CN111995700A - 一种甘草素/修饰环糊精包合物及其制备方法 - Google Patents
一种甘草素/修饰环糊精包合物及其制备方法 Download PDFInfo
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- CN111995700A CN111995700A CN202010547863.6A CN202010547863A CN111995700A CN 111995700 A CN111995700 A CN 111995700A CN 202010547863 A CN202010547863 A CN 202010547863A CN 111995700 A CN111995700 A CN 111995700A
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- Prior art keywords
- liquiritigenin
- solution
- cyclodextrin
- inclusion compound
- modified cyclodextrin
- Prior art date
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Abstract
本发明公开了一种甘草素/修饰环糊精包合物的制备方法，同时对其溶出度、稳定性进行检测。以β‑环糊精为原料在室温碱性溶液中合成了单‑6‑O‑(对甲苯磺酰基)‑β‑环糊精，然后与N‑(2‑羟乙基)‑乙二胺反应得到修饰环糊精。采用共蒸发法制备了一种新型的甘草素/修饰环糊精包合物，包合物的溶出度及稳定性检测结果显示，发生包合作用后的甘草素累积溶出度与保留率分别提高到80.1%、92.7%。本发明中的包合物制备工艺简单、可靠，改善了甘草素的溶出度和稳定性。
Description
技术领域
本发明涉及日用化妆品与医药辅助制剂等领域，具体涉及一种甘草素/修饰环糊精包合物的制备方法及其溶出度、稳定性检测。
背景技术
甘草，多年生豆科草本植物，传统中医药学认为甘草可“补脾益气，清热解毒，祛痰止咳，缓急止痛”。甘草素是甘草黄酮的主要组分之一，属二氢黄酮类。研究显示甘草素在抗病毒、抗癌、抑菌、清除自由基等方面具有明显的药理作用。但甘草素自身存在的水溶性差、不稳定等特性，导致其口服效果差、难溶于产品配方中，限制了其在医药、日化用品等行业中的应用。
近些年来环糊精包合技术的应用越来越广泛，通过制备包合物来提高主体的溶解度及稳定性，易于人体吸收利用，提高其生物利用度。但β-环糊精也存在水溶性差的缺点，严重限制了其应用。研究证明在环糊精的化学修饰过程中引入N原子，可以增加药物的识别位点，提高药物和主体间的键合能力，显著提高了药物的水溶性与稳定性。
文献（迟绍明等，花旗松素、槲皮素和桑色素与丙二胺桥联β-环糊精的包合作用及抗氧化活性，分析化学，2020, 48(2): 215-223）考察了花旗松素、槲皮素和桑色素在溶液和固相中与丙二胺桥联β-环糊精的包合行为。相关专利有：专利CN110051550A（杜志云等，一种具有杀菌抗炎作用的芳姜黄酮包合物及其制备方法）采用自乳化干混制备固体制剂，有效地解决芳姜黄酮水溶性差、口感不佳等使用限制性问题。专利CN109007834A（吴振强等，一种番石榴果叶提取物环糊精包合物及其制备方法与应用）中通过将番石榴果和/或叶经过提取后，真空浓缩，浓缩液采用环糊精进行包合，过滤，干燥粉碎，得到番石榴果叶提取物环糊精包合物。当前，采用修饰环糊精包合甘草素的文献和专利未见报道，本发明通过以β-环糊精为原料合成修饰环糊精，采用共蒸发法制备甘草素/修饰环糊精包合物并对其进行表征，同时进一步对其溶出度及稳定性进行检测，为改善天然黄酮化合物在水中溶解度低、稳定性差的缺点提供一定的理论与实践支持。
发明内容
本发明的目的在于提供一种制备甘草素/修饰环糊精包合物的方法，通过以下步骤制备：
1. 修饰环糊精的制备
称取50~300 g的β-环糊精，随后加入500~1000 mL蒸馏水，机械搅拌20~60 min后缓慢向其中滴加10~40 wt%的NaOH溶液，得到澄清溶液。称取5~20 g对甲苯磺酰氯溶解在乙腈中，逐滴加入到上述澄清溶液中，继续搅拌1~5 h后减压抽滤得清液，调节pH至中性，然后冷藏保存1~24 h使其充分沉淀，得到的白色固体干燥后即得到白色中间体单-6-O-(对甲苯磺酰基)-β-环糊精。
称取2~5 g上述中间体超声溶解于N, N-二甲基甲酰胺（DMF）中，再加入2.0~7.0 gN-(2-羟乙基)-乙二胺，在N2氛围下50~80℃搅拌反应3~12 h，得到淡黄色溶液，冷却至室温后除去溶液中DMF，剩余溶液中缓慢加入大量冷丙酮 （4℃），有淡黄色沉淀的生成，将其溶于甲醇溶液中，再加入冷丙酮析出，搅拌1~4 h后减压抽滤得到固体，重复上述操作五次，将沉淀过G-25葡萄糖凝胶柱，除去反应中生成的无机盐和其他小分子，收集洗脱液烘干后可获得较纯的白色产物N-(2-羟乙基)-乙二胺基-β-环糊精（以下简称为“主体”）。
2. 甘草素/修饰环糊精包合物的制备
称取0.01~0.05 mmol的修饰环糊精超声溶解于蒸馏水中，称取0.01~0.05 mmol甘草素溶解于乙醇中，接着将其注射入主体溶液中，然后在30~80℃下搅拌加热反应1~24 h。反应结束后蒸出乙醇，剩余溶液使用0.45 μm微孔滤膜过滤除去未反应的甘草素，最后将溶液烘干后得到黄色固体产物。
3. 包合物溶出度及稳定性检测
精密吸取0.001~0.05 mol/L盐酸溶液配制一定甘草素浓度为20~40 μg/mL的甘草素和包合物溶液，分别在不同时间精密吸取3~10 mL溶液，同时补充等体积盐酸溶液，吸取的溶液过滤除去不溶物后在λ=277 nm处测定吸光度，分别计算甘草素及包合物各时间的累积溶出百分率。
精确配制甘草素浓度为10~50 μg/mL的包合物和甘草素溶液各10~100 mL于棕色容量瓶中，避光储存放置，每隔一段时间取样测定溶液中甘草素含量，记录其在一个月内甘草素相对含量的变化。
附图说明：
图1为中间体与主体的红外谱图；
图2为主体的核磁氢谱；
图3为主体的质谱；
图4为包合物的紫外-可见吸收光谱；
图5为包合物红外光谱；
图6为包合物的粒径分析；
图7为包合物溶出度的测定曲线；
图8为包合物相对保留率的测定。
具体实施方式：
以下结合实施例对本发明做具体的说明：
实施例1：修饰环糊精的制备
精密称取126 g β-环糊精待用，随后加入900 mL蒸馏水，机械搅拌30 min后缓慢向其中滴加30 wt%的NaOH溶液30 mL，搅拌1 h后得到澄清溶液。精密称取18 g对甲苯磺酰氯溶解在36 mL乙腈中，搅拌的同时逐滴加入到上述澄清溶液中，继续搅拌3 h后减压抽滤得清液，使用稀盐酸调节pH至7.0，然后置于冰箱中4℃下冷藏保存12 h使其充分沉淀得到的白色固体，随后在60℃下真空干燥48 h，即得到白色固体单-6-O-(对甲苯磺酰基)-β-环糊精。
精密称取2.6 g上述反应中得到的单-6-O-(对甲苯磺酰基)-β-环糊精超声溶解于30 mL DMF中，再加入5.0 g N-(2-羟乙基)-乙二胺，在N2氛围下80℃搅拌反应9 h，得到淡黄色溶液，冷却至室温后减压蒸发除去DMF，将剩余溶液搅拌的同时缓慢加入大量冷丙酮，可以发现淡黄色沉淀的生成，减压抽滤后将其溶于甲醇溶液中，再加入一定体积冷丙酮析出，搅拌3 h后减压抽滤得到固体，重复上述操作五次，将沉淀过G-25葡萄糖凝胶柱，以蒸馏水为洗脱剂，除去反应中生成的无机盐和其他小分子，收集洗脱液烘干后可获得较纯的白色产物N-(2-羟乙基)-乙二胺基-β-环糊精。
从图1可以看出中间体与修饰环糊精红外谱图之间的不同在于中间体红外谱图中的1360 cm-1处伸缩振动峰（来自S=O）在主体的红外谱图中消失，证实了反应过程中中间体分子中C-O-S键发生了断裂，生成了新的产物。从图2可以看出信号峰1在化学位移2.72-2.82 ppm处出现了两个位置非常靠近的峰，对其积分可知拥有四个氢，由于诱导效应的存在，-OH的电负性大于-NH，与其连接与同一个碳原子上的氢的共振峰向低场移动，因此这两个峰依次分别是归属于N-CH2-C、C-CH2-O的两个特征峰，信号峰2在化学位移2.20-2.28 ppm处出现了归属于N-CH2-CH2-N的特征峰，结果表明主体已经成功合成。从图3可以看出其准分子离子[M+H]+质荷比为1221，说明主体的成功合成，且谱图上杂峰相对较少，表明合成得到的主体纯度较高。
实施例2：一种甘草素/修饰环糊精包合物的制备
精密称取0.03 mmol主体超声溶解于20 mL蒸馏水中，随后倒入50 mL圆底烧瓶中，精密称取0.035mmol甘草素溶解于10 mL乙醇中，接着将其缓慢注射入主体溶液中，然后在40℃下搅拌加热反应12 h。反应结束后，减压蒸馏蒸出乙醇，剩余溶液使用0.45 μm微孔滤膜过滤除去未反应的甘草素，滤液80℃下挥发剩余溶剂。将烘干后的产物用20 mL蒸馏水重新超声溶解完全后使用0.45 μm微孔滤膜过滤，除去剩余的未反应甘草素，最后将溶液烘干后得到黄色固体产物。
从图4可以看出主体在扫描范围内无紫外吸收，与甘草素对比，包合物在277 nm处的吸收峰基本未发生移动，在312 nm处的吸收峰红移了15 nm。这可能是由于主体空腔内存在较高密度的电子云，对客体分子甘草素产生电子云微扰，以及主体影响到了甘草素分子空间构型，使甘草素的振动和转动能级均产生变化，这一现象说明甘草素进入主体的空腔内并与其形成了包合物。从图5可以看出包合物的红外特征如下：3381 cm-1处为-OH的伸缩振动峰，相比于主体宽而钝，表明分子间氢键的形成。在1600-1200 cm-1范围内出现了甘草素的特征吸收带，表明包合物的成功制备。图6可以看出可知包合物的颗粒粒径分布在220～460 nm内，其平均粒径为D=328 nm。
实施例3：包合物溶出度及稳定性的检测
精密吸取0.01 mol/L盐酸溶液50 mL为溶剂配制甘草素浓度为36 μg/mL的甘草素和包合物溶液，设置搅拌速度为100 r/min，温度为37±0.5℃，分别在5、10、20、30、45和60 min时精密吸取5 mL溶液，同时补充等体积盐酸溶液，吸取的溶液过滤除去不溶物后在λ=277nm处测定吸光度，分别计算甘草素及包合物各时间的累积溶出百分率。
精确配制含甘草素浓度为35 μg/mL的包合物和甘草素溶液各50 mL于棕色容量瓶中，避光储存放置一个月，每隔一定时间取样测定溶液中甘草素含量，记录其在一个月内甘草素相对含量的变化。
从图7可以看出在以0.01 mol/L盐酸溶液为介质60 min内，甘草素的累积溶出度仅达到33.7%，反映出甘草素难溶于水。而包合物在60 min内的累积溶出度达到了80.1%。从图8可以看出甘草素及包合物均随时间的延长而发生保留率的降低，但包合物的降解程度要低于甘草素，储存时间达到30天后，甘草素的保留率下降了18.6%，而包合物的保留率仅下降了7.3%，其保留率分别为81.4%、92.7%。稳定性试验结果表明形成包合物后甘草素的稳定性得到提升，这是由于包合物对甘草素的包合作用增加了其稳定性。
Claims (3)
1.一种甘草素/修饰环糊精包合物及其制备方法，其特征在于：
适量β-环糊精中加入500~1000 mL蒸馏水，机械搅拌20~60 min后滴加10~40 wt%的NaOH溶液，搅拌；5~20 g对甲苯磺酰氯溶解在乙腈中，加入上述澄清溶液中，继续搅拌1~5 h后减压抽滤得清液，调节pH至中性，置于冰箱中冷藏保存0~24 h，得到的白色固体干燥后即为中间体单-6-O-对甲苯磺酰基-β-环糊精；取2~5 g中间体超声溶解于N, N-二甲基甲酰胺中，再加入2.0~7.0 g N-2-羟乙基-乙二胺，在N2氛围下50~80℃搅拌反应3~12 h，冷却至室温后除去N, N-二甲基甲酰胺，缓慢加入大量4℃丙酮得到淡黄色沉淀，经除杂工艺后获得较纯的修饰环糊精，即N-2-羟乙基-乙二胺基-β-环糊精。
2.称取0.01~0.05 mmol的权利要求1所获得的修饰环糊精，超声溶解于蒸馏水中，称取0.01~0.05 mmol甘草素溶解于乙醇中，接着将其缓慢注射入修饰环糊精溶液中，然后在40~80℃下搅拌加热反应1~24 h；反应结束后，减压蒸出乙醇，剩余溶液使用0.45 μm微孔滤膜过滤除去未反应的甘草素，最后将溶液烘干后得到黄色的甘草素/修饰环糊精包合物。
3.权利要求2制备的甘草素/修饰环糊精包合物的溶出度及稳定性检测结果显示，发生包合作用后的甘草素累积溶出度与保留率分别提高到80.1%、92.7%，改善了甘草素的溶出度和稳定性。
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