CN108822309B - 一种具有缓释性能的纳米纤维/微乳液复合水凝胶的制备方法 - Google Patents
一种具有缓释性能的纳米纤维/微乳液复合水凝胶的制备方法 Download PDFInfo
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- CN108822309B CN108822309B CN201810532675.9A CN201810532675A CN108822309B CN 108822309 B CN108822309 B CN 108822309B CN 201810532675 A CN201810532675 A CN 201810532675A CN 108822309 B CN108822309 B CN 108822309B
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- Colloid Chemistry (AREA)
Abstract
本发明公开了一种具有缓释性能的纳米纤维/微乳液复合水凝胶的制备方法，包括以下步骤：(1)原料经机械处理后获得纳米纤维分散液。(2)将水相、油相和表面活性剂按照一定比例缓慢滴加混合，经过2‑72小时不停搅拌得到澄清透明的水包油型(O/W)微乳液。(3)将纳米纤维分散液与微乳液混合均匀，经过凝固浴得到纳米纤维/微乳液复合水凝胶。本发明方法简单，可操作性强，所制备的纳米纤维/微乳液复合水凝胶具有良好形态、机械性能和缓释性能。该复合水凝胶在药物缓释等生物医药领域具有良好的应用前景。
Description
技术领域
本发明涉及纳米纤维和微乳液的应用技术领域，涉及可由微乳液包载实际药物后运用于药物缓释医药领域，具体涉及一种纳米纤维/微乳液复合水凝胶的制备方法。
背景技术
纤维素是高等植物细胞壁的主要成分，几丁质结构类似于纤维素，几丁质大量存在于海洋节肢动物(如虾、蟹)的甲壳中，也存在于昆虫、藻类细胞膜和高等植物的细胞壁中。纤维素和几丁质是自然界中分布最广、含量最多的两种结构多糖。借助于纳米材料的各种特殊性质，科学家们在各个领域都取得了突破性的成果。利用纤维素和几丁质制备的生物纳米纤维材料被广泛应用于生物医学、生物催化、国防科技等。实际上，纳米颗粒早在17世纪以前就被人们应用相关于陶瓷染色和治疗疾病，到20世纪90年代纳米给药系统逐渐成为药剂学领域的研究热点之一。
纳米给药系统是指药物与药用材料一起形成粒径小于1000nm的药物输送系统，微乳液由互不相容液体乳化形成粒径2-100nm之间，水包油(O/W)或者油包水(W/O)两种稳定体系。随着人们对药物利用率的要求提高和对药物缓释、控释的日益重视，乳液载药成为提高药物利用率的有效方法之一。亲水性药物口服后容易被胃蛋白酶严重破坏，利用油包水(W/O型)微乳液可以增强亲水性药物在肠道粘膜上的通透性，提高亲水性药物的生物利用度。水包油(O/W型)微乳液可以包埋不溶于水中的药物，提高脂溶性药物的利用效率。研究发现，不管是水溶性药物还是油溶性药物，在微乳液中的增溶量并不简单地等同于药物在水中和油中的溶解度之和，而是高出很多，且在需要的情况下可同时增溶油溶性和水溶性药物。
发明内容
发明目的：针对现有技术中存在的不足，本发明的目的是提供一种纳米纤维/微乳液复合水凝胶的制备方法，采用简单的物理复合法即可实现具有药物缓释性能复合水凝胶的制备，方法简单且可操作性强；水凝胶制备过程不涉及有毒试剂，绿色安全。
为实现上述发明目的，本发明采用的技术方案如下：
一种制备纳米纤维水凝胶包埋微乳液的方法，包括如下步骤：
(1)纳米纤维的制备：取纤维素或几丁质原料，经机械处理，得到纤维素或几丁质纳米纤维分散液；
(2)微乳液的制备：将药物、水相、油相和表面活性剂按照一定比例混合至澄清透明，得到水包油型(O/W)纳米微乳液(ME)；
(3)复合水凝胶的制备：将步骤(1)中的纳米纤维分散液和步骤(2)中的微乳液均匀混合，然后经过凝固浴，得到纳米纤维/微乳液复合水凝胶。
步骤(1)中纤维素或几丁质原料经预处理后进行机械处理，预处理方法包含化学法、物理法、生物法、或它们的组合。包含TEMPO氧化、高温碱处理、酸处理、过氧化氢降解等在内的化学法；超微粉碎等在内的物理法；脱乙酰酶处理、漆酶氧化在内的生物法，以及结合法预处理。
步骤(1)中机械处理方法包括匀浆处理、超声处理、高速搅拌、胶体磨、超微粉碎、微射流等。
步骤(1)中的纤维素原料来源为棉、麻、竹材、甘蔗渣、秸秆类纤维素、草类纤维素、藻类植物纤维素、木材类纤维素和动物纤维素，几丁质原料来源为节肢动物如蟹、虾的外骨骼，鱿鱼顶骨、昆虫的角质层以及某些真菌的细胞壁。
步骤(1)中纳米纤维浓度为0.01-5％(w/w)。
步骤(1)中的水性分散介质包含酸性水溶液、中性水溶液、碱性水溶液。
步骤(2)中微乳液油相为酯类或醚类化合物，包含肉豆蔻酸异丙酯、油酸乙酯、乙酸乙酯、玉米油、橄榄油等，表面活性剂有Tween系列、Span系列。
步骤(2)中，水相、油相、表面活性剂经过搅拌微乳液粒径在2-100nm左右。
步骤(2)中微乳液包埋的药物为疏水性药物，包括姜黄素、尼罗红、泊洛沙姆、丙泊酚、醋酸甲基孕酮。
步骤(3)中，凝固浴包括稀氨水等碱性凝固浴和稀醋酸等酸性凝固浴，处理时间为0.1-72小时。
步骤(3)中复合水凝胶为中性。
所述的纳米纤维/微乳液复合水凝胶具有药物缓释性能，缓释时间达到48小时以上，药物缓释率可达100％。
有益效果：与现有技术相比，本发明的具有以下优势：
本发明纳米纤维/微乳液复合水凝胶的制备方法，方法简单且可操作性强，可实现水凝胶的药物缓释。所制备的微乳液粒径稳定均一，水凝胶制备过程不涉及有毒试剂，通过简单的凝固浴条件即可得到良好机械性能和丰富网络结构的物理水凝胶，并且具有良好的药物包埋效果，所制备的复合水凝胶具有生物相容性和无毒无害等优点，在生物医药方面具有良好的应用前景。
本发明结合了纳米纤维无毒无害以及自身独特优势和微乳液的载药增溶特点，将纳米纤维水凝胶与微乳液结合，成功制备纳米纤维/微乳液复合水凝胶进行缓释研究。该复合水凝胶是纳米材料技术领域与生物医学领域的结合，为医学界提供了全新的思路。
本发明所提供的制备纳米纤维/微乳液复合水凝胶的方法既不需要通过复杂的化学交联过程，也不需要额外添加高分子化合物，并且所制备的复合水凝胶具有较高的机械强度和良好的缓释性能。
附图说明
图1是纳米纤维的AFM图；图中，a为几丁质纳米纤维AFM图，b为纤维素纳米纤维AFM图；
图2是纳米纤维水凝胶/微乳液复合水凝胶数码照片图；图中，a为几丁质纳米纤维水凝胶/微乳液复合水凝胶数码照片，b为纤维素纳米纤维水凝胶/微乳液复合凝胶数码照片；
图3是纳米纤维水凝胶孔隙图；图中，a为几丁质纳米纤维水凝胶孔隙图；b为纤维素纳米纤维水凝胶孔隙图；
图4是几丁质纳米纤维/微乳液复合水凝胶缓释性能图；
图5是纤维素纳米纤维/微乳液复合凝胶缓释性能图。
具体实施方式：
以下结合具体实施例对本发明作进一步的阐述。实施例是为说明而非限制本发明。本领域中任何普通技术人员能够理解这些实施例不以任何方式限制本发明，可做适当的修改而不违背本发明的实质和偏离本发明的范围。
实施例1：几丁质纳米分散液的制备
1)几丁质原料的制备
螃蟹壳剪成1cm2大小，1mol/L NaOH浸泡12h以上除去蛋白质，蒸馏水洗涤至中性后继而用1mol/L HCl浸泡12h以上除去矿物质，洗涤至中性。以上步骤重复三次。配置0.5％(w/w)的NaClO2、醋酸调节至pH5后，70℃水浴漂白2h，间歇搅拌，将几丁质洗涤至中性。榨汁机粉碎处理，过滤除水，4℃冰箱中保存，平衡水分1-2天。
2)部分脱乙酰几丁质制备
称取1g纯化后的几丁质(干重)，浸泡于50mL 35％(w/w)NaOH溶液中，90℃水浴、搅拌4h进行部分脱乙酰处理。反应结束后，洗涤至中性，收集固体。4℃冰箱保存，水分平衡。
3)几丁质纳米分散液的制备
配置质量比0.3％(w/w)的几丁质/水混合体系于200mL烧杯中，将醋酸溶液滴加至几丁质分散液中使溶液维持在pH3-4，充分溶胀后，进行匀浆机匀质30s和超声分散5min各五次。离心10000rpm/min、5min除去未分散的固体，收集上清液倾倒至试剂瓶中收集，此即为纳米分散液。未分散的固体进行烘干称重，计算得率。
实施例2：纳米纤维素分散液制备
1)纤维素原料的制备
取亚硫酸盐蔗渣纸浆为例，用蒸馏水将其清洗至中性。配制质量分数为0.5％NaClO2(亚氯酸钠)溶液，将纸浆加入NaClO2溶液中至纸浆完全被浸没。向浸有纸浆的NaClO2溶液中添加醋酸溶液，将体系的pH调至5以下。然后把整个体系置于70℃水浴锅中水浴处理2小时，期间每隔15-20分钟进行间歇搅拌。漂白完成后，用蒸馏水将漂白纸浆洗至中性，得到漂白后的蔗渣纸浆，置于4℃冰箱中保存。
2)TEMPO氧化纤维素
称取纤维素样品干重1g、NaBr 0.1g、TEMPO 0.016g和100mL蒸馏水加入烧杯，搅拌均匀，充分溶解。向体系中加入6mmol次氯酸钠，滴加5M盐酸调节总体系pH为10，开始氧化。使用自动滴定仪自动滴加0.5M氢氧化钠维持总体系pH为10。当体系几乎不消耗氢氧化钠溶液后，滴加少量乙醇溶液种植反应，加入少量0.5M盐酸将pH调至中性。离心清洗氧化纤维素，取不溶物置于4℃冰箱保存。
3)纳米纤维素分散液制备
取0.2g干重氧化纤维素加入100mL蒸馏水进行匀浆，超声操作，循环5-6次，溶液澄清透明即可8000rpm/min离心去除沉淀。上清液即为制得的纳米纤维素分散液。
实施例3：配置载药微乳液
烧杯需要避光处理，用铝箔纸将烧杯包裹完全。Tween80、Span20、IPM(肉豆蔻酸异丙酯)按照27:1.27:4质量比进行称重，配置过程中需不停搅拌混合均匀，量取去离子水用微量滴定管缓慢贴壁滴加不停搅拌24h，直至溶液澄清透明不分层。按照载药量为总体系0-10％添加，搅拌至完全溶解。
实施例4：
1)包埋微乳液的几丁质纳米纤维水凝胶
量取2mL纳米几丁质分散液与220μL的微乳液混合均匀，倾倒至培养皿中，取250mL烧杯将氨水与水按照1:1配置得到稀氨水溶液，将小培养皿放置于大烧杯中以保鲜膜封口，处理24h后取出小培养皿，制备得到均一且透光良好的纳米纤维/微乳液复合水凝胶。
2)包埋微乳液的纳米纤维素复合凝胶
量取2mL纳米纤维素分散液与110μL的微乳液混合均匀，倾倒至培养皿中，取250mL烧杯将醋酸与水按照1:1配置得到稀醋酸溶液，将小培养皿放置于大烧杯中以保鲜膜封口，处理24h后取出小培养皿，制备得到均一且透光良好的纳米纤维素/微乳液复合水凝胶。
纳米纤维的AFM图如图1所示，a为几丁质纳米纤维AFM图，b为纤维素纳米纤维AFM图；由图可知，几丁质和纤维素纳米纤维被成功制备，直径分布于3-20nm。
纳米纤维水凝胶/微乳液复合水凝胶数码照片如图2所示，a为几丁质纳米纤维水凝胶/微乳液复合水凝胶数码照片，b为纤维素纳米纤维水凝胶/微乳液复合凝胶数码照片；由图可知，复合水凝胶均一稳定，未见分层或絮凝，说明纳米纤维水凝胶成功的将微乳液包埋其中，且复合水凝胶具有良好的机械性能。
纳米纤维水凝胶孔隙图如图3所示，a为几丁质纳米纤维水凝胶孔隙图；b为纤维素纳米纤维水凝胶孔隙图；由图可知，几丁质和纤维素纳米纤维凝胶具有丰富的孔隙以及纳米纤维网络结构，为微乳液的包埋和缓释提供了结构基础。
实施例5：
1)包埋微乳液的几丁质纳米纤维中性水凝胶
量取3mL纳米几丁质分散液与110μL的微乳液混合均匀，倾倒至培养皿中，取250mL烧杯将氨水与水按照1:1配置得到稀氨水溶液，将小培养皿放置于大烧杯中以保鲜膜封口，处理24h后取出小培养皿，制备得到均一且透光良好的几丁质纳米纤维/微乳液复合水凝胶。取250mL烧杯配置稀醋酸溶液，按照醋酸与水1:1比例配置得到稀酸溶液，将小培养皿放置于大烧杯中以保鲜膜封口，处理一段时间后测定凝胶pH值，直至凝胶达到中性。
2)包埋微乳液的纳米纤维素中性水凝胶
量取3mL纳米纤维素分散液与220μL的微乳液混合均匀，倾倒至培养皿中，取250mL烧杯将醋酸与水按照1:1配置得到稀醋酸溶液，将小培养皿放置于大烧杯中以保鲜膜封口，处理24h后取出小培养皿，制备得到均一且透光良好的纳米纤维素/微乳液复合水凝胶。取250mL烧杯配置稀氨水溶液，按照氨水与水1:1比例配置得到稀氨水溶液，将小培养皿放置于大烧杯中以保鲜膜封口，处理一段时间后测定凝胶pH值，直至凝胶达到中性。
实施例6；纳米纤维/微乳液复合水凝胶的缓释
取150mL的锥形瓶进行避光处理，倒入100mL，75mM，pH7.4的磷酸缓冲液，从培养皿中得到的完整水凝胶至于缓冲液中，在37℃，100rpm条件下进行缓释，按照一定时间取样，并替补相同体积的缓冲液。利用酶标仪或者紫外分光光度计进行缓释浓度测定，结果表明纳米纤维/微乳液复合水凝胶缓释时间为48h以上，可达60h，缓释程度大于60％，可达100％。
纳米纤维/微乳液复合水凝胶缓释性能如图4和图5所示，由图可知，在PBS缓冲液中，未负载疏水性化合物的微乳液在纳米纤维/微乳液复合水凝胶中的缓释程度大于60％，负载了疏水性化合物的微乳液在纳米纤维/微乳液复合水凝胶中的缓释程度达到100％，缓释时间均大于48h。
Claims (8)
1.一种具有缓释性能的纳米纤维/微乳液复合水凝胶的制备方法，其特征在于，包括如下步骤：
（1）取纤维素或几丁质原料，经预处理结合机械处理或经直接机械处理，得到质量浓度为0.01-5%的纤维素或几丁质纳米纤维分散液；
（2）将药物、水相、油相和表面活性剂按照比例混合至澄清透明，得到水包油型纳米微乳液；其中，微乳液粒径为2~100nm；药物为疏水性药物，包括姜黄素、尼罗红、泊洛沙姆、丙泊酚、醋酸甲基孕酮；
（3）将步骤（1）中的纳米纤维分散液和步骤（2）中的微乳液均匀混合，然后经过凝固浴，得到纳米纤维/微乳液复合水凝胶。
2.根据权利要求1所述的具有缓释性能的纳米纤维/微乳液复合水凝胶的制备方法，其特征在于，步骤（1）中，纤维素或几丁质原料经预处理后进行机械处理，预处理方法为化学法、物理法、生物法，或它们的组合。
3.根据权利要求1或2所述的具有缓释性能的纳米纤维/微乳液复合水凝胶的制备方法，其特征在于，步骤（1）中，机械处理方法包括匀浆处理、超声处理、高速搅拌、胶体磨、超微粉碎、微射流。
4.根据权利要求1或2所述的具有缓释性能的纳米纤维/微乳液复合水凝胶的制备方法，其特征在于，步骤（1）中，纤维素原料来源为木材类纤维素、草类纤维素、棉纤维素、麻纤维素、甘蔗渣纤维素、藻类植物纤维素和动物纤维素，几丁质原料来源为节肢动物的外骨骼，鱿鱼顶骨、昆虫的角质层以及真菌的细胞壁。
5.根据权利要求1或2所述的具有缓释性能的纳米纤维/微乳液复合水凝胶的制备方法，其特征在于，步骤（1）中，纳米纤维分散液的分散介质选自酸性水溶液，中性水溶液，碱性水溶液；酸性水溶液选自醋酸、葡萄糖酸、衣康酸、柠檬酸、抗坏血酸、盐酸、乳酸、硫酸。
6.根据权利要求1或2所述的具有缓释性能的纳米纤维/微乳液复合水凝胶的制备方法，其特征在于，步骤（2）中，微乳液油相为酯类或醚类化合物，包含肉豆蔻酸异丙酯、油酸乙酯、乙酸乙酯、玉米油、橄榄油、石油醚、润滑油，表面活性剂有Tween系列、Span系列。
7.根据权利要求1或2所述的具有缓释性能的纳米纤维/微乳液复合水凝胶的制备方法，其特征在于，步骤（3）中，凝固浴包括稀氨水的碱性凝固浴和稀醋酸的酸性凝固浴，处理时间为0.1-72小时，复合水凝胶为中性。
8.权利要求1-7任一项所述的具有缓释性能的纳米纤维/微乳液复合水凝胶的制备方法所获得的纳米纤维/微乳液复合水凝胶，其特征在于，所述的纳米纤维/微乳液复合水凝胶具有药物缓释性能，缓释时间达到48小时以上，药物缓释率可达到100%。
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| CN105748408A (zh) * | 2014-12-17 | 2016-07-13 | 北京盈科瑞药物研究院有限公司 | 微乳、微乳制剂及其制备方法 |
| CN105820352A (zh) * | 2016-04-06 | 2016-08-03 | 南京林业大学 | 一种正电性几丁质纳米纤维水凝胶及气凝胶的制备方法 |
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