CN110947005A - 一种叶黄素纳米粒子的制备方法及应用 - Google Patents

一种叶黄素纳米粒子的制备方法及应用 Download PDF

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CN110947005A
CN110947005A CN202010020606.7A CN202010020606A CN110947005A CN 110947005 A CN110947005 A CN 110947005A CN 202010020606 A CN202010020606 A CN 202010020606A CN 110947005 A CN110947005 A CN 110947005A
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lutein
glycolic acid
nanoparticles
polylactic acid
sophorolipid
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洪明芳
林劲冬
陶正国
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GUANGZHOU LEADER BIO-TECHNOLOGY CO LTD
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Abstract

一种叶黄素纳米粒子的制备方法及应用，按如下步骤进行：（1）将PLGA和叶黄素溶于丙酮中，作为有机相；（2）将槐糖脂溶于水中，作为水相；（3）将（1）中有机相逐滴加入到磁力搅拌的水相中；（4）将（3）自发形成的纳米粒子用去离子水透析后置于恒温磁力搅拌器上搅拌2 h，去除有机溶剂。本发明所得的叶黄素聚乳酸‑羟基乙酸纳米粒子的优势在于：稳定性好；使用可生物降解、生物相溶性好的表面活性剂槐糖脂，安全性高；该叶黄素聚乳酸‑羟基乙酸纳米粒子可载入凝胶材料中制成滴眼剂，改善普通滴眼液在眼部滞留时间短的缺陷，从而减少给药次数，延缓药物释放，提高生物利用度。

Description

一种叶黄素纳米粒子的制备方法及应用
技术领域
本发明涉及一种叶黄素聚乳酸-羟基乙酸纳米粒子的制备方法及应用，属于纳米制剂领域。
背景技术
叶黄素(Lutein)是一种广泛存在于蔬菜、花卉、水果中的含氧类胡萝卜素，又名黄体素，因其对人体重要的生理活性、抗氧化性以及着色性受到研究者的关注。叶黄素不能通过人体自身合成，必须从食物中摄取。研究表明：饮食补充叶黄素或者食用含有叶黄素丰富的蔬菜和水果可以预防某些癌症、心血管疾病、老年性视网膜黄斑性变等疾病。
叶黄素具有保护视力的功能。目前，越来越多人使用带有蓝光的电子设备，如电视、电脑、智能手机等，这些电子设备的显示器发出的蓝光波长为400-500 nm与紫外光的波长400-435 nm很近，它是所有能达到视网膜的可见光中能量最高，潜在危害性最大的一种光，它能引起视网膜色素上皮和感光细胞损伤。而叶黄素的最大吸收波长恰处于蓝光的波长范围，它在人眼视网膜内形成蓝光过滤器，减少蓝光到达光感受器及视网膜神经细胞的概率，从而对视网膜细胞具有保护作用。叶黄素还具有抗氧化作用，通过物理或化学作用消灭单线态氧，从而抑制氧自由基的活性，阻止氧自由基对人体细胞的破坏，增强机体的免疫功能。
但是，叶黄素的性质很不稳定，易受光照、高温和氧气的影响，一旦它被氧化就会失去其原有的功效。此外，叶黄素属于脂溶性的类胡萝卜素，所以在水介质中难以溶解或均匀分散。叶黄素的不稳定性和水不溶性限制了它在食品、药品、饲料等方面的广泛应用。
如果能够选择合适的载体物质，在简单的实验条件下，与叶黄素形成包合物，从而保护叶黄素免于降解，将极大提高其可用性。同时，将包合物颗粒尺寸降低至纳米级别，可以改善生物体对叶黄素的吸收效率，并提高它的分散稳定性。
在众多材料中，PLGA由于在生物体内可被安全无毒地降解，且降解产物（乳酸和乙醇酸）均为人体内源物质，可被Krebs循环代谢清除等优点而备受亲睐。但在合成PLGA纳米粒子过程往往需要添加表面活性剂，如聚乙烯醇（PVA）、聚乙烯基吡咯烷酮（PVP）等，这些表面活性剂在体内不可降解具有潜在毒性。
为了解决这一问题，本发明以生物可降解的槐糖脂为表面活性剂，制备了一种槐糖脂包埋叶黄素聚乳酸-羟基乙酸纳米粒子，该纳米粒子可以与离子型凝胶相结合制成叶黄素纳米凝胶，该凝胶与眼部泪液中的Ca2+、Na+、K+等阳离子发生络合作用发生相转变，由液态转化为凝胶，使其能够黏附于结膜囊和角膜表面，改善普通滴眼液在眼部滞留时间短的缺陷，从而减少给药次数，延缓药物释放，提高生物利用度。
发明内容
本发明是这样实现的：首先将PLGA和叶黄素溶解在与水有一定互溶的有机溶剂中，然后将溶有PLGA叶黄素的有机相滴加到不断搅拌的水相中，水相中含有表面活性剂槐糖脂，利用溶剂的快速扩散使聚合物在水相和有机相的界面瞬间沉淀，形成纳米粒子。滴加完毕后，用去离子水透析后持续搅拌除去有机溶剂，即制得槐糖脂包埋叶黄素聚乳酸-PLGA和叶黄素溶解在与水互溶的有机溶剂中，然后将溶有PLGA和叶黄素的有机相滴加到不断搅拌的水相中，水相中含有表面活性剂槐糖脂，利用溶剂的快速扩散使聚合物在水相和有机相的界面瞬间沉淀，形成纳米粒子。滴加完毕后，用去离子水透析后持续搅拌除去有机溶剂，即制得槐糖脂包埋叶黄素聚乳酸-羟基乙酸纳米粒子。具体包括以下步骤：
（1）称取25 mg PLGA聚合物固体、2.5 mg 叶黄素晶体溶解在2 mL丙酮中，作为有机相；
（2）配置15 mL 0.05%（W/V）的槐糖脂溶液，作为水相；
（3）将（1）中有机相逐滴加入到磁力搅拌（635 rpm）的水相中即15 mL 0.05%（W/V）的槐糖脂溶液；
（4）将（3）得到的纳米溶液于透析管（截留分子量20000 Da）中透析30 min，然后置于恒温磁力搅拌器上搅拌2 h，去除丙酮。
（5）将（4）得到的产物以12000 rpm 4℃离心15 min收集纳米粒子，用去离子水洗两次；
（6）将洗涤好的纳米颗粒真空冷冻干燥，即得槐糖脂包埋的叶黄素聚乳酸-羟基乙酸纳米粒子。
本发明还提供一种过程制备的槐糖脂包埋的叶黄素/聚乳酸-羟基乙酸纳米粒子在滴眼剂中的应用技术，具体包括如下步骤：以去乙酰结冷胶为凝胶基质，海藻酸钠为粘附性材料，制备空白离子型凝胶，然后将上述制备的叶黄素聚乳酸-羟基乙酸纳米粒子冻干粉末与空白离子型凝胶混合均匀，即得叶黄素纳米凝胶；将该叶黄素纳米凝胶分散在滴眼液载体中，即为纳米叶黄素滴眼液。该滴眼液可经0.45 µm微孔滤膜过滤后采用HPLC测定叶黄素含量。
本发明与现有技术相比具有以下优点：
1. 本发明所用的PLGA具有良好的生物相容性和生物可降解性，且无毒、无刺激性，PLGA作为叶黄素载体在体内可水解成乳酸和羧酸乙基两种单体，通过三羧酸酯循环最终代谢成二氧化碳和水，对人体不会产生不良反应。
2. 使用槐糖脂作为稳定剂，其活性受温度、pH、盐度等条件影响小，且可降解，低毒无刺激。
3. 本发明制备的叶黄素/聚乳酸-羟基乙酸纳米粒子可载入凝胶材料中制成滴眼剂，改善普通滴眼液在眼部滞留时间短的缺陷，从而减少给药次数，延缓药物释放，提高叶黄素的生物利用度。
具体实施方式
下面结合具体实施案例对本发明作进一步详细说明，本发明并不限于此。
实施例1
叶黄素聚乳酸-羟基乙酸纳米粒子的制备，包括以下步骤：
（1）称取25 mg PLGA聚合物固体、2.5 mg 叶黄素晶体溶解在2 mL丙酮中，作为有机相；
（2）配置15 mL 0.05%（W/V）的槐糖脂溶液，作为水相；
（3）将（1）中有机相逐滴加入到磁力搅拌（635 rpm）的水相中即15 mL 0.05%（W/V）的槐糖脂溶液；
（4）将（3）得到的纳米溶液于透析管（截留分子量20000 Da）中透析30 min，然后置于恒温磁力搅拌器上搅拌2 h，去除丙酮；
（5）将（4）得到的产物以12000 rpm 4℃离心15 min收集纳米粒子，用去离子水洗两次；
（6）将洗涤好的纳米颗粒真空冷冻干燥，即得槐糖脂包埋的叶黄素聚乳酸-羟基乙酸纳米粒子。
实施例2
叶黄素纳米凝胶的制备，包括以下步骤：
（1）称取0.1 g去乙酰结冷胶，加入20 mL超纯水在90℃下溶胀溶解，称取0.04 g海藻酸钠在搅拌的条件下缓慢加入其中，置于4℃下冷藏至聚合物完全溶胀，即得空白凝胶；
（2）将实施例1中的叶黄素纳米粒子冻干粉末与上述空白凝胶混合均匀，即得叶黄素纳米凝胶。
实施例3
叶黄素负载量的测定，包括以下步骤：
（1）称取0.5 g叶黄素纳米凝胶，加入适量正己烷超声30 min至溶解后定容，样品经0.45 µm微孔滤膜过滤后采用HPLC测定叶黄素含量；
（2）HPLC测定条件：固定相为正相硅胶柱（内径4.6 mm，长250 mm，粒度5 µm），流动相为正己烷：乙酸乙酯：异丙醇（体积比73：27：1.5），流速为1.5 mL/min，检测波长为446 nm，进样量为20 µL。
实施例4
叶黄素的体外释放，包括以下步骤：
称取50 mg叶黄素纳米粒子凝胶混悬于5 mL的释放介质（PBS，pH7.4，含0.1%（v/v）Tween-80）中，置于截留分子量为8000的透析袋中，扎紧透析袋两端，把透析袋悬浮于100mL具塞锥形瓶中，锥形瓶中加入45 mL的释放介质，将其置于恒温振荡器中，以37℃，转速100 rpm/min持续振荡，于不同时间点吸取透析袋外5 mL介质并用HPLC测定叶黄素的浓度，并立即补充5 mL同温度的新鲜释放介质，计算其累计释放药物的量。

Claims (4)

1.一种叶黄素纳米粒子的制备方法及应用，其特征在于，首先将聚乳酸-羟基乙酸和叶黄素溶解在与水互溶的有机溶剂中，然后将溶有聚乳酸-羟基乙酸和叶黄素的有机相滴加到不断搅拌的水相中，水相中含有槐糖脂、透明质酸，利用溶剂的快速扩散使聚合物在水相和有机相的界面瞬间沉淀，形成纳米粒子。
2.滴加完毕后，用去离子水透析后持续搅拌除去有机溶剂，即制得叶黄素聚乳酸-羟基乙酸纳米粒子。
3.根据权利要求1所述的叶黄素聚乳酸-羟基乙酸纳米粒子的制备方法及应用，其特征在于，包括以下步骤：
（1）称取25 mg 聚乳酸-羟基乙酸固体、2.5 mg 叶黄素晶体溶解在2 mL丙酮中，作为有机相；
（2）配置10 mL 0.05%（W/V）的槐糖脂溶液，将两者混合均匀，作为水相；
（3）将（1）中有机相逐滴加入到磁力搅拌的水相中；
（4）将（3）得到的纳米溶液于透析管（截留分子量20000 Da）中透析30 min，然后置于恒温磁力搅拌器上搅拌2 h，去除丙酮；
（5）将（4）得到的产物以12000 rpm 4℃离心15 min收集纳米粒子，用去离子水洗两次；
（6）将洗涤好的纳米颗粒真空冷冻干燥，即得槐糖脂包埋的叶黄素聚乳酸-羟基乙酸纳米粒子。
4.根据权利要求1制备的叶黄素纳米粒子在滴眼剂中的用途，其特征在于，将叶黄素聚乳酸-羟基乙酸纳米粒子冻干粉末与去乙酰结冷胶、海藻酸钠制成的离子型空白凝胶混合均匀，得到叶黄素纳米凝胶；将该叶黄素纳米凝胶分散到滴眼液载体里，制备叶黄素滴眼液。
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