TW201041873A - Solid preparation - Google Patents

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

201041873. VI. Description of the Invention: ^ Technical Field of the Invention The present invention relates to a solid preparation which exhibits improved solubility properties of a drug derived from a preparation. [Prior Art] Hypertension is one of the most common diseases in adults. According to a basic study of 2,000 circulating diseases conducted by the Ministry of Health, Labor and Welfare of Japan, the number of hypertensive patients in Japan (with a systolic blood pressure of not less than 140 mmHg or a diastolic blood pressure of not less than 90 mmHg) or taking antihypertensive agents has reached the date. 31,000 to 38 million. Hypertension is a high risk factor for all circulatory diseases, including cerebrovascular disease and myocardial infarction. Therefore, proper control of blood pressure is important to improve the prognosis of patients and to reduce the burden on individuals and society. A variety of drugs have been developed (eg, decompressive diuretics, alpha blockers, stone blockers, angi〇tensin converting enzyme ' ACE ) inhibitors, calcium antagonists, angiotensin η As a therapeutic drug for hypertension, and many patients diagnosed with high stress are treated with such antihypertensive agents. For example, a compound represented by the following formula (1) or a salt thereof:

(wherein R1 is a monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom, R2 is a carboxyl group which is optionally esterified, and R3 is optionally substituted with a lower 3 321 939 201041873 alkyl group)) An angiotensin II receptor antagonist that exhibits excellent antihypertensive effects and organ protection. JP-B-2514282 discloses 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1Η-tetrazol-5-yl)biphenyl-4-yl A methyl]benzimidazole-7-carboxylate (candesartan cilexetil) is exemplified as a representative agent. According to J-HOME's study (Japanese family-to-office blood pressure measurement assessment study), about 40% of hypertensive patients receiving drug therapy have reached the required blood pressure (the random blood pressure of outpatients is less than 140/90 mmHg). This indicates that some patients cannot adequately control their blood pressure even with existing medications. In order to increase the proportion of blood pressure required, more effective antihypertensive treatment is needed. For the treatment of drugs that exert a stronger antihypertensive effect, a combination therapy using a plurality of drugs can be mentioned. For example, WO 01/15674 discloses the combined use of a renin-angiotensin inhibitor and other antihypertensive agents, cholesterol lowering drugs, diuretics and the like. W002/43807 discloses the combined use of angiotensin II receptor antagonists and other antihypertensive agents or statins. However, the use of multiple agents at different times 曰 may have a negative impact on the patient's medication compliance, which is worrying and inadvertently causing blood pressure control failure. For clinical practice, in order to more appropriately control blood pressure, a combination preparation containing a plurality of antihypertensive agents in a single drug is strongly required because it is an ideal agent for exhibiting a strong decompression effect and maintaining patient compliance. A combined preparation containing an angiotensin 11 receptor antagonist and a calcium antagonist is recommended as the combined preparation. W〇92/i〇〇97 discloses a combination preparation containing angiotensin 4 321939 201041873 . II receptor antagonist and other agents (for example, diuretics, calcium antagonists, etc.). Jj>_a_2006_290899 discloses a combined preparation of an imidazole carboxylate-containing blood, a pipetting hormone II dimeric antagonist (e.g., olmesartan medoxomil, etc.) and a calcium antagonist. U.S. Patent No. 6,204,281 discloses valsartan (a vasopressin receptor receptor antagonist) and a guanidine dihydropyridine compound (for example, amlodipine or the like as a calcium antagonist). Combination preparation. Jp_B_293〇252 Unexpressed with 2·butyl-4-chloro-1-[(2,-(1Η-tetrazol-5-yl)biphenyl-4-yl)methyl hydrazino] miso-5- Or a pharmaceutically acceptable salt thereof (each of which is an angiotensin π receptor antagonist) and a combination preparation of diltiazem (diltiazem): In addition, (4) _3〇57471 discloses a benzene-containing scented street- ^ ^ Angiotensin receptor antagonist) and a group of diuretics or anti-agents. Accepted by two === derivatives (for vascular collection: 〇 饤 饤 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( _ Adding heart to reduce side effects, so its clinical record (4). (4) Use of Η乍 然而 However 'in order to stabilize the effectiveness and safety of pharmaceutical products = the effectiveness of the active ingredients and the reading is important, the heart, the drug solubility properties It is also extremely important. For example, i: The music is self-medicated (4) When the age is too slow, the blood concentration of the drug is effective, and the method can fully demonstrate its efficacy. Aspect 321939 5 201041873 Tian medicine from 4 drugs The dissolution of the preparation is too fast, the blood of the drug; the degree of farming will rise rapidly, causing a high risk of side effects. In other words, in addition to effectiveness and safety, the pharmaceutical product needs to ensure a special level of drug dissolution. It meets the compatibility with various additives and the different conditions required for each active ingredient. Therefore, it is often difficult to develop with all of these conditions, compared with the system containing the mono-components. In detail, because Benzopyrene The organism (which is an angiotensin π-converting antagonist) is a poorly soluble compound, and the solubility properties of the preparation may be lowered by the nature of the additive and active ingredient to be combined. When the drug is released from the delayed release of the combined preparation, Reduce the absorption, decrease, bioavailability of the drug (ie, reduce the efficacy of the active ingredient) and reduce the value of the combined agent. Therefore, for the pharmaceutical preparation to be practically applied, it is necessary to adjust the composition of the preparation to make the active ingredient in the gastrointestinal tract. The present invention is intended to solve the problems of the present invention. The present invention aims to provide a stable benzoxazole-containing organism (with angiotensin 11 receptor antagonist action) and a commission. The solid preparation of the anti-agent is controlled to optimize the solubility properties of the drugs from the preparation in the gastrointestinal tract. Solution to Problem A The inventor of the present invention conducted intensive research in an attempt to solve the above problems and found that (1) a compound represented by the formula (1) or a salt thereof, ((1) a sugar alcohol, and a preparation of a (m) guanidine antagonist" in the human stomach In the middle of the road, it is suitable for the solubility properties of the control. In particular, they have paid special attention to the excipients, and found that the solubility properties of the drug from the solid preparation can be improved by using a highly water-soluble sugar alcohol, thus completing the present invention. Accordingly, the present invention relates to [1] a solid preparation comprising (i) a compound represented by the formula (I) or a salt thereof, R1

(wherein R1 is a monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom, R2 is a carboxyl group which is optionally esterified, and R3 is a lower-alkyl group which may be optionally substituted), (ii) a sugar alcohol And (iii) a solid preparation according to the above [1], wherein R2 is a lower alkyl group having a carbon number of 1 to 4 as needed (which is optionally selected from the following 1 to 3) Substituted by a substituent: a hydroxyl group, an amine group, a halogen atom, a lower q-order alkyl alkoxy group having a carbon number of 2 to 6, a lower cycloalkyloxy group having a carbon number of 4 to 7, and having a carbon number of 1 a carbonyloxy group of a lower alkoxy group to 6th, a carbonyloxy group having a lower cycloalkoxy group having 3 to 7 carbon atoms, and an acetonyl group having a lower alkoxy group having 1 to 4 carbon atoms; [1B] The solid preparation of the above [1], wherein R2 is 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl or carboxyl; [2] the solid of the above [1], [1A] or [1B] a preparation wherein the compound of the formula (I) or a salt thereof is 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1Η-tetrazole-5-) Base) 7 321939 201041873 Biphenyl phenyl] methyl] stupid and saliva-1 2 · fine, 2-ethoxy-H[2, _ (1 H_本广基]Methyl]-ιη_benzimidazole_2·carboxylic acid, 2_ethoxy[[2 -(4,5----5-oxy-124Π55-山1礼礼,4- %_azole_3_yl) phenylene-4-yl]methyl]-1 Η-benzimidazole _7-carboxylic acid or a salt thereof; [3] above [1], [2], [1~ or _ a solid preparation, wherein the compound of the formula (1) or a salt thereof is 1 (% hexyloxyoxy)ethyl 2 -ethoxythio)biphenyl-4-yl]methyl] a savory vinegar or a salt thereof; [4] a solid preparation of the above [1], [2], [1Α]4 [1β], wherein the compound represented by the formula g) or a salt thereof is 2~ Ethoxy-bu[[2'-(4,5-dihydro-5-oxo-1,2,4-indenyl.sodium-3-yl)biphenyl-4-yl]methyl]-1Η- a benzimidazole- 7-carboxylic acid or a salt thereof; [5] The solid preparation of the above [1], [2], [3], [4], [1Α] or [1Β], wherein the sugar alcohol is mannose Alcohol, sorbitol or erythritol; 8 321939 1 Solid preparation of the above [1], [2], [3], [4], [5], [1Α] or [1Β], wherein the sugar alcohol Is a mannitol; 2 solid preparation of the above [1], [2], [3] '[4], [5], [6], [1Α] or [1Β], wherein the calcium antagonist is a Azelnidipine, ammonia Amlodipine, aranidipine, efenidipine, cilnidipine, nicardipine, nisoldipine, nitrendipine, nitrate Nifedipine, nilvadipine 'barnidipine, felodipine, benidipine, manidipine 201041873 . (manidipine) or its salt; -[8] a solid preparation of [1], [2], [3], [4], [5], [6], [7], [1A] or [IB], wherein the feeding antagonist is amlodipine or Salt; '[9] Solid preparations of the above [1], [2], [3], [4], [5], [6], [7], [8], [1A] • or [1B] [10] The solid preparation of the above [9], wherein the polyethylene glycol has a molecular weight of 1, 〇〇〇 to 10,000; [11] a solid preparation 'which includes (i) 丨―(Cyclohexyloxycarbonyloxy)ethyl 2_acetoxy+ [[2'-(1Η-tetras-5-yl)biphenyl-4-yl]indenyl]benzopyrene-7 a carboxylic acid ester or a salt thereof, (ϋ) mannitol, and (丨^) amlodipine or a salt thereof; ', .[11A] [11] The solid preparation of [1] comprises polyethylene glycol; [11B] The solid preparation of the above [11A], wherein the polyethylene glycol has a molecular weight of 1,000 to 10,000 (preferably 3, 〇〇〇 The solid preparation of the above [11B], wherein the content of the polyethylene glycol is from 00 to 5% by weight; [IID] the solid preparation of the above [11B], wherein the polyethylene The content of the diol is up to 3% by weight; [12] a solid preparation comprising (1) 2-ethoxy+[[2,-(4,5-dihydro-5-oxo-1'2'4 咛2 Zyridin-3-yl)biphenyl-4-yl]methyl]-1H-benzoimidine-7-tagamic acid or a salt thereof, ((1) mannitol and (iii) amlodipine or a salt thereof; [12A The solid preparation of the above [12], which comprises a polyethylene glycol; [12B] The solid preparation of the above [12A], wherein the 'polyethylene glycol has a molecular weight of ^000 321939 9 201041873 to 10,000 (preferably 3) [12] The solid preparation of the above [12B], wherein the content of the polyethylene glycol is from 1 to 5% by weight; [12D] the solid preparation of the above [12B], wherein the polyethylene The content of the diol is from 1 to 3% by weight; [13] The above [1], [2], [3], [4], [5], [6] [7], [8], [9], [10], [11], [12], [1A], [IB], [11A], [11B], [11C], [11D], [12A [11], [12], [12], [12] ], [8], [9], [10], [11], [12], [1A], [IB], [11A], [11B], [lie], [11D], [12A], The solid preparation of [12B], [12C] or [12D] is a single layer tablet; [15] The above [1], [2], [3], [4], [5], [6], [7] ], [8], [9], [10], [11], [12], [13], [14], .1A], [IB], [11A], [11B], [lie] The solid preparation of [11D], [12A], [12B], [12C] or [12D] is a prophylactic or therapeutic drug for hypertension, heart failure, diabetic nephropathy or arteriosclerosis; [16] above [1] , [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [ 14], [1A], [IB], [HA], [11B], [11C], [11D], [12A], [12B], [12C] or [12D] solid preparations are blood pressure, etc. Preventive or therapeutic drugs; and the like. EFFECTS OF THE INVENTION According to the present invention, a solid preparation can be obtained in which the compound (or a salt thereof) of the above formula (I) and the calcium antagonist are appropriately controlled in the gastrointestinal tract from the preparation of the 321939 10 201041873 dissolution, and fine Maintain its stability in the formulation. Namely, the solid preparation of the present invention is excellent in the properties of the compound represented by the above formula (1) or a salt thereof and a calcium antagonist dissolved from the preparation and its stability. [Embodiment] The solid preparation of the present invention will be described in detail below. The solid preparation of the present invention is a solid preparation comprising the following: (a compound represented by the formula (I) or a salt thereof:

Wherein R1 has a cleavable group, r2 is an esterified and alkyl group as needed; (ii) a sugar alcohol; and a monocyclic nitrogen-containing heterocyclic ring having a hydrogen atom which may be derivatized is required to be a silk And r3 is a low diol to be substituted; and (H is also a solid preparation which is hereinafter referred to as a low-substituted solid preparation which is optionally substituted). For example, it may be a tetrazolyl group or a lower formula. The group shown is equivalent to the above formula (I), and as the R1 monocyclic nitrogen-containing heterocyclic group, for example, hydrazine

And having a deprotonated hydrogen atom, wherein i is -0- or ·_s_, wherein m is 〇, i or 2

J is >(>0, > C=S or >S(0; K 〇, 1 or 2. The preferred group may be tetrazolyl, 4,5 1,2' 4 oxadiazole _3_基等. Dihydro~5-sideoxy_-1,2'4-oxadiazole_3_ group contains three tautomers (a', b' as shown by the following formula 321939 11 201041873 And c'): N-°x li >=〇~N Η Ν -〇Ν

A_b.c' and the 4,5-dihydro-5-o-oxy-1,2,4-oxadiazol-3-yl group includes all of the above a', b' and c'. In the above formula (1), examples of the carboxyl group which is required to be esterified by R2 include a carboxyl group which is esterified with a lower alkyl group having a carbon number of 1 to 4 as needed. The above lower alkyl group may be optionally substituted with from 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of hydroxyl groups, amine groups, halogen atoms, and carbon number 2 to 6 a lower calcined oxy group (for example, acetyloxy group, pivaloyloxy group, etc.), a lower naphthyloxy group having a carbon number of 4 to 7, and having a carbon number a carbonyloxy group of a lower alkoxy group of 1 to 6 (e.g., a decyloxycarbonyloxy group, an ethoxycarbonyloxy group, etc.), a carbonyloxy group having a lower cycloalkoxy group having a carbon number of 3 to 7 ( For example, a cyclohexyloxycarbonyloxy group or the like) and a lower alkoxy group having a carbon number of 1 to 4. Preferred groups may be 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, carboxy and the like. In the above formula (1), the lower alkyl group which is required to be substituted as R3 may be a lower alkyl group having a carbon number of 1 to 5, which may optionally be one to five selected from the group consisting of the following (preferably) Substituted by 1 to 3 substituents: a hydroxyl group, an amine group, a halogen atom, and a lower alkoxy group having 1 to 4 carbon atoms. More preferably, it is a lower alkyl group having 2 to 3 carbon atoms, more preferably an ethyl group. The salt of the compound represented by the above formula (I) need only be a pharmaceutically acceptable salt, and for example, a compound represented by the formula (I) and an inorganic base can be mentioned. 12 321 939 201041873. Salt, and organic base a salt formed, a salt formed with an inorganic acid, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, or the like. Preferred examples of the salt formed with the inorganic base include: alkali metal salts such as sodium salts, potassium salts and the like; alkaline earth metal salts such as calcium salts, magnesium salts and the like; aluminum salts; ammonium salts and the like. Preferred examples of the salt formed with the organic base include: with trimethylamine, triethylamine, ratio bit, methyl ratio picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine , Ν, Ν '-dibenzyl extended ethyl diamine and the like formed by the salt. Preferred examples of the salt formed with the inorganic acid include salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of the salt formed with an organic acid include: with citric acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, apple, acid, a salt formed by sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or the like. Preferred examples of the salt formed with the basic acid include: a salt formed with arginine, lysine, ornithine or the like. Preferred examples of the salt formed with the acidic amino acid include a salt formed with aspartic acid, glutamic acid or the like. Q The compound represented by the above formula (1) or a salt thereof may be a hydrate or a non-hydrate, and may be a solvate or an unsolvate. Further, the compound represented by the above formula (I) or a salt thereof is preferably in a crystalline form and has a melting point of from 100 ° C to 250 ° C, preferably from 120 ° C to 200 ° C, especially 130 ° C. To the melting point of 180 °C. As the solid preparation of the present invention, the compound represented by the above formula (I) or a salt thereof is used. Preferable examples of the compound or a salt thereof include: 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1Η-tetrazol-5-yl)biphenyl- 4-yl]methyl]benzimidazole-7-carboxylate, 13 321939 201041873 2-ethoxytetrazole-5-yl)biphenyl-glycolyl]f-based]]indolezimidazole-7-carboxylic acid , trimethyl ethoxy fluorenyl 2 ethoxy sing - ie - tetraindole _5 phenyl-4-yl] methyl]-1H-benzimidazole _7-carboxylate, soil 2 Oxyl is a small [[2 -(4,5·dihydro)) phenoxy]methyl]_1 Η benzo benzopyrene _7_ decanoic acid and its salts. It is preferably anthracene hexyloxy group) ethyl 2_ethoxy small [[2,_(ιη_tetradecyl)biphenyl-4-yl]methyl]benzopyrene-7, acid Vinegar and its salt, hydrazino-4-yl]methyl]-1Η-benzopyrazine-7-decanoic acid and its salts. In the present invention, the compound represented by the above formula (1) or a salt thereof is in a range of from Ο to 60% by weight, preferably from % by weight, more preferably from % to 卯 by weight (in free form) It is included in the fixing agent of the present invention. As the sugar alcohol used in the present invention, any kind of sugar alcohol can be used as long as the sugar alcohol can simultaneously establish the above formula (the compound of the ride or the salt thereof; the stability of the agent and the dissolution property of the self-formulation, And can be used for pharmaceutical production =. Examples of the sugar alcohol used in the present invention include: a single-transfer alcohol such as butyl hydrazine = (for example, 'erythritol, D. threitol (D_threit 〇 1), L' S Sugar alcohols, etc.), pentaerythritol (eg, D_arabitol, xylitol, etc.), hexitols (eg, '1) _iditol, galactitol (sweet alcohol), D-glucitol ( Sorbitol), mannitol, cyclosaccharide (eg, cyclohexanol, etc.), etc., disaccharide sugar alcohols, such as hydrogenated maltose, lactose 〇ac chest) 'reduced paratinose (reduced paratinose, bar Sugar alcohol (i_alt)), etc.; oligo-sugar alcohols, 321939 14 201041873 > such as neopentyl alcohol, hydrogenated maltose starch syrup, etc.; sugar alcohols are preferred. More preferably, it is mannitol, sorbet, and the like. Among them, monosaccharide is preferably mannitol, and D_mannitol is T and erythritol. Special - a sugar alcohol, or a combination of two or more. Can be used alone • A stable sterol that can simultaneously achieve a calcium antagonist in a formulation. In addition, the sugar alcohol is of a qualitative nature. And dissolution thereof from the preparation, the sugar alcohol is in a solid preparation of 15 to 85 to 80% by weight, more preferably 25 to 75% by weight, preferably 20% by weight. Examples of the calcium antagonists to be included in the present invention for use in the present invention include, for example, adipine, amlodipine, aridodihydropyridine, 'sinidipine, nicardipine, nisoldipine, and nitrile Erdi, rifampicin, 'nilvadipine, bainidipine, felodipine, benipine, nifedipine, benzodiazepine compound, manididi; (diltiazem); etc. Wait. For use in the present invention, for example, 'Di Taizan' describes the salts as calcium antagonists. The antagonists also include the calcium antagonists previously used as the present invention, and the alkaloids, especially amlodipine or a salt thereof. More preferably, it is a salt of amlodipine, and particularly preferably is aini〇(jipine beSyiate). In the present invention, the calcium antagonist is usually 0.05 to 6% by weight, preferably A ratio of from 0.1 to 40% by weight, more preferably from 5 to 2% by weight, based on the free form, is included in the solid preparation of the present invention. Specifically, for example, the content ratio of amlodipine (in terms of The free form is usually from 0.05 to 60% by weight, preferably from 0 to 1% to 4% by weight, and more preferably from 0.5 to 20% by weight. The solid preparation of the present invention may comprise alkylene oxide. Examples of alkylene oxide polymers include extended ethylene oxide polymers, propyl oxide polymers, trimethylene oxide polymers or tetrahydrogen. The π-fu or the like (preferably an epi-ethyl oxide polymer). The molecular weight of the alkylene oxide polymer is preferably from 1,000 to 10,000, more preferably from 3,000 to 10,000. The material may be a stretch-based oxide copolymer, Examples of the stretching-based oxide copolymer include a copolymer of two or more of the foregoing alkylene oxides having a molecular weight of 1,000 to 10,000 (preferably 3, 〇〇〇 to 1 〇, 〇〇〇). A stretch-based oxide polymer may be used alone or in combination of two or more kinds of extender-based oxide polymers. As the extender-based oxide polymer used in the present invention, polyethylene is preferred. The diol is more preferably a polyethylene glycol having a molecular weight of 1,000 to 10,000, particularly preferably a polyethylene glycol having a molecular weight of 3, 〇〇〇 to 1 〇, 〇〇〇 (for example, polyethylene glycol 4000, Polyethylene glycol 6000, polyethylene glycol 1〇00〇). In the present invention, the alkylene oxide polymer is preferably contained in a ratio of from 丨 to $, more preferably from 1 to 3% by weight. In the solid preparation of the present invention, a preferred embodiment of the solid preparation of the present invention comprises: a solid preparation wherein the compound represented by the above formula (1) or a salt thereof is 1-(cyclohexyloxycarbonyloxy)ethyl 2-Ethoxy_1_[[2,_(1Η_tetrasa_5_美)biphenyl-4-yl]indolyl]benzimidazole_7-carboxylate (hereinafter sometimes referred to as '^匕3219 39 16 201041873 体2' and sleeve resistance agent amlodipine; solid I agent, wherein the above formula (1) shows ethoxyl-1-[[2,-(45_- 气ς卜观兵兵孤2- _ 虱~5-oxy-1,2,4-oxadiazol-3-yl) phenyl] 4] methyl]-1Η-benzopyrene _7 turbidity 4-base] (Hereinafter referred to as "compound Β,,, or,, orphan," and the calcium antagonist is abbreviated amlodipine; and the like. As the solid preparation of the present invention, for example, a solid agent suitable for oral administration such as a tablet, a granule, a fine granule (fine gr_ie),

A capsule, a piu or the like is preferably a tablet, more preferably a single layer. When the solid preparation of the present invention is a tablet, it may be in the form of any of a round oval shape, a rectangle, and the like. The size of the lozenge can vary depending on the tablet form (circular, elliptical caplet, rectangle, etc.) and any size is possible as long as the patient is easy to take. When the solid preparation of the present invention is a single-layer tablet, it is easy to take because of its small size. Specific examples of the solid preparation of the present invention include: (1) A granulated preparation solid preparation comprising a compound represented by the formula (I) or a salt thereof, a sterol and a calcium antagonist (preferably: A mixture of the compound (1) or a salt thereof, a sugar alcohol, a dance antagonist, and a polyethylene glycol) is granulated, and the obtained granulated material is obtained by compression molding (for example, 'a set of granulated single-layer tablets) (2) Two-component granulation preparation (a) A solid preparation obtained by mixing and compression molding the following first and second parts (for example, a two-component granulated tablet); (b) a solid preparation obtained by compression molding (without mixing) of the following 321939 17 201041873: obtained in the first part and the second part (for example, a multilayer bond (C) solid preparation by The following individual granulation fractions and one of the second parts are coated with another one, and the other is a compound of the formula (1) or a salt thereof (Comparative (1) a compound of the formula or a salt thereof, and a part of polyethylene glycol)... Part II: Parts containing sugar alcohols and calcium antagonists, etc. A preferred embodiment of the solid formulation of the present invention is a set of granulation formulations (e.g., a set of granulated monolayer spinners). The solid preparation of the present invention may comprise an additive conventionally used in the field of medicine. Examples of the additive include an excipient, a disintegrant, a binder, a lubricant, a pH adjuster, a colorant, a surfactant, a stabilizer, an acidifier, a shoulder taste 4, a glidant (gHdant), and the like. These additives are used in the amounts used in the conventional pharmaceutical field. Further, these additives may be used in a mixture of two or more kinds in an appropriate ratio. Examples of excipients include starch (eg, corn starch, potato starch, wheat flour, rice starch, partially pre-gelatinized powder, pre-gelatinized powder, porous starch, etc.); sugars (eg, lactose, fructose, glucose, Sucrose, etc.); anhydrous θ ® cultural dance, crystalline cellulose, microcrystalline cellulose, licorice (Glycyrrhiza uralensis), sodium sulphate, sulphuric acid, sulfuric acid dance, acid sulphate | bow, sacred carbonic acid i bow, sulphuric acid J bow and so on. Examples of disintegrants include amino acid 'starch, corn starch, carboxymethyl 18 321939 201041873. Cellulose, carboxymethylcellulose calcium, sodium methyl starch, carboxymethyl cellulose, sodium (carmellose sodium), Carmellose calcium, cross-linked slow-sodium cellulose, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, and the like. In the present invention, the disintegrating agent is contained in the solid preparation of the present invention in a ratio of preferably 〇.丨 to % by weight, more preferably 1 to 10% by weight. Examples of the binder include crystalline cellulose (for example, microcrystalline cellulose), propyl cellulose, propyl fluorenyl cellulose (hypr〇mell〇se), polyethylidene pyrrolidone, gelatin, starch, Acacia gum powder, tragacanth, carboxymethyl cellulose, sodium alginate, pullulan, glycerin, and the like. In the present invention, the binder is contained in the solid preparation of the present invention in a proportion of preferably from 1 to 40% by weight, more preferably from 1 to 10% by weight. Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, talc (purified talc), sucrose ester of fatty acid, sodium stearyl fumarate, and the like. Examples of the lubricant include citric acid and salts thereof, phosphoric acid and salts thereof, carbonic acid and salts thereof, tartaric acid and salts thereof, fumaric acid and salts thereof, acetic acid and salts thereof, amino acids and salts thereof and the like. . Examples of the coloring agent include food coloring agents such as food coloring yellow No. 5, food coloring red No. 2, food coloring blue No. 2, etc.; food lake color, for example, food coloring yellow No. 4 aluminum lake; Iron oxide pigments, for example, red iron oxide (c〇lc〇thar), yellow iron oxide, iron oxide (black iron oxide), and the like; and the like. Examples of surfactants include sodium lauryl sulfate, polysorbate 8〇19 321939 201041873 (Polysorbate 80), polyoxyethylene (16〇) polyoxypropyl propyl (3...diol, etc. Stabilizer Examples include fertility, tetrasodium edetate, nicotinamide, cyclodextrin, etc. Examples of the acidifying agent include ascorbic acid, citric acid, tartaric acid, malic acid, etc. Examples of the flavoring agent include menthol , peppermint oil, lemon oil, vanillin, etc. Examples of the glidant include light anhydrous citric acid, hydrated cerium oxide, etc. The solid preparation of the present invention can be applied by using a fimin coating (for example, 'coating The base agent, the coating additive, and the like are processed into a film-coated preparation. Examples of the film coating preparation include a sugar-coating preparation, a sustained-release film coating preparation, an enteric preparation, and the like. Preferred examples include: a sugar-based base, a water-soluble film base, an enteric film base, a sustained release film base, etc. As for the sugar-based base, a curtain sugar is used. One or more Talc, precipitated calcium carbonate, gelatin, gum arabic, polytriglucose, palm wax, etc. Examples of water-soluble film coating agents include: cellulose polymers, for example, propyl cellulose [eg, NISSO HPC (grade ( Grade) : L, SL, SL-T, SSL) (trade name)·, Nippon Soda Co., Ltd.], two-group methyl cellulose [eg, TC-5 (grade: MW, E, EW, R, RW) ) ^ Product name); Shin-Etsu Chemical Co., Ltd.]], hydroxyethyl cellulose, methyl ethyl cellulose, etc.; synthetic polymer, such as polyvinyl acetal diethylacetate vinegar (polyvinyl acetal) Diethylaminoacetate), Amino 20 321939 201041873 . Pyridyl propyl phthalate copolymer e [Eutragit E (trade name.); manufactured by Rohm and Haas Japan], polyvinylpyrrolidone, etc.; Polysaccharides' such as polytriglucose, etc.; and the like. - Examples of enteric film-coating agents include: cellulosic polymers such as propyl mercapto cellulose stearate, hydroxypropyl decyl cellulose acetate succinate, carboxymethyl ethyl fiber , cellulose acetate phthalate, etc.; acrylic polymer, such as methacrylic acid copolymer L [Utech L (trade name)], methacrylic acid copolymer LD [Yutz L-30D55 ( Product name); manufactured by 〇罗门哈斯日本公司], thiol acrylate copolymer S [Etech S (trade name); manufactured by Rohm and Haas Japan], etc.; naturally occurring polymer, 'eg shellac, etc.; etc. Wait. Examples of the sustained-release film-coating base include: a cellulose polymer, for example, such as ethyl cellulose, etc.; an acrylic polymer such as an aminoalkylalkyl acrylate copolymer RS [Utech RS (trade name) ); manufactured by Rohm and Haas Japan Co., Ltd., ethyl acrylate-methyl methacrylate copolymer suspension [Utchi ❹ NE (trade name); Rohm and Haas 制造 manufactured by the company], etc.; Preferable examples of the coating additive include: a light protective agent such as titanium oxide or the like, a glidant such as talc, etc.; a coloring agent such as red iron oxide, yellow iron oxide, etc.; a plasticizer such as polyethylene glycol [For example, polyethylene glycol 6000 (macrogol 6000) (trade name); manufactured by Sanyo Chemical Industry Co., Ltd.], triethyl citrate, castor oil, polysorbate, etc.; organic acids such as citric acid, tartaric acid, malic acid , ascorbic acid, etc.; The solid preparation of the present invention can be produced by a known method (for example,

Japanese Pharmacopoeia 15th Edition, General Principles Medium 21 321939 Method described in 201041873). Examples of methods include operations such as mixing, tanning, granulating, compression molding, film coating, and the like, and suitable combinations of such operations. For example, mixing is performed using, for example, a mixer (such as a horizontal cylindrical mixer, a V-type mixer, a tumbler mixer, etc.); and a rotary vessel type tanning machine (for example, a ball mill or the like) is used, Fixed container type tanning machine (such as spiral tanning machine, Henschel mixer, etc.), tanning; rolling tanning machine (such as rolling mill, push rolling machine, etc.); . Granulation is carried out by the following method: stirring granulation method using a high-speed stirring granulator, use of a container (pot container, cone-shaped container, multi-stage cone-shaped container (multi -stage conical drum type), rolling granulation method with agitating roll, vibrating container, etc., fluidized bed granulation and drying method, spray drying granulation method, extrusion Granulation method, method using a granulator (for example, Roller-compactor), etc., for example, by molding (using an extrusion molding machine) or ingot (using an early punch key machine (single) Punch molding machine), rotary hitting machine, etc.) are compression molded. When compression grinding is performed using a single stroke tableting machine, a rotary tableting machine, etc., it is generally preferred to use 1 to 35 kilonewtons per square centimeter (kN/cm2) (more preferably 5 to 35 kN). /cm2) The tableting pressure. Further, in order to prevent capping, a taper cutting die is preferably used. 22 321939 201041873 For example, film coating is carried out by using a pan coating machine such as a horizontal type or a tilt type; a fluid coating machine such as a horizontal rotary type or a swash plate type (fluid coating) Machine); fluidized bed type, jet bed type, tumbling fluidized bed type, etc.; For example, the solid preparation of the present invention can be produced by the following production steps: (1) If the solid preparation of the present invention is a set of granulated preparations, the compound represented by the formula (1) or a salt thereof, a sugar alcohol and A mixture of a calcium antagonist (compared to a compound represented by the formula (I) or a salt thereof, a sugar alcohol, an about antagonist, and a polyethylene glycol) is granulated, and the obtained granulated material is compression-molded to obtain. A solid preparation of the invention (a set of granulated monolayer tablets) is obtained. - Specifically, a compound represented by the above formula (1) or a salt thereof, a calcium antagonist and an additive (for example, an excipient, a sugar alcohol (e.g., 0-mannitol), etc.) Y granulated mixture' is mixed and sprayed with a solvent (eg, water) A liquid obtained by dispersing or dissolving polyethylene glycol and adding a Q agent (such as a binder). (4) If an additive such as a disintegrator or a lubricant is added to the obtained granulated material 'mixed, the mixture is molded to obtain a lean agent. The blowing agent is coated with a film solution containing a coating agent or the like to obtain a solid of the present invention (a set of granulated single-layer tablets). ^ (2) If the solid preparation of the present invention is a two-part granulation preparation (a) a two-component granulated single-layer preparation; mixing the compound represented by the above formula (1) or a salt thereof, an additive (such as a job, etc.), The mixture is granulated and sprayed with a liquid (which is obtained by dispersing or dissolving polyethylene glycol 321939 23 201041873) and an additive (such as a binder) dissolved in a solvent such as water. In another aspect, a calcium antagonist and an additive (such as an excipient, a sugar alcohol (such as D-mannitol), etc.) are mixed, the mixture is granulated, and the polyethylene glycol and the additive are sprayed with a solvent (eg, water). Disperse or dissolve the resulting liquid (such as a binder). An additive such as a disintegrator, a lubricant or the like is added to the obtained granulated material containing the compound represented by the above formula (I) or a salt thereof, and added to the obtained granulated material containing the about antagonist, and after mixing, the compression mold This mixture was prepared to obtain a solid preparation (two-component granulated tablet) of the present invention. (b) a multi-layer tablet; mixing the compound of the above formula (I) or a salt thereof, an additive (such as an excipient, etc.), granulating the mixture, and spraying the solvent (for example, water) to polyethylene glycol and An additive (such as a binder) disperses or dissolves the resulting liquid. An additive such as a disintegrant, a lubricant or the like is added to the obtained granulated material to obtain a mixed granule. In another aspect, a calcium antagonist and an additive (such as an excipient, a sugar alcohol (such as D-mannitol), etc.) are mixed, the mixture is granulated, and the polyethylene glycol and the additive are sprayed with a solvent (eg, water). Disperse or dissolve the resulting liquid (such as a binder). An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material to obtain a mixed granule. The resulting mixed granules containing the compound of the above formula (I) or a salt thereof, and the resulting mixed granules containing a calcium antagonist are stacked one upon another and compression-molded to obtain a solid preparation (multilayer tablet) of the present invention. (c) dry coated tablets; 24 321939 201041873

* Mixing calcium antagonists and additives (such as excipients, sugar alcohols (such as D * mannitol), etc.) 'granulation mixture, and spraying with solvents (such as water) to disperse additives (such as adhesives, etc.) The resulting liquid is dissolved. An additive such as a disintegrator, a lubricant or the like is added to the obtained granulated material, and after mixing, the mixture is compression-molded to obtain a tablet. The recording agent is coated with a film solution containing a coating base or the like to prepare a core tablet. Another aspect of 'mixing the compound of the above formula (1) or a salt thereof, an additive (such as an excipient, etc.) into a granulation mixture, and spraying with a solvent (for example, water), polyethylene glycol, and an additive (such as a binder) The agent, etc.) disperses or dissolves the resulting liquid. An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material to obtain a mixed granule. The mixed granule is added as an outer layer to the above-mentioned core spinning agent, and is compression-molded to obtain the solid preparation of the present invention (dry coating key). When the solid preparation of the present invention is a granule or a fine granule, it can be borrowed The above method is produced. In the case of the present invention, the compound of the formula (1) or the second compound can be obtained by using the agent into a capsule containing gelatin, (tetra)methylcellulose or the like. , hoof, and _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The compound or its salt (4) is obtained by the above formula. The anti-agent is encapsulated into a shape and the surface is embossed for identification or the solid preparation of the present invention can be printed on the table 321939 25 201041873. In addition, it can be divided into engravings. The solid preparation of the present invention is low in toxicity and can be safely administered as a mammal by oral or parenteral administration (for example, human m horse, cow, mouse, rat, guinea pig, dog, rabbit, etc.). The compound of the formula (I) or a salt thereof has strong angiotensin n antagonistic activity. The solid preparation of the present invention is suitable for use as an inferior prophylactic or therapeutic drug: (1) due to stenosis or growth of blood vessels. Development (or promotion of disease) of the disease or through angiotensin n And the abnormal organ manifested, (2) the disease that develops (or promotes its development) due to the presence of blood f-constriction π or (3) develops (or promotes) the factor induced by vasoconstrictor π present in the above mammalian body. The disease of the above (1) to (3) includes: hypertension, blood pressure circadian rhythm abnormality, heart disease (for example, cardiac hypertrophy, acute heart failure, chronic heart) Failure (including heart failure), impaired dysfunction, cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, myocardial infarction, etc., cerebrovascular disease (eg, asymptomatic cerebrovascular disease, transient brain) Ischemia, stroke, cerebrovascular dementia, hypertensive brain lesions, cerebral embolism, etc.), cerebral edema, cerebral circulation disorders, recurrence and sequelae of cerebrovascular diseases (eg 'neurological symptoms, mental symptoms, subjective symptoms, Abnormal activity of daily living, etc.), ischemic peripheral circulation disorder, myocardial ischemia, varicose veins, heart function after myocardial infarction Development, kidney disease (eg, nephritis, glomerulonephritis, renal glomerulosclerosis, renal failure, thrombotic vascular disease, diabetic nephropathy, dialysis complications, organ damage (including nephropathy caused by radiation exposure), etc.) 321939 26 201041873 Arteriosclerosis (including atherosclerosis) (eg 'aneurysm, coronary artery stiffness, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular hypertrophy, interventional therapy (eg, percutaneous coronary angioplasty) Vascular hypertrophy or occlusion and organ damage after surgery, stent placement, coronary endoscopy, intravascular ultrasound, dounce thrombolysis, etc., revascularization or restenosis after bypass surgery, erythrocytosis, high Blood pressure, organ damage or vascular hypertrophy after transplantation, rejection after transplantation, eye diseases (eg, glaucoma, high intraocular pressure, etc.), thrombosis, multiple organ disorders, vascular endothelial cell dysfunction, sputum, blood pressure, tinnitus, others Cardiovascular disease (eg, deep vein thrombosis) obstructive peripheral circulatory disease, arteriosclerotic occlusion, blood Inflammatory vascular occlusion, ischemic cerebral circulatory disorder, Raynaud's disease (Raynaud's disease), Boge Shi • disease (Berger disease), etc.), metabolic and / or nutritional disorders (eg, obesity. Hyperlipidemia, hypercholesterolemia, hyperuricemia, hyperkalemia, hypernatremia, etc.), neurodegenerative diseases (eg, Alzheimes sease Parkinson's syndrome) ), amyotrophic spinal cord lateral sclerosis AIDS brain lesions, etc.), central nervous system disorders (eg, such as cerebral hemorrhage and cerebral infarction and its sequelae and complications, head damage, spinal cord injury, cerebral edema, old age) Dementia, sensory dysfunction, sensory dysfunction, autonomic nervous system disorders, autonomic nervous system dysfunction, multiple sclerosis, etc., dementia, memory impairment, disturbance of consciousness, amnesia, anxiety, nervousness, discomfort Mental state, mental illness (eg, sorrow, epilepsy, secret wine, etc.), inflammatory disease (eg, arthritis, such as wind shoulder, arthritis, osteoarthritis, rheumatoid myelitis, periostitis, etc.; surgery Or inflammation after inflammation, swelling relief; pharyngitis; cystitis; pneumonia; different 27 321939 201041873 dermatitis; inflammatory bowel disease, such as Crohn's disease (Crohn's Disease), ulcerative colitis, etc.; meningitis; inflammatory eye disease; inflammatory lung disease, such as pneumonia, spleen lung disease, pulmonary sarcoma (pulmonary sarcoidosis, tuberculosis, etc.) For example, allergic rhinitis, conjunctivitis, digestive tract allergy, hay fever, anaphylaxis, etc., chronic obstructive pulmonary disease, interstitial pneumonia, pneumocytis carinni pneumonia, collagen disease (collagen diseases) (eg, systemic lupus erythematosus, scleroderma, polyarteritis, etc.), liver disease (eg, hepatitis (including chronic hepatitis), cirrhosis, etc.), portal sorghum) blood pressure (portal hypertension), digestion Systemic disorders (eg, gastritis, gastric ulcer, stomach cancer, postoperative gastric disorders, dyspepsia, esophageal ulcers, pancreatitis, colon polyps, gallstones, acne disorders, rupture of the esophagus and stomach), blood and/or hematopoiesis Sexual diseases (eg, erythrocytosis, vascular purpura, autoimmune hemolytic anemia, diffuse intravascular coagulation syndrome (d Isseminated intravascular coagulation syndrome), bone disease (eg, fracture, refracture, C,) osteoporosis, osteomalacia, bone Paget's disease, sclerosis Spondylitis, rheumatoid arthritis, dysfunction of joint tissue caused by osteoarthrosis of the knee and similar disorders), solid tumors, tumors (eg, malignant melanoma, malignant lymphoma, digestive organs (eg, stomach) , intestines, etc.), cancer, and malignant diseases caused by cancer, metastasis cancer, endocrine diseases (for example, Addison's disease, Cushing's syndrome, Phenochromocytoma, tyrosone, primary 28 321939 201041873 corticosterone, etc., Kuzd's disease, urinary organs and/or male genital diseases (eg, bladder) Inflammation, prostate enlargement, prostate cancer, sexually transmitted diseases, etc.), gynecological diseases (for example, menopausal disorders, pregnancy poisoning, intrauterine Membrane dysplasia, uterine fibroids, ovarian disease, breast disease, sexually transmitted diseases, etc., diseases related to environmental or occupational factors (eg, light hazard; ultraviolet hazard, far infrared or laser beam damage; mountain sickness) Etc., respiratory diseases (such as 'cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis and pulmonary embolism, etc.), infectious diseases (for example, via cytomegalovirus, influenza virus, sore virus, etc.) Viral infectious diseases; rickettsiosis; bacterial infectious diseases, etc., toxemias (eg, sepsis, septic shock, endotoxic shock, gram-negative sepsis) ), toxic shock, etc., • Otolaryngology (such as 'Meniere's syndrome, tinnitus, taste disorder, dizziness, imbalance, difficulty swallowing, etc.), skin diseases (eg, keloid) , hemangioma, cognac, etc.), intradialytic hypotension, myasthenia gravis, systemic diseases (such as chronic Fatigue syndrome, etc.) and so on. The solid preparation of the present invention comprises a compound represented by the formula (1) or a salt thereof, a combination of a calcium antagonist, and is suitable for use as a prophylactic or therapeutic drug for the above diseases (preferably, blood pressure, heart failure, diabetic nephropathy or arteries). A prophylactic or therapeutic drug for sclerosis). Further, the solid preparation of the present invention can reduce the dose of the compound of the formula (1) or a salt thereof or a mother antagonist as compared with the compound represented by the formula (1) or a salt thereof or a calcium antagonist. The dose of the compound of the formula (1) or a salt thereof is changed according to the target, the administration of the 321939 29 201041873 route, the target disease, the symptoms, etc., and the dose per human (weight (eight) kg (kg)) is released. The form is based on a ratio of about 500 mg (mg), preferably from about mg to 100 mg, more preferably from i to ι 〇〇 mg, and particularly preferably from 2 to 40 gram. For example, a human adult human (10) weighing 60 kg) is about i to 8 mg, preferably 2 to μ mg, and the compound is administered to a human adult (body weight 6 kg) daily dose. It is about 1 to 50 mg, preferably 1 to 4 mg. The dose of the calcium antagonist varies depending on the administration of the target, the route of administration, the target disease, the symptoms, and the like. For example, amlodipine or a salt thereof (based on the form of the swim) is a human adult (body weight 6). 〇 kg) of each dose is about 1 to 50 mg, preferably 2. 5 to 1 mg. The solid preparation of the present invention preferably has a frequency of administration to the above mammals of from 1 to 3 times per day, more preferably once a day. Specific examples of the solid preparation of the present invention include. Each ingot contains 8 I grams of compound a and 6. A single layer of 93 mg of benzathine ammonia sulphate (5 oz of gas and gas),; contains 8 mg of compound 8 and 3 47 mg of sulfonate ammonia sulphate (amlodipine is 2 . 5 mg) of a single-layer tablet";, each tablet contains 4 mg of Compound A and 6 93 g of benzoic acid amlodipine (5 mg of galenicin) of a single layer of ', The ingot contains 4 * grams of compound A and 3. 47 mg of alumic acid amlodipine (ammonia level is 2. 5 mg) of a single-layer tablet,;; spin contains 40 mg of compound B and 6. 93 mg benzene acid ammoniapine (5 mg of amlodipine) single layer binder"; 321939 30 201041873 • Ingot contains 40 mg of compound B and 3 47 mg of sulfonic acid ammonia gas - flat (amlodipine) Then 2. 5 mg) of a single-layer tablet"; "Each tablet contains 20 mg of compound B and 6." 93 mg of benzenesulfonate-ammonia-flat (ammonium chloride is 5 mg) of a single-layer tablet"; each tablet contains 20 mg of compound B and 3. 47 mg of benzenesulfonic acid ammonia gas • Flat (amlodipine is 2. 5 mg) of a single-layer tablet"; each tablet contains 10 mg of compound 3 and 6 93 mg of amlodipine besylate (5 mg of clopidogrel) of single-layer tablets"; and 〇 "1G per ingot" Mg of compound B and 3. 47 mg of benzalkonium chloride (air and gas level is 2. 5 mg) of a single layer of a key." The solid preparation of the present invention can be used in combination with one or more different pharmaceutical agents (hereinafter referred to as "concomitant drug"). • The shellfish of the combined use of music includes: a therapeutic agent for diabetes, a therapeutic agent for diabetes mellitus, a therapeutic agent for hyperlipidemia, an antihypertensive agent, a slimming agent, a diuretic, and the like. Here, for example, a therapeutic agent for diabetes may be: an insulin preparation (for example, an animal insulin preparation extracted from the pancreas of a cow or a pig; a human insulin preparation synthesized by a genetic engineering method from coliform or yeast; zinc) Insulin, protamine zinc insulin, a fragment or derivative of insulin (for example INS-1), an oral insulin preparation), an insulin sensitizer (for example, pioglitazone or a salt thereof (preferably a hydrochloride) σ is more than Rosiglitazone or its salt (maleic acid), metaglidasen, AMG-131, Balaglitaz〇ne, MBX-2044 , raminone (Rjv〇giitaz〇ne), Argreza 31 321939 201041873 (Aleglitazar), Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT -505, HR-0921, and W02007/013694, W02007/018314, WO2008/093639 or W02008/099794), glycosylase inhibitors (eg, voglibose, acarbose) (acarbose), miglitol, Emiglitate, biguanides (eg, metformin, n-butyl bismuth (buformin) or a salt thereof (eg, hydrochloride, fumarate, succinate)) Insulin secretagogues (eg, sulfonylureas (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, torah yellow) Tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole, gligle Repaglinide, nateglinide, miteglinide or its bow hydrate, and a fourth type of dipeptidyl peptidase IV inhibitor (eg, Agger) Columns; butyl or its salts (preferably benzoate), vildagliptin, sitagliptin, salsa, saxagliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, 2-[[6-[(3R) 3-amino-1,pyridyl]-3,4-dihydro-3-indolyl-2,4-dioxy-1(2H)-pyrimidinyl]indenyl]-4-fluorobenzonitrile or a salt, a /5 3 agonist (eg, N-5984), a GPR40 agonist (eg, WO2004/041266, WO2004/106276, W02005/063729, WO2005/063725, WO2005/087710, 32321939 201041873 W02005/095338, W02007/ a compound described in 013689 or W02008/001931), a GLP-1 receptor agonist (eg, GLP-1, GLIMMI1, Liraglutide, Exenatide, AVE-0010, BIM-) 51077, Aib (8,35) hGLP-1 (7,37) NH2, CJC-im, Albiglutide, amyloid agonist (eg pramlintide), acidified tyrosine Phosphatase inhibitors (such as sodium vanadate), inhibitors of sugar nascent action (such as hepatic glycophosphorylase inhibitors, glucose-6-cansin inhibitors, blood glucose hormone antagonists, FBP enzyme inhibitors), SGULT2 (Sodium-glucose co-transport 2) inhibitors (for example, Depagliflozin, AVE2268, TS-033, YM543, TA-7284, Remogliflozin, ASP194 1), • SGLT1 inhibitor, 11 cold hydroxyl steroid dehydrogenase inhibitors (eg BVT-3498, INCB-13739), Adiponectin or its agonist, IKK inhibitor (eg AS_2868), lipophyllin (leptin) a hypertonic drug, a somatostatin receptor agonist, a Glucokinase Activator (eg, Pegigline, Piragliatin, AZD1656, AZD6370, TTP-355, and WO2006/112549, WO2007/028135, WO2008/047821, W02008/050821, W02008A36428 or WO2008/156757), GIP (glucose-dependent insulinotropic peptide, GPR119 agonist, FGF21) , FGF analogs, and the like. Can be used as a therapeutic agent for diabetic complications: aldose reductase inhibitors (eg 't〇lrestat, epalrestat, catch 33 321939 201041873 prasat (zopolrestat), non Didastat (fidarestat), CT-112, ranirestat (AS-3201), lidorestat, neurotrophic factor and its enhancer (eg, NGF, NT-3, BDNF, in WO) Neurotrophin manufacturing/secretion promoter described in 01/14372 (for example, 4-(4-phenylphenyl)-2-(2-mercapto-1-imidazolyl)-5-[3-(2-indenyl) Phenoxy)propyl]carbazole, described in WO2004/039365), PKC inhibitors (eg, ruboxistaurin, AGE inhibitors) (eg, ALT946, brominated N-benzene) Mercaptothiazolidine (ALT766), EXO-226, 11-pyridorin, pyridoxamine, GABA receptor agonist (eg, gabapan, gabapentin, Pregabalin, serotonin and norepinephrine reuptake inhibitors (eg, duloxetine), sodium channel inhibitors (eg, pull) An amine (lacosamide), an active oxygen scavenger (eg, lipoic acid), a cerebral vasodilator (eg, tiapuride, mexiletine), a somatostatin receptor agonist (eg, BIM23190) ), apoptotic signal-regulated kinase-1 (ASK-1) inhibitor, and the like. As a therapeutic agent for hyperlipidemia, there are: HMG-CoA reductase inhibitors (for example, pravastatin, simvastatin, simvastatin, lovastatin, ato Atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or a salt thereof (eg, sodium salt, calcium salt), squalene synthetase inhibitor (For example, a compound described in WO97/10224, for example, N-[[(3R,5S)-l-(3-acetoxy-2,2-dimercaptopropyl)-7-chloro-5- ( 2,3-dioxanylphenyl)-2-keto-1,2,3,5-tetrahydro 34 321939 201041873 -4,1-benzoxephen-3-yl]ethenyl]piperidin Pyridin_4_acetic acid), fibrate compound (for example, bezafibmte, clofibrate, simfibrate, clinofibrate )), anion exchange resin (for example, colestyramine), pilobuquer (pr〇buc〇1), nicotinic acid drugs (for example, nicomol, niceritr) 〇1), Novo Nia (niaspan), ethyl ic〇sapentate, phytosterols (eg, 'soy sterol, r-glutenol), cholesterol absorption inhibitors (eg, 皙夏( Zechia)), a CETP inhibitor (for example, dalcetrapib, anacetrapib), an omega-3 fatty acid preparation (for example, omega-3 acid ethyl ester 90), and the like. As an anti-high-pressure agent, there are: angiotensin-converting enzyme inhibitors (for example, captopril, enalapril, deLapril, etc.), angiotensin I Antagonists (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan) , valsartan, telmisartan, irbesartan, tasosartan, olmesart, olmesartan medoxomil, aziz Azilsartan, etc., calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine, ammonia Clodipine, cilnidipine, etc., and blockers (eg, metoprolol, atenolol, 35 321939 201041873 propranolol, caffeine (carvedil〇1), 吲哚olol ( Pindolol), ci〇nidine, etc. Can be used as a weight loss agent: monoamine absorption inhibitors (eg, phentermine, Sibutramine, mazindol, fluoxetine, barrelsofen) Tesofensine, serotonin 2C receptor agonist (eg, lorcaserin), serotonin 6 receptor agonist, histamine H3 receptor, GABA-regulating drug (eg 'toxin π ratio g T〇piramate )), neuropeptide gamma antagonists (eg, 'velneperit'), marijuana receptor antagonists (eg, rimonabant, taranabant), hunger Hormone (ghrelinant) agonist, ghrelin receptor antagonist, ghreiin acyiati〇n enzyme inhibitor, opioid receptor antagonist (eg, GSK-1521498), orexin Receptor antagonist, melanocortin 4 receptor agonist, 11 cold-hydroxysteroid dehydrogenase inhibitor (eg, AZD-4017) 'pancreatic lipase inhibitor (eg, let you (orlistat), Cetilita, /5 3 agonist , N-5984), diacylglycerol acyltransferase 1 ' DGAT1 inhibitor, acetaminophen coenzyme a sulfatase (ACC ) inhibitor, acetaminophen coenzyme A desaturase inhibitor, acid glycerol Ester transfer protein inhibitors (eg, R-256918), Na-glucose co-transport inhibitors (eg, JNJ-28431754, remogliflozin), NF/c B inhibitors (eg, HE- 3286), PPAR agonists (eg 'GFT-505, DRF-11605'), serotonic acid citrate 36 321939 201041873 • Teng inhibitors (eg sodium vanadate, trodusquemin).  GPR119 agonist (eg, PSN-821), glucokinase activator (eg, AZD-1656), leptin, leptin derivatives (eg, metrepeptin), CNTF (ciliary neurotrophy) Ciiiary neurotrophic factor, BDNF (brain-derived neurotrophic factor), cholecystokinin agonist, glucagon-like peptide-1 (GLP-1) preparation (for example, GLP from cattle or pigs) 1 preparation; human GLP_1 preparation synthesized by coliform or yeast by genetic engineering method; GLP-1 fragment or derivative (such as 'exenatide, liraglutide)), amyloid agonist (for example, pramlint) Peptide, AC-2307), neuropeptide Y agonist (eg, pyy3_36, PYY3-36 derivative, obinepitide, TM-30339, TM-30335), acid modulator preparation; FGF21 preparation (eg, pumping An animal fgF2 1 - preparation from cattle or pigs; a human FGF21 preparation synthesized by coliform bacteria or yeast by genetic engineering methods; a FGF21 fragment or derivative)), a food resistance factor (for example, ρ·57), and the like. As a diuretic, for example, xanthine derivatives (for example, theobromine sodium, salicylate, theobromine salicylate, etc.), thiazide preparations (for example, Ethyl tidyum, cyclopentanyl tillage, trimethyl thiophenanthine, dihydrogen thiocyanate, hydrofluorinated thiophenanthine, hydrazine double hydrogen beta sulphide, pentafluoro sulphide, multi n n 卩 well Compounds, xenon thioxides, etc., anti-aldosterone preparations (for example, spironolactone, triamterene, etc.), carbonate inhibitors (eg 'acetazolamide') Et, chlorobenzene sulfonamide preparation (for example, chlortalidone 'mefruside, indapamide, etc.), azosemide, isosorbide 321939 37 201041873 ( Isosorbide), ethacrynic acid, pitetanide, bumetanide, furosemide, and the like. As an antithrombotic agent, for example, heparin (for example, heparin sodium, heparin #5, enoxaparin sodium, dalteparin sodium), warfarins (for example, Anti-thrombin drugs (eg, aragatroban, dabigatran), Fxa inhibitors (eg, rivaroxaban, apaxaban) Apixaban), edoxaban, YM150, and W002/06234, W02004/048363, W02005/030740, WO2005/058823, or WO2005/113504), thrombolytic agents (eg, urokinase, Tisokinase, alteplase, nateplase, monteplase, pampiteplase, platelet aggregation inhibitors (eg, tetainin) (ticlopidine) hydrochloride, cilostazol, clopidogrel, prasugrel, E5555, SHC530348, ceroxazole, ethyl hexacarboxylate, berapoulol Sodium (beraprost sodium), sapoprozate (sarpogrei Ate) hydrochloride) and so on. When the solid preparation of the present invention is used in combination with a concomitant drug, their administration time is not limited, and they may be administered to the subject at the same time or administered in a staggered manner. Further, the solid preparation of the present invention and the concomitant drug may be administered as a separate preparation; and it may be administered as a single preparation containing the solid preparation of the present invention and a concomitant drug. 38 321939 201041873 The dose of the combined drug can be appropriately determined according to the clinical dose of each drug. The mixing ratio of the solid preparation of the present invention and the concomitant drug can be appropriately determined according to the following: the target, the administration route, the target disease, the symptom, the composition, and the like. For example, 'when the target is human, the solid form preparation of the present invention can be used. 01 to 100 parts by weight of the combined drug. α This way makes a heat, providing the following superior effects: υ promoting the effect of the solid preparation of the present invention or the combination of drugs (the synergistic effect of the action of the agent); 〇 2) reducing the effect of the solid preparation of the present invention or the dose of the concomitant drug (The effect of reducing the dose of the drug compared to the single administration); 3) Reducing the side effects of the solid preparation or the combined use of the present invention.  (secondary action) effect; and so on. • The present invention also provides a method for promoting the solubility properties of the following: a compound of the formula (I) or a salt thereof and/or a calcium antagonist, which is contained in a solid preparation containing a sugar alcohol; . According to the present invention, the solubility property of the compound of the formula (I) or a salt thereof in the solid preparation is remarkably improved. EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples, which are not to be construed as limiting. In the following examples and test examples, the composition (additive) which is not an active ingredient can be used with the Japanese Pharmacopoeia 15th Edition, the Japanese Pharmacopoeia Japanese Pharmaceutical Codex, or Japanese pharmaceutical excipients 2003 39 321939 201041873 (Japanese Pharmaceutical Excipients 2003 ) compatible products. In the following examples, the compound A or the compound B is used as the compound represented by the above formula (I) or a salt thereof. Example 1 Table 1 Composition of each preparation (130 mg) Compound A 8 mg Abnormal acid ammonia level 6. 93 mg (ammonia level, 5 mg) D-mannitol 82. 754 mg microcrystalline cellulose 20 mg hydroxypropyl cellulose 4 mg macrogol 6000 1. 8 mg croscarmellose sodium 5. 6 mg magnesium stearate 0. 9 mg red iron oxide 0. 016 mg total 130 mg (1) will be propyl cellulose (720. 0 g) and macrogol 6000 (324. 0 g) Dissolved in pure water (9000 g) to obtain a binder I. Will be red iron oxide (2. 880 g) was dispersed in pure water (2880 g) to obtain a dispersion I. Mixed binder I, dispersion 1 and pure water (720. 0 §) to obtain the binder 11. Fluidized bed granulator (FD-S2, POWREX Co. , Ltd. Lieutenant sulfonate ammonia flat (1253 g), compound A (1449 g), D-mannitol (14880 g) and microcrystalline cellulose (3600 g) are uniformly mixed, granulating the mixture and spraying the binder II, followed by drying to obtain granules. For screening mills (P-3, Showa 40 321939 201041873 • KagakukikaiCo. ,Ltd. a part of the obtained granules is 1. 5mm .  The p punched sieve plate is ground to obtain a ground granule. (2) croscarmellose sodium (1848 g) and magnesium stearate (297. 0 g) Add to the obtained ground granules (40760 g (2 batches)) on a drum mixer (TM20-0-0, Suehiro Kakoki Co. ,Ltd. Mix in to obtain a mixed granule. (3) The mixed granules obtained as above were used in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho). 0 mm punching straight 打 打 ( (ingot pressure: 10 kN, weight per spindle: 130 mg) to obtain a plain tablet of the composition shown in Table 1. Example 2 Table 2 Composition of each formulation (130 mg) Compound A 8 mg Ammonia terephthalate 6. 93 mg (amlodipine, 5 mg) D-mannitol 82. 705 mg microcrystalline cellulose 20 mg hydroxypropyl cellulose 4 mg macrogol 6000 1. 8 mg croscarmellose sodium 5. 6 mg magnesium stearate 0. 9 mg red iron oxide 0. 065 mg total 130 mg 41 321939 201041873 (1) hydroxypropyl cellulose (720. 0 g) and macrogol 6000 (324. 0 g) Dissolved in pure water (9900 g) to obtain a binder I. Red iron oxide (11·70 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mixed binder I, dispersion I and pure water (540. 0 g) to obtain the binder II. Fluidized bed granulator (FD-S2, POWREX Co.) , Ltd. Ammonia terephthalate (1253 g), compound A (1449 g), D-mannitol (14870 g) and microcrystalline cellulose (3600 g) were uniformly mixed, granulating the mixture and spraying the binder II And then dried to obtain granules. In the screening mill (P-3, Showa KagakukikaiCo. ,Ltd. In the middle, a part of the obtained granules was ground with a l_5 mm P punched sieve to prepare a milled granule. (2) croscarmellose sodium (1848 g) and magnesium stearate (297. 0 g) Add to the obtained ground granules (40760 g (2 batches)) on a drum mixer (TM20-0-0, Suehiro Kakoki Co. ,Ltd. Mix in to obtain a mixed granule. (3) The mixed granules obtained as above were used in a rotary snoring machine (AQUARIUS-36K, Kikusui Seisakusho). 5 mm long diameter punching and 5. A 0 mm short-diameter punching ingot (dye pressure: 8 kN, weight per tablet: 130 mg) to obtain a tablet of the composition shown in Table 2. Example 3 Table 3 Composition of each preparation (130 mg) Compound A 8 mg Ammonia terephthalate 3. 47 mg 42 323939 201041873 (Amlodipine, 2. 5 mg) D-mannitol 86. 165 mg microcrystalline cellulose 20 mg hydroxypropyl cellulose 4 mg macrogol 6000 1. 8 mg croscarmellose sodium 5. 6 mg magnesium stearate 0. 9 mg red iron oxide 0. 065 mg total 130 mg (1) will be propyl cellulose (720. 0 g) and macrogol 6000 (324. 0 g) Dissolved in pure water (9900 g) to obtain a binder I. Will be red iron oxide (11. 70 ' g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mixed binder I, 'dispersion I and pure water (540. 0 g) to obtain the binder II. Fluidized bed granulator (FD-S2, POWREX Co.) ,Ltd. Lieutenant amlodipine besylate (627. 7 g), Compound A (1449 g), D-mannitol (15550 g) and microcrystalline cellulose (3600 g) were uniformly mixed, granulated and sprayed with the binder II, followed by drying to obtain granules. In the screening mill (p_3, Showa KagakukikaiCo. ,Ltd. a part of the obtained granules is 1. A 5 mm p punched sieve was ground to obtain a ground granule. (2) croscarmellose sodium (1848 g) and magnesium stearate (297. 0 g) Add to the obtained ground granules (40760 g (2 batches)) on a drum mixer (TM20-0-0, Suehiro Kakoki C〇. ,Ltd. Mix in to obtain a mixed granule. 43 321939 201041873 (3) The mixed granules obtained as described above were used in a rotary keying machine (AQUARIUS-36K, Kikusui Seisakusho). 5 mm long diameter punching and 5. A 0 mm short-diameter punching ingot (dyeing pressure: 8 kN' per suspect weight: 130 mg) to obtain a tablet of the composition shown in Table 3. Example 4 Table 4 Composition of each preparation (130 mg) _ Compound A 4 mg Benzoic acid amlodipine 6. 93 mg (amlodipine, 5 mg) D-mannitol 86. 705 mg microcrystalline cellulose 20 mg hydroxypropyl cellulose 4 mg macrogol 6000 1. 8 mg croscarmellose sodium 5. 6 mg magnesium stearate 0. 9 mg red iron oxide 0. 065 mg total 130 mg (1) hydroxypropyl cellulose (720. 0 g) and macrogol 6000 (324. 0 g) Dissolved in pure water (9900 g) to obtain a binder I. Will be red iron oxide (11. 70 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mixed binder I, dispersion I and pure water (540. 0 g) to obtain the binder II. Fluidized bed granulator (FD-S2, POWREX Co.) ,Ltd. Lieutenant amlodipine besylate 44 321939 201041873 (1253 g), compound a (724. 3 g), D-mannitol (156 〇〇 g) and microcrystalline cellulose (3600 g) were uniformly mixed with the granulated mixture and sprayed with the viscous liquid I, and dried to obtain granules. For screening mills (p_3, showa KagakukikaiCo. ,Ltd. A, a part of the obtained granules was ground with a umm Φ punching sieve to prepare a ground electrode. (2) Cross-linked methyl cellulose sodium (1848 g) and magnesium stearate (297. 0 g) Add to the obtained ground granules (40760 g (2 batches)) on a drum mixer (TM20-0-0, Suehiro Kakoki C〇. ,Ltd. Mix in order to obtain a mixed granule. (3) The mixed granules obtained as above were punched at a diameter of 7 mm in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) • Ingots (ingot pressure: 10 kN, weight per spindle: 130 mg) to obtain A lozenge of the composition shown in Table 4. Example 5 Table 5 组成 Composition of each preparation (13Omg) Compound A 4 mg Amlodipine besylate 3. 47 mg (amlodipine, 2. 5 mg) D-mannitol 90. 165 mg microcrystalline cellulose 20 mg hydroxypropyl cellulose 4 mg macrogol 6000 1. 8 mg 45 321939 201041873 Cross-linked methyl cellulose sodium ——— 5. 6 mg magnesium stearate 0. 9 mg yellow iron oxide ------- 0. 065 mg total ·_ II --- 130 mg (1) will be propyl cellulose (720. 0 g) and macrogol 6000 (324. 0 g) Dissolved in pure water (99 〇〇 g) to obtain a binder I. Yellow iron oxide (11. 70 g) was dispersed in pure water (18 〇〇 g) to obtain a dispersion I. Mixed binder I, dispersion 1 and pure water (540. 0 g) to obtain the binder II. Fluidized bed granulator (FD-S2, P〇WREX c〇·, Ltd. Lieutenant amlodipine besylate (627. 7 g), compound a (724. 3 g), D-mannitol (16200 g) and microcrystalline cellulose (3600 g) were uniformly mixed, the mixture was granulated and the binder π was sprayed, followed by drying to obtain granules. Screening mill (P-3, Showa)

In Kagakukikai C〇., Ltd.), a part of the obtained granules was ground with a 1.5 mm < SP punching sieve to obtain a milled granule. (2) Add croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) to the obtained milled granules (40760 g (2 batches)) in a roller mixer (TM20-0) -0, Suehiro Kakoki Co., Ltd.) was mixed to obtain a mixed granule. (3) The mixed granules obtained as above were punched in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) with a diameter of 7 mm (ingot pressure: 10 kN, weight per tablet 130 mg). A cyclin consisting of the composition shown in Table 5. Example 6 Table 6 46 321939 201041873 Composition of parent preparation (13 〇mg) Compound A 8 mg Amlodipine benzalkonate 6.93 mg (Amlodipine, 5 mg) D-mannitol 82.666 mg Microcrystalline cellulose 20 Mg hydroxypropylcellulose 4 mg macrogol 6〇〇〇1.8 mg croscarmellose sodium 5.6 mg magnesium stearate 0.9 mg red iron oxide 0.104 mg total 130 mg (1) propylcellulose (720.0) g) and macrogol 6000 (324.0 g) were dissolved in pure water (9900 g) to obtain a binder I. Red iron oxide (18.7 2 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mix the binder I, the hydrazine dispersion I and the pure water (540.0 g) to obtain the binder II. Amlodipine besylate (1248 g), Compound A (1446 g), D-mannitol (14870 g) and microcrystals in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the viscous liquid was sprayed, and the granules were obtained by the receiver. A part of the obtained granules was ground in a 1.5 mm p punched sieve in a division mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule. (2) Add croscarmellose sodium (924.0 g) and magnesium stearate 47 321939 201041873 (148.5 g) to the obtained milled granules (20380 g) in a roller mixer (TM20-0- 0, Suehiro Kakoki Co., Ltd.) mixed in 'to obtain mixed granules. (3) The mixed granules obtained as above were punched in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) with a punch diameter of 8.5 mm and a short diameter of 5.0 mm (key press pressure: 8 kN, each key) Weight: 130 mg) A precipitant having the composition shown in Table 6 was obtained. Example 7 Table 7 Composition of each formulation (130 mg) Compound A 8 mg Amlodipine Benzateate 3.47 mg (Amlodipine, 2.5 mg) D-mannitol 86.126 mg Microcrystalline cellulose 20 mg Hydroxypropyl fiber 4 mg macrogol 6000 1.8 mg croscarmellose sodium 5.6 mg magnesium stearate 0.9 mg yellow iron oxide 0.104 mg total 130 mg (1) hydroxypropyl cellulose (720.0 g) and macrogol 6000 (324.0 g) ) dissolved in pure water (9900 g) to obtain a binder I. Yellow iron oxide (18.72 48 321939 201041873 ' is dispersed in pure water (18〇〇g) to obtain dispersion i. Mixing the binder, dispersion I and pure water (540.0 g) to obtain the binder π. Amlodipine benzoate (625.2 g), compound a (1446 g), D-mannitol (15500 g) and a fluidized bed granulator (FD-S2, P〇WREX Co., Ltd.) The microcrystalline cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder η was sprayed, and dried to obtain granules. In the sieving mill (P-3, Showa)

In Kagakukikai Co., Ltd.), a part of the obtained granules was ground with a 15 mm φ punching sieve to prepare a ground granule. 〇 (2) Add the parent hydrazine methylcellulose (924.0 g) and stearic acid meter (148.5 g) to the obtained granulated granules (20380 g) in a roller mixer (TM20-0-0, Mix in Suehiro Kakoki Co., Ltd.) to obtain a mixed granule. • (3) Mixed granules obtained as above, punched in a rotary swirling machine (AQUARIUS-36K, Kikusui Seisakusho) with 8·5 mm long diameter punching and 5.0 mm short diameter punching (insulation pressure: 8kN) , weight per ingot: q 130 mg) to obtain a tablet of the composition shown in Table 7. Example 8 Table 8 Composition of each formulation (130 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (Amlodipine, 5 mg) D-mannitol 83.166 mg 49 321939 201041873 Microcrystalline cellulose 20 mg Hydroxyl Propylcellulose 4 mg macrogol 6000 1.3 mg croscarmellose sodium 5.6 mg stearic acid 0.9 mg red iron oxide 0.104 mg total 130 mg (1) hydroxypropyl cellulose (144.0 g) dissolved in pure Water (1980 g) was obtained to obtain the binder I. Yellow iron oxide (3.744 g) was dispersed in pure water (360.0 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (108.0 g) to obtain the binder II. Macrogol 6000 (4.680 g) was dissolved in the binder 11 (259.6 g) to obtain a binder III. Amlodipine behenate (24.95 g), Compound A (28.80 g), D-mannitol (299.4 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder III was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule. (2) Add croscarmellose sodium (16.80 g) and magnesium stearate (2.700 g) to the obtained milled granules (370.5 g), and mix in a polyethylene bag (4.9 L) to A mixed granule is obtained. (3) The mixed granules obtained above were punched in a rotary tableting machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 7.5 kN, per Ingot weight: 130 mg) A flavonoid having the composition shown in Table 8 obtained as 50 321 939 201041873. Example 9 Table 9

Composition of parenteral preparation 丄l3〇mg) Compound A 8 mg Amlodipine besylate 6.93 mg (Amlodipine, 5 mg) D-mannitol 80.566 mg Microcrystalline cellulose 20 mg propylcellulose 4 Mg macrogol 60〇〇3.9 mg croscarmellose sodium 5.6 mg magnesium stearate 0.9 mg red iron oxide 0.104 mg total 130 mg (1) Dissolve hydroxypropylcellulose (丨44.0 g) in pure water ( In 1980 g) to obtain the binder I. Red iron oxide (3.744 g) was dispersed in pure water (36 〇.〇 g) to obtain a dispersion I. Mix the binder, dispersion j and pure water (1〇8 〇g) to obtain the binder II. Dissolve macrogol 6000 (14.04 g) in the binder 11 (259.6 g) to obtain the binder π in the fluidized bed granulator POWREX Co., Ltd.) to amlodipine besylate (24 95 phantom, compound) j Α (28·80 g), D-mannitol (η Λ ^ at 290.0 gb, human u, phantom and twin cellulose (72.00 g): Ground δ, granulate the mixture and spray red $ , , , W, and then dried to obtain $ 321939 51 201041873. A portion of the obtained granules was sieved through a sieve (16 mesh) to prepare a ground granule. (2) Cellulose sodium (16.80 g) and magnesium stearate (2.700 g) were added to the obtained milled granules (370.5 g), and mixed in a polyethylene bag (4.9 L) to obtain a mixed granule. (3) The mixed granules obtained above were punched in a rotary tableting machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 7.5 kN, weight per spindle: 130 mg) to obtain a suspected agent of the composition shown in Table 9. Example 10 Table 10 Composition of each formulation (130 mg) Compound A 8 mg Amlodipine besylate 6.93 mg (Ammonia chloride Ping, 5 mg) D-mannitol 77.966 mg microcrystalline cellulose 20 mg hydroxypropylcellulose 4 mg macrogol 6000 6.5 mg croscarmellose sodium 5.6 mg magnesium stearate 0.9 mg red iron oxide 0.104 mg Total 130 mg 52 321939 201041873 (1) Dissolve propyl cellulose (144.0 g) in pure water (1980 g) to obtain a binder I. Disperse red iron oxide (3.744 g) in pure water (360.0 g) To obtain dispersion I. Mix the binder I, dispersion I and pure water (108.0 g) to obtain the binder Π. Dissolve macrogol 6000 (23.40 g) in the binder 11 (259.6 g) to obtain the binder III. Amlodipine besylate (24·95 g), Compound A (28.80 g), D-mannitol (280.7 g) and micro in a fluidized bed granulator 1 in POWREX Co., Ltd. The crystalline cellulose (72 〇〇g) was uniformly mixed with the granulated mixture and sprayed with the viscous liquid III, followed by drying to obtain a granule granule. A part of the obtained granule was sieved by a net (16 division) to prepare a granule. Grinded granules. (2) Add croscarmellose sodium cellulose (16.8 〇g) and magnesium stearate (2.700 g) to the obtained granulated granules (3) 70.5 g), mixed in a polyethylene bag (49 L) to obtain a mixed granule. (3) The mixed granules obtained as above were punched in a rotary tableting machine ((: 〇rrect 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5 〇mm ( (ingot pressure) : 7.5 kN, weight per tablet: 13 〇 mg) To obtain a tablet of the composition shown in Table 10. Example 11 Table 11 Composition of each formulation (130 mg) Compound A 8 mg Amlodipine benzoic acid 6.93 Mg (amlodipine, 5 mg) 321939 53 201041873 D-mannitol 74.066 mg microcrystalline cellulose 20 mg hydroxypropylcellulose 4 mg macrogol 6000 10.4 mg croscarmellose sodium 5.6 mg magnesium stearate 0.9 mg red iron oxide 0.104 mg total 130 mg (1) Dissolve hydroxypropyl cellulose (144.0 g) in pure water (1980 g) to obtain a binder I. Disperse red iron oxide (3.744 g) in pure water (360.0 g) to obtain dispersion I. Mix the binder I, dispersion I and pure water (108.0 g) to obtain the binder II. Dissolve macrogol 6000 (37.44 g) in the binder 11 (259.6 g) Obtaining the cement ill. Amlodipine besylate (24.95 g), compound in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) A (28.80 g), D-mannitol (266.6 g) and microcrystalline cellulose (72.00 g) were uniformly mixed with the 'granulation mixture and sprayed with the binder in, followed by drying to obtain granules. Hole) A portion of the obtained granules is sieved to obtain a milled granule. (2) Crosslinked retinoic cellulose (16.80 g) and stearic acid (2.700 g) are added to the obtained ground granules. Granules (370.5 g) were mixed in a polyethylene bag (4.9 L) to obtain a mixed granule. (3) The mixed granules obtained as above were used in a rotary keying machine (c〇rrect 19K, Kikusui Seisakusho) Punching with a diameter of 8.5 mm and 5.0 mm 321939 54 201041873 . Short-diameter punching (ingot pressure: 7.5kN, weight per spindle: 13〇mg) to obtain a prime ingot as shown in Table 11. Example 12 Table 12 Composition of each formulation (135 mg) Compound B 40 mg Amlodipine besylate 6.93 mg (Amlodipine, 5 mg) D-mannitol 40.1 mg Microcrystalline cellulose 9.72 mg Hydroxypropyl Cellulose 5.2 mg macrogol 6000 4 mg crospovidone 9.75 mg microcrystalline cellulose 13 mg magnesium stearate 1.3 mg premix I 5 mg total 135 mg (1) Hydroxypropylcellulose (208.0 g) and macrogol 6000 (160·0 g) were dissolved in pure water (2392.0 g) to obtain a binder. Amlodipine besylate (277.2 g), Compound B (1605.0 g), D·mannitol (1599.0 g) and microcrystals in a fluidized bed granulator (FD-5S, POWREX Co., Ltd.) The cellulose (388.8 g) was uniformly mixed, the mixture was granulated and a binder was sprayed, followed by drying to obtain granules. Screening mill (P-3, Showa Kagakukikai 55 321939 201041873

In Co., Ltd.), a part of the obtained granules was ground with a 1.5 mmp punched sieve to prepare a milled granule. (2) crospovidone (331.5 g), microcrystalline cellulose (442.0 g) and magnesium stearate (44.201 g) were added to the obtained milled granules (3602.0 g) in a roller mixer (TM) -15, Suehiro Kakoki co., Ltd.) was mixed to obtain a mixed granule. (3) The mixed granules obtained as above were punched with a 7·0 mm diameter punch in a rotary tableting machine (Correct 12HUK, Kikusui Seisakusho) (key press pressure: 4 kN, each key: weight: 130 mg) to obtain a core Rotating agent. (4) Premix I (240.4 g) was dissolved in pure water (2160.0 g) to obtain a film coating solution. In a film coater (drc-5 00, POWREX Co., Ltd.), a film coating solution was uniformly sprayed on a core tablet (3120.0 g) to form a film coat 'to obtain a film having the composition shown in Table 12 Clothes key (weight per plate: 135 mg). Here, the premix I is a premixed powder. The composition of Premix I is shown in Table 12a. Table 12a Composition weight ratio of premix I hydroxypropyl fluorenyl cellulose 9.0 macrogol 6000 2.0 cerium oxide 1.0 yellow iron oxide 0.2 Example 13 Table 13 321939 201041873 Composition of each formulation (135 mg) Compound B 20 mg benzenesulfonic acid Amlodipine 6.93 mg (Amlodipine, 5 mg) D-mannitol 60.1 mg Microcrystalline cellulose 9.72 mg Propylcellulose 5.2 mg macrogol 6000 4 mg crospovidone 9.75 mg Microcrystalline cellulose 13 mg Magnesium stearate 1.3 mg Premix I 5 mg Total 135 mg (1) Light propyl cellulose (20.80 g) and macrogol 6000 (16.00 g) were dissolved in pure water (239.2 g) to obtain a viscous liquid. Amlodipine besylate (27.72 g), Compound B (80.00 g), D-mannitol (240.4 g) and micro in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The crystalline cellulose (38.88 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule. (2) crospovidone (34.13 g), microcrystalline cellulose (45.50 g) and magnesium stearate (4.550 g) were added to the obtained milled granules (370.8 g) in a polyethylene bag (4.9 Mix in L) to obtain a mixed granule. 57 321939 201041873 (3) The mixed granules obtained above were swirled with a 7.0 mm diameter punch in a rotary tableting machine (VEL-5, Kikusui Seisakusho) (ingot: pressure: 41 < ^, weight per spindle: 13〇11^) to obtain the core lozenge. (4) Premix I (40.00 g) was dissolved in pure water (360.0 g) to obtain a film coating solution. In the film coating machine (〇10:-200,?0\¥1^ parent (:〇., 1^(1.), uniformly spray the film coating solution on the core tablet (200.0 g) to form a film coat To obtain a film coat of the composition shown in Table 13: (per spin weight: 135 mg) Here, the premix I was a premixed powder. The composition of the premix I is shown in Table 13a. Composition Weight Ratio of Premix I to propylmethylcellulose 9.0 macrogol 6000 2.0 Titanium Dioxide 1.0 Yellow Iron Oxide 0.2 Example 14 Table 14 Composition of each formulation (135 mg) Compound B 20 mg Amlodipine besylate 3.47 mg ( Amlodipine, 2.5 mg) D-mannitol 63.56 mg 58 321939 201041873 Microcrystalline cellulose 9.72 mg propylcellulose 5.2 mg macrogol 6000 4 mg crospovidone 9.75 mg microcrystalline cellulose 13 mg stearic acid Magnesium 1.3 mg Premix I 5 mg Total 135 mg (1) Dissolve hydroxypropylcellulose (20.80 g) and macrogol 6000 (16.00 Ο g) in pure water (239.2 g) to obtain a binder. (Lab-1, POWREX Co., Ltd.) Lithium Amlodipine Besylate (13 μg), Compound B (8〇.00 g), D- The granules (254.2 g) and the microcrystalline vesicles (38.88 g) were uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. The obtained granules were sieved (16 mesh). A knives are sifted to produce granulated granules. 〇 (2) crospovidone (34.13 g), microcrystalline cellulose (45.50 g) and magnesium magnesium sulphate (4.550 g) The obtained granulated granules (370.8 g) were mixed in a polyhexene bag (4.9 L) to obtain a mixed granule. (3) The granules obtained as above were applied to a rotary tableting machine ^,

Kikusui Seisakusho) was swirled with a 7.0 mm diameter punch (force: 4 kN, weight per spindle: 130 mg) to obtain a core lozenge. (4) Premix I (40.00 g) was dissolved in pure water (360.0 g) to obtain a film coating solution. In a film coater (DRC-200, POWREX Co., Ltd.), 59 32l939 201041873 uniformly sprayed a film coating solution on a core tablet (200.0 g) to form a film coat to obtain a composition as shown in Table 14. Membrane ingots (weight per plate: 135 mg). Example 15 Table 15 Composition of each formulation (135.154 mg) Compound B 10 mg Amlodipine besylate 3.465 mg (Amlodipine, 5 mg) D-mannitol 83.535 mg Microcrystalline cellulose 13 mg Hydroxypropyl Cellulose 3.9 mg macrogol 6000 1.8 mg Low-substituted hydroxypropylcellulose 13 mg Magnesium stearate 1.3 mg crospovidone 3.829 mg Titanium dioxide 0.512 mg macrogol 6000 0.768 mg Red iron oxide 0.011 mg Yellow iron oxide 0.034 mg Total 135.154 Mg (1) Dissolve propylcellulose (35.10 g) and macrogol 6000 (16.20 g) in pure water (403.7 g) to obtain a binder. Amlodipine besylate (10.40 60 321939 201041873 • g), compound in a fluidized bed granulator (1^1>1,?0\^1^ again (:〇.,1^(1.)) B (30.00 g), D-mannitol (25 〇·6 g) and microcrystalline cellulose, (39.00 g) were uniformly mixed, granulated and sprayed with a binder' followed by drying to obtain granules. (16 mesh) A portion of the obtained granules was sieved to obtain a milled granule. (2) A low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added thereto. The ground granules (289.3 g) were mixed in a polyethylene bag (4.9 L) to obtain a mixed granule. (3) The granules obtained as above were used in a rotary tableting machine (VEL-5, 〇Kikusui) In Seisakusho), 6.5 mm direct-controlled punching (spiking pressure: 5kN, weight per spindle: 130 mg) to obtain core lozenges. (4) Cross-linked povidone (57.44 g) and macrogol 6000 (11.52 g) • Dissolved in pure water (375.0 g) to obtain a film coating solution 1. Disperse titanium dioxide (7.680 g), red iron oxide (0.1650 g) and yellow iron oxide (0.5100 g) in pure water (330.0 g) Obtaining Dispersion I. Mixing Coating solution I, dispersion j and pure water (68.25 g) to obtain a film coating solution π. In a film coating machine (dRC__200, ❹POWREX Co., Ltd.), a film coat was uniformly sprayed on the core tablet (120.0 g). Solution II was formed into a film coat to obtain a film-coated tablet having a composition as shown in Table 15 (weight per tablet: 135.154 mg). Example 16 Table 16 Composition of each formulation (135.154 mg) Compound B 10 mg benzenesulfonic acid Amlodipine 6.93 mg --- 321939 61 201041873 (ammonia level, 5 mg) D-mannitol 80.07 mg microcrystalline cellulose 13 mg hydroxypropylcellulose 3.9 mg macrogol 6000 1.8 mg low-substituted hydroxypropyl fiber 13 mg magnesium stearate 1.3 mg crospovidone 3.829 mg titanium dioxide 0.512 mg macrogol 6000 0.768 mg red iron oxide 0.011 mg yellow iron oxide 0.034 mg total 135.154 mg (1) hydroxypropyl cellulose (35.10 g) and Macrogol 6000 (16.20 g) was dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (20.79 g) was added to a fluidized bed granulator (Lab-1, POWREX Co., Ltd.). ), Compound B (30.00 g), D-mannitol (240.2 g) and microcrystalline cellulose (39.00 g) are homogeneous Mixing, granulating mixture was sprayed adhesive solution, and then dried to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule. (2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained milled granules (289.3 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained. 62 321939 201041873 , (3) The mixed granules obtained above were punched in a 6.5 mm diameter in a rotary tableting machine (VEL-5, . Kikusui Seisakusho) (ingot pressure: 5 kN, weight per spindle: 130 Mg) to obtain a core lozenge. (4) The crospovidone (57.44 g) and the macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g), red iron oxide (0.1650 g) and yellow iron oxide (0.5100 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. The film coating solution I, the dispersion ϊ and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, 〇POWREX Co., Ltd.), the film coating solution II was uniformly sprayed on the core tablet (120.0 g) to form a film coat to obtain a composition as shown in Table 16. Membrane ingots (weight per liter: 135.154 mg). Example 17 Table 17 Composition of each formulation (135.119 mg) Compound B 20 mg Amlodipine besylate 3.465 mg (Amlodipine, 2.5 mg) D-mannitol 73.535 mg Microcrystalline cellulose 13 mg Hydroxypropyl Cellulose 3.9 mg macrogol 6000 1.8 mg Low-substituted hydroxypropylcellulose 13 mg Magnesium stearate 1.3 mg 63 321939 201041873 Cross-linked povidone 3.829 mg Titanium dioxide 0.512 mg macrogol 6000 0.768 mg Red iron oxide 0.01 mg Total 135.119 mg ( 1) Dissolve propylcellulose (35.10 lv) and 111&<:1' 〇 吕〇 1 6000 (16.20 g) in pure water (403.7 g) to obtain a binder. Amlodipine besylate (10.40 g), Compound B (60.00 g), D-mannitol (220.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule. (2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained milled granules (289.3 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained. (3) The mixed granules obtained as above were punched with a 6.5 mm diameter punch in a rotary tableting machine (VEL-5, Kikusui Seisakusho) (key press pressure: 5 kN, weight per tablet 130 mg) to obtain a core ingot Agent. (4) The parent solution t-ketone (57.44 g) and macrogol 6000 (11 '52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g) and red iron oxide (0.15 〇〇 g) were dispersed in pure water (33 〇 〇 g) to obtain a dispersion I. The film coating solution I, the dispersion and pure water (68 25 g) were mixed to obtain a film coating solution II. In a film coating machine (DRC-200, p〇WREX Co., Ltd.), a core coating (ηο.ο g) is formed from a film coating solution π μ彡 into a film coating, 64 321 939 201041873, to obtain Film ingots of the composition shown in Table 17 (weight per liter: 135.119 mg). Example 18 Table 18 组成 Composition of each formulation (135.119 mg) Compound B 20 mg Amlodipine besylate 6.93 mg (Amlodipine, 5 mg) D-mannitol 70.07 mg Microcrystalline cellulose 13 mg Hydroxypropyl Cellulose 3.9 mg macrogol 6000 1.8 mg Low-substituted hydroxypropylcellulose 13 mg Magnesium stearate 1.3 mg crospovidone 3.829 mg Titanium dioxide 0.512 mg macrogol 6000 0.768 mg Red iron oxide 0.01 mg Total 135.119 mg (1) Propylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (20.79 g), Compound B (60.00 g), D-mannitol (210.2 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying at 65 321 939 201041873 to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule. (2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained milled granules (289.3 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained. (3) The mixed granules obtained as above were punched in a 6.5 mm diameter in a rotary keying machine (VEL-5, Kikusui Seisakusho) (key press pressure: 5 kN, weight per spindle: 130 mg) to obtain a core ingot Agent. (4) The cross-linked polyglycol g (57.44 g) and macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g) and red iron oxide (0.1500 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a coating solution II. In a film coater (DRC-200, POWREX Co., Ltd.), a film coating solution η was uniformly sprayed on a core bond (120.0 g) to form a film coat, to obtain a film having the composition shown in Table 18 Ingot (weight per plate: 135.119 mg). Example 19 Table 19 Composition of each formulation (135.155 mg) -------- Compound B 40 mg Amlodipine besylate 3.465 mg (Amlodipine, 2.5 mg) D-mannitol 53.535 mg Micro Crystalline cellulose 13 mg 66 321939 201041873 Hydroxypropyl cellulose 3.9 mg macrogol 6000 1.8 mg Low-substituted hydroxypropyl cellulose 13 mg Magnesium stearate 1.3 mg Cross-linked povidone 3.829 mg Titanium dioxide 0.512 mg macrogol 6000 0.768 mg Yellow Iron oxide 0.046 mg Total 135.155 mg (1) Dissolve propyl cellulose (35.10 g) and macrogol 6000 (16.20 g) in pure water (403.7 g) to obtain a binder. Amlodipine besylate (10.40 • g), compound B (120.0 g), D-mannitol (160.6 g) and a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The microcrystalline cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved through a sieve (16 mesh) to prepare a milled granule. (2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained milled granules (289.3 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained. (3) The mixed granules obtained above were suspected by punching at a diameter of 6.5 mm in a rotary tableting machine (VEL-5, Kikusui Seisakusho) (ingot pressure: 51^, weight per key: 13〇11^) To obtain the core blowing agent. (4) Dissolving crospovidone (57.44 g) and macrogol 6000 (11.52 g) 67 321939 201041873 in pure water (375.0 g) to obtain a film coating solution, titanium dioxide (7.680 g) and yellow iron oxide (0.6900) g) Disperse in pure water (330.0 g) to obtain dispersion I. Membrane solution I, dispersion I and pure water (68 25 g) were mixed to obtain a film coating solution II. In a film coating machine (DRC-200, POWREX Co., Ltd.), a film coating was uniformly sprayed on a core suspect (120.0 g) to form a film to obtain a film having the composition shown in Table 19. Sweater (each spin weight: 135.155 mg). Example 20 Composition of Table 20, · Λ t# _ A "--------- Compound B 40 mg ~-__ Shigao's Friends" 1 rr. ' -- Ben ^ 1 Ammonia Level 6.93 Mg (ammonia, 2.5 mg) ------ mannitol 50.07 mg ------- 44/1 曰 Λ amp & 士--- Micro-day fiber often 13 mg --- -- Hydroxypropyl ~- 3.9 mg macrogol 6000 1.8 mg ---- m-substituted propyl fiber sound 13 mg ---------- into B匕匕扣一·- 々更/3曰Warm Town 1.3 mg one ~~~^ *s*r Xi^tk λα ,• One parent% povidone 3.829 mg -I I 1 Record ^ '------- 0.512 mg macrogol 6000 0.768 mg A / 1 ^+ϊ- ^-- KO iron oxide 0.046 mg 5 Ί 135.155 mg 321939 68 201041873 (1) Dissolve light propyl cellulose (35.i〇g) and macrogol 6〇00 (16.20 g) in pure water ( 403_7 g) to obtain a binder. Amlodisulfonate (20.79 g), Compound B (120.0 g), D-mannitol (150.2 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule. (2) Low-substituted hydroxypropylcellulose (32.50 g) and magnesium stearate (3.250 g) were added to the obtained milled granules (289.3 g), and mixed in a polyethylene bag (4.9 L). To obtain mixed granules. (3) The mixed granules obtained above were punched in a rotary spindle (VEL_5, Kikusui Seisakusho) at a diameter of 7.0 mm (ingot pressure: 5 kN, weight per tablet 130 mg) to obtain a core bond Agent. (4) The crospovidone (57.44 g) and the macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution j. Titanium dioxide (7.680 Q S) and yellow iron oxide (Ο·6900 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, POWREX Co., Ltd.), the film coating solution π was uniformly sprayed on the core bond (120.0 g) to form a film coat to obtain a film having the composition shown in Table 20. Ingot (weight per spindle: Π 5.155 mg). Example 21 Table 21 Composition of each formulation (260 mg) 69 321939 201041873 Compound A 8 mg Benzoic acid ammoniapine 6.93 mg (Ammoniapine, 5 mg) D-mannitol 92.554 mg Microcrystalline cellulose 20 mg Lactose hydrate 89.384 mg Corn starch 20 mg Cross-linked poly _ 4 mg Hydroxypropyl cellulose 4 mg macrogol 6000 2.6 mg Croscarmellose sodium 11.2 mg Magnesium stearate 1.3 mg Red iron oxide 0.032 mg Total 260 Mg (1) Dissolved crospovidone (720.0 g) in pure water (9000 g) to obtain a binder I. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion I. Dispersion I and pure water (720.0 g) were mixed in the binder I to obtain a binder II. Amlodipine besylate (1249 g), D-mannitol (16660 g) and microcrystalline cellulose (36〇0 g) in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The mixture is uniformly mixed, the mixture is granulated and the binder II is sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 15 mm history punching sieve in a sieving mill (p_3, Sh〇wa Kagakukikai Co., Ltd.) to prepare a ground granule. 70 321939 201041873 (2) Dissolve propylcellulose (720.0 g) and macrogol 6000 (468.0 g) in pure water (9000 g) to obtain a binder III. Red iron oxide (2'880 was dispersed in pure water (2880 g) to obtain dispersion II. Dispersion II and pure water (720.0 g) were mixed in the binder III to obtain a binder Iv. Compound A (1436 g), lactose hydrate (16〇9〇g) and corn starch (36〇〇g) were uniformly mixed in a bed granulator (FD-S2, POWREX Co" Ltd.' granulation mixture And spraying the binder IV' and then drying to obtain granules. In a sieving mill (p_3, Showa Kagakukikai Co., Ltd.), a part of the obtained granules was ground with a 1.5 mm p punched sieve. Preparation of ground granules II. (3) Cross-linking of sodium methine cellulose (1848 g) and magnesium stearate (214.5

- g) added to the obtained milled granule I (20380 g) and ground granule II (20460 g) on a shoulder mixer (TM20-0-0, Suehiro Kakoki Co.,

Mix in Ltd.) to obtain mixed granules. (4) The mixed granules obtained as above were punched in a rotary ingot machine (AQUARIUS-36K, Kikusui Seisakusho) at a diameter of 8.5 mm (ingot pressure: 10 kN, weight per spindle: 26 〇 mg) A tablet of the composition shown in Table 21 was obtained. Example 22 Table 22 Composition of each formulation (260 mg) Compound A 8 mg Benzoic acid Ammoniapine 6.93 mg 321939 201041873 (Amlodipine, 5 mg) D-mannitol 92.554 mg Microcrystalline cellulose 20 mg Lactose Hydrate 89.384 mg corn starch 20 mg crospovidone 4 mg hydroxypropyl cellulose 4 mg macrogol 6000 2.6 mg croscarmellose cellulose # 5.6 mg carboxymethylcellulose calcium 5.6 mg stearic acid town 1.3 mg Red iron oxide 0.032 mg Total 260 mg (1) Dissolve cross-linked poly _ (72 〇.〇g) in pure water (9000 g) to obtain a binder I. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion enthalpy. The binder I, the dispersion I, and the pure water (720.0 g) were mixed to obtain a binder 11. Amlodipine besylate (1249 g), D-mannitol (1666 〇g) and microcrystalline cellulose (3600 g) in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) Mix evenly, granulate the mixture and spray the binder II' and then dry to obtain granules. In a sieving mill (p_3, sh〇wa Kagakukikai Cc^Ltd.), a part of the obtained granules was ground with a 5 mm p punched sieve to prepare a ground granule 1 〇 (2) Sodium decyl cellulose (924 〇 及 and magnesium stearate 72 321939 201041873 (148.5 g) was added to the obtained ground granule I (20380 g) 'in a roller mixer (TM-60, ShowaKagakukikai Co., Ltd .) Mix in 'to obtain mixed granules I. (3) Dissolve hydroxypropylcellulose (720.0 g) and macrogol 6000 (468.0 g) in pure water (9000 g) to obtain a binder hydrazine. Iron (2.880 g) was dispersed in pure water (2880 g) to obtain dispersion II. Dispersion II and pure water (720.0 g) were mixed in the binder III to obtain a binder IV. In a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The compound 〇A (1436 g), lactose hydrate (16090 g) and corn starch (3600 g) were uniformly mixed, the mixture was granulated and the binder IV was sprayed. Then, it was dried to obtain granules. In a sieving mill (P-3, Showa Kagakukikai Co., Ltd.), a part of the obtained granules was ground with a 1.5 mmp punching sieve to Grinded granules II. (4) Calcium carboxymethylcellulose (924.0 g) and magnesium stearate (66.00 g) were added to the obtained ground granule II (20460 g) in a tumble mixer ( TM-60, q Showa Kagakukikai Co., Ltd.) was mixed to obtain a mixed granule η.

(5) The mixed granule 1 (130 mg) obtained as above and the mixed granule π (ΐ3〇mg) were used in a rotary tableting machine (HT-CVX54LS-UW/C& 3L, HATAIRON WORKS Co" Ltd.) The ingot was punched at a diameter of 8.5 mm (spinning pressure: 9 kN, weight per key: 260 mg) to obtain a multi-layer tablet of the composition shown in Table 22. Example 23 Table 23 Per part (239 mg) Composition 321939 73 201041873 Compound B 40 mg Lactose hydrate 29.3 mg Corn starch 13 mg Microcrystalline cellulose 13 mg Propylcellulose 4 mg macrogol 6000 4 mg Low-substituted hydroxypropylcellulose 13 mg Microcrystalline cellulose 13 mg Magnesium stearate 0.7 mg Amlodipine besylate 6.93 mg (Ammoniapine, 5 mg) D-mannitol 68.94 mg Microcrystalline cellulose 15.33 mg Propylcellulose 3.1 mg Carboxymethylcellulose calcium 5 mg Magnesium stearate 0.7 mg Premix I 9 mg Total 239 mg (1) Hydroxypropyl cellulose (155.0 g) was dissolved in pure water (1395.0 g) to obtain a binder I. In a fluidized bed granulator ( FD-5S, POWREX Co., Ltd.) Ammoniadipine besylate (346.7 g), D-mannitol (2447.0 g) and microcrystalline cellulose (766.7 g) Mixing, granulating the mixture and spraying the binder I, followed by drying to obtain a granule with amlodipine besylate layer. In a sieve mill (P-3, ShowaKagakukikai Co., Ltd.), the obtained 74 321939 201041873 A portion of the granules were ground with a 1.5 mm p punched sieve to obtain a ground granule of amlodipine besylate. (2) Hydroxypropylcellulose (280.1 g) and macrogol 6000 (280.0 g) Dissolved in pure water (2520.2 g) to obtain a binder II. Compound B (2808.4 g), lactose hydrate (2043.5 g) in a fluidized bed granulator (FD-5S, POWREX Co., Ltd.) Corn starch (910.3 g) and microcrystalline cellulose (910.2 g) were uniformly mixed, granulated and sprayed with a binder π, followed by drying to obtain a granule of Compound B. In a screening mill (P- 3, Showa Kagakukikai Co., Ltd.), a part of the obtained granules was ground with a 1.5 mm P punched sieve to obtain a ground granule of the compound B layer. (3) Carboxymethylcellulose calcium (200.0 g) and magnesium stearate (28.000 g) • Added to the obtained amlodipine besylate layer of ground granules (3 7 72.0 g) in a roller mixer (TM-15, Suehiro Kakoki co., Ltd.) was mixed to obtain a mixed granule of a benzoic acid amlodipine layer. (4) A low-substituted hydroxypropylcellulose (455.0 g), microcrystalline cellulose Q (455.1 g) and magnesium stearate (24.53 g) were added to the obtained compound B layer of the ground granule (3616.1 g) It was mixed in a tumble mixer (TM-15, Suehiro Kakoki co., Ltd.) to obtain a mixed granule of the compound B layer. (5) The mixed granule of the amlodipine besylate layer and the mixed granule of the compound B layer obtained as above, in a rotary tableting machine (HT-X12SS-UW & 2L, HATA IRON WORKS Co., Ltd.) The punch was punched with a diameter of 8.0 mm (ingot pressure: 7 kN, weight per spindle: 230 mg (amlodipine besylate: 100 mg; compound B layer: 130 mg)) to obtain a multilayer core tablet. (6) The premix I (252.0 g) was dissolved in pure water (2268.0 g) to obtain a film coating solution of 75 321 939 201041873. In a film coater (DRC-500, POWREX Co., Ltd.), a film coating solution was uniformly sprayed on a core tablet (3120.0 g) to form a film coat to obtain a film coat bond having the composition shown in Table 23 (weight per key: 239 mg). Here, the premix I is a premixed powder. The composition of premix I is shown in Table 23a. Table 23a Composition weight ratio of premix I crospovidone 9.0 macrogol 6000 2.0 titanium dioxide 1.0 yellow iron oxide 0.2 Example 24 Table 24 Composition of each formulation (130 mg) Compound A 8 mg Amlodipine amlodipine 6.93 mg (Ammonia level, 5 mg) D-mannitol 82.666 mg Microcrystalline cellulose 20 mg Hydroxypropyl cellulose 4 mg macrogol 4000 1.8 mg Cross-linked carboxymethyl cellulose Sodium 5.6 mg 76 321939 201041873 Barium stearate 0.9 Mg red iron oxide 0.104 mg total ^--- 130 mg Ο

(1) Propylcellulose (80.00 g) and macrogol 4000 (36.00 g) were dissolved in pure water (1100 g) to obtain a binder I. Red iron oxide (2.080 g) was dispersed in pure water (200.1 g) to obtain a dispersion I. Mix the binder I, the dispersion 1 and the pure water (60.00 g) to obtain the binder II. Amlodipine besylate (24·95 g), Compound A (28.80 g), D·mannitol (297.6 g) and a fluidized bed granulator (Lab, 1, POWREX Co., Ltd.) The microcrystalline cellulose (72·g) was uniformly mixed, the mixture was granulated and a viscous liquid 266 (266·1 g) was sprayed, followed by drying to obtain granules. A portion of the granules to be granulated is sieved with a sieve (a sieve) to prepare a milled granule. (2) conjugated sodium carboxymethyl cellulose (16.81 g) and magnesium stearate (added to the obtained ground granules (370.5 g), and kneaded in a polyethylene bag (4.9 L) to obtain Mixed granules. (3) Mixed granules obtained as above, punched with 8.5 mm long diameter and 5.0 mm short straight punched in a rotary rotary machine (Correct 19K, Ui SeiSakush〇) : 8 5 kN, weight per spindle: 13 () ing) to obtain a tablet of the composition shown in Table 24. Example 2s Table 25 Maternal preparation mg

~~~^UOmg) Composition Compound A 77 321939 201041873 Benzoic Acid Ammoniapine 6.93 mg (Amlodipine, 5 mg) D-mannitol 82.666 mg Microcrystalline Cellulose 20 mg Hydroxypropyl Cellulose 4 mg macrogol 10000 1.8 mg croscarmellose sodium 5.6 mg magnesium stearate 0.9 mg red iron oxide 0.104 mg total 130 mg (1) Hydroxypropyl cellulose (80.00 g) and macrogol 10000 (36.00 g) are dissolved in pure Water (1100 g) was obtained to obtain a binder I. Red iron oxide (2.080 g) was dispersed in pure water (200.1 g) to obtain a dispersion I. The binder I, the dispersion I and the pure water (60.10 g) were mixed to obtain a binder II. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (297.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder 11 (266.1 g) was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule. (2) Add croscarmellose sodium (16.80 g) and magnesium stearate (2.710 g) to the obtained milled granules (370.5 g), and mix in a polyethylene bag (4.9 L) to A mixed granule is obtained. (3) The mixed granules obtained above were punched with 8.5 mm long diameter and 5.0 mm short-diameter punching in a rotary tableting machine (Correct 19K, 78 321939 201041873 • Kikusui Seisakusho) (ingot pressure: 8.5 kN 'per spindle weight: 130 mg) to obtain a prime spinning agent having the composition shown in Table 25. Comparative Example 1 Table 26 Composition of each formulation (130 mg) Compound A 8 mg Amlodipine benzalkonate 6.93 mg (Amlodipine, 5 mg) Lactose hydrate 82.454 mg Corn porridge powder 20 mg Hydroxypropyl cellulose 4 Mg macrogol 6000 2.6 mg Vitamin calcium 5.6 mg Magnesium stearate _ a _m 0.4 mg Red iron oxide ------- 0.016 mg Total---------- 130 mg (1) Will be propyl Cellulose (720.0 g) and macrogol 6000 (468.0 g) were placed in pure water (9000 g) to obtain a binder I. Dissolve red iron oxide (2.880 knives in pure water (2880 g) to obtain dispersion I. Mix viscous liquid I, knives 1 and pure water (720.0 g) to obtain viscous liquid enthalpy. Machine (FD~S2, POWREX Co,, Ltd.) amlodipine besylate (1253 g), compound A (1449 g), lactose hydrate (14830 g) and corn 79 321939 201041873 starch (3600 g) The mixture was uniformly mixed, the mixture was granulated and sprayed with a binder Π 'then dried to obtain granules. In a sieving mill (Ρ-3, Showa Kagakukikai Co., Ltd.), a part of the obtained granules was i. A 5 mm p punched sieve was ground to obtain a milled granule. (2) Carboxymethylcellulose calcium (1848 g) and magnesium stearate (丨32.0 g) were added to the obtained milled granules. (40920 g (2 batches)), mixed in a tumble mixer (TM20-0-0, Suehiro Kakoki co., Ltd.) to obtain mixed granules. (3) Mixed granules obtained as above, in rotation A tableting machine (AQUARIUS-36K, Kikusui Seisakusho) was punched with a 7.0 mm diameter (ingot pressure: 9 kN, weight per spindle: 130 mg) to obtain a tablet of the composition shown in Table 26 Test Example 1 Dissolution test 1 Active ingredient (Compound A) The dissolution properties of the tablets obtained from Examples 1 to 11, 24, 25 and Comparative Example 1 were determined by dissolution test (1.0 (w/w) % Polysorbate 20 solution, 900 mL, 37. (:, Paddle Method, rotation number 50 rpm). Dissolution test according to Japanese Pharmacopoeia, 15th Edition, Dissolution Test, Apparatus 2 (Paddle Method) The results are shown in Table 27. Table 27 shows the average, maximum and minimum values of the dissolution rate 15 minutes after the start of dissolution. Examples 1, 4, 5, 8 to 11, 24, 25 and Comparative Example 1, The average, maximum and minimum values of the glutamine rate of the six bonds were listed, while Examples 2, 3, 6 and 7 listed the average of the dissolution rates of the 12 tablets, 80 321939 201041873 t Maximum and minimum values. Table 27 Sample dissolution rate (%) Average value Minimum value after 15 minutes Comparison Example 1 43 47 39 Example 1 56 60 51 Example 2 78 84 64 Example 3 75 81 70 Implementation Example 4 68 75 61 Example 5 67 72 64 Example 6 74 82 65 Example 7 74 79 69 Example 8 75 80 71 Example 9 74 78 71 Example 10 62 65 57 Example 11 49 56 39 Example 24 75 83 68 Example 25 82 85 75 As shown in Table 27, compared with Comparative Example 1 All of the primes of Examples 1 to 11, 24, 25 containing sugar alcohols as excipients showed excellent solubility properties of Compound A compared to sugar alcohol-containing tablets. Test Example 2 Dissolution test 2 81 321939 201041873 The active ingredient (Compound B) from the dissolution properties of the film-coated ingot obtained in Example 20 was determined by the dissolution test (the Japanese Pharmacopoeia, 15th Edition, 2nd fluid f〇r dissolution test, 900 mL, 370C, slurry, rotation number 50 rpm) evaluation. The dissolution test was carried out according to the Japanese Pharmacopoeia, 15th Edition, Dissolution Test, Apparatus 2 (Paddle Method). The results are shown in Table 28. Table 28 shows the average value, the maximum value, and the minimum value of the dissolution rates of the six bonding agents at each time point from 5 to 60 minutes after the start of the dissolution. Table 28 Measurement time (minutes, after dissolution starts) Dissolution rate (〇/〇) Average value Minimum value 5 34 30 — A 37 10 77 . A 74 81 15 90 88 92 20 92 90 95 25 94 92 — — 96 30 95 ------ 93 a ... 96 45 96 , Μ ------ 94 99 60 97 ----- 95 101 As shown in Table 28, the film B of Example 20 is excellent. Solubility properties. 321939 82 201041873 Test Example 3 Stability test The tablet tablets of Examples 1, 4 and 5 were stored in a sealed glass bottle at 25 ° C / 60% RH for 12 months. The quality of the analog derived from Compound A or amlodipine besylate was measured and the preservation stability was evaluated based on this. The results are shown in Table 29. The values shown in Table 29 are the ratios (%) of all analogs derived from Compound A or amlodipine besylate when Compound A or amlodipine besylate is 100% (Compound A; 8) 〇mg or 4 mg / oxydipine besylate; 6.93 mg or 3.47 mg). Table 29 Sample conditions Analogs derived from Compound A Totally derived from analogs of amlodipine besylate Total Example 1 0.21% 0.12% at the beginning of the test 25°C/60% RH 12 months Preserved product 0.86% 0.18% Example 4 0.49% at the beginning of the test 0.12% 25 ° C / 60% RH 12 months storage product 1.21% 0.21% Example 5 0.48% at the beginning of the test 0.18% 25 ° C / 60% RH12 months Storage product 1.12% 0.29 % As shown in Table 29, the prime bonds of Examples 1, 4 and 5: the agent showed excellent retention of 83 321 939 201041873. Industrial Applicability The present invention provides a solid preparation comprising a compound represented by the formula (1) or a salt thereof, a sugar alcohol, and a calcium antagonist, which suitably controls a compound represented by the formula (I) or a salt thereof in the gastrointestinal tract, and calcium antagonism The dissolution properties of the agent from the solid preparation and maintain its good stability in the solid preparation. The present application is based on the present patent application No. 2009-111381 and 2010-68625, the entire contents of which are incorporated herein by reference. [Simple description of the diagram] None. [Main component symbol description] None 0 84 321939

Claims (1)

201041873 VII. Patent application scope: .. - A solid axis comprising (1) a compound represented by formula (1) or a salt thereof: human C t ^0-R3 • N (I) wherein '2R 4 has deprotonatable The monocyclic nitrogen-containing heterocyclic group 'R of a hydrogen atom' is a filament of the desired clock (4) and r3 is a lower alkyl group which is optionally substituted by a money; (ii) a sugar alcohol and (iii) a calcium antagonist. 2. The solid preparation according to item 1 of the patent application, wherein the compound represented by the formula (1) or a salt thereof is: (cyclohexyloxyoxy)ethyl 2-ethoxy [[ 2 (1Η-tetrazole_5-yl)biphenyl_4_yl]methyl]benzimidazole·7_carboxyindole, ethoxy_1_[[2,-(1H_tetras-5-) Biphenyl) thiol] mercapto HH-benzimidazole _7-carboxylic acid, 2-ethoxylate small [[2,·(4,5•dihydrosoleoxy-1,2,4-anthracene) Defensin _3_yl)biphenyl _4·yl] hydrazinium iιη benzopyrene succinic acid, or a salt thereof. 3. The solid preparation according to claim 1, wherein the compound of the formula (I) or a salt thereof is: anthracene hexyloxyoxy)ethyl 2-ethoxy-1-[[2 '-(1Η-Tetrasin-5-yl)biphenyl-4-yl-methyl]benzimidazole or a salt thereof. 4. The solid preparation of claim S1, wherein the chemical substance represented by the formula (1) or a salt thereof is 2-ethoxylated [[2,_(4,5-diaza_5_side oxygen) Base 1 '2,4-% monoazole-3-yl)biphenyl-4-yl]indenyl]·1H_benzimidazole-7-carboxylic acid or a salt thereof. 321939 85 201041873 5. The solid preparation of claim 1, wherein the sugar alcohol is mannitol, sorbitol or erythritol. 6. The solid preparation of claim 1, wherein the sugar alcohol is mannitol. 7. The solid preparation according to claim 1, wherein the calcium antagonist is azelnidipine, aml〇dipine, aranidipine, efenidipine, Cilendipine, nicardipine, nisoldipine, nitrendipine, nifedipine, niivadipine, barnidipine, non A salt of fei〇dipine, benidipine, manidipine, or the like. 8. The solid preparation according to claim 1, wherein the calcium antagonist is amlodipine or a salt thereof. 9. For example, the solid preparation of claim 1 includes polyethylene glycol. 10. The solid preparation according to claim 9, wherein the polyethylene glycol has a molecular weight of 1,000 to 10,000. A solid preparation comprising (i) 1-(cyclohexyloxycarbonyloxy)ethyl 2_ethoxy-1-[[2'-(1Η-tetrazol-5-yl)biphenyl_4 And the imidazole-7-carboxylate or a salt thereof, (ii) mannitol, and (iii) amlodipine or a salt thereof. 12. A solid preparation comprising (1) 2-ethoxy. ι_[|; 2,-(4,5-dihydroo-oxy-1,2,4-oxadiazol-3-yl) phenyl 4 -yl]methyl]_1Η_stupid imidazole-7-carboxylic acid or a salt thereof, (ii) mannitol, and (iii) amlodipine or a salt thereof. 321939 86 201041873 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: None. There is no schema in this case. % T 5. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: 2 321939