CN116139089A - 一种壳聚糖与纳米中药配伍的纳米制剂及其制备方法与应用 - Google Patents
一种壳聚糖与纳米中药配伍的纳米制剂及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种壳聚糖与纳米中药配伍的纳米制剂及其制备方法与应用。属于保健食品技术领域。将姜黄素和白藜芦醇加入油相，使用匀浆机剪切分散后，得到初级Cur‑RV纳米晶混悬液，再使用高压均质机制备Cur‑RV纳米晶混悬液。将水相(包括聚乙烯醇、壳聚糖和冰醋酸)加入Cur‑RV纳米晶混悬液中，匀浆得到Cur‑RV纳米初乳，再将Cur‑RV纳米初乳加入高压均质机中，制备得到壳聚糖与纳米中药配伍的纳米制剂。本发明制备的纳米制剂同时负载了两种中药活性成分，能在较长时间内保持中药活性成分的缓慢释放，减少给药次数，同时，增加了壳聚糖的配伍，提高了纳米制剂的安全性和生物利用度。
Description
技术领域
本发明涉及保健食品技术领域，更具体的说是涉及一种壳聚糖与纳米中药配伍的纳米制剂及其制备方法与应用。
背景技术
姜黄素(Curcumin,Cur)是一种从姜黄属植物如姜黄、莪术、菖蒲、郁金等根茎中提取出的酸性多酚类化合物，它具有抗炎、抗菌、抗氧化、抗肿瘤、保肝利胆、调节血脂等药理活性。然而，姜黄素属于亲脂类物质，水溶性差，以固体颗粒、悬浮液等方式服入体内生物利用率低，难以达到应有的保健作用。
白藜芦醇(Resveratrol,Res)是来源于植物的一种非黄酮类多酚化合物，主要用于治疗原发性肝癌、乳腺癌、皮肤癌、心血管疾病和高血压等。其自身具有易氧化、代谢快、半衰期短等特点，导致给药后生物利用度低，不能达到理想的有效治疗水平。
综上，如何提供一种合适的药物输送系统以提高姜黄素和白藜芦醇的稳定性及生物利用度是本领域技术人员亟需解决的问题。
发明内容
有鉴于此，本发明提供了一种壳聚糖与纳米中药配伍的纳米制剂及其制备方法与应用。将姜黄素和白藜芦醇原料药(Cur-RV)，加入油相(溶解有聚乳酸-羟基乙酸共聚物(PLGA)的二氯甲烷溶液)，使用匀浆机剪切分散后，得到初级Cur-RV纳米晶混悬液，再使用高压均质机制备Cur-RV纳米晶混悬液。将水相(聚乙烯醇的质量浓度为0.1～3％，壳聚糖的质量浓度为0.1～2％，冰醋酸的体积浓度占水相的0.1～2％)加入Cur-RV纳米晶混悬液中，匀浆得到Cur-RV纳米初乳，再将Cur-RV纳米初乳加入高压均质机中，制备得到壳聚糖与纳米中药配伍的纳米制剂。
为了实现上述目的，本发明采用如下技术方案：
一种壳聚糖与纳米中药配伍的纳米制剂，包括姜黄素、白藜芦醇、油相和水相；
所述油相为溶解有聚乳酸-羟基乙酸共聚物的二氯甲烷溶液；
所述水相包括聚乙烯醇、壳聚糖和冰醋酸。
所取得的有益效果：纳米载药体系能够有效发挥材料对药物的保护作用，协助药物跨越黏膜屏障，通过高通透性和滞留(Enhancedpermeabilityand retention,EPR)效应增强药物在靶点部位的累积，改变药物在体内的分布，减少系统性毒性，目前已成为现代药物研究的重要方向。因此，本发明利用纳米球或微球递送系统通过缓释和控释来克服姜黄素和白藜芦醇的自身缺陷，同时跟壳聚糖配伍，达到协同增效的目的。
进一步的，所述聚乳酸-羟基乙酸共聚物与二氯甲烷的质量体积比为2～5:10g/ml。
进一步的，所述水相中聚乙烯醇的质量浓度为0.1～3％，壳聚糖的质量浓度为0.1～2％，冰醋酸的体积浓度占水相的0.1～2％。
进一步的，所述聚乙烯醇的脱乙酰度为85～95％。
进一步的，所述壳聚糖的Mw为9kDa～100kDa。
进一步的，还包括甘露糖。
上述的壳聚糖与纳米中药配伍的纳米制剂的制备方法，包括如下步骤：
(1)将聚乳酸-羟基乙酸共聚物溶解在二氯甲烷中，得到油相；
(2)将姜黄素和白藜芦醇加入到油相中，高压均质，得到Cur-RV纳米晶混悬液；
(3)溶解聚乙烯醇至水中，同时加入冰醋酸和壳聚糖，得到水相；
(4)将Cur-RV纳米晶混悬液加入到水相中，高压均质，得到乳剂A；
(5)将乳剂A加入甘露糖溶液后冷冻干燥，即得壳聚糖与纳米中药配伍的纳米制剂。
进一步的，所述步骤(2)中高压均质的时间为1min；
所述步骤(4)中高压均质的时间为5min。
进一步的，所述甘露糖溶液的质量浓度为5％。
上述的壳聚糖与纳米中药配伍的纳米制剂在制备治疗肺部炎症药物中的应用。
经由上述的技术方案可知，与现有技术相比，本发明取得的有益效果为：本发明所制备的纳米制剂同时负载了两种中药活性成分，能在较长时间内保持中药活性成分的缓慢释放，减少给药次数，经纳米乳化后，显著提高了难溶性小分子药物的水溶性，细胞吸收及生物利用度；壳聚糖本身难溶于水，有腥味，粉末状，很难下咽，且吸收效果差。通过纳米制剂共载后，可以极大提高其生物利用度。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据提供的附图获得其他的附图。
图1附图为本发明壳聚糖与纳米中药配伍的纳米制剂的制备流程图；
图2附图为本发明实施例1所制备的纳米制剂的表征结果，其中：A为粒径分布结果，B为扫描电镜结果，C为紫外吸收光谱；
图3附图为本发明实施例1所制备的纳米制剂抑制小鼠肺部炎症实验结果，其中：A为构建小鼠肺炎/急性肺损伤模型图，B为肺部图；
图4附图为本发明实施例1所制备的纳米制剂生物利用度结果，其中：A为显微镜下图片，B为各个器官图；
图5附图为本发明实施例1所制备的纳米制剂的安全性评价结果，其中：A为细胞的活性结果，B为红细胞溶血实验结果，C为对血清内谷丙转氨酶(ALT)、谷草转氨酶(AST)的影响。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明所需药剂为常规实验药剂，采购自市售渠道；未提及的实验方法为常规实验方法，在此不再一一赘述。
实施例1
(1)称取1.0gPLGA分散在10ml二氯甲烷中，得到油相。
(2)将150姜黄素和150mg白藜芦醇加入油相，使用匀浆机剪切分散后，得到初级Cur-RV纳米晶混悬液，再使用高压均质机乳化1min制备Cur-RV纳米晶混悬液；
(3)溶解1％PVA(脱乙酰度85％)，同时加入0.2％的冰醋酸溶液及壳聚糖，壳聚糖浓度为0.5％，水相体积50ml，作为水相；
(4)水相加入Cur-RV纳米晶混悬液中，匀浆得到Cur-RV纳米初乳，再将Cur-RV纳米初乳加入高压均质机中乳化5min，得到乳剂A；
(5)所得乳剂A加入5％甘露糖冷冻干燥，得到壳聚糖与纳米中药配伍的纳米制剂，4℃冰箱中保存；
(6)使用时，将纳米制剂分散在2％壳聚糖溶液中，与壳聚糖配伍联合增效。
实验1
对实施例1制备的纳米制剂进行表征，方法如下：
将纳米制剂分散在生理盐水中，采用激光纳米粒度仪(ZetasizerNano ZS)检测纳米制剂的粒径分布。
扫描电镜检测纳米制剂形貌的方法：
1.样品用DI水稀释十倍后，常温下超声10分钟；
2.将超声后的样品滴到硅片(SiliconChip)上；并在常温下于洁净台上过夜挥发；
3.将载有样品的硅片镀金(CoatingPt)后黏附于载物台并传送至SEM样品分析仓。
紫外可见吸收谱的检测方法：将纳米制剂以或中药成分，分散在介质中(水或二甲基亚砜)，采用紫外分光光度计进行全波长扫描。
结果如图2所示。
图2A表明纳米球粒径大概分布在500nm左右；图2B表明扫描电镜显示呈规则的球形；图2C的紫外吸收光谱显示，纳米制剂成功负载了姜黄素(Cur)和白藜芦醇(RV)。
下面的实验2-实验4，是将纳米制剂分散到壳聚糖溶液中使用。
实验2
探究实施例1制备的纳米制剂对肺炎小鼠模型的作用。
8周龄C57野生型小鼠经腹腔注射脂多醣(Lipopolysaccharide，LPS)(剂量8mg/kg)24小时，构建小鼠肺炎/急性肺损伤模型。造膜前三小时，小鼠滴鼻原药或纳米制剂干预(图3A)，其中，原药：姜黄素(5mg/kg)和白藜芦醇(5mg/kg)的混合物；纳米制剂：5mg/kg(以包载在纳米粒中的姜黄素和白藜芦醇的浓度计量)。
结果如图3B所示，经滴鼻给药后，与鼻原药相比，纳米制剂显著降低了肺部炎性细胞的浸润。
实验3
探究实施例1制备的纳米制剂的生物利用度。结果如图4所示。
纳米制剂可以显著提高药物在细胞和机体内的生物利用度。图4A采用肺泡上皮细胞HBE与标记荧光maker的中药共同孵育3小时后，PBS洗3遍，去除未被吸收的中药，在活细胞荧光显微镜下成像。图4A可以观察到，纳米中药可以更多被细胞吸收。图4B构建小鼠肺炎模型，滴鼻荧光标记的纳米中药后4小时后，收集各个器官，图中可以观察到，纳米载体可以显著增加药物在肺组织的富集和滞留，从而较长时间发挥药效。
实验4
探究实施例1制备的纳米制剂的安全性。结果如图5所示。
图5A表明中药或纳米中药跟HBE细胞孵育24小时后，对细胞的活性不会造成影响。图5B为红细胞溶血实验：通过中药跟红细胞孵育3小时后发现，中药和纳米化中药都不会引起红细胞溶血，说明体内安全性良好。图5C为肺炎小鼠滴鼻中药制剂24小时后，对血清内谷丙转氨酶(ALT)、谷草转氨酶(AST)不会造成显著影响，说明中药制剂不会造成肝功能受损。
本说明书中各个实施例采用递进的方式描述，每个实施例重点说明的都是与其他实施例的不同之处，各个实施例之间相同相似部分互相参见即可。
对所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
Claims (9)
1.一种壳聚糖与纳米中药配伍的纳米制剂，其特征在于，包括姜黄素、白藜芦醇、油相和水相；
所述油相为溶解有聚乳酸-羟基乙酸共聚物的二氯甲烷溶液；
所述水相包括聚乙烯醇、壳聚糖和冰醋酸。
2.如权利要求1所述的壳聚糖与纳米中药配伍的纳米制剂，其特征在于，所述聚乳酸-羟基乙酸共聚物与二氯甲烷的质量体积比为2～5:10g/ml。
3.如权利要求1所述的壳聚糖与纳米中药配伍的纳米制剂，其特征在于，所述水相中聚乙烯醇的质量浓度为0.1～3％，壳聚糖的质量浓度为0.1～2％，冰醋酸的体积浓度占水相的0.1～2％。
4.如权利要求1所述的壳聚糖与纳米中药配伍的纳米制剂，其特征在于，所述聚乙烯醇的脱乙酰度为85～95％。
5.权利要求1～4任一所述的壳聚糖与纳米中药配伍的纳米制剂，其特征在于，还包括甘露糖。
6.权利要求5所述的壳聚糖与纳米中药配伍的纳米制剂的制备方法，其特征在于，包括如下步骤：
(1)将聚乳酸-羟基乙酸共聚物溶解在二氯甲烷中，得到油相；
(2)将姜黄素和白藜芦醇加入到油相中，高压均质，得到Cur-RV纳米晶混悬液；
(3)溶解聚乙烯醇至水中，同时加入冰醋酸和壳聚糖，得到水相；
(4)将Cur-RV纳米晶混悬液加入到水相中，高压均质，得到乳剂A；
(5)将乳剂A加入甘露糖溶液后冷冻干燥，即得成品。
7.如权利要求6所述的制备方法，其特征在于，所述步骤(2)中高压均质的时间为1min；
所述步骤(4)中高压均质的时间为5min。
8.如权利要求6所述的制备方法，其特征在于，所述甘露糖溶液的质量浓度为5％。
9.权利要求5所述的壳聚糖与纳米中药配伍的纳米制剂、权利要求6～8任一所述的制备方法制备的壳聚糖与纳米中药配伍的纳米制剂在制备治疗肺部炎症药物中的应用。
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