CN116421675B - 一种用于治疗非酒精性脂肪性肝病的中药组合物及其应用 - Google Patents
一种用于治疗非酒精性脂肪性肝病的中药组合物及其应用 Download PDFInfo
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Abstract
本发明公开了一种用于治疗非酒精性脂肪性肝病的中药组合物，包括以下原料药物：干地黄、山药、山茱萸、泽泻、茯苓、牡丹皮、桂枝、黑顺片、白术、山楂、决明子、丹参。本发明的中药组合物以及制得的中药复方制剂，改善衰老相关非酒精性脂肪性肝病临床症状快、效果好，可改善代谢水平和提高患者生存质量，具有补肾健脾，清肝调脂，化瘀祛浊等作用，通过改善氧化应激，减低炎症反应，阻遏细胞衰老，疗效迅速，价格低廉。
Description
技术领域
本发明设计中药复方研究领域，特别涉及一种用于治疗非酒精性脂肪性肝病的中药组合物及其应用。
背景技术
非酒精性脂肪性肝病（Non-alcoholic Fatty Liver Disease, NAFLD）发病率与日剧增，中国庞大的NAFLD基数及相关肝外危害已成为影响我国社会发展的重大公共卫生问题之一。目前NAFLD 的发病机制尚未明确，目前尚无针对NAFLD治疗的特效药。
控制体重、改善饮食等调整生活方式可对NAFLD起到预防和改善的作用。但生活方式干预的依从性却不理想，因此，对于依从性不佳的患者需要适当给予药物治疗。
西医治疗NAFLD目前主要从改善血脂、调整血糖，减肥等入手，如噻唑烷二酮类、胰高血糖素样肽-1受体激动剂。但每种药物的长期安全性及有效性仍需要进行大样本的研究予以验证。中医药对于改善NAFLD症状有确切疗效，但是对于衰老相关的非酒精性脂肪肝尚无有效验方。肝细胞衰老加剧是非酒精性脂肪性肝病的重要特征之一，肝细胞衰老程度与非酒精性脂肪性肝病病情进展密切相关，衰老的肝细胞可以通过传染引发周边细胞衰老,导致非酒精性脂肪性肝病向终末期肝病发展。此类病患呈现本虚标实特性，有必要针对衰老相关的非酒精性脂肪肝疾病开发新的有效药物。
发明内容
本发明的目的在于提供一种用于治疗非酒精性脂肪性肝病的中药组合物，从而克服现有技术中对于非酒精性脂肪性肝病无临床特效药物，且西药长期治疗容易引起肌病和肝脏不良反应的技术问题。
本发明采用的技术方案是：
一种用于治疗非酒精性脂肪性肝病的中药组合物，所述中药组合物包括以下原料药物：干地黄、山药、山茱萸、泽泻、茯苓、牡丹皮、桂枝、黑顺片、白术、山楂、决明子、丹参。
进一步，所述中药组合物由下列重量份的原料药物组成：干地黄5~10份、山药3~6份、山茱萸3~6份、泽泻1~4份、茯苓1~4份、牡丹皮1~4份、桂枝1~3份、黑顺片1~3份、白术1~4份、山楂1~4份、决明子1~4份、丹参1~4份。
优选所述中药组合物由下列重量份的原料药物组成：干地黄7~8份、山药3~4份、山茱萸3~4份、泽泻2~3份、茯苓2~3份、牡丹皮2~3份、桂枝1~2份、黑顺片1~2份、白术2~3份、山楂2~3份、决明子2~3份、丹参2~3份。
更优选所述中药组合物由下列重量份的原料药物组成：干地黄7.5份、山药3.75份、山茱萸3.75份、泽泻2.5份、茯苓2.5份、牡丹皮2.5份、桂枝1份、黑顺片1份、白术2.5份、山楂2.5份、决明子2.5份、丹参2.5份。
非酒精性脂肪性肝病中医病机在于：归属于中医“痰证”、“瘀血”、“胁痛”、“积证”、“肥气”等范畴。主要致病因素有饮食不节、劳逸过度、情志不畅、久病体虚、先天禀赋等，其病机以肝脏的体用失调，脾肾阳气亏虚为主要特点，其中痰、湿、浊、瘀、热为主要病理产物。主要定义为元气渐衰，痰浊瘀阻于肝而发病；属本虚标实、虚实夹杂之证。
本发明在研究治疗NAFLD的药方时，法宗《内经》“阳化气，阴成形”理论，从“气”切入，参仲景“病痰饮者，当以温药和之”，提出“阳化气不足，阴成形太过”为NAFLD的发病病机，引入“助阳化气，化瘀祛浊”法治疗本病，临床上运用本方治疗代谢相关疾病取得了良好疗效，值得临床推广。
本发明的中药组合物由干地黄、山药、山茱萸、泽泻、茯苓、牡丹皮、桂枝、黑顺片、白术、山楂、决明子、丹参组成。
《本草图经》云：“地黄具有补血、滋阴、益血、填髓之功。”地黄性寒，味甘、苦，归心经、肝经、肾经，滋阴养血、生精补髓、壮骨，为补益肝肾之要药。
《本草纲目》：“山药，益肾气，健脾胃，止泄痢，化痰涎，润皮毛。”
《神农本草经》：“山茱萸，味酸，补益肝肾，收敛固脱，温中，逐寒湿痹，去三虫，久服轻身。”
《神农本草经》：“泽泻，归肾、膀胱经，利水消肿，渗湿，泄热。”
《本草纲目》：茯苓气味淡而渗，其性上行，生津液，开腠理，滋水源而下降，利小便，故张洁古谓其属阳，浮而升，言其性也；东垣谓其为阳中之阴，降而下，言其功也。
《神农本草经》：“牡丹皮，归心、肝、肾经，具有清热凉血，活血祛瘀的功效。”
《神农本草经》：“桂枝，味辛温，主百病，养精神，和颜色，利关节，补中益气。为诸药先聘通使，久服通神，轻身不老。”
《本草纲目》：“黑顺片，治三阴经证，及阴毒伤寒，阴阳易病。”
《药性论》：白术能主大风顽痹，多年气痢，心腹胀痛。破消宿食，开胃，去痰涎，除寒热，止下泄。主面光悦，驻颜，去蕓。治水肿胀满。止呕逆、腹内冷痛、吐泻不住及胃气虚冷痢。
《本草纲目》：“山楂化饮食，消肉积，症瘕，痰饮痞满吞酸，滞血痛胀。”《本草再新》云：治脾虚湿热，消食磨积，利大小便。
《中华本草》述决明子的应用较为广泛，载曰：“清肝益肾，明目，利水通便。主治目赤肿痛，羞明泪多、青盲、雀目、头痛头晕、视物昏暗、肝硬化腹水、小便不利，习惯性便秘。外治肿毒、癣疾。”
《本经》：丹参，主心腹邪气，肠鸣幽幽如走水，寒热积聚，破症除瘕，止烦满，益气。
本方中，干地黄、山药阴阳双补，肾虚得复，元气充足，从而激发和推动全身各脏腑组织器官的生理功能，山茱萸补益肝肾，收敛固脱，温中，方中泽泻、茯苓、牡丹皮淡渗利湿，桂枝、黑顺片，量少，取少火生气之意，白术健脾祛湿，山楂降脂活血，决明子清肝调脂，丹参祛瘀通络，四药相伍，健脾保肝降脂，活血通络，与肾气丸合用，共奏补肾健脾，化瘀祛浊之功效。
本发明还提供所述用于治疗非酒精性脂肪性肝病的中药组合物制备得到的用于治疗非酒精性脂肪性肝病的中药复方制剂。
所述的用于治疗非酒精性脂肪性肝病的中药复方制剂的剂型包括片剂、胶囊剂、散剂、丸剂、流浸膏剂或汤剂等。各种剂型中可加入各类人体可接受的药用辅料。优选采用汤剂或流浸膏剂。
本发明还提供所述所述用于治疗非酒精性脂肪性肝病的中药组合物或用于治疗非酒精性脂肪性肝病的中药复方制剂在制备治疗非酒精性脂肪性肝病的药物中的应用。
进一步，所述非酒精性脂肪性肝病为衰老相关的非酒精性脂肪性肝病。
与现有技术相比，本发明具有如下有益效果：
本发明提供的中药组合物以及中药复方制剂，改善衰老相关非酒精性脂肪性肝病临床症状快、效果好，改善代谢水平和提高患者生存质量，具有补肾健脾，清肝调脂，化瘀祛浊等作用，通过改善氧化应激，减低炎症反应，阻遏细胞衰老，疗效迅速，价格低廉，具有良好的商业价值和前景。
附图说明
图1 为中药组合物对小鼠血清甘油三酯、总胆固醇、谷丙转氨酶、谷草转氨酶以及低密度脂蛋白、高密度脂蛋白的影响结果图。
图2 小鼠肝组织病理HE染色和油红O染色图。图2中，上排三幅图为油红O染色图，下排三幅图为HE染色图。
图3 小鼠肝脏细胞电镜照片。
具体实施方式
为使本申请的目的、技术方案和优点更加清楚明白，下文中将结合实施例对本发明的技术方案进行详细说明，但本发明的保护范围不限于此。
实施例1
干地黄、山药、山茱萸、泽泻、茯苓、牡丹皮、桂枝、黑顺片、白术、山楂、决明子、丹参按质量比7.5: 3.75: 3.75: 2.5: 2.5: 2.5: 1: 1：2.5: 2.5: 2.5:2.5混合，把药材用冷水浸泡15分钟,再加入12-14质量倍的水煎煮两次,每次2小时,将两次煎煮得到的药汁去渣后进行浓缩,浓缩至含水量15-20%，制得流浸膏待用。
将制得的中药组合物流浸膏进行质谱检测分析，其中主要成分如下表1所示：
表1
实施例2
动物实验
1、建立高脂饮食诱导的NAFLD小鼠模型
56 只健康雄性 8 周龄 C57BL/6J 小鼠，SPF 级。上海市西普尔必凯实验动物有限公司提供。适应性饲养 1 周，随机分为正常组、模型组、治疗组；其中正常组、模型组每组各 24 只，治疗组 8 只。正常组小鼠每天予普通饲料喂养；模型组、治疗组小鼠每天予高脂饲料(10%熟猪油、5%蛋黄粉、2%胆固醇、0.5% 3号胆盐、普通饲料82.5%)，连续造模4周。
2、干预实验
从造模第5周起治疗组小鼠连续灌服24g/kg /d的本发明中药组合物20周(按实施例1方法制备，由干地黄、山药、山茱萸、泽泻、茯苓、牡丹皮、桂枝、黑顺片、白术、山楂、决明子、丹参组成，按 7.5: 3.75: 3.75: 2.5: 2.5: 2.5: 1: 1：2.5: 2.5: 2.5:2.5 的比例，制成流浸膏剂)，正常组和模型组小鼠灌服等容量蒸馏水 20 周；在第 8 周末、第 16 周末处理正常组和模型组各 8 只小鼠，第24 周末处理 3 组剩余全部小鼠。
3、处理方法：空腹麻醉下取血分离血清，取肝组织部分在10%中性甲醛固定后常规石蜡包埋，部分-80℃保存待用。指标检测： HE、Masson 染色观察组织病理学特点，电镜观察细胞超微结构；进行血脂等生化指标的测定：通过全自动生化仪分析检测血清中的谷丙转氨酶(ALT)、谷草转氨酶(AST)以及低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、总胆固醇(TCHO)、甘油三酯(TRIG)等生化指标，对比正常组、模型组、治疗组终点相关指标的变化，采用SPSS17 .0统计软件处理数据，非配对t检验，计算两组之间的差异以及95％的可信区间。计量资料以均数±标准差(x±s)表示，计数资料以率(％)表示，比较采用x2检验。以p<0 .05为检验水准。 正常组 vs 模型组（*，p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001）；治疗组vs 模型组（#，p<0.05; ##, p<0.01; ###, p<0.001;####, p<0.0001）。
所得结果如图1所示。在给予高脂饮食后，模型组小鼠肝损伤相关指标谷丙转氨酶(ALT)、谷草转氨酶(AST)，较正常小鼠显著升高（p<0 .05），药物治疗能显著降低转氨酶水平（p<0 .05），提示药物有助于改善高脂饮食造成的肝损伤。在给予高脂饮食后，模型组小鼠脂质代谢相关指标低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、总胆固醇(TCHO)、甘油三酯(TRIG)，较正常小鼠显著异常（p<0 .05），药物治疗能显著改善脂质代谢指标异常（p<0 .05），提示药物有助于改善高脂饮食造成的脂质代谢紊乱。
对小鼠肝脏组织进行HE染色和油红O染色，照片如图2所示，放大倍数为200。其中上排三幅图为油红O染色，下排三幅图为HE染色。油红O染色结果反应肝脏内的脂质堆积情况。如图2所示，高脂饮食能造成小鼠肝脏内的脂质大量堆积，出现与脂肪肝疾病表现一致。药物干预后，能显著减少小鼠肝脏内的脂质堆积，提示药物具有治疗非酒精性脂肪性肝病的潜力。HE染色结果显示，模型组小鼠的肝脏内炎性细胞募集，提示较正常组，模型组小鼠肝组织出现炎症及损伤。经药物治疗后，小鼠肝脏内的炎症及损伤较模型组有所改善。
电镜下观察肝细胞超微结构变化，电镜照片如图3所示，放大倍数为1000倍。相较于正常小鼠肝细胞，模型组小鼠的肝细胞细胞核核骨架成分改变，核纤层的结构松散，提示此时肝细胞存在衰老现象。核纤层对核膜具有支撑作用，细胞老化会造成核纤层的结构松散，对核的支撑作用降低。经药物治疗后，小鼠肝细胞细胞核清晰可见，核纤层结构松散的现象明显改善。
图1结果表明：治疗组的总胆固醇、谷丙转氨酶、谷草转氨酶以及低密度脂蛋白、高密度脂蛋白均相对模型组显著下降。
图2显示：本发明中药组合物能调节高脂饮食诱导的NAFLD大鼠脂质代谢紊乱、减轻肝脏组织学病变，阻遏非酒精性脂肪性肝病的进一步发展。
图3显示：相较于正常小鼠肝细胞，模型组小鼠的肝细胞细胞核核骨架成分改变，核纤层的结构松散，提示此时肝细胞存在衰老现象。核纤层对核膜具有支撑作用，细胞老化会造成核纤层的结构松散，对核的支撑作用降低。经药物治疗后，小鼠肝细胞细胞核清晰可见，核纤层结构松散的现象明显改善。
Claims (7)
1.一种用于治疗非酒精性脂肪性肝病的中药组合物，其特征在于所述中药组合物由下列重量份的原料药物组成：干地黄5~10份、山药3~6份、山茱萸3~6份、泽泻1~4份、茯苓1~4份、牡丹皮1~4份、桂枝1~3份、黑顺片1~3份、白术1~4份、山楂1~4份、决明子1~4份、丹参1~4份。
2.如权利要求1所述的中药组合物，其特征在于所述中药组合物由下列重量份的原料药物组成：干地黄7~8份、山药3~4份、山茱萸3~4份、泽泻2~3份、茯苓2~3份、牡丹皮2~3份、桂枝1~2份、黑顺片1~2份、白术2~3份、山楂2~3份、决明子2~3份、丹参2~3份。
3.如权利要求2所述的中药组合物，其特征在于所述中药组合物由下列重量份的原料药物组成：干地黄7.5份、山药3.75份、山茱萸3.75份、泽泻2.5份、茯苓2.5份、牡丹皮2.5份、桂枝1份、黑顺片1份、白术2.5份、山楂2.5份、决明子2.5份、丹参2.5份。
4.如权利要求1~3之一所述的用于治疗非酒精性脂肪性肝病的中药组合物制备得到的用于治疗非酒精性脂肪性肝病的中药复方制剂。
5.如权利要求4所述的用于治疗非酒精性脂肪性肝病的中药复方制剂，其特征在于所述用于治疗非酒精性脂肪性肝病的中药复方制剂的剂型包括片剂、胶囊剂、散剂、丸剂、流浸膏剂或汤剂。
6.如权利要求1~3之一所述的用于治疗非酒精性脂肪性肝病的中药组合物或权利要求4或5所述的用于治疗非酒精性脂肪性肝病的中药复方制剂在制备治疗非酒精性脂肪性肝病的药物中的应用。
7.如权利要求6所述的应用，其特征在于所述非酒精性脂肪性肝病为衰老相关的非酒精性脂肪性肝病。
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| CN1090770A (zh) * | 1993-01-09 | 1994-08-17 | 李庆恩 | 八味双补药物 |
| CN111973697A (zh) * | 2019-05-22 | 2020-11-24 | 吉岩科技有限公司 | 中药复方在制备用于防治代谢综合征的药物组合物中的用途 |
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| CN1090770A (zh) * | 1993-01-09 | 1994-08-17 | 李庆恩 | 八味双补药物 |
| CN111973697A (zh) * | 2019-05-22 | 2020-11-24 | 吉岩科技有限公司 | 中药复方在制备用于防治代谢综合征的药物组合物中的用途 |
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| 中药自拟方治疗痰瘀互结型非酒精性脂肪性肝病的用药规律研究;刘龙辉等;中医临床研究;第13卷(第4期);23-26 * |
| 肾气丸对非酒精性脂肪性肝炎大鼠肝细胞脂性凋亡的影响;吴黎艳等;中国中西医结合消化杂志;-;第19卷(第06期);366-369 * |
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