CN117186267A - 一种羟丁基甲壳素、羟丁基甲壳素水凝胶及制备方法 - Google Patents
一种羟丁基甲壳素、羟丁基甲壳素水凝胶及制备方法 Download PDFInfo
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Abstract
本发明公开了一种羟丁基甲壳素、羟丁基甲壳素水凝胶及制备方法。经过甲壳素的粉碎、溶解、环氧丁烷修饰和纯化，得到终产物羟丁基甲壳素。该法制备的羟丁基甲壳素在纯化水中具有良好的溶解性，可形成低固含量的水凝胶。羟丁基甲壳素水凝胶将在生物医药、可吸收材料等领域等方面可能具有广泛的应用前景。
Description
技术领域
本发明属于材料技术领域，涉及一种羟丁基甲壳素水凝胶及其制备方法。
背景技术
甲壳素是一种线型多糖天然高分子，其重复单元是2-乙酰氨基-(1，4)-β-葡萄糖。甲壳素广泛存在于自然界中，来源主要集中在鱼虾蟹等动物外壳及真菌生物的细胞壁。甲壳素是自然界中数量最多的含氮有机物，也是自然界中含量最多的高分子之一。甲壳素具有很多优异的性质，例如优异的生物相容性、较低的免疫原性、较好的止血性等，在生物医药、可吸收材料等领域有广阔的应用前景。
甲壳素衍生物水凝胶是一类优良的可吸收材料。由于甲壳素分子内或分子间的糖间相互作用和氢键、以及容易引起分子致密堆砌的线型分子结构等，甲壳素的溶解性差，在自然界中多为甲壳类的结构材料。使用一些试剂对甲壳素进行修饰，所得甲壳素衍生物的分子致密堆积能力下降、水溶性得到提升。通过改变试剂的种类和用量，可以调节甲壳素衍生物分子亲水性和疏水性的平衡，得到甲壳素衍生物水凝胶。常见的甲壳素改性试剂有两类，一类为卤代烃试剂，另一类为环氧类试剂。卤代烃试剂有氯乙酸、氯乙醇等，通过甲壳素羟基的取代反应，得到的羧甲基甲壳素、羟乙基甲壳素。常见的环氧类试剂有环氧丙烷等，所得衍生物为羟丙基甲壳素。以上甲壳素衍生物均可通过物理交联形成水凝胶，成为目前研究的热点之一。
发明内容
本发明的目的是发现新的甲壳素衍生物、探索新型的甲壳素水凝胶，制备的羟丁基甲壳素具有在水相良好的分散性，可制备为物理水凝胶，在组织工程、细胞培养、III类医疗器械等方面具有广泛的应用前景。为此，经过发明人的研究和实验结果，提出以下技术方案：
根据本发明的第一个方面，本发明采用以下技术方案：
一种羟丁基甲壳素的制备方法，其特征在于：包括以下步骤：
(1)甲壳素在碱性水溶液中低温静置分散；
(2)将环氧丁烷或稀释后的环氧丁烷加入至甲壳素水相体系，搅拌反应；
(3)反应结束后，经过透析、冻干，得到羟丁基甲壳素。
在采用上述技术方案的基础上，本发明还可采用或组合采用以下的进一步技术方案，以组成各种不同的进一步优化的技术方案：
步骤(1)中，将上甲壳素粉末加入至碱性水溶液后，在-20℃至室温下处理1-30天。
步骤(2)中，在加入至甲壳素碱性水溶液前，环氧丁烷由混合试剂进行稀释，以便调节羟丁基甲壳素的凝胶效果；所述混合试剂包括：甲醇、乙醇、异丙醇、正丁醇的一种或几种(所有醇类试剂占混合试剂的体积分数优选为20％-80％)；纯化水(占混合试剂的体积分数优选为20％-80％)；十二烷基硫酸钠、碘化钠、碘化钾的一种或几种(在混合试剂的总浓度优选为0-0.1g/mL)；氯化锂、氯化钠、氯化钾、氯化铯的一种或几种(在混合试剂的总浓度优选为0-0.1g/mL)。其配制方法为：向环氧丁烷中，按顺序依次加入醇类试剂、纯化水、盐类试剂，搅拌均匀即可使用。
步骤(2)中，将环氧丁烷或稀释后的环氧丁烷加入至甲壳素碱性水溶液中，在0℃-45℃下搅拌反应1-7天。
步骤(3)中，将反应后体系用纯化水稀释1-20倍后透析、冻干。
根据本发明的第二个方面，本发明采用以下技术方案：
一种羟丁基甲壳素水凝胶的制备方法，其特征在于：包括以下制备步骤：
将以上任一制备方法制得的羟丁基甲壳素加入至纯化水，在0℃-30℃下搅拌，待全部溶解后，形成羟丁基甲壳素水凝胶。
根据本发明的第三个方面，本发明采用以下技术方案：
一种羟丁基甲壳素，其特征在于它为采用包括上述制备步骤的制备方法制得的羟丁基甲壳素。
根据本发明的第四个方面，本发明采用以下技术方案：
一种羟丁基甲壳素水凝胶，其特征在于它为采用包括上述步骤的制备方法制得的羟丁基甲壳素水凝胶。
发明人在本发明中尝试用环氧丁烷改性甲壳素，并制备出羟丁基甲壳素及其水凝胶。相比已报导的甲壳素改性试剂，环氧丁烷的疏水性更强，适合于改性比甲壳素更亲水的聚合物(如壳聚糖等)，在甲壳素改性反应与产物纯化中会有更多的困难，比如反应中的相分离、提纯中的不可控沉淀等。然而，考虑到调节甲壳素衍生物亲水性/疏水性平衡，羟丁基甲壳素及其水凝胶会展现出新的性质。羟丁基甲壳素及其水凝胶的研发，对于进一步探索物理水凝胶的凝胶机制，发掘新的甲壳素修饰方法，发现新的甲壳素衍生物水凝胶特性，具有重要的意义。
本发明的羟丁基甲壳素产品为白色海绵状固体，易吸潮。根据实验证明本发明的羟丁基甲壳素在纯化水中具有较好的分散能力，其固含量可在2.0％至2.5％。
以下结合附图和实施例对本发明做出进一步说明。
附图说明
图1是本发明制备的羟丁基甲壳素的红外谱图。
图2是1％质量分数下4种羟丁基甲壳素的水相体系效果图。自左向右依次为羟丁基甲壳素1，羟丁基甲壳素2，羟丁基甲壳素3，羟丁基甲壳素4。
图3是2％质量分数下4种羟丁基甲壳素的水相体系效果图。自左向右依次为羟丁基甲壳素1，羟丁基甲壳素2，羟丁基甲壳素3，羟丁基甲壳素4。
图4是2.5％质量分数下4种羟丁基甲壳素的水相体系效果图。自左向右依次为羟丁基甲壳素1，羟丁基甲壳素2，羟丁基甲壳素3，羟丁基甲壳素4。
具体实施方式
为了进一步理解本发明，下面结合实施例对本发明提供的，一种在水相高度分散甲壳素的制备方法进行具体描述。但本发明并不限于这些实施例，该领域技术人员在本发明核心指导思想下做出的非本质改进和调整，仍然属于本发明的保护范围。
实施例1，甲壳素溶液的制备
(1)甲壳素粉末制备。称取20.00g甲壳素，置于中药粉碎机中，研磨2—5分钟。取出磨碎的甲壳素，依次过20目和50目的筛网，得甲壳素粉末。
(2)碱性水溶液制备。精确称取129.42gNaOH，缓慢、多次加入1L纯化水中。待NaOH完全溶解、体系温度降至常温后，向溶液中加入47.06g尿素，搅拌溶解、冷却至室温。
(3)甲壳素粉末的溶解分散。取1.85g甲壳素粉末，加入至1L碱性水溶液中，搅拌分散。将整个体系浸于-20℃低温介质中，处理24小时。取出后恢复至室温，搅拌1小时，再次浸于-20℃低温介质，低温下静置20天。取出后恢复室温，可得分散较好、粘度较高的甲壳素碱性水溶液。
实施例2，羟丁基甲壳素的制备
通过改变环氧丁烷与混合试剂的体积比，配制4种甲壳素改性试剂。4种试剂依次为：改性试剂1(环氧丁烷体积为100％，混合试剂体积占0％)，改性试剂2(环氧丁烷体积为75％，混合试剂体积占25％)，改性试剂3(环氧丁烷体积为25％，混合试剂体积占75％)，改性试剂4(环氧丁烷体积为0％，混合试剂体积占100％)。
混合试剂的组分、比例如下：醇类试剂占混合试剂的体积比为60％(以下均为每种试剂占混合试剂的体积比)，其中异丙醇20％，乙醇20％，甲醇20％。纯化水体积比为40％。氯化钠浓度为0.01g/mL，碘化钠的浓度为0.01g/mL。
以改性试剂2为例，其配制方法如下：准确量取30mL环氧丁烷，依次向其中加入2mL异丙醇，2mL乙醇，2mL甲醇，搅拌均匀。称取0.1g氯化钠、0.1g碘化钠，依次加入4mL纯化水，搅拌溶解。将氯化钠与碘化钠的纯化水溶液滴加入环氧丁烷与醇类的混合溶液中，搅拌均匀得混合试剂2。按照以上方法制备改性试剂1-4。
取4种改性试剂(每种试剂均为5mL)，分别滴入至50mL实施例1制备的甲壳素溶液中，4℃下搅拌反应2天。改性反应与所得产物的对应关系如下：改性试剂1修饰产物为羟丁基甲壳素1，改性试剂2修饰的产物为羟丁基甲壳素2，改性试剂3修饰的产物为羟丁基甲壳素3，改性试剂4修饰的产物为羟丁基甲壳素4。
实施例3，羟丁基甲壳素的纯化
(1)将实施例2中的水相体系取出，加入150mL纯化水，搅拌均匀。
(2)滤除体系中的不溶物，用5000的纤维素酯透析袋透析，每次透析的纯化水量为5L。每隔4小时换一次水，连续4次；后每隔12小时换一次水，连续6次。
(3)待透析结束，取出袋中液体冻干，得羟丁基甲壳素。羟丁基甲壳素2红外数据如图1所示。
实施例4，羟丁基甲壳素水凝胶的制备
称取一定量的4种羟丁基甲壳素，再加入3.5mL纯化水。分别配制4种羟丁基甲壳素在1％、2％、2.5％质量分数下的体系。室温下震荡3分钟，置于4℃冰箱内静置0.5小时。取出样品，在4℃下搅拌15小时，得稳定的羟丁基甲壳素水相体系。其中，羟丁基甲壳素1的溶解分散时间需12小时以上，其他羟丁基甲壳素的分散溶解时间为5-8小时。
如图2所示，在1％质量分数下，羟丁基甲壳素1形成粘稠的液体，羟丁基甲壳素2、3、4形成流动性好的溶液。室温下放置14天后，羟丁基甲壳素4体系中出现絮状沉淀。
如图3所示，在2％质量分数下，羟丁基甲壳素1、2形成水凝胶，羟丁基甲壳素3、4形成流动性好的溶液。羟丁基甲壳素1所需分散时间较长(12小时左右)。室温下放置14天后，羟丁基甲壳素1水凝胶会渗出少量纯化水，凝胶稳定性不高；羟丁基甲壳素4体系中出现絮状沉淀。
如图4所示，继续增加质量分数到2.5％，羟丁基甲壳素1、2、3形成水凝胶，羟丁基甲壳素4形成流动性好的溶液。羟丁基甲壳素1所需分散时间仍然较长(12小时左右)。室温下放置14天后，羟丁基甲壳素1水凝胶会渗出少量纯化水，凝胶稳定性不理想；羟丁基甲壳素4体系中出现絮状沉淀。
综合考虑羟丁基甲壳素的分散时间、固含量、以及水凝胶稳定性，羟丁基甲壳素2的表现较优，在2％-2.5％固含量下，通过5-8小时形成羟丁基甲壳素水凝胶。
结论：
本发明将甲壳素进行分散，得到分散性良好的甲壳素碱性水相体系。向其中加入环氧丁烷或稀释后的环氧丁烷，对甲壳素进行改性。经过对样品体系的稀释、透析、冻干得到新的羟丁基甲壳素。羟丁基甲壳素可以在2％-2.5％的固含量下，形成均一稳定的物理交联水凝胶。羟丁基甲壳素水凝胶将进一步开发为新型的组织工程支架等可降解材料，在III类医疗器械领域发挥重要的作用。
Claims (8)
1.一种羟丁基甲壳素的制备方法，其特征在于：包括以下步骤：
(1)甲壳素在碱性水溶液中低温分散；
(2)将环氧丁烷加入至甲壳素水相体系，搅拌反应；
(3)反应结束后，经过透析、冻干，得到羟丁基甲壳素。
2.根据权利要求1所述的羟丁基甲壳素制备方法，其特征在于：步骤(2)中，将环氧丁烷加入至甲壳素碱性水溶液中，在0℃-45℃下搅拌反应1-7天。
3.根据权利要求1或2所述的羟丁基甲壳素制备方法，其特征在于：步骤(2)中，在加入至甲壳素碱性水溶液前，环氧丁烷由混合试剂进行稀释，以便调节羟丁基甲壳素的凝胶效果；所述混合试剂包括：甲醇、乙醇、异丙醇、正丁醇的一种或几种，纯化水，十二烷基硫酸钠、碘化钠、碘化钾的一种或几种，氯化锂、氯化钠、氯化钾、氯化铯的一种或几种。
4.根据权利要求3所述的羟丁基甲壳素制备方法，其特征在于：所有醇类试剂占混合试剂的体积分数为20％-80％，纯化水占混合试剂的体积分数为20％-80％；所述十二烷基硫酸钠、碘化钠、碘化钾的一种或几种在混合试剂的总浓度为0-0.1g/mL；所述氯化锂、氯化钠、氯化钾、氯化铯的一种或几种在混合试剂的总浓度为0-0.1g/mL。
5.根据权利要求1所述的羟丁基甲壳素制备方法，其特征在于：步骤(3)中，将反应后体系用纯化水稀释1-20倍后透析、冻干。
6.一种羟丁基甲壳素水凝胶的制备方法，其特征在于：包括以下制备步骤：
将权利要求1至5之任一所述制备方法制得的羟丁基甲壳素加入至纯化水，在0℃-30℃下搅拌，待全部溶解后，形成羟丁基甲壳素水凝胶。
7.一种羟丁基甲壳素，其特征在于它为采用包括权利要求1至5之任一所述制备方法制得的羟丁基甲壳素。
8.一种羟丁基甲壳素水凝胶，其特征在于它为采用包括权利要求6所述制备步骤的制备方法制得的羟丁基甲壳素水凝胶。
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