CN107233542B - 龙虎人丹在制备预防和/或治疗肝纤维化药物中的应用 - Google Patents

龙虎人丹在制备预防和/或治疗肝纤维化药物中的应用 Download PDF

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CN107233542B
CN107233542B CN201710301074.2A CN201710301074A CN107233542B CN 107233542 B CN107233542 B CN 107233542B CN 201710301074 A CN201710301074 A CN 201710301074A CN 107233542 B CN107233542 B CN 107233542B
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longhurendan
hepatic fibrosis
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CN107233542A (zh
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丁礼琴
金家骅
汪弼晔
曹无介
朱丽
兰天
杨桂智
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Shanghai Zhonghua Pharmaceutical Co ltd
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Abstract

本发明涉及龙虎人丹在制备预防和/或治疗肝纤维化药物中的应用，属于肝纤维化药物制备技术领域。本发明提供了龙虎人丹在制备预防和/或治疗肝纤维化药物中的应用，本发明中龙虎人丹的使用能够显著改善纤维化的作用，其抗肝纤维化和肝保护效果与阳性药水飞蓟宾相当。

Description

龙虎人丹在制备预防和/或治疗肝纤维化药物中的应用
技术领域
本发明涉及肝纤维化药物制备技术领域，尤其涉及龙虎人丹在制备预防和/或治疗肝纤维化药物中的应用。
背景技术
肝纤维化是各种慢性肝损伤过程中一种普遍存在的损伤修复反应，其主要特点是细胞外基质(ECM)的大量沉积。而肝纤维化如果没有及时治疗，最后发展成肝硬化。同时，肝纤维化也被认为是肝癌的一个重要诱因。从通过及时合理的干预，肝纤维化可以被逆转。目前，针对肝纤维化治疗，尚没有有效的治疗药物。通常采用化学药物对肝纤维化进行治疗，但化疗安全性低、毒性大、成本高，对人体产生的副作用大。因此，寻找一个肝纤维化有效的治疗药，成为国内外研究的热点。
发明内容
本发明的目的在于提供龙虎人丹在制备预防和/或治疗肝纤维化药物中的应用，本发明中龙虎人丹的使用能够显著改善纤维化的作用，其抗肝纤维化和肝保护效果与阳性药水飞蓟宾相当。
本发明提供了龙虎人丹在制备预防和/或治疗肝纤维化药物中的应用。
优选的是，所述龙虎人丹每1000g包括以下质量份的成分：薄荷脑32～48g、冰片24～36g、丁香20～30g、砂仁20～30g、八角茴香12～18g、肉桂32～48g、胡椒12～18g、木香12～18g、干姜20～30g、儿茶160～240g、甘草291.28～436.92g、糯米粉144～216g、苯甲酸钠4～6g、红氧化铁11.6～17.4g、二甲硅油0.08～0.12ml、石墨0.16～0.24g、滑石粉0.16～0.24g和糊精3.16～4.74g。
优选的是，所述龙虎人丹的剂型包括片剂、粉剂、粒剂、丸剂、胶囊。
优选的是，所述龙虎人丹的有效作用剂量为100mg～200mg/kg。
本发明提供了龙虎人丹在制备预防和/或治疗肝纤维化药物中的应用。在本发明中，所述龙虎人丹能够显著改善肝纤维化，其抗肝纤维化和肝保护效果与阳性药水飞蓟宾相当。且龙虎人丹的副作用小，安全性高。试验结果表明，龙虎人丹在低中药物浓度下具有显著改善纤维化的作用，其抗肝纤维化和肝保护效果与阳性药水飞蓟宾相当。
附图说明
图1为本发明实施例1提供的龙虎人丹对CCl4诱导肝纤维化小鼠血清学指标的影响结果图，其中，图1A为小鼠血清AST活性结果图，图1B为小鼠血清ALT活性结果图；
图2为本发明实施例1提供的龙虎人丹对CCl4诱导肝纤维化小鼠病理指标的影响结果图，图2A为小鼠肝脏HE染色结果图，图2B为小鼠肝脏天狼猩红(Sirius Red)染色结果图，图2C为小鼠肝脏α-SMA免疫组化染色结果图。
具体实施方式
本发明提供了龙虎人丹在制备预防和/或治疗肝纤维化药物中的应用。
在本发明中，所述龙虎人丹每1000g包括以下质量份的成分：薄荷脑32～48g、冰片24～36g、丁香20～30g、砂仁20～30g、八角茴香12～18g、肉桂32～48g、胡椒12～18g、木香12～18g、干姜20～30g、儿茶160～240g、甘草291.28～436.92g、糯米粉144～216g、苯甲酸钠4～6g、红氧化铁11.6～17.4g、二甲硅油0.08～0.12ml、石墨0.16～0.24g、滑石粉0.16～0.24g和糊精3.16～4.74g。本发明对所述龙虎人丹的来源没有特殊的限定，采用本领域技术人员熟知的龙虎人丹的市售产品即可，如上海中华药业有限公司出售的龙虎人丹。本发明所述龙虎人丹在现有技术中的常规作用为开窍醒神、祛湿化浊、和中止呕功效，具有调理脾胃、化浊健运之功效；在本发明中，所述龙虎人丹能够实现对肝纤维化的预防和/或治疗。
在本发明中，所述龙虎人丹的剂型包括片剂、粉剂、粒剂、丸剂、胶囊。
在本发明中，所述龙虎人丹的有效作用剂量为100mg/kg～200mg/kg。
在本发明中，龙虎人丹的使用方法中优选包括稀释用药剂，在本发明中，所述龙虎人丹的稀释用药剂没有特殊的限制，采用本领域技术人员熟知的药物载体即可，如羟甲基纤维素钠(CMC-Na)。在本发明中，所述羟甲基纤维素钠在龙虎人丹中的质量浓度优选为0.5％。在本发明中，所述稀释用药剂是为了保证施药量，本发明优选采取灌胃给药方式。在本发明中，所述稀释用药剂羟甲基纤维素钠对纤维化无明显影响，仅作为药剂中的常用助悬剂，属于惰性分子，没有明显生物活性。
本发明对所述的制备方法没有特殊的限定，采用本领域技术人员熟知的龙虎人丹市售产品的制备方法即可。如所述制备方法可参照申请号为200910194559.1的专利中对制备方法的限定，具体包括以下步骤：(1)软材的制备：a.儿茶浆的配制：根据上述质量份将儿茶与纯化水按质量比1∶1混合搅拌，控制蒸汽压力0.25～0.5Mpa，温度60～95℃，加热至溶解，过滤得儿茶溶液；然后将苯甲酸钠、儿茶溶液及上述糯米粉量的5～18％，分批搅拌3～5分钟，打浆10～30分钟，出料；b.混合粉的制备：取上述质量份糯米粉、砂仁粉、八角茴香粉、肉桂粉、胡椒粉、木香粉、干姜粉、丁香粉及甘草粉混合投料，喷入预先经熔化过滤的挥发性原料，边喷边混合，喷液结束后，出料；c.将上述混合粉、儿茶浆，混合搅拌15～30分钟，出料即可；(2)丸剂的制备：a.将软材制成圆整、大小均匀的湿毛丸；b.将湿毛丸进行拉光，加糊精溶液搅匀，吹风，滚动至表面光亮后撒入红氧化铁，再滴入二甲硅油，包衣时间在0.5～2.5小时；c.干燥灭菌，挑选丸径在4.0mm～4.5mm之间的丸药，加入石墨粉与滑石粉打光。
下面结合具体实施例对本发明提供的龙虎人丹在制备预防和/或治疗肝纤维化药物中的应用做进一步详细的介绍，本发明的技术方案包括但不限于以下实施例。
实施例1
实验动物：SPF级C57小鼠，8周龄，雌雄各半，广东省医学实验动物中心提供，饲养于屏障环境动物房(SPF级)，并保持饮水和饲料充足。合格证[SCXK(粤)2013-0002]。
实验药物与试剂如表1所示：
表1实验药物与试剂
Figure BDA0001283953060000031
实验设备如表2所示：
表2实验设备
Figure BDA0001283953060000041
实验设计
给药情况：取32粒龙虎人丹，置于研钵中研碎，用20mL的0.5％CMC-Na将其溶解，吸入50mL离心管中，涡旋使其完全溶解后定容至32mL(A液)。取6个5mL EP管，每管分装3mL(即高剂量组一天给药量)。另取50mL管，吸取A液9mL，加9mL 0.5％CMC-Na，混匀，取6个5mL EP管，每管分装3mL(即中剂量组一天给药量)。另取一个50mL离心管，吸取A液4.5mL，加0.5％CMC-Na溶液至18mL，混匀，取6个5mL EP管，每管分装3mL(即低剂量组一天给药量)。持续6周，共6×32粒＝192粒，约4盒药。
水飞蓟宾的配制：取50mL离心管，加10～12mL的0.5％CMC-Na，将4粒胶囊内颗粒倒入，溶解，之后用0.5％CMC-Na定容至20mL，混匀。取6个5mL EP管每管分装3mL(即一天给药量)。持续6周，共6×4粒＝24粒，约2盒药。
造模、分组及给药方法
取健康昆明种小鼠60只，随机分为6组，每组8只。即：空白对照组、CCl4模型组、水飞蓟宾阳性对照组、龙虎人丹低、中、高剂量组。各组均正常饮食，空白对照组和CCl4模型组每日灌胃给等体积的0.5％CMC-Na，水飞蓟宾组按70mg/kg/d的剂量给药，实验组小鼠按龙虎人丹低剂量组100mg/kg/d，中剂量组200mg/kg/d、高剂量组400mg/kg/d给药，每天一次，连续6周。
血清学指标：
禁食12h后摘除眼球取血，分离血清，按谷丙转氨酶(ALT)和谷草转氨酶(AST)试剂盒测定ALT、AST活性。
图1为龙虎人丹对CCl4诱导肝纤维化小鼠血清学指标的影响结果图，图1A为小鼠血清AST活性结果图，图1B为小鼠血清ALT活性结果图。由图1结果显示：与CCl4组相比，阳性药水飞蓟宾和龙虎人丹三个剂量组的AST均显著降低(P<0.05)，而ALT除了龙虎人丹高剂量组400mg/kg没有改善以外，低、中剂量组均显著降低(P<0.05)。
病理指标：
HE染色、天狼猩红染色、平滑肌肌动蛋白α-SMA免疫组化。使用ImageJ软件统计天狼星红和免疫组化的阳性染色面积，用GraphPadPrism处理数据作图，并进行t检验分析，以P<0.05为有统计学意义。
首先对小鼠肝脏切片进行HE染色，观察大体形态，图2为龙虎人丹对CCl4诱导肝纤维化小鼠病理指标的影响结果图，图2A为小鼠肝脏HE染色结果图，图2B为小鼠肝脏天狼猩红(Sirius Red)染色结果图，图2C为小鼠肝脏α-SMA免疫组化染色结果图。由图2A可以看出，与Oil组比较，CCl4组有明显的炎症浸润和肝细胞损伤；与CCl4模型组相比，水飞蓟宾组和龙虎人丹三个剂量组的炎症浸润和肝损伤都有不同程度的改善，其中100mg/kg和200mg/kg改善较为明显。随后进行天狼星红染色(图2B)和免疫组化(α-SMA)(图2C)观察，同样发现水飞蓟宾和龙虎人丹三个剂量均能显著改善小鼠肝纤维化程度。
龙虎人丹在低中药物浓度下(100mg/kg和200mg/kg)具有显著改善纤维化的作用，其抗肝纤维化和肝保护效果与阳性药水飞蓟宾相当。当龙虎人丹药物溶度过高，可能由于药物制剂体系不稳定或具有胃肠道刺激、药物吸收差等，导致肝保护和抗肝纤维化效果降低。
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。

Claims (3)

1.龙虎人丹在制备预防和/或治疗肝纤维化药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述龙虎人丹每1000g由以下成分制成：薄荷脑32～48g、冰片24～36g、丁香20～30g、砂仁20～30g、八角茴香12～18g、肉桂32～48g、胡椒12～18g、木香12～18g、干姜20～30g，儿茶160～240g、甘草291.28～436.92g、糯米粉144～216g、苯甲酸钠4～6g、红氧化铁11.6～17.4g、二甲硅油0.08～0.12ml、石墨0.16～0.24g、滑石粉0.16～0.24g和糊精3.16～4.74g。
3.根据权利要求1所述的应用，其特征在于，所述龙虎人丹的有效作用剂量为100mg/kg～200mg/kg。
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