CN101596195B - 降低血压的口服药物组合物 - Google Patents
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Abstract
本发明涉及一种治疗高血压症的口服药物组合物，其特征是含有阿折地平和坎地沙坦酯，通过阿折地平和坎地沙坦酯在作用机制上的互补作用，在保证疗效的前提下，降低了用药剂量，以及长期用药所带来的不良反应。
Description
技术领域：
本发明涉及一种治疗高血压的口服药物组合物。
背景技术：
血压是指血液在人的血管中流动时对血管壁产生的压力，高血压病是指在静息状态下动脉收缩压和/或舒张压增高(＞＝140/90mmHg)，常伴有脂肪和糖代谢紊乱以及心、脑、肾和视网膜等器官功能性或器质性改变，以器官重塑为特征的全身性疾病。休息5分钟以上，2次以上非同日测得的血压＞＝140/90mmHg可以诊断为高血压。该病可由多种发病因素和复杂的发病机制所致，中枢神经系统功能失调，肾脑血管压力感受器的功能异常等均可导致高血压病。
高血压是最常见的心血管疾病，其并发症是造成人类死亡的主要原因之一，是世界范围内威胁人类健康的重大疾病之一。随着社会的发展，人类生活方式的改变以及人口老龄化的加剧，高血压患病率呈现迅猛的上升趋势，这一发展态势日益凸显。已被喻为“威胁人类健康的第一杀手”。我国高血压患病率正在快速增加，有资料报道，成年人中估计的高血压的患者1.7亿，每年新增高血压患者600万，且患者呈年轻化趋势。
有文献报道，目前高血压的控制遭遇到了单药控制率不足60％的瓶颈，因此，如何在高血压治疗中联合用药，已成为日益关注并且急需解决的重要问题。
阿折地平(Azelnidipine)是日本三共公司最新推出的新一代钙拮抗剂。该药由日本三共制药与宇部(Ube)株式会社联合开发，属1，4-二氢吡啶钙拮抗剂(DHP)。2003年2月，阿折地平获准在日本上市，商品名为“Calblock”。本品作用于L型Ca通道拮抗作用，导致血管扩张而具有降压作用。
阿折地平是一种新型二氢吡啶类钙通道阻滞剂，它具有一般钙拮抗剂所不具备的特点，它能减慢心率，与血管组织具有高亲和性，因其作用缓和，极少引起反射性心动过速。
坎地沙坦酯是由日本武田制药公司研制开发，为一前体药物，在体内经肠道吸收，完全水解为去酯形成坎地沙坦的活性代谢物。本品高度选择与ATl受体结合，为非肽类ATl受体拮抗剂。
本品在体内经肠道吸收，完全水解为去酯坎地沙坦的活性代谢物。本品选择性地与AT受体的亚型(ATl)结合，为非肽类ATl受体拮抗剂。坎地沙坦主要通过尿液和粪便以原药形式排泄(通过胆汁)。少量通过肝脏代谢成非活性代谢物。
本发明人经过研究，并通过临床实验的反复验证，惊奇的发现通过坎地沙坦酯和阿折地平的联合用药，在保证治疗效果的同时，降低了药物的服用量。
本发明药物组合物的两种活性组分在作用机制上有着互补作用，联合用药后加强了降压作用。再者，联合用药降低了各活性组分的相对用量，降低了药物的不良反应，提高了患者的药物依从性，从而提高了患者的生活质量。
本发明的目的在于向人们提供一种服用量小、疗效确切、不良反应率低的复方降压组合物。
技术方案
本发明是在大量临床研究的基础上总结得来的。本发明的技术方案是：一种口服药物组合物，其特征在于含有阿折地平和坎地沙坦酯。
本发明口服药物组合物，其特征在于含有阿折地平0.3-4重量份，坎地沙坦酯1重量份。
本发明口服药物组合物，优选的技术方案是含有阿折地平0.3-3.5重量份，坎地沙坦酯1重量份。
本发明口服药物组合物，优选的技术方案是含有阿折地平0.7-4重量份，坎地沙坦酯1重量份。
本发明口服药物组合物，优选的技术方案是含有阿折地平0.7-3重量份，坎地沙坦酯1重量份。
本发明药物组合物，以阿折地平4-16mg，坎地沙坦酯4-12mg为最佳技术方案。
本发明药物组合物可以是片剂、颗粒剂、胶囊，口服液。按行业内常规方法制备。
本发明药物组合物的制备方法，记载在实施例中。
下面的实施例、试验例可更详细地说明本发明，但不以任何形式限制本发明。
实施例1、
处方：阿折地平8g，坎地沙坦酯4g，甘露醇64g，低取代羟丙基纤维素16g，羧甲基淀粉钠24g，碳酸钠4g，2％羟丙基甲基纤维素适量，硬脂酸镁0.6g，滑石粉2.4g，微粉硅胶1.2g，欧巴代约30g，乙醇适量。制成1000片或1000粒胶囊。
制备工艺：预处理：处方量的羟丙基甲基纤维素(HPMCE50)，加纯化水使溶解。加处方量的甘露醇、一半低取代羟丙基纤维素、碳酸钠、羧甲基淀粉钠分别过80目筛，混合均匀。加处方量的阿折地平，过100目筛，与上述物料等量递增混合均匀，存放待用。
制粒：在混合粉中加入适量粘合剂制软材，24目筛制粒，50℃通风干燥约2小时，20目筛整粒，加入处方量的坎地沙坦酯、硬脂酸镁、滑石粉、另一半低取代羟丙基纤维素和微粉硅胶，混合均匀，装胶囊或压片。
实验例2
处方：
阿折地平6g，坎地沙坦酯3g，甘露醇64g，低取代羟丙基纤维素16g，羧甲基淀粉钠60g，吐温-80 3g，2％羟丙基甲基纤维素适量，硬脂酸镁0.6g，滑石粉5g，制成1000片或1000粒胶囊。制备工艺参考实施例1。
实施例3：
处方：阿折地平4g，坎地沙坦酯12g，甘露醇64g，低取代羟丙基纤维素20g，羧甲基淀粉钠38g，碳酸钠4g，吐温-80 3g，硬脂酸镁0.6g，滑石粉2.4g，制成1000片或1000粒胶囊。制备工艺同实施例1。
实施例4、
处方：阿折地平6g，坎地沙坦酯6g，甘露醇64g，低取代羟丙基纤维素20g，羧甲基淀粉钠38g，碳酸钠4g，吐温-80 3g，硬脂酸镁0.6g，滑石粉2.4g，制成1000片或1000粒胶囊。
实施例5、
处方：阿折地平14g，坎地沙坦酯2g，甘露醇64g，低取代羟丙基纤维素20g，羧甲基淀粉钠38g，碳酸钠4g，吐温-80 3g，硬脂酸镁0.6g，滑石粉2.4g，制成1000片或1000粒胶囊。
实施例6、
处方：阿折地平4g，坎地沙坦酯12g，甘露醇64g，低取代羟丙基纤维素20g，羧甲基淀粉钠38g，碳酸钠4g，吐温-80 3g，硬脂酸镁0.6g，滑石粉2.4g，制成1000片或1000粒胶囊。
试验例
研究对象
病例的选择：门诊及住院的25-60岁的未经治疗或已经使用降压药物的轻、中、高度高血压患者共60例，其中男性35例，女性25例，服安稳剂后坐位舒张压为95-109mmHg(1mmHg＝0.133kPa)，坐位收缩压180mmHg。排除标准：继发性高血压、有心脑血管疾病发作史，需要用药物治疗的心律失常，对药物成分过敏，药物滥用或嗜酒者、妊娠和哺乳期，严重肝、肾功能不全。
研究方法
将入选患者随机分为3组，每组20人。试验前均停用降压药物2周，服用安稳剂(用赋形剂制成的与试验中药物形状、大小、颜色相同)。1组，服用实施例2的组合物，一日一次，一次1片；2组服用坎地沙坦酯片剂(本公司产品)，8mg/片，一日一次；3组服用阿折地平片剂(本公司产品)，16mg/片，一日一次。
观察指标：
服用安稳剂后于药物治疗开始前每隔半小时测量患者坐位右上肢血压1次，连续测量3次，取平均值作为治疗前的基础血压；治疗期间每周测量患者坐位右上肢血压1次，共服药8周，取其平均值为治疗后血压。
降压疗效判定：参照卫生部统一规定的高血压疗效评定标准进行疗效评定。
显效：舒张压下降大于10mmHg，并降至正常；或舒张压下降大于20mmHg。
有效：舒张压下降小于10mmHg，但已经达到正常；或舒张压下降10-19mmHg；或收缩压下降大于30mmHg。
无效：未达到上述标准。
总有效率(％)＝(显效例数+有效例数)/总例数×100％
统计学方法：计量资料以x±s表示，采用t检验，有效率以x2检验方法进行统计处理。p＜0.05差异有显著性。
结果
表1治疗8周血压变化：见表1
注：与治疗前比较，P小于0.001。
表2 3组患者降压疗效比较
| 组别 | 例数 | 显效 | 有效 | 无效 | 总有效率％ |
| 1 | 20 | 10 | 9 | 1 | 95 |
| 2 | 20 | 7 | 10 | 3 | 85 |
| 3 | 20 | 8 | 10 | 3 | 90 |
通过以上试验数据比较可以发现，通过坎地沙坦酯与阿折地平的联合用药，在保证治疗效果的前提下，大大降低了坎地沙坦酯和阿折地平的使用量。
Claims (3)
1.一种降低血压的口服药物组合物，其活性组分由阿折地平和坎地沙坦酯组成。
2.按照权利要求1的组合物，其活性组分由阿折地平0.7-3重量份，坎地沙坦酯1重量份组成。
3.按照权利要求1的组合物，其单位剂量的组合物活性组分由阿折地平6mg，坎地沙坦酯3mg组成。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2005048979A2 (en) * | 2003-10-06 | 2005-06-02 | Torrent Pharmaceuticals Limited | Pharmaceutical composition having casing with multiple micro tablets |
| WO2007001065A2 (en) * | 2005-06-27 | 2007-01-04 | Daiichi Sankyo Company, Limited | Method for the preparation of a wet granulated drug product |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005048979A2 (en) * | 2003-10-06 | 2005-06-02 | Torrent Pharmaceuticals Limited | Pharmaceutical composition having casing with multiple micro tablets |
| WO2007001065A2 (en) * | 2005-06-27 | 2007-01-04 | Daiichi Sankyo Company, Limited | Method for the preparation of a wet granulated drug product |
Non-Patent Citations (4)
| Title |
|---|
| 刘汉英.AT1 受体拮抗剂坎地沙坦的联合用药及不良反应.《现代医药卫生》.2008,第24卷(第5期),参见第712-713页. * |
| 王瑞.坎地沙坦西酯片治疗原发性高血压的临床观察.《中国医药导报》.2008,第5卷(第4期),参见第47页. * |
| 秦树琴.非洛地平联合坎地沙坦治疗高血压40 例疗效观察.《中西医结合心脑血管病杂志》.2007,第5卷(第12期),参见第1280-1281页. * |
| 陈刚等.持续型钙通道阻滞剂阿折地平的研究进展.《中国医院药学杂志》.2008,第28卷(第24期),参见第2124-2126页. * |
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