TWI438201B - Solid preparation - Google Patents

Description

固體製劑solid preparations

本發明係有關一種固體製劑，該製劑顯現了來自製劑的藥物之改良溶解性質。The present invention relates to a solid formulation which exhibits improved solubility properties of the drug from the formulation.

高血壓是成人最常發生的疾病之一。根據日本厚生勞動省所作之2000種循環疾病之基礎研究，日本的高血壓患者(收縮壓不低於140 mmHg或舒張壓不低於90 mmHg者，或服用降壓劑者)人數已達約3千1百萬至3千8百萬。高血壓是所有循環疾病(包括腦血管疾病及心肌梗塞)之高危險因子。因此，適當控制血壓，對改善患者的預後及減輕個人和社會的負擔來說都是重要的。Hypertension is one of the most common diseases in adults. According to the basic research of 2000 kinds of circulating diseases made by the Ministry of Health, Labor and Welfare of Japan, the number of hypertensive patients in Japan (with a systolic blood pressure of not less than 140 mmHg or a diastolic blood pressure of not less than 90 mmHg, or taking antihypertensive agents) has reached about 3 Thousands of million to 38 million. Hypertension is a high risk factor for all circulatory diseases, including cerebrovascular disease and myocardial infarction. Therefore, proper control of blood pressure is important to improve the prognosis of patients and reduce the burden on individuals and society.

已研發出多種藥物(例如，減壓利尿劑、α阻斷劑、β阻斷劑、血管收縮素轉化酶(angiotensin converting enzyme，ACE)抑制劑、鈣拮抗劑、血管收縮素II受體拮抗劑等等)作為高血壓的治療藥物，且許多診斷為高血壓的患者係接受此等降壓劑的治療。例如，下列式(I)所示之化合物或其鹽：A variety of drugs have been developed (eg, decompressive diuretics, alpha blockers, beta blockers, angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, angiotensin II receptor antagonists) Etc.) As a therapeutic drug for hypertension, and many patients diagnosed with hypertension are treated with such antihypertensive agents. For example, a compound represented by the following formula (I) or a salt thereof:

(其中R¹ 為具有可去質子化的氫原子之單環含氮雜環基，R² 為視需要經酯化之羧基及R³ 係視需要經取代之低級烷基)便是已知的血管收縮素II受體拮抗劑，其展現優異的降壓效果及器官保護作用。JP-B-2514282便揭露了2-乙氧基-1-[[2’-(1H-四唑-5-基)聯苯-4-基]甲基]苯并咪唑-7-羧酸1-(環己氧基羰氧基)乙酯(坎地沙坦酯(candesartan cilexetil))作為代表性藥劑的實例。(wherein R ¹ is a monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom, R ² is a carboxyl group which is optionally esterified, and a lower alkyl group which is optionally substituted by R ³ ) is known. Angiotensin II receptor antagonist, which exhibits excellent antihypertensive effects and organ protection. JP-B-2514282 discloses 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid 1 - (Cyclohexyloxycarbonyloxy)ethyl ester (candesartan cilexetil) as an example of a representative agent.

根據J-HOME的研究(日本家庭對辦公室血壓測量評估研究)，接受藥物治療的高血壓患者約有40%已達到所要求的血壓(門診病患之隨機血壓低於140/90mmHg)，這表示即使使用現有的藥物治療，仍有部分病患無法充分控制血壓。為提高達到所要求血壓的比例，需要更有效的降壓治療。According to J-HOME's study (Japanese family-to-office blood pressure measurement assessment study), about 40% of hypertensive patients receiving drug therapy have reached the required blood pressure (the random blood pressure of outpatients is less than 140/90mmHg), which means Even with existing medications, some patients are unable to adequately control their blood pressure. In order to increase the proportion of blood pressure required, more effective antihypertensive treatment is needed.

對於發揮更強之降壓效果的藥物治療，可提及使用多種藥物的組合治療。例如，WO01/15674揭露了腎素-血管收縮素抑制劑(rennin-angiotensin inhibitor)和其他降壓劑、降膽固醇藥物、利尿劑等的組合使用。WO02/43807則揭示了血管收縮素II受體拮抗劑和其他降壓劑或士他汀(statin)的組合使用。然而，不同時機服用多種藥劑之組合使用可能對患者的服藥順從性(drug compliance)有不利的影響，而令人擔心因疏忽造成血壓控制失敗。對臨床實務來說，為了更適當地控制血壓，強烈地需要於單一藥劑中含有多種降壓劑之組合製劑，因為其為展現強減壓效果且維持患者之服藥順從性之理想藥劑。For the treatment of drugs that exert a stronger antihypertensive effect, a combination therapy using a plurality of drugs can be mentioned. For example, WO 01/15674 discloses the combined use of a renin-angiotensin inhibitor and other antihypertensive agents, cholesterol lowering drugs, diuretics and the like. WO 02/43807 discloses the combined use of angiotensin II receptor antagonists and other antihypertensive agents or statins. However, the combined use of multiple agents at different times may have an adverse effect on the patient's drug compliance, and may cause fear of inadvertent blood pressure control failure. For clinical practice, in order to more appropriately control blood pressure, it is strongly required to contain a combination preparation of various antihypertensive agents in a single agent because it is an ideal agent that exhibits a strong decompression effect and maintains patient compliance with medication.

含血管收縮素II受體拮抗劑及鈣拮抗劑之組合製劑被推薦作為此組合製劑。WO92/10097揭露了含血管收縮素II受體拮抗劑及其他藥劑(例如，利尿劑、鈣拮抗劑等)之組合製劑。JP-A-2006-290899揭示了含咪唑羧酸酯型血管收縮素II受體拮抗劑(例如，奧美沙坦酯(olmesartan medoxomil)等)及鈣拮抗劑之組合製劑。美國專利第6204281號揭露了含纈沙坦(valsartan，為血管收縮素II受體拮抗劑)及1,4-二氫吡啶化合物(例如，氨氯地平(amlodipine)等，為鈣拮抗劑)等之組合製劑。JP-B-2930252揭示了含2-丁基-4-氯-1-[(2’-(1H-四唑-5-基)聯苯-4-基)甲基]咪唑-5-羧酸或其醫藥上可接受之鹽(其各為血管收縮素II受體拮抗劑)及地爾硫卓(diltiazem，為鈣拮抗劑)的組合製劑。此外，JP-B-3057471則揭露了含苯並咪唑衍生物(為血管收縮素受體拮抗劑)及利尿劑或鈣拮抗劑的組合製劑。A combined preparation containing an angiotensin II receptor antagonist and a calcium antagonist is recommended as the combined preparation. WO 92/10097 discloses a combination preparation comprising an angiotensin II receptor antagonist and other agents (e.g., diuretics, calcium antagonists, etc.). JP-A-2006-290899 discloses a combination preparation containing an imidazole carboxylate type angiotensin II receptor antagonist (for example, olmesartan medoxomil, etc.) and a calcium antagonist. U.S. Patent No. 6,240,281 discloses valsartan (an angiotensin II receptor antagonist) and a 1,4-dihydropyridine compound (for example, amlodipine, etc. as a calcium antagonist). Combination preparation. JP-B-2930252 discloses 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid Or a combination of pharmaceutically acceptable salts thereof, each of which is an angiotensin II receptor antagonist, and diltiazem (a calcium antagonist). Further, JP-B-3057471 discloses a combined preparation containing a benzimidazole derivative (which is an angiotensin receptor antagonist) and a diuretic or calcium antagonist.

臨床實務上，預期含有苯並咪唑衍生物(為血管收縮素II受體拮抗劑)及鈣拮抗劑的製劑，能同時顯現苯並咪唑衍生物(為具有高度器官保護效果之血管收縮素II受體拮抗劑)之功效及鈣拮抗劑(具有強的減壓效果)之功效。此外，因為依其組合方式可使其作用加強且降低副作用，所以其臨床實用性極高。In clinical practice, it is expected that a preparation containing a benzimidazole derivative (which is an angiotensin II receptor antagonist) and a calcium antagonist can simultaneously exhibit a benzimidazole derivative (which is a highly organ protective effect of angiotensin II). The efficacy of a body antagonist and the effect of a calcium antagonist (with a strong decompression effect). In addition, because of its combined manner, its action can be enhanced and side effects are reduced, so its clinical utility is extremely high.

然而，為了能穩固醫藥產物的有效性及安全性，不僅其本身活性成分之有效性及安全性是重要的，醫藥製劑的性質如體內之藥物溶解性質等也極為重要。舉例來說，當藥物自醫藥製劑溶解太慢時，藥物的血中濃度便無法達到有效的水平，且可能無法充分展示其預期功效。另一方面，當藥物自醫藥製劑之溶解太快，藥物的血中濃度會快速攀升，造成副作用的高風險。However, in order to stabilize the effectiveness and safety of the pharmaceutical product, not only the effectiveness and safety of the active ingredient itself are important, but also the nature of the pharmaceutical preparation such as the dissolution property of the drug in the body is extremely important. For example, when the drug dissolves too slowly from the pharmaceutical preparation, the blood concentration of the drug cannot reach an effective level and may not fully demonstrate its intended efficacy. On the other hand, when the drug is dissolved too quickly from the pharmaceutical preparation, the blood concentration of the drug will rise rapidly, causing a high risk of side effects.

換句話說，除了有效性及安全性，醫藥產物需確保具有特定的藥物溶解水平。組合製劑需能符合與各種添加劑及各活性成分所需之不同條件的相容性。因此，與含有單一活性成分之製劑相比，符合所有此等條件之製劑的研發通常是困難的。詳言之，因為苯並咪唑衍生物(為血管收縮素II受體拮抗劑)是難溶性化合物，製劑的溶解性質會因為欲進行組合之添加劑及活性成分的性質而降低。當藥物自投予之組合製劑的延遲釋放時，導致降低藥物吸收性、降低生物可用率(意即，降低活性成分的功效)及降低組合藥劑的價值。因此，對欲實際應用的醫藥製劑來說，需要調整製劑的組成以使活性成分於胃腸道中的溶解率最適化。In other words, in addition to effectiveness and safety, pharmaceutical products need to ensure a specific level of drug dissolution. The combination preparation should be compatible with the various conditions required for the various additives and the respective active ingredients. Therefore, the development of formulations that meet all of these conditions is often difficult compared to formulations containing a single active ingredient. In particular, since the benzimidazole derivative (which is an angiotensin II receptor antagonist) is a poorly soluble compound, the solubility properties of the preparation may be lowered by the nature of the additive to be combined and the active ingredient. When the drug is released from the delayed release of the combined preparation, it results in a decrease in drug absorption, a decrease in bioavailability (i.e., a decrease in the efficacy of the active ingredient), and a decrease in the value of the combination agent. Therefore, for a pharmaceutical preparation to be practically applied, it is necessary to adjust the composition of the preparation to optimize the dissolution rate of the active ingredient in the gastrointestinal tract.

因此，本發明之一目的為提供一種穩定含有苯並咪唑衍生物(具血管收縮素II受體拮抗劑作用)及鈣拮抗劑的固體製劑，其係經控制以於胃腸道中使此等藥物自製劑的溶解性質最適化。Accordingly, it is an object of the present invention to provide a solid preparation containing a benzimidazole derivative (with angiotensin II receptor antagonist action) and a calcium antagonist which is controlled to cause such drugs in the gastrointestinal tract. The solubility properties of the formulation are optimized.

本案發明人進行了密集的研究，企圖解決上述的問題，並因此發現包括(i)式(I)所示之化合物或其鹽、(ii)糖醇以及(iii)鈣拮抗劑之製劑，該製劑在人類胃腸道中展現適當控制之溶解性質。具體而言，他們已特別注意賦形劑，並發現藥物自固體製劑的溶解性質可藉由使用高水溶性糖醇而改善，因而得完成本發明。The inventors of the present invention conducted intensive studies in an attempt to solve the above problems, and thus found a preparation comprising (i) a compound represented by the formula (I) or a salt thereof, (ii) a sugar alcohol, and (iii) a calcium antagonist, The formulation exhibits suitably controlled solubility properties in the human gastrointestinal tract. Specifically, they have paid particular attention to excipients, and found that the solubility properties of the drug from the solid preparation can be improved by using a highly water-soluble sugar alcohol, and thus the present invention has been completed.

因此，本發明係關於[1]固體製劑，其包括(i)式(I)所示之化合物或其鹽： (其中R¹ 為具有可去質子化的氫原子之單環含氮雜環基，R² 為視需要經酯化之羧基及R³ 為視需要經取代之低級烷基)、(ii)糖醇以及(iii)鈣拮抗劑；[1A]上述[1]之固體製劑，其中，R² 為視需要經具有碳數為1至4之低級烷基(其視需要經選自下列之1至3個取代基所取代：羥基、胺基、鹵素原子、具碳數為2至6之低級烷醯氧基、具碳數為4至7之低級環烷醯氧基、具有碳數為1至6之低級烷氧基的羰氧基、具有碳數為3至7之低級環烷氧基的羰氧基，以及具碳數為1至4之低級烷氧基)酯化的羧基；[1B]上述[1]之固體製劑，其中，R² 為1-(環己氧基羰氧基)乙氧基羰基或羧基；[2]上述[1]、[1A]或[1B]之固體製劑，其中，式(I)所示之化合物或其鹽為2-乙氧基-1-[[2’-(1H-四唑-5-基)聯苯-4-基]甲基]苯并咪唑 -7-羧酸1-(環己氧基羰氧基)乙酯、2-乙氧基-1-[[2’-(1H-四唑-5-基)聯苯-4-基]甲基]-1H-苯并咪唑-7-羧酸、2-乙氧基-1-[[2’-(4,5-二氫-5-氧-1,2,4-二唑-3-基)聯苯-4-基]甲基]-1H-苯并咪唑-7-羧酸或其鹽；[3]上述[1]、[2]、[1A]或[1B]之固體製劑，其中，式(I)所示之化合物或其鹽為2-乙氧基-1-[[2’-(1H-四唑-5-基)聯苯-4-基]甲基]苯并咪唑-7-羧酸1-(環己氧基羰氧基)乙酯或其鹽；[4]上述[1]、[2]、[1A]或[1B]之固體製劑，其中，式(I)所示之化合物或其鹽為2-乙氧基-1-[[2’-(4,5-二氫-5-氧-1,2,4-二唑-3-基)聯苯-4-基]甲基]-1H-苯并咪唑-7-羧酸或其鹽；[5]上述[1]、[2]、[3]、[4]、[1A]或[1B]之固體製劑，其中，糖醇為甘露糖醇、山梨糖醇或赤藻糖醇；[6]上述[1]、[2]、[3]、[4]、[5]、[1A]或[1B]之固體製劑，其中，糖醇為甘露糖醇；[7]上述[1]、[2]、[3]、[4]、[5]、[6]、[1A]或[1B]之固體製劑，其中，鈣拮抗劑為阿折地平(azelnidipine)、氨氯地平(amlodipine)、阿雷地平(aranidipine)、依福地平(efonidipine)、西尼地平(cilnidipine)、尼卡地平(nicardipine)、尼索地平(nisoldipine)、尼群地平(nitrendipine)、硝苯地平(nifedipine)、尼伐地平(nilvadipine)、巴尼地平(barnidipine)、非洛地平(felodipine)、貝尼地平(benidipine)、馬尼地平 (manidipine)或其鹽；[8]上述[1]、[2]、[3]、[4]、[5]、[6]、[7]、[1A]或[1B]之固體製劑，其中，鈣拮抗劑為氨氯地平或其鹽；[9]上述[1]、[2]、[3]、[4]、[5]、[6]、[7]、[8]、[1A]或[1B]之固體製劑，復包括聚乙二醇；[10]上述[9]之固體製劑，其中，聚乙二醇具有1,000至10,000的分子量；[11]固體製劑，其包括(i)2-乙氧基-1-[[2’-(1H-四唑-5-基)聯苯-4-基]甲基]苯并咪唑-7-羧酸1-(環己氧基羰氧基)乙酯或其鹽、(ii)甘露糖醇以及(iii)氨氯地平或其鹽；[11A]上述[11]之固體製劑，復包括聚乙二醇；[11B]上述[11A]之固體製劑，其中，聚乙二醇具有1,000至10,000的分子量(較佳為3,000至10,000)；[11C]上述[11B]之固體製劑，其中，聚乙二醇的含量為1至5重量%；[11D]上述[11B]之固體製劑，其中，聚乙二醇的含量為1至3重量%；[12]固體製劑，其包括(i)2-乙氧基-1-[[2’-(4,5-二氫-5-氧-1,2,4-二唑-3-基)聯苯-4-基]甲基]-1H-苯并咪唑-7-羧酸或其鹽、(ii)甘露糖醇以及(iii)氨氯地平或其鹽；[12A]上述[12]之固體製劑，復包括聚乙二醇；[12B]上述[12A]之固體製劑，其中，聚乙二醇具有1,000至10,000的分子量(較佳為3,000至10,000)；Accordingly, the present invention relates to [1] a solid preparation comprising (i) a compound of the formula (I) or a salt thereof: (wherein R ¹ is a monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom, R ² is a carboxyl group which is optionally esterified, and R ³ is a lower alkyl group which may be optionally substituted), (ii) a sugar The solid preparation of the above [1], wherein R ² is a lower alkyl group having a carbon number of 1 to 4 as needed (which is optionally selected from the following 1 to Substituted by three substituents: a hydroxyl group, an amine group, a halogen atom, a lower alkyl alkoxy group having a carbon number of 2 to 6, a lower cycloalkyloxy group having a carbon number of 4 to 7, and having a carbon number of 1 to a carbonyloxy group of a lower alkoxy group of 6, a carbonyloxy group having a lower cycloalkoxy group having 3 to 7 carbon atoms, and a carboxyl group esterified with a lower alkoxy group having 1 to 4 carbon atoms; [1B The solid preparation of the above [1], wherein R ² is a 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl group or a carboxyl group; [2] the solid preparation of the above [1], [1A] or [1B] Wherein the compound of the formula (I) or a salt thereof is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzo Imidazole-7-carboxylic acid 1-(cyclohexyloxycarbonyloxy)ethyl ester, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl] Methyl]-1H-benzimidazole-7 -carboxylic acid, 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4- Azoxa-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof; [3] above [1], [2], [1A] or [1B A solid preparation wherein the compound of the formula (I) or a salt thereof is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]- 1-(cyclohexyloxycarbonyloxy)ethyl ester of benzimidazole-7-carboxylic acid or a salt thereof; [4] The solid preparation of the above [1], [2], [1A] or [1B], Wherein the compound of the formula (I) or a salt thereof is 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4- Azoxa-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof; [5] above [1], [2], [3], [4] The solid preparation of [1A] or [1B], wherein the sugar alcohol is mannitol, sorbitol or erythritol; [6] the above [1], [2], [3], [4] The solid preparation of [5], [1A] or [1B], wherein the sugar alcohol is mannitol; [7] the above [1], [2], [3], [4], [5], [ 6) The solid preparation of [1A] or [1B], wherein the calcium antagonist is azelnidipine, amlodipine, aranidipine, efonidipine, sini Lidnidipine, nicardipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, barnidipine, felodipine (felodipine), benidipine, manidipine or its salt; [8] above [1], [2], [3], [4], [5], [6], [ 7] The solid preparation of [1A] or [1B], wherein the calcium antagonist is amlodipine or a salt thereof; [9] the above [1], [2], [3], [4], [5] , [6], [7], [8], [1A] or [1B] solid system [10] The solid preparation of the above [9], wherein the polyethylene glycol has a molecular weight of 1,000 to 10,000; [11] a solid preparation comprising (i) 2-ethoxy- 1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid 1-(cyclohexyloxycarbonyloxy)ethyl ester or a solid preparation of the above [11], which comprises a polyethylene glycol; [11B] a solid preparation of the above [11A], wherein The polyethylene glycol has a molecular weight of 1,000 to 10,000 (preferably 3,000 to 10,000); [11C] The solid preparation of the above [11B], wherein the content of the polyethylene glycol is from 1 to 5% by weight; [11D] above [ a solid preparation of 11B], wherein the content of the polyethylene glycol is 1 to 3% by weight; [12] a solid preparation comprising (i) 2-ethoxy-1-[[2'-(4,5- Dihydro-5-oxo-1,2,4- Azoxa-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof, (ii) mannitol, and (iii) amlodipine or a salt thereof; 12A] The solid preparation of the above [12], which comprises a polyethylene glycol; [12B] The solid preparation of the above [12A], wherein the polyethylene glycol has a molecular weight of 1,000 to 10,000 (preferably 3,000 to 10,000);

[12C]上述[12B]之固體製劑，其中，聚乙二醇的含量為1至5重量%；[12] The solid preparation of the above [12B], wherein the content of the polyethylene glycol is from 1 to 5% by weight;

[12D]上述[12B]之固體製劑，其中，聚乙二醇的含量為1至3重量%；[12D] The solid preparation of the above [12B], wherein the content of the polyethylene glycol is from 1 to 3% by weight;

[13]上述[1]、[2]、[3]、[4]、[5]、[6]、[7]、[8]、[9]、[10]、[11]、[12]、[1A]、[1B]、[11A]、[11B]、[11C]、[11D]、[12A]、[12B]、[12C]或[12D]之固體製劑為錠劑；[13] above [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12 a solid preparation of [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D] is a tablet;

[14]上述[1]、[2]、[3]、[4]、[5]、[6]、[7]、[8]、[9]、[10]、[11]、[12]、[1A]、[1B]、[11A]、[11B]、[11C]、[11D]、[12A]、[12B]、[12C]或[12D]之固體製劑為單層錠劑；[14] above [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12 a solid preparation of [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D] is a single layer tablet;

[15]上述[1]、[2]、[3]、[4]、[5]、[6]、[7]、[8]、[9]、[10]、[11]、[12]、[13]、[14]、[1A]、[1B]、[11A]、[11B]、[11C]、[11D]、[12A]、[12B]、[12C]或[12D]之固體製劑為高血壓、心衰竭、糖尿病腎病變或動脈硬化之預防藥物或治療藥物；[15] above [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12 ], [13], [14], [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D] The solid preparation is a prophylactic or therapeutic drug for hypertension, heart failure, diabetic nephropathy or arteriosclerosis;

[16]上述[1]、[2]、[3]、[4]、[5]、[6]、[7]、[8]、[9]、[10]、[11]、[12]、[13]、[14]、[1A]、[1B]、[11A]、[11B]、[11C]、[11D]、[12A]、[12B]、[12C]或[12D]之固體製劑為高血壓等之預防藥物或治療藥物；及類似者。[16] above [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12 ], [13], [14], [1A], [1B], [11A], [11B], [11C], [11D], [12A], [12B], [12C] or [12D] The solid preparation is a prophylactic or therapeutic drug for hypertension or the like; and the like.

根據本發明，可獲得一種固體製劑，其中上述式(I)所示之化合物(或其鹽)及鈣拮抗劑於胃腸道中自製劑之溶解係經適當控制，且精細地維持其於製劑中之安定性。也就是說，本發明之固體製劑在上述式(I)所示之化合物或其鹽及鈣拮抗劑自製劑溶解之性質及其安定性方面表現優異。According to the present invention, a solid preparation can be obtained, wherein the compound of the above formula (I) (or a salt thereof) and the calcium antagonist are appropriately controlled in the gastrointestinal tract from the dissolution of the preparation, and are finely maintained in the preparation. Stability. That is, the solid preparation of the present invention is excellent in the properties of the compound represented by the above formula (I) or a salt thereof and a calcium antagonist dissolved from the preparation and its stability.

本發明之固體製劑將詳述如下。The solid preparation of the present invention will be described in detail below.

本發明之固體製劑為包括下列者之固體製劑：The solid preparation of the present invention is a solid preparation including the following:

(i)下式(I)所示之化合物或其鹽：(i) a compound represented by the following formula (I) or a salt thereof:

其中R¹ 為具有可去質子化的氫原子之單環含氮雜環基，R² 為視需要經酯化之羧基及R³ 為視需要經取代之低級烷基；(ii)糖醇；以及(iii)鈣拮抗劑(後文中亦稱為本發明之固體製劑)。Wherein R ¹ is a monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom, R ² is a carboxyl group which is optionally esterified, and R ³ is a lower alkyl group which is optionally substituted; (ii) a sugar alcohol; And (iii) a calcium antagonist (hereinafter also referred to as a solid preparation of the present invention).

於上述式(I)中，作為R¹ 之具有可去質子化的氫原子之單環含氮雜環基者，例如可為四唑基及下式所示之基團等：In the above formula (I), the monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom as R ¹ may, for example, be a tetrazolyl group or a group represented by the following formula:

其中，i為-O-或-S-，j為>C=O、>C=S或>S(O)_m Where i is -O- or -S-, j is >C=O, >C=S or >S(O) _m

其中，m為0、1或2。較佳的基團可為四唑基、4,5-二氫-5-側氧基-1,2,4-二唑-3-基等。Where m is 0, 1, or 2. Preferred groups may be tetrazolyl, 4,5-dihydro-5-sideoxy-1,2,4- Diazol-3-yl and the like.

4,5-二氫-5-側氧基-1,2,4-二唑-3-基含有如下式所示之3個互變異構物(a’、b’及c’)：4,5-dihydro-5-sideoxy-1,2,4- The oxazol-3-yl group contains three tautomers (a', b' and c') as shown in the following formula:

且該4,5-二氫-5-側氧基-1,2,4-二唑-3-基包含所有上述之a’、b’及c’。And the 4,5-dihydro-5-sideoxy-1,2,4- The oxazol-3-yl group includes all of the above a', b' and c'.

上述式(I)中，R² 之視需要經酯化之羧基的實例包括視需要經具有碳數為1至4之低級烷基酯化的羧基。上述之低級烷基可視需要經選自下列所組成群組中之1至5個(較佳為1至3個)取代基所取代：羥基、胺基、鹵素原子、具碳數為2至6之低級烷醯氧基(例如：乙醯氧基(acetyloxy group)、三甲基乙醯氧基(pivaloyloxy group)等)、具碳數為4至7之低級環烷醯氧基、具有碳數為1至6之低級烷氧基的羰氧基(例如：甲氧基羰氧基、乙氧基羰氧基等)、具有碳數為3至7之低級環烷氧基的羰氧基(例如：環己氧基羰氧基等)以及具碳數為1至4之低級烷氧基。較佳的基團可為1-(環己氧基羰氧基)乙氧基羰基及羧基等等。In the above formula (I), examples of the carboxyl group which is required to be esterified by R ² include a carboxyl group which is esterified with a lower alkyl group having a carbon number of 1 to 4 as necessary. The above lower alkyl group may be optionally substituted with 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of a hydroxyl group, an amine group, a halogen atom, and a carbon number of 2 to 6 a lower alkyl alkoxy group (for example, acetyloxy group, pivaloyloxy group, etc.), a lower cycloalkyloxy group having a carbon number of 4 to 7, and having a carbon number a carbonyloxy group of a lower alkoxy group of 1 to 6 (for example, a methoxycarbonyloxy group, an ethoxycarbonyloxy group, etc.), a carbonyloxy group having a lower cycloalkyloxy group having a carbon number of 3 to 7 ( For example, a cyclohexyloxycarbonyloxy group or the like) and a lower alkoxy group having a carbon number of 1 to 4. Preferred groups may be 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, carboxy and the like.

上述式(I)中，作為R³ 之視需要經取代之低級烷基可為具有碳數為1至5之低級烷基，其可視需要經選自下列所組成群組中之1至5個(較佳為1至3個)取代基所取代：羥基、胺基、鹵素原子、碳數為1至4之低級烷氧基。較佳為碳數為2至3之低級烷基，更佳為乙基。In the above formula (I), the lower alkyl group which is required to be substituted as R ³ may be a lower alkyl group having a carbon number of 1 to 5, which may optionally be one to five selected from the group consisting of the following: The substituent (preferably 1 to 3) is substituted with a hydroxyl group, an amine group, a halogen atom, and a lower alkoxy group having 1 to 4 carbon atoms. It is preferably a lower alkyl group having 2 to 3 carbon atoms, more preferably an ethyl group.

上述式(I)所示之化合物的鹽僅需為醫藥上可接受之鹽，且例如可提及式(I)所示之化合物與無機鹼所形成之鹽、與有機鹼所形成之鹽、與無機酸所形成之鹽、與有機酸所形成之鹽、與鹼性或酸性胺基酸所形成之鹽等。與無機鹼所形成之鹽的較佳實例包含：鹼金屬鹽類，諸如鈉鹽、鉀鹽等；鹼土金屬鹽類，諸如鈣鹽、鎂鹽等；鋁鹽；銨鹽等。與有機鹼所形成之鹽的較佳實例包含：與三甲基胺、三乙基胺、吡啶、甲基吡啶(picoline)、乙醇胺、二乙醇胺、三乙醇胺、二環己胺、N,N'-二苄基伸乙基二胺等所形成之鹽。與無機酸所形成之鹽的較佳實例包含：與鹽酸、氫溴酸、硝酸、硫酸、磷酸等所形成之鹽。與有機酸所形成之鹽的較佳實例包含：與甲酸、乙酸、三氟乙酸、反丁烯二酸、草酸、酒石酸、順丁烯二酸、檸檬酸、琥珀酸、蘋果酸、甲磺酸、苯磺酸、對甲苯磺酸等所形成之鹽。與鹼性胺基酸所形成之鹽的較佳實例包含：與精胺酸、離胺酸、鳥胺酸等所形成之鹽。與酸性胺基酸所形成之鹽的較佳實例包含：與天冬胺酸、麩胺酸等所形成之鹽。The salt of the compound represented by the above formula (I) is only required to be a pharmaceutically acceptable salt, and, for example, a salt formed of the compound represented by the formula (I) and an inorganic base, a salt formed with an organic base, or the like, a salt formed with an inorganic acid, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, or the like. Preferable examples of the salt formed with the inorganic base include: alkali metal salts such as sodium salts, potassium salts and the like; alkaline earth metal salts such as calcium salts, magnesium salts and the like; aluminum salts; ammonium salts and the like. Preferred examples of the salt formed with the organic base include: with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N' - a salt formed by dibenzyl exoethyl diamine or the like. Preferred examples of the salt formed with the inorganic acid include a salt formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid or the like. Preferred examples of the salt formed with an organic acid include: with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid a salt formed by benzenesulfonic acid, p-toluenesulfonic acid or the like. Preferred examples of the salt formed with the basic amino acid include salts formed with arginine, lysine, ornithine, and the like. Preferred examples of the salt formed with the acidic amino acid include salts formed with aspartic acid, glutamic acid and the like.

上述式(I)所示之化合物或其鹽可為水合物或非水合物，且可為溶劑合物或非溶劑合物。The compound represented by the above formula (I) or a salt thereof may be a hydrate or a non-hydrate, and may be a solvate or an unsolvate.

此外，上述式(I)所示之化合物或其鹽較佳係呈結晶形式，且具有100℃至250℃之融點，較佳為120℃至200℃，尤其是130℃至180℃之融點。Further, the compound represented by the above formula (I) or a salt thereof is preferably in a crystalline form and has a melting point of from 100 ° C to 250 ° C, preferably from 120 ° C to 200 ° C, especially from 130 ° C to 180 ° C. point.

作為本發明之固體製劑，係使用上述式(I)所示之化合物或其鹽。該化合物或其鹽的較佳實例包括：2-乙氧基-1-[[2’-(1H-四唑-5-基)聯苯-4-基]甲基]苯并咪唑-7-羧酸1-(環己氧基羰氧基)乙酯、 2-乙氧基-1-[[2’-(1H-四唑-5-基)聯苯-4-基]甲基]-1H-苯并咪唑-7-羧酸、2-乙氧基-1-[[2’-(1H-四唑-5-基)聯苯-4-基]甲基]-1H-苯并咪唑-7-羧酸三甲基乙醯氧基甲酯、2-乙氧基-1-[[2’-(4,5-二氫-5-側氧基-1,2,4-二唑-3-基)聯苯-4-基]甲基]-1H-苯并咪唑-7-羧酸及其鹽。其中，特佳為2-乙氧基-1-[[2’-(1H-四唑-5-基)聯苯-4-基]甲基]苯并咪唑-7-羧酸1-(環己氧基羰氧基)乙酯及其鹽、2-乙氧基-1-[[2’-(4,5-二氫-5-側氧基-1,2,4-二唑-3-基)聯苯-4-基]甲基]-1H-苯并咪唑-7-羧酸及其鹽。As the solid preparation of the present invention, a compound represented by the above formula (I) or a salt thereof is used. Preferable examples of the compound or a salt thereof include: 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7- 1-(Cyclohexyloxycarbonyloxy)ethyl carboxylate, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]- 1H-benzimidazole-7-carboxylic acid, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole -7-carboxylic acid trimethylacetoxymethyl ester, 2-ethoxy-1-[[2'-(4,5-dihydro-5-pentaoxy-1,2,4- Azoxa-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid and salts thereof. Among them, particularly preferred is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid 1-(cyclo) Hexyloxycarbonyloxy)ethyl ester and its salt, 2-ethoxy-1-[[2'-(4,5-dihydro-5-o-oxy-1,2,4- Azoxa-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid and salts thereof.

於本發明中，上述式(I)所示之化合物或其鹽係以0.1至60重量%，較佳為1至40重量%，更佳為3至30重量%的比例(以游離形式為基準計)包含在本發明之固體製劑中。In the present invention, the compound represented by the above formula (I) or a salt thereof is used in a ratio of 0.1 to 60% by weight, preferably 1 to 40% by weight, more preferably 3 to 30% by weight (based on the free form) It is included in the solid preparation of the present invention.

作為用於本發明之糖醇，可使用任何種類的糖醇，只要該糖醇能同時建立上述式(I)所示之化合物或其鹽於製劑中的安定性及其自製劑之溶解性質，並且能用於醫藥產物。用於本發明之糖醇的實例包括：單醣糖醇類，如丁醣醇(例如，赤藻糖醇、D-蘇糖醇(D-threitol)、L-蘇糖醇等)、戊五醇(例如，D-***糖醇、木糖醇等)、己糖醇(例如，D-艾杜糖醇、半乳糖醇(甜醇)、D-葡萄糖醇(山梨糖醇)、甘露糖醇、環糖醇(例如，環己六醇等)等；雙醣糖醇類，如氫化麥芽糖、乳糖醇(lactitol)、還原巴拉金糖(reduced paratinose，巴糖醇(isomalt))等；寡醣糖醇類，如新戊四醇、氫化麥芽糖澱粉糖漿等；等等。其中以單醣糖醇類為佳。更佳為甘露糖醇、山梨糖醇及赤藻糖醇。特別是以甘露糖醇為佳，而D-甘露糖醇為特佳。可單獨使用一種糖醇，或組合使用兩種或更多種的糖醇。此外，糖醇能同時實現鈣拮抗劑於製劑中的安定性及其自製劑之溶解性質質。As the sugar alcohol to be used in the present invention, any kind of sugar alcohol can be used as long as the sugar alcohol can simultaneously establish the stability of the compound represented by the above formula (I) or a salt thereof in the preparation and the dissolution property thereof from the preparation, And can be used in pharmaceutical products. Examples of the sugar alcohol to be used in the present invention include: monosaccharide sugar alcohols such as butanol (for example, erythritol, D-threitol, L-threitol, etc.), penta-5 Alcohols (eg, D-arabitol, xylitol, etc.), hexitols (eg, D-iditol, galactitol (sweet alcohol), D-glucitol (sorbitol), mannitol , a cyclic sugar alcohol (for example, cyclohexanol, etc.), etc.; a disaccharide sugar alcohol such as hydrogenated maltose, lactitol, reduced paratinose (isomalt), etc.; Sugar sugar alcohols, such as neopentyl alcohol, hydrogenated maltose starch syrup, etc.; among them, monosaccharide sugar alcohols are preferred. More preferably mannitol, sorbitol and erythritol, especially nectar Sugar alcohol is preferred, and D-mannitol is particularly preferred. A sugar alcohol can be used alone, or two or more sugar alcohols can be used in combination. In addition, the sugar alcohol can simultaneously achieve the stability of the calcium antagonist in the preparation. Sex and its self-formulation solubility properties.

於本發明中，糖醇係以15至85重量%，較佳為20至80重量%，更佳為25至75重量%的比例包含在本發明之固體製劑中。In the present invention, the sugar alcohol is contained in the solid preparation of the present invention in a proportion of 15 to 85% by weight, preferably 20 to 80% by weight, more preferably 25 to 75% by weight.

用於本發明之鈣拮抗劑的實例包括：二氫吡啶化合物，例如，阿折地平、氨氯地平、阿雷地平、依福地平、西尼地平、尼卡地平、尼索地平、尼群地平、硝苯地平、尼伐地平、巴尼地平、非洛地平、貝尼地平、馬尼地平等；苯二氮平(benzodiazepine)化合物，例如，迪太贊(diltiazem)等；等等。用於本發明之鈣拮抗劑亦包含前述作為鈣拮抗劑者之鹽類。Examples of calcium antagonists for use in the present invention include: dihydropyridine compounds, for example, adipine, amlodipine, adipine, efavidipine, cilnidipine, nicardipine, nisoldipine, nitrendipine , nifedipine, nilvadipine, bainidipine, felodipine, benidipine, mandipine; benzodiazepine compounds, for example, diltiazem, etc.; Calcium antagonists for use in the present invention also include the aforementioned salts as calcium antagonists.

作為用於本發明之鈣拮抗劑，較佳為二氫吡啶化合物，特別是氨氯地平或其鹽。其中，更佳為氨氯地平之鹽，特佳為苯磺酸氨氯地平(amlodipine besylate)。As the calcium antagonist used in the present invention, a dihydropyridine compound, particularly amlodipine or a salt thereof, is preferred. Among them, a salt of amlodipine is more preferred, and amlodipine besylate is particularly preferred.

於本發明中，鈣拮抗劑係以通常為0.05至60重量%，較佳為0.1至40重量%，更佳為0.5至20重量%的比例(以游離形式為基準計)包含在本發明之固體製劑中。具體而言，例如，氨氯地平之含量比例(以游離形式為基準計)通常為0.05至60重量%，較佳為0.1至40重量%，更佳為0.5至20重量%。In the present invention, the calcium antagonist is included in the present invention in a ratio of usually from 0.05 to 60% by weight, preferably from 0.1 to 40% by weight, more preferably from 0.5 to 20% by weight, based on the free form. In solid preparations. Specifically, for example, the content ratio of amlodipine (based on the free form) is usually from 0.05 to 60% by weight, preferably from 0.1 to 40% by weight, more preferably from 0.5 to 20% by weight.

本發明之固體製劑可復包含伸烷基氧化物聚合物(alkylene oxide polymer)。伸烷基氧化物聚合物的實例包括：伸乙基氧化物聚合物、伸丙基氧化物聚合物、三亞甲基氧化物(trimethylene oxide)聚合物或四氫呋喃或類似者(較佳為伸乙基氧化物聚合物)。伸烷基氧化物聚合物的分子量較佳為1,000至10,000，更佳為3,000至10,000。伸烷基氧化物聚合物可為伸烷基氧化物共聚物，伸烷基氧化物共聚物的實例包括2種或更多種前述伸烷基氧化物之共聚物，其具有1,000至10,000(較佳為3,000至10,000)的分子量。The solid preparation of the present invention may further comprise an alkylene oxide polymer. Examples of the alkylene oxide polymer include a stretched ethyl oxide polymer, a propylated oxide polymer, a trimethylene oxide polymer or tetrahydrofuran or the like (preferably an ethylidene group). Oxide polymer). The molecular weight of the alkylene oxide polymer is preferably from 1,000 to 10,000, more preferably from 3,000 to 10,000. The alkylene oxide polymer may be an alkylene oxide copolymer, and examples of the alkylene oxide copolymer include copolymers of two or more of the foregoing alkylene oxides, which have from 1,000 to 10,000 (more) A molecular weight of preferably 3,000 to 10,000).

可單獨使用一種伸烷基氧化物聚合物，或組合使用兩種或更多種的伸烷基氧化物聚合物。An alkylene oxide polymer may be used alone or in combination of two or more alkylene oxide polymers.

作為用於本發明之伸烷基氧化物聚合物，較佳為聚乙二醇，更佳為分子量為1,000至10,000的聚乙二醇，特佳為分子量為3,000至10,000的聚乙二醇(例如，聚乙二醇4000、聚乙二醇6000、聚乙二醇10000)。As the alkylene oxide polymer used in the present invention, polyethylene glycol is preferred, polyethylene glycol having a molecular weight of 1,000 to 10,000 is more preferred, and polyethylene glycol having a molecular weight of 3,000 to 10,000 is particularly preferred. For example, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 10000).

於本發明中，伸烷基氧化物聚合物係以較佳為1至5重量%，更佳為1至3重量%的比例包含在本發明之固體製劑中。In the present invention, the alkylene oxide polymer is contained in the solid preparation of the present invention in a proportion of preferably from 1 to 5% by weight, more preferably from 1 to 3% by weight.

本發明之固體製劑的較佳具體實施例包含：固體製劑，其中，上述式(I)所示之化合物或其鹽為2-乙氧基-1-[[2’-(1H-四唑-5-基)聯苯-4-基]甲基]苯并咪唑-7-羧酸1-(環己氧基羰氧基)乙酯(後文中有時稱為“化 合物A”)或其鹽，且鈣拮抗劑為苯磺酸氨氯地平；固體製劑，其中，上述式(I)所示之化合物或其鹽為2-乙氧基-1-[[2’-(4,5-二氫-5-側氧基-1,2,4-二唑-3-基)聯苯-4-基]甲基]-1H-苯并咪唑-7-羧酸(後文中有時稱為“化合物B”)或其鹽，且鈣拮抗劑為苯磺酸氨氯地平；等等。A preferred embodiment of the solid preparation of the present invention comprises: a solid preparation wherein the compound represented by the above formula (I) or a salt thereof is 2-ethoxy-1-[[2'-(1H-tetrazole- 1-(cyclohexyl-4-yl)methyl]benzimidazole-7-carboxylic acid 1-(cyclohexyloxycarbonyloxy)ethyl ester (hereinafter sometimes referred to as "Compound A") or a salt thereof And the calcium antagonist is amlodipine besylate; a solid preparation, wherein the compound represented by the above formula (I) or a salt thereof is 2-ethoxy-1-[[2'-(4,5-di) Hydrogen-5-sideoxy-1,2,4- Azoxa-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (hereinafter sometimes referred to as "Compound B") or a salt thereof, and the calcium antagonist is benzene Amlodipine sulfonate; and so on.

作為本發明之固體製劑，例如可為適於口服之固體製劑如：錠劑、粒劑(granule)、細粒劑(fine granule)、囊劑(capsule)、丸劑(pill)等等，較佳為錠劑，更佳為單層錠劑。當本發明之固體製劑為錠劑時，其形式可為圓形、橢圓形、矩形等等中的任一者。錠劑尺寸可依錠劑形式(圓形、橢圓形錠(caplet)、矩形等等)改變，任何尺寸都是可能的只要患者容易服用即可。當本發明之固體製劑為單層錠劑時，因其錠劑尺寸小，所以很容易服用。The solid preparation of the present invention may, for example, be a solid preparation suitable for oral administration such as a tablet, a granule, a fine granule, a capsule, a pill or the like, preferably It is a tablet, more preferably a single layer tablet. When the solid preparation of the present invention is a tablet, it may be in the form of a circle, an ellipse, a rectangle or the like. The size of the lozenge can vary depending on the tablet form (round, oval, caplet, rectangle, etc.) and any size is possible as long as the patient is easy to take. When the solid preparation of the present invention is a single-layer tablet, it is easy to take because of its small size.

本發明之固體製劑的具體實施例包括：Specific examples of the solid preparation of the present invention include:

(1)一組粒化製劑(granulated preparation)(1) A set of granulated preparations

固體製劑，係將包含式(I)所示之化合物或其鹽、糖醇及鈣拮抗劑(較佳為：式(I)所示之化合物或其鹽、糖醇、鈣拮抗劑及聚乙二醇)之混合物粒化，並令所得粒化材料進行壓縮模製而獲得(例如，一組粒化單層錠劑)；The solid preparation comprises a compound represented by the formula (I) or a salt thereof, a sugar alcohol and a calcium antagonist (preferably: a compound represented by the formula (I) or a salt thereof, a sugar alcohol, a calcium antagonist, and a polyethylene a mixture of diols granulated and obtained by compression molding the obtained granulated material (for example, a set of granulated single-layer tablets);

(2)二組粒化製劑(2) Two-component granulation preparation

(a)固體製劑，係藉由混合及壓縮模製下列個別粒化而得之第一部分及第二部分所獲得(例如，二組粒化單層錠劑)；(a) a solid preparation obtained by mixing and compression molding the following individual granulation to obtain the first part and the second part (for example, a two-component granulated tablet);

(b)固體製劑，係藉由壓縮模製(毋需混合)下列個別粒化而得之第一部分及第二部分所獲得(例如，多層錠劑)；(b) a solid preparation obtained by compression molding (without mixing) of the following individual granulation to obtain the first part and the second part (for example, a multilayer tablet);

(c)　固體製劑，係藉由將下列個別粒化而得之第一部分及第二部分中的一者以另一者塗佈所獲得(例如，乾式塗佈錠劑)；(c) a solid preparation obtained by coating one of the first part and the second part obtained by granulating the following separately (for example, a dry coated tablet);

第一部分：包含式(I)所示之化合物或其鹽(較佳為：式(I)所示之化合物或其鹽，及聚乙二醇)的部分The first part: a part comprising a compound represented by the formula (I) or a salt thereof (preferably: a compound represented by the formula (I) or a salt thereof, and a polyethylene glycol)

第二部分：包含糖醇及鈣拮抗劑的部分Part II: Parts containing sugar alcohols and calcium antagonists

等等。and many more.

本發明之固體製劑的較佳具體實施例為一組粒化製劑(例如，一組粒化單層錠劑)。A preferred embodiment of the solid formulation of the present invention is a set of granulated formulations (e.g., a set of granulated monolayer tablets).

本發明之固體製劑可包含習用於醫藥領域的添加劑。添加劑的實例包括：賦形劑、崩解劑、黏結劑、潤滑劑、pH調控劑、著色劑、界面活性劑、安定劑、酸化劑、調味劑、助流劑(glidant)等。這些添加劑係以習知醫藥領域中所用之用量來使用。此外，此等添加物可以適當比例之兩種或更多種之混合物來使用。The solid preparation of the present invention may contain an additive conventionally used in the field of medicine. Examples of the additive include an excipient, a disintegrator, a binder, a lubricant, a pH adjuster, a colorant, a surfactant, a stabilizer, an acidifier, a flavoring agent, a glidant, and the like. These additives are used in the amounts used in the field of conventional medicine. Further, these additives may be used in a mixture of two or more kinds in an appropriate ratio.

賦形劑之實例包括澱粉(例如玉米澱粉、馬鈴薯澱粉、小麥澱粉、米澱粉、部分預糊化澱粉、預糊化澱粉、多孔澱粉等)；醣類(例如乳糖、果糖、葡萄糖、蔗糖等)；無水磷酸鈣、結晶纖維素、微晶纖維素、甘草(Glycyrrhiza uralensis)、碳酸氫鈉、磷酸鈣、硫酸鈣、碳酸鈣、沈澱碳酸鈣、矽酸鈣等。Examples of excipients include starch (eg, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, porous starch, etc.); sugars (eg, lactose, fructose, glucose, sucrose, etc.) Anhydrous calcium phosphate, crystalline cellulose, microcrystalline cellulose, licorice (Glycyrrhiza uralensis), sodium hydrogencarbonate, calcium phosphate, calcium sulfate, calcium carbonate, precipitated calcium carbonate, calcium citrate, and the like.

崩解劑之實例包括胺基酸、澱粉、玉米澱粉、羧甲基纖維素、羧甲基纖維素鈣、羧甲基澱粉鈉、羧甲基纖維素鈉(carmellose sodium)、羧甲基纖維素鈣(carmellose calcium)、交聯羧甲基纖維素鈉、交聯聚維酮(crospovidone)、低取代之羥丙基纖維素、羥丙基澱粉等。Examples of the disintegrant include amino acid, starch, corn starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, sodium carboxellose sodium, carboxymethyl cellulose. Carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropyl starch, and the like.

於本發明中，崩解劑係以較佳為0.1至30重量%，更佳為1至10重量%的比例包含在本發明之固體製劑中。In the present invention, the disintegrating agent is contained in the solid preparation of the present invention in a proportion of preferably from 0.1 to 30% by weight, more preferably from 1 to 10% by weight.

黏結劑之實例包括結晶纖維素(例如，微晶纖維素)、羥丙基纖維素、羥丙基甲基纖維素(hypromellose)、聚乙烯吡咯啶酮、明膠、澱粉、***膠粉末、黃蓍膠、羧甲基纖維素、海藻酸鈉、聚三葡萄糖(pullulan)、甘油等。Examples of the binder include crystalline cellulose (for example, microcrystalline cellulose), hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, gelatin, starch, gum arabic powder, and jaundice. Gum, carboxymethyl cellulose, sodium alginate, pullulan, glycerin, and the like.

於本發明中，黏結劑係以較佳為0.1至40重量%，更佳為1至10重量%的比例包含在本發明之固體製劑中。In the present invention, the binder is contained in the solid preparation of the present invention in a proportion of preferably from 0.1 to 40% by weight, more preferably from 1 to 10% by weight.

潤滑劑之實例包括硬脂酸鎂、硬脂酸、硬脂酸鈣、滑石(純化滑石)、脂肪酸之蔗糖酯、反丁烯二酸硬脂酸鈉鹽(sodium stearyl fumarate)等。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.

潤滑劑之實例包括檸檬酸及其鹽、磷酸及其鹽、碳酸及其鹽、酒石酸及其鹽、反丁烯二酸及其鹽、乙酸及其鹽、胺基酸及其鹽等。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.

著色劑之實例包括食用色素，例如食用色素黃色5號、食用色素紅色2號、食用色素藍色2號等；食用色澱色素(food lake color)，例如，食用色素黃色四號鋁色澱；氧化鐵顏料，例如，紅色氧化鐵(鐵丹(colcothar))、黃色氧化鐵、四氧化三鐵(黑色氧化鐵)等；及類似者。Examples of the coloring agent include food coloring agents such as food coloring yellow No. 5, food coloring red No. 2, food coloring blue No. 2, etc.; food lake color, for example, food coloring yellow No. 4 aluminum lake; Iron oxide pigments, for example, red iron oxide (colcothar), yellow iron oxide, triiron tetroxide (black iron oxide), and the like; and the like.

界面活性劑之實例包括月桂基硫酸鈉、聚山梨醇酯80(Polysorbate 80)、聚氧伸乙基(160)聚氧伸丙基(30)二醇等。Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, polyoxyethylene ethyl (160) polyoxypropyl propylene (30) diol, and the like.

安定劑之實例包括生育酚、乙二胺四乙酸四鈉(tetrasodium edetate)、菸鹼醯胺、環糊精等。Examples of stabilizers include tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin, and the like.

酸化劑之實例包括抗壞血酸、檸檬酸、酒石酸、蘋果酸等。Examples of the acidifying agent include ascorbic acid, citric acid, tartaric acid, malic acid, and the like.

調味劑之實例包括薄荷醇、薄荷油、檸檬油、香草醛等。Examples of the flavoring agent include menthol, peppermint oil, lemon oil, vanillin, and the like.

助流劑之實例包含輕質無水矽酸、水合二氧化矽等。Examples of the glidant include light anhydrous citric acid, hydrated cerium oxide, and the like.

本發明之固體製劑可藉由使用模衣(film coating)(例如，塗佈基劑、塗佈用添加劑等)而加工為膜衣製劑(film-coated preparation)。膜衣製劑的實例包括：糖衣製劑、持續釋放型膜衣製劑、腸溶性製劑等。The solid preparation of the present invention can be processed into a film-coated preparation by using a film coating (for example, a coating base, a coating additive, or the like). Examples of the film coating preparation include a sugar coating preparation, a sustained release type film coating preparation, an enteric preparation, and the like.

塗佈基劑之較佳實例包括：糖衣基劑、水溶性膜衣基劑、腸溶性膜衣基劑、持釋型膜衣基劑等。Preferred examples of the coating base include a sugar-based base, a water-soluble film-coating agent, an enteric film-coating agent, a sustained-release film-coating agent, and the like.

至於糖衣基劑，係使用蔗糖。此外，亦可組合使用選自下列之一或多種：滑石、沈澱之碳酸鈣、明膠、***膠、聚三葡萄糖、棕櫚蠟等。As for the sugar-coated base, sucrose is used. Further, one or more selected from the group consisting of talc, precipitated calcium carbonate, gelatin, gum arabic, polytriglucose, palm wax and the like may also be used in combination.

水溶性膜衣基劑之實例包括：纖維素聚合物，例如，羥丙基纖維素[例如，NISSO HPC(等級(grade)：L、SL、SL-T、SSL)(商品名稱)；Nippon Soda有限公司]、羥丙基甲基纖維素[例如，TC-5(等級：MW、E、EW、R、RW)(商品名稱)；Shin-Etsu化學有限公司]]、羥乙基纖維素、甲基羥乙基纖維素等；合成聚合物，例如聚乙烯醇縮乙醛二乙胺基乙酸酯(polyvinyl acetal diethylaminoacetate)、胺基烷基甲基丙烯酸酯共聚物E[尤特奇E(Eudragit E，商品名稱)；羅門哈斯日本公司製造]、聚乙烯吡咯啶酮等；多糖，例如聚三葡萄糖等；等等。Examples of the water-soluble film coating base include: a cellulose polymer such as hydroxypropyl cellulose [for example, NISSO HPC (grade: L, SL, SL-T, SSL) (trade name); Nippon Soda Ltd.], hydroxypropyl methylcellulose [eg, TC-5 (grade: MW, E, EW, R, RW) (trade name); Shin-Etsu Chemical Co., Ltd.]], hydroxyethyl cellulose, Methyl hydroxyethyl cellulose, etc.; synthetic polymer, such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Etech E ( Eudragit E, trade name); manufactured by Rohm and Haas Japan, polyvinylpyrrolidone, etc.; polysaccharides such as polytriglucose, etc.;

腸溶性膜衣基劑之實例包括：纖維素聚合物，例如羥丙基甲基纖維素苯二甲酸酯、羥丙基甲基纖維素乙酸酯琥珀酸酯、羧甲基乙基纖維素、纖維素乙酸酯苯二甲酸酯等；丙烯酸聚合物，例如甲基丙烯酸共聚物L[尤特奇L(商品名稱)]、甲基丙烯酸共聚物LD[尤特奇L-30D55(商品名稱)；羅門哈斯日本公司製造]、甲基丙烯酸共聚物S[尤特奇S(商品名稱)；羅門哈斯日本公司製造]等；自然存在聚合物，例如蟲膠等；等等。Examples of enteric film-coating agents include: cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose , cellulose acetate phthalate, etc.; acrylic polymer, such as methacrylic acid copolymer L [Utech L (trade name)], methacrylic acid copolymer LD [Yutz L-30D55 (commodity Name); manufactured by Rohm and Haas Japan], methacrylic acid copolymer S [Utech S (trade name); manufactured by Rohm and Haas Japan], etc.; naturally occurring polymers such as shellac, etc.;

持續釋放型膜衣基劑之實例包括：纖維素聚合物，例如乙基纖維素等；丙烯酸聚合物，例如胺基烷基甲基丙烯酸酯共聚物RS[尤特奇RS(商品名稱)；羅門哈斯日本公司製造]、丙烯酸乙酯-甲基丙烯酸甲酯共聚物懸浮液[尤特奇NE(商品名稱)；羅門哈斯日本公司製造]等；等等。Examples of the sustained release type film coating base include: a cellulose polymer such as ethyl cellulose or the like; an acrylic polymer such as an aminoalkyl methacrylate copolymer RS [Utchi RS (trade name); Solomon Manufactured by Haas Japan Co., Ltd., ethyl acrylate-methyl methacrylate copolymer suspension [Utchi NE (trade name); manufactured by Rohm and Haas Japan], etc.;

塗佈用添加劑之較佳實例包括：輕質保護劑，例如氧化鈦等；助流劑，例如滑石等；著色劑，例如紅色氧化鐵、黃色氧化鐵等；塑化劑，例如聚乙二醇[例如聚乙二醇6000(macrogol 6000)(商品名稱)；三洋化學工業有限公司製造]、檸檬酸三乙酯、蓖麻油、聚山梨醇酯等；有機酸，例如檸檬酸、酒石酸、蘋果酸、抗壞血酸等；等等。Preferable examples of the coating additive include: a light protective agent such as titanium oxide or the like; a glidant such as talc; a coloring agent such as red iron oxide, yellow iron oxide, etc.; a plasticizer such as polyethylene glycol [For example, polyethylene glycol 6000 (macrogol 6000) (trade name); manufactured by Sanyo Chemical Industry Co., Ltd.], triethyl citrate, castor oil, polysorbate, etc.; organic acids such as citric acid, tartaric acid, malic acid , ascorbic acid, etc.;

本發明之固體製劑可使用已知的方法製作(例如，Japanese Pharmacopoeia 15th Edition,General Principles中所述的方法)。The solid preparation of the present invention can be produced by a known method (for example, the method described in Japanese Pharmacopoeia 15th Edition, General Principles).

方法的實例包括如混合、揉製、粒化、壓縮模製、膜覆等操作，以及此等操作之適當組合。Examples of methods include operations such as mixing, tanning, granulating, compression molding, film coating, and the like, and suitable combinations of such operations.

舉例而言，使用例如混合機(諸如橫置式圓柱形混合機(horizontal cylindrical mixer)、V型混合機、滾筒混合機等)進行混合；及使用旋轉容器型揉製機(例如球磨機等)、固定容器型揉製機(例如螺旋式揉製機、享混合機(Henschel mixer)等)、進行揉製；滾動式揉製機(例如滾軋機、推拔滾軋機等)；等等進行揉製。粒化係藉由下列方法進行：使用高速攪拌粒化機之攪拌粒化法(stirring granulation method)、使用容器(盆式容器、錐形捲筒式容器、多級錐形捲筒式容器(multi-stage conical drum type)、具攪拌片之捲筒式容器、振動式容器等)之滾動粒化法(rolling granulation method)、流體化床粒化及乾燥法、噴霧乾燥粒化法、擠壓粒化法、使用粒化機(例如輾壓機(Roller-compactor))之方法等等。For example, mixing is carried out using, for example, a mixer (such as a horizontal cylindrical mixer, a V-type mixer, a tumbler mixer, etc.); and using a rotary vessel type tanning machine (for example, a ball mill, etc.), fixing A container type tanning machine (for example, a screw type tanning machine, a Henschel mixer, etc.), a tanning machine, a rolling tanning machine (for example, a rolling mill, a push-rolling machine, etc.); Granulation is carried out by the following method: stirring granulation method using a high-speed stirring granulator, use of a container (pot container, cone-shaped container, multi-stage cone-shaped container (multi Rolling granulation method, fluidized bed granulation and drying method, spray drying granulation method, extrusion granules for -stage conical drum type), roll container with agitating plate, vibrating container, etc. a method, a method using a granulator (for example, a Roller-compactor), and the like.

舉例而言，藉由模製(使用押出成形機)或打錠(使用單沖打錠機(single punch tableting machine)、旋轉打錠機等)進行壓縮模製。For example, compression molding is carried out by molding (using an extrusion molding machine) or by ingot (using a single punch tableting machine, a rotary tableting machine, etc.).

當使用單衝打錠機(single stroke tableting machine)、旋轉打錠機等進行壓縮磨製時，一般較佳係利用l至35千牛頓/平方公分(kN/cm² )(更佳係5至35 kN/cm² )的打錠壓力。另外，為防止頂裂(capping)，較佳係使用錐度切割模(taper cutting die)。When compression grinding is performed using a single stroke tableting machine, a rotary tableting machine, etc., it is generally preferred to use 1 to 35 kilonewtons per square centimeter (kN/cm ² ) (more preferably 5 to 5). 35 kN/cm ² ) tableting pressure. Further, in order to prevent capping, a taper cutting die is preferably used.

舉例而言，藉由下列方式進行膜覆：使用水平式、傾斜式等之盆式塗佈機(pan coating machine)；水平轉盤式、斜板式等之流體式塗佈機(fluid coating machine)；流體化床式、噴流床式、翻滾流體化床式等之流體式塗佈機；等等。For example, the film coating is performed by using a pan coating machine such as a horizontal type or a tilt type; a fluid coating machine such as a horizontal rotary type or a swash plate type; Fluidized bed machines, fluidized bed type, tumbling fluidized bed type, etc.; and the like.

舉例而言，本發明之固體製劑可藉下列製作步驟而製作：For example, the solid preparation of the present invention can be produced by the following production steps:

(1)　若本發明之固體製劑為一組粒化製劑(1) If the solid preparation of the present invention is a group of granulation preparations

將包含式(I)所示之化合物或其鹽、糖醇及鈣拮抗劑(較佳為：式(I)所示之化合物或其鹽、糖醇、鈣拮抗劑及聚乙二醇)之混合物粒化，並令所得粒化材料進行壓縮模製以獲得本發明之固體製劑(一組粒化單層錠劑)。A compound represented by the formula (I) or a salt thereof, a sugar alcohol, and a calcium antagonist (preferably, a compound represented by the formula (I) or a salt thereof, a sugar alcohol, a calcium antagonist, and a polyethylene glycol) are contained. The mixture was granulated, and the obtained granulated material was subjected to compression molding to obtain a solid preparation of the present invention (a set of granulated single-layer tablets).

具體言之，混合上述式(I)所示之化合物或其鹽、鈣拮抗劑及添加劑(例如賦形劑、糖醇(如D-甘露糖醇)等)，粒化混合物，並噴塗以溶劑(如，水)將聚乙二醇及添加劑(如黏結劑等)分散或溶解所得之液體。Specifically, a compound represented by the above formula (I) or a salt thereof, a calcium antagonist and an additive (for example, an excipient, a sugar alcohol (such as D-mannitol), etc.) are mixed, the mixture is granulated, and sprayed with a solvent. (eg, water) A liquid obtained by dispersing or dissolving polyethylene glycol and an additive such as a binder.

將例如崩解劑、潤滑劑等之添加劑加至所獲得之粒化材料，混合後，壓縮模製該混合物以獲得錠劑。以含有塗佈基劑等之膜溶液塗佈該錠劑，以製得本發明之固體製劑(一組粒化單層錠劑)。An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material, and after mixing, the mixture is compression molded to obtain a tablet. The tablet is coated with a film solution containing a coating base or the like to prepare a solid preparation of the present invention (a set of granulated single-layer tablets).

(2)　若本發明之固體製劑為二組粒化製劑(2) If the solid preparation of the present invention is a two-component preparation

(a)　二組粒化單層製劑；(a) a two-part granulated monolayer preparation;

混合上述式(I)所示之化合物或其鹽、添加劑(如賦形劑等)，粒化混合物，並噴塗液體(其分散或溶解聚乙二醇所獲得)及溶於溶劑(如，水)中之添加劑(如黏結劑等)。Mixing the compound of the above formula (I) or a salt thereof, an additive (such as an excipient, etc.), granulating the mixture, and spraying a liquid (which is obtained by dispersing or dissolving polyethylene glycol) and dissolving in a solvent (for example, water) Additives (such as binders).

另一方面，混合鈣拮抗劑及添加劑(例如賦形劑、糖醇(如D-甘露糖醇)等)，粒化混合物，並噴塗以溶劑(如，水)將聚乙二醇及添加劑(如黏結劑等)分散或溶解所得之液體。In another aspect, a calcium antagonist and an additive (such as an excipient, a sugar alcohol (such as D-mannitol), etc.) are mixed, the mixture is granulated, and the polyethylene glycol and the additive are sprayed with a solvent (eg, water) ( The resulting liquid is dispersed or dissolved, such as a binder.

將例如崩解劑、潤滑劑等之添加劑加至含有上述式(I)所示之化合物或其鹽的所得粒化材料，以及添加至含有鈣拮抗劑之所得粒化材料，混合後，壓縮模製該混合物以獲得本發明之固體製劑(二組粒化單層錠劑)。An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material containing the compound represented by the above formula (I) or a salt thereof, and added to the obtained granulated material containing the calcium antagonist, and after mixing, the compression mold This mixture was prepared to obtain a solid preparation (two-component granulated tablet) of the present invention.

(b)多層錠劑；(b) a multilayer tablet;

混合上述式(I)所示之化合物或其鹽、添加劑(如賦形劑等)，粒化混合物，並噴塗以溶劑(如，水)將聚乙二醇及添加劑(如黏結劑等)分散或溶解所得之液體。將例如崩解劑、潤滑劑等之添加劑加至所獲得之粒化材料以獲得混合粒劑。Mixing the compound of the above formula (I) or a salt thereof, an additive (such as an excipient, etc.), granulating the mixture, and spraying the solvent (for example, water) to disperse the polyethylene glycol and the additive (such as a binder). Or dissolve the resulting liquid. An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material to obtain a mixed granule.

另一方面，混合鈣拮抗劑及添加劑(例如賦形劑、糖醇(如D-甘露糖醇)等)，粒化混合物，並噴塗以溶劑(如，水)將聚乙二醇及添加劑(如黏結劑等)分散或溶解所得之液體。將例如崩解劑、潤滑劑等之添加劑加至所獲得之粒化材料以獲得混合粒劑。In another aspect, a calcium antagonist and an additive (such as an excipient, a sugar alcohol (such as D-mannitol), etc.) are mixed, the mixture is granulated, and the polyethylene glycol and the additive are sprayed with a solvent (eg, water) ( The resulting liquid is dispersed or dissolved, such as a binder. An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material to obtain a mixed granule.

將含有上述式(I)所示之化合物或其鹽的所得混合粒劑，以及含有鈣拮抗劑之所得混合粒劑互疊，並壓縮模製以獲得本發明之固體製劑(多層錠劑)。The resulting mixed granules containing the compound of the above formula (I) or a salt thereof, and the resulting mixed granules containing a calcium antagonist are stacked one on another and compression-molded to obtain a solid preparation (multilayer tablet) of the present invention.

(c)乾式塗佈錠劑；(c) a dry coated tablet;

混合鈣拮抗劑及添加劑(例如賦形劑、糖醇(如D-甘露糖醇)等)，粒化混合物，並噴塗以溶劑(如，水)將添加劑(如黏結劑等)分散或溶解所得之液體。將例如崩解劑、潤滑劑等之添加劑加至所獲得之粒化材料，混合後，壓縮模製該混合物以獲得錠劑。以含有塗佈基劑等之膜溶液塗佈該錠劑，以製得內核錠劑。Mixing calcium antagonists and additives (such as excipients, sugar alcohols (such as D-mannitol), etc.), granulating the mixture, and spraying or dissolving or dissolving additives (such as binders) in a solvent (eg, water). Liquid. An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material, and after mixing, the mixture is compression molded to obtain a tablet. The tablet is coated with a film solution containing a coating base or the like to prepare a core tablet.

另一方面，混合上述式(I)所示之化合物或其鹽、添加劑(如賦形劑等)，粒化混合物，並噴塗以溶劑(如，水)將聚乙二醇及添加劑(如黏結劑等)分散或溶解所得之液體。將例如崩解劑、潤滑劑等之添加劑加至所獲得之粒化材料以獲得混合粒劑。On the other hand, a compound represented by the above formula (I) or a salt thereof, an additive (such as an excipient, etc.) is mixed, the mixture is granulated, and a polyethylene glycol and an additive (such as a binder) are sprayed with a solvent (for example, water). The agent, etc.) disperses or dissolves the resulting liquid. An additive such as a disintegrating agent, a lubricant or the like is added to the obtained granulated material to obtain a mixed granule.

混合粒劑係作為外層而加至上述之內核錠劑，且將其壓縮模製以獲得本發明之固體製劑(乾式塗佈錠劑)A mixed granule is added as an outer layer to the core tablet described above, and compression-molded to obtain a solid preparation of the present invention (dry coated tablet)

當本發明之固體製劑是粒劑或細粒劑，其可藉由類似上述方法來製作。When the solid preparation of the present invention is a granule or a fine granule, it can be produced by a method similar to the above.

當本發明之固體製劑是囊劑時，其可藉由將上述粒劑或細粒劑填充至含有明膠、羥丙基甲基纖維素等的膠囊中而製得。此外，硬膠囊可藉由將上述式(I)所示之化合物或其鹽、鈣拮抗劑，與糖醇及其他賦形劑等一起填充入含有明膠、羥丙基甲基纖維素等的膠囊中而製得。另外，軟膠囊可藉由以含明膠及塑化劑(如甘油等)的基劑將上述式(I)所示之化合物或其鹽、鈣拮抗劑封裝成既定形狀而製得。When the solid preparation of the present invention is a capsule, it can be obtained by filling the above granules or fine granules into capsules containing gelatin, hydroxypropylmethylcellulose or the like. Further, the hard capsule can be filled into a capsule containing gelatin, hydroxypropylmethylcellulose or the like by the compound represented by the above formula (I) or a salt thereof, a calcium antagonist, together with a sugar alcohol and other excipients and the like. Made in the middle. Further, the soft capsule can be obtained by encapsulating the compound represented by the above formula (I) or a salt thereof and a calcium antagonist into a predetermined shape with a base containing gelatin and a plasticizer (e.g., glycerin or the like).

本發明之固體製劑可於其表面具有辨識用之壓紋或印刷字體。此外，其可具有分割用刻線。The solid preparation of the present invention may have an embossed or printed typeface for identification on its surface. Further, it may have a scribe line for division.

本發明之固體製劑係低毒性的，且可安全地以經口或非腸胃道的投予方式作為哺乳類(例如人類、猴、貓、豬、馬、牛、小鼠、大鼠、天竺鼠、犬、兔等)之用藥。The solid preparation of the present invention is low in toxicity and can be safely administered as a mammal by oral or parenteral administration (for example, human, monkey, cat, pig, horse, cow, mouse, rat, guinea pig, dog) , rabbits, etc.).

由於式(I)所示之化合物或其鹽具有強的血管收縮素II拮抗活性，本發明之固體製劑係適用於作為下列之預防性或治療性藥物：(1)因血管狹窄或生長而發展(或促進其發展)的疾病或透過血管收縮素II受體而表現的器官異常，(2)因血管收縮素II的存在而發展(或促進其發展)的疾病或(3)因上述哺乳類體內存在之血管收縮素II引發的因子而發展(或促進其發展)的疾病。Since the compound represented by the formula (I) or a salt thereof has strong angiotensin II antagonist activity, the solid preparation of the present invention is suitable for use as a prophylactic or therapeutic drug as follows: (1) development due to stenosis or growth of blood vessels (or promote its development) diseases or organ abnormalities expressed by angiotensin II receptors, (2) diseases that develop (or promote their development) due to the presence of angiotensin II or (3) due to the above-mentioned mammals A disease in which a factor caused by angiotensin II is developed (or promotes its development).

上述(1)至(3)之疾病的實例包括：高血壓、血壓晝夜節律異常(blood pressure circadian rhythm abnormality)、心臟疾病(例如，心肌肥厚、急性心臟衰竭、慢性心臟衰竭(包括心衰竭)、擴張功能受損、心肌症、心絞痛、心肌炎、心房纖維顫動、心律不整、心跳過速、心肌梗塞等)、腦血管疾患(例如，無症狀腦血管疾患、短暫性腦缺血、腦中風、腦血管性失智症、高血壓性腦病變、腦栓塞等)、腦水腫、腦循環疾患、腦血管疾患之復發及後遺症(例如，神經症狀、精神症狀、主觀症狀、日常生活活動異常等)、缺血性周邊循環疾患、心肌缺血、靜脈曲張、心肌梗塞後演進之心功能不全發展、腎疾病(例如，腎炎、腎絲球腎炎、腎絲球硬化症、腎衰竭、血栓性血管病變、糖尿病腎病變、透析之併發症、器官損傷(包括輻射照射引起之腎病變)等)、動脈硬化(包括動脈粥狀硬化)(例如，動脈瘤、冠狀動脈硬化、腦動脈硬化、周邊動脈硬化等)、血管肥厚、介入性治療(例如，經皮冠狀動脈血管成形術、支架置放術、冠狀動脈內視鏡、血管內超音波、dounce血栓溶解療法等)後之血管肥厚或閉塞及器官損傷、繞道手術後之血管再閉塞或再狹窄、紅血球增多症、高血壓、移植後之器官損傷或血管肥厚、移植後排斥、眼部疾病(例如，青光眼、高眼內壓等)、血栓、多重器官失調、血管內皮層細胞功能障礙、高血壓性耳鳴、其他心血管疾病(例如，深部靜脈栓塞、阻塞性周邊循環疾患、動脈硬化性閉塞、血栓血管炎性閉塞、缺血性腦循環疾患、雷諾氏症(Raynaud's disease)、柏格氏症(Berger disease)等)、代謝及/或營養失調(例如，肥胖、高脂血症、高膽固醇血症、高尿酸血症、高鉀血症、高鈉血症等)、神經退化性疾病(例如，阿茲海默症(Alzheimer's disease)、帕金森氏症(Parkinson's syndrome)、肌萎縮脊髓側索硬化症、AIDS腦病變等)、中樞神經系統疾患(例如，諸如腦出血及腦梗塞等傷害及其後遺症與併發症、頭部損傷、脊髓損傷、腦水腫、老年性癡呆、感官異常、感官功能失調、自律神經系統失調、自律神經系統功能異常、多發性硬化症等)、失智症、記憶功能缺陷、意識障礙、失憶症、焦慮症、緊張症、不適的心理狀態、精神病(例如，憂鬱症、癲癇、酗酒等)、發炎性疾病(例如，關節炎，如風濕性關節炎、骨關節炎、風濕性脊髓炎、骨膜炎等；手術或損傷後發炎；腫脹的緩解；咽頭炎；膀胱炎；肺炎；異位性皮膚炎；發炎性腸道疾患，如克隆氏症(Crohn's disease)、潰瘍性大腸炎等；髓膜炎；發炎性眼部疾病；發炎性肺部疾病，如肺炎、矽肺症、肺部類肉瘤症(pulmonary sarcoidosis)、肺結核等)、過敏疾病(例如，過敏性鼻炎、結膜炎、消化道過敏、花粉症、全身性過敏反應(anaphylaxis)等)、慢性阻塞性肺疾病、間質性肺炎、卡氏肺囊蟲肺炎(pneumocytis carinni pneumonia)、膠原疾病(collagen diseases)(例如，全身性紅斑狼瘡、硬皮病、多動脈炎等)、肝疾病(例如，肝炎(包括慢性肝炎)、肝硬化等)、門靜脈高血壓(portal hypertension)、消化系統疾患(例如，胃炎、胃潰瘍、胃癌、手術後胃疾患、消化不良、食道潰瘍、胰臟炎、結腸息肉、膽結石、痔瘡疾病、食道及胃之靜脈曲張破裂等)、血液及/或造血性疾病(例如，紅血球增多症、血管性紫斑症、自體免疫溶血性貧血、瀰散性血管內凝血症候群(disseminated intravascular coagulation syndrome)、多發性脊髓病變等)、骨疾病(例如，骨折、再骨折(refracture)、骨質疏鬆症、骨軟化、骨之佩吉特氏症(bone Paget's disease)、硬化性脊髓炎、風濕性關節炎、由膝部之骨關節病及類似疾患所造成的關節組織之官能障礙)、固態腫瘤、腫瘤(例如，惡性黑色素瘤、惡性淋巴瘤、消化器官(例如，胃、腸等)之癌症等)、癌症及隨癌症產生之惡質病、轉移癌(metastasis cancer)、內分泌病變(例如，艾狄森氏症(Addison's disease)、庫興氏症候群(Cushing's syndrome)、嗜鉻細胞瘤(pheochromocytoma)、醛固酮過多症、原發性皮質醛酮過多症等)、庫茲德賈克氏病、泌尿器官及/或雄性生殖器之疾病(例如，膀胱炎、***腫大、***癌、性傳染疾病等)、婦科疾患(例如，更年期疾患、妊娠中毒、子宮內膜異位症、子宮肌瘤、卵巢疾病、乳腺疾病、性傳染疾病等)、與環境或職業因素相關之疾病(例如，輻射危害；紫外線危害、遠紅外線或雷射光束之危害；高山症等)、呼吸疾病(例如，寒症(cold syndrome)、肺炎、氣喘、肺高血壓、肺血栓及肺栓塞等)、傳染性疾病(例如，經由巨細胞病毒、流感病毒、疱疹病毒等之病毒傳染性疾病；立克次體症(rickettsiosis)；細菌傳染性疾病等)、毒血症(toxemias)(例如，敗血症、敗血性休克、內毒性休克、格蘭氏陰性敗血症(Gram-negative sepsis)、中毒休克症等)、耳鼻咽喉疾病(例如，梅尼爾氏症(Meniere's syndrome)、耳鳴、味覺障礙、暈眩、失衡、吞嚥困難等)、皮膚疾病(例如，瘢痕瘤(keloid)、血管瘤、乾癬等)、透析中低血壓(intradialytic hypotension)、重症肌無力、全身性疾病(systemic diseases)(如慢性疲勞症候群等)等等。Examples of the diseases (1) to (3) above include: hypertension, blood pressure circadian rhythm abnormality, heart disease (for example, cardiac hypertrophy, acute heart failure, chronic heart failure (including heart failure), Impaired expansion, cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, myocardial infarction, etc., cerebrovascular disease (eg, asymptomatic cerebrovascular disease, transient cerebral ischemia, stroke, brain Vascular dementia, hypertensive brain lesions, cerebral embolism, etc.), cerebral edema, cerebral circulation disorders, recurrence and sequelae of cerebrovascular diseases (eg, neurological symptoms, mental symptoms, subjective symptoms, abnormal activities of daily living, etc.), Ischemic peripheral circulatory disorders, myocardial ischemia, varicose veins, progression of cardiac insufficiency after myocardial infarction, renal disease (eg, nephritis, glomerulonephritis, renal glomerulosclerosis, renal failure, thrombotic angiopathy, Diabetic nephropathy, complications of dialysis, organ damage (including nephropathy caused by radiation exposure), arteriosclerosis (including atherosclerosis) For example, aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular hypertrophy, interventional therapy (eg, percutaneous coronary angioplasty, stent placement, coronary endoscopy, intravascular ultrasound) Vascular hypertrophy or occlusion and organ damage after sonication, dounce thrombolytic therapy, etc., revascularization or restenosis after bypass surgery, erythrocytosis, hypertension, organ damage after transplantation or vascular hypertrophy, post-transplant rejection, eye Diseases (eg, glaucoma, high intraocular pressure, etc.), thrombosis, multiple organ disorders, vascular endothelial cell dysfunction, hypertensive tinnitus, other cardiovascular diseases (eg, deep vein thrombosis, obstructive peripheral circulation disorders, arteries) Sclerosing occlusion, thromboembolic occlusion, ischemic cerebral circulation disorder, Raynaud's disease, Berger disease, etc., metabolic and/or nutritional disorders (eg, obesity, hyperlipemia) Disease, hypercholesterolemia, hyperuricemia, hyperkalemia, hypernatremia, etc.), neurodegenerative diseases (eg, Alzheimer's dis Ease), Parkinson's syndrome, amyotrophic lateral sclerosis, AIDS brain lesions, etc., central nervous system disorders (eg, injuries such as cerebral hemorrhage and cerebral infarction and their sequelae and complications, head Injury, spinal cord injury, cerebral edema, senile dementia, sensory abnormalities, sensory dysfunction, autonomic nervous system disorders, autonomic nervous system dysfunction, multiple sclerosis, etc., dementia, memory impairment, disturbance of consciousness, amnesia , anxiety, nervousness, mental state of discomfort, mental illness (eg, depression, epilepsy, alcoholism, etc.), inflammatory diseases (eg, arthritis, such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periosteum Inflammation, etc.; inflammation after surgery or injury; relief of swelling; pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory bowel disease, such as Crohn's disease, ulcerative colitis, etc. Inflammatory eye disease; inflammatory lung disease such as pneumonia, silicosis, pulmonary sarcoidosis, tuberculosis, etc., allergic diseases (eg , allergic rhinitis, conjunctivitis, digestive tract allergy, hay fever, systemic allergic reaction (anaphylaxis), chronic obstructive pulmonary disease, interstitial pneumonia, pneumocytis carinni pneumonia, collagen disease ( Collagen diseases) (eg, systemic lupus erythematosus, scleroderma, polyarteritis, etc.), liver diseases (eg, hepatitis (including chronic hepatitis), cirrhosis, etc.), portal hypertension, digestive disorders ( For example, gastritis, gastric ulcer, stomach cancer, postoperative gastric disease, dyspepsia, esophageal ulcer, pancreatitis, colon polyps, gallstones, acne disease, rupture of the esophagus and stomach, etc.), blood and/or hematopoietic diseases ( For example, erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple spinal cord disease, etc., bone disease (eg, fracture, refracture) , osteoporosis, osteomalacia, bone Paget's disease, sclerosing myelitis, rheumatoid arthritis a dysfunction of joint tissue caused by osteoarthrosis of the knee and a similar condition), a solid tumor, a tumor (for example, a malignant melanoma, a malignant lymphoma, a cancer of a digestive organ (for example, a stomach, an intestine, etc.), Cancer and malignant diseases with cancer, metastasis cancer, endocrine diseases (eg, Addison's disease, Cushing's syndrome, pheochromocytoma, aldosterone) Hyperactivity, primary corticosterone, etc.), Kuzd's disease, urinary organs and/or male genital diseases (eg, cystitis, prostate enlargement, prostate cancer, sexually transmitted diseases, etc.), Gynecological disorders (eg, menopausal disorders, gestational toxicity, endometriosis, uterine fibroids, ovarian disease, breast disease, sexually transmitted diseases, etc.), diseases associated with environmental or occupational factors (eg, radiation hazards; UV hazards) , the danger of far-infrared or laser beam; alpine disease, etc.), respiratory diseases (for example, cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis and pulmonary embolism) ), infectious diseases (for example, viral infectious diseases such as cytomegalovirus, influenza virus, herpes virus, etc.; rickettsiosis; bacterial infectious diseases, etc.), toxemias (for example, Sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock, etc., otolaryngology (eg, Meniere's syndrome, tinnitus, taste disorder, halo Dizziness, imbalance, difficulty swallowing, etc.), skin diseases (eg, keloid, hemangioma, dryness, etc.), intradialytic hypotension, myasthenia gravis, systemic diseases (eg chronic Fatigue syndrome, etc.) and so on.

本發明之固體製劑包括式(I)所示之化合物或其鹽、鈣拮抗劑的組合，適用於作為上述疾病之預防或治療藥物(較佳為，高血壓、心衰竭、糖尿病腎病變或動脈硬化之預防或治療藥物)。此外，相較於單獨使用式(I)所示之化合物或其鹽、鈣拮抗劑，本發明之固體製劑可減少式(I)所示之化合物或其鹽、鈣拮抗劑的劑量。The solid preparation of the present invention comprises a compound of the formula (I) or a salt thereof, a combination of a calcium antagonist, and is suitable for use as a prophylactic or therapeutic drug for the above diseases (preferably, hypertension, heart failure, diabetic nephropathy or arteries). A prophylactic or therapeutic drug for sclerosis). Further, the solid preparation of the present invention can reduce the dose of the compound of the formula (I) or a salt thereof, a calcium antagonist, compared to the compound of the formula (I) or a salt thereof or a calcium antagonist.

式(I)所示之化合物或其鹽之劑量係依投予標的、投予途徑、目標疾病、症狀等而改變，而人類成人(體重為60公斤(kg))的每日劑量(以游離形式為基準計)係約0.05至500毫克(mg)，較佳係0.1至100mg，更佳係1至100毫克，尤佳係2至40毫克。舉例來說，化合物A之人類成人(體重60公斤)的每日劑量係約1至80毫克，較佳係2至32毫克，而化合物B之人類成人(體重60公斤)的每日劑量係約1至50毫克，較佳係10至40毫克。The dose of the compound of the formula (I) or a salt thereof varies depending on the administration target, the administration route, the target disease, the symptoms, and the like, and the daily dose of the human adult (weight: 60 kg (kg)) (free The form is from about 0.05 to 500 milligrams (mg), preferably from 0.1 to 100 mg, more preferably from 1 to 100 mg, and especially preferably from 2 to 40 mg. For example, the daily dose of Compound A human adult (body weight 60 kg) is about 1 to 80 mg, preferably 2 to 32 mg, and the daily dose of Compound B human adult (body weight 60 kg) is about 1 to 50 mg, preferably 10 to 40 mg.

鈣拮抗劑之劑量係依投予投予標的、投予途徑、目標疾病、症狀等而改變，舉例而言，氨氯地平或其鹽(以遊離形式為基準計)之人類成人(體重60公斤)的每日劑量係約1至50毫克，較佳係2.5至10毫克。The dose of the calcium antagonist varies depending on the administration of the target, the route of administration, the target disease, the symptoms, etc., for example, amlodipine or a salt thereof (based on the free form) of a human adult (body weight 60 kg) The daily dose is about 1 to 50 mg, preferably 2.5 to 10 mg.

本發明之固體製劑對上述哺乳類的投予頻率較佳為每天1至3次，更佳為每天1次。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.

本發明之固體製劑特佳的特定實例包括“每錠含有8毫克化合物A及6.93毫克苯磺酸氨氯地平(氨氯地平則為5毫克)的單層錠劑”；“每錠含有8毫克化合物A及3.47毫克苯磺酸氨氯地平(氨氯地平則為2.5毫克)的單層錠劑”；“每錠含有4毫克化合物A及6.93毫克苯磺酸氨氯地平(氨氯地平則為5毫克)的單層錠劑”；“每錠含有4毫克化合物A及3.47毫克苯磺酸氨氯地平(氨氯地平則為2.5毫克)的單層錠劑”；“每錠含有40毫克化合物B及6.93毫克苯磺酸氨氯地平(氨氯地平則為5毫克)的單層錠劑”；“每錠含有40毫克化合物B及3.47毫克苯磺酸氨氯地平(氨氯地平則為2.5毫克)的單層錠劑”；“每錠含有20毫克化合物B及6.93毫克苯磺酸氨氯地平(氨氯地平則為5毫克)的單層錠劑”；“每錠含有20毫克化合物B及3.47毫克苯磺酸氨氯地平(氨氯地平則為2.5毫克)的單層錠劑”；“每錠含有10毫克化合物B及6.93毫克苯磺酸氨氯地平(氨氯地平則為5毫克)的單層錠劑”；以及“每錠含有10毫克化合物B及3.47毫克苯磺酸氨氯地平(氨氯地平則為2.5毫克)的單層錠劑”。Specific examples of particularly preferred solid preparations of the present invention include "a single layer tablet containing 8 mg of Compound A per bene and 6.93 mg of amlodipine besylate (5 mg of amlodipine)"; "8 mg per ingot" Compound A and 3.47 mg of amlodipine besylate (2.5 mg of amlodipine) in a single-layer tablet"; "4 mg of Compound A per bene and 6.93 mg of amlodipine besylate (amlodipine is 5 mg) of a single-layer tablet"; "a single-layer tablet containing 4 mg of Compound A per serving and 3.47 mg of amlodipine besylate (2.5 mg of amlodipine)"; "40 mg of compound per ingot" B and 6.93 mg of amlodipine besylate (5 mg of amlodipine) in a single-layer tablet"; "40 mg of Compound B per ingot and 3.47 mg of amlodipine besylate (amlodipine is 2.5) a single layer tablet of "mg"; "a single-layer tablet containing 20 mg of Compound B per bene and 6.93 mg of amlodipine besylate (5 mg of amlodipine)"; "20 mg of Compound B per ingot" And 3.47 mg of amlodipine besylate (2.5 mg of amlodipine) in a single-layer tablet"; "10 mg per spindle" Compound B and 6.93 mg of amlodipine besylate (5 mg of amlodipine) in a single layer"; and "10 mg of Compound B per ingot and 3.47 mg of amlodipine besylate (amlodipine) Then it is 2.5 mg) of a single-layer tablet."

本發明之固體製劑可與一種或多種不同的藥劑(後文有時縮寫為「併用藥物(concomitant drug)」)組合使用。「併用藥物」的實例包括：糖尿病的治療劑、糖尿病併發症的治療劑、高脂血症的治療劑、抗高血壓劑、減肥劑、利尿劑等。The solid preparation of the present invention can be used in combination with one or more different pharmaceutical agents (hereinafter sometimes abbreviated as "concomitant drugs"). Examples of the "concomitant drug" include a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, a slimming agent, a diuretic, and the like.

於此，舉例來說，可作為糖尿病治療劑者有：胰島素製劑(例如，由牛或豬之胰臟抽出之動物胰島素製劑；以遺傳工程方法由大腸菌或酵母菌合成的人胰島素製劑；鋅胰島素，魚精蛋白鋅胰島素，胰島素的片段或衍生物(例如INS-1)，胰島素口服製劑)、胰島素增敏劑(例如，皮利酮(pioglitazone)或其鹽(較佳為鹽酸鹽)、吡羅格列酮(Rosiglitazone)或其鹽(順丁烯二酸鹽為佳)、美達格申(metaglidasen)、AMG-131、巴格列銅(Balaglitazone)、MBX-2044、雷米那酮(Rivoglitazone)、阿格列札(Aleglitazar)、西格列札(Chiglitazar)、洛貝格列酮(Lobeglitazone)、PLX-204、PN-2034、GFT-505、HR-092l，及WO2007/013694,WO2007/018314、WO2008/093639或WO2008/099794中所述的化合物)、α-配糖酶抑制劑(例如伏格列波糖(voglibose)、阿卡波糖(acarbose)、米格列醇(miglitol)、乙格列酯(emiglitate))、雙胍類(biguanides)(例如二甲雙胍(metformin)、N-丁基雙胍(buformin)或其鹽(例如鹽酸鹽、反丁烯二酸鹽、琥珀酸鹽))、胰島素促泌劑素(例如，磺醯脲(例如甲苯磺丁脲(tolbutamide)、格列本脲(glibenclamide)、格列齊特(gliclazide)、氯磺丙脲(chlorpropamide)、妥拉磺脲(tolazamide)、醋酸己脲(acetohexamide)、格列吡脲(glyclopyramide)、格列美脲(glimepiride)、格列吡嗪(glipizide)、格列丁唑(glybuzole))、瑞格列奈(repaglinide)、那格列奈(nateglinide)、米格列奈(miteglinide)或其鈣鹽水合物)、第四型雙胜肽蛋白水解酶(dipeptidyl peptidase IV)抑制劑(例如，阿格列汀或其鹽(較佳為苯甲酸鹽)、維達列汀(vildagliptin)、西他列汀(sitagliptin)、莎莎列汀(saxagliptin)、BI1356、GRC8200、MP-513、PF-00734200、PHX1149、SK-0403、ALS2-0426、TA-6666、TS-021、KRP-104、2-[[6-[(3R)-3-胺基-1-吡啶基]-3,4-二氫-3-甲基-2,4-二氧-1(2H)-嘧啶基]甲基]-4-氟苄腈或其鹽)、β3激動劑(例如N-5984)、GPR40激動劑(例如，WO2004/041266、WO2004/106276、WO2005/063729、WO2005/063725、WO2005/087710、WO2005/095338、WO2007/013689或WO2008/001931中所述之化合物)，GLP-1受體激動劑(例如GLP-1、GLP-1MR劑、利拉魯肽(Liraglutide)、艾塞那肽(Exenatide)、AVE-0010、BIM-51077、Aib(8,35)hGLP-1(7,37)NH₂ 、CJC-1131、阿必魯肽(Albiglutide))、澱粉素激動劑(例如普蘭林肽(pramlintide))、磷酸化酪胺酸磷酸酶抑制劑(例如釩酸鈉)、醣新生作用抑制劑(例如肝糖磷酸化酶抑制劑、葡萄醣-6-磷酸酶抑制劑、升血糖激素拮抗劑、FBP酶抑制劑)、SGULT2(鈉-葡萄糖共同輸送體2)抑制劑(例如，的帕格列弗洛林(Depagliflozin)、AVE2268、TS-033、YM543、TA-7284、雷莫格列弗洛林(Remogliflozin)、ASP1941)、SGLT1抑制劑、11β-羥類固醇脫氫酶抑制劑(例如BVT-3498、INCB-13739)、脂締素(Adiponectin)或其激動劑、IKK抑制劑(例如AS-2868)、脂瘦素(leptin)阻抗性增進藥物、體抑素(somatostatin)受體激動劑、葡萄糖激酶化劑(Glucokinase Activator)(例如，派洛格列汀(Piragliatin)、AZD1656、AZD6370、TTP-355，及WO2006/112549、WO2007/028135、WO2008/047821、WO2008/050821、WO2008/136428或WO2008/156757中所述的化合物)、GIP(葡萄糖依賴型胰島素控制胜肽(glucose-dependent insulinotropic peptide)、GPR119激動劑、FGF21、FGF類似物等。Here, for example, as a therapeutic agent for diabetes, there are: an insulin preparation (for example, an animal insulin preparation extracted from a pancreas of a cow or a pig; a human insulin preparation synthesized by a genetically engineered method from a coliform or a yeast; zinc insulin) a protamine zinc insulin, a fragment or derivative of insulin (for example, INS-1), an insulin oral preparation), an insulin sensitizer (for example, pioglitazone or a salt thereof (preferably a hydrochloride), Rosiglitazone or its salt (maleate), metaglidasen, AMG-131, balaglintazone, MBX-2044, reminate (Rivoglitazone), Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT-505, HR-092l, and WO2007/013694, a compound described in WO2007/018314, WO2008/093639 or WO2008/099794), an α-glycosidase inhibitor (for example, voglibose, acarbose, miglitol) ), emiglitate, biguanides (eg metformin, N-butyl) Buformin or a salt thereof (eg, hydrochloride, fumarate, succinate), insulin secretagogue (eg, sulfonylurea (eg, tolbutamide, glibenclamide) Glubenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glycopyramide, glimepiride ), glipizide, glybuzole, repaglinide, nateglinide, miteglinide or its calcium salt hydrate, A fourth type of dipeptidyl peptidase IV inhibitor (eg, alogliptin or a salt thereof (preferably benzoate), vildagliptin, sitagliptin ), saxagliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, 2-[[6-[ (3R)-3-amino-1-pyridyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-4-fluorobenzyl Nitrile or a salt thereof), a β3 agonist (eg N-5984), a GPR40 agonist (eg WO2004/041266, WO2004/106276, WO2005/063729, WO2005/063725, WO2005/087710, WO2005/095338, WO2007/013689 or WO2008/001931), GLP-1 receptor agonists (eg GLP-1) , GLP-1MR agent, Liraglutide, Exenatide, AVE-0010, BIM-51077, Aib (8,35) hGLP-1 (7,37) NH ₂ , CJC-1131 , Albiglutide, amyloid agonist (eg pramlintide), phosphorylated tyrosine phosphatase inhibitor (eg sodium vanadate), inhibitor of gluconeogenesis (eg glycophosphoric acid) Inhibitors of enzymes, glucose-6-phosphatase inhibitors, blood glucose hormone antagonists, FBPase inhibitors, SGULT2 (sodium-glucose co-transporter 2) inhibitors (eg, paclifraflozin) ), AVE2268, TS-033, YM543, TA-7284, Remogliflozin, ASP1941), SGLT1 inhibitor, 11β-hydroxysteroid dehydrogenase inhibitor (eg BVT-3498, INCB-13739) ), Adiponectin or its agonist, IKK inhibitor (eg AS-2868), leptin resistance enhancing drug, somatostatin An agonist, Glucokinase Activator (eg, Piragliatin, AZD1656, AZD6370, TTP-355, and WO2006/112549, WO2007/028135, WO2008/047821, WO2008/050821, WO2008/ 136428 or a compound described in WO2008/156757), GIP (glucose-dependent insulinotropic peptide), GPR119 agonist, FGF21, FGF analog, and the like.

可作為糖尿病併發症的治療劑者有：醛糖還原酶抑制劑(例如，托瑞司他(tolrestat)、依帕司他(epalrestat)、捉頗司他(zopolrestat)、非達司他(fidarestat)、CT-112、雷尼司他(ranirestat，AS-3201)、利多司他(lidorestat))、神經營養因子及其增進劑(例如，NGF、NT-3、BDNF、於WO 01/14372中描述的神經營養素製造/分泌促進劑(例如，4-(4-氯苯基)-2-(2-甲基-1-咪唑基)-5-[3-(2-甲基苯氧基)丙基]唑)、WO2004/039365中描述者)、PKC抑制劑(例如，魯波西林(ruboxistaurin)甲磺酸鹽)、AGE抑制劑(例如，ALT946、溴化N-苯甲醯甲基噻唑鎓(ALT766)、EXO-226、吡哆啉(pyridorin)、吡哆胺(pyridoxamine))、GABA受體激動劑(例如，加巴潘汀(gabapentin)、普瑞巴林(pregabalin))、血清素及正腎上腺素再吸收抑制劑(例如，度洛西汀(duloxetine))、鈉通道抑制劑(例如，拉柯胺(lacosamide))、活性氧清除劑(例如，硫辛酸)、腦血管擴張劑(例如，太普萊(tiapuride)、慢心利(mexiletine))、體抑素受體激動劑(例如，BIM23190)、細胞凋亡訊號調控激酶-1(ASK-1)抑制劑等。Agents that can be used as a remedy for diabetes are: aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat) , CT-112, ranirestat (AS-3201), lidorestat, neurotrophic factors and their enhancers (eg, NGF, NT-3, BDNF, described in WO 01/14372) Neurotrophin manufacturing/secretion promoter (for example, 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propane base] Oxazole), described in WO2004/039365), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, N-benzhydrylmethylthiazolium bromide (ALT766) ), EXO-226, pyridorin, pyridoxamine, GABA receptor agonists (eg, gabapentin, pregabalin), serotonin, and adrenal gland Reuptake inhibitors (eg, duloxetine), sodium channel inhibitors (eg, lacosamide), reactive oxygen scavengers (eg, lipoic acid), cerebral vasodilators (eg, Tiapuride, mexiletine, a somatostatin receptor agonist (eg, BIM23190), an apoptotic signal-regulated kinase-1 (ASK-1) inhibitor, and the like.

可作為高脂血症的治療劑者有：HMG-CoA還原酶抑制劑(例如，普拉伐他汀(pravastatin)、辛伐他汀(simvastatin)、洛伐他汀(lovastatin)、阿托伐他汀(atorvastatin)、福路伐他汀(fluvastatin)、羅素代他汀(rosuvastatin)、匹塔伐他汀(pitavastatin)、或其鹽(例如，鈉鹽、鈣鹽))、角鯊烯合成酶抑制劑(例如，WO97/10224中描述之化合物，例如N-[[(3R,5S)-1-(3-乙醯氧基-2,2-二甲基丙基)-7-氯-5-(2,3-二甲氧苯基)-2-酮基-1,2,3,5-四氫-4,1-苯并吖庚因-3-基]乙醯基]哌啶-4-乙酸)、纖維酸酯(fibrate)化合物(例如，倍紮纖維酸酯(bezafibrate)、克洛纖維酸酯(clofibrate)、辛纖維酸酯(simfibrate)、克利諾纖維酸酯(clinofibrate))、陰離子交換樹脂(例如，可勒烯胺(colestyramine))、匹洛布克(probucol)、菸鹼酸藥物(例如，尼可目(nicomol)、百脂喜妥(niceritrol)、諾之平(niaspan))、廿六碳五烯酸乙酯(ethyl icosapentate)、植物固醇(例如，大豆固醇、γ-谷維醇)、膽固醇吸收抑制劑(例如，晢夏(zechia))、CETP抑制劑(例如，達賽曲匹(dalcetrapib)、阿那曲匹(anacetrapib))、ω-3脂肪酸製劑(例如，ω-3酸乙酯90)等。Among the therapeutic agents for hyperlipidemia are: HMG-CoA reductase inhibitors (for example, pravastatin, simvastatin, lovastatin, atorvastatin) ), fluvastatin, rosuvastatin, pitavastatin, or a salt thereof (eg, sodium salt, calcium salt), squalene synthetase inhibitor (eg, WO97) a compound described in /10224, for example, N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3- Dimethoxyphenyl)-2-keto-1,2,3,5-tetrahydro-4,1-benzo Indomethacin-3-yl]ethinyl]piperidine-4-acetic acid), fibrate compound (for example, bezafibrate, clofibrate, octane fiber) Sodium (simfibrate), clinofibrate, anion exchange resin (eg, colestyramine), probucol, nicotinic acid (eg, nicocamine) Nicomol), niceritrol, niaspan, ethyl icosapentate, phytosterols (eg, soy sterol, γ-glutenol), cholesterol Absorption inhibitors (eg, zechia), CETP inhibitors (eg, dalcetrapib, anacetrapib), omega-3 fatty acid preparations (eg, omega-3 acid ethyl ester 90) )Wait.

可作為抗高血壓劑者有：血管收縮素轉化酶抑制劑(例如，卡托普利(captopril)、依那普利(enalapril)、德拉普利(delapril)等)、血管收縮素II拮抗劑(例如，肯德沙坦西酯(candesartan cilexetil)、肯德沙坦(candesartan)、羅沙坦(losartan)、羅沙坦鉀(losartan potassium)、愛普洛沙坦(eprosartan)、瓦沙坦(valsartan)、特密沙坦(telmisartan)、爾貝沙坦(irbesartan)、塔索沙坦(tasosartan)、奧美沙坦(olmesart)、奧美沙坦酯(olmesartan medoxomil)、阿齊沙坦(azilsartan)等)、鈣拮抗劑(例如，馬尼地平(manidipine)、硝苯地平(nifedipine)、氨氯地平(amlodipine)、依福地平(efonidipine)、尼卡地平(nicardipine)、氨氯地平、西尼地平(cilnidipine)等)、β阻斷劑(例如，美托洛爾(metoprolol)、阿替洛爾(atenolol)、普萘洛爾(propranolol)、卡菲蒂蘿(carvedilol)、吲哚洛爾(pindolol)等)、可樂寧(clonidine)等。Can be used as antihypertensive agents: angiotensin converting enzyme inhibitors (for example, captopril, enalapril, deLapril, etc.), angiotensin II antagonist Agents (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, wasa Valsartan, telmisartan, irbesartan, tasosartan, olmesart, olmesartan medoxomil, azilsartan Azilsartan), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efenidipine, nicardipine, amlodipine, Cilendipine, etc., beta blockers (eg, metoprolol, atenolol, propranolol, carvedilol, guanidine) Pilodol, etc., clonidine, and the like.

可作為減肥劑者有：單胺吸收抑制劑(例如，酚特明(phentermine)、***(sibutramine)、氯苯咪吲哚(mazindol)、氟西汀(fluoxetine)、桶特索芬辛(tesofensine))、血清素2C受體激動劑(例如，綠卡色林(lorcaserin))、血清素6受體激動劑、組織胺H3受體、GABA調控藥物(例如，托吡酯(topiramate))、神經肽Y拮抗劑(例如，表利貝特(velneperit))、***鹼受體拮抗劑(例如，利莫那班(rimonabant)、泰倫那班(taranabant))、飢餓激素(ghrelinant)激動劑、飢餓激素受體(ghrelin receptor)拮抗劑、飢餓激素醯化酶抑制劑(ghrelin acy1ation enzyme inhibitor)、類鴉片受體拮抗劑(例如，GSK-1521498)、食慾素受體拮抗劑、黑皮質素(melanocortin)4受體激動劑、11β-羥類固醇去氫酶抑制劑(例如，AZD-4017)、胰脂肪酶抑制劑(例如，讓你酷(orlistat)、西替利達(cetilistat))、β3激動劑(例如，N-5984)、二酸甘油脂醯基轉移酶1(diacylglycerol acyltransferase 1，DGAT1)抑制劑、乙醯輔酶A羧化酶(ACC)抑制劑、乙醯輔酶A去飽和酶抑制劑、酸甘油酯轉換蛋白質抑制劑(例如，R-256918)、Na-葡萄糖共運輸抑制劑(例如，JNJ-28431754、瑞默格列弗洛辛(remogliflozin))、NFκB抑制劑(例如，HE-3286)、PPAR激動劑(例如，GFT-505、DRF-11605)、磷酸酪胺酸磷酸脢抑制劑(例如，釩酸鈉、杜德司奎明(Trodusquemin))、GPR119激動劑(例如，PSN-821)、葡萄糖激酶活化劑(例如，AZD-1656)、瘦體素、瘦體素衍生物(例如，美曲普汀(metreleptin))、CNTF(睫狀神經營養性因子(ciliary neurotrophic factor))、BDNF(腦衍生神經滋養因子)、膽囊收縮素激動劑、胰高血糖素樣肽-1(GLP-1)製劑(例如，抽自牛或豬之動物GLP-1製劑；以遺傳工程方法由大腸菌或酵母菌合成的人GLP-1製劑；GLP-1片段或衍生物(例如，艾塞那肽、利拉魯肽))、澱粉素激動劑(例如普蘭林肽、AC-2307)、神經肽Y激動劑(例如，PYY3-36、PYY3-36衍生物、奧尼匹肽(obinepitide)、TM-30339、TM-30335)、調酸素製劑；FGF21製劑(例如，抽自牛或豬之動物FGF21製劑；以遺傳工程方法由大腸菌或酵母菌合成的人FGF21製劑；FGF21片段或衍生物))、阻食因子(例如，P-57)等。Can be used as a weight loss agent: monoamine absorption inhibitors (eg, phentermine, sibutramine, mazindol, fluoxetine, barrelsofen) Tesofensine, serotonin 2C receptor agonist (eg, lorcaserin), serotonin 6 receptor agonist, histamine H3 receptor, GABA-regulating drug (eg, topiramate), Neuropeptide Y antagonists (eg, velneperit), cannabinoid receptor antagonists (eg, rimonabant, taranabant), ghrelinant agonists , ghrelin receptor antagonist, ghrelin acy1ation enzyme inhibitor, opioid receptor antagonist (eg, GSK-1521498), orexin receptor antagonist, melanocortin (melanocortin) 4 receptor agonist, 11β-hydroxysteroid dehydrogenase inhibitor (eg, AZD-4017), pancreatic lipase inhibitor (eg, orlistat, cetialat), β3 Agonist (eg, N-5984), diglyceride thiol transferase 1 (diacylglycerol acylt) Ransferase 1, DGAT1) inhibitor, acetaminophen coenzyme A carboxylase (ACC) inhibitor, acetaminophen coenzyme A desaturase inhibitor, acid glyceride conversion protein inhibitor (eg, R-256918), Na-glucose Transport inhibitors (eg, JNJ-28431754, remogliflozin), NFκB inhibitors (eg, HE-3286), PPAR agonists (eg, GFT-505, DRF-11605), phosphonate Ammonium phosphate inhibitor (eg, sodium vanadate, trodusquemin), GPR119 agonist (eg, PSN-821), glucokinase activator (eg, AZD-1656), leptin, Leptin derivatives (eg, metrepeptin), CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonist, pancreatic hyperglycemia a peptide-like peptide-1 (GLP-1) preparation (for example, an animal GLP-1 preparation derived from cattle or pigs; a human GLP-1 preparation synthesized by coliform bacteria or yeast by genetic engineering methods; a GLP-1 fragment or derivative (eg, exenatide, liraglutide), amyloid agonists (eg, pramlintide, AC-2307), neuropeptide Y agonists (for example, PYY3-36, PYY3-36 derivative, obinepitide, TM-30339, TM-30335), a modulating agent preparation; FGF21 preparation (for example, an animal FGF21 preparation derived from cattle or pigs; Genetic engineering methods are human FGF21 preparations synthesized by Escherichia coli or yeast; FGF21 fragments or derivatives), anti-feeding factors (for example, P-57) and the like.

可作為利尿劑者有，例如：黃嘌呤衍生物(例如，可可鹼鈉(theobromine sodium)、水楊酸鹽、可可鹼水楊酸鈣等)、噻化物(thiazide)製劑(例如，乙噻化物、環戊噻化物、三氯甲噻化物、雙氫氯噻化物、氫氟甲噻化物、苄雙氫氯噻化物、五氟噻化物、多噻化物、甲氯噻化物等)、抗醛固酮製劑(例如，螺旋內酯固醇(spironolactone)、三胺喋呤(triamterene)等)、碳酸酐酶抑制劑(例如，乙醯唑胺(acetazolamide)等)、氯苯磺醯胺製劑(例如，氯噻酮(chlortalidone)、倍可降(mefruside)、達帕胺(indapamide)等)、阿佐西邁(azosemide)、異山梨糖醇(isosorbide)、利尿酸(ethacrynic acid)、皮瑞塔耐(piretanide)、丁苯氧酸(bumetanide)、利尿磺胺(furosemide)等。It can be used as a diuretic, for example, xanthine derivatives (for example, theobromine sodium, salicylate, theobromine calcium salicylate, etc.), thiophene Thiazide preparation (eg, ethyl thiazide) Hexathiophene Compound, trichloromethylthio Compound, hydrochlorothiazide Hydrofluorothiazide Benzyldihydrochlorothiazide Hexafluorothiazide Compound, polythiazide Compound, methyl chloride Compounds, etc., anti-aldosterone preparations (for example, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (for example, acetazolamide, etc.), chlorobenzenesulfonate Indoleamine preparations (for example, chlortalidone, mefruside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid , pitetanide, bumetanide, furosemide, and the like.

可作為抗血栓劑者有，例如：肝素(例如，肝素鈉、肝素鈣、依諾肝素鈉(enoxaparin sodium)、達特杷寧鈉(dalteparin sodium))、殺鼠靈(warfarins)(例如，殺鼠靈鉀)、抗凝血酶藥物(例如，阿拉加本(aragatroban)、達比加群酯(dabigatran))、Fxa抑制劑(例如，利伐沙班(rivaroxaban)、阿哌沙班(apixaban)、依杜沙班(edoxaban)、YM150，及WO02/06234、WO2004/048363、WO2005/030740、WO2005/058823或WO2005/113504中所描述的化合物)、血栓溶解劑(例如，尿激酶、替索激酶(tisokinase)、阿替普酶(alteplase)、那替普酶(nateplase)、蒙替普酶(monteplase)、帕米替普酶(pamiteplase))、血小板凝集抑制劑(例如，得泰寧(ticlopidine)鹽酸鹽、西羅塔唑(cilostazol)、氯格雷(clopidogrel)、普拉格雷(prasugrel)、E5555、SHC530348、西羅塔唑、廿六碳五烯酸乙酯、貝拉普洛鈉(beraprost sodium)、莎波酸酯(sarpogrelate)鹽酸鹽)等。It can be used as an antithrombotic agent, for example, heparin (for example, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarins (for example, killing) Mouse spirit potassium), antithrombin drugs (eg, aragatroban, dabigatran), Fxa inhibitors (eg, rivaroxaban, apixaban (apixaban) ), edoxaban, YM150, and WO02/06234, WO2004/048363, WO2005/030740, WO2005/058823, or WO2005/113504), thrombolytic agents (eg, urokinase, esoteric) Kinase (tisokinase), alteplase, nateplase, monteplase, pamiteplase, platelet aggregation inhibitors (eg, tetainin) Ticlopidine) hydrochloride, cilostazol, clopidogrel, prasugrel, E5555, SHC530348, ceroxazole, ethyl hexacarboxylate, berapprost sodium (beraprost sodium), sarpogrelate hydrochloride, and the like.

當本發明固態製劑與併用藥物組合使用時，彼等之投予時間並未受限，且彼等可同時投予至投予標的，或以錯開方式投予。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.

此外，本發明固態製劑與併用藥物可呈分離製劑投予；以含有本發明固態製劑與併用藥物之單一製劑投予。Further, the solid preparation of the present invention and the concomitant drug may be administered in a separate preparation; and administered in a single preparation containing the solid preparation of the present invention and a concomitant drug.

併用藥物之劑量可根據各藥物之臨床使用劑量適當決定。本發明固態製劑與併用藥物之混合比率，可根據投與標的、投與途徑、目標疾病、症狀、組合物等適當予以決定。例如，當投予標的為人類時，每1重量份本發明固態製劑可使用0.01至100重量份之併用藥物。The dose of the combined drug can be appropriately determined according to the clinical use dose of each drug. The mixing ratio of the solid preparation of the present invention and the concomitant drug can be appropriately determined depending on the administration target, the administration route, the target disease, the symptom, the composition, and the like. For example, when the target is administered to a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the solid preparation of the present invention.

以此方式使用之併用藥物，提供下述優越效果：The combination of drugs used in this way provides the following superior effects:

1)促進本發明固態製劑或併用藥物之作用的效果(藥劑作用之協同效果)；1) an effect of promoting the action of the solid preparation or the concomitant drug of the present invention (the synergistic effect of the action of the agent);

2)降低本發明固態製劑或併用藥物之劑量的效果(相較於單一投予，藥劑劑量減少之效果)；2) the effect of reducing the dose of the solid preparation or the combined medicine of the present invention (the effect of reducing the dose of the medicine compared to the single administration);

3)減輕本發明固態製劑或併用藥物之副作用(secondary action)的效果；等等。3) the effect of alleviating the secondary action of the solid preparation or the combined use of the present invention; and the like.

本發明亦提供促進下列者之溶解性質的方法及安定下列者的方法：式(I)所示之化合物或其鹽及/或鈣拮抗劑，其係包含在含有添加糖醇之固體製劑中。根據本發明，固體製劑中的式(I)所示之化合物或其鹽之溶解性質有顯著的改善。The present invention also provides a method for promoting the solubility properties of the following compounds: a compound of the formula (I) or a salt thereof and/or a calcium antagonist, which is contained in a solid preparation containing an added sugar alcohol. According to the present invention, the solubility property of the compound of the formula (I) or a salt thereof in the solid preparation is remarkably improved.

實施例Example

後文中將參照實施例、試驗實施例更詳細地說明本發明，惟彼等並不會對本發明構成限制。The invention will be described in more detail hereinafter with reference to the examples and the experimental examples, which are not to be construed as limiting.

下述實施例、試驗實施例中，非屬活性成分的組成(添加劑)，可使用與日本藥典第15版(Japanese Pharmacopoeia 15 th Edition)、日本醫藥品集(the Japanese Pharmacopoeia Japanese Pharmaceutical Codex)或日本醫藥賦形劑2003(Japanese Pharmaceutical Excipients 2003)相容之產品。In the following examples and test examples, the composition (additive) which is not an active ingredient can be used with the Japanese Pharmacopoeia 15th Edition, the Japanese Pharmacopoeia Japanese Pharmaceutical Codex, or Japan. Pharmaceutical Excipients 2003 (Japanese Pharmaceutical Excipients 2003) compatible products.

下列實施例中，使用化合物A或化合物B作為上述式(I)所示之化合物或其鹽。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.

實施例1Example 1

(1)　將羥丙基纖維素(720.0 g)及macrogol 6000(324.0 g)溶於純水(9000 g)中，以獲得黏結液I。將紅色氧化鐵(2.880 g)分散於純水(2880 g)中以獲得分散液I。混合黏結液I、分散液I及純水(720.0 g)以獲得黏結液II。於流體化床粒化機(FD-S2,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(1253 g)、化合物A(1449 g)、D-甘露醇(14880 g)及微晶纖維素(3600 g)均勻地混合，粒化混合物並噴塗黏結液II，接著乾燥以獲得粒劑。於篩分研磨機(P-3,ShowaKagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以製得經研磨之粒劑。(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9000 g) to obtain a binder I. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (720.0 g) to obtain the binder II. Amlodipine besylate (1253 g), Compound A (1449 g), D-mannitol (14880 g) and microcrystals in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, ShowaKagakukikai Co., Ltd.) to prepare a ground granule.

(2)　將交聯羧甲基纖維素鈉(1848 g)及硬脂酸鎂(297.0 g)加至所得經研磨之粒劑(40760 g(2批))，於滾筒混合機(TM20-0-0,Suehiro Kakoki Co.,Ltd.)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(AQUARIUS-36K,Kikusui Seisakusho)中以7.0 mm沖孔直徑打錠(打錠壓力：10kN，每錠重：130 mg)以獲得如表1所示之組成的素錠劑(plain tablet)。(3) The mixed granules obtained as above were subjected to a spindle punching diameter of 7.0 mm in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) (ingoting pressure: 10 kN, weight per spindle: 130 mg) to obtain The tablet tablet of the composition shown in Table 1.

實施例2Example 2

(1)將羥丙基纖維素(720.0 g)及macrogol 6000(324.0 g)溶於純水(9900 g)中以獲得黏結液I。將紅色氧化鐵(11.70 g)分散於純水(1800 g)中以獲得分散液I。混合黏結液I、分散液I及純水(540.0 g)以獲得黏結液II。於流體化床粒化機(FD-S2,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(1253 g)、化合物A(1449 g)、D-甘露醇(14870 g)及微晶纖維素(3600 g)均勻地混合，粒化混合物並噴塗黏結液II，接著乾燥以獲得粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以製得經研磨之粒劑。(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9900 g) to obtain a binder I. Red iron oxide (11.70 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (540.0 g) to obtain the binder II. Amlodipine besylate (1253 g), Compound A (1449 g), D-mannitol (14870 g) and microcrystals in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2)　將交聯羧甲基纖維素鈉(1848 g)及硬脂酸鎂(297.0 g)加至所得經研磨之粒劑(40760 g(2批))，於滾筒混合機(TM20-0-0,Suehiro Kakoki Co.,Ltd.)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(AQUARIUS-36K,Kikusui Seisakusho)中以8.5 mm長直徑沖孔及5.0 mm短直徑沖孔打錠(打錠壓力：8kN，每錠重：130 mg)以獲得如表2所示之組成的素錠劑。(3) The mixed granules obtained above were punched in a rotary ingot machine (AQUARIUS-36K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 8 kN, each ingot) Weight: 130 mg) A flavonoid having the composition shown in Table 2 was obtained.

實施例3Example 3

(1)　將羥丙基纖維素(720.0 g)及macrogol 6000(324.0 g)溶於純水(9900 g)中以獲得黏結液I。將紅色氧化鐵(11.70 g)分散於純水(1800 g)中以獲得分散液I。混合黏結液I、分散液I及純水(540.0 g)以獲得黏結液II。於流體化床粒化機(FD-S2,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(627.7 g)、化合物A(1449 g)、D-甘露醇(15550 g)及微晶纖維素(3600 g)均勻地混合，粒化混合物並噴塗黏結液II，接著乾燥以獲得粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以製得經研磨之粒劑。(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9900 g) to obtain a binder I. Red iron oxide (11.70 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (540.0 g) to obtain the binder II. Amlodipine besylate (627.7 g), Compound A (1449 g), D-mannitol (15550 g) and microcrystals in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2)　將交聯羧甲基纖維素鈉(1848 g)及硬脂酸鎂(297.0 g)加至所得經研磨之粒劑(40760 g(2批))，於滾筒混合機(TM20-0-0,Suehiro Kakoki Co.,Ltd.)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(AQUARIUS-36K,Kikusui Seisakusho)中以8.5 mm長直徑沖孔及5.0 mm短直徑沖孔打錠(打錠壓力：8kN，每錠重：130 mg)以獲得如表3所示之組成的素錠劑。(3) The mixed granules obtained above were punched in a rotary ingot machine (AQUARIUS-36K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 8 kN, each ingot) Weight: 130 mg) A tablet tablet having the composition shown in Table 3 was obtained.

實施例4Example 4

(1)　將羥丙基纖維素(720.0 g)及macrogol 6000(324.0 g)溶於純水(9900 g)中以獲得黏結液I。將紅色氧化鐵(11.70 g)分散於純水(1800 g)中以獲得分散液I。混合黏結液I、分散液I及純水(540.0 g)以獲得黏結液II。於流體化床粒化機(FD-S2,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(1253 g)、化合物A(724.3 g)、D-甘露醇(15600 g)及微晶纖維素(3600 g)均勻地混合，粒化混合物並噴塗黏結液II，接著乾燥以獲得粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以製得經研磨之粒劑。(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9900 g) to obtain a binder I. Red iron oxide (11.70 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (540.0 g) to obtain the binder II. Amlodipine besylate (1253 g), Compound A (724.3 g), D-mannitol (15600 g) and microcrystals in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2)　將交聯羧甲基纖維素鈉(1848 g)及硬脂酸鎂(297.0 g)加至所得經研磨之粒劑(40760 g(2批))，於滾筒混合機(TM20-0-0,Suehiro Kakoki Co.,Ltd.)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(AQUARIUS-36K,Kikusui Seisakusho)中以7 mm直徑沖孔打錠(打錠壓力：10kN，每錠重：130 mg)以獲得如表4所示之組成的素錠劑。(3) The mixed granules obtained as above were punched in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) at a diameter of 7 mm (ingot pressure: 10 kN, weight per spindle: 130 mg) to obtain A tablet of the composition shown in Table 4.

實施例5Example 5

(1)　將羥丙基纖維素(720.0 g)及macrogol 6000(324.0 g)溶於純水(9900 g)中以獲得黏結液I。將黃色氧化鐵(11、70 g)分散於純水(1800 g)中以獲得分散液I。混合黏結液I、分散液I及純水(540.0 g)以獲得黏結液II。於流體化床粒化機(FD-52,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(627.7 g)、化合物A(724.3 g)、D-甘露醇(16200 g)及微晶纖維素(3600 g)均勻地混合，粒化混合物並噴塗黏結液II，接著乾燥以獲得粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以製得經研磨之粒劑。(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9900 g) to obtain a binder I. Yellow iron oxide (11, 70 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (540.0 g) to obtain the binder II. Amlodipine besylate (627.7 g), Compound A (724.3 g), D-mannitol (16200 g) and microcrystals in a fluidized bed granulator (FD-52, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2)　將交聯羧甲基纖維素鈉(1848 g)及硬脂酸鎂(297.0 g)加至所得經研磨之粒劑(40760 g(2批))，於滾筒混合機(TM20-0-0,Suehiro Kakoki Co.,Ltd.)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(AQUARIUS-36K,Kikusui Seisakusho)中以7 mm直徑沖孔打錠(打錠壓力：10kN，每錠重：130 mg)以獲得如表5所示之組成的素錠劑。(3) The mixed granules obtained as above were punched in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) at a diameter of 7 mm (ingot pressure: 10 kN, weight per spindle: 130 mg) to obtain A tablet of the composition shown in Table 5.

實施例6Example 6 表6Table 6

(1)　將羥丙基纖維素(720.0 g)及macrogol 6000(324.0 g)溶於純水(9900 g)中以獲得黏結液I。將紅色氧化鐵(18.72 g)分散於純水(1800 g)中以獲得分散液I。混合黏結液I、分散液I及純水(540.0 g)以獲得黏結液II。於流體化床粒化機(FD-S2,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(1248 g)、化合物A(1446 g)、D-甘露醇(14870 g)及微晶纖維素(3600 g)均勻地混合，粒化混合物並噴塗黏結液II，接著乾燥以獲得粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以製得經研磨之粒劑。(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9900 g) to obtain a binder I. Red iron oxide (18.72 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (540.0 g) to obtain the binder II. Amlodipine besylate (1248 g), Compound A (1446 g), D-mannitol (14870 g) and microcrystals in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2)　將交聯羧甲基纖維素鈉(924.0 g)及硬脂酸鎂(148.5 g)加至所得經研磨之粒劑(20380 g)，於滾筒混合機(TM20-0-0,Suehiro Kakoki Co.,Ltd.)中混合，以獲得混合粒劑。(2) Add croscarmellose sodium (924.0 g) and magnesium stearate (148.5 g) to the obtained milled granules (20380 g) in a roller mixer (TM20-0-0, Suehiro) Kakoki Co., Ltd.) was mixed to obtain a mixed granule.

(3)　如上所獲之混合粒劑，於旋轉打錠機(AQUARIUS-36K,Kikusui Seisakusho)中以以8.5 mm長直徑沖孔及5.0 mm短直徑沖孔打錠(打錠壓力：8kN，每錠重：130 mg)以獲得如表6所示之組成的素錠劑。(3) The mixed granules obtained as above were punched in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 8 kN, per Ingot weight: 130 mg) A tablet tablet having the composition shown in Table 6 was obtained.

實施例7Example 7

(1)　將羥丙基纖維素(720.0 g)及macrogol 6000(324.0 g)溶於純水(9900 g)中以獲得黏結液I。將黃色氧化鐵(18.72 g)分散於純水(1800 g)中以獲得分散液I。混合黏結液I、分散液I及純水(540.0 g)以獲得黏結液II。於流體化床粒化機(FD-S2,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(625.2 g)、化合物A(1446 g)、D-甘露醇(15500 g)及微晶纖維素(3600 g)均勻地混合，粒化混合物並噴塗黏結液II，接著乾燥以獲得粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以製得經研磨之粒劑。(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in pure water (9900 g) to obtain a binder I. Yellow iron oxide (18.72 g) was dispersed in pure water (1800 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (540.0 g) to obtain the binder II. Amlodipine besylate (625.2 g), Compound A (1446 g), D-mannitol (15500 g) and microcrystals in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The cellulose (3600 g) was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2)　將交聯羧甲基纖維素鈉(924.0 g)及硬脂酸鎂(148.5 g)加至所得經研磨之粒劑(20380 g)，於滾筒混合機(TM20-0-0,Suehiro Kakoki Co.,Ltd.)中混合，以獲得混合粒劑。(2) Add croscarmellose sodium (924.0 g) and magnesium stearate (148.5 g) to the obtained milled granules (20380 g) in a roller mixer (TM20-0-0, Suehiro) Kakoki Co., Ltd.) was mixed to obtain a mixed granule.

(3)　如上所獲之混合粒劑，於旋轉打錠機(AQUARIUS-36K,Kikusui Seisakusho)中以8.5 mm長直徑沖孔及5.0 mm短直徑沖孔打錠(打錠壓力：8kN，每錠重：130 mg)以獲得如表7所示之組成的素錠劑。(3) The mixed granules obtained above were punched in a rotary ingot machine (AQUARIUS-36K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 8 kN, each ingot) Weight: 130 mg) A flavonoid having the composition shown in Table 7 was obtained.

實施例8Example 8

(1)　將羥丙基纖維素(144.0 g)溶於純水(1980 g)中以獲得黏結液I。將黃色氧化鐵(3.744 g)分散於純水(360.0 g)中以獲得分散液I。混合黏結液I、分散液I及純水(108.0 g)以獲得黏結液II。將macrogol 6000(4.680 g)溶於黏結液II(259.6 g)中以獲得黏結液III。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(24.95 g)、化合物A(28.80 g)、D-甘露醇(299.4 g)及微晶纖維素(72.00 g)均勻地混合，粒化混合物並噴塗黏結液III，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (144.0 g) was dissolved in pure water (1980 g) to obtain a binder I. Yellow iron oxide (3.744 g) was dispersed in pure water (360.0 g) to obtain a dispersion I. The binder I, the dispersion I and the pure water (108.0 g) were mixed to obtain a binder II. Macrogol 6000 (4.680 g) was dissolved in the binder II (259.6 g) to obtain a binder III. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (299.4 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder III was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將交聯羧甲基纖維素鈉(16.80 g)及硬脂酸鎂(2.700 g)加至所得經研磨之粒劑(370.5 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(Correct 19K,Kikusui Seisakusho)中以以8.5 mm長直徑沖孔及5.0 mm短直徑沖孔打錠(打錠壓力：7.5kN，每錠重：130 mg)以獲得如表8所示之組成的素錠劑。(3) The mixed granules obtained as above were punched in a rotary tableting machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 7.5 kN, per Ingot weight: 130 mg) A tablet tablet having the composition shown in Table 8 was obtained.

實施例9Example 9

(1)　將羥丙基纖維素(144.0 g)溶於純水(1980 g)中以獲得黏結液I。將紅色氧化鐵(3.744 g)分散於純水(360.0 g)中以獲得分散液I。混合黏結液I、分散液I及純水(108.0 g)以獲得黏結液II。將macrogol 6000(14.04 g)溶於黏結液II(259.6 g)中以獲得黏結液III。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(24.95 g)、化合物A(28.80 g)、D-甘露醇(290.0 g)及微晶纖維素(72.00 g)均勻地混合，粒化混合物並噴塗黏結液III，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (144.0 g) was dissolved in pure water (1980 g) to obtain a binder I. Red iron oxide (3.744 g) was dispersed in pure water (360.0 g) to obtain a dispersion I. The binder I, the dispersion I and the pure water (108.0 g) were mixed to obtain a binder II. Macrogol 6000 (14.04 g) was dissolved in the binder II (259.6 g) to obtain a binder III. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (290.0 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder III was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將交聯羧甲基纖維素鈉(16.80 g)及硬脂酸鎂(2.700 g)加至所得經研磨之粒劑(370.5 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(Correct 19K,Kikusui Seisakusho)中以以8.5 mm長直徑沖孔及5.0 mm短直徑沖孔打錠(打錠壓力：7.5kN，每錠重：130 mg)以獲得如表9所示之組成的素錠劑。(3) The mixed granules obtained as above were punched in a rotary tableting machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 7.5 kN, per Ingot weight: 130 mg) A tablet tablet having the composition shown in Table 9 was obtained.

實施例10Example 10

(1)　將羥丙基纖維素(144.0 g)溶於純水(1980 g)中以獲得黏結液I。將紅色氧化鐵(3.744 g)分散於純水(360.0 g)中以獲得分散液I。混合黏結液I、分散液I及純水(108.0 g)以獲得黏結液II。將macrogol 6000(23.40 g)溶於黏結液II(259.6 g)中以獲得黏結液III。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(24.95 g)、化合物A(28.80 g)、D-甘露醇(280.7 g)及微晶纖維素(72.00 g)均勻地混合，粒化混合物並噴塗黏結液III，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (144.0 g) was dissolved in pure water (1980 g) to obtain a binder I. Red iron oxide (3.744 g) was dispersed in pure water (360.0 g) to obtain a dispersion I. The binder I, the dispersion I and the pure water (108.0 g) were mixed to obtain a binder II. Macrogol 6000 (23.40 g) was dissolved in the binder II (259.6 g) to obtain a binder III. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (280.7 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder III was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將交聯羧甲基纖維素鈉(16.80 g)及硬脂酸鎂(2.700 g)加至所得經研磨之粒劑(370.5 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(Correct 19K,Kikusui Seisakusho)中以以8.5 mm長直徑沖孔及5.0 mm短直徑沖孔打錠(打錠壓力：7.5kN，每錠重：130 mg)以獲得如表10所示之組成的素錠劑。(3) The mixed granules obtained as above were punched in a rotary tableting machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 7.5 kN, per Ingot weight: 130 mg) A tablet tablet having the composition shown in Table 10 was obtained.

實施例11Example 11

(1)　將羥丙基纖維素(144.0 g)溶於純水(1980 g)中以獲得黏結液I。將紅色氧化鐵(3.744 g)分散於純水(360.0 g)中以獲得分散液I。混合黏結液I、分散液I及純水(108.0 g)以獲得黏結液II。將macrogol 6000(37.44 g)溶於黏結液II(259.6 g)中以獲得黏結液III。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(24.95 g)、化合物A(28.80 g)、D-甘露醇(266.6 g)及微晶纖維素(72.00 g)均勻地混合，粒化混合物並噴塗黏結液III，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (144.0 g) was dissolved in pure water (1980 g) to obtain a binder I. Red iron oxide (3.744 g) was dispersed in pure water (360.0 g) to obtain a dispersion I. The binder I, the dispersion I and the pure water (108.0 g) were mixed to obtain a binder II. Macrogol 6000 (37.44 g) was dissolved in the binder II (259.6 g) to obtain a binder III. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (266.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder III was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將交聯羧甲基纖維素鈉(16.80 g)及硬脂酸鎂(2.700 g)加至所得經研磨之粒劑(370.5 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(Correct 19K,Kikusui Seisakusho)中以以8.5 mm長直徑沖孔及5.0 mm短直徑沖孔打錠(打錠壓力：7.5kN，每錠重：130 mg)以獲得如表11所示之組成的素錠劑。(3) The mixed granules obtained as above were punched in a rotary tableting machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 7.5 kN, per Ingot weight: 130 mg) A tablet tablet having the composition shown in Table 11 was obtained.

實施例12Example 12

(1)將羥丙基纖維素(208.0 g)及macrogol 6000(160.0 g)溶於純水(2392.0 g)中以獲得黏結液。於流體化床粒化機(FD-5S,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(277.2 g)、化合物B(1605.0 g)、D-甘露醇(1599.0 g)及微晶纖維素(388.8 g)均勻地混合，粒化混合物並噴塗黏結液，接著乾燥以獲得粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以製得經研磨之粒劑。(1) Hydroxypropylcellulose (208.0 g) and macrogol 6000 (160.0 g) were dissolved in pure water (2392.0 g) to obtain a binder. Amlodipine besylate (277.2 g), Compound B (1605.0 g), D-mannitol (1599.0 g) and microcrystals in a fluidized bed granulator (FD-5S, POWREX Co., Ltd.) The cellulose (388.8 g) was uniformly mixed, the mixture was granulated and a binder was sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2)　將交聯聚維酮(331.5 g)、微晶纖維素(442.0 g)及硬脂酸鎂(44.201 g)加至所得經研磨之粒劑(3602.0 g)，於滾筒混合機(TM-15,Suehiro Kakokico.,Ltd.)中混合，以獲得混合粒劑。(2) crospovidone (331.5 g), microcrystalline cellulose (442.0 g) and magnesium stearate (44.201 g) were added to the obtained milled granules (3602.0 g) in a roller mixer (TM) -15, Suehiro Kakokico., Ltd.) was mixed to obtain a mixed granule.

(3)　如上所獲之混合粒劑，於旋轉打錠機(Correct 12HUK,Kikusui Seisakusho)中以7.0 mm直徑沖孔打錠(打錠壓力：4kN，每錠重：130 mg)以獲得內核錠劑。(3) The mixed granules obtained as above were punched in a rotary tableting machine (Correct 12HUK, Kikusui Seisakusho) at a diameter of 7.0 mm (ingot pressure: 4 kN, weight per spindle: 130 mg) to obtain a core ingot Agent.

(4)　將預混合物I(240.4 g)溶於純水(2160.0 g)中以獲得膜衣溶液(film coating solution)。於膜覆機(DRC-500,POWREX Co.,Ltd.)中，在內核錠劑(3120.0 g)上均勻噴灑膜衣溶液而形成膜衣，以獲得如表12所示之組成的膜衣錠(每錠重：135 mg)。此處，預混合物I係預混合的粉末。預混合物I的組成如表12a所示。(4) Premix I (240.4 g) was dissolved in pure water (2160.0 g) to obtain a film coating solution. In a film coater (DRC-500, POWREX Co., Ltd.), a film coating solution was uniformly sprayed on a core tablet (3120.0 g) to form a film coat to obtain a film ingot having the composition shown in Table 12 (weight per plate: 135 mg). Here, the premix I is a premixed powder. The composition of Premix I is shown in Table 12a.

實施例13Example 13 表13Table 13

(1)　將羥丙基纖維素(20.80 g)及macrogol 6000(16.00 g)溶於純水(239.2 g)中以獲得黏結液。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(27.72 g)、化合物B(80.00 g)、D-甘露醇(240.4 g)及微晶纖維素(38.88 g)均勻地混合，粒化混合物並噴塗黏結液，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (20.80 g) and macrogol 6000 (16.00 g) were dissolved in pure water (239.2 g) to obtain a binder. Amlodipine besylate (27.72 g), Compound B (80.00 g), D-mannitol (240.4 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (38.88 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將交聯聚維酮(34.13 g)、微晶纖維素(45.50 g)及硬脂酸鎂(4.550 g)加至所得經研磨之粒劑(370.8 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(2) crospovidone (34.13 g), microcrystalline cellulose (45.50 g) and magnesium stearate (4.550 g) were added to the obtained milled granules (370.8 g) in a polyethylene bag (4.9 Mix in L) to obtain a mixed granule.

(3)　如上所獲之混合粒劑，於旋轉打錠機(VEL-5,Kikusui Seisakusho)中以7.0 mm直徑沖孔打錠(打錠壓力：4kN，每錠重：130 mg)以獲得內核錠劑。(3) The mixed granules obtained as above were punched in a rotary tableting machine (VEL-5, Kikusui Seisakusho) at a diameter of 7.0 mm (ingot pressure: 4 kN, weight per spindle: 130 mg) to obtain a core. Lozenges.

(4)　將預混合物I(40.00 g)溶於純水(360.0 g)中以獲得膜衣溶液。於膜覆機(DRC-200,POWREX Co.,Ltd.)中，在內核錠劑(200.0 g)上均勻噴灑膜衣溶液而形成膜衣，以獲得如表13所示之組成的膜衣錠(每錠重：135 mg)。此處，預混合物I係預混合的粉末。預混合物I的組成物如表13a所示。(4) Premix I (40.00 g) was dissolved in pure water (360.0 g) to obtain a film coating solution. In a film coater (DRC-200, POWREX Co., Ltd.), a film coating solution was uniformly sprayed on a core tablet (200.0 g) to form a film coat to obtain a film ingot having the composition shown in Table 13 (weight per plate: 135 mg). Here, the premix I is a premixed powder. The composition of Premix I is shown in Table 13a.

實施例14Example 14

(1)　將羥丙基纖維素(20.80 g)及macrogol 6000(16.00 g)溶於純水(239.2 g)中以獲得黏結液。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(13.88 g)、化合物B(80.00 g)、D-甘露醇(254.2 g)及微晶纖維素(38.88 g)均勻地混合，粒化混合物並噴塗黏結液，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (20.80 g) and macrogol 6000 (16.00 g) were dissolved in pure water (239.2 g) to obtain a binder. Amlodipine besylate (13.88 g), compound B (80.00 g), D-mannitol (254.2 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (38.88 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將交聯聚維酮(34.13 g)、微晶纖維素(45.50 g)及硬脂酸鎂(4.550 g)加至所得經研磨之粒劑(370.8 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(2) crospovidone (34.13 g), microcrystalline cellulose (45.50 g) and magnesium stearate (4.550 g) were added to the obtained milled granules (370.8 g) in a polyethylene bag (4.9 Mix in L) to obtain a mixed granule.

(3)　如上所獲之混合粒劑，於旋轉打錠機(VEL-5,Kikusui Seisakusho)中以7.0 mm直徑沖孔打錠(打錠壓力：4kN，每錠重：130 mg)以獲得內核錠劑。(3) The mixed granules obtained as above were punched in a rotary tableting machine (VEL-5, Kikusui Seisakusho) at a diameter of 7.0 mm (ingot pressure: 4 kN, weight per spindle: 130 mg) to obtain a core. Lozenges.

(4)　將預混合物I(40.00 g)溶於純水(360.0 g)中以獲得膜衣溶液。於膜覆機(DRC-200,POWREX Co.,Ltd.)中，在內核錠劑(200.0g)上均勻噴灑膜衣溶液而形成膜衣，以獲得如表14所示之組成的膜衣錠(每錠重：135mg)。(4) Premix I (40.00 g) was dissolved in pure water (360.0 g) to obtain a film coating solution. In a film coater (DRC-200, POWREX Co., Ltd.), a film coating solution was uniformly sprayed on a core tablet (200.0 g) to form a film coat to obtain a film ingot having the composition shown in Table 14. (weight per tablet: 135mg).

實施例15Example 15

(1)將羥丙基纖維素(35.10g)及macrogol 6000(16.20g)溶於純水(403.7g)中以獲得黏結液。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(10.40 g)、化合物B(30.00 g)、D-甘露醇(250.6 g)及微晶纖維素(39.00 g)均勻地混合，粒化混合物並噴塗黏結液，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (10.40 g), compound B (30.00 g), D-mannitol (250.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將低取代之羥丙基纖維素(32.50 g)及硬脂酸鎂(3.250 g)加至所得經研磨之粒劑(289.3 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(VEL-5,Kikusui Seisakusho)中以6.5 mm直徑沖孔打錠(打錠壓力：5kN，每錠重：130 mg)以獲得內核錠劑。(3) The mixed granules obtained as above were punched in a 6.5 mm diameter in a rotary tableting machine (VEL-5, Kikusui Seisakusho) (ingot pressure: 5 kN, weight per spindle: 130 mg) to obtain a core Lozenges.

(4)　將交聯聚維酮(57.44 g)及macrogol 6000(11.52 g)溶於純水(375.0 g)中以獲得膜衣溶液I。將二氧化鈦(7.680 g)、紅色氧化鐵(0.1650 g)及黃色氧化鐵(0.5100 g)分散於純水(330.0 g)中以獲得分散液I。混合膜衣溶液I、分散液I及純水(68.25 g)以獲得膜衣溶液II。於膜覆機(DRC-200,POWREX Co.,Ltd.)中，在內核錠劑(120.0 g)上均勻噴灑膜衣溶液II而形成膜衣，以獲得如表15所示之組成的膜衣錠(每錠重：135.154 mg)。(4) The crospovidone (57.44 g) and macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g), red iron oxide (0.1650 g) and yellow iron oxide (0.5100 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, POWREX Co., Ltd.), the film coat solution II was uniformly sprayed on the core tablet (120.0 g) to form a film coat to obtain a film coat having the composition shown in Table 15. Ingot (weight per spindle: 135.154 mg).

實施例16Example 16

(1)　將羥丙基纖維素(35.10 g)及macrogol 6000(16.20 g)溶於純水(403.7 g)中以獲得黏結液。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(20.79 g)、化合物B(30.00 g)、D-甘露醇(240.2 g)及微晶纖維素(39.00 g)均勻地混合，粒化混合物並噴塗黏結液，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (20.79 g), Compound B (30.00 g), D-mannitol (240.2 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將低取代之羥丙基纖維素(32.50 g)及硬脂酸鎂(3.250 g)加至所得經研磨之粒劑(289.3 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(VEL-5,Kikusui Seisakusho)中以6.5 mm直徑沖孔打錠(打錠壓力：5kN，每錠重：130 mg)以獲得內核錠劑。(3) The mixed granules obtained as above were punched in a 6.5 mm diameter in a rotary tableting machine (VEL-5, Kikusui Seisakusho) (ingot pressure: 5 kN, weight per spindle: 130 mg) to obtain a core Lozenges.

(4)　將交聯聚維酮(57.44 g)及macrogol 6000(11.52 g)溶於純水(375.0 g)中以獲得膜衣溶液I。將二氧化鈦(7.680 g)、紅色氧化鐵(0.1650 g)及黃色氧化鐵(0.5100 g)分散於純水(330.0 g)中以獲得分散液I。混合膜衣溶液I、分散液I及純水(68.25 g)以獲得膜衣溶液II。於膜覆機(DRC-200,POWREX Co.,Ltd.)中，在內核錠劑(120.0 g)上均勻噴灑膜衣溶液II而形成膜衣，以獲得如表16所示之組成的膜衣錠(每錠重：135.154 mg)。(4) The crospovidone (57.44 g) and macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g), red iron oxide (0.1650 g) and yellow iron oxide (0.5100 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, POWREX Co., Ltd.), the film coat solution II was uniformly sprayed on the core tablet (120.0 g) to form a film coat to obtain a film coat having the composition shown in Table 16. Ingot (weight per spindle: 135.154 mg).

實施例17Example 17

(1)　將羥丙基纖維素(35.10 g)及macrogol 6000(16.20 g)溶於純水(403.7 g)中以獲得黏結液。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(10.40 g)、化合物B(60.00 g)、D-甘露醇(220.6 g)及微晶纖維素(39.00 g)均勻地混合，粒化混合物並噴塗黏結液，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (10.40 g), Compound B (60.00 g), D-mannitol (220.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將低取代之羥丙基纖維素(32.50 g)及硬脂酸鎂(3.250 g)加至所得經研磨之粒劑(289.3 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(VEL-5,Kikusui Seisakusho)中以6.5 mm直徑沖孔打錠(打錠壓力：5kN，每錠重：130 mg)以獲得內核錠劑。(3) The mixed granules obtained as above were punched in a 6.5 mm diameter in a rotary tableting machine (VEL-5, Kikusui Seisakusho) (ingot pressure: 5 kN, weight per spindle: 130 mg) to obtain a core Lozenges.

(4)　將交聯聚維酮(57.44 g)及macrogol 6000(11.52 g)溶於純水(375.0 g)中以獲得膜衣溶液I。將二氧化鈦(7.680 g)及紅色氧化鐵(0.1500 g)分散於純水(330.0 g)中以獲得分散液I。混合膜衣溶液I、分散液I及純水(68.25 g)以獲得膜衣溶液II。於膜覆機(DRC-200,POWREX Co.,Ltd.)中，在內核錠劑(120.0 g)上均勻噴灑膜衣溶液II而形成膜衣，以獲得如表17所示之組成的膜衣錠(每錠重：135.119 mg)。(4) The crospovidone (57.44 g) and macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g) and red iron oxide (0.1500 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, POWREX Co., Ltd.), the film coating solution II was uniformly sprayed on the core tablet (120.0 g) to form a film coat to obtain a film coat having the composition shown in Table 17. Ingot (weight per spindle: 135.119 mg).

實施例18Example 18

(1)　將羥丙基纖維素(35.10 g)及macrogol 6000(16.20 g)溶於純水(403.7 g)中以獲得黏結液。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(20.79 g)、化合物B(60.00 g)、D-甘露醇(210.2 g)及微晶纖維素(39.00 g)均勻地混合，粒化混合物並噴塗黏結液，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (20.79 g), compound B (60.00 g), D-mannitol (210.2 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將低取代之羥丙基纖維素(32.50 g)及硬脂酸鎂(3.250 g)加至所得經研磨之粒劑(289.3 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(VEL-5,Kikusui Seisakusho)中以6.5 mm直徑沖孔打錠(打錠壓力：5kN，每錠重：130 mg)以獲得內核錠劑。(3) The mixed granules obtained as above were punched in a 6.5 mm diameter in a rotary tableting machine (VEL-5, Kikusui Seisakusho) (ingot pressure: 5 kN, weight per spindle: 130 mg) to obtain a core Lozenges.

(4)　將交聯聚維酮(57.44 g)及macrogol 6000(11.52 g)溶於純水(375.0 g)中以獲得膜衣溶液I。將二氧化鈦(7.680 g)及紅色氧化鐵(0.1500 g)分散於純水(330.0 g)中以獲得分散液I。混合膜衣溶液I、分散液I及純水(68.25 g)以獲得膜衣溶液II。於膜覆機(DRC-200,POWREX Co.,Ltd.)中，在內核錠劑(120.0 g)上均勻噴灑膜衣溶液II而形成膜衣，以獲得如表18所示之組成的膜衣錠(每錠重：135.119 mg)。(4) The crospovidone (57.44 g) and macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g) and red iron oxide (0.1500 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, POWREX Co., Ltd.), the film coat solution II was uniformly sprayed on the core tablet (120.0 g) to form a film coat to obtain a film coat having the composition shown in Table 18. Ingot (weight per spindle: 135.119 mg).

實施例19Example 19

(1)　將羥丙基纖維素(35.10 g)及macrogol 6000(16.20 g)溶於純水(403.7 g)中以獲得黏結液。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(10.40 g)、化合物B(120.0 g)、D-甘露醇(160.6 g)及微晶纖維素(39.00 g)均勻地混合，粒化混合物並噴塗黏結液，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (10.40 g), Compound B (120.0 g), D-mannitol (160.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將低取代之羥丙基纖維素(32.50 g)及硬脂酸鎂(3.250 g)加至所得經研磨之粒劑(289.3 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(VEL-5,Kikusui Seisakusho)中以6.5 mm直徑沖孔打錠(打錠壓力：5kN，每錠重：130 mg)以獲得內核錠劑。(3) The mixed granules obtained as above were punched in a 6.5 mm diameter in a rotary tableting machine (VEL-5, Kikusui Seisakusho) (ingot pressure: 5 kN, weight per spindle: 130 mg) to obtain a core Lozenges.

(4)　將交聯聚維酮(57.44 g)及macrogol 6000(11.52 g)溶於純水(375.0g)中以獲得膜衣溶液I。將二氧化鈦(7.680g)及黃色氧化鐵(0.6900g)分散於純水(330.0g)中以獲得分散液I。混合膜衣溶液I、分散液I及純水(68.25g)以獲得膜衣溶液II。於膜覆機(DRC-200,POWREX Co.,Ltd.)中，在內核錠劑(120.0g)上均勻噴灑膜衣溶液II而形成膜衣，以獲得如表19所示之組成的膜衣錠(每錠重：135.155mg)。(4) The crospovidone (57.44 g) and macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g) and yellow iron oxide (0.6900 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, POWREX Co., Ltd.), the film coat solution II was uniformly sprayed on the core tablet (120.0 g) to form a film coat to obtain a film coat having the composition shown in Table 19. Ingot (weight per spindle: 135.155 mg).

實施例20Example 20

(1)　將羥丙基纖維素(35.10 g)及macrogol 6000(16.20 g)溶於純水(403.7 g)中以獲得黏結液。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(20.79 g)、化合物B(120.0 g)、D-甘露醇(150.2 g)及微晶纖維素(39.00 g)均勻地混合，粒化混合物並噴塗黏結液，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in pure water (403.7 g) to obtain a binder. Amlodipine besylate (20.79 g), compound B (120.0 g), D-mannitol (150.2 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) The cellulose (39.00 g) was uniformly mixed, the mixture was granulated and the binder was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將低取代之羥丙基纖維素(32.50 g)及硬脂酸鎂(3.250 g)加至所得經研磨之粒劑(289.3 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(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)　如上所獲之混合粒劑，於旋轉打錠機(VEL-5,Kikusui Seisakusho)中以7.0 mm直徑沖孔打錠(打錠壓力：5kN，每錠重：130 mg)以獲得內核錠劑。(3) The mixed granules obtained above were punched in a rotary tableting machine (VEL-5, Kikusui Seisakusho) at a diameter of 7.0 mm (ingot pressure: 5 kN, weight per spindle: 130 mg) to obtain a core. Lozenges.

(4)　將交聯聚維酮(57.44 g)及macrogol 6000(11.52 g)溶於純水(375.0 g)中以獲得膜衣溶液I。將二氧化鈦(7.680 g)及黃色氧化鐵(0.6900 g)分散於純水(330.0 g)中以獲得分散液I。混合膜衣溶液I、分散液I及純水(68.25 g)以獲得膜衣溶液II。於膜覆機(DRC-200,POWREX Co.,Ltd.)中，在內核錠劑(120.0 g)上均勻噴灑膜衣溶液II而形成膜衣，以獲得如表20所示之組成的膜衣錠(每錠重：135.155 mg)。(4) The crospovidone (57.44 g) and macrogol 6000 (11.52 g) were dissolved in pure water (375.0 g) to obtain a film coating solution I. Titanium dioxide (7.680 g) and yellow iron oxide (0.6900 g) were dispersed in pure water (330.0 g) to obtain a dispersion I. Membrane solution I, dispersion I and pure water (68.25 g) were mixed to obtain a film coating solution II. In the film coater (DRC-200, POWREX Co., Ltd.), the film coating solution II was uniformly sprayed on the core tablet (120.0 g) to form a film coat to obtain a film coat having the composition shown in Table 20. Ingot (weight per spindle: 135.155 mg).

實施例21Example 21 表21Table 21 每份製劑(260 mg)的組成Composition of each preparation (260 mg)

(1)　將交聯聚維酮(720.0 g)溶於純水(9000 g)中以獲得黏結液I。將紅色氧化鐵(2.880 g)分散於純水(2880 g)中以獲得分散液I。將分散液I及純水(720.0 g)混合於黏結液I中以獲得黏結液II。於流體化床粒化機(FD-S2,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(1249 g)、D-甘露醇(16660 g)及微晶纖維素(3600 g)均勻地混合，粒化混合物並噴塗黏結液II，接著乾燥以獲得粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以製得經研磨之粒劑I。(1) The crospovidone (720.0 g) was dissolved in pure water (9000 g) to obtain a binder I. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion I. Dispersion I and pure water (720.0 g) were mixed in the binder I to obtain a binder II. Uniform amlodipine besylate (1249 g), D-mannitol (16660 g) and microcrystalline cellulose (3600 g) in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The mixture is mixed, the mixture is granulated and the binder II is sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieve mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule I.

(2)　將羥丙基纖維素(720.0 g)及macrogol 6000(468.0 g)溶於純水(9000 g)中以獲得黏結液III。將紅色氧化鐵(2.880 g)分散於純水(2880 g)中以獲得分散液II。將分散液II及純水(720.0 g)混合於黏結液III中以獲得黏結液IV。於流體化床粒化機(FD-S2,POWREX Co.,Ltd.)中將化合物A(1436 g)、乳糖水合物(16090 g)及玉米澱粉(3600 g)均勻地混合，粒化混合物並噴塗黏結液IV，接著乾燥以獲得粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以製得經研磨之粒劑II。。(2) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (468.0 g) were dissolved in pure water (9000 g) to obtain a binder III. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion II. Dispersion II and pure water (720.0 g) were mixed in the binder III to obtain a binder IV. Compound A (1436 g), lactose hydrate (16090 g) and corn starch (3600 g) were uniformly mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated and The binder IV is sprayed and then dried to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieve mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule II. .

(3)　將交聯羧甲基纖維素鈉(1848 g)及硬脂酸鎂(214.5 g)加至所得經研磨之粒劑I(20380 g)及經研磨之粒劑II(20460 g)，於滾筒混合機(TM20-0-0,Suehiro Kakoki Co.,Ltd.)中混合，以獲得混合粒劑。(3) croscarmellose sodium (1848 g) and magnesium stearate (214.5 g) were added to the obtained milled granule I (20380 g) and ground granule II (20460 g). It was mixed in a tumble mixer (TM20-0-0, Suehiro Kakoki Co., Ltd.) to obtain a mixed granule.

(4)　如上所獲之混合粒劑，於旋轉打錠機(AQUARIUS-36K,Kikusui Seisakusho)中以8.5 mm直徑沖孔打錠(打錠壓力：10kN，每錠重：260 mg)以獲得如表21所示之組成的素錠劑。(4) The mixed granules obtained as above were punched in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) at a diameter of 8.5 mm (ingot pressure: 10 kN, weight per spindle: 260 mg) to obtain A tablet of the composition shown in Table 21.

實施例22Example 22

(1)　將交聯聚維酮(720.0 g)溶於純水(9000 g)中以獲得黏結液I。將紅色氧化鐵(2.880 g)分散於純水(2880 g)中以獲得分散液I。混合黏結液I、分散液I及純水(720.0 g)以獲得黏結液II。於流體化床粒化機(FD-S2,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(1249 g)、D-甘露醇(16660 g)及微晶纖維素(3600 g)均勻地混合，粒化混合物並噴塗黏結液II，接著乾燥以獲得粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以製得經研磨之粒劑I。(1) The crospovidone (720.0 g) was dissolved in pure water (9000 g) to obtain a binder I. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (720.0 g) to obtain the binder II. Uniform amlodipine besylate (1249 g), D-mannitol (16660 g) and microcrystalline cellulose (3600 g) in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) The mixture is mixed, the mixture is granulated and the binder II is sprayed, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieve mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule I.

(2)　將交聯羧甲基纖維素鈉(924.0 g)及硬脂酸鎂(148.5 g)加至所得經研磨之粒劑I(20380 g)，於滾筒混合機(TM-60,Showa Kagakukikai Co.,Ltd.)中混合，以獲得混合粒劑I。(2) Add croscarmellose sodium (924.0 g) and magnesium stearate (148.5 g) to the obtained ground granule I (20380 g) in a roller mixer (TM-60, Showa Kagakukikai) Co., Ltd.) was mixed to obtain a mixed granule I.

(3)　將羥丙基纖維素(720.0 g)及macrogol 6000(468.0 g)溶於純水(9000 g)中以獲得黏結液III。將紅色氧化鐵(2.880 g)分散於純水(2880 g)中以獲得分散液II。將分散液II及純水(720.0 g)混合於黏結液III中以獲得黏結液IV。於流體化床粒化機(FD-S2,POWREX Co.,Ltd.)中將化合物A(1436 g)、乳糖水合物(16090 g)及玉米澱粉(3600 g)均勻地混合，粒化混合物並噴塗黏結液IV，接著乾燥以獲得粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以製得經研磨之粒劑II。(3) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (468.0 g) were dissolved in pure water (9000 g) to obtain a binder III. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion II. Dispersion II and pure water (720.0 g) were mixed in the binder III to obtain a binder IV. Compound A (1436 g), lactose hydrate (16090 g) and corn starch (3600 g) were uniformly mixed in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated and The binder IV is sprayed and then dried to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieve mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule II.

(4)　將羧甲基纖維素鈣(924.0 g)及硬脂酸鎂(66.00 g)加至所得經研磨之粒劑II(20460 g)，於滾筒混合機(TM-60,Showa Kagakukikai Co.,Ltd.)中混合，以獲得混合粒劑II。(4) Carboxymethylcellulose calcium (924.0 g) and magnesium stearate (66.00 g) were added to the obtained ground granule II (20460 g) in a tumble mixer (TM-60, Showa Kagakukikai Co. , Ltd.) mixed to obtain mixed granules II.

(5)　如上所獲之混合粒劑I(130 mg)及混合粒劑II(130 mg)，於旋轉打錠機(HT-CVX54LS-UW/C&3L,HATA IRON WORKS Co.,Ltd.)中以8.5 mm直徑沖孔打錠(打錠壓力：9kN，每錠重：260 mg)以獲得如表22所示之組成的多層素錠劑。(5) The mixed granule I (130 mg) and the mixed granule II (130 mg) obtained as above were used in a rotary tableting machine (HT-CVX54LS-UW/C&3L, HATA IRON WORKS Co., Ltd.) A 8.5 mm diameter punching tablet (pressing pressure: 9 kN, weight per spindle: 260 mg) to obtain a multilayer tablet of the composition shown in Table 22.

實施例23Example 23 表23Table 23 每份製劑(239 mg)的組成Composition of each preparation (239 mg)

(1)　將羥丙基纖維素(155.0 g)溶於純水(1395.0 g)中以獲得黏結液I。於流體化床粒化機(FD-5S,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(346.7 g)、D-甘露醇(2447.0 g)及微晶纖維素(766.7 g)均勻地混合，粒化混合物並噴塗黏結液I，接著乾燥以獲得具苯磺酸氨氯地平層之粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以獲得苯磺酸氨氯地平層之經研磨粒劑。(1) Hydroxypropylcellulose (155.0 g) was dissolved in pure water (1395.0 g) to obtain a binder I. Uniform amlodipine besylate (346.7 g), D-mannitol (2447.0 g) and microcrystalline cellulose (766.7 g) in a fluidized bed granulator (FD-5S, POWREX Co., Ltd.) The mixture is granulated, the mixture is granulated and the binder I is sprayed, followed by drying to obtain a granule having a layer of amlodipine besylate. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to obtain a ground granule of amlodipine besylate.

(2)　將羥丙基纖維素(280.1 g)及macrogol 6000(280.0 g)溶於純水(2520.2 g)中以獲得黏結液II。於流體化床粒化機(FD-5S,POWREX Co.,Ltd.)中將化合物B(2808.4 g)、乳糖水合物(2043.5 g)、玉米澱粉(910.3 g)及微晶纖維素(910.2 g)均勻地混合，粒化混合物並噴塗黏結液II，接著乾燥以獲得化合物B層之粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以獲得化合物B層之經研磨粒劑。(2) Hydroxypropylcellulose (280.1 g) and macrogol 6000 (280.0 g) were dissolved in pure water (2520.2 g) to obtain a binder II. Compound B (2808.4 g), lactose hydrate (2043.5 g), corn starch (910.3 g) and microcrystalline cellulose (910.2 g) in a fluidized bed granulator (FD-5S, POWREX Co., Ltd.) The mixture was uniformly mixed, the mixture was granulated and the binder II was sprayed, followed by drying to obtain a granule of the compound B layer. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to obtain a ground granule of the compound B layer.

(3)　將羧甲基纖維素鈣(200.0 g)及硬脂酸鎂(28.000 g)加至所得苯磺酸氨氯地平層之經研磨粒劑(3772.0 g)，於滾筒混合機(TM-15,Suehiro Kakoki co.,Ltd.)中混合，以獲得苯磺酸氨氯地平層之混合粒劑。(3) Carboxymethylcellulose calcium (200.0 g) and magnesium stearate (28.000 g) were added to the obtained amlodipine besylate layer of ground granules (3772.0 g) in a roller mixer (TM- 15, Suehiro Kakoki co., Ltd.) was mixed to obtain a mixed granule of amlodipine besylate.

(4)　將低取代之羥丙基纖維素(455.0 g)、微晶纖維素(455.1 g)及硬脂酸鎂(24.53 g)加至所得化合物B層之經研磨粒劑(3616.1 g)，於滾筒混合機(TM-15,Suehiro Kakoki co.,Ltd.)中混合，以獲得化合物B層之混合粒劑。(4) A low-substituted hydroxypropylcellulose (455.0 g), microcrystalline cellulose (455.1 g), and magnesium stearate (24.53 g) were added to the obtained compound B layer of the ground granule (3616.1 g). It was mixed in a tumble mixer (TM-15, Suehiro Kakoki co., Ltd.) to obtain a mixed granule of the compound B layer.

(5)　如上所獲之苯磺酸氨氯地平層之混合粒劑及化合物B層之混合粒劑，於旋轉打錠機(HT-X12SS-UW＆2L,HATA IRON WORKS Co.,Ltd.)中以8.0 mm直徑沖孔打錠(打錠壓力：7kN，每錠重：230 mg(苯磺酸氨氯地平層：100 mg；化合物B層：130 mg))以獲得多層內核錠劑。(5) The mixed granule of the amlodipine besylate layer obtained as described above and the mixed granule of the compound B layer are used in a rotary tableting machine (HT-X12SS-UW & 2L, HATA IRON WORKS Co., Ltd.) 8.0 mm diameter punched ingot (ingoting pressure: 7 kN, weight per spindle: 230 mg (amlodipine besylate: 100 mg; compound B layer: 130 mg)) to obtain a multilayer core tablet.

(6)　將預混合物I(252.0 g)溶於純水(2268.0 g)中以獲得膜衣溶液。於膜覆機(DRC-500,POWREX Co.,Ltd.)中，在內核錠劑(3120.0 g)上均勻噴灑膜衣溶液而形成膜衣，以獲得如表23所示之組成的膜衣錠(每錠重：239 mg)。此處，預混合物I係預混合的粉末。預混合物I的組成如表23a所示。(6) Premix I (252.0 g) was dissolved in pure water (2268.0 g) to obtain a film coating solution. In a film coater (DRC-500, POWREX Co., Ltd.), a film coating solution was uniformly sprayed on a core tablet (3120.0 g) to form a film coat to obtain a film ingot having the composition shown in Table 23 (weight per tablet: 239 mg). Here, the premix I is a premixed powder. The composition of Premix I is shown in Table 23a.

實施例24Example 24

(1)　將羥丙基纖維素(80.00 g)及macrogol 4000(36.00 g)溶於純水(1100 g)中以獲得黏結液I。將紅色氧化鐵(2.080 g)分散於純水(200.1 g)中以獲得分散液I。混合黏結液I、分散液I及純水(60.00 g)以獲得黏結液II。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(24.95 g)、化合物A(28.80 g)、D-甘露醇(297.6 g)及微晶纖維素(72.00 g)均勻地混合，粒化混合物並噴塗黏結液II(266.1 g)，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (80.00 g) and macrogol 4000 (36.00 g) were dissolved in pure water (1100 g) to obtain a binder I. Red iron oxide (2.080 g) was dispersed in pure water (200.1 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (60.00 g) to obtain the binder II. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (297.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) Cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder II (266.1 g) was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將交聯羧甲基纖維素鈉(16.81 g)及硬脂酸鎂(2.700 g)加至所得經研磨之粒劑(370.5 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(2) croscarmellose sodium (16.81 g) and magnesium stearate (2.700 g) were added to the obtained ground granules (370.5 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3)　如上所獲之混合粒劑，於旋轉打錠機(Correct 19K,Kikusui Seisakusho)中以8.5 mm長直徑沖孔及5.0 mm短直徑沖孔打錠(打錠壓力：8.5kN，每錠重：130 mg)以獲得如表24所示之組成的素錠劑。(3) The mixed granules obtained above were punched in a rotary ingot machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 8.5 kN, each ingot) Weight: 130 mg) A flavonoid having the composition shown in Table 24 was obtained.

實施例25Example 25

(1)　將羥丙基纖維素(80.00 g)及macrogol 10000(36.00 g)溶於純水(1100 g)中以獲得黏結液I。將紅色氧化鐵(2.080 g)分散於純水(200.1 g)中以獲得分散液I。混合黏結液I、分散液I及純水(60.10 g)以獲得黏結液II。於流體化床粒化機(Lab-1,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(24.95 g)、化合物A(28.80 g)、D-甘露醇(297.6 g)及微晶纖維素(72.00 g)均勻地混合，粒化混合物並噴塗黏結液II(266.1 g)，接著乾燥以獲得粒劑。以篩網(16篩孔)將所得粒劑的一部分過篩以製得經研磨之粒劑。(1) Hydroxypropylcellulose (80.00 g) and macrogol 10000 (36.00 g) were dissolved in pure water (1100 g) to obtain a binder I. Red iron oxide (2.080 g) was dispersed in pure water (200.1 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (60.10 g) to obtain the binder II. Amlodipine besylate (24.95 g), Compound A (28.80 g), D-mannitol (297.6 g) and microcrystals in a fluidized bed granulator (Lab-1, POWREX Co., Ltd.) Cellulose (72.00 g) was uniformly mixed, the mixture was granulated and the binder II (266.1 g) was sprayed, followed by drying to obtain granules. A portion of the obtained granules was sieved with a sieve (16 mesh) to prepare a milled granule.

(2)　將交聯羧甲基纖維素鈉(16.80 g)及硬脂酸鎂(2.710 g)加至所得經研磨之粒劑(370.5 g)，於聚乙烯袋(4.9 L)中混合，以獲得混合粒劑。(2) croscarmellose sodium (16.80 g) and magnesium stearate (2.710 g) were added to the obtained ground granules (370.5 g), and mixed in a polyethylene bag (4.9 L) to A mixed granule is obtained.

(3)　如上所獲之混合粒劑，於旋轉打錠機(Correct 19K,Kikusui Seisakusho)中以8.5 mm長直徑沖孔及5.0 mm短直徑沖孔打錠(打錠壓力：8.5kN，每錠重：130 mg)以獲得如表25所示之組成的素錠劑。(3) The mixed granules obtained above were punched in a rotary ingot machine (Correct 19K, Kikusui Seisakusho) with a diameter of 8.5 mm and a short diameter of 5.0 mm (ingot pressure: 8.5 kN, each ingot) Weight: 130 mg) A flavonoid having the composition shown in Table 25 was obtained.

比較實施例1Comparative Example 1

(1)　將羥丙基纖維素(720.0 g)及macrogol 6000(468.0 g)溶於純水(9000 g)中以獲得黏結液I。將紅色氧化鐵(2.880 g)分散於純水(2880 g)中以獲得分散液I。混合黏結液I、分散液I及純水(720.0 g)以獲得黏結液II。於流體化床粒化機(FD-S2,POWREX Co.,Ltd.)中將苯磺酸氨氯地平(1253 g)、化合物A(1449 g)、乳糖水合物(14830 g)及玉米澱粉(3600 g)均勻地混合，粒化混合物並噴塗黏結液II，接著乾燥以獲得粒劑。於篩分研磨機(P-3,Showa Kagakukikai Co.,Ltd.)中，將所得粒劑的一部分以1.5 mmφ沖孔篩板研磨，以製得經研磨之粒劑。(1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (468.0 g) were dissolved in pure water (9000 g) to obtain a binder I. Red iron oxide (2.880 g) was dispersed in pure water (2880 g) to obtain a dispersion I. Mix the binder I, the dispersion I and the pure water (720.0 g) to obtain the binder II. Amlodipine besylate (1253 g), Compound A (1449 g), lactose hydrate (14830 g) and corn starch in a fluidized bed granulator (FD-S2, POWREX Co., Ltd.) 3600 g) Evenly mixed, granulated the mixture and sprayed the binder II, followed by drying to obtain granules. A part of the obtained granules was ground in a 1.5 mmφ punching sieve in a sieving mill (P-3, Showa Kagakukikai Co., Ltd.) to prepare a ground granule.

(2)　將羧甲基纖維素鈣(1848 g)及硬脂酸鎂(132.0 g)加至所得經研磨之粒劑(40920 g(2批))，於滾筒混合機(TM20-0-0,Suehiro Kakoki co.,Ltd.)中混合，以獲得混合粒劑。(2) Calcium carboxymethylcellulose (1848 g) and magnesium stearate (132.0 g) were added to the obtained milled granules (40920 g (2 batches)) in a roller mixer (TM20-0-0) , Suehiro Kakoki co., Ltd.) was mixed to obtain a mixed granule.

(3)　如上所獲之混合粒劑，於旋轉打錠機(AQUARIUS-36K,Kikusui Seisakusho)中以7.0 mm直徑沖孔打錠(打錠壓力：9kN，每錠重：130 mg)以獲得如表26所示之組成的素錠劑。(3) The mixed granules obtained as above were punched in a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) at a diameter of 7.0 mm (ingot pressure: 9 kN, weight per spindle: 130 mg) to obtain The lozenge of the composition shown in Table 26.

試驗實施例1Test Example 1 溶解測試1Dissolution test 1

活性成分(化合物A)自實施例1至11、24、25及比較實施例1所得之素錠劑的溶解性質，係藉由溶解測試(1.0(w/w)%聚山梨醇酯20溶液、900 mL、37℃、漿式(Paddle Method)、旋轉數50 rpm)評估。依據Japanese Pharmacopoeia,15th Edition,Dissolution Test,Apparatus 2(Paddle Method)，進行溶解測試。結果示於表27。表27係顯示溶解開始後15分鐘之溶解率的平均值、最大值及最小值。實施例1、4、5、8至11、24、25及比較實施例1，係列出6個錠劑之溶解率的平均值、最大值及最小值，而實施例2、3、6及7則列出12個錠劑之溶解率的平均值、最大值及最小值。The solubility properties of the active ingredient (Compound A) from the flavonoids obtained in Examples 1 to 11, 24, 25 and Comparative Example 1 were determined by dissolution test (1.0 (w/w)% polysorbate 20 solution, 900 mL, 37 ° C, Paddle Method, rotation number 50 rpm). The dissolution test was carried out in accordance with Japanese Pharmacopoeia, 15th Edition, Dissolution Test, Apparatus 2 (Paddle Method). The results are shown in Table 27. Table 27 shows the average value, maximum value, and minimum value of the dissolution rate 15 minutes after the start of dissolution. In Examples 1, 4, 5, 8 to 11, 24, 25 and Comparative Example 1, the average, maximum and minimum values of the dissolution rates of the six tablets were serialized, while Examples 2, 3, 6 and 7 were carried out. The average, maximum and minimum values of the dissolution rates of the 12 tablets are listed.

如表27所示，與比較實施例1之不含糖醇的錠劑相比，含有糖醇作為賦形劑之實施例1至11、24、25的所有素錠劑顯示了化合物A之優良溶解性質。As shown in Table 27, the all-flavored tablets of Examples 1 to 11, 24, and 25 containing a sugar alcohol as an excipient showed superiority of Compound A as compared with the sugar alcohol-free tablet of Comparative Example 1. Solubility properties.

試驗實施例2Test Example 2 溶解測試2Dissolution test 2

活性成分(化合物B)自實施例20所得之膜衣錠的溶解性質，係藉由溶解測試(the Japanese Pharmacopoeia,15th Edition,2nd fluid for dissolution test,900 mL、37℃、漿式、旋轉數50 rpm)評估。依據the Japanese Pharmacopoeia,15th Edition,Dissolution Test,Apparatus 2(Paddle Method)，進行溶解測試。結果示於表28。表28係顯示溶離開始後5至60分鐘之每個時間點的6個錠劑之溶解率的平均值、最大值及最小值。The dissolution property of the active ingredient (Compound B) from the film-coated tablet obtained in Example 20 was determined by the dissolution test (the Japanese Pharmacopoeia, 15th Edition, 2nd fluid for dissolution test, 900 mL, 37 ° C, slurry type, rotation number 50). Rpm) evaluation. The dissolution test was carried out according to the Japanese Pharmacopoeia, 15th Edition, Dissolution Test, Apparatus 2 (Paddle Method). The results are shown in Table 28. Table 28 shows the average value, maximum value, and minimum value of the dissolution rates of 6 tablets at each time point 5 to 60 minutes after the start of the dissolution.

如表28所示，實施例20之膜衣錠顯示了化合物B之優良溶解性質。As shown in Table 28, the film ingot of Example 20 showed the excellent solubility properties of Compound B.

試驗實施例3Test Example 3 安定性測試Stability test

實施例1、4及5之素錠劑，以密封玻璃瓶、25℃/60%RH的條件保存12個月。測量衍生自化合物A或苯磺酸氨氯地平之類似物的質量，並以此為基準評估保存安定性。結果示於表29。表29所示之值係表示當化合物A或苯磺酸氨氯地平之含量為100%時，所有衍生自化合物A或苯磺酸氨氯地平之類似物的比率(%)(化合物A；8 mg或4 mg/苯磺酸氨氯地平；6.93 mg或3.47 mg)。The lozenges of Examples 1, 4 and 5 were stored in a sealed glass bottle at 25 ° C / 60% RH for 12 months. The mass of the analog derived from Compound A or amlodipine besylate was measured, and the preservation stability was evaluated based on this. The results are shown in Table 29. The values shown in Table 29 are the ratios (%) of all analogs derived from Compound A or amlodipine besylate when Compound A or amlodipine besylate is 100% (Compound A; 8) Mg or 4 mg / amlodipine besylate; 6.93 mg or 3.47 mg).

如表29所示，實施例1、4及5之素錠劑顯示優良的保存安定性。As shown in Table 29, the tablet tablets of Examples 1, 4 and 5 showed excellent preservation stability.

產業利用性Industrial utilization

本發明提供固體製劑，該固體製劑包含式(I)所示之化合物或其鹽、糖醇以及鈣拮抗劑，其適當控制了胃腸道中式(I)所示之化合物或其鹽、鈣拮抗劑自固體製劑之溶解性質，並維持其於固體製劑中之良好安定性。The present invention provides a solid preparation comprising a compound represented by the formula (I) or a salt thereof, a sugar alcohol, and a calcium antagonist, which suitably controls a compound represented by the formula (I) or a salt thereof, a calcium antagonist in the gastrointestinal tract The solubility properties of the solid preparations are maintained and their good stability in solid preparations is maintained.

本申請案是以日本專利申請案案號2009-111381及2010-68625為基礎，並以引用方式將全文納入本文中。The present application is based on Japanese Patent Application Nos. 2009-111381 and 2010-68625, the entire contents of each of which are incorporated herein by reference.

本案無圖式。There is no schema in this case.

Claims (4)

一種固體製劑，其包括：(i)選自2-乙氧基-1-[[2’-(1H-四唑-5-基)聯苯-4-基]甲基]苯并咪唑-7-羧酸1-(環己氧基羰氧基)乙酯和2-乙氧基-1-[[2’-(4,5-二氫-5-側氧基-1,2,4-二唑-3-基)聯苯-4-基]甲基]-1H-苯并咪唑-7-羧酸之化合物或其鹽、(ii)甘露糖醇、(iii)氨氯地平或其鹽以及(iv)具有分子量為3,000至10,000的聚乙二醇。A solid preparation comprising: (i) selected from the group consisting of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7 -carboxylic acid 1-(cyclohexyloxycarbonyloxy)ethyl ester and 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxooxy-1,2,4- a compound of oxazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof, (ii) mannitol, (iii) amlodipine or a salt thereof And (iv) polyethylene glycol having a molecular weight of 3,000 to 10,000. 如申請專利範圍第1項所述之固體製劑，其中，該化合物或其鹽為2-乙氧基-1-[[2’-(1H-四唑-5-基)聯苯-4-基]甲基]苯并咪唑-7-羧酸1-(環己氧基羰氧基)乙酯或其鹽。 The solid preparation according to claim 1, wherein the compound or a salt thereof is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl ]Methyl]benzimidazole-7-carboxylic acid 1-(cyclohexyloxycarbonyloxy)ethyl ester or a salt thereof. 如申請專利範圍第1項所述之固體製劑，其中，該化合物或其鹽為2-乙氧基-1-[[2’-(4,5-二氫-5-側氧基-1,2,4-二唑-3-基)聯苯-4-基]甲基]-1H-苯并咪唑-7-羧酸或其鹽。The solid preparation according to claim 1, wherein the compound or a salt thereof is 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxy-1). 2,4- Azoxa-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof. 如申請專利範圍第1項所述之固體製劑，其中，該氨氯地平或其鹽為苯磺酸氨氯地平。The solid preparation according to claim 1, wherein the amlodipine or a salt thereof is amlodipine besylate.