CN107961239B - 一种三联药物组合物及其在治疗肠胃炎方面的应用 - Google Patents
一种三联药物组合物及其在治疗肠胃炎方面的应用 Download PDFInfo
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Abstract
本发明涉及一种三联药物组合物及其在治疗肠胃炎方面的应用，具体涉及一种药物组合物，该药物组合物的有效成分为紫丁香苷、没食子酸和鞣花酸三种成分，其中紫丁香苷、没食子酸、鞣花酸的质量比为1:1:1。本发明药物组合物对易感病毒(轮状病毒、诺沃克病毒、星状病毒和肠腺病毒)和胃肠道易感致病菌(幽门螺杆菌、金黄色葡萄球菌、大肠埃希菌、铜绿假单孢菌、大肠埃希菌(产肠毒素株)、福氏志贺菌、伤寒沙门菌、鼠伤寒沙门菌、肠炎沙门菌、变形杆菌、肺炎克雷伯菌、白色假丝酵母菌)的抑制作用强于单一成分及飞扬肠胃炎胶囊和喜炎平注射液，有望被开发用于治疗以腹泻、腹痛等为主症的肠胃炎。
Description
技术领域
本发明属于医药领域，具体涉及一种三联药物组合物及其在治疗肠胃炎方面的应用。
背景技术
紫丁香苷(Syringin，SY)属于苯丙素类化合物，具有止血、抗炎、镇痛、增强免疫、保护肝脏、抗抑郁、抗肿瘤等药理作用，常用于止血和抗肝毒药。没食子酸(Gallic acid，GA)，亦称“五倍子酸”、“棓酸”，学名“3,4,5-三羟基苯甲酸”，广泛存在于掌叶大黄、大叶桉、山茱萸等植物中，具有抗炎、抗突变、抗氧化、抗自由基等多种生物学活性。鞣花酸(Ellagicacid，EA)是一种多酚二内酯，是没食子酸的二聚衍生物，具有抗氧化功能、抗癌等多种生物活性。
轮状病毒(RV)、诺沃克病毒(NV)、星状病毒(ASTV)和肠腺病毒(ADV)是引起小儿腹泻、腹痛等肠胃炎的常见病毒；此外，许多胃肠道易感细菌感染也是引起腹泻、腹痛等肠胃炎的常见病因。因此，急需开发一种毒副作用小，并且能有效抑制上述病毒和致病菌的药物，本发明提供一种三联药物组合物，能有效抑制上述病毒及致病菌，有望开发作为治疗腹泻的药物。
发明内容
本发明提供一种药物组合物，该药物组合物的有效成分为紫丁香苷、没食子酸和鞣花酸三种成分，其中紫丁香苷、没食子酸、鞣花酸的质量比为1:1:1。该药物组合物还可包括适量的药学上可接受的药用辅料(例如药学上可接受的载体、稀释剂或赋形剂，包括增溶剂、表面活性剂、成膜剂、抗氧剂、稳定剂、粘合剂、润滑剂等)。
本发明所述的上述药物组合物的剂型可以是固体制剂、液体制剂或半固体制剂，优选片剂、胶囊、注射剂、膜制剂、乳膏或喷雾剂，包括缓释片剂、缓释胶囊、缓释注射剂。
本发明的另一实施方案提供上述药物组合物在制备预防和/或治疗由易感病毒和/或细菌感染引起的疾病的药物中的应用。所述易感病毒优选轮状病毒、诺沃克病毒、星状病毒、肠腺病毒中的一种或几种，所述细菌优选幽门螺杆菌、金黄色葡萄球菌、大肠埃希菌、铜绿假单孢菌、大肠埃希菌(产肠毒素株)、福氏志贺菌、伤寒沙门菌、鼠伤寒沙门菌、肠炎沙门菌、变形杆菌、肺炎克雷伯菌、白色假丝酵母菌中的一种或几种。
本发明的另一实施方案提供上述药物组合物在制备预防和/或治疗肠胃炎药物中的应用。所述肠胃炎的临床症状主要表现为腹泻、腹痛、呕吐恶心。
本发明上述药物组合物中的紫丁香苷包括紫丁香苷以及药学上可接受的紫丁香苷盐；没食子酸包括没食子酸以及药学上可接受的没食子酸盐；鞣花酸包括鞣花酸以及药学上可接受的鞣花酸盐。
本发明上述药物组合物制剂的制备方法，可按照中国专利申请号：201710594462.4中记载的制剂的制备方法进行制备。
与现有技术相比，本发明的优点在于：(1)本发明药物组合物对轮状病毒、诺沃克病毒、星状病毒和肠腺病毒及致病菌的抑制作用强于飞扬肠胃炎胶囊和喜炎平注射液；(2)本发明公开了药物组合物中的有效成分，并具体公开的三种成分的配比，三种有效成分缺一不可，只有当三者质量比为1:1:1时其对病毒和/或致病菌的抑制作用最强；(3)本发明药物组合物不仅具有更好的抗病毒效果，而且在安全性方面有了很大的提高，治疗指数TI为3.73-5.60，优于单一成分及飞扬肠胃炎胶囊和喜炎平注射液。
具体实施方式
为了便于对本发明的进一步理解，下面提供的实施例对其做了更详细的说明。但是这些实施例仅供更好的理解发明而并非用来限定本发明的范围或实施原则，本发明的实施方式不限于以下内容。
本发明以下实施例中各剂型的制备是按照中国专利申请号：201710594462.4中记载的方法制备得到的。
实施例1
原料药：紫丁香苷1份、没食子酸1份、鞣花酸1份
按上述重量份，取紫丁香苷10g，没食子酸10g、鞣花酸10g，可制备得片剂。
实施例2
原料药：紫丁香苷1份、没食子酸1份、鞣花酸1份
按上述重量份，取紫丁香苷5g，没食子酸5g、鞣花酸5g，可制备得纳米胶囊缓释制剂。
实施例3原料药：紫丁香苷1份、没食子酸锑钠1份、鞣花酸1份
按上述重量份，取紫丁香苷10g，没食子酸10g、鞣花酸10g，可制备得注射用无菌粉末。
实施例4原料药：紫丁香苷1份、没食子酸锑钠1份、鞣花酸1份
按上述重量份，取紫丁香苷10g，没食子酸10g、鞣花酸10g，可制备得亚微乳剂。
实施例5
原料药：紫丁香苷1份、没食子酸1份
按上述重量份，取紫丁香苷10g，没食子酸10g，可制备得片剂。
实施例6
原料药：紫丁香苷1份、鞣花酸1份
按上述重量份，取紫丁香苷10g，鞣花酸10g，可制备得片剂。
实施例7
原料药：没食子酸1份、鞣花酸1份
按上述重量份，取没食子酸10g、鞣花酸10g，可制备得片剂。
实施例8
原料药：紫丁香苷2份、没食子酸1份、鞣花酸1份
按上述重量份，取紫丁香苷20g，没食子酸10g、鞣花酸10g，可制备得片剂。
实施例9
原料药：紫丁香苷1份、没食子酸2份、鞣花酸3份
按上述重量份，取紫丁香苷10g，没食子酸20g、鞣花酸30g，可制备得片剂。
实施例10本发明药物组合物原料药及阳性药对病毒株的抑制作用
1.方法
(1)病毒的扩增将病毒株(RV、NV、ASTV、ADV)200μL接种于已经长成单层的Hep-2和RD细胞上，吸附30min后加入10mL 2％1640和DMEM维持液置37℃、5％CO2病毒培养箱中培养并设细胞对照，其中细胞对照相同操作将毒株换成维持液，每隔4h观察一次，当细胞出现90％以上的病变时，取出，反复冻融3次，吹打离心(1000rpm，20min)，取上清液定量分装于小青瓶中，胶布封口，放于-80℃超低温冰箱内保存待用。
(2)病毒毒力的测定将细胞培养瓶内Hep-2、RD细胞消化，以105个/mL细胞浓度接种96孔板，每孔100μL，37℃、5％CO2培养箱中培养，24h后使用。将上述扩增好的病毒用2％培养液做10倍比系列稀释，稀释10个梯度，纵向重复5孔，依次接种于己长好细胞的96孔板中，同时设细胞对照，空白对照，置37℃、5％CO2病毒培养箱中培养，倒置显微镜逐日观察，细胞出现90％以上病变时终止培养，每孔加10μL CCK-8染色，置37℃、5％CO2病毒培养箱中培养3h，用酶标仪在540nm波长处测定吸光度(OD)值。根据Reed-Muench公式计算病毒液的半数感染浓度TCID50。
(3)药物对细胞毒性的测定将试药用2％维持液按二倍比稀释7个浓度梯度，依次接种于己经长好细胞的96孔板中，并设5个复孔、细胞对照孔和空白对照孔，置37℃、5％CO2病毒培养箱中培养，倒置显微镜下观察，细胞出现90％病变时终止培养，每孔加10μL CCK-8染色，置37℃、5％CO2病毒培养箱中培养3h，用酶标仪在540nm波长处测定OD值；应用Reed-Muench公式计算药物半数中毒浓度TC50，并确定最大无毒浓度TC0。
(4)试药对病毒直接杀灭作用试药由无毒浓度起，用2％维持液按二倍比稀释7个浓度梯度，与等体积100倍TCID50浓度的病毒液相互作用2h，每孔100μL依次接种于己经长好的Hep-2细胞的96孔板中，并设5个复孔、细胞对照孔、阳性对照孔和空白对照孔，置37℃、5％CO2病毒培养箱中培养，倒置显微镜下观察，细胞出现90％病变时终止培养，每孔加10μLCCK-8染色，置37℃、5％CO2病毒培养箱中培养3h，用酶标仪在540nm波长测定吸光度OD值，计算细胞存活率，应用Reed-Muench公式计算药物半数有效浓度(EC50)和治疗指数(TI)。
2.测试结果
按照上述方法进行测试，本发明药物组合物原料药及阳性药对病毒株(RV、NV、ASTV、ADV)的抑制作用，结果见表1。
表1
注：TC50与EC50的单位是mg/mL。
由上述测试结果，可以看出本发明药物组合物对轮状病毒、诺沃克病毒、星状病毒和肠腺病毒的抑制作用强于单一成分及飞扬肠胃炎胶囊和喜炎平注射液；当本发明药物组合物中三种有效成分质量比为1:1:1时其对病毒的抑制作用最强；本发明药物组合物不仅具有更好的抗病毒效果，而且在安全性方面有了很大的提高，治疗指数TI为3.73-5.60。
实施例11本发明药物组合物原料药及阳性药对细菌的抑制作用
1.对标准菌株的抑菌作用，MIC(mg/mL；n＝5)，见表2。
标准细菌株：幽门螺杆菌(ATCC43504)、金黄色葡萄球菌(ATCC29213)、大肠埃希菌(ATCC25922)、铜绿假单孢菌(ATCC27853)、大肠埃希菌(CMCC44813(产肠毒素株))、福氏志贺菌(CMCC51285)、伤寒沙门菌(CMCC50319)、鼠伤寒沙门菌(CMCC50220)、肠炎沙门菌(CMCC50040)、变形杆菌(CMCC 49027)、肺炎克雷伯菌(CMCC46117)、白色假丝酵母菌(CMCC85021)，以上实验菌株均由中国科学院武汉病毒研究所提供。
表2
2.对临床分离菌株的MIC(mg/mL；n＝5)，见表3。
临床分离菌株：大肠埃希菌80株(编号EC001-EC80)、伤寒沙门菌30株(编号TY001-TY030)、肠炎沙门菌30株(编号ET001-ET030)、福氏志贺菌20株(编号SY001-SY020)、肺炎克雷伯菌50株(编号KE001-KE050)、变形杆菌50株(编号PR001-PR050)，以上菌株均由中国科学院武汉病毒研究所经Take-II全自动数字细菌鉴定仪鉴定，共计260株细菌株分离并提供实验。
表3
Claims (12)
1.一种药物组合物，该药物组合物的有效成分为紫丁香苷、没食子酸和鞣花酸三种成分，其中紫丁香苷、没食子酸、鞣花酸的质量比为1:1:1。
2.权利要求1所述的药物组合物，其特征在于该药物组合物还包括适量的药学上可接受的药用辅料。
3.权利要求2所述的药物组合物，其特征在于所述的药用辅料选自药学上可接受的载体、稀释剂或赋形剂。
4.权利要求1-3任一项所述的药物组合物，其特征在于所述药物组合物的剂型选自固体制剂、液体制剂或半固体制剂。
5.权利要求4所述的药物组合物，其特征在于所述药物组合物的剂型选自片剂、胶囊、注射剂、膜制剂、乳膏或喷雾剂。
6.权利要求5所述的药物组合物，其特征在于所述药物组合物的剂型选自缓释片剂、缓释胶囊、缓释注射剂。
7.权利要求1-3任一项所述的药物组合物，其特征在于所述药物组合物中的紫丁香苷选自紫丁香苷以及药学上可接受的紫丁香苷盐；没食子酸选自没食子酸以及药学上可接受的没食子酸盐；鞣花酸选自鞣花酸以及药学上可接受的鞣花酸盐。
8.权利要求1-7任一项所述的药物组合物在制备预防和/或治疗由病毒和/或细菌感染引起的疾病的药物中的应用。
9.权利要求8所述的应用，其特征在于所述病毒选自轮状病毒、诺沃克病毒、星状病毒、肠腺病毒中的一种或几种。
10.权利要求8所述的应用，其特征在于所述细菌选自幽门螺杆菌、金黄色葡萄球菌、大肠埃希菌、铜绿假单孢菌、大肠埃希菌、福氏志贺菌、伤寒沙门菌、鼠伤寒沙门菌、肠炎沙门菌、变形杆菌、肺炎克雷伯菌、白色假丝酵母菌中的一种或几种。
11.权利要求1-7任一项所述的药物组合物在制备预防和/或治疗肠胃炎药物中的应用。
12.权利要求11所述的应用，其特征在于所述肠胃炎的临床症状为腹泻、腹痛、呕吐恶心。
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