CN104116751A - 桃叶珊瑚苷在制备治疗肝纤维化药物中的应用 - Google Patents
桃叶珊瑚苷在制备治疗肝纤维化药物中的应用 Download PDFInfo
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- CN104116751A CN104116751A CN201410376463.8A CN201410376463A CN104116751A CN 104116751 A CN104116751 A CN 104116751A CN 201410376463 A CN201410376463 A CN 201410376463A CN 104116751 A CN104116751 A CN 104116751A
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Abstract
本发明涉及中药提取物用途领域，具体提供了桃叶珊瑚苷在制备治疗肝纤维化药物中的应用。所述桃叶珊瑚苷优选为杜仲翅果提取物，其中桃叶珊瑚苷纯度为98%以上。
Description
技术领域
本发明属于中药提取物用途领域，具体涉及桃叶珊瑚苷的新用途。
背景技术
肝纤维化是肝脏对肝实质损伤的修复反应，是各种慢性肝病的共同病理基础。致病因子的持续性或过度刺激，导致肝内结缔组织异常增生，肝内弥漫性细胞外基质过度沉积，影响肝组织的正常结构，严重者可发展成肝硬化，并出现各种终末期肝病并发症。肝纤维化及肝硬化已成为消化道疾病中死亡率最高的疾病之一。肝纤维化是不断变化的动态过程，在一定情况下可以逆转。因此，对逆转因素的研究将为进一步了解肝纤维化和肝硬化的发生机制提供重要线索，并为肝纤维化的有效治疗提供重要依据。
桃叶珊瑚苷(aucubin，AU)属环烯醚萜苷类，分子式为C15H22O9，分子量346.33，熔点181℃，易溶于水、甲醇和乙醇等极性溶剂，几乎不溶于氯仿、乙醚和石油醚等弱极性溶剂。该化合物主要存在于杜仲Eucommia ulmoides Oliver、山茱萸科植物桃叶珊瑚属(Aucubachinensis)、车前科植物车前属(Plantago)等植物中，是杜仲、车前草、地黄等中草药的有效成分之一，具有保肝解毒、抗炎、抗氧化、促进胶原合成、抗骨质疏松及营养神经元细胞等众多药理活性。桃叶珊瑚苷结构式如下：
杜仲为杜仲科植物杜仲的干燥树皮，是中国名贵滋补药材。具补肝肾、强筋骨、降血压、安胎等诸多功效，它是中国特有药材，其药用历史悠久，在临床有着广泛的应用。杜仲翅果是杜仲产业的副产品，含有杜仲胶、油脂、蛋白质、环烯醚萜等，其中桃叶珊瑚苷含量高达7％-11％。桃叶珊瑚苷具有解毒保肝、抗炎、抗氧化、抗菌抗病毒、抗骨质疏松等药理活性，因其性质活泼、生物活性明显但不易获得，被称为“明星分子”，极具开发价值。研究报道，桃叶珊瑚苷能够解除а-鹅膏覃素对大鼠的毒性作用，该解毒效果与桃叶珊瑚苷竞争性地抑制а-鹅膏覃素对肝RNA合成的抑制作用有关。目前国内外还没有对桃叶珊瑚苷对肝纤维化作用的报道。
桃叶珊瑚苷在现有技术中有多种成熟的制备方法，但是目前，从杜仲翅果中提取桃叶珊瑚苷的工艺方法研究较少。中国专利201010297478.7、公开了“一种从杜仲果中提取桃叶珊瑚苷的工艺方法”，主要包括闪式或超声提取、大孔树脂吸附纯化，但该工艺得到桃叶珊瑚苷纯度仅在50％，而且试剂消耗量大、操作繁琐、工业化产生产周期长、成本高，不利于桃叶珊瑚苷单体的工业化生产及开发利用。中国专利201310028642.8公开了“一种从杜仲中快速高效制备桃叶珊瑚苷单体的方法”，该方法经提取-结晶两步即可制得桃叶珊瑚苷，但收率较低，资源浪费严重。中国专利CN 101863938 A公开了“一种制备高纯度桃叶珊瑚苷的方法”，该方法以高分子填料固定相色谱柱、硅胶柱层析、重结晶来分离得到桃叶珊瑚苷，步骤多、产品收率较低、生产周期较长。
发明内容
本发明的目的旨在提供一种桃叶珊瑚苷的新用途。我们研究发现桃叶珊瑚苷对肝纤维化具有防治作用，可用于制备治疗肝纤维化的药物。
为实现上述目的，本发明的技术方案是：
桃叶珊瑚苷在制备治疗肝纤维化药物中的应用。
所述桃叶珊瑚苷优选为杜仲翅果提取物，其中桃叶珊瑚苷纯度为98％以上。
所述桃叶珊瑚苷进一步优选是以杜仲翅果为原料，通过杜仲翅果脱壳，果仁粉碎，经过石油醚脱脂，乙醇提取，加丙酮冷却结晶，再经硅胶柱纯化，得桃叶珊瑚苷单体。
更进一步优选，所述桃叶珊瑚苷是通过以下制备方法得到的，包括以下步骤：
①脱脂：将干燥的杜仲翅果脱壳得果仁，果仁粉碎，石油醚脱脂，得到脱脂粗料；所述石油醚用量为杜仲翅果果仁质量的6-10倍量，脱脂次数为2-4次，脱脂时间为1.5-4小时；
②提取：将所述脱脂粗料加入乙醇进行提取，过滤，合并提取液，40℃-60℃浓缩至提取液体积的1/5-1/12，得到浓缩提取液；所述乙醇用量为杜仲翅果质量的6-12倍量，提取次数为3-5次，每次提取时间为2-5小时；
③结晶：将所述浓缩提取液加入丙酮饱和溶解，冷却结晶，得到桃叶珊瑚苷粗晶体；
④硅胶柱层析：将所述桃叶珊瑚苷粗晶体加乙酸乙酯饱和溶解，再加入硅胶层析柱，其中层析用硅胶与桃叶珊瑚苷粗粗晶体的质量比为6:1-11:1，然后用乙酸乙酯和甲醇组成的溶液依次洗脱，收集洗脱液；所述依次洗脱时所用乙酸乙酯和甲醇组成的溶液中乙酸乙酯的浓度由高至低逐渐降低；
⑤浓缩干燥：将所述洗脱液在40℃-60℃浓缩，冷冻干燥，得桃叶珊瑚苷单体产品。
优选方案：骤①中所述粉碎后为40-50目。
优选方案：步骤①中石油醚用量为杜仲翅果果仁的8-9倍量，脱脂次数为3-4次，脱脂时间为2-3小时。
优选方案：步骤②中乙醇用量为原料的8-10倍量，提取次数为3-4次，每次提取时间为3-4小时。
优选方案：步骤③中乙酸乙酯饱和溶解后，将溶解液置于4-10℃冷却,结晶12-72小时。
优选方案：步骤④中层析用硅胶与桃叶珊瑚苷粗粗晶体的质量比为8:1-10:1。
优选方案：步骤④中用乙酸乙酯和甲醇组成的溶液依次洗脱的顺序为：依次按质量比例乙酸乙酯比甲醇为1:0、10:1、6:1、4:1的次序洗脱，用量分别为3-5BV、3-6BV、4-6BV、3-5BV。
下面对本发明做进一步解释和说明
本发明所述的桃叶珊瑚苷优选为杜仲翅果提取物，可以通过采用选自粉碎、压榨、煅烧、研磨、过筛、渗漉、萃取、水提、醇提、水沉、醇沉、酯提、酮提、层析、过滤等方法得到。以该提取物为活性物质可制成药物制剂，所述提取物可以是浸膏形式的物质，可以是干浸膏也可以是流浸膏，可以是粉末状物质，根据制剂的不同需要制成不同的状态。
本发明还提及桃叶珊瑚苷经过加工制备的适合服用的任何单位剂量形式的药物制剂，这些药物制剂选自以下剂型：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂，需要时可以制成缓释制剂、肠溶制剂。
本发明的桃叶珊瑚苷，在制备成药物制剂时可加入药物可接受的载体，所述药物可接受的载体选自：抗氧剂、鳌合剂表面活性剂填充剂崩解剂润湿剂分散剂润滑剂溶剂缓释材料肠溶材料pH调节剂、矫味剂、色素等，常用的载体如：甘露糖醇、右旋糖苷、乳糖、葡萄糖、山梨醇、甘露醇、木糖醇、氯化钠、硅衍生物、纤维素及纤维素衍生物、亚硫酸钠、焦亚硫酸钠、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、吐温80、琼脂、碳酸钙、碳酸氢钙、聚乙二醇、环糊精、β-环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的桃叶珊瑚苷的药物制剂，是通过将杜仲翅果经过提取或其他方式加工，制成药物活性物质，随后，以该活性物质为原料，需要时加入药物可接受的载体，按照制剂学的常规技术制成药物制剂。
具体实施方式
下面通过实施例对本发明做进一步的解释和说明，实施例中所述百分含量均为质量百分含量。
实施例1 杜仲翅果提取物桃叶珊瑚苷的制备
将杜仲翅果脱壳，果仁粉碎至40目，取10kg投入提取罐，加60L石油醚脱脂，脱脂2次，每次3小时，滤出药渣为脱脂粗料。加80L乙醇至脱脂粗料超声提取2小时，提取3次，合并提取液。提取液40℃减压浓缩至原体积的1/8并回收乙醇。浓缩液加丙酮饱和溶解，7℃结晶48小时，粗晶体加乙酸乙酯饱和溶解。取10L硅胶装柱，将饱和液加入硅胶柱，依次用3BV乙酸乙酯(质量比乙酸乙酯:甲醇＝1:0)、4BV10:1乙酸乙酯/甲醇(质量比乙酸乙酯:甲醇＝10:1)、5BV6:1乙酸乙酯/甲醇(质量比乙酸乙酯:甲醇＝6:1)、4BV4:1乙酸乙酯/甲醇溶液洗脱(质量比乙酸乙酯:甲醇＝4:1)，同时用薄层色谱法检测，收集桃叶珊瑚苷流分，合并洗脱液，40℃减压浓缩，冷冻干燥，得到桃叶珊瑚苷单体410g，经HPLC法测定，其含量达98.7％。
实施例2 杜仲翅果提取物桃叶珊瑚苷的制备
将杜仲翅果脱壳，果仁粉碎至50目，取10kg投入提取罐，加80L石油醚脱脂，脱脂3次，每次4小时，滤出药渣为脱脂粗料。加100L乙醇至脱脂粗料超声提取4小时，提取5次，合并提取液。提取液40℃减压浓缩至原体积的1/10并回收乙醇。浓缩液加丙酮饱和溶解，4℃结晶72小时，粗晶体加乙酸乙酯饱和溶解。取10L硅胶装柱，将饱和液加入硅胶柱，依次用3BV乙酸乙酯(质量比乙酸乙酯:甲醇＝1:0)、4BV10:1乙酸乙酯/甲醇(质量比乙酸乙酯:甲醇＝10:1)、5BV6:1乙酸乙酯/甲醇(质量比乙酸乙酯:甲醇＝6:1)、4BV4:1乙酸乙酯/甲醇溶液洗脱(质量比乙酸乙酯:甲醇＝4:1)，，同时用薄层色谱法检测，收集桃叶珊瑚苷流分，合并洗脱液，40℃减压浓缩，冷冻干燥，得到桃叶珊瑚苷单体480g，经HPLC法测定，其含量达99.2％。
实施例3
将实施例1和实施例2所得到的桃叶珊瑚苷以及市售的桃叶珊瑚苷(购于上海源叶生物科技有限公司)用于实施例3的对肝纤维化的保护实验研究。
1.实验方法
1.1剂量设计和分组
实验分为正常对照组、模型组、桃叶珊瑚苷低剂量组(1mg/kg)、中剂量组(5mg/kg)、高剂量组(10mg/kg)、市售的桃叶珊瑚苷(10mg/kg)以及替米沙坦阳性对照组(10mg/kg)。
表1 试验分组和剂量设计
1.2实验步骤
健康雄性SD大鼠70只(体重250～300g)，随机抽取60只为实验组，用40％CCl4豆油溶液，5mL/kg皮下注射给药，每周注射2次，连续注药8周。正常对照组皮下注射等体积的生理盐水作为对照(A组)。将模型组随机分为6组：模型组(B组)、桃叶珊瑚苷低、中、高剂量组(C、D、E组)，，市售的桃叶珊瑚苷组(F组)、替米沙坦阳性对照组(G组)。自造模日起，每日实验前将桃叶珊瑚苷、替米沙坦用生理盐水按剂量配制成相应浓度，现配现用，按10mL/kg灌胃给药，1次/日，连续8周。A、B两组每次给予等体积生理盐水，1次/日，连续8周。第8周末剖杀大鼠，剖杀前12小时禁食不禁水，剖杀时腹腔注射5％戊巴比妥钠(1mL/kg)进行麻醉，取出肝脏组织，称重，计算肝系数(肝脏重量/体重×100％)。取部分右叶肝脏以10％中性福尔马林固定，石蜡包埋，HE染色，进行病理学检测。
1.3检测指标
HE染色，光镜下观察肝组织病理学改变，肝纤维化病理学分级参照2002年上海会议上由中华医学会肝脏病学分会、中华医学会传染病与寄生虫病学分会联合修订的慢性肝炎分级分期标准：
0级：无胶原纤维增生；
1级：汇管区纤维化扩大，限局窦周及小叶内纤维化；
2级：汇管区周围纤维化，纤维间隔形成，小叶结构保留：
3级：纤维间隔伴小叶结构紊乱，无肝硬化；
4级：早期肝硬化。
1.4统计方法：
采用SPSS16.0进行统计分析，统计学意义的水平设定为P<0.05。采用均数±标准差用Leven’s test方法检验正态性和方差齐性。如果符合正态性和方差齐性，用单因素方差分析(One-way ANOVA)和post Hoc LSD进行统计分析；如果不符合正态性和方差不齐，则用Kruskal-Wallis检验。如果Kruskal-Wallis检验有统计学意义(P<0.05)，则用Dunnett’s Test(非参数方法)进行比较分析。评价时考虑统计学差异和生物学意义。
2实验结果
桃叶珊瑚苷对肝脏病理学的影响
正常对照组肝细胞呈单核，肝小叶网状纤维结构完整，分界清楚，无肝细胞变性坏死，无炎性细胞浸润及纤维组织增生。模型组大鼠肝小叶结构异常，肝组织肿胀、普遍空泡性变性，可见明显的点状和灶状坏死，炎性细胞浸润，小叶周围纤维组织增生明显。提示肝纤维化模型造模成功。桃叶珊瑚苷高剂量组、市售的桃叶珊瑚苷以及替米沙坦对照组与模型组相比，肝组织结构完整，汇管区轻度炎症，肝脏纤维化程度轻，肝纤维化情况有所好转。
表2 桃叶珊瑚苷对肝纤维化病理学的影响
注：与正常对照组比较，++P<0.01，与模型组比较，*P<0.05。
3实验小结
上述结果表明，桃叶珊瑚苷高剂量组、市售的桃叶珊瑚苷能显著改善肝纤维化模型的肝小叶结构异常，肝组织肿胀、变性，炎性细胞浸润，小叶周围纤维组织增生等症状，对肝纤维化有一定的改善作用。
Claims (10)
1.桃叶珊瑚苷在制备治疗肝纤维化药物中的应用。
2.根据权利要求1所述应用，其特征是，所述桃叶珊瑚苷为杜仲翅果提取物，其中桃叶珊瑚苷纯度为98％以上。
3.根据权利要求1或2所述应用，其特征是，所述桃叶珊瑚苷是以杜仲翅果为原料，通过杜仲翅果脱壳，果仁粉碎，经过石油醚脱脂，乙醇提取，加丙酮冷却结晶，再经硅胶柱纯化，得桃叶珊瑚苷单体。
4.根据权利要求3所述应用，其特征是，所述桃叶珊瑚苷的制备方法包括以下步骤：
①脱脂：将干燥的杜仲翅果脱壳得果仁，果仁粉碎，石油醚脱脂，得到脱脂粗料；所述石油醚用量为杜仲翅果果仁质量的6-10倍量，脱脂次数为2-4次，脱脂时间为1.5-4小时；
②提取：将所述脱脂粗料加入乙醇进行提取，过滤，合并提取液，40℃-60℃浓缩至提取液体积的1/5-1/12，得到浓缩提取液；所述乙醇用量为杜仲翅果质量的6-12倍量，提取次数为3-5次，每次提取时间为2-5小时；
③结晶：将所述浓缩提取液加入丙酮饱和溶解，冷却结晶，得到桃叶珊瑚苷粗晶体；
④硅胶柱层析：将所述桃叶珊瑚苷粗晶体加乙酸乙酯饱和溶解，再加入硅胶层析柱，其中层析用硅胶与桃叶珊瑚苷粗粗晶体的质量比为6:1-11:1，然后用乙酸乙酯和甲醇组成的溶液依次洗脱，收集洗脱液；所述依次洗脱时所用乙酸乙酯和甲醇组成的溶液中乙酸乙酯的浓度由高至低逐渐降低；
⑤浓缩干燥：将所述洗脱液在40℃-60℃浓缩，冷冻干燥，得桃叶珊瑚苷单体产品。
5.根据权利要求4所述应用，其特征是，步骤①中所述粉碎后为40-50目。
6.根据权利要求4所述应用，其特征是，步骤①中石油醚用量为杜仲翅果果仁的8-9倍量，脱脂次数为3-4次，脱脂时间为2-3小时。
7.根据权利要求4所述应用，其特征是，步骤②中乙醇用量为原料的8-10倍量，提取次数为3-4次，每次提取时间为3-4小时。
8.根据权利要求4所述应用，其特征是，步骤③中乙酸乙酯饱和溶解后，将溶解液置于4-10℃冷却,结晶12-72小时。
9.根据权利要求4所述应用，其特征是，步骤④中层析用硅胶与桃叶珊瑚苷粗粗晶体的质量比为8:1-10:1。
10.根据权利要求4所述应用，其特征是，步骤④中用乙酸乙酯和甲醇组成的溶液依次洗脱的顺序为：依次按质量比例乙酸乙酯比甲醇为1:0、10:1、6:1、4:1的次序洗脱，用量分别为3-5BV、3-6BV、4-6BV、3-5BV。
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| CN102872067A (zh) * | 2012-10-25 | 2013-01-16 | 广西中医药大学 | 一种抗肝炎的药物制剂 |
| CN102911222A (zh) * | 2012-10-30 | 2013-02-06 | 薛宏宇 | 一种桃叶珊瑚苷的提取方法及桃叶珊瑚苷的应用 |
| KR20140070735A (ko) * | 2012-11-26 | 2014-06-11 | 전북대학교산학협력단 | 두충 추출물로부터 분리된 화합물을 유효성분으로 함유하는 간보호 및 간 질환의 예방 및 치료용 조성물 |
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| CN102872067A (zh) * | 2012-10-25 | 2013-01-16 | 广西中医药大学 | 一种抗肝炎的药物制剂 |
| CN102911222A (zh) * | 2012-10-30 | 2013-02-06 | 薛宏宇 | 一种桃叶珊瑚苷的提取方法及桃叶珊瑚苷的应用 |
| KR20140070735A (ko) * | 2012-11-26 | 2014-06-11 | 전북대학교산학협력단 | 두충 추출물로부터 분리된 화합물을 유효성분으로 함유하는 간보호 및 간 질환의 예방 및 치료용 조성물 |
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