CN103948620A - 一种含有山栀苷甲酯的药物组合物及应用 - Google Patents
一种含有山栀苷甲酯的药物组合物及应用 Download PDFInfo
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Abstract
本发明公开了一种含有山栀苷甲酯的药物组合物，该药物组合物由活性成分和药用辅料制备而成，其中所述的活性成分由阿司匹林和山栀苷甲酯组成。本发明的进步性体现在两种活性成分可协同抗血栓，从而更好地发挥防治血栓性疾病的作用。
Description
技术领域
本发明属于医药技术领域，涉及一种防治血栓性疾病的药物组合物，特别涉及一种含有山栀苷甲酯的药物组合物及应用。
背景技术
血栓性疾病是指由血栓形成和血栓栓塞两种病理过程所引起的疾病。血栓性疾病严重威胁人类的生命健康，其发病率高居各种疾病之首，且近年来还有渐增之势，是当代医学研究的重点和热点之一。血栓形成是指在一定条件下，血液有形成分在血管内(多数为小血管)形成栓子，造成血管部分或完全堵塞，相应部位血液供应障碍的病理过程。依血栓组成成分可分为血小板血栓、红细胞血栓、纤维蛋白血栓、混合血栓等。血栓栓塞是血栓由形成部位脱落，在随血流移动的过程中部分或全部堵塞某些血管，引起相应组织和/或器官缺血、缺氧、坏死(动脉血栓)及淤血、水肿(静脉血栓)的病理过程。
山栀苷甲酯（Shanzhiside methyl ester，Dipsacoside B）是从双 子 叶 植 物 唇 形 科 Labiatae 独 一 味 Lamiophlomis rotata （Benth.） Kudo. 的根及根状茎或全草提取而得，是独一味中环烯醚萜类化合物之一。张承忠等人(藏药独一味中的环烯醚萜甙.中草药.1992年第23卷第10期第509、510和560页)首次从藏药独一味中得到山栀苷甲酯。
目前，现有技术还没有关于阿司匹林和山栀苷甲酯联合应用的报道，尤其没有二者联合应用后抗血栓的报。
发明内容
本发明根据动物实验结果创造性地提出将阿司匹林和山栀苷甲酯联合用于预防血栓形成。因此，本发明的目的是开发山栀苷甲酯在血栓性疾病中的医药用途，从而提供一种预防血栓形成的药物组合物。
具体地，本发明的目的是这样实现的：
一种含有山栀苷甲酯的药物组合物，该药物组合物由活性成分和药用辅料制备而成，其中所述的活性成分由阿司匹林和山栀苷甲酯组成。
本发明药物组合物中可用的“药用辅料”可以是药物制剂领域中任何常规的载体，特定载体的选择将取决于用于治疗特定患者的给药方式或疾病类型和状态。用于特定给药模式的合适药物组合物的制备方法完全在药物领域技术人员的知识范围内。例如，所述药用辅料包括药学领域常规的稀释剂、载体、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体和润滑剂等。必要时，还可以在药物组合物中加入香味剂、防腐剂和甜味剂等。
优选地，如上所述的药物组合物，其中阿司匹林和山栀苷甲酯的重量比为1：1-10。
进一步优选地，如上所述的药物组合物，其中阿司匹林和山栀苷甲酯的重量比为1：2-5。
再进一步优选地，如上所述的药物组合物，其中阿司匹林和山栀苷甲酯的重量比为1：2.5-3.2。
本发明所述的药物组合物优选制备成固体口服制剂，如片剂、胶囊剂。进一步优选地，其中每一单位固体口服制剂含有阿司匹林50mg和山栀苷甲酯50-500mg。再进一步优选地，其中每一单位固体口服制剂含有阿司匹林50mg和山栀苷甲酯100-250mg。
本发明采用小鼠肺血栓模型、FeCl3诱导大鼠颈动脉血栓实验性血栓模型，考察山栀苷甲酯的抗血栓形成作用。结果发现，山栀苷甲酯与阿司匹林联用后，可显著提高胶原蛋白-肾上腺素混合诱导剂所致肺血栓小鼠的存活率，延长FeC13诱导大鼠颈动脉血栓形成时间，并减轻血栓湿质量，这预示着阿司匹林与山栀苷甲酯可协同延长血栓形成时间并降低血栓质量，从而更为显著地提高血栓形成抑制率。因此，本发明的第二个目的在于提供一种医药新用途，即所述的含阿司匹林与山栀苷甲酯的组合物在制备预防血栓形成的药物中的应用。
另外，根据上述研究成果，本发明的第三个目的在于提供一种医药新用途，即所述的含阿司匹林与山栀苷甲酯的组合物在制备预防或/和治疗血栓性疾病的药物中的应用。
本发明所述的血栓性疾病选自心肌梗死、卒中、心绞痛、脑缺血、外周动脉疾病、心房颤动、脑梗塞、冠心病、血栓性脉管炎、微循环障碍、动脉粥样硬化、弥散性小动脉硬化、玻璃样变和纤维化、高粘滞血症、动脉硬化性闭塞症、血栓闭塞性脉管炎、肢体缺血症、缺血性脑血管病、糖尿病、肺梗死、深层静脉血栓形成、高脂血症、红细胞增多、高纤维蛋白原血症、炎症所致的高黏滞综合征及循环障碍。
与现有技术相比，本发明的优点和进步性在于提供了含有阿司匹林与山栀苷甲酯的药物组合物，且这两种活性成分可协同抗血栓，从而更好地发挥防治血栓性疾病的作用。由于在组成固定复方时，各单药的剂量均有减少，因此生产和包装成本降低，治疗费用不仅不会增加，反而会有下降，使得治疗的效益/费用比有明显提高。
具体实施方式
以下通过动物试验例的形式对本发明的上述内容再作进一步的详细说明，但不应将此理解为本发明上述主题的范围仅限于以下的实例，凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1阿司匹林与山栀苷甲酯联用对小鼠肺血栓形成的试验研究
取昆明小鼠60只，体质量18～22g，雌雄各半，随机分成四组，即：模型对照组、阿司匹林组、山栀苷甲酯组、联合用药组，每组15只。各组小鼠按如下剂量给予相应的受试物：
模型对照组：10mL／kg生理盐水；
阿司匹林组：8mg／kg阿司匹林；
山栀苷甲酯组：20mg／kg山栀苷甲酯；
联合用药组：4mg／kg阿司匹林 + 10mg／kg山栀苷甲酯。
小鼠分别灌胃给药15d，1次／d，给药体积为10mL／kg，末次给药2h后，参照Diminno的方法[Diminno G，Silver MJ．Mouse antithrombotic assay：a simple method for the evaluation of anti-thrombotic agents in vivo．Potentiation of antithrombotic activity of ethyl alcohol [J]． Pharmaco1.Exp.Ther．，1983；225：57450.]，尾静脉注射胶原蛋白(10mg／kg)与肾上腺素(1mg/kg)混合诱导剂，观察5min内小鼠死亡数，计算小鼠存活率，结果见表1。
表1 各组对小鼠肺栓塞的抑制作用比较
| 组别 | n | 死亡数（只） | 存活率（%） |
| 模型对照组 | 15 | 14 | 6.7 |
| 阿司匹林组 | 15 | 10 | 33.3 |
| 山栀苷甲酯组 | 15 | 12 | 20.0 |
| 联合用药组 | 15 | 3 | 80.0 |
通过表1的试验结果可以看出，山栀苷甲酯对由胶原蛋白和肾上腺素混合诱导剂引发的肺血栓有一定的保护作用，当其与阿司匹林联用后，小鼠的存活率分别达到80.0%，与模型对照组(存活率为6.7％)以及各单药组比较，可显著抑制小鼠的死亡，提高小鼠肺栓塞的存活率。
实施例2 阿司匹林与山栀苷甲酯联用对FeC1
3
诱导大鼠颈动脉血栓形成的试验研究
取雄性清洁级Wistar大鼠50只，随机分成如下五组：假手术组、模型对照组、阿司匹林组、山栀苷甲酯组、联合用药组，每组10只。各组大鼠按如下剂量给予相应的受试物：
假手术组：10mL／kg生理盐水；
模型对照组：10mL／kg生理盐水；
阿司匹林组：5mg／kg阿司匹林；
山栀苷甲酯组：16mg／kg山栀苷甲酯；
联合用药组：2.5mg／kg阿司匹林 + 8mg／kg山栀苷甲酯。
各组动物灌胃给药15d，每日给药1次，给药体积为10mL／kg，末次给药1h后腹腔注射乌拉坦(1.5g／kg)麻醉，按如下方法制作颈总动脉血栓模型：分离左侧颈总动脉2cm，下方置小片塑料薄膜(3cm×1.5cm)，用于保护血管周围组织，将吸有70％ FeCl3溶液的滤纸片(1cm×1cm)敷于暴露的动脉表面上，假手术组敷生理盐水滤纸片，用半导体点式温度计监测动脉表面温度变化，记录从敷上滤纸片开始计时，至温度突然下降的时间为血栓形成时间，剪下血栓发生部位的血管放于滤纸上吸干残血，以电子分析天平测其质量，并按如下公式计算血栓形成抑制率：血栓形成抑制率（%）=[（对照组血栓质量 - 给药组血栓质量）/对照组血栓质量]×100％。统计各组试验数据，见表2。
表2 各组对对FeCl3诱导大鼠颈总动脉血栓形成时间及质量的影响
| 组别 | n | 血栓形成时间（s） | 血栓质量（mg） | 血栓形成抑制率（%） |
| 假手术组 | 10 | - | - | - |
| 模型对照组 | 9 | 497.5±80.1 | 10.74±1.30 | - |
| 阿司匹林组 | 10 | 784.2±72.6* | 7.10±1.93* | 33.89 |
| 山栀苷甲酯组 | 10 | 610.4±89.4 | 8.96±1.27 | 16.57 |
| 联合用药组 | 10 | 1196.3±102.5**￥$$ | 4.22±0.94**￥$$ | 60.71 |
与模型对照组比较，* P＜0.05，** P＜0.01；
与阿司匹林组比较，￥ P＜0.05，￥￥ P＜0.01；
与山栀苷甲酯组比较，$ P＜0.05，$$ P＜0.01。
通过表2的试验结果可以看出，假手术组无血栓形成，模型对照组左侧颈总动脉可见有闭塞性血栓形成。与模型对照组比较，各给药组均能延长血栓形成时间并降低血栓质量，尤其是联合用药组的效果更为显著，与单药组相比也有显著性差异，这预示着阿司匹林与山栀苷甲酯可协同延长血栓形成时间并降低血栓质量，从而更为显著地提高血栓形成抑制率。
Claims (9)
1.一种含有山栀苷甲酯的药物组合物，该药物组合物由活性成分和药用辅料制备而成，其特征在于：所述的活性成分由阿司匹林和山栀苷甲酯组成。
2.根据权利要求1所述的药物组合物，其特征在于：阿司匹林和山栀苷甲酯的重量比为1：1-10。
3.根据权利要求2所述的药物组合物，其特征在于：阿司匹林和山栀苷甲酯的重量比为1：2-5。
4.根据权利要求3所述的药物组合物，其特征在于：阿司匹林和山栀苷甲酯的重量比为1：2.5-3.2。
5.根据权利要求1-4任一项所述的药物组合物，其特征在于：所述的药物组合物是固体口服制剂。
6.根据权利要求5所述的药物组合物，其特征在于：每一单位固体口服制剂含有阿司匹林50mg和山栀苷甲酯50-500mg。
7.根据权利要求6所述的药物组合物，其特征在于：每一单位固体口服制剂含有阿司匹林50mg和山栀苷甲酯100-250mg。
8.权利要求1-4任一项所述的药物组合物在制备预防血栓形成的药物中的应用。
9.权利要求1-4任一项所述的药物组合物在制备预防或/和治疗血栓性疾病的药物中的应用。
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