypromellose [for example, TC-5 (grade: MW, E, EW, R, RW) (trade (brand) name); Shin-Etsu Chemical Co., Ltd.], hydroxyethyl-cellulose, methyl hydroxyethylcellulose or the like, synthetic polymer, polyethylene acetal lignocaine acetas for example, methacrylic acid aminoalkyl ester copolymer E [Eudragit E (trade (brand) name); ROHM AND HAAS JAPAN KK. produces], polyvinylpyrrolidone or the like, polysaccharide, for example amylopectin or the like; Or the like.

The example of enteric film coating base material comprises: cellulosic polymer; Hydroxypropyl methyl cellulose phtalate for example, hydroxypropyl emthylcellulose acetic acid succinate, carboxymethylethylcellulose; Cellulose acetate-phthalate or the like; Acrylate copolymer, EUDRAGIT S100 L [Eudragit L (trade (brand) name)] for example, EUDRAGIT S100 LD [Eudragit L-30D55 (trade (brand) name); ROHM AND HAAS JAPAN KK. produces], EUDRAGIT S100 S [Eudragit S (trade (brand) name); ROHM AND HAAS JAPAN KK. produces] or the like, natural polymer, for example lac or the like; Or the like.

The example of sustained release film coat base material comprises: cellulosic polymer, ethyl cellulose or the like for example, acrylate copolymer, for example aminoalkyl methacrylate copolymer RS [Eudragit RS (trade (brand) name); ROHM AND HAAS JAPAN KK. produces], EUDRAGIT NE 30 D EUDRAGIT NE 30D suspension [Eudragit NE (trade (brand) name); ROHM AND HAAS JAPAN KK. produces] or the like; Or the like.

The preferred example of coating additive comprises: bright protective agent, titanium dioxide or the like for example, fluidizer, for example Talcum or the like; Coloring agent, red ferric oxide for example, yellow ferric oxide or the like; Plasticizer, for example Polyethylene Glycol [for example, polyethylene glycol 6000 (macrogol 6000) (trade (brand) name); Sanyo Chemical Industries, Ltd. produces], triethyl citrate, Oleum Ricini, polysorbate or the like, organic acid, citric acid for example, tartaric acid, malic acid, ascorbic acid or the like; Or the like.

Can utilization itself the known method preparation of solid preparation of the present invention (for example, Pharmacopeia of Japan 15 editions, the method described in the general provisions).

The example of this method comprises following operations: for example, mix, stir, granulate, compression molding, film coating, or the like and the appropriate combination of these operations.

For example using, blender mixes; For example; Horizontal cylindrical shape blender; The V-type blender, barrel mixer (tumbler mixer) or the like, and use rotary container type kneader (for example ball mill or the like), fixed container type kneader (for example screw type kneader, Henschel blender or the like), rolling kneader (for example roller mill, taper rolling mill or the like) or the like to mediate.Utilize following method to granulate: the stirring method of granulating that uses the high-speed stirred comminutor; Use tray type, conical drum type, multi-stage taper drum type, the cylinder type that is equipped with stirrer paddle, the rolling method of granulating of oscillatory type container; Fluidized bed granulation and drying means, spray-drying process method, extruding method of granulating; Use the method for comminutor (for example roller compaction machine or the like), or the like.

Carry out compression molding as follows: for example, utilize extrusion molding machinery to form, or use one-shot head tablet machine, rotary tablet machine or the like to carry out film-making.

When using single-stroke tablet machine, rotary tablet machine or the like to carry out compression molding, preferably use 1 usually to 35kN/cm ²(preferred 5 to 35kN/cm ²) film-making pressure, further, use the sharp cone distal blanking die split so that prevent the top.

Carry out film coating as follows: for example, use the tray coating machine of horizontal, inclination type or the like, the liquid coatings machine of horizontal slewing circle disc type, hang plate type or the like, the liquid coatings machine of fluidized bed type, spouted bed type, rolling fluidized bed type or the like.

For example, utilize following preparation steps, can prepare solid preparation of the present invention.

(1) when solid preparation of the present invention is list group pelletize preparation

It is (preferred to comprise above-mentioned formula (I) representative compound or its salt, sugar alcohol and calcium antagonist; Formula (I) representative compound or its salt; Sugar alcohol; Calcium antagonist and Polyethylene Glycol) mixture pelleting, and with the granulating raw material extrusion molding that is obtained, obtain solid preparation of the present invention (single group pelletize monolayer tablet).

Specifically; With above-mentioned formula (I) representative compound or its salt, calcium antagonist and additive (for example excipient), sugar alcohol (for example; The D-mannitol) or the like mix, and with this mixture pelleting, simultaneously spraying liquid; This liquid obtains as follows: Polyethylene Glycol and additive (for example binding agent or the like) are dispersed or dissolved in the solvent (for example, water).

Additive (for example disintegrating agent, lubricant or the like) is joined in the thus obtained granulation raw material, after the mixing,, obtain tablet this mixture extrusion molding.Tablet with the coating solution coating that comprises coating base material or the like, is prepared solid preparation of the present invention (single group pelletize monolayer tablet) thus.

(2) when solid preparation of the present invention is two group pelletize preparation

(a) two groups of pelletize monolayer tablets

Above-mentioned formula (I) representative compound or its salt and additive (for example excipient) or the like are mixed; And with this mixture pelleting; The while spraying liquid, this liquid obtains as follows: Polyethylene Glycol and additive (for example binding agent or the like) are dispersed or dissolved in the solvent (for example, water).

On the other hand, calcium antagonist and additive (for example excipient), sugar alcohol (for example, D-mannitol) or the like are mixed; And with this mixture pelleting; The while spraying liquid, this liquid obtains as follows: additive (for example binding agent or the like) is dispersed or dissolved in the solvent (for example, water).

With additive (disintegrating agent for example; Lubricant or the like) joins in thus obtained, as to comprise above-mentioned formula (I) representative compound or its salt granulation raw material and thus obtained, as the to comprise calcium antagonist granulation raw material; After the mixing; With this mixture extrusion molding, obtain solid preparation of the present invention (two groups of pelletize monolayer tablets).

(b) multilayer tablet

Above-mentioned formula (I) representative compound or its salt and additive (for example excipient) or the like are mixed; And with this mixture pelleting; The while spraying liquid, this liquid obtains as follows: Polyethylene Glycol and additive (for example binding agent or the like) are dispersed or dissolved in the solvent (for example, water).Additive (for example disintegrating agent, lubricant or the like) is joined in the thus obtained granulation raw material, obtain hybrid particles.

On the other hand, calcium antagonist and additive (for example excipient), sugar alcohol (for example, D-mannitol) or the like are mixed; And with this mixture pelleting; The while spraying liquid, this liquid obtains as follows: additive (for example binding agent or the like) is dispersed or dissolved in the solvent (for example, water).Additive (for example disintegrating agent, lubricant or the like) is joined in the thus obtained granulation raw material, obtain hybrid particles.

Hybrid particles and thus obtained, as to comprise calcium antagonist hybrid particles thus obtained, that comprise above-mentioned formula (I) representative compound or its salt are stacked laying each other, and extrusion molding, solid preparation of the present invention (multilayer tablet) obtained.

(c) dry coationg tablet

With calcium antagonist and additive (for example excipient), sugar alcohol (for example; The D-mannitol) or the like mix, and with this mixture pelleting, simultaneously spraying liquid; This liquid obtains as follows: additive (for example binding agent or the like) is dispersed or dissolved in the solvent (for example, water).Additive (for example disintegrating agent, lubricant or the like) is joined in the granulation raw material that is obtained, after the mixing,, obtain tablet this mixture extrusion molding.With tablet coating, obtain the kernel sheet with the coating solution that comprises coating base material or the like.

On the other hand; Above-mentioned formula (I) representative compound or its salt and additive (for example excipient) or the like are mixed, and with this mixture pelleting, the while spraying liquid; This liquid obtains as follows: Polyethylene Glycol and additive (for example binding agent or the like) are dispersed or dissolved in the solvent (for example, water).Additive (for example disintegrating agent, lubricant or the like) is joined in the granulation raw material that is obtained, obtain hybrid particles.

Add the skin of hybrid particles,, obtain solid preparation of the present invention (dry coationg tablet) they extrusion moldings as above-mentioned kernel sheet.

When solid preparation of the present invention is granule or microgranule, can utilize with the said method similar methods to prepare them.

When solid preparation of the present invention is capsule, can be prepared as follows: above-mentioned granule or microgranule are filled in the capsule that comprises gelatin, hypromellose or the like.In addition, hard capsule can be prepared as follows: above-mentioned formula (I) representative compound or its salt and calcium antagonist are filled in the capsule that comprises gelatin, hypromellose or the like with sugar alcohol and other excipient or the like.In addition, soft capsule can be prepared as follows: with above-mentioned formula (I) representative compound or its salt and calcium antagonist with the base material that comprises gelatin and plasticizer (for example glycerin or the like) seal be molded as given shape.

Solid preparation of the present invention can have punch mark and be used for differentiating or lip-deep print pattern.In addition, can have the line of weakness that is used to cut apart.

Solid preparation of the present invention is hypotoxic preparation, and can be used as drug oral or parenteral gives mammal (for example, people, monkey, cat, pig, horse, cattle, mice, rat, Cavia porcellus, Canis familiaris L., rabbit or the like).

Formula (I) representative compound or its salt has intensive angiotensin-ii receptor antagonism; Therefore; Solid preparation of the present invention can be used as following prevention or medicine in above-mentioned mammal: (1) vasoconstriction or propagation form the disease of (or promoting to form) or the organ disease of expressing through angiotensin-ii receptor; (2) owing to there is the formed disease of Angiotensin II (or promote form), or (3) are because the factor that exists Angiotensin II to cause forms the disease of (or promoting formation).

The example of above-mentioned (1) to the disease of (3) comprising: vascular hypertension, and the blood pressure circadian rhythm is unusual, heart disease (for example, cardiac hypertrophy, acute heart failure, chronic heart failure comprises heart failure; Vasodilation weakens, heart myopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia; Myocardial infarction or the like), cerebrovascular disease (for example, no disease property cerebrovascular disease, TCI, apoplexy, vascular dementia, hypertensive encephalopathy; Cerebral infarction or the like), cerebral edema, cerebral circulation disease, the recurrence of cerebrovascular disease and sequela (for example, neuropathy symptom, mental symptom, subjective symptoms; Disease of ADL or the like), ischemic peripheral circulation disease, myocardial ischemia, venous insufficiency, the development gradually of the cardiac insufficiency after the myocardial infarction, kidney disease (for example, nephritis; Glomerulonephritis, glomerulosclerosis, renal failure, thrombosis vascular lesion, diabetic nephropathy, the complication of dialysis, organ injury; Comprise nephropathy that radiation irradiation causes or the like), arteriosclerosis comprises atherosclerosis (for example, aneurysm, coronary atherosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis disease or the like); Vascular hypertrophy is intervened vascular hypertrophy or obturation and organ injury after (for example percutaneous transluminal coronary angioplasty, support, coronary angioscopy, intravascular ultrasound, ICT or the like); Vascular reocclusion after the bypass and restenosis, the erythrocytosis after the transplanting, vascular hypertension, organ injury and vascular hypertrophy, the rejection after the transplanting, ophthalmic (for example, glaucoma, ocular hypertension or the like); Thrombosis, many organs disease, endothelial function disturbance, hypertensive cerebral tinnitus, other cardiovascular disease (for example, venous thrombosis; Blood circulation disease around the occlusive, atherosclerosis obliterans, beurger disease, ischemic brain circulation system disease, Raynaud ' s disease, Berger disease or the like); Metabolism and/or nutritional disorder (for example, obesity, hyperlipidemia, hypercholesterolemia, hyperuricemia, potassemia; Hypernatronemia or the like), neurodegenerative disease (for example, Alzheimer, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy or the like); Central nervous system disorders (for example, damage, for example cerebral hemorrhage and cerebral infarction and their sequela and complication, craniocerebral injury, spinal cord injury; Cerebral edema, senile dementia, sensing dysfunction, sensing function sexual disorders, disorder of vegetative system, autonomic nervous system dysfunction; Multiple cerebral sclerosis or the like), dementia, memory impairment, disturbance of consciousness, amnesia, anxiety neurosis; Stress symptom, the mental status is uncomfortable, psychosis (for example, depression, epilepsy, alcoholism or the like); Diseases associated with inflammation (for example, arthritis, rheumatoid arthritis for example, osteoarthritis, rheumatoid characteristic of disease myelitis, periostitis or the like; Operation and post-traumatic inflammation; The remission of swelling; Pharyngitis; Cystitis; Pneumonia; Atopic dermatitis; Inflammatory bowel disease, Crohn disease for example, ulcerative colitis or the like; Meningitis; Struvite disease of eye; Struvite lung disease, pneumonia for example, pneumosilicosis, pulmonary sarcoidosis, pulmonary tuberculosis or the like), allergic disease (for example, allergic rhinitis; Conjunctivitis, gastrointestinal is irritated, pollinosis, irritated or the like), chronic obstructive pulmonary disease, interstitial pneumonia, pneumocystis carinii pneumonia; Collagen (for example, systemic lupus erythematosus (sle), scleroderma, multiple arteritis or the like), (for example, hepatitis comprises chronic hepatitis to hepatic disease; Liver cirrhosis of liver or the like), portal hypertension, digestive system disease (for example, gastritis, gastric ulcer, gastric cancer, postoperative gastropathy disease; Dyspepsia, esophageal ulcer, pancreatitis, polyp of colon, cholelithiasis, hemorrhoidal diseases, phleborrhexis of esophagus stomach function regulating or the like); Blood and/or myelocyte disease (for example, erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple myelopathy or the like), skeletal diseases is (for example; Fracture, bone is rolled over again, osteoporosis, osteomalacia, textured bone property osteitis, interstitial myelitis, rheumatoid arthritis; The osteoarthritis of knee with by caused joint tissue dysfunction of the disease similar or the like with these), solid tumor, tumor (for example, malignant melanoma, malignant lymphoma, digestive organs (for example, stomach; Intestinal tube or the like) cancer or the like), the cachexia after cancer and the cancer, the metastasis cancer, endocrinopathy (for example, Addison's disease (Addison ' s disease), Cushing's syndrome (Cushing ' s syndrome), pheochromocytoma; Aldosteronism, primary aldosteronism or the like), restrain refined syndrome (Creutzfeldt-Jakob disease), urinary system device and/or male genital disease (for example, cystitis, prostate hyperplasia, carcinoma of prostate; Sexually transmitted disease or the like), gynecological diseases (for example, climacteric disease, gestosis, endometriosis, hysteromyoma, ovarian disease; Cystic hyperplasia of breast, sexually transmitted disease or the like), with environment and occupational factor diseases associated (for example, radiation hazradial bundle, ultraviolet danger, infrared or laser beam, altitude sickness or the like); Respiratory system disease (for example, sympotoms caused by cold factors, pneumonia, asthma, pulmonary hypertension disease, lung thrombosis and pulmonary infarction or the like); Infectious disease (for example) owing to the viral disease that cytomegalovirus, influenza virus, herpesvirus or the like cause, rickettsiosis, bacterial infectious disease or the like, toxemia (for example, septicemia; Septic shock, endotoxin shock, the Gram-negative deteriorated blood is levied, toxic shock syndrome or the like), ENT disease (for example, Meniere disease (Meniere ' s syndrome); Tinnitus, dysgeusia, dizziness, disequilibrium, dysphagia or the like), dermatosis is (for example; Keloid, hemangioma, psoriasis or the like), hemodialysis hypotension, myasthenia gravis, systemic disease is chronic fatigue syndrome or the like for example.

The solid preparation of the present invention of combination that comprises formula (I) representative compound or its salt and calcium antagonist is (preferred as the prevention of above-mentioned disease or medicine; Vascular hypertension, heart failure, diabetic nephropathy or arteriosclerotic prevention or medicine; More preferably, the prevention of vascular hypertension or medicine).In addition, compare with independent use, solid preparation of the present invention can reduce the dosage of formula (I) representative compound or its salt and calcium antagonist.

Although the dosage of formula (I) representative compound or its salt changes according to administration patient, route of administration, targeting disease, symptom or the like; But based on the adult's (body weight 60kg) of free state daily dose is about 0.05 to 500mg; Preferred 0.1 to 100mg; More preferably 1 to 100mg, is more preferably 2 to 40mg.For example, for adult (body weight 60kg), the daily dose of compd A is approximately 1 to 80mg, and preferred 2 to 32mg, and compd B is about 1 to 50mg for adult's (body weight 60kg) daily dose, and preferred 10 to 40mg.

Although the dosage of calcium antagonist changes according to administration patient, route of administration, targeting disease, symptom or the like, be about 1 to 50mg based on the adult's (body weight 60kg) of free state daily dose (for example amlodipine or its salt), preferred 2.5 to 10mg.

For above-mentioned mammal, preferred, the administration frequency of solid preparation of the present invention is every day 1 to 3 time, more preferably once a day.

The especially preferred object lesson of solid preparation of the present invention comprises:

" monolayer tablet, each tablet comprise the compd A of 8mg and the Amlodipine Besylate Tablet of 6.93mg (5mg amlodipine) ";

" monolayer tablet, each tablet comprise the compd A of 8mg and the Amlodipine Besylate Tablet of 3.47mg (2.5mg amlodipine) ";

" monolayer tablet, each tablet comprise the compd A of 4mg and the Amlodipine Besylate Tablet of 6.93mg (5mg amlodipine) ";

" monolayer tablet, each tablet comprise the compd A of 4mg and the Amlodipine Besylate Tablet of 3.47mg (2.5mg amlodipine) ";

" monolayer tablet, each tablet comprise the compd B of 40mg and the Amlodipine Besylate Tablet of 6.93mg (5mg amlodipine) ";

" monolayer tablet, each tablet comprise the compd B of 40mg and the Amlodipine Besylate Tablet of 3.47mg (2.5mg amlodipine) ";

" monolayer tablet, each tablet comprise the compd B of 20mg and the Amlodipine Besylate Tablet of 6.93mg (5mg amlodipine) ";

" monolayer tablet, each tablet comprise the compd B of 20mg and the Amlodipine Besylate Tablet of 3.47mg (2.5mg amlodipine) ";

" monolayer tablet, each tablet comprise the compd B of 10mg and the Amlodipine Besylate Tablet of 6.93mg (5mg amlodipine) "; With

" monolayer tablet, each tablet comprise the compd B of 10mg and the Amlodipine Besylate Tablet of 3.47mg (2.5mg amlodipine) ".

Solid preparation of the present invention can use with one or more different types of medicine (being abbreviated as " and medicament " hereinafter sometimes) combination.The example of " and medicament " comprising: the treatment of diabetes agent, and the therapeutic agent of diabetic complication, the therapeutic agent of hyperlipidemia, hypotensive agent, antiobesity agent, diuretic, the antithrombotic drug agent, or the like.

Among this paper,, can mention as the treatment of diabetes agent, for example, insulin preparation (the animal insulin preparation that for example, extracts from the pancreas of cattle and pig; Use the synthetic human insulin preparation of escherichia coli (Escherichia coli) or yeast heredity; Insulin zinc; Protamine zinc insulin; The fragment of insulin or derivant (for example, INS-1), Macrulin), euglycemic agent (for example, pioglitazone or its salt (preferred, hydrochlorate), rosiglitazone or its salt are (preferred; Maleate), Metaglidasen, AMG-131, Ba Gelie ketone, MBX-2044, Li Gelie ketone, Aleglitazar; Xi Gelie carboxylic (Chiglitazar), Lip river balaglitazone (Lobeglitazone), PLX-204, PN-2034, GFT-505, THR-0921 is described in the chemical compound among WO2007/013694, WO2007/018314, WO2008/093639 or the WO2008/099794); Alpha-glucosidase inhibitor (for example, Fu Gelie alcohol, acarbose, miglitol, emiglitate), biguanide (for example, metformin; Buformin or its salt (for example, hydrochlorate, fumarate, succinate)), insulin secretagogue agent (sulfonylureas (for example, tolbutamide, glibenclamide; Gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide; Glybuzole), repaglinide, Na Gelie naphthalene, Mitiglinide or its calcium salt hydrate), (for example, A Luoli stops (Alogliptin) or its salt (preferred, benzoate) to inhibitors of dipeptidyl IV; Vildagliptin (vildagliptin), sitagliptin, Sha Gelieting (Saxagliptin), BI1356, GRC8200, MP-513, PF-00734200; PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104,2-[[6-[(3R)-and 3-amino-piperidino]-3; 4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidine radicals] methyl]-4-fluoro benzonitrile or its salt), β 3 agonist (for example, N-5984), GPR40 agonist (for example, being described in the chemical compound among WO2004/041266, WO2004/106276, WO2005/063729, WO2005/063725, WO2005/087710, WO2005/095338, WO2007/013689 or the WO2008/001931), the GLP-1 receptor stimulating agent is (for example; GLP-1, GLP-1MR medicament, Li Lalu peptide (Liraglutide), Exenatide (Exenatide), AVE-0010, BIM-51077; Aib (8,35) hGLP-1 (7,37) NH2, CJC-1131, A Bilutai (Albiglutide)), the dextrin agonist is (for example; AC-137), phosphotyrosine phosphatase inhibitor (for example, vanadic acid sodium), gluconeogenesis inhibitor (for example, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitor; Glucagon antagonist, the FBP enzyme inhibitor), SGLT2 (sodium glucose co-transporter 2 white 2) inhibitor (for example, Depagliflozin, AVE2268, TS-033; YM543, TA-7284, Remogliflozin, ASP1941), and the SGLT1 inhibitor, 11 beta-hydroxysteroid dehydrogenase inhibitor are (for example; BVT-3498, INCB-13739), adiponectin or its agonist, (for example, AS-2868), leptin patience is improved medicine to the IKK inhibitor; The somatostatin receptor agonist, activators of glucokinase (for example, Piragliatin, AZD1656, AZD6370, TTP-355; Be described in the chemical compound among WO2006/112549, WO2007/028135, WO2008/047821, WO2008/050821, WO2008/136428 or the WO2008/156757), GIP (Fructus Vitis viniferae glucose-dependent insulinotropic peptide), the GPR119 agonist (for example, PSN821), FGF21, FGF analog or the like.

For the therapeutic agent of diabetic complication, can mention aldose reductase inhibitor (for example, Tuo Ruisita, epalrestat, zopolrestat; Take charge of him to method, CT-112, Lei Nisita (AS-3201), benefit department he (lidorestat)), neurotrophic factor (for example improves medicament with it; NGF, NT-3, BDNF is described in neurotrophy product/secernent among the WO01/14372 (for example, 4-(4-chlorphenyl)-2-(2-methyl isophthalic acid-imidazole radicals)-5-[3-(2-methylphenoxy) propyl group] oxazole); Be described in the chemical compound among the WO2004/039365), pkc inhibitor (for example, methanesulfonic acid Lu Baisita), the AGE inhibitor is (for example; ALT946, N-bromination benzoyl thiazole (ALT766), EXO-226, Pyridorin; Pyridoxamine), GABA receptor stimulating agent (for example, gabapentin, pregabalin); Serotonin and NRI (for example, duloxetine), sodium channel inhibitor (for example, scheme for lacosamide (lacosamide)); Active oxygen scavenger (for example, thioctic acid), cerebral blood vessel expander (for example, tiapuride; Mexiletine), and the somatostatin receptor agonist (for example, BIM23190), apoptosis Signal Regulation kinases-1 (ASK-1) inhibitor or the like.

For the therapeutic agent of hyperlipidemia, can mention HMG-CoA reductase inhibitor (for example, pravastatin, simvastatin, lovastatin; Atorvastatin, fluvastatin, rosuvastatin, Pitavastatin or its salt (for example, sodium salt; Calcium salt)), and squalene synthetase inhibitor (for example, be described in the chemical compound among the WO97/10224, for example, N-[[(3R; 5S)-and 1-(3-acetoxyl group-2,2-dimethylpropyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3; 5-tetrahydrochysene-4,1-benzo oxygen azepine

-3-yl] acetyl group] piperidines-4-acetic acid), shellfish special type of (fibrate) chemical compound (for example, bezafibrate, chlorine Bei Te; Simfibrate (Simfibrate), clinofibrate), anion exchange resin (for example, colestyramine); Probucol, nicotinic acid medicine (for example, cholexamin, niceritrol; Niaspan), 26 alkane pentaene acetoacetic ester, plant sterol (for example, Generol 122; γ oryzanol (gamma oryzanol)), (for example, zechia), the CETP inhibitor (for example for cholesterol absorption inhibitor; Reach plug bent (dalcetrapib), anacetrapib), omega-fatty acid preparation (for example, ω-3-acetoacetic ester 90) or the like.

For antihypertensive, can mention angiotensin-convertion enzyme inhibitor (for example, captopril, enalapril, delapril or the like), the Angiotensin II antagonist is (for example; Candesartan Cilexetil, Candesartan, losartan, Losartan Potassium, Eprosartan, the third penta husky smooth; Telmisartan, Irb, Tasosartan, Olmesartan (olmesart), olmesartan medoxomil, A Qishatan (azilsartan) or the like); Calcium antagonist (for example, Manidipine, nifedipine, amlodipine, efonidipine; Nicardipine, amlodipine, cilnidipine or the like), Beta receptor blockers (for example, metoprolol; Atenolol, propranolol, carvedilol, pindolol or the like), clonidine or the like.

For anti-obesity agents, can mention monoamine absorption inhibitor (for example, Duromine, sibutramine, mazindol; Fluoxetine, tesofensine), serotonin 2C receptor stimulating agent (for example, lorcaserin), serotonin 6 receptor antagonists; Histamine H 3 receptor, GABA-regulates medicine (for example, topiramate), neuropeptide tyrosine antagonist (for example, Wei lifibrate (velneperit)); Cannabinoid receptor antagonists (for example, Rimonabant, taranabant), ghrelin agonist, ghrelin receptor antagonist; Ghrelin acylated enzyme inhibitor, and opioid receptor antagonists (for example, GSK-1521498), orexin (orexin) receptor antagonist, melanocortin 4 receptor stimulating agents; 11 beta-hydroxysteroid dehydrogenase inhibitor (for example, AZD-4017), pancreatic lipase inhibitor (for example, orlistat, Sai Lisita (cetilistat)); β 3 agonist (for example, N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitor, acetyl-CoA carboxylase (ACC) inhibitor, stearic acid CoA dehydrogenase enzyme inhibitor; The microsomal triglyceride transfer protein inhibitor (for example, R-256918), the white inhibitor of sodium glucose co-transporter 2 (for example, JNJ-28431754, remogliflozin); The NF kB inhibitor (for example, HE-3286), the PPAR agonist (for example, GFT-505, DRF-11605); The phosphotyrosine phosphatase inhibitor (for example, vanadic acid sodium, Trodusquemin), the GPR119 agonist is (for example, PSN-821); Activators of glucokinase (for example, AZD-1656), leptin, leptin derivant (for example, metreleptin (metreleptin)); CNTF (CNTF), BDNF (neurotrophic factor derived from brain), cholecystokinin agonist, glucagon-like-peptide-1 (GLP-1) preparation (the animal GLP-1 preparation that for example, extracts from the pancreas of cattle and pig; Use escherichia coli, the synthetic people GLP-1 preparation of yeast heredity; The fragment of GLP-1 or derivant (for example, Exenatide (exenatide), Li Lalu peptide (liraglutide))), the dextrin preparation is (for example; AC-137, AC-2307), neuropeptide Y agaonists (for example, PYY3-36; The derivant of PYY3-36, a Buddhist nun difficult to understand peptide (obinepitide), TM-30339; TM-30335), oxyntomodulin preparation: FGF21 preparation (the animal FGF21 preparation that for example, extracts from the pancreas of cattle and pig; Use escherichia coli, the synthetic people FGF21 preparation of yeast heredity; The fragment of FGF21 or derivant)), anti-feedant is (for example, P-57) or the like.

For diuretic, can mention, for example, and xanthine derivative (for example, theobromine sodium salicylate, diucalcin or the like), the thiazine preparation is (for example; Ethiazide, cyclopenthiazide, naqua, Hydrochlorothiazide, naclex, benzyl Hydrochlorothiazide; Penflutizide, many thiazines, chloromethane thiazine or the like), aldosterone antagonist preparation (for example, spironolactone, Ademine or the like); Carbonic anhydrase inhibitors (for example, acetazolamide or the like), chlorobenzene sulfonamide medicament (for example, chlortalidone, mefruside, indapamide or the like); Azosemide, isosorbide, etacrynic acid, piretanide, bumetanide, furosemide or the like.

For the antithrombotic drug agent, can mention, for example, heparin (for example, heparin sodium, calciparine; Enoxaparin Sodium, dalteparin sodium), warfarin (for example, potassium warfarin), antithrombotic drug is (for example; Argatroban, dabigatran (dabigatran)), (for example, profit is cut down husky class (rivaroxaban) to the FXa inhibitor, the husky class of Ah piperazine (apixaban); Her many Saipans (edoxaban), YM150 is described in the chemical compound among WO02/06234, WO2004/048363, WO2005/030740, WO2005/058823 or the WO2005/113504), thrombolytic agent (for example, urokinase; Tisokinase (tisokinase), alteplase, Nateplase, Monteplase, pamiteplase); Anticoagulant (for example, ticlopidine hydrochloride, clopidogrel, prasugrel (prasugrel), E5555; SHC530348, cilostazol, 26 alkane pentaene acetoacetic ester, beraprost sodium, sarpogrelate hydrochloride) or the like.

When solid preparation of the present invention with and medicament combination when using, to the not restriction of its administration time, can give the administration object simultaneously, or can give with interlace mode.

In addition, solid preparation of the present invention with and medicament can give with independent dosage form, or with comprise solid preparation of the present invention with and the single dosage form of medicament give.

Based on the dosage that uses clinically of each medicine, can suitably confirm the also dosage of medicament.Can come suitably to confirm solid preparation of the present invention and and the mixed proportion of medicament according to the patient of administration, route of administration, targeting disease, symptom, combination or the like.For example, when the administration patient is a man-hour,, can use the also medicament of 0.01 to 100 parts by weight with respect to the solid preparation of the present invention of 1 parts by weight.

Use in this way and medicament, can obtain the effect of following excellence:

1) raising solid preparation of the present invention or the also effect (pharmaceutically-active cooperative effect) of the effect of medicament;

2) reduction solid preparation of the present invention or the also effect of the dosage of medicament (reducing effect) with individually dosed drug dose of comparing;

3) reduction solid preparation of the present invention or the also effect of the side effect of medicament;

Or the like.

The present invention also provide formula (I) representative compound or its salt that raising solid preparation (it comprises the sugar alcohol of interpolation) comprised and/or calcium antagonist solubility property method with make formula (I) representative compound or its salt and/or the stable method of calcium antagonist.According to the present invention, the solubility property of the formula in the solid preparation (I) representative compound or its salt is significantly improved.

Embodiment

Can explain the present invention in more detail with reference to embodiment and EXPERIMENTAL EXAMPLE below, but should it be interpreted as restrictive.

Among below the embodiment and EXPERIMENTAL EXAMPLE; For the component except active component (additive), can use the compatibility product among Pharmacopeia of Japan 15 editions, Japanese Pharmacopoeia Japanese Pharmaceutical Codex or the Japanese Pharmaceutical Excipients 2003.

Among the embodiment,, use compd A or compd B below for the compound or its salt of above-mentioned formula (I) representative.

Embodiment 1

Table 1

The composition of each preparation (130mg)

Compd A	8mg
		Amlodipine Besylate Tablet	6.93mg

	(amlodipine 5mg)
		The D-mannitol	82.754mg
Microcrystalline Cellulose	20mg
		Hydroxypropyl cellulose	4mg
Polyethylene glycol 6000	1.8mg
		Cross-linked carboxymethyl cellulose sodium	5.6mg
Magnesium stearate	0.9mg
		Red ferric oxide	0.016mg
Add up to	130mg

(1) hydroxypropyl cellulose (720.0g) and polyethylene glycol 6000 (324.0g) are dissolved in the purified water (9000g), obtain adhesive solution I.Red ferric oxide (2.880g) is dispersed in the purified water (2880g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (720.0g), obtain adhesive solution II.With Amlodipine Besylate Tablet (1253g), compd A (1449g), D-mannitol (14880g) and microcrystalline Cellulose (3600g) at fluidized bed pelletizer (FD-S2; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution II simultaneously sprays; And after drying obtains granule.At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

punching mesh screen granule of being obtained of a part of milling, the granule that obtains milling.

(2) in the granule of milling that is obtained (40760g (2 batches)), add cross-linked carboxymethyl cellulose sodium (1848g) and magnesium stearate (297.0g), and (TM20-0-0, Suehiro Kakoki Co. Ltd.) the middle mixing, obtain hybrid particles at barrel mixer with them.

(3) utilize rotary tablet machine (AQUARIUS-36K, Kikusui Seisakusho) (drift) with 7.0mm diameter, with the hybrid particles film-making of top acquisition (film-making pressure 10kN, sheet is heavy: 130mg), the plain sheet of the composition that obtains being shown in Table 1.

Embodiment 2

Table 2

The composition of each preparation (130mg)

(1) hydroxypropyl cellulose (720.0g) and polyethylene glycol 6000 (324.0g) are dissolved in the purified water (9900g), obtain adhesive solution I.Red ferric oxide (11.70g) is dispersed in the purified water (1800g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (540.0g), obtain adhesive solution II.With Amlodipine Besylate Tablet (1253g), compd A (1449g), D-mannitol (14870g) and microcrystalline Cellulose (3600g) at fluidized bed pelletizer (FD-S2; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution II simultaneously sprays; And after drying obtains granule.At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

(3) utilize rotary tablet machine (AQUARIUS-36K; Kikusui Seisakusho) (the drift of minor axis) with major diameter and 5.0mm of 8.5mm; With the hybrid particles film-making of top acquisition (film-making pressure 8kN, sheet is heavy: 130mg), the plain sheet of the composition that obtains being shown in Table 2.

Embodiment 3

Table 3

The composition of each preparation (130mg)

(1) hydroxypropyl cellulose (720.0g) and polyethylene glycol 6000 (324.0g) are dissolved in the purified water (9900g), obtain adhesive solution I.Yellow ferric oxide (11.70g) is dispersed in the purified water (1800g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (540.0g), obtain adhesive solution II.With Amlodipine Besylate Tablet (627.7g), compd A (1449g), D-mannitol (15550g) and microcrystalline Cellulose (3600g) at fluidized bed pelletizer (FD-S2; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution II simultaneously sprays; And after drying obtains granule.At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

(3) utilize rotary tablet machine (AQUARIUS-36K; Kikusui Seisakusho) (the drift of minor axis) with major diameter and 5.0mm of 8.5mm; With the hybrid particles film-making of top acquisition (film-making pressure 8kN, sheet is heavy: 130mg), the plain sheet of the composition that obtains being shown in Table 3.

Embodiment 4

Table 4

The composition of each preparation (130mg)

(1) hydroxypropyl cellulose (720.0g) and polyethylene glycol 6000 (324.0g) are dissolved in the purified water (9900g), obtain adhesive solution I.Red ferric oxide (11.70g) is dispersed in the purified water (1800g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (540.0g), obtain adhesive solution II.With Amlodipine Besylate Tablet (1253g), compd A (724.3g), D-mannitol (15600g) and microcrystalline Cellulose (3600g) at fluidized bed pelletizer (FD-S2; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution II simultaneously sprays; And after drying obtains granule.At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

(3) utilize rotary tablet machine (AQUARIUS-36K, Kikusui Seisakusho) (drift) with 7mm diameter, with the hybrid particles film-making of top acquisition (film-making pressure 10kN, sheet is heavy: 130mg), the plain sheet of the composition that obtains being shown in Table 4.

Embodiment 5

Table 5

The composition of each preparation (130mg)

(1) hydroxypropyl cellulose (720.0g) and polyethylene glycol 6000 (324.0g) are dissolved in the purified water (9900g), obtain adhesive solution I.Yellow ferric oxide (11.70g) is dispersed in the purified water (1800g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (540.0g), obtain adhesive solution II.With Amlodipine Besylate Tablet (627.7g), compd A (724.3g), D-mannitol (16220g) and microcrystalline Cellulose (3600g) at fluidized bed pelletizer (FD-S2; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution II simultaneously sprays; And after drying obtains granule.At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

(3) utilize rotary tablet machine (AQUARIUS-36K, Kikusui Seisakusho) (drift) with 7.0mm diameter, with the hybrid particles film-making of top acquisition (film-making pressure 10kN, sheet is heavy: 130mg), the plain sheet of the composition that obtains being shown in Table 5.

Embodiment 6

Table 6

The composition of each preparation (130mg)

(1) hydroxypropyl cellulose (720.0g) and polyethylene glycol 6000 (324.0g) are dissolved in the purified water (9900g), obtain adhesive solution I.Red ferric oxide (18.72g) is dispersed in the purified water (1800g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (540.0g), obtain adhesive solution II.With Amlodipine Besylate Tablet (1248g), compd A (1446g), D-mannitol (14870g) and microcrystalline Cellulose (3600g) at fluidized bed pelletizer (FD-S2; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution II simultaneously sprays; And after drying obtains granule.At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

(2) in the granule of milling (20380g) that is obtained, add cross-linked carboxymethyl cellulose sodium (924.0g) and magnesium stearate (148.5g), and (TM20-0-0, Suehiro Kakoki Co. Ltd.) the middle mixing, obtain hybrid particles at barrel mixer with them.

(3) utilize rotary tablet machine (AQUARIUS-36K; Kikusui Seisakusho) (the drift of minor axis) with major diameter and 5.0mm of 8.5mm; With the hybrid particles film-making of top acquisition (film-making pressure 8kN, sheet is heavy: 130mg), the plain sheet of the composition that obtains being shown in Table 6.

Embodiment 7

Table 7

The composition of each preparation (130mg)

(1) hydroxypropyl cellulose (720.0g) and polyethylene glycol 6000 (324.0g) are dissolved in the purified water (9900g), obtain adhesive solution I.Yellow ferric oxide (18.72g) is dispersed in the purified water (1800g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (540.0g), obtain adhesive solution II.With Amlodipine Besylate Tablet (625.2g), compd A (1446g), D-mannitol (15500g) and microcrystalline Cellulose (3600g) at fluidized bed pelletizer (FD-S2; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution II simultaneously sprays; And after drying obtains granule.At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

(3) utilize rotary tablet machine (AQUARIUS-36K; Kikusui Seisakusho) (the drift of minor axis) with major diameter and 5.0mm of 8.5mm; With the hybrid particles film-making of top acquisition (film-making pressure 8kN, sheet is heavy: 130mg), the plain sheet of the composition that obtains being shown in Table 7.

Embodiment 8

Table 8

The composition of each preparation (130mg)

(1) hydroxypropyl cellulose (144.0g) is dissolved in the purified water (1980g), obtains adhesive solution I.Yellow ferric oxide (3.744g) is dispersed in the purified water (360.0g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (108.0g), obtain adhesive solution II.Polyethylene glycol 6000 (4.680g) is dissolved among the adhesive solution II (259.6g), obtains adhesive solution III.With Amlodipine Besylate Tablet (24.95g), compd A (28.80g), D-mannitol (299.4g) and microcrystalline Cellulose (72.00g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution III simultaneously sprays; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(2) in the granule of milling (370.5g) that is obtained, add cross-linked carboxymethyl cellulose sodium (16.80g) and magnesium stearate (2.700g), and they are mixed in Polythene Bag (4.9L), obtain hybrid particles.

(3) utilize rotary tablet machine (Correct 19K; Kikusui Seisakusho) (the drift of minor axis) with major diameter and 5.0mm of 8.5mm; With the hybrid particles film-making of top acquisition (film-making pressure 7.5kN, sheet is heavy: 130mg), the plain sheet of the composition that obtains being shown in Table 8.

Embodiment 9

Table 9

The composition of each preparation (130mg)

(1) hydroxypropyl cellulose (144.0g) is dissolved in the purified water (1980g), obtains adhesive solution I.Red ferric oxide (3.744g) is dispersed in the purified water (360.0g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (108.0g), obtain adhesive solution II.Polyethylene glycol 6000 (14.04g) is dissolved among the adhesive solution II (259.6g), obtains adhesive solution III.With Amlodipine Besylate Tablet (24.95g), compd A (28.80g), D-mannitol (290.0g) and microcrystalline Cellulose (72.00g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution III simultaneously sprays; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(3) utilize rotary tablet machine (Correct 19K; Kikusui Seisakusho) (the drift of minor axis) with major diameter and 5.0mm of 8.5mm; With the hybrid particles film-making of top acquisition (film-making pressure 7.5kN, sheet is heavy: 130mg), the plain sheet of the composition that obtains being shown in Table 9.

Embodiment 10

Table 10

The composition of each preparation (130mg)

(1) hydroxypropyl cellulose (144.0g) is dissolved in the purified water (1980g), obtains adhesive solution I.Red ferric oxide (3.744g) is dispersed in the purified water (360.0g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (108.0g), obtain adhesive solution II.Polyethylene glycol 6000 (23.40g) is dissolved among the adhesive solution II (259.6g), obtains adhesive solution III.With Amlodipine Besylate Tablet (24.95g), compd A (28.80g), D-mannitol (280.7g) and microcrystalline Cellulose (72.00g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution III simultaneously sprays; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(3) utilize rotary tablet machine (Correct 19K; Kikusui Seisakusho) (the drift of minor axis) with major diameter and 5.0mm of 8.5mm; With the hybrid particles film-making of top acquisition (film-making pressure 7.5kN, sheet is heavy: 130mg), the plain sheet of the composition that obtains being shown in Table 10.

Embodiment 11

Table 11

The composition of each preparation (130mg)

(1) hydroxypropyl cellulose (144.0g) is dissolved in the purified water (1980g), obtains adhesive solution I.Red ferric oxide (3.744g) is dispersed in the purified water (360.0g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (108.0g), obtain adhesive solution II.Polyethylene glycol 6000 (37.44g) is dissolved among the adhesive solution II (259.6g), obtains adhesive solution III.With Amlodipine Besylate Tablet (24.95g), compd A (28.80g), D-mannitol (266.6g) and microcrystalline Cellulose (72.00g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution III simultaneously sprays; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(3) utilize rotary tablet machine (Correct 19K; Kikusui Seisakusho) (the drift of minor axis) with major diameter and 5.0mm of 8.5mm; With the hybrid particles film-making of top acquisition (film-making pressure 7.5kN, sheet is heavy: 130mg), the plain sheet of the composition that obtains being shown in Table 11.

Embodiment 12

Table 12

The composition of each preparation (135mg)

(1) hydroxypropyl cellulose (208.0g) and polyethylene glycol 6000 (160.0g) are dissolved in the purified water (2392.0g), obtain adhesive solution.With Amlodipine Besylate Tablet (277.2g), compd B (1605.0g), D-mannitol (1599.0g) and microcrystalline Cellulose (388.8g) at fluidized bed pelletizer (FD-5S; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, the adhesive solution of spraying simultaneously; And after drying obtains granule.At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

(2) in the granule of milling (3602.0g) that is obtained, add crospovidone (331.5g), microcrystalline Cellulose (442.0g) and magnesium stearate (44.201g); And with them at barrel mixer (TM-15; Suehiro Kakoki co. Ltd.) the middle mixing, obtains hybrid particles.

(3) utilize rotary tablet machine (Correct 12HUK, Kikusui Seisakusho) (drift), with hybrid particles film-making (film-making pressure 4kN, the sheet weight: 130mg), obtain core tablet of top acquisition with 7.0mm diameter.

(4) premix I (240.0g) is dissolved in the purified water (2160.0g), obtains film coating solution.The film coating machine (DRC-500, POWREX Co., Ltd.) in, film coating solution is sprayed on the core tablet (3120.0g) equably, form film coating, (sheet is heavy: 135mg) for the film-coated tablet of the composition that obtains being shown in Table 12.Among this paper, premix I is the premix powder.The composition of premix I is shown among the table 12a.

Table 12a

The composition of premix I

	Weight ratio
		Hypromellose	9.0
Polyethylene glycol 6000	2.0
		Titanium dioxide	1.0
Yellow ferric oxide	0.2

Embodiment 13

Table 13

The composition of each preparation (135mg)

(1) hydroxypropyl cellulose (20.80g) and polyethylene glycol 6000 (16.00g) are dissolved in the purified water (239.2g), obtain adhesive solution.With Amlodipine Besylate Tablet (27.72g), compd B (80.00g), D-mannitol (240.4g) and microcrystalline Cellulose (38.88g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, the adhesive solution of spraying simultaneously; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(2) in the granule of milling (370.8g) that is obtained, add crospovidone (34.13g), microcrystalline Cellulose (45.50g) and magnesium stearate (4.550g), and they are mixed in Polythene Bag (4.9L), obtain hybrid particles.

(3) utilize rotary tablet machine (VEL-5, Kikusui Seisakusho) (drift), with hybrid particles film-making (film-making pressure 4kN, the sheet weight: 130mg), obtain core tablet of top acquisition with 7.0mm diameter.

(4) premix I (40.00g) is dissolved in the purified water (360.0g), obtains film coating solution.The film coating machine (DRC-200, POWREX Co., Ltd.) in, with film coating solution be sprayed at equably core tablet (core tablet) (200.0g) on, form film coating, (sheet is heavy: 135mg) for the film-coated tablet of the composition that obtains being shown in Table 13.Among this paper, premix I is the premix powder.The composition of premix I is shown among the table 13a.

Table 13a

The composition of premix I

	Weight ratio
		Hypromellose	9.0
Polyethylene glycol 6000	2.0
		Titanium dioxide	1.0

Yellow ferric oxide

0.2

Embodiment 14

Table 14

The composition of each preparation (135mg)

(1) hydroxypropyl cellulose (20.80g) and polyethylene glycol 6000 (16.00g) are dissolved in the purified water (239.2g), obtain adhesive solution.With Amlodipine Besylate Tablet (13.88g), compd B (80.00g), D-mannitol (254.2g) and microcrystalline Cellulose (38.88g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, the adhesive solution of spraying simultaneously; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(4) premix I (40.00g) is dissolved in the purified water (360.0g), obtains film coating solution.The film coating machine (DRC-200, POWREX Co., Ltd.) in, film coating solution is sprayed on the core tablet (200.0g) equably, form film coating, (sheet is heavy: 135mg) for the film-coated tablet of the composition that obtains being shown in Table 14.Among this paper, premix I is the premix powder.The composition of premix I is shown among the table 14a.

Table 14a

The composition of premix I

Embodiment 15

Table 15

The composition of each preparation (135.154mg)

(1) hydroxypropyl cellulose (35.10g) and polyethylene glycol 6000 (16.20g) are dissolved in the purified water (403.7g), obtain adhesive solution.With Amlodipine Besylate Tablet (10.40g), compd B (30.00g), D-mannitol (250.6g) and microcrystalline Cellulose (39.00g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, the adhesive solution of spraying simultaneously; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(2) in the granule of milling (289.3g) that is obtained, add low substituted hydroxypropyl cellulose (32.50g) and magnesium stearate (3.250g), and they are mixed in Polythene Bag (4.9L), obtain hybrid particles.

(3) utilize rotary tablet machine (VEL-5, Kikusui Seisakusho) (drift), with hybrid particles film-making (film-making pressure 5kN, the sheet weight: 130mg), obtain core tablet of top acquisition with 6.5mm diameter.

(4) hypromellose (57.44g) and polyethylene glycol 6000 (11.52g) are dissolved in the purified water (375.0g), obtain the film coating solution I.Titanium dioxide (7.680g), red ferric oxide (0.1650g) and yellow ferric oxide (0.5100g) are dispersed in the purified water (330.0g), obtain dispersion I.Film coating solution I, dispersion I and purified water (68.25g) are mixed, obtain the film coating solution II.The film coating machine (DRC-200, POWREX Co., Ltd.) in, the film coating solution II is sprayed on the core tablet (120.0g) equably, form film coating, (sheet is heavy: 135.154mg) for the film-coated tablet of the composition that obtains being shown in Table 15.

Embodiment 16

Table 16

The composition of each preparation (135.154mg)

(1) hydroxypropyl cellulose (35.10g) and polyethylene glycol 6000 (16.20g) are dissolved in the purified water (403.7g), obtain adhesive solution.With Amlodipine Besylate Tablet (20.79g), compd B (30.00g), D-mannitol (240.2g) and microcrystalline Cellulose (39.00g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, the adhesive solution of spraying simultaneously; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(4) hypromellose (57.44g) and polyethylene glycol 6000 (11.52g) are dissolved in the purified water (375.0g), obtain the film coating solution I.Titanium dioxide (7.680g), red ferric oxide (0.1650g) and yellow ferric oxide (0.5100g) are dispersed in the purified water (330.0g), obtain dispersion I.Film coating solution I, dispersion I and purified water (68.25g) are mixed, obtain the film coating solution II.The film coating machine (DRC-200, POWREX Co., Ltd.) in, the film coating solution II is sprayed on the core tablet (120.0g) equably, form film coating, (sheet is heavy: 135.154mg) for the film-coated tablet of the composition that obtains being shown in Table 16.

Embodiment 17

Table 17

The composition of each preparation (135.119mg)

(1) hydroxypropyl cellulose (35.10g) and polyethylene glycol 6000 (16.20g) are dissolved in the purified water (403.7g), obtain adhesive solution.With Amlodipine Besylate Tablet (10.40g), compd B (60.00g), D-mannitol (220.6g) and microcrystalline Cellulose (39.00g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, the adhesive solution of spraying simultaneously; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(4) hypromellose (57.44g) and polyethylene glycol 6000 (11.52g) are dissolved in the purified water (375.0g), obtain the film coating solution I.Titanium dioxide (7.680g) and red ferric oxide (0.1500g) are dispersed in the purified water (330.0g), obtain dispersion I.Film coating solution I, dispersion I and purified water (68.25g) are mixed, obtain the film coating solution II.The film coating machine (DRC-200, POWREX Co., Ltd.) in, the film coating solution II is sprayed on the core tablet (120.0g) equably, form film coating, (sheet is heavy: 135.119mg) for the film-coated tablet of the composition that obtains being shown in Table 17.

Embodiment 18

Table 18

The composition of each preparation (135.119mg)

(1) hydroxypropyl cellulose (35.10g) and polyethylene glycol 6000 (16.20g) are dissolved in the purified water (403.7g), obtain adhesive solution.With Amlodipine Besylate Tablet (20.79g), compd B (60.00g), D-mannitol (210.2g) and microcrystalline Cellulose (39.00g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, the adhesive solution of spraying simultaneously; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(4) hypromellose (57.44g) and polyethylene glycol 6000 (11.52g) are dissolved in the purified water (375.0g), obtain the film coating solution I.Titanium dioxide (7.680g) and red ferric oxide (0.1500g) are dispersed in the purified water (330.0g), obtain dispersion I.Film coating solution I, dispersion I and purified water (68.25g) are mixed, obtain the film coating solution II.The film coating machine (DRC-200, POWREX Co., Ltd.) in, the film coating solution II is sprayed on the core tablet (120.0g) equably, form film coating, (sheet is heavy: 135.119mg) for the film-coated tablet of the composition that obtains being shown in Table 18.

Embodiment 19

Table 19

The composition of each preparation (135.155mg)

(1) hydroxypropyl cellulose (35.10g) and polyethylene glycol 6000 (16.20g) are dissolved in the purified water (403.7g), obtain adhesive solution.With Amlodipine Besylate Tablet (10.40g), compd B (120.0g), D-mannitol (160.6g) and microcrystalline Cellulose (39.00g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, the adhesive solution of spraying simultaneously; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(4) hypromellose (57.44g) and polyethylene glycol 6000 (11.52g) are dissolved in the purified water (375.0g), obtain the film coating solution I.Titanium dioxide (7.680g) and yellow ferric oxide (0.6900g) are dispersed in the purified water (330.0g), obtain dispersion I.Film coating solution I, dispersion I and purified water (68.25g) are mixed, obtain the film coating solution II.The film coating machine (DRC-200, POWREX Co., Ltd.) in, the film coating solution II is sprayed on the core tablet (120.0g) equably, form film coating, (sheet is heavy: 135.155mg) for the film-coated tablet of the composition that obtains being shown in Table 19.

Embodiment 20

Table 20

The composition of each preparation (135.155mg)

(1) hydroxypropyl cellulose (35.10g) and polyethylene glycol 6000 (16.20g) are dissolved in the purified water (403.7g), obtain adhesive solution.With Amlodipine Besylate Tablet (20.79g), compd B (120.0g), D-mannitol (150.2g) and microcrystalline Cellulose (39.00g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, the adhesive solution of spraying simultaneously; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(3) utilize rotary tablet machine (VEL-5, Kikusui Seisakusho) (drift), with hybrid particles film-making (film-making pressure 5kN, the sheet weight: 130mg), obtain core tablet of top acquisition with 7.0mm diameter.

(4) hypromellose (57.44g) and polyethylene glycol 6000 (11.52g) are dissolved in the purified water (375.0g), obtain the film coating solution I.Titanium dioxide (7.680g) and yellow ferric oxide (0.6900g) are dispersed in the purified water (330.0g), obtain dispersion I.Film coating solution I, dispersion I and purified water (68.25g) are mixed, obtain the film coating solution II.The film coating machine (DRC-200, POWREX Co., Ltd.) in, the film coating solution II is sprayed on the core tablet (120.0g) equably, form film coating, (sheet is heavy: 135.155mg) for the film-coated tablet of the composition that obtains being shown in Table 20.

Embodiment 21

Table 21

The composition of each preparation (260mg)

(1) hypromellose (720.0g) is dissolved in the purified water (9000g), obtains adhesive solution I.Red ferric oxide (2.880g) is dispersed in the purified water (2880g), obtains dispersion I.Dispersion I and purified water (720.0g) are mixed in adhesive solution I, obtain adhesive solution II.(FD-S2, POWREX Co. mix in Ltd.) equably at fluidized bed pelletizer with Amlodipine Besylate Tablet (1249g), D-mannitol (16660g) and microcrystalline Cellulose (3600g); And with this mixture pelleting; The adhesive solution II that sprays simultaneously, and after drying obtains granule.At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

punching mesh screen granule of being obtained of a part of milling, the granule I that obtains milling.

(2) hydroxypropyl cellulose (720.0g) and polyethylene glycol 6000 (468.0g) are dissolved in the purified water (9000g), obtain adhesive solution III.Red ferric oxide (2.880g) is dispersed in the purified water (2880g), obtains dispersion II.Dispersion II and purified water (720.0g) are mixed in adhesive solution III, obtain adhesive solution IV.(FD-S2, POWREX Co. mix in Ltd.) equably, and with this mixture pelleting, the adhesive solution IV that sprays simultaneously, and after drying obtains granule at fluidized bed pelletizer with compd A (1436g), lactose hydrate (16090g) and corn starch (3600g).At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

punching mesh screen granule of being obtained of a part of milling, the granule II that obtains milling.

(3) in mill the granule I (20380g) and the granule II (20460g) that mills that are obtained, add cross-linked carboxymethyl cellulose sodium (1848g) and magnesium stearate (214.5g); And with them at barrel mixer (TM20-0-0; Suehiro Kakoki Co. Ltd.) the middle mixing, obtains hybrid particles.

(4) utilize rotary tablet machine (AQUARIUS-36K, Kikusui Seisakusho) (drift) with 8.5mm diameter, with the hybrid particles film-making of top acquisition (film-making pressure 10kN, sheet is heavy: 260mg), the plain sheet of the composition that obtains being shown in Table 21.

Embodiment 22

Table 22

The composition of each preparation (260mg)

(1) hypromellose (720.0g) is dissolved in the purified water (9000g), obtains adhesive solution I.Red ferric oxide (2.880g) is dispersed in the purified water (2880g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (720.0g), obtain adhesive solution II.(FD-S2, POWREX Co. mix in Ltd.) equably at fluidized bed pelletizer with Amlodipine Besylate Tablet (1249g), D-mannitol (16660g) and microcrystalline Cellulose (3600g); And with this mixture pelleting; The adhesive solution II that sprays simultaneously, and after drying obtains granule.At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

(2) in the granule of milling (20380g) that is obtained, add cross-linked carboxymethyl cellulose sodium (924.0g) and magnesium stearate (148.5g), and (TM-60, Showa Kagakukikai Co. Ltd.) the middle mixing, obtain hybrid particles I at barrel mixer with them.

(3) hydroxypropyl cellulose (720.0g) and polyethylene glycol 6000 (468.0g) are dissolved in the purified water (9000g), obtain adhesive solution III.Red ferric oxide (2.880g) is dispersed in the purified water (2880g), obtains dispersion II.Dispersion II and purified water (720.0g) are mixed in adhesive solution III, obtain adhesive solution IV.(FD-S2, POWREX Co. mix in Ltd.) equably, and with this mixture pelleting, the adhesive solution IV that sprays simultaneously, and after drying obtains granule at fluidized bed pelletizer with compd A (1436g), lactose hydrate (16090g) and corn starch (3600g).At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With punching mesh screen granule of being obtained of a part of milling, the granule II that obtains milling.

(4) in the granule II (20460g) that mills that is obtained, add croscarmellose calcium (924.0g) and magnesium stearate (66.00g), and (TM-60, Showa Kagakukikai Co. Ltd.) the middle mixing, obtain hybrid particles II at barrel mixer with them.

(5) utilize rotary tablet machine (HT-CVX54LS-UW/C & 3L; HATA IRON WORKS Co.; Ltd.) (drift) with 8.5mm diameter; With the hybrid particles I (130mg) of top acquisition and hybrid particles II (130mg) film-making (film-making pressure 9kN, sheet is heavy: 260mg), the plain sheet of the multilamellar of the composition that obtains being shown in Table 22.

Embodiment 23

Table 23

The composition of each preparation (239mg)

(1) hydroxypropyl cellulose (155.0g) is dissolved in the purified water (1395.0g), obtains adhesive solution I.With Amlodipine Besylate Tablet (346.7g), D-mannitol (2447.0g) and microcrystalline Cellulose (766.7g) at fluidized bed pelletizer (FD-5S; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution I simultaneously sprays; And after drying obtains the granule of Amlodipine Besylate Tablet layer.At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

punching mesh screen granule of being obtained of a part of milling, obtain the granule of milling of Amlodipine Besylate Tablet layer.

(2) hydroxypropyl cellulose (280.1g) and polyethylene glycol 6000 (280.0g) are dissolved in the purified water (2520.2g), obtain adhesive solution II.With compd B (2808.4g), lactose hydrate (2043.5g), corn starch (910.3g) and microcrystalline Cellulose (910.2g) at fluidized bed pelletizer (FD-5S; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution II simultaneously sprays; And after drying obtains the granule of compd B layer.At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

punching mesh screen granule of being obtained of a part of milling, obtain the granule of milling of compd B layer.

(3) in the granule of milling (3772.0g) of the Amlodipine Besylate Tablet layer that is obtained, add carboxymethylcellulose calcium (200.0g) and magnesium stearate (28.000g); And with them at barrel mixer (TM-15; Suehiro Kakoki co.; Ltd.) mix in, obtain the hybrid particles of Amlodipine Besylate Tablet layer.

(4) in the granule of milling (3616.1g) of the compd B layer that is obtained, add low substituted hydroxypropyl cellulose (455.0g), microcrystalline Cellulose (455.1g) and magnesium stearate (24.53g); And with them at barrel mixer (TM-15; Suehiro Kakoki co.; Ltd.) mix in, obtain the hybrid particles of compd B layer.

(5) utilize rotary tablet machine (HT-X12SS-UW & 2L; HATA IRON WORKS Co.; Ltd.) (drift) with 8.0mm diameter, with the hybrid particles film-making of the hybrid particles and the compd B layer of the Amlodipine Besylate Tablet layer of top acquisition (film-making pressure 7kN, sheet is heavy: 230mg (Amlodipine Besylate Tablet layer: 100mg; Compd B layer: 130mg)), obtain the multilamellar core tablet.

(6) premix I (252.0g) is dissolved in the purified water (2268.0g), obtains film coating solution.The film coating machine (DRC-500, POWREX Co., Ltd.) in, film coating solution is sprayed on the core tablet (3120.0g) equably, form film coating, (sheet is heavy: 239mg) for the film-coated tablet of the composition that obtains being shown in Table 23.Among this paper, premix I is the premix powder.The composition of premix I is shown among the table 23a.

Table 23a

The composition of premix I

	Weight ratio
		Hypromellose	9.0
Polyethylene glycol 6000	2.0

Titanium dioxide	1.0
		Yellow ferric oxide	0.2

Embodiment 24

Table 24

The composition of each preparation (130mg)

(1) hydroxypropyl cellulose (80.00g) and Macrogol 4000 (36.00g) are dissolved in the purified water (1100g), obtain adhesive solution I.Red ferric oxide (2.080g) is dispersed in the purified water (200.1g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (60.00g), obtain adhesive solution II.With Amlodipine Besylate Tablet (24.95g), compd A (28.80g), D-mannitol (297.6g) and microcrystalline Cellulose (72.00g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution II (266.1g) simultaneously sprays; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(2) in the granule of milling (370.5g) that is obtained, add cross-linked carboxymethyl cellulose sodium (16.81g) and magnesium stearate (2.700g), and they are mixed in Polythene Bag (4.9L), obtain hybrid particles.

(3) utilize rotary tablet machine (Correct 19K; Kikusui Seisakusho) (the drift of minor axis) with major diameter and 5.0mm of 8.5mm; With the hybrid particles film-making of top acquisition (film-making pressure 8.5kN, sheet is heavy: 130mg), the plain sheet of the composition that obtains being shown in Table 24.

Embodiment 25

Table 25

The composition of each preparation (130mg)

(1) hydroxypropyl cellulose (80.00g) and cetomacrogol 1000 0 (36.00g) are dissolved in the purified water (1100g), obtain adhesive solution I.Red ferric oxide (2.080g) is dispersed in the purified water (200.1g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (60.10g), obtain adhesive solution II.With Amlodipine Besylate Tablet (24.95g), compd A (28.80g), D-mannitol (297.6g) and microcrystalline Cellulose (72.00g) at fluidized bed pelletizer (Lab-1; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution II (266.1g) simultaneously sprays; And after drying obtains granule.The granule that a part obtained is sieved the granule that obtains milling with sieve (16 order).

(2) in the granule of milling (370.5g) that is obtained, add cross-linked carboxymethyl cellulose sodium (16.80g) and magnesium stearate (2.710g), and they are mixed in Polythene Bag (4.9L), obtain hybrid particles.

(3) utilize rotary tablet machine (Correct 19K; Kikusui Seisakusho) (the drift of minor axis) with major diameter and 5.0mm of 8.5mm; With the hybrid particles film-making of top acquisition (film-making pressure 8.5kN, sheet is heavy: 130mg), the plain sheet of the compositions that obtains being shown in Table 25.

Comparative Examples 1

Table 26

The composition of each preparation (130mg)

(1) hydroxypropyl cellulose (720.0g) and polyethylene glycol 6000 (468.0.0g) are dissolved in the purified water (9000g), obtain adhesive solution I.Red ferric oxide (2.880g) is dispersed in the purified water (2880g), obtains dispersion I.Adhesive solution I is mixed with dispersion I and purified water (720.0g), obtain adhesive solution II.With Amlodipine Besylate Tablet (1253g), compd A (1449g), lactose hydrate (14830g) and corn starch (3600g) at fluidized bed pelletizer (FD-S2; POWREX Co.; Ltd.) mix equably in, and with this mixture pelleting, adhesive solution II simultaneously sprays; And after drying obtains granule.At screen mill (P-3; Showa Kagakukikai Co.; Ltd.) in; With

(2) in the granule of milling that is obtained (40920g (2 batches)), add carboxymethylcellulose calcium (1848g) and magnesium stearate (132.0g), and (TM20-0-0, Suehiro Kakoki Co. Ltd.) the middle mixing, obtain hybrid particles at barrel mixer with them.

(3) utilize rotary tablet machine (AQUARIUS-36K, Kikusui Seisakusho) (drift) with 7.0mm diameter, with the hybrid particles film-making of top acquisition (film-making pressure 9kN, sheet is heavy: 130mg), the plain sheet of the composition that obtains being shown in Table 26.

EXPERIMENTAL EXAMPLE 1

Dissolution test 1

Utilize dissolution test (1.0 (w/w) % polysorbate 20 (polysorbate 20) solution; 900mL, 37 ℃, the paddle board method; Rotary speed: 50rpm), estimate the performance of active component (compd A) from embodiment 1 to 11,24,25 and Comparative Examples 1 stripping the plain sheet that obtains.Carry out dissolution test according to Pharmacopeia of Japan (the 15th edition, dissolution test, Apparatus 2 (paddle board method)).The result is shown in Table 27.Table 27 has shown that stripping begins meansigma methods, maximum and the minima of 15 minutes dissolution rates afterwards.Embodiment 1,4,5,8 to 11,24,25 and Comparative Examples 1 have shown meansigma methods, maximum and the minima of the dissolution rate of 6 tablets, and embodiment 2,3,6 and 7 has shown meansigma methods, maximum and the minima of the dissolution rate of 12 tablets.

Table 27

Shown in table 27, compare with the not sugar alcohol contained plain sheet of Comparative Examples 1, comprise sugar alcohol has all shown compd A as the sheet of being always or usually as specified of the embodiment 1 to 11,24,25 of excipient good dissolving out capability.

EXPERIMENTAL EXAMPLE 2

Dissolution test 2

Utilize dissolution test (the Pharmacopeia of Japan, the 15th edition, second fluid of dissolution test, 900mL, 37 ℃, paddle board method, rotary speed: 50rpm), estimate the performance of active component (compd B) from embodiment 20 stripping the film-coated tablet that obtains.Carry out dissolution test according to Pharmacopeia of Japan (the 15th edition, dissolution test, Apparatus 2 (paddle board method)).The result is shown in Table 28.5 to 60 minutes meansigma methods, maximum and the minima of dissolution rate of each time point that table 28 has shown 6 tablets after stripping begins.

Table 28

Shown in table 28, the film-coated tablet of embodiment 20 has shown the good dissolving out capability of compd B.

EXPERIMENTAL EXAMPLE 3

Stability test

Under the condition of sealed glass jars and 25 ℃/60%RH, the plain sheet of embodiment 1,4 and 5 was preserved 12 months, measure quality, and estimate storage stability based on it derived from the analog of compd A or Amlodipine Besylate Tablet.The result is shown in Table 29.Content (compd A when compd A or Amlodipine Besylate Tablet; 8mg or 4mg/ Amlodipine Besylate Tablet; 6.93mg be 100% o'clock or 3.47mg), the numeric representation in the table 29 derived from the ratio (%) of whole analog of compd A or Amlodipine Besylate Tablet.

Table 29

Shown in table 29, embodiment 1,4 and 5 plain sheet have all shown good storage stability.

Industrial applicibility

The invention provides solid preparation; It comprises compound or its salt, sugar alcohol and the calcium antagonist of formula (I) representative; It can suitably control compound or its salt and calcium antagonist stripping from this solid preparation in gastrointestinal tract of formula (I) representative, and can keep its stability good in this solid preparation.

The application is attached to its full content among this paper with the mode of quoting as proof based on patent application 2009-111381 and 2010-68625 (in japanese publication).

Claims

1. solid preparation, it comprises:

(i) compound or its salt of formula (I) representative,

R wherein ¹But be monocycle nitrogen heterocyclic ring group with deprotonation hydrogen atom, R ²Be optional esterified carboxyl, R ³Be optional substituted low alkyl group,

(ii) sugar alcohol and

(iii) calcium antagonist.

2. according to the solid preparation of claim 1; Wherein said formula (I) representative compound or its salt is 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 1-(cyclohexyl oxygen base ketonic oxygen base) ethyl ester; 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid; 2-ethyoxyl-1-[[2 '-(4; 5-dihydro-5-oxo-1; 2,4-

diazole-3-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid, or its salt.

3. according to the solid preparation of claim 1, wherein said formula (I) representative compound or its salt is 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 1-(cyclohexyl oxygen base ketonic oxygen base) ethyl ester or its salt.

4. according to the solid preparation of claim 1; The compound or its salt of wherein said formula (I) representative is 2-ethyoxyl-1-[[2 '-(4; 5-dihydro-5-oxo-1; 2,4-

diazole-3-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid or its salt.

5. according to the solid preparation of claim 1, wherein said sugar alcohol is mannitol, Sorbitol or erythritol.

6. according to the solid preparation of claim 1, wherein said sugar alcohol is a mannitol.

7. according to the solid preparation of claim 1, wherein said calcium antagonist is an azelnidipine, amlodipine, aranidipine, efonidipine; Cilnidipine, nicardipine, nisoldipine, nitrendipine, nifedipine; Nilvadipine, barnidipine, felodipine, benidipine, Manidipine or its salt.

8. according to the solid preparation of claim 1, wherein said calcium antagonist is amlodipine or its salt.

9. according to the solid preparation of claim 1, it further comprises Polyethylene Glycol.

10. according to the solid preparation of claim 9, wherein said Polyethylene Glycol has 1000 to 10000 molecular weight.

11. a solid preparation, it comprises:

(i) 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 1-(cyclohexyl oxygen base ketonic oxygen base) ethyl ester or its salt,

(ii) mannitol and

(iii) amlodipine or its salt.

12. a solid preparation, it comprises:

(i) 2-ethyoxyl-1-[[2 '-(4; 5-dihydro-5-oxo-1; 2; 4-

diazole-3-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid or its salt

(ii) mannitol and

(iii) amlodipine or its salt.