CN101632673A - 含有氯沙坦、吡格列酮和瑞舒伐他汀的药物组合物及其新用途 - Google Patents
含有氯沙坦、吡格列酮和瑞舒伐他汀的药物组合物及其新用途 Download PDFInfo
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- CN101632673A CN101632673A CN200810133757A CN200810133757A CN101632673A CN 101632673 A CN101632673 A CN 101632673A CN 200810133757 A CN200810133757 A CN 200810133757A CN 200810133757 A CN200810133757 A CN 200810133757A CN 101632673 A CN101632673 A CN 101632673A
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- losartan
- pioglitazone
- hypertension
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- rosuvastatin
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Abstract
本发明涉及医药领域,具体涉及一种用于治疗高血压的含有氯沙坦、吡咯列酮和瑞舒伐他汀的复方药物组合物及其用于制备治疗代谢综合症的药物中的用途。目的在于提供一种新的复方药物组合物,使其在治疗高血压疾病的同时有效控制相关的心血管疾病的发生,更好的改善高血压患者的生存预后。实验证明本发明提供的含有活性成分氯沙坦、盐酸吡咯列酮和瑞舒伐他汀钙的药物组合物在治疗并控制高血压所引起的各种心脑血管并发症方面取得了很好的协同作用和意想不到的效果。
Description
技术领域
本发明涉及医药领域,具体涉及一种用于治疗高血压的含有氯沙坦、吡格列酮和瑞舒伐他汀的复方药物组合物及其用于制备治疗代谢综合症的药物中的用途。
背景技术
高血压病主要损害人体血管。它能促使动脉管壁变硬,管腔变狭窄即平时所说的“动脉硬化”,高血压病若合并糖尿病,则会加速、加重血管损害,使病情迅速恶化,应该积极治疗。高血压病是最常见的心血管疾病之一,又与人类死亡的主要疾病如冠心病、脑血管疾病等密切相关,我国高血压病的发病率虽然不如西方国家高,但却呈逐年升高趋势,随着人们生活水平的不断提高和环境的恶化,患有高血压、高血脂、高胆固醇类的心血管病人也在不断增加,据有关资料报道截至2003年年底,我国高血压患者已达1.5亿人,并以每年500万人的速度增加。世界各国均十分重视高血压病从发病机理以致临床防治的研究。
沙坦类药物是抗高血压一线治疗用药,具有全新的降压机理,降压平稳、疗效好、作用时间长、患者耐受性好,沙坦家族包括氯沙坦、厄贝沙坦、坎地沙坦、他索沙坦、依普沙坦、替米沙坦、缬沙坦等。其中氯沙坦(Losartan)是由默克公司开发的第一代口服非肽类血管紧张素II受体抑制剂,在全球沙坦类药物中名列榜首,1994年6月氯沙坦钾首先在瑞典上市,1996年获得中国行政保护。血管紧张素II(Ang II)受体有四种亚型,即AT1、AT2、AT3和AT4,在人体心血管、肾上腺皮质和肾脏中,AT1受体占绝对优势,目前用于临床治疗的药物是具有选择性的AT1受体抑制剂,比如氯沙坦,可以阻断内源性及外源性的血管紧张素II所产生的各种药理作用(包括促使血管收缩,醛固酮释放等作用),还可选择性地作用于AT1受体,不影响其他激素受体或心血管中重要的离子通道的功能,也不抑制降解缓激肽的血管紧张素转化酶(激肽酶II),不影响血管紧张素II及缓激肽的代谢过程。氯沙坦作为抗高血压的一线用药,其药效强、作用时间长、耐受性好、具有极少发生干咳不良反应的优点,同时还具有对肾脏的保护作用机制。
瑞舒伐他汀钙(Rosuvastatin Calcium)由日本盐野义公司(大阪Shionogi公司)研制开发,属于合成类他汀药物,1998年4月转让给英国阿斯利康公司。瑞舒伐他汀是一种选择性3-羟基3-甲基异戊二酰辅酶A(HMG-CoA)还原酶抑制剂,可用来治疗动脉粥样硬化、血脂过高、家族性血胆甾醇过多以及相似的疾病。瑞舒伐他汀钙的分子式如下:
从目前已有的临床验证结果和与同类他汀类产品的比较两方面来看,瑞舒伐他汀钙都不愧被称为“超级他汀”,其降脂效果非常好,是迄今为止的最强效的降脂药物。
中国发明专利申请CN200480002407.2公开了一种含有替米沙坦和阿托伐他汀用于制备一种那些需要预防或治疗心血管、心肺或肾脏疾病的人或哺乳动物的药剂的用途。
青岛大学医学院学报2005年2期《缬沙坦与阿托伐他汀联合治疗对高血压病人颈动脉内膜中层厚度的影响》结论表明缬沙坦联合阿托伐他汀应用与单用比较,对逆转原发性高血压病人颈动脉内膜中层厚度的效果显著。
以上专利申请和文献中沙坦类和他汀类的联合应用虽然能够在抗高血压的同时进行降脂治疗,但心血管疾病是高血压患者的高发疾病,仅仅在治疗高血压的同时降脂是不够的,长期高血压可能导致心血管系统、肾脏等重要器官的损害,所以说,降压治疗不仅要将血压降至靶目标水平,而且要纠正同时存在的心血管疾病等危险因素,并选用合适药物,改善代谢紊乱及患者的预后,因此,寻找一种在治疗高血压疾病的同时有效控制与其相关的心血管疾病的发生,更好的改善高血压患者的生存预后的多药联合治疗方式已成为临床治疗中亟需解决的问题。
发明内容
本发明的目的在于提供一种在治疗高血压疾病的同时有效控制与其相关的心血管疾病的发生,更好的改善高血压患者的生存预后的新的复方药物组合物,在降压治疗将血压降至靶目标水平的同时,纠正同时存在的心血管疾病等危险因素,并改善代谢紊乱及患者的预后,提高高血压患者的生存率。
本发明提供了一种用于治疗高血压的新的药物组合物,该药物组合物含有活性成分氯沙坦、盐酸吡格列酮和瑞舒伐他汀钙。本发明人根据临床对于高血压治疗的最新研究进展情况和高血压患者的疾病发展趋势,创造性的在现有降压方案中引入用于治疗糖尿病的胰岛素增敏剂盐酸吡格列酮,取得了非常好的治疗效果,实验证明本发明药物组合物不但将血压控制在一定的目标水平,而且还能有效减少长期高血压导致心血管系统、肾脏等重要器官的损害,有效纠正同时存在的心血管疾病等危险因素,改善代谢紊乱及患者的预后,在治疗并控制高血压所引起的各种心脑血管并发症方面取得了很好的协同作用和意想不到的效果。由实施例8和实施例9可以看出本发明在降压方面有相当明显的优势,心血管疾病是高血压患者的高发疾病,通过对大鼠心肌肥厚、颈动脉内中膜厚度的测定可以发现本发明能够逆转心肌肥厚,有效的控制心血管疾病的发生,证明了其在防治心血管疾病方面的优势;通过对大鼠尿微量白蛋白的测定说明本发明组合物对肾脏有一定的保护作用,可以有效减缓高血压患者肾脏的损伤。
本发明药物组合物含有活性成分氯沙坦、盐酸吡格列酮和瑞舒伐他汀钙。在本发明药物组合物各成分的重量比中盐酸吡格列酮以吡格列酮计,本发明药物组合物的活性成分中氯沙坦∶盐酸吡格列酮∶瑞舒伐他汀钙的重量比为1∶0.01~4∶0.01~3.5,氯沙坦∶盐酸吡格列酮∶瑞舒伐他汀钙的重量比优选为1∶0.02~1∶0.02~1,氯沙坦∶盐酸吡格列酮∶瑞舒伐他汀钙的重量比最优选为1∶0.1~1∶0.02~0.5。
本发明还保护了该药物组合物在用于制备治疗代谢综合症的药物中的用途。代谢综合症是指多种代谢异常同时存在于一个人身上的病理现象,包括肥胖(尤其是腹型肥胖)、胰岛素抵抗、糖调节受损或糖尿病、高血压、血脂紊乱、微量白蛋白尿、高尿酸血症等等,由实施例10可知本发明药物组合物能有效降低代谢综合症患者的总胆固醇TC、高密度脂蛋白胆固醇HDLC、糖化血红蛋白(HbAlC)、空腹血糖(FBG)、空腹胰岛素(FINS)及纤维蛋白原(Fg)含量,有效控制相关的心血管疾病,降低病残率和病死率。
根据药物的性质和患者用药方便的需要,我们将本发明的药物组合物制备成固体药物制剂,如片剂、胶囊、颗粒剂、丸剂、滴丸等。其中片剂包括普通片、包衣片、糖衣片、薄膜衣片、肠溶衣片、泡腾片、咀嚼片、多层片、崩解片、分散片、舌下片、口含片、植入片、溶液片、缓释片等。本发明采用固体药物制剂具有携带、使用方便,给药途径简单、易行的优点,易于为患者接受。
本发明的药物组合物按照通常的制剂技术配制,可以使用以下添加剂按常规技术制备:赋形剂(例如乳糖、蔗糖、葡萄糖、甘露糖醇、山梨糖醇、淀粉、糊精、结晶纤维素、阿拉伯胶、葡聚糖等),润滑剂(硬脂酸镁、硬脂酸钙、滑石粉、微粉硅胶、硼酸、十二烷基硫酸钠等),粘合剂(羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚乙二醇等),崩解剂(低取代羟丙基纤维素、羧甲基纤维素、羧甲基淀粉、交联聚乙烯吡咯烷酮等),乳化剂(膨润土、氢氧化镁、氢氧化铝、十二烷基硫酸钠等),稳定剂(对羟基苯甲酸甲酯、苯甲醇、苯乙醇、苯酚、山梨酸、脱氢乙酸等),矫味剂(蔗糖、香料、阿斯巴甜、环糊精等),稀释剂等。
我们还可以结合现在高血压患者的需求将本发明的药物组合物制备成缓释片,它能够高效、安全的调节血压,缓慢释放维持较为平稳的血药浓度和更长的作用时间,具有毒副作用减小、服用更加方便的优点。
本发明中的缓释片剂以纤维素衍生物或乙烯基聚合物为缓释基质,这些缓释基质可以是甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、羧乙基纤维素、微晶纤维素、淀粉、聚乙烯吡咯烷酮、丙烯酸树脂其中的一种或几种的混合。
本发明组合物的优势体现在下列几个方面:
一、本发明创造性的在现有降压方案的基础上引入用于治疗糖尿病的胰岛素增敏剂盐酸吡格列酮,取得了非常好的协同降压效果,血管紧张素II受体拮抗剂氯沙坦与HMG-CoA还原酶抑制剂瑞舒伐他汀钙、胰岛素增敏剂盐酸吡格列酮的联合应用在实验研究和临床观察中取得了很好的协同降压作用。
二、本发明药物组合物的不良反应的发生率和不良反应程度显著减轻。本发明由于联合使用了降压药物+降糖药物+降脂药物的三联治疗方案,在治疗高血压方面取得了显著的协同作用,全面联合,协同降压,用药剂量显著减小,同时使不良反应的发生率和不良反应程度显著减轻。
三、长期使用本发明药物组合物,对高血压患者的长期生存率具有有益作用,对患者的预后产生积极的影响,这也是本发明所解决的最具有意义的临床治疗问题。一般降压药物都对高血压所引起的脑卒中、肾脏损伤、冠心病等并发症没有很好的预防和治疗作用,但本发明药物组合物能够在治疗高血压疾病的同时有效控制与其相关的心血管疾病的发生,更好的改善高血压患者的生存预后,在降压治疗将血压降至靶目标水平的同时,纠正同时存在的心血管疾病等危险因素,并改善代谢紊乱及患者的预后,提高高血压患者的生存率。
四、本发明药物组合物的适用范围广。本发明由于其协同作用机制适用于多种类型的高血压患者,尤其适用于卒中型高血压患者和高血压病合并肾脏损害者。另外对于高血压合并冠心病心绞痛、周围血管疾病、老年高血压、妊娠期高血压、顽固性高血压都有很好的效果。
五、本发明的药物组合物对现在社会中发病率很高的代谢综合症取得了很理想的效果!
具体实施方式
现通过如下实施例对本发明作进一步的阐述,但本发明的应用范围并不限于下列实施例,对于本领域普通技术人员显而易见的改变和修饰也包括在本发明范围之内。
实施例1 高血压复方普通片剂
瑞舒伐他汀钙 5g
氯沙坦 50g
盐酸吡格列酮 5g
淀粉 140g
糊精 120g
50%乙醇 适量
硬脂酸镁 1.0g
制备工艺:称取处方量的瑞舒伐他汀钙、氯沙坦、盐酸吡格列酮、淀粉、糊精混合均匀。另将适量的50%乙醇加入于混合粉末中,混合均匀,制软材,通过18目尼龙筛制成湿粒,60℃左右干燥,干粒水分应控制在1.5%以下。20目筛整粒,再与硬脂酸镁混匀,压片,即得。
实施例2 高血压复方胶囊剂
瑞舒伐他汀钙 1g
氯沙坦 50g
盐酸吡格列酮 1g
微晶纤维素 300g
微粉硅胶 12g
制备工艺:将瑞舒伐他汀钙、氯沙坦、盐酸吡格列酮、微晶纤维素、微粉硅胶粉碎过100目筛混匀,直接填装胶囊即得。
实施例3 高血压复方双层片剂
瑞舒伐他汀钙 25g
甘露醇 10g
乳糖 40g
微晶纤维素 20g
6%PVP的95%乙醇溶液 120g
硬酯酸镁 2g
制备工艺a:瑞舒伐他汀钙过100目筛,甘露醇、乳糖、微晶纤维素过80目筛,称取处方量的烟酸和甘露醇、乳糖、微晶纤维素混合均匀,加入6%PVP的95%乙醇溶液适量制粒,60℃干燥,16目筛整干颗粒,干颗粒中加入处方量的硬脂酸镁。
氯沙坦 25g
盐酸吡格列酮 25g
预胶化淀粉 50g
甘露醇 50g
6%PVP的95%乙醇溶液 100g
微粉硅胶 5g
制备工艺b:氯沙坦和盐酸吡格列酮过100目筛,预胶化淀粉、甘露醇过80目筛,称取处方量的氨氯地平、吡格列酮和预胶化淀粉、甘露醇混合均匀,加入6%PVP的95%乙醇溶液适量制粒,60℃干燥,16目筛整干颗粒,干颗粒中加入处方量的硬脂酸镁。将上述两种制备工艺a和b的颗粒组分采用双层压片机冲压即得双层片。
实施例4 高血压复方分散片
瑞舒伐他汀钙 25g
氯沙坦 50g
盐酸吡格列酮 25g
羧甲基纤维素钙 15g
交联聚乙烯吡咯烷酮 15g
微晶纤维素 140g
10%淀粉浆 适量
硬脂酸镁 6g
制备工艺:将处方量的瑞舒伐他汀钙、氯沙坦和盐酸吡格列酮过100目筛,羧甲基纤维素钙、交联聚乙烯吡咯烷酮、微晶纤维素过80目筛,混匀后加入适量10%淀粉浆制粒,加入硬脂酸镁后压片即可。
实施例5 高血压复方颗粒剂
瑞舒伐他汀钙 35g
氯沙坦 10g
盐酸吡格列酮 40g
淀粉 200g
糊精 50g
蔗糖粉 50g
80%乙醇 适量
制备工艺:称取处方量的瑞舒伐他汀钙、氯沙坦、盐酸吡格列酮、淀粉、糊精、蔗糖粉混合均匀。另将适量的80%乙醇加入于混合粉末中,混合均匀,制软材,通过18目尼龙筛制成湿粒,60℃左右干燥,20目筛整粒,分装,即得。
实施例6 高血压复方崩解片
瑞舒伐他汀钙 1g
氯沙坦 100g
盐酸吡格列酮 1g
交联羧甲基纤维素钠 10g
微晶纤维素 100g
聚乙烯吡咯烷酮 20g
5%PVP 60%醇溶液 适量
微粉硅胶 5g
制备工艺:按处方量称取瑞舒伐他汀钙、氯沙坦、盐酸吡格列酮,以微晶纤维素为填充剂,交联羧甲基纤维素钠、聚乙烯吡咯烷酮为崩解剂,5%PVP 60% 醇溶液为黏合剂,微粉硅胶为助流剂,用流化床一步制粒,然后压片,即得。
实施例7 高血压复方缓释片
瑞舒伐他汀钙 10g
氯沙坦 50g
盐酸吡格列酮 15g
羟丙甲基纤维素 80g
聚乙烯吡咯烷酮 100g
乳糖 85g
微粉硅胶 100g
制备工艺:将处方量的瑞舒伐他汀钙、氯沙坦、盐酸吡格列酮和缓释剂混合均匀加入粘合剂聚乙烯吡咯烷酮制粒,在40℃-80℃下干燥,整干颗粒,在干颗粒中加入处方量的润滑剂微粉硅胶,混匀,异型冲压片即可。
实施例8 高血压复方对自发性高血压大鼠血压和心肌肥厚的治疗效果
1.实验动物及实验分组
自发性高血压大鼠88只,雄性,山东新时代药业有限公司新药药理中心提供,体重(300±20)g,适应性饲养一周后,随机分为8组,每组11只。
模型对照组:灌胃给予同体积生理盐水;
吡组:0.5mg/(kg.d)吡格列酮;
氯组:5mg/(kg.d)氯沙坦;
瑞组:0.5mg/(kg.d)瑞舒伐他汀钙;
氯+瑞组:5mg/(kg.d)氯沙坦+0.5mg/(kg.d)瑞舒伐他汀钙;
吡+瑞组:0.5mg/(kg.d)吡格列酮+0.5mg/(kg.d)瑞舒伐他汀钙;
氯+吡组:5mg/(kg.d)氯沙坦+0.5mg/(kg.d)吡格列酮;
复方组:5mg/(kg.d)氯沙坦+0.5mg/(kg.d)吡格列酮+0.5mg/(kg.d)瑞舒伐他汀钙;
各组均为灌胃给药,每天一次,共10周。实验过程中,每日观察动物饮食、存活情况及行为活动,每日测量体重,根据体重调整药物用量。10周后处死动物,取心脏测左室重量,计算左室指数。
2.实验方法和实验结果
2.1高血压复方对自发性高血压大鼠血压的影响
温度控制在18℃-22℃,温度45%-65%,室内自然光线。用BP-2006A智能无创血压计(北京软隆有限公司提供)测量大鼠清醒状态下尾动脉压。在给药后的第一周、第三周、第五周、第八周分别测量血压,均在灌胃给药后2小时到5小时之间测量5次,取其均值作为该样本的血压。
表1 高血压复方对自发性高血压大鼠血压的影响(X±S,n=11)(mmHg)
●与模型组比较p<0.05,●●与模型组比较p<0.01;
#与氯+瑞组比较p<0.05。
结果表明,瑞舒伐他汀、氯沙坦和吡格列酮复方对自发性高血压大鼠的降压效应上取得了很好的协同作用,三种药物联合用药,无论在氯沙坦和瑞舒伐他汀合用的基础上加用吡格列酮,还是在吡格列酮和瑞舒伐他汀合用的基础上加用氯沙坦,还是在氯沙坦和吡格列酮合用的基础上加用瑞舒伐他汀,都在第五周和第七周的血压测量数据上表现出良好的协同作用。
2.2心脏重量、左室重量、体重及左室肥厚指数(左室重量/体重)测定:
10%氯化钾(2mmol/L,1ml/只)处死大鼠后,测体重,取出心脏,去除大血管及心脏外结缔组织,冲洗干净,滤纸吸干后称量心脏重量;再去除心房称左室重量,计算左室重量与体重比值。
表2 高血压复方对自发性高血压大鼠心肌肥厚的影响(X±S,n=8)(g)
●与模型组比较p<0.05,●●与模型组比较p<0.01;
#与氯+瑞组比较p<0.05。
结果表明,瑞舒伐他汀、氯沙坦和吡格列酮复方能有效逆转高血压大鼠左室心肌肥厚,三药联用对自发性高血压大鼠心肌肥厚的治疗取得了很好的协同作用。无论是在氯沙坦+瑞舒伐他汀钙联用的基础上加用吡格列酮,还是在吡格列酮和瑞舒伐他汀钙联用的基础上加用氯沙坦,还是在氯沙坦+吡格列酮联用的基础上加用瑞舒伐他汀钙,都取得了很好的协同作用。
实施例9高血压复方对自发性高血压大鼠尿微量白蛋白和颈动脉内中膜厚度的治疗效果
1.实验动物及实验分组
自发性高血压大鼠64只,雄性,山东新时代药业有限公司新药药理中心提供,体重(300±20)g,适应性饲养一周后,随机分为8组,每组8只,
模型对照组:灌胃给予同体积生理盐水;
吡组:1.5mg/(kg.d)吡格列酮;
氯组:5mg/(kg.d)氯沙坦;
瑞组:1mg/(kg.d)瑞舒伐他汀组;
氯+瑞组:5mg/(kg.d)氯沙坦+1mg/(kg.d)瑞舒伐他汀钙;
吡+瑞组:1.5mg/(kg.d)吡格列酮+1mg/(kg.d)瑞舒伐他汀钙;
氯+吡组:5mg/(kg.d)氯沙坦+1.5mg/(kg.d)吡格列酮;
复方剂量组:5mg/(kg.d)氯沙坦+1.5mg/(kg.d)吡格列酮+1mg/(kg.d)瑞舒伐他汀钙;
各组均为灌胃给药,每天一次,同时本实验的所有大鼠给予高糖高脂饲料喂养,共6个月。实验过程中,每日观察动物饮食、存活情况及行为活动,每日测量体重,根据体重调整药物用量。
2.实验方法和实验结果
2.1尿中微量白蛋白的测定:
试剂:
1、10%(v/v)的冰醋酸溶液(PH2.8)。
2、0.303mol/L甘氨酸-冰醋酸缓冲液(PH3.0):称取22.72g甘氨酸,用10%冰醋酸溶液稀释成1000ml,加NaN3100mg,室温密封可稳定1年。
3、溴酚蓝(1.924mmol/L)贮存液:精确称取257、36mgBPB,用无水乙醇溶至200ml,4℃冰箱可稳定1年。
4、溴酚蓝(0.231mmol/L)显色剂:取60mlBPB贮存液,加入2.5mlTriton X-100,用甘氨酸-冰醋酸缓冲液稀释至500ml,室温密封可保存1年。
标本的采集和检测:于第4周、8周、12周和16周将大鼠分别放于代谢笼中饲养,收集隔夜12小时尿,准确记录尿量。取4ml,叠氮钠处理后,离心(2000r/min)10min,取上清液置-20℃冰箱保存待测尿白蛋白。量取储存的大鼠尿液2ml,各加显色剂1ml,混匀(防止产生气泡),用紫外分光光度计于600nm下测定吸光度A。
表3 高血压复方对自发性高血压大鼠尿微量白蛋白的影响(X±S)
●与模型组比较p<0.05,●●与模型组比较p<0.01.
#与氯+瑞组比较p<0.01。
结果表明,瑞舒伐他汀、氯沙坦和吡格列酮复方能够降低尿微量白蛋白、保护高血压对肾脏的损害,三药联用在影响自发性高血压大鼠尿微量白蛋白方面取得了很好的协同作用。无论是在氯沙坦+瑞舒伐他汀钙联用的基础上加用吡格列酮,还是在吡格列酮和瑞舒伐他汀钙联用的基础上加用氯沙坦,还是在氯沙坦+吡格列酮联用的基础上加用瑞舒伐他汀钙,都取得了很好的协同作用。
2.2颈动脉内中膜厚度的测定
动物麻醉和固定后,经股动脉注入Even’s蓝染料(60mg/kg),30min后用0.9%生理盐水为灌注液,采用经心灌注法,灌注压力13.3kPa,至流出液清亮后,改用4%多聚甲醛生理盐水灌注10min,进行原位固定(压力同上)。取Even’s蓝着色颈动脉段,放入福尔马林液进一步固定后,取前、中、后三部分进行石蜡包埋,非连续切片8~10层,行HE染色,随机取3个血管断面输入计算机图像处理系统,进行计算机图像测量,计算内中膜厚度。
表4 高血压复方对自发性高血压大鼠内中膜厚度的影响(X±S,n=8)
●与模型组比较p<0.05,●●与模型组比较p<0.01;
#与氯+瑞组比较p<0.05。
结果表明,瑞舒伐他汀、氯沙坦和吡格列酮复方能有效改善自发性高血压大鼠内中膜厚度,三药联用在影响自发性高血压大鼠颈动脉内中膜厚度方面取得了很好的协同作用。无论是在氯沙坦+瑞舒伐他汀钙联用的基础上加用吡格列酮,还是在吡格列酮和瑞舒伐他汀钙联用的基础上加用氯沙坦,还是在氯沙坦+吡格列酮联用的基础上加用瑞舒伐他汀钙,都取得了很好的协同作用。
实施例10 高血压复方对代谢综合症患者的治疗效果
1.一般资料:
选取2007年3月到2008年6月在临沂人民医院治疗的代谢综合症患者64例,随机分为对照组和实验组。
对照组:男21例,女11例,年龄在61-72岁,体重指数(BMI)26-30;
实验组:男19例,女13例,年龄在62-70岁,体重指数(BMI)25.5-31;
治疗前全部患者均进行血脂分析(包括总胆固醇TC、高密度脂蛋白胆固醇HDLC)、糖化血红蛋白(HbAlC)、空腹血糖(FBG)、空腹胰岛素(FINS)及纤维蛋白原(Fg)检测。
入选标准根据WHO1999年2型糖尿病、高血压的诊断标准,并参考2000年美国国家胆固醇教育计划成人治疗组(NCEP-ATPIII)指南有关代谢综合症诊断标准,选择符合代谢综合症患者,并排除原发性高血压、心衰II级以上、肝肾及血液系统疾病等。
2.治疗方案:
入选患者对照组服用吡格列酮,15mg每次,每日一次;实验组按实施例1中的比例服用氯沙坦50mg,吡格列酮5mg,瑞舒伐他汀5mg,每日一次,连续治疗8周后,复查上述指标,其中应用己糖激酶法检测血糖,酯酶法检测血脂,应用凝固法和户色底物法检测纤维蛋白原,应用层析柱法检测HbAlC,用化学发光免疫法检测空腹胰岛素。
统计学处理:采用SPSS软件,显著性检验采用配对样本t检验。
3.治疗结果
表5治疗前后Fg、FINS、HbAlC、TC/HDLC的变化(X±S)
*与治疗前实验组比较,p<0.05;#与治疗后对照组比较,p<0.05。
由表5可知,本发明高血压复方药物组合物在治疗代谢综合症中FBG、FINS、HbAlC、TC/HDLC、Fg与治疗前比较均有显著性差异,治疗后高血压复方组与吡格列酮单用组比较FBG、FINS、HbAlC、TC/HDLC、Fg均有显著性差异,说明本发明高血压复方组合物在代谢综合症治疗中疗效确切,作用明显。
Claims (5)
1、一种用于治疗高血压的药物组合物,其特征在于它含有活性成分氯沙坦、盐酸吡咯列酮和瑞舒伐他汀钙。
2、如权利要求1所述的药物组合物,其特征在于氯沙坦∶盐酸吡咯列酮∶瑞舒伐他汀钙的重量比为1∶0.01~4∶0.01~3.5。
3、如权利要求1所述的药物组合物,其特征在于氯沙坦∶盐酸吡咯列酮∶瑞舒伐他汀钙的重量比为1∶0.02~1∶0.02~1。
4、如权利要求1所述的药物组合物,其特征在于它是片剂、胶囊或颗粒剂。
5、如权利要求1所述的药物组合物在用于制备治疗代谢综合症的药物中的用途。
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CN102652747A (zh) * | 2011-03-02 | 2012-09-05 | 鲁南制药集团股份有限公司 | 一种用于治疗高血压的复方药物组合物 |
CN109498622A (zh) * | 2018-12-28 | 2019-03-22 | 成都恒瑞制药有限公司 | 一种氯沙坦钾与罗格列酮组合物及其制备方法 |
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BR112015022103A2 (pt) * | 2013-03-12 | 2017-07-18 | Lg Life Sciences Ltd | composição farmacêutica, método para preparar uma composição farmacêutica, uso de uma composição farmacêutica, e, método para prevenir ou tratar uma doença |
KR101771766B1 (ko) * | 2013-12-30 | 2017-08-28 | 알보젠코리아 주식회사 | 안지오텐신-Ⅱ 수용체 차단제 및 HMG-CoA 환원효소 저해제를 포함하는 약제학적 복합제제 |
JP2016169198A (ja) * | 2015-03-13 | 2016-09-23 | 大原薬品工業株式会社 | ロスバスタチンカルシウムを含有する錠剤 |
KR101677151B1 (ko) * | 2015-06-12 | 2016-11-17 | 공주대학교 산학협력단 | 표면 실장기의 갠트리 구동시간을 최소화하는 방법 |
JOP20210280A1 (ar) * | 2019-04-17 | 2023-01-30 | Cardiopharma Inc | توليفة ذات جرعة ثابتة مضادة لارتفاع ضغط الدم ومخفضة للكوليسترول وطريقة لتصنيعها |
CN111759872A (zh) * | 2020-08-13 | 2020-10-13 | 贺俊杰 | 一种治疗高血压的药物及制备方法 |
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GB0001662D0 (en) * | 1999-02-06 | 2000-03-15 | Zeneca Ltd | Pharmaceutical compositions |
AU2003256419A1 (en) * | 2002-08-21 | 2004-03-11 | Merck & Co., Inc. | Combination therapy using a dual ppar alpha/gamma agonist and an angiotensin ii type i receptor antagonist |
CN101229372B (zh) * | 2007-01-26 | 2010-09-01 | 鲁南制药集团股份有限公司 | 一种治疗高血压的药物组合物 |
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Cited By (3)
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CN102652747A (zh) * | 2011-03-02 | 2012-09-05 | 鲁南制药集团股份有限公司 | 一种用于治疗高血压的复方药物组合物 |
CN102652747B (zh) * | 2011-03-02 | 2015-06-10 | 鲁南制药集团股份有限公司 | 一种用于治疗高血压的复方药物组合物 |
CN109498622A (zh) * | 2018-12-28 | 2019-03-22 | 成都恒瑞制药有限公司 | 一种氯沙坦钾与罗格列酮组合物及其制备方法 |
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KR101515490B1 (ko) | 2015-04-29 |
EP2322175A4 (en) | 2011-11-23 |
US20110118288A1 (en) | 2011-05-19 |
EP2322175A1 (en) | 2011-05-18 |
KR20110033867A (ko) | 2011-03-31 |
JP5968927B2 (ja) | 2016-08-10 |
JP2014098016A (ja) | 2014-05-29 |
CN101632673B (zh) | 2011-08-10 |
US8815286B2 (en) | 2014-08-26 |
WO2010009618A1 (zh) | 2010-01-28 |
JP2011528669A (ja) | 2011-11-24 |
EP2322175B1 (en) | 2017-06-07 |
KR20140061486A (ko) | 2014-05-21 |
ES2634090T3 (es) | 2017-09-26 |
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