CN113264926A - 一种牡荆素与利血平的共晶及其制备方法 - Google Patents
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Abstract
本发明公开一种牡荆素与利血平的共晶及其制备方法。所述的共晶中，牡荆素与利血平的摩尔比为1:1，两者采用氢键相连。运用X‑射线粉末衍射、差示扫描量热分析和红外光谱对牡荆素‑利血平的共晶进行了全面表征。本发明所述的共晶目的是为了降低服用利血平后带来的副作用。本发明还公开了该共晶的制备方法，该制备方法简单，具有可重复性和可控性强，易于扩大工业化生产，耗能低等优点。
Description
技术领域
本发明涉及药物结晶技术领域，具体涉及一种牡荆素与利血平的共晶及其制备方法。
技术背景
利血平，一种吲哚型生物碱，化学结构如下式所示，分子式C33H40N2O9。存在于萝芙木属多种植物中，在催吐萝芙木中含量最高可达1％。无色棱状晶体。利血平具有降压和安定作用，对精神病性狂躁病有安定功效。作为肾上腺素能神经抑制药，可阻止肾上腺素能神经末梢内介质的贮存，将囊泡中具有升压作用的介质耗竭，通过耗竭周围交感神经末梢的肾上腺素和心、脑等组织的儿茶酚胺和5-羟色胺达到抗高血压、减慢心率和抑制中枢神经系统的作用。降压作用主要通过减少心输出量和降低外周阻力、部分抑制心血管反射实现。减慢心率的作用对正常心率者不明显，但对于窦性心动过速者则明显。此外，利血平可作用于下丘脑部位产生镇静作用，但无致嗜睡和麻醉作用，不改变睡眠时脑电图，可缓解高血压病人焦虑、紧张和头痛。因为作用缓慢、温和而持久，对轻、中度早期高血压疗效显著，多数患者血压稳定于正常范围内，长期服用无耐药性和蓄积作用。临床主要用于高血压症、甲状腺机能亢进以及兴奋状态为主的精神病，尚有抗菌和抗癌作用。但利血平不良反应较多，常见不良反应有鼻塞、口干、抑郁、胃酸增多、腹泻、皮疹等，大剂量可出现面红、心律失常、心绞痛样综合征，心动过缓，偶可产生帕金森综合征。
牡荆素(vitexin)又名牡荆苷，是一种天然植物黄酮碳苷类化合物,广泛分布于自然界几十种植物中，化学结构如下式所示，分子式为C21H20O10，相对分子质量432.4。牡荆素的外观呈黄色粉末，难溶于水，毒性极低。现代药理学研究证明，牡荆素对缺血性心肌损伤具有良好的保护作用，其作用可能与增加冠脉和心肌的血流量、降低血管射血阻力、降低全血及血浆粘度、提高红细胞变形能力、抑制血栓形成等有关。除此之外，牡荆素还有抗炎镇痛、降血压、抗菌、抗氧化等多种药理作用。
综上所述，将牡荆素和利血平这两种药物活性分子通过非共价键作用形成药物-药物共晶，对开发牡荆素和利血平在降压方面的应用具有重要意义。目前尚未有牡荆素和利血平共晶的公开报道。
发明内容
基于以上事实，通过制备牡荆素与利血平共晶，两种药物可以产生协同的治疗效果，并改善利血平的不良反应。其制备方法简便易行，结构中同时包含牡荆素和利血平两种药物分子。并对晶体进行了全面的表征。
1.本发明提供的牡荆素与利血平的共晶晶体在X-射线粉末衍射图谱中 2θ＝6.70±0.2°、7.26±0.2°、7.56±0.2°、10.30±0.2°、11.78±0.2°、12.16±0.2°、 13.92±0.2°、15.34±0.2°、17.52±0.2°、18.40±0.2°、19.62±0.2°、20.82±0.2°、 21.88±0.2°、23.76±0.2°、24.92±0.2°、26.86±0.2°、32.26±0.2°、33.46±0.2°处有特征峰，如附图1所示。
2.本发明提供的牡荆素与利血平的共晶，用差示扫描量热仪(DSC)测定，在259.67±1℃一个熔化吸热峰，如附图2所示。测试条件范围40-500℃，升温 10℃/min，保护N2为50mL/min。。
3.本发明提供的牡荆素与利血平的共晶，所述共晶中的牡荆素与利血平的比例为摩尔比1:1。
4.本发明提供的牡荆素与利血平的共晶制备方法如下：将牡荆素和利血平以摩尔比1:1的比例置于有机溶剂中混悬，室温搅拌24-48h，离心或过滤，收集固体，干燥，得到牡荆素-利血平共晶。
5.所述有机溶剂为甲醇、乙醇或丙酮。
6.本发明提供的牡荆素与利血平的共晶制备方法如下：将牡荆素和利血平以摩尔比1:1的比例置于有机溶剂中溶解，室温搅拌24-48h，静置，室温挥发，析晶，真空干燥，得到牡荆素-利血平共晶。
7.所述有机溶剂为二甲基亚砜，二甲基甲酰胺或是N-甲基吡咯烷酮。
8.所述牡荆素的浓度为0.1-0.3M，优选0.15-0.25M；利血平的的浓度为 0.1-0.3M，优选0.15-0.25M。
9.所述干燥温度为40-60℃，干燥时间为12-24h。
本发明提供的牡荆素与利血平的共晶及其制备方法，与原有的降压药利血平相比，制备的共晶晶胞中同时含有两种药物活性成分，将继承原料药物原有的活性，协同进行降压作用，并可改善服用利血平后产生的不良反应。且制备方法简单，可重复性高，低能耗，易于工业化生产，获得的共晶晶体结晶度高，晶型完整。
附图说明：
图1为本发明实施例1制备的共晶化合物的X-射线粉末衍射图谱。
图2为本发明实施例1制备的共晶化合物、牡荆素和利血平的DSC比图。
图3为本发明实施例1的共晶化合物的红外图。
具体实施方式
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，而可依照说明书的内容予以实施，下面结合了优选的实施例和附图对本发明进行清楚、完整的描述。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
实施例1
将0.54g的牡荆素和0.76g利血平加入5mL乙醇中，搅拌使其混悬36h，离心，收集固体，45℃烘干，获得牡荆素和利血平的共晶。用于XRD，DSC和红外光谱的检测。
实施例2
将77.6mg的牡荆素和133.7mg利血平加入1mL二甲基亚砜中，搅拌使其完全溶解后，继续搅拌30h，放置室温，静置挥发溶剂，析晶后，50℃真空干燥，获得牡荆素和利血平的共晶。
实施例3
将64mg的牡荆素和和91.2mg利血平加入1mL二甲基甲酰胺，搅拌使其完全溶解待用，继续搅拌36h放置室温，静置挥发溶剂，析晶后，45℃真空干燥，获得牡荆素和利血平的共晶。
实施例4
将0.43g的牡荆素和0.60g利血平加入5mL丙酮中，搅拌使其混悬48h，离心，收集固体，45℃烘干，获得牡荆素和胡椒利血平的共晶。
Claims (9)
1.一种牡荆素与利血平的共晶，其特征在于该晶体在X-射线粉末衍射图谱中2θ＝6.70±0.2°、7.26±0.2°、7.56±0.2°、10.30±0.2°、11.78±0.2°、12.16±0.2°、13.92±0.2°、15.34±0.2°、17.52±0.2°、18.40±0.2°、19.62±0.2°、20.82±0.2°、21.88±0.2°、23.76±0.2°、24.92±0.2°、26.86±0.2°、32.26±0.2°、33.46±0.2°处有特征峰。
2.根据权利要求1所述的牡荆素与利血平的共晶，其特征在于，所述共晶的熔点为259.67±1℃。
3.根据权利要求1所述的牡荆素与利血平的共晶，其特征在于，所述共晶中的牡荆素与利血平的比例为摩尔比1:1。
4.一种如权利要求1-3中任意一项所述的牡荆素与利血平共晶的制备方法，其特征在于，将牡荆素和利血平以摩尔比1:1的比例置于有机溶剂中混悬，室温搅拌24-48h，离心或过滤，收集固体，干燥，得到牡荆素-利血平共晶。
5.根据权利要求4所述的牡荆素与利血平共晶的制备方法，其特征在于，有机溶剂为甲醇、乙醇、丙酮。
6.一种如权利要求1-3中任意一项所述的牡荆素与利血平共晶的制备方法，其特征在于，将牡荆素和利血平以摩尔比1:1的比例置于有机溶剂中溶解，室温搅拌24-48h后，静置室温挥发溶剂，析晶，真空干燥，得到牡荆素-利血平共晶。
7.根据权利要求6所述的牡荆素与利血平共晶的制备方法，其特征在于，牡荆素的浓度为0.1-0.3M，利血平的的浓度为0.1-0.3M。
8.根据权利要求6所述的牡荆素与利血平共晶的制备方法，其特征在于，有机溶剂为二甲基亚砜，二甲基甲酰胺，N-甲基吡咯烷酮。
9.根据权利要求6所述的牡荆素与利血平共晶的制备方法，其特征在于，真空干燥温度为40-60℃，干燥时间为24-48h。
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