CN103877170B - 一种虎杖的乙酸乙酯提取物及其制备方法和应用 - Google Patents
一种虎杖的乙酸乙酯提取物及其制备方法和应用 Download PDFInfo
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- CN103877170B CN103877170B CN201210556632.7A CN201210556632A CN103877170B CN 103877170 B CN103877170 B CN 103877170B CN 201210556632 A CN201210556632 A CN 201210556632A CN 103877170 B CN103877170 B CN 103877170B
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- rhizoma polygoni
- polygoni cuspidati
- ethyl acetate
- extract
- acetate extract
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Abstract
本发明涉及一种虎杖的乙酸乙酯提取物及其制备方法和应用,所述虎杖的乙酸乙酯提取物由以下方法制备:虎杖,用石油醚浸泡后渗滤,回收残渣,挥干残渣中的溶剂,然后用乙醇提取,提取液浓缩至无醇味,然后用与浓缩液等体积的乙酸乙酯萃取,收集上层提取液,蒸干得乙酸乙酯提取物。本发明提供的虎杖的乙酸乙酯提取物可防治老年痴呆。
Description
技术领域
本发明涉及虎杖的提取物,具体涉及一种虎杖的乙酸乙酯提取物及其制备方法和应用。
背景技术
老年痴呆症是严重威胁人类健康的神经退行性疾病。Alzheimerdisease(简称AD)是一种主要老年痴呆症,表现为记忆、理解、计算、判断、定向、语言、抽象思维、自我控制等能力障碍,导致患者独立生活和工作能力丧失。随着社会老龄化的加速,AD已成为第4大引起人类死亡的疾病,我国即将进入老龄社会,而且该病逐渐呈现的年轻化趋势,发病率在逐年增高。迄今为止尚未有治愈老年痴呆症的有效手段,但服用乙酰胆碱酯酶抑制剂(ACHEI)是目前治疗老年痴呆症最有效的治疗方式。临床上使用的多奈哌齐(donepezil),美曲膦酯(metrifonate)和石杉碱甲(huperzine A)等药物普遍存在外周副作用较大,长期治疗效果不理想的现象。新研究表明,给予大鼠大脑皮层内灌注选择性丁酰胆碱酶抑制剂(BuCHEI)可使乙酰胆碱浓度增加15倍,且未发现胆碱样副作用。临床试验也表明,脑脊液中BuCHE抑制与AD患者的认知功能具有相关性。因此这为寻找疗效AD病,具有成本低廉、效果好,毒副作用小的活性化合物提供了新的方法。
虎杖,来源于唇形科植物虎杖Salvia miltiorrhiza Bge.的干燥根及根茎,其性微苦、微寒,归肝、胆、肺经;功效有活血定痛、清热攻下、解毒利湿、化痰止咳等。主要含蒽醌类化合物、白藜芦醇苷、水溶性多糖和鞣质等成分,具有如下作用:改善微循环、抗休克作用;对血管的调节作用;强心作用;降脂作用;保肝作用;抗菌、抗病毒作用;抗炎、抗氧化作用;抗肿瘤作用等。
目前虎杖的乙醇提取物或乙醇、乙酸乙酯等浸泡提取方面有很多报道。但是,迄今为止,尚未有关于虎杖的乙酸乙酯提取物及其在制备抑制丁酰胆碱酯酶应用的报道。
发明内容
本发明的目的是提供一种虎杖的乙酸乙酯提取物。
本发明的另一目的是提供虎杖的乙酸乙酯提取物的制备方法。
本发明的另一目的是提供虎杖的乙酸乙酯提取物的应用。
本发明提供的一种虎杖的乙酸乙酯提取物,该提取物由以下方法制备:虎杖,用石油醚浸泡后渗滤,回收残渣,挥干残渣中的溶剂,然后用乙醇提取,提取液浓缩至无醇味,然后用与浓缩液等体积的乙酸乙酯萃取,收集上层清液,蒸干得乙酸乙酯提取物。
优选地,所述虎杖的乙酸乙酯提取物,由以下方法制备:虎杖,用虎杖重量3-5倍量体积的石油醚浸泡18-36h后,用石油醚渗漉,得到虎杖重量5-7倍量体积的石油醚渗滤液,回收残渣,挥干残渣中的溶剂,然后用虎杖重量3-7倍体积的70%-90%的乙醇提取2-3次,每次提取时间为1-3小时,合并提取液,然后浓缩至无醇味,再用与浓缩液等体积的乙酸乙酯萃取,收集上层清液,蒸干得乙酸乙酯提取物。
进一步优选,所述虎杖的乙酸乙酯提取物,由以下方法制备:虎杖,用虎杖重量3-4倍量体积的石油醚浸泡18-24h后,用石油醚渗漉,得到虎杖重量5-6倍量体积的渗滤液,回收残渣,将残渣挥干溶剂,然后用用虎杖重量3-5倍体积的70-80%的乙醇提取2-3次,每次提取时间为1.5-2小时,合并提取液,然后浓缩至无醇味,再用与浓缩液等体积的乙酸乙酯萃取,收集上层清液,蒸干得乙酸乙酯提取物。
进一步优选,所述虎杖的乙酸乙酯提取物,由以下方法制备:虎杖,用虎杖重量3倍量体积的石油醚浸泡24h后,用石油醚渗漉,得到虎杖重量5倍量体积的渗滤液,回收残渣,将残渣挥干溶剂,然后用虎杖重量5倍体积的80%的乙醇提取2次,每次提取时间为2小时,合并提取液,然后浓缩至无醇味,再用与浓缩液等体积的乙酸乙酯萃取,收集上层清液,蒸干得乙酸乙酯提取物。
上述虎杖的乙酸乙酯提取物:
所述石油醚为60-90℃的石油醚。
本发明还提供了上述虎杖的乙酸乙酯提取物的制备方法,该方法包括以下步骤:虎杖,石油醚浸泡后渗滤,回收残渣,挥干残渣中的溶剂,然后用乙醇提取,提取液浓缩至无醇味,然后用与浓缩液等体积的乙酸乙酯萃取,收集上层清液,蒸干。
本发明还提供了含上述虎杖的乙酸乙酯提取物的制剂,该制剂由虎杖的乙酸乙酯提取物单独制成或由虎杖的乙酸乙酯提取物和药学上可接受的载体组成。
所述制剂为片剂、胶囊、颗粒或丸剂。
所述药学上可接受的载体或稀释剂是指药学领域常规的药物载体,选自填充剂、粘合剂、崩解剂、润滑剂、助悬剂、润湿剂、溶剂、表面活性剂或矫味剂中的一种或几种。
所述填充剂选自淀粉、蔗糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素或葡萄糖等;
所述粘合剂选自纤维素衍生物、藻酸盐、淀粉、糊精、明胶或聚乙烯吡咯烷酮等;
所述崩解剂选自微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙基纤维素或交联羧甲基纤维素钠;
所述润滑剂选自硬脂酸、聚乙二醇、碳酸钙、碳酸氢钠、微粉硅胶、滑石粉或硬脂酸镁;
所述助悬剂选自微粉硅胶、蜂蜡、纤维素、固态聚乙二醇;
所述润湿剂选自甘油、吐温-80、乙氧基氢化蓖麻油或卵磷脂;
所述溶剂选自乙醇、液态聚乙二醇、异丙醇、吐温-80、甘油、丙二醇或植物油,所述植物油选自大豆油、蓖麻油、花生油、调和油等;
所述表面活性剂选自十二烷基苯磺酸钠、硬脂酸、聚氧乙烯-聚氧丙烯共聚物、脂肪酸山梨坦或聚山梨酯(吐温)等;
所述矫味剂选自阿斯巴甜、蔗糖素、香精、柠檬酸或糖精钠。
本发明还提供了虎杖的乙酸乙酯提取物的质量控制方法,该方法是用超高效液相色谱/四级杆-飞行时间质谱(UPLC-Q-TOF-MS)对虎杖提取物进行分析,以获得乙酸乙酯提取物的总离子图谱。
所述色谱分析条件为:色谱柱:Waters ACQUITY UPLCTM BEHC18Column(50mm×2.1mm.i d.,1.7μm);二元梯度洗脱,A相为水溶液;B相为乙腈,流速为0.4ml/min;质谱条件为:ESI离子源,正离子模式检测;自动3级质谱。
优选地,所述色谱条件:
所述质谱条件为:ESI离子源,正离子模式检测;雾化器N2压力50psi;干燥气N2,流速15L/min;质量扫描范围50-1200;自动3级质谱。
本发明还提供了虎杖的乙酸乙酯提取物的在制备抗老年痴呆的药物中的应用。其作用机理是抑制丁酰胆碱酯酶活性。
本发明还提供了虎杖的乙酸乙酯提取物在制备丁酰胆碱酯酶病毒药物中的应用,其用量即每日服用量为0.05g-3g。
本发明提供的一种虎杖的乙酸乙酯提取物具有以下优点:
1、本发明提供了的虎杖的乙酸乙酯提取物,该提取物是虎杖经过石油醚浸泡,然后渗滤,回收的残渣经过醇提,乙酸乙酯萃取得到的。
2、本发明首次提供了虎杖提取物在制备抗丁酰胆碱酯酶的药物中的应用。
3、本发明应用超高效液相色谱-质谱联机分析技术及结果构建虎杖提取物指纹图谱的方法。该方法包括虎杖提取物的UPLC-MS分析条件。色谱峰的特征、色谱组分的质谱提供的化合物结果信息等。本发明公开的UPLC及UPLC-Q-TOF/MS图谱及其技术可用于虎杖的乙酸乙酯提取物的质量监控。
在ESI(+)检测模式得到的总离子流色谱中,含有的蒽醌类化合物组分峰面积之和占全部组分色谱峰面积的85.3%。其中虎杖提取物中的蒽醌类化合物含量较高。
经UPLC-Q-TOF-MS分析,虎杖提取物中的蒽醌类化合物,主要包括白藜芦醇、大黄素-8-O-β-吡喃葡萄糖苷、大黄素、芒果苷、大黄酚、大黄素甲醚、大黄酸。
4、经过体外试验可知,本发明提供的虎杖乙酸乙酯提取物可防治老年痴呆,其机理是抑制丁酰胆碱酯酶活性。
附图说明
图1:虎杖的乙酸乙酯提取物的UPLC色谱图;
图2:虎杖的乙酸乙酯提取物UPLC-Q-TOF-MS总离子色谱图。
具体实施方式
以下实施例用于说明本发明,但不用来限制本发明的范围。
本发明如无特殊说明,所用的乙醇浓度为体积百分比;所述重量倍数的体积,例如虎杖为500g,其重量3倍体积为1500ml。
实施例1:虎杖的乙酸乙酯提取物
1、虎杖粉碎成粗粉,称取500g虎杖,用虎杖重量3倍量体积即1500ml石油醚浸泡24h,用石油醚渗漉,至渗漉液颜色变浅(得到2500ml的石油醚渗滤液),回收残渣;
2、挥干残渣中的溶剂,然后将残渣用2500ml浓度为80%乙醇提取2次,每次提取时间为2h,合并两次醇提液,将其减压浓缩至无醇味,然后与等体积的乙酸乙酯萃取,收集上层清液,提取液蒸干分别得乙醇提取物和乙酸乙酯提取物6.69g(收率为1.34%)。
实施例2:虎杖的乙酸乙酯提取物
1、虎杖粉碎成粗粉,称取500g虎杖,用虎杖重量5倍量体积(2500ml)的石油醚浸泡36h后,用石油醚渗漉,至渗漉液颜色变浅(得到3500ml的石油醚渗滤液),回收残渣;
2、挥干残渣中的溶剂,然后将残渣用3500ml浓度为90%的乙醇提取2次,提取时间依次为3小时、2小时,合并提取液,然后浓缩至无醇味,然后与等体积的乙酸乙酯萃取,收集上层清液,蒸干得乙酸乙酯提取物4.014g(收率为0.803%)。
实施例3:虎杖的乙酸乙酯提取物
1、虎杖粉碎成粗粉,称取500g用虎杖重量3倍量体积(2000ml)的石油醚浸泡18h后,渗漉,至渗漉液颜色变浅(得到3000ml的石油醚渗滤液),回收残渣;
2、挥干残渣中的溶剂,然后将残渣用1500ml浓度为70%的乙醇提取3次,提取时间依次为2小时、1.5小时、1.5小时,合并提取液,将其减压浓缩至无醇味,然后与等体积的乙酸乙酯萃取,收集上层清液,蒸干得乙酸乙酯提取物5.352g(收率为1.07%)。
实施例4:虎杖乙酸乙酯提取物的胶囊
1、组成:虎杖的石油醚提取物(实施例1的方法制备)50g,淀粉15g,硬脂酸镁5g。
2、制备方法:按照配比称取原辅料,混合均匀,分装胶囊。
实施例5:含虎杖的乙酸乙酯提取物的片剂
1、组成:虎杖的乙醇提取物(实施例2的方法制备)50g,淀粉25g,微晶纤维素20g,硬脂酸镁5g。
2、制备方法:按照配比称取原辅料,混合均匀,分装胶囊。
实施例6:含鸡屎藤的乙酸乙酯提取物的颗粒剂
1、组成:虎杖的乙酸乙酯提取物(实施例3的方法制备)50g,淀粉15g,微晶纤维素20g,硬脂酸镁6g。
2、制备方法:按照配比称取原辅料,按照等量递加法混合均匀,直接压片。
实验例1:治疗老年痴呆的药效实验
1、实验原理
丁酰胆碱酯酶(BuChE)水解丁酰胆碱(BuCh)生成胆碱及丁酸,胆碱可以与巯基显色剂5,5-二硫双硝基苯甲酸(DTNB)反应生成TNB黄色化合物,根据颜色深浅进行比色定量,水解产物胆碱的数量可以反应BuChE的活力。
2、实验药物:
BuChE,底物BuCh,显色剂DTNB,均购自Acros公司;四异丙基甲基焦磷酰胺(Iso-OMPA),购自SIGMA公司;
二甲基亚砜(DMSO),购自上海市欣诚化工有限公司。
3、实验分组及方法
3.1实验分组:
实施例1-3组:根据实施例1-3制备;
阳性对照药:四异丙基甲基焦磷酰胺(Iso-OMPA)。
3.2实验方法:
在酶反应体系中,50μg/mL的待测化合物(即阳性对照组和各实施例组)与BuChE悬浮于反应缓冲液中(pH7.2),加入底物BuCh20μL及显色剂DTNB20μL,37°C孵育60分钟后,在波长412nm测定吸光值。
反应体系的吸光值可以反映体系中消耗BuCh的量。根据吸光值的改变可以计算化合物对BuChE活性的抑制率。
3、实验结果:见表1
虎杖的乙酸乙酯提取物溶液:将实施例1制备得到的虎杖乙酸乙酯提取物用蒸馏水溶解至浓度为50ug/ml;
阳性对照药,四异丙基甲基焦磷酰胺的浓度为50ug/ml。
2、实验模型:
3、实验结果:见表1
表1:对丁酰胆碱酯酶酶的半数抑制浓度(IC50)(ug/ml)
表1结果显示:四异丙基甲基焦磷酰胺IC50(ug/ml)为8.95,实施例1为IC50(ug/ml)=11.29。半数抑制浓度越低,其抗体的灵敏度越高,表1中实施例1为三个实例中IC50最小,说明其抗丁酰胆碱酯酶的效果较好。
实验结果表明:本发明提供的虎杖的乙酸乙酯提取物可治疗老年痴呆。
实验例2:虎杖的乙酸乙酯提取物的超高效液相色谱/四级杆-飞行时间质谱(UPLC-Q-TOF-MS)分析及图谱的指纹特征分析
1、实验试剂:
甲醇为色谱纯,美国Fisher公司;超纯水,实验室ELGA PURELABClassic-UVF纯水机,英国;
其他试剂均为市售国产分析纯。
2、试验样品:
采用实施例1方法制备的虎杖的乙酸乙酯提取物。
3、实验仪器和色谱条件:
美国Waters AcquityTM UPLC/Q-TOF Premier;MassL-ynxV4.1工作站。
色谱条件为:二元梯度洗脱,A相为水溶液;B相为乙腈,流速为0.4ml/min,见下表2。
表2:色谱条件
质谱条件为:ESI离子源,正离子模式(ESI(+))检测;雾化器N2压力50psi;干燥气N2,流速15L/min;质量扫描范围50-1200;自动3级质谱。
4、结果与分析:结果见图1、2
图1为虎杖的乙酸乙酯提取物的UPLC色谱,共8个特征峰;
图2为UPLC-Q-TOF-MS(+)分析图1虎杖的8个特征峰进行分析得到总离子流色谱图,分析其色谱峰组分指纹信息,得到结果见表2:
表3:虎杖乙酸乙酯提取物中活性组分分析
表3结果:经查阅中外文献,分析鉴定出虎杖乙酸乙酯提取物中的8个色谱峰,其中1号峰为白藜芦醇,2号峰为大黄素-8-O-β-吡喃葡萄糖苷,4号峰为大黄素,5号峰为芒果苷,6号峰为大黄酚,7号峰为大黄酸,8号峰为大黄素甲醚。
结果显示:在ESI(+)检测模式得到的总离子流色谱中,含有的蒽醌类化合物组分峰面积之和占全部组分色谱峰面积的85.3%。其中虎杖提取物中的蒽醌类化合物含量较高。
经UPLC-Q-TOF-MS分析,虎杖提取物中的蒽醌类化合物,主要包括白藜芦醇、大黄素-8-O-β-吡喃葡萄糖苷、大黄素、芒果苷、大黄酚、大黄素甲醚、大黄酸。
结果表明:虎杖的乙酸乙酯提取物含有蒽醌类化合物,也是抗丁酰胆碱酯酶活性的有效成分。
虽然,上文中已经用一般性说明、具体实施方式及试验,对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (6)
1.一种虎杖的乙酸乙酯提取物,其特征在于,该提取物由以下方法制备:虎杖,用虎杖重量3-4倍量体积的石油醚浸泡18-24h后,用石油醚渗漉,得到虎杖重量5-6倍量体积的渗滤液,回收残渣,将残渣挥干溶剂,然后用虎杖重量3-5倍量体积的70-80%的乙醇提取2-3次,每次提取时间为1.5-2小时,合并提取液,然后浓缩至无醇味,再用与浓缩液等体积的乙酸乙酯萃取,收集上层提取液,蒸干,即得。
2.根据权利要求1所述的提取物,其特征在于,由以下方法制备:虎杖,用虎杖重量3倍量体积的石油醚浸泡24h后,用石油醚渗漉,得到虎杖重量5倍量体积的渗滤液,回收残渣,将残渣挥干溶剂,然后用虎杖重量5倍量体积的80%的乙醇提取2次,每次提取时间为2小时,合并提取液,然后浓缩至无醇味,再用与浓缩液等体积的乙酸乙酯萃取,收集上层提取液,蒸干得乙酸乙酯提取物。
3.一种制备权利要求1或2所述的提取物的方法,其特征在于,该方法包括以下步骤:虎杖,用虎杖重量3-4倍量体积的石油醚浸泡18-24h后,用石油醚渗漉,得到虎杖重量5-6倍量体积的渗滤液,回收残渣,将残渣挥干溶剂,然后用虎杖重量3-5倍量体积的70-80%的乙醇提取2-3次,每次提取时间为1.5-2小时,合并提取液,然后浓缩至无醇味,再用与浓缩液等体积的乙酸乙酯萃取,收集上层提取液,蒸干,即得。
4.含权利要求1或2所述的提取物的制剂,其特征在于,该制剂由虎杖的乙酸乙酯提取物单独制成或由虎杖的乙酸乙酯提取物和药学上可接受的载体组成。
5.权利要求1或2所述的提取物的检测方法,其特征在于,该方法是用超高效液相色谱-电喷雾串联质仪对虎杖提取物进行分析,以获得乙酸乙酯提取物的总离子图谱,其中,所述色谱分析条件为:色谱柱:Waters ACQUITY UPLCTM BEH C18 Column(50mm×2.1mm.id.,1.7μm);二元梯度洗脱,A相为水溶液;B相为乙腈,流速为0.4ml/min;质谱条件为:ESI离子源,正离子模式检测;自动3级质谱;
所述梯度洗脱方法为:
所述质谱条件为:ESI离子源,正离子模式检测;雾化器N2压力50psi;干燥气N2,流速15L/min;质量扫描范围50-1200;自动3级质谱。
6.根据权利要求1或2所述的提取物在制备抑制抗老年痴呆的药物中的应用。
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