CN111632060A - 一种含黄芩苷和二甲双胍的组合物及其制备方法与应用 - Google Patents
一种含黄芩苷和二甲双胍的组合物及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种含黄芩苷和二甲双胍的组合物及其制备方法与应用。本发明所提供的含有黄芩苷和二甲双胍的组合物较单独的黄芩苷或单独的二甲双胍，其降低血脂，降低氧化应激水平，降低转氨酶的作用更好，同时还可以激活AMPK的表达，从而更好地发挥治疗NAFLD作用。
Description
技术领域
本发明涉及中药领域，具体涉及一种含黄芩苷和二甲双胍的组合物及其制备方法与在制备抗非酒精性脂肪肝产品中的应用。
背景技术
众所周知，过度食用高脂食物和久坐不动的生活方式可导致非酒精性脂肪肝(NAFLD)。大量证据表明，NAFLD的发生与游离脂肪酸(FFA)代谢受损和氧化应激过程有关，细胞中过量释放FFA和氧自由基(ROS)等的物质，可引起NAFLD的发生和进展。尽管患有非酒精性脂肪肝的人通常在没有症状的情况下生活几十年，并没有出现具有临床意义的脂肪肝症状，但是肝脏容易受到继发性炎症应激引起的损伤，并可能发展为肝硬化和肝细胞癌。但是到目前为止，还没有明确有效的治疗NAFLD的方法，因此迫切需要治疗肥胖相关脂肪肝疾病的药物。
近年来，在NAFLD发病机制中，AMPK(AMP依赖的蛋白激酶)在细胞和系统水平上已成为脂质代谢的重要调节因子，肝AMPK功能障碍是遗传性肥胖啮齿动物和高脂喂养小鼠和大鼠肝脏脂质积聚和高脂血症伴肝脂肪变性的关键机制。
氧化应激在NAFLD的发病机制中发挥重要的作用，其中，氧自由基(ROS)，丙二醛(MDA)是引起NAFLD细胞损伤的关键因素之一，过多的ROS/MDA的产生可引起氧化应激，引起肝损伤。而抗氧化反应元件，如超氧化物歧化酶(SOD)、谷胱甘肽(GSH)等抗氧化因子，可减少ROS、MDA的释放，从而减轻氧化应激和肝损伤。
黄芩苷是一种多酚类化合物，是从黄芩中提取的主要生物活性黄酮类化合物。最新研究证据表明黄芩苷可以预防胰岛素抵抗、糖异生和血脂异常、降低高血糖、高血脂、脂肪肝、肥胖和糖尿病。此外，这黄酮类物质对正常的上皮细胞几乎没有毒性，AMPK激活剂二甲双胍和噻唑烷二酮类已被证实能降低肝脏脂肪，改善脂肪性肝病，为NAFLD的治疗提供了新的途径，但是其无法解决肝脏氧化应激过程，无法减少因氧化应激引起的肝损害。
发明内容
发明目的：本发明所要解决的技术问题是针对现有技术的不足，提供一种含黄芩苷和二甲双胍的组合物及其制备方法与应用。
发明思路：前期实验在高脂饮食诱导的NAFLD动物模型中，研究结果表明，黄芩苷可显著降低高脂饮食小鼠血浆总胆固醇和甘油三酯水平。同时，研究结果表明黄芩苷和二甲双胍的混合物较单独的黄芩苷/二甲双胍具有更好的降低模型鼠体重，降低血脂和降低转氨酶，更好的起到治疗NAFLD的作用。含黄芩苷和二甲双胍的组合物完美的弥补了二甲双胍的缺陷，此混合物可以降低氧化应激水平，同时还可以激活AMPK的表达，从而起到降低血清和肝脏脂质水平，从而发挥治疗NAFLD作用。这是之前任何一个药物均没有的作用，也是本发明提出的目的—提供一种安全有效的混合物，可以通过氧化应激水平/AMPK途径治疗脂肪肝，提出一种新型的治疗NAFLD的策略。
为了解决上述技术问题，本发明公开了一种组合物，包括黄芩苷和双胍类化合物。
其中，所述的双胍类化合物为二甲双胍、苯乙双胍、丁二胍、二甲双胍盐、苯乙双胍盐和丁二胍盐中的任意一种或几种组合；其中，所述的二甲双胍盐优选为盐酸二甲双胍；进一步优选地，所述的双胍类化合物为二甲双胍。
其中，所述的黄芩苷和双胍类化合物的质量比为0.1:1～10:1。
优选地，所述的黄芩苷和双胍类化合物的质量比为0.5:1～8:1。
进一步优选地，所述的黄芩苷和双胍类化合物的质量比为1:1～5:1。
更进一步优选地，所述的黄芩苷和双胍类化合物的质量比为1:1、2:1和3:1中的任意一种。
其中，上述剂型的给药方式包括但不限于静脉或腹腔注射给药。
上述组合物剂型包括但不限于片剂、颗粒剂、胶囊剂和口服溶液中的任意一种。
其中，所述的片剂、颗粒剂、胶囊剂和口服溶液制备方法是本领域普通技术人员熟知的常规技术。
上述组合物在制备具有抗脂肪肝、降脂和降低氧化应激中任意一种或几种作用的产品中的应用。
其中，所述的抗脂肪肝包括预防脂肪肝、治疗脂肪肝。
其中，所述的产品包括但不限于药物、保健品等。
其中，所述的脂肪肝为非酒精性脂肪肝。
其中，所述的组合物通过改善氧化应激，提高AMP依赖的蛋白激酶(Adenosine 5‘-monophosphate(AMP)-activated protein kinase，AMPK)的表达水平，降低肝脏炎症及肝脏内脂质沉积的途径抗脂肪肝。
有益效果：与现有技术相比，本发明具有如下优势：
本发明所提供的含有黄芩苷和二甲双胍的组合物较单独的黄芩苷/二甲双胍具有更好的降低血脂和降低转氨酶，更好的起到治疗NAFLD的作用。同时，含黄芩苷和二甲双胍的组合物完美的弥补了二甲双胍的缺陷，可以更好的降低血脂，降低氧化应激水平，同时还可以激活AMPK的表达，从而起到降低血清和肝脏脂质水平，从而发挥治疗NAFLD作用。
附图说明
下面结合附图和具体实施方式对本发明做更进一步的具体说明，本发明的上述和/或其他方面的优点将会变得更加清楚。
图1为实施例3中各组肝脏HE染色。
图2为实施例3中各组治疗前后ALT水平。
图3为实施例4中肝脏匀浆TG的水平。
图4为实施例5中肝脏中AMPK的表达水平。
图5为是合理6中各组肝脏GSH水平(图5A)、SOD活性(图5B)和MDA水平(图5C)。
具体实施方式
实施例1组合物的制备
降糖药物组合物制备方法：按下表1配制不同比例的组合物。
表1组合物成分配比
| 配比比例 | 黄芩苷(g) | 二甲双胍(g) |
| 0.1:1 | 1 | 10 |
| 0.5:1 | 5 | 10 |
| 1:1 | 10 | 10 |
| 2:1 | 20 | 10 |
| 3:1 | 30 | 10 |
| 4:1 | 40 | 10 |
| 5:1 | 50 | 10 |
| 8:1 | 80 | 10 |
| 10:1 | 100 | 10 |
按上述表格将黄芩苷和二甲双胍按不同比例混匀，溶于生理盐水中制成不同组合物配比的溶液，避光保存。
实施例2不同配比药物疗效对比
高脂喂养C57BL/6J小鼠为常用的非酒精性脂肪肝小鼠模型，购于上海南模生物有限公司，在SPF环境饲养进行本实验。实验选用8周龄雄性C57BL/6J小鼠，同实施例3喂养8周造模，每组6只，HE证明造模成功后，口服给药4周(100mg·kg-1)。各组药品用生理盐水稀释后给药，频率为1mL/1次/天，持续治疗。
下表所示为不同配比组合物作用下的谷丙转氨酶(ALT)，为小鼠禁食12小时后的空腹检测，治疗前为未开始治疗的ALT，治疗后为给药4周后的ALT。
表2不同配比的组合物治疗NAFLD模型鼠效果结果
从上表可以看出，黄芩苷和二甲双胍配比为1:1-3:1的疗效最为显著，且明显优于单独使用黄芩苷组和二甲双胍的组别，在此表中，1:1配比使用效果最佳。因此，后续实验中均以1:1配比使用。
实施例3黄芩苷和二甲双胍的组合物改善了肝脏细胞损伤
本实验从肝脏HE、血清ALT等方面来探究该组合物可改善肝脏的损伤。
3.1HE染色显示组合物可改善NAFLD模型的肝脏炎症
实验选用8周龄雄性C57BL/6J小鼠，予以高脂饮食8周后，经HE染色证明形成NAFLD模型组，予以不同药物治疗，每组10只，口服给药。其中使用黄芩苷和二甲双胍组合物的为组合治疗组[(100mg·kg-1)，黄芩苷：二甲双胍＝1:1]，仅使用二甲双胍的为二甲双胍组(100mg·kg-1)，使用黄芩苷治疗的为黄芩苷治疗组(100mg·kg-1)，使用生理盐水的为安慰剂组，另有一组10只8周龄C57BL/6J雄性小鼠喂养普通饮食8周为正常组。给药频率为1次/天，1次1mL，口服持续治疗4周后，杀鼠，取肝脏切片，固定，进行HE染色。具体图见图1。
图1为治疗4周结果，组合物治疗组小鼠HE染色肝脏损伤显著低于安慰剂组及二甲双胍组及黄芩苷组，最接近正常水平。且肝脏内HE染色中脂滴含量也显示综合治疗组少于黄芩苷组、二甲双胍组及安慰剂组可见，从HE染色图可见，组合物能有效改善肝脏损伤减少肝脏内脂质的含量，且较单独黄芩苷组和二甲双胍者效果更好。
3.2组合物可改善NAFLD模型鼠的ALT水平
小鼠分组及治疗方案同实施例3.1。治疗4周后，杀鼠取血，抗凝后取血清，按照生化试剂盒行ALT检测。结果如图2。
如图2所示，与安慰剂组相比，组合治疗组和二甲双胍组、黄芩苷组均可以起到降低丙转氨酶(ALT)的作用，保护肝损伤，且组合物组较单独黄芩苷及二甲双胍组有协同降酶作用，但组合治疗组降低ALT效果更好。(P<0.01)。
实施例4该组合物改善NAFLD模型小鼠的肝脏甘油三酯水平
高脂是NAFLD肝脏损伤的诱因之一，降低肝脏血脂可以降低肝脏的炎症。
小鼠分组及治疗方案同实施例3.1。治疗4周后，杀鼠，取肝脏组织，做成肝脏匀浆，根据试剂盒行肝脏甘油三酯(TG)水平检测。结果如图4。
如图3所示，与黄芩苷组组相比，组合治疗组可明显降低肝脏匀浆中TG的含量，但在二甲双胍组，结果显示二甲双胍减低TG的效果不明显(**P<0.01)。可见，黄芩苷与二甲双胍组合物不仅能用于非酒精性脂肪肝的治疗，还能降低血脂，起到预防非酒精性脂肪肝的作用。
实施例5黄芩苷和二甲双胍的组合物可以提高肝脏内AMPK的表达水平
实施例4中显示肝脏中TG水平升高，而在NAFLD发病机制中，AMPK在细胞和系统水平上已成为脂质代谢的重要调节因子，因此检测肝脏中的AMPK水平。
小鼠分组及治疗方案同实施例3.1。治疗4周后，杀鼠，取肝脏组织，对各组肝脏中的AMPK进行Western blot分析。从图4可看出，组合治疗组较二甲双胍及二甲双胍组可以明显的提高AMPK的表达水平，从而起到更佳的治疗效果。
实施例6黄芩苷和二甲双胍的组合物改善NAFLD模型小鼠的氧化应激的水平
氧化应激反应在NAFLD的发病机制中发挥重要的作用，而该组合物可提高抗氧化因子如GSH水平和SOD的活性，可降低氧化应激产物MDA的水平。
小鼠分组及治疗方案同实施例3.1。治疗4周后，杀鼠，取肝脏组织，做成肝脏匀浆，根据超氧化物歧化酶(SOD)检测试剂盒(Sigma-Aldrich，19160-1KT-F)检测SOD的水平，通过谷胱甘肽(GSH)检测试剂盒(Sigma-Aldrich，CS0260-1KT)来测定肝脏GSH的水平，通过Lipid Peroxidation(MDA)检测试剂盒(abcam，ab118970)来检测MDA的水平，具体方法和步骤见试剂盒说明书。结果如图5(A,B,C)。如下图5所示，与安慰剂组相比，组合物治疗组降低肝脏氧化应激(P<0.05)。下图为各组肝脏GSH水平(图5A)、SOD活性(图5B)和MDA水平(图5C)。
本发明提供了一种含黄芩苷和二甲双胍的组合物及其制备方法与应用的思路及方法，具体实现该技术方案的方法和途径很多，以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。本实施例中未明确的各组成部分均可用现有技术加以实现。
Claims (10)
1.一种组合物，其特征在于，包括黄芩苷和双胍类化合物。
2.根据权利要求1所述的组合物，其特征在于，所述的双胍类化合物为二甲双胍、苯乙双胍、丁二胍、二甲双胍盐、苯乙双胍盐和丁二胍盐中的任意一种或几种组合。
3.根据权利要求1所述的组合物，其特征在于，所述的黄芩苷和双胍类化合物的质量比为0.1:1～10:1。
4.根据权利要求3所述的组合物，其特征在于，所述的黄芩苷和双胍类化合物的质量比为0.5:1～8:1。
5.根据权利要求4所述的组合物，其特征在于，所述的黄芩苷和双胍类化合物的质量比为1:1～5:1。
6.根据权利要求5所述的组合物，其特征在于，所述的黄芩苷和双胍类化合物的质量比为1:1、2:1和3:1中的任意一种。
7.根据权利要求1～6中任意一项所述的组合物，其特征在于，所述的组合物剂型为片剂、颗粒剂、胶囊剂和口服溶液中的任意一种。
8.权利要求1～6中任意一项所述的组合物在制备具有抗脂肪肝、降脂和降低氧化应激中任意一种或几种作用的产品中的应用。
9.根据权利要求8所述的应用，其特征在于，所述的脂肪肝为非酒精性脂肪肝。
10.根据权利要求8所述的应用，其特征在于，所述的组合物通过改善氧化应激，提高AMP依赖的蛋白激酶的表达水平，降低肝脏炎症及肝脏内脂质沉积的途径抗脂肪肝。
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