CN113425893A - 一种载药水凝胶的制备方法及其应用 - Google Patents

一种载药水凝胶的制备方法及其应用 Download PDF

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CN113425893A
CN113425893A CN202110845568.3A CN202110845568A CN113425893A CN 113425893 A CN113425893 A CN 113425893A CN 202110845568 A CN202110845568 A CN 202110845568A CN 113425893 A CN113425893 A CN 113425893A
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hydrogel
gelatin
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protocatechuic acid
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张琨
梁嘉恒
关帅猛
李敬安
关方霞
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Zhengzhou University
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Abstract

本发明公开了一种载药水凝胶的制备方法及其应用，该方法步骤A为氧化葡聚糖的制备：葡聚糖单体有大量的羟基；步骤B为接枝有原儿茶酸的明胶的制备；步骤C为可注射水凝胶的制备：将氧化葡聚糖溶液和接枝原儿茶酸的明胶溶液混合，通过席夫碱反应交联成胶，得到GT‑PCA/Odex水凝胶。该水凝胶可应用于可在急性皮肤损伤病灶处、糖尿病皮肤损伤病灶处或烧伤皮肤损伤病灶处构建一种多功能水凝胶敷料，该水凝胶具有良好的多种性能，可明显促进伤口愈合。

Description

一种载药水凝胶的制备方法及其应用
技术领域
本发明涉及氧化葡聚糖的制备技术，具体涉及一种载药水凝胶的制备方法及其应用。
背景技术
皮肤是保护人体的重要屏障，而皮肤损伤愈合是目前临床医学急需解决的问题之一。皮肤损伤包括急性伤口和慢性伤口，急性伤口是一种通过有序的阶段愈合的伤口，往往愈合较快。慢性伤口是指在愈合过程中因为过度和长期的炎症和缺血，伤口不能正常愈合并且容易被感染，需要长期护理的伤口。而急性伤口的数量比慢性伤口更多。正常有序的伤口愈合包括止血、炎症、增殖和重塑四个典型阶段，其中涉及多种细胞、细胞因子和细胞外基质。对创面的止血、炎症、增殖和重塑进行有效干预可以促进创面愈合的进程。
水凝胶作为一种独特的皮肤组织工程创面敷料，已成为近几十年来的研究热点。它含有大量的水分，在为患者缓解疼痛的同时，为愈合提供了一个湿润的环境。此外，其结构和组成与天然细胞外基质相似，有利于诱导组织再生。明胶(Gelatin)是一种可生物降解的蛋白质衍生物。具有独特的生物相容性、生物降解性、无毒性、可塑性和粘着性等优点。此外，由于其非免疫原性、细胞粘附性和凝血特性，被认为有利于伤口愈合。明胶能激活血小板，介导血小板聚集，从而提高止血效率。并且其在体内降解过程中产生的炎症反应最小，能支持细胞粘附，促进细胞增殖。葡聚糖(Dextran)是一种具有生物相容性的细菌多糖，多羟基的结构赋予其良好的亲水性和反应活性，在生物医学领域有着广泛的应用。优点是具有良好的细胞培养效果，可降解性。氧化葡聚糖(Oxidized-dextran, Odex)是葡聚糖通过简单化学方法氧化得到的多醛基物质，易与含氨基大分子发生席夫碱反应成胶。优点是成胶快速且方法简单，不引入有毒交联剂，光引发剂或酶。原儿茶酸( Protocatechuic acid,PCA) 是一种水溶性酚酸成分，并且是很多中药的活性物质，其不仅具有抑菌、抗炎、镇痛等药理活性，还具有抗氧化、抗肿瘤和神经保护作用。
发明内容
针对现有技术中存在的上述问题，本发明提供一种载药水凝胶的制备方法及其应用，通过该方法以明胶、原儿茶酸和氧化葡聚糖为原材料构建了一种兼具可注射性、止血性、抗氧化性和良好细胞相容性的新型水凝胶，对于皮肤损伤修复及功能重建具有重要意义。
为了解决上述技术问题，本发明提供了一种载药水凝胶的制备方法，包括以下步骤：
步骤A、氧化葡聚糖的制备：
1)将1g葡聚糖溶解在的50ml去离子水中得到葡聚糖溶液；向葡聚糖溶液中滴加2-2.7g高碘酸钠溶液室温下避光反应3-5h，其中葡聚糖溶液的葡聚糖单体与高碘酸钠摩尔比为1：（1.5-2）；
2)反应结束后，滴加1ml乙二醇终止反应，然后将反应液利用透析分子量8000D的透析袋透析3天后，取溶液放置于-80℃温度下冷冻24 h，最后使用冷冻干燥机处理1-2天可得白色饼状物，即为带有醛基的氧化葡聚糖；
步骤B、接枝原儿茶酸的明胶的制备：
1)将2g-4g明胶溶解在的50ml去离子水中于40℃搅拌得到明胶溶液，调PH 4-5；将1g-1.5g原儿茶酸溶解在的50ml去离子水中得到原儿茶酸溶液，调PH 4-5；
2)向明胶溶液中充入氮气30min，同时在原儿茶酸溶液中加入1g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸(EDC)和0.6g N-羟基琥珀酰亚胺(NHS)活化30min，将活化后的原儿茶酸溶液加入到明胶溶液中继续充氮气30min，然后封口隔绝外界空气磁力搅拌反应24h，将反应液利用透析分子量8000D的透析袋透析3天后，取溶液放置于-80℃冰箱中冷冻12 h，最后使用冷冻干燥机处理2天可得灰白色饼状物，即为接枝原儿茶酸的明胶；
步骤C、载药水凝胶的制备：
1)先采用去离子水制备浓度为2%的氧化葡聚糖溶液；同时采用去离子水配置浓度梯度依次为0.6%-1.4%的接枝原儿茶酸的明胶溶液；
2）然后按照体积比1：1的反应体系将明胶溶液与不同氧化葡聚糖溶液吹打均匀，制备过程中避免气泡的产生，通过席夫碱反应交联制备出载药水凝胶。
如上述的载药水凝胶的制备方法，步骤A中通过高碘酸钠将葡聚糖进行氧化，采用滴定法测定葡聚糖的氧化率；核磁共振氢谱测定氧化葡聚糖醛基的化学位移。
如上述的载药水凝胶的制备方法，步骤A中得到的氧化葡聚糖够与斐林试剂产生砖红色沉淀。
2.如上述的载药水凝胶的制备方法的方法，载药水凝胶应用于可在急性皮肤损伤病灶处构建一种多功能水凝胶敷料，还可以在病症较轻微的慢性皮肤损病灶处构建一种多功能水凝胶敷料。
如上述的载药水凝胶的应用，载药水凝胶应用于促进肤伤口愈合，席夫碱反应交联成胶过程，水凝胶反应时间保持在15min以内，满足可注射操作。
本发明的过程和机理主要分为三个部分。第一部分为氧化葡聚糖的制备：葡聚糖单体有大量的羟基，通过与高碘酸钠反应，羟基可以被氧化为醛基，然后透析冷冻干燥得到氧化葡聚糖；第二部分为接枝原儿茶酸的明胶的制备：原儿茶酸单体上具有羧基，通过与1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸和 N-羟基琥珀酰亚胺反应，羧基被活化，与明胶单体上的氨基结合形成酰胺键，然后透析冷冻干燥得到接枝原儿茶酸的明胶；第三部分为可注射水凝胶的制备：将接枝原儿茶酸的明胶和氧化葡聚糖溶液混合，通过席夫碱反应交联成胶，该水凝胶具有良好的多种性能，可明显促进伤口愈合。
与现有技术相比，本发明可以获得包括以下技术效果：
1、所制备的新型多功能水凝胶支架兼具可注射性、止血性、抗氧化性和良好细胞相容性，可以有效促进皮肤伤口愈合，为皮肤组织工程的研究开辟新思路，对于皮肤损伤修复及功能重建具有重要意义。
2、该水凝胶支架的制备工艺简单易操作，成胶速度可控，不引入有毒交联剂，光引发剂或酶。无需昂贵复杂的设备，工艺成本较低，效果显著。
附图说明
图1为氧化葡聚糖的制备原理图；
图2为接枝原儿茶酸的明胶的制备原理图；
图3为本发明方法中水凝胶成胶原理示意图；
图4为氧化葡聚糖核磁图；
图5为接枝原儿茶酸的明胶核磁图；
图6为水凝胶成胶示意图:；
图7为水凝胶的自愈合性；
图8为不同浓度接枝原儿茶酸的明胶水凝胶的成胶时间；
图9为不同浓度接枝原儿茶酸的明胶水凝胶的含水率；
图10为不同浓度接枝原儿茶酸的明胶水凝胶溶血率；
图11为水凝胶止血性；
图12为不同浓度接枝原儿茶酸的明胶水凝胶抗氧化性；
图13为水凝胶可注射性及微观结构；
图14为不同浓度接枝原儿茶酸的明胶水凝胶对L929成纤维细胞的细胞相容性；
图15为不同浓度接枝原儿茶酸的明胶水凝胶的降解速率。
具体实施方式
以下将配合实施例来详细说明本发明的实施方式，藉此对本发明如何应用技术手段来解决技术问题并达成技术功效的实现过程能充分理解并据以实施。
实施例1
参见图1、图2与图3，本发明的第一种具体实施方式是，基于急性皮肤损伤，例如锐器伤和钝器伤等机械损伤和术后伤口。采用氧化葡聚糖和接枝原儿茶酸的明胶，通过醛基与氨基发生席夫碱反应，制备出可注射水凝胶。在急性皮肤损伤病灶处构建一种多功能水凝胶敷料，其步骤为：
A、氧化葡聚糖的制备：将1g葡聚糖溶解在的50ml去离子水中得到葡聚糖溶液；向葡聚糖溶液中加入2g高碘酸钠粉末室温下避光反应4h，其中葡聚糖溶液的葡聚糖单体与高碘酸钠摩尔比为1：1.5；反应结束后，滴加1ml乙二醇终止反应1h，然后将反应液利用透析分子量8000D的透析袋透析3天后，取溶液放置于-80℃冰箱中冷冻12 h，最后使用冷冻干燥机处理2天可得白色棉状物，待用；
B、接枝原儿茶酸的明胶的制备：将4g明胶溶解在的50ml去离子水中于40℃磁力搅拌得到明胶溶液，调PH 4-5；将1g原儿茶酸溶解在的50ml去离子水中得到原儿茶酸溶液，调PH 4-5；向明胶溶液中充入氮气30min，同时在PCA溶液中加入1g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸(EDC)和0.6g N-羟基琥珀酰亚胺(NHS)活化30min，将活化后的PCA溶液加入到明胶溶液中继续充氮气30min，然后封口隔绝外界空气磁力搅拌反应24h，将反应液利用透析分子量8000D的透析袋透析3天后，取溶液放置于-80℃冰箱中冷冻12 h，最后使用冷冻干燥机处理2天可得灰白色饼状物，待用；
C、在急性皮肤损伤病灶部位构建可注射水凝胶伤口敷料：将氧化葡聚糖和接枝原儿茶酸的明胶灭菌处理；配置2%的氧化葡聚糖溶液和12%的接枝原儿茶酸的明胶溶液，完全溶解后按照体积比1：1的反应体系将两种溶液混合吹打均匀，注射到急性皮肤损伤病灶部位，静置10min后形成GT-PCA/Odex水凝胶伤口敷料，水凝胶敷料要定期更换来避免伤口感染，提高治疗效果。
实施例2
参见图1、图2与图3，本发明的第一种具体实施方式是，基于病症较轻微的慢性皮肤损伤修复，例如糖尿病足溃疡、褥疮和腿部静脉溃疡。采用氧化葡聚糖和接枝原儿茶酸的明胶，通过醛基与氨基发生席夫碱反应，制备出可注射水凝胶。在慢性皮肤损伤病灶处构建一种多功能水凝胶敷料，其步骤为：
A、氧化葡聚糖的制备：将1g葡聚糖溶解在的50ml去离子水中得到葡聚糖溶液；向葡聚糖溶液中加入2g高碘酸钠粉末室温下避光反应4h，其中葡聚糖溶液的葡聚糖单体与高碘酸钠摩尔比为1：1.5；反应结束后，滴加1ml乙二醇终止反应1h，然后将反应液利用透析分子量8000D的透析袋透析3天后，取溶液放置于-80℃冰箱中冷冻12 h，最后使用冷冻干燥机处理2天可得白色棉状物，待用；
B、接枝原儿茶酸的明胶的制备：将3g明胶溶解在的50ml去离子水中于40℃磁力搅拌得到明胶溶液，调PH 4-5；将1.5g原儿茶酸溶解在的50ml去离子水中得到原儿茶酸溶液，调PH 4-5；向明胶溶液中充入氮气30min，同时在PCA溶液中加入1g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸(EDC)和0.6g N-羟基琥珀酰亚胺(NHS)活化30min，将活化后的PCA溶液加入到明胶溶液中继续充氮气30min，然后封口隔绝外界空气磁力搅拌反应24h，将反应液利用透析分子量8000D的透析袋透析3天后，取溶液放置于-80℃冰箱中冷冻12 h，最后使用冷冻干燥机处理2天可得灰白色饼状物，待用；
C、在慢性皮肤损伤病灶部位构建可注射水凝胶伤口敷料：将氧化葡聚糖和接枝原儿茶酸的明胶灭菌处理；配置2%的氧化葡聚糖溶液和12%的接枝原儿茶酸的明胶溶液，完全溶解后按照体积比1：1的反应体系将两种溶液混合吹打均匀，注射到慢性皮肤损伤病灶部位，静置10min后形成GT-PCA/Odex水凝胶伤口敷料，水凝胶敷料要定期更换来避免伤口感染，提高治疗效果。
本发明可用其他的不违背本发明的精神或主要特征的具体形式来概述。因此，无论从哪一点来看，本发明的上述实施方案都只能认为是对本发明的说明而不能限制发明，权利要求书指出了本发明的范围，而上述的说明并未指出本发明的范围，因此，在与本发明的权利要求书相当的含义和范围内的任何变化，都应认为是包括在权利要求书的范围内。

Claims (5)

1.一种载药水凝胶的制备方法，其特征在于，包括以下步骤：
步骤A、氧化葡聚糖的制备：
将1g葡聚糖溶解在的50ml去离子水中得到葡聚糖溶液；向葡聚糖溶液中滴加2-2.7g高碘酸钠溶液室温下避光反应3-5h，其中葡聚糖溶液的葡聚糖单体与高碘酸钠摩尔比为1：（1.5-2）；
反应结束后，滴加1ml乙二醇终止反应，然后将反应液利用透析分子量8000D的透析袋透析3天后，取溶液放置于-80℃温度下冷冻24 h，最后使用冷冻干燥机处理1-2天可得白色饼状物，即为带有醛基的氧化葡聚糖；
步骤B、接枝原儿茶酸的明胶的制备：
将2g-4g明胶溶解在的50ml去离子水中于40℃搅拌得到明胶溶液，调PH 4-5；将1g-1.5g原儿茶酸溶解在的50ml去离子水中得到原儿茶酸溶液，调PH 4-5；
向明胶溶液中充入氮气30min，同时在原儿茶酸溶液中加入1g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸(EDC)和0.6g N-羟基琥珀酰亚胺(NHS)活化30min，将活化后的原儿茶酸溶液加入到明胶溶液中继续充氮气30min，然后封口隔绝外界空气磁力搅拌反应24h，将反应液利用透析分子量8000D的透析袋透析3天后，取溶液放置于-80℃冰箱中冷冻12 h，最后使用冷冻干燥机处理2天可得灰白色饼状物，即为接枝原儿茶酸的明胶；
步骤C、载药水凝胶的制备：
1)先采用去离子水制备浓度为2%的氧化葡聚糖溶液；同时采用去离子水配置浓度梯度依次为0.6%-1.4%的接枝原儿茶酸的明胶溶液；
2）然后按照体积比1：1的反应体系将明胶溶液与不同氧化葡聚糖溶液吹打均匀，制备过程中避免气泡的产生，通过席夫碱反应交联制备出载药水凝胶。
2.据权利要求1所述的载药水凝胶的制备方法，其特征在于，步骤A中通过高碘酸钠将葡聚糖进行氧化，采用滴定法测定葡聚糖的氧化率；核磁共振氢谱测定氧化葡聚糖醛基的化学位移。
3.根据权利要求1所述的载药水凝胶的制备方法，其特征在于，步骤A中得到的氧化葡聚糖够与斐林试剂产生砖红色沉淀。
4.根据权利要求1所述的载药水凝胶的制备方法的方法，其特征在于，载药水凝胶应用于可在急性皮肤损伤病灶处构建一种多功能水凝胶敷料，还可以在病症较轻微的慢性皮肤损病灶处构建一种多功能水凝胶敷料。
5.根据权利要求1所述的载药水凝胶的应用，其特征在于，载药水凝胶应用于促进肤伤口愈合，席夫碱反应交联成胶过程，水凝胶反应时间保持在15min以内，满足可注射操作。
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