CN113521082A - 雷公藤甲素在制备预防和/或治疗肝病的药物中的应用 - Google Patents
雷公藤甲素在制备预防和/或治疗肝病的药物中的应用 Download PDFInfo
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- CN113521082A CN113521082A CN202110965614.3A CN202110965614A CN113521082A CN 113521082 A CN113521082 A CN 113521082A CN 202110965614 A CN202110965614 A CN 202110965614A CN 113521082 A CN113521082 A CN 113521082A
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- Prior art keywords
- triptolide
- liver
- preparation
- fibrosis
- pharmaceutically acceptable
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Abstract
本发明公开了雷公藤甲素在制备预防和/或治疗肝病的药物中的应用，具体为雷公藤甲素或其药学上可接受的盐在制备预防和/或治疗非酒精性脂肪肝或肝脏纤维化中的应用。本发明实验结果表明，雷公藤甲素能够明显降低血清肝酶水平，还具有延缓肝脏脂肪变性、炎症及纤维化的作用，能够显著降低α‑SMA、collagen I、fibronectin等纤维化相关蛋白的表达量，对非酒精性脂肪肝病的治疗作用确切，为临床用药提供了一种新的选择。
Description
技术领域
本发明属于医药技术领域，具体涉及雷公藤甲素在制备预防和/或治疗肝病的药物中的应用。
背景技术
非酒精性脂肪肝病是指除长期大量饮酒和其他明确的损肝因素所引起的，以甘油三酯为主的脂质在肝细胞中蓄积为病理改变的肝脏代谢性疾病，包括从单纯的肝脂肪变性到非酒精性脂肪性肝炎，以致一部分最终发展为肝硬化，甚至演变为肝细胞癌。近年来，随着肥胖发病率的日益提高，非酒精性脂肪肝病发病率逐年增高。因此，寻求非酒精性脂肪肝病的有效治疗药物，具有重要意义。
目前还没有获批治疗非酒精性肝炎的药物。雷公藤甲素是从传统药物雷公藤中提取出来的环氧二萜内酯类化合物，俗称雷公藤内酯醇，分子式为C20H24O6，分子量为360.4，化学结构如下：
雷公藤甲素主要存在于雷公藤的根、叶、花及果实当中。现代药理研究表明，雷公藤甲素具有多种药理活性，如抗炎、抗肿瘤、调节免疫等。但是，将雷公藤甲素用于肝病防治还鲜有报道。
发明内容
针对上述现有技术，本发明提供雷公藤甲素用于制备防治肝病的药物的用途。
为了达到上述目的，本发明所采用的技术方案是：
本发明提供了雷公藤甲素或其药学上可接受的盐在制备预防和/或治疗非酒精性脂肪肝或肝脏纤维化的药物中的应用。
本发明在上述技术方案的基础上，还可以做如下进一步的改进。
进一步，药物是以雷公藤甲素或其药学上可接受的盐为活性成分，加入药学上可接受的辅料或者辅助性成分，制备而成的制剂。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐、酯通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“药学上可接受的盐”是指本发明化合物与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：肠胃外(静脉内、肌肉内或皮下)、口服和局部给药。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明所述药学上可接受的辅料，是指除活性成分以外包含在剂型中的物质。
本发明所述药学上可接受的辅助性成分，它具有一定生理活性，但该成分的加入不会改变上述药物组合物在疾病治疗过程中的主导地位，而仅仅发挥辅助功效，这些辅助功效仅仅是对该成分已知活性的利用，是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明药物组合物配合使用，仍然应属于本发明保护的范围。
进一步，每单位制剂含有雷公藤甲素5.5μg。
本发明的有益效果是：本发明提供了雷公藤甲素在制备防治肝病的药物中的用途，实验结果表明，雷公藤甲素能够明显降低血清肝酶水平，还具有延缓肝脏脂肪变性、炎症及纤维化的作用，能够显著降低α-SMA、collagen I、fibronectin等纤维化相关蛋白的表达量，对非酒精性脂肪肝病的治疗作用确切，为临床用药提供了一种新的选择。
附图说明
图1为雷公藤甲素延缓NASH小鼠肝脏纤维化的染色及评分结果图；
图2为α-平滑肌肌动蛋白α-SMA、VI型胶原COL-VI、纤连蛋白FN等纤维化标志蛋白的表达情况图；
图3为非酒精性脂肪肝病小鼠肝脏组织油红O染色图；
图4为非酒精性脂肪肝病小鼠血清肝酶、血脂水平检测结果图；
图5为非酒精性脂肪肝病小鼠肝脏组织H&E及MASSON染色图。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
下面结合实施例对本发明的具体实施方式做详细的说明。
实施例1雷公藤甲素延缓肝脏纤维化的作用
实验动物：野生C57BL/6J小鼠。实验前至少1周恒温环境下标准化实验日粮饲养，饮水不限。
动物分组：将小鼠24只分为3组：①对照饲料组8只；②蛋氨酸胆碱缺乏饲料(MCD)组8只；③雷公藤甲素治疗组(50μg/kg/d)8只。
造模方法：8周龄C57BL/6J雄性小鼠予MCD饲料喂养5周建立非酒精性肝炎模型。5周后抽取各组小鼠心脏血并留取肝脏组织收集标本。
给药方法：饲喂MCD饲料3周后开始采用腹腔注射方式给予50μg/kg/d雷公藤甲素，连续14天；MCD模型组造模后在相同时间灌喂同等剂量生理盐水。
实验结果：
1、雷公藤甲素抑制小鼠肝脏纤维化的染色及评分结果(见图1)
MASSON染色：显微镜下发现，对照饲料组的染色图片具有完整的肝脏结构，没有明显的肝脏脂肪变性，没有炎性细胞浸润和纤维化。MCD模型组可见肝脏脂肪变性，MASSON染色蓝色区域明显(蓝色区域表示纤维化病变的程度)。使用雷公藤甲素治疗后，肝脏脂肪变性改善，MASSON染色蓝色区域明显少于MCD模型组。
以上结果表明，在MCD模型组中，小鼠肝脏发生明显纤维化；使用雷公藤甲素进行治疗后，可以显著抑制肝脏纤维化的程度。
病理学诊断常规进行NAFLD活度积分和纤维化分期。评分的评分标准参考Brunt评分系统。NASH评分(0-8分)：(1)肝细胞脂肪变：0分(<5％)；1分(5％～33％)；2分(34％～66％)；3分(>66％)。(2)小叶内炎症(20倍镜计数坏死灶)：0分，无；1分(<2个)；2分(2～4个)；3分(>4个)。(3)肝细胞气球样变：0分，无；1分，少见；2分，多见。汇总三个评分，NAS<3分可排除NASH，NAS>4分则可诊断NASH，介于两者之间者判为可能。采用Masson三色染色法观察肝脏组织纤维增生情况并分期。肝纤维化分期标准：0期，无纤维化；1a期，肝腺泡3区轻度窦周纤维化；1b期，肝腺泡3区中度窦周纤维化；lc期，仅有门脉周围纤维化；2期，腺泡3区窦周纤维化合并门脉周围纤维化；3期，桥接纤维化；4期，高度可疑或确诊肝硬化，包括NASH合并肝硬化、脂肪性肝硬化以及隐源性肝硬化。
评分结果：MCD组评分较对照饲料组显著增高，雷公藤甲素治疗组评分显著低于MCD模型组评分。
2、Western Blot检测α-平滑肌肌动蛋白(α-SMA)、VI型胶原(col I)、IV型胶原(col IV)、纤连蛋白(FN)等纤维化标志蛋白的表达情况(见图2)
α-SMA、collagen VI(COL-VI)、fibronectin(FN)蛋白的表达量能够反映肝脏纤维化的程度。从图2可以看出，雷公藤甲素能显著抑制α-SMA、COL-VI、FN蛋白的表达，治疗肝脏纤维化的作用非常明显。
3、油红O检测肝脏脂滴沉积(见图3)
从图3结果发现雷公藤甲素能显著抑制非酒精性脂肪肝病肝脏脂滴沉积，可以确证治疗非酒精性脂肪肝的作用。
实施例2雷公藤甲素治疗非酒精性脂肪肝病的作用
实验动物：SPF级雄性瘦素受体基因缺陷(db/db)小鼠。实验前至少1周恒温环境下标准化实验日粮饲养，饮水不限。
动物分组：将小鼠24只分为3组：①正常对照组8只；②非酒精性脂肪肝病模型组8只；③雷公藤甲素治疗组8只。
造模方法：db/db小鼠由于瘦素受体基因缺陷，会自发形成非酒精性脂肪肝病。18周后处死小鼠，腹主动脉取血，留取肝脏组织。
给药方法：50μg/kg雷公藤甲素于db/db小鼠8周龄时开始采用静脉注射方式给药，连续10周；模型组在相同时间静脉注射等剂量生理盐水。
实验结果：
1、血清肝酶和血脂
实验动物取血后离心保留血清，使用Beckman全自动生化分析仪检测血清肝酶、血脂，检测结果见图4。从图4可以看出，雷公藤甲素能显著降低血谷丙转氨酶(ALT)和甘油三酯(TG)水平，具备改善肝功能的作用。
2、H&E及MASSON染色
从图5可以看出，正常对照组的染色图片具有完整的肝脏结构，没有明显的肝脏脂肪变性，没有炎性细胞浸润和纤维化。非酒精性脂肪肝病模型组可见肝脏脂肪变性，MASSON染色蓝色区域明显(蓝色区域表示纤维化病变的程度)。使用雷公藤甲素治疗后，肝脏脂肪变性改善，MASSON染色蓝色区域明显少于非酒精性脂肪肝模型组。
以上结果表明，雷公藤甲素可以显著抑制非酒精性脂肪肝病小鼠肝脏纤维化的程度。
虽然结合实施例和附图对本发明的具体实施方式进行了详细地描述，但不应理解为对本专利的保护范围的限定。在权利要求书所描述的范围内，本领域技术人员不经创造性劳动即可作出的各种修改和变形仍属本专利的保护范围。
Claims (5)
1.雷公藤甲素或其药学上可接受的盐在制备预防和/或治疗非酒精性脂肪肝或肝脏纤维化的药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述药物是以雷公藤甲素或其药学上可接受的盐为活性成分，加入药学上可接受的辅料或者辅助性成分，制备而成的制剂。
3.根据权利要求2所述的应用，其特征在于：所述雷公藤甲素药学上可接受的盐为雷公藤甲素的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
4.根据权利要求2所述的应用，其特征在于：所述制剂的剂型包括胶囊剂、片剂、丸剂、散剂、颗粒剂、乳液、溶液、悬浮液、糖浆、酊剂、软膏剂、散剂、贴剂、喷射剂、吸入剂或静脉制剂。
5.根据权利要求4所述的应用，其特征在于：每单位制剂含有雷公藤甲素5.5μg。
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