CN108976758B - 一种光敏性聚乙二醇基抗菌水凝胶敷料及其制备方法 - Google Patents
一种光敏性聚乙二醇基抗菌水凝胶敷料及其制备方法 Download PDFInfo
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- polyethylene glycol
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 18
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Abstract
本发明涉及一种光敏性聚乙二醇基抗菌水凝胶敷料及其制备方法，该敷料是在聚乙二醇水凝胶基体上共价接枝有抗生素。其制备方法包括：将小分子抗生素通过紫外光可断裂分子修饰到末端带双键的聚乙二醇大分子链，得到紫外光可断裂的聚乙二醇基大分子，与未修饰的含末端双键的聚乙二醇分子共混作为单体，在交联剂、引发剂作用下通过热引发双键交联制备得到具有光敏性抗菌性能的水凝胶敷料。本发明的原料具有良好的生物形容性，得到的水凝胶敷料具有一定的力学性能和吸水溶胀性能，且在365nm波长的紫外光照射下能够实现抗生素的有效控制释放，具备良好的紫外光响应性抗菌性能，适用于创面的保护和感染治疗。
Description
技术领域
本发明涉及水凝胶敷料及其制备方法，特别涉及一种光敏性聚乙二醇基抗菌水凝胶敷料及其制备方法。
背景技术
皮肤是人体最大的器官，日常生活中主要起到调节体温，保护内部器官免受物理化学的损伤，提供物理屏障的作用。然而皮肤大面积暴露在外，日产生活中极易受到各种各样的损伤，如机械创伤、烧伤、慢性溃疡等。皮肤的修复及再生是临床上的一项重大难题，同时创面护理过程中由微生物等导致的创面感染是最常见的并发症，严重者可导致死亡。目前创面护理过程中最常用的手段是伤口敷料，如纱布、碘片及负载抗菌剂的敷料材料等，这些伤口敷料在为创面提供物理屏障保护创面免受进一步损伤的同时也能够为创面提供湿润的环境加快创面愈合。针对创面感染，以载抗生素的伤口敷料最为常用。传统的抗菌伤口敷料，抗生素大多通过自由扩散的方式作用于创面，因此实际应用中无法控制抗生素的用量，同时为了达到有效抗菌浓度，往往需要增加抗生素的用量，抗生素的大量使用不仅会导致细菌的耐药性，也会损坏正常的组织和器官。另外，频繁的更换伤口敷料也会给病人带来极大痛苦。因此，发展新型的伤口敷料材料，实现抗生素的有效控制释放，避免抗生素大量使用带来的副作用，对创面护护理及伤口修复具有重大意义。近年来，刺激响应性材料在组织工程、药物传递领域取得了广泛应用，包括温度响应、pH响应、光响应、磁响应、酶响应及氧化还原响应等。其中光由于其高效、便捷、可远程操控等优点在肿瘤治疗、纳米成像等领域具有其独特的优势。然而利用光在创面部位实现抗生素的传递却少有研究。因此，本发明利用紫外光的独特优势，实现抗生素在创面部位的有效控制释放。
发明内容
本发明的目的是提供一种光敏性聚乙二醇基抗菌水凝胶敷料及其制备方法，该敷料具有紫外光响应的抗菌特性，能够实现抗生素的控制释放，避免抗生素大量使用带来的副作用。
本发明的水凝胶敷料中抗生素通过共价作用接枝到基体上；其中水凝胶由改性的聚乙二醇丙烯酸酯与未改性的聚乙二醇丙烯酸酯共混作为单体在交联剂、引发剂的作用下通过热引发双键交联得到
本发明所用的抗生素为氨基糖苷类的硫酸庆大霉素，其在水凝胶中的负载方式为共价接枝。
水凝胶敷料制备方法中所用的改性聚乙二醇丙烯酸酯为庆大霉素通过紫外光可断裂的苄硝基分子共价修饰到聚乙烯醇丙烯酸酯上。具体步骤如下：
第一步：将硫酸庆大霉素和紫外光可断裂的苄硝基分子溶解于四氢呋喃和水的混合溶剂中，在混合溶液中加入少量三乙胺，室温条件下避光反应12h；
第二步：反应结束后，将反应液加入溶解有叠氮聚乙二醇丙烯酸酯的四氢呋喃溶液中搅拌混合均匀，混合溶液通氮气除氧后，加入催化剂抗坏血酸钠和硫酸铜，氮气环境下避光进行点击反应。12h后，将溶剂旋干，溶于水中，过滤除去不溶物，透析袋透析三天后冻干得到改性的聚乙二醇丙烯酸酯。
所述的改性的聚乙二醇丙烯酸酯与未改性的聚乙二醇丙烯酸酯共混，其共混比例为7:1(w/w)。
本发明所用的交联剂为聚乙二醇双丙烯酸酯(DAPEGDA)，分子量2000，所用的引发剂为过硫酸铵(APS)和四甲基乙二胺(TEMED)
所述的热引发的温度为90℃，交联时间为30min。
本发明中所用的紫外光可断裂的苄硝基分子制备方法如下：第一步：将4-羟基-5-甲氧基-邻硝基苯乙酮与碳酸钾溶于无水乙腈混合，加入3-溴丙炔，100℃氮气氛围下回流反应3h，将反应液旋蒸浓缩后，加盐酸水溶液溶解，用三氯甲烷萃取3次，得有机层，再用硫酸镁干燥过滤，减压干燥得到的微黄色固体。
第二步：将上步产物溶于四氢呋喃甲醇混合溶剂中，加入硼氢化钠，冰浴下搅拌3h，将反应液旋蒸浓缩后，加盐酸水溶液溶解，用三氯甲烷萃取3次，得有机层，再用硫酸镁干燥过滤，减压干燥得到的微黄色固体。
第三步：将上步产物溶于无水乙腈中，加入N,N'-二琥珀酰亚胺基碳酸酯，并在反应液中加入少量三乙胺，氮气氛围下室温搅拌5h。将反应液旋蒸浓缩后，加盐酸水溶液溶解，用三氯甲烷萃取3次，得有机层，再用饱和碳酸氢钠清洗三次，硫酸镁干燥，过滤，减压干燥得到所需的紫外光可断裂的苄硝基分子。
所述的改性聚乙二醇丙烯酸酯制备方法中用的硫酸庆大霉素：紫外光可断裂的苄硝基：叠氮聚乙二醇丙烯酸酯＝1.2:1:1(摩尔比)。
本发明的原料具有良好的生物形容性，得到的水凝胶敷料具有一定的力学性能和吸水溶胀性能，且在365nm波长的紫外光照射下能够实现抗生素的有效控制释放，具备良好的紫外光响应性抗菌性能，适用于创面的保护和感染治疗。
附图说明
图1为光敏性聚乙二醇基抗菌水凝胶敷料的抗菌机理示意图；
图2为改性聚乙二醇丙烯酸酯合成路线图；
图3为实施例1中该水凝胶敷料的宏观(A1,A2)和微观(A3,A4)结构图；
图4为实施例1和4中制得水凝胶敷料的生物相容性分析图；
图5为实施例1和4中制得水凝胶敷料的体外光照不同时间的抑菌圈效果图(a)和抑菌圈直径统计分析(b)。
具体实施方式
下面结合实例对本发明作详细说明。
实例1
a)紫外光可断裂的苄硝基分子合成
第一步：将0.5g(2.36mmol)4-羟基-5-甲氧基-邻硝基苯乙酮与0.476g(3.44mmol)碳酸钾溶于25mL无水乙腈(先氢化钙除水)混合，加入0.28ml(3.64mmol)3-溴丙炔，100℃氮气氛围下回流反应3h，将反应液旋蒸浓缩后，加50mL水和5mL 2M HCl溶解，用3*50mL三氯甲烷萃取3次，得有机层，用硫酸镁进行干燥，过滤，减压干燥得到的微黄色固体。
第二步：将上步产物0.57g溶于20ml四氢呋喃和40ml的甲醇混合溶剂中，加入0.69g(13.728mmol)硼氢化钠，冰浴下搅拌3h，将反应液旋蒸浓缩后，加50mL水和5mL 2MHCl，用3*50mL三氯甲烷萃取3次，得有机层，用硫酸镁进行干燥过滤，减压干燥得到的微黄色固体。
第三步：将上步产物0.55g溶于25ml无水乙腈中，加入1.68g(6.57mmol)N,N'-二琥珀酰亚胺基碳酸酯，并在反应液中加入1mL(4mmol)三乙胺，氮气氛围下室温搅拌5h。将反应液旋蒸浓缩后，加30mL水和5mL 2M HCl，用3*50mL三氯甲烷萃取3次，得有机层，再用饱和碳酸氢钠3*100mL清洗三次，再用硫酸镁干燥，过滤，减压干燥得到所需的紫外光可断裂的苄硝基分子。
b)改性聚乙二醇丙烯酸酯合成
第一步:取127mg(220μmol)硫酸庆大霉素和85mg(200μmol)紫外光可断裂的苄硝基分子溶解于24ml四氢呋喃和水的混合溶剂中(2：1v/v)，在混合溶液中加入1ml三乙胺，室温条件下避光反应12h；
第二步：反应结束后，将反应液加入溶解有1g叠氮聚乙二醇丙烯酸酯的50ml四氢呋喃溶液中搅拌混合均匀，混合溶液通氮气除氧0.5h后，加入催化剂抗坏血酸钠200μl(0.1M,乙炔基团的10mol％)，硫酸铜100μl(0.1M,乙炔基团的5mol％)，氮气环境下避光进行点击反应。12h后，将溶剂旋干，溶于水中，过滤除去不溶物，截留分子量3500的透析袋透析三天后冻干得到改性的聚乙二醇丙烯酸酯。
c)光敏性聚乙二醇基抗菌水凝胶敷料的制备(50％)
200mg聚乙二醇丙烯酸酯(150mg未改性聚乙二醇丙烯酸酯+50mg改性聚乙二醇丙烯酸酯)溶于1ml PBS中，加入100mg的交联剂聚乙二醇双丙烯酸酯，然后加入60μl APS(100mg/ml)与60μl TEMED(8mg/ml)，溶液混合均匀后90℃加热30min成胶。PBS反复漂洗除掉过量引发剂备用。
实例2
光敏性聚乙二醇基抗菌水凝胶敷料的制备(25％)
200mg聚乙二醇丙烯酸酯(150mg未改性聚乙二醇丙烯酸酯+50mg改性聚乙二醇丙烯酸酯)溶于1mlPBS中，加入50mg的交联剂聚乙二醇双丙烯酸酯，然后加入50μl APS(100mg/ml)与50μl TEMED(8mg/ml)，溶液混合均匀后90℃加热30min成胶。PBS反复漂洗除掉过量引发剂备用。
实例3
光敏性聚乙二醇基抗菌水凝胶敷料的制备(75％)
200mg聚乙二醇丙烯酸酯(150mg未改性聚乙二醇丙烯酸酯+50mg改性聚乙二醇丙烯酸酯)溶于1ml PBS中，加入150mg的交联剂聚乙二醇双丙烯酸酯，然后加入70μl APS(100mg/ml)与70μl TEMED(8mg/ml)，溶液混合均匀后90℃加热30min成胶。PBS反复漂洗除掉过量引发剂备用。
实例4
无光敏性聚乙二醇基抗菌水凝胶敷料的制备(25％)
200mg未改性的聚乙二醇丙烯酸酯溶于1ml PBS中，加入50mg的交联剂聚乙二醇双丙烯酸酯，然后加入60μl APS(100mg/ml)与60μl TEMED(8mg/ml)，溶液混合均匀后90℃加热30min成胶。PBS反复漂洗除掉过量引发剂备用。
Claims (5)
1.一种光敏性聚乙二醇基抗菌水凝胶敷料，其特征在于，该水凝胶敷料中含抗生素，且抗生素通过共价作用接枝到基体上 ；所述的水凝胶由改性的聚乙二醇丙烯酸酯与未改性的聚乙二醇丙烯酸酯共混作为单体在交联剂、引发剂的作用下通过热引发双键交联得到；所述的改性的聚乙二醇丙烯酸酯为硫酸庆大霉素通过紫外光可断裂的苄硝基分子共价接枝修饰到叠氮聚乙二醇丙烯酸酯上；所述的紫外光可断裂的苄硝基分子为1-（5-甲氧基-2-硝基-4-丙-2-炔氧基苯基）乙基N-琥珀酰亚胺碳酸酯。
2.根据权利要求1所述的一种光敏性聚乙二醇基抗菌水凝胶敷料，其特征在于，所述的改性聚乙二醇丙烯酸酯为硫酸庆大霉素通过紫外光可断裂的苄硝基分子共价接枝修饰到叠氮聚乙二醇丙烯酸酯上，其制备方法如下：
第一步：将硫酸庆大霉素和紫外光可断裂的苄硝基分子溶解于四氢呋喃和水的混合溶剂中，在混合溶液中加入三乙胺，室温条件下避光反应12h；
第二步：反应结束后，将反应液加入溶解有叠氮聚乙二醇丙烯酸酯的四氢呋喃溶液中搅拌混合均匀，混合溶液通氮气除氧后，加入催化剂抗坏血酸钠和硫酸铜，氮气环境下避光进行点击反应，12h后，将溶剂旋干，溶于水中，过滤除去不溶物，透析袋透析三天后冻干得到改性的聚乙二醇丙烯酸酯。
3.根据权利要求2所述的一种光敏性聚乙二醇基抗菌水凝胶敷料，其特征在于，所述的紫外光可断裂的苄硝基分子其制备方法包括以下步骤：
第一步：将4-羟基-5-甲氧基-邻硝基苯乙酮与碳酸钾溶于无水乙腈混合，加入3-溴丙炔，100℃氮气氛围下回流反应3h，将反应液旋蒸浓缩后，加盐酸水溶液溶解，用三氯甲烷萃取3次，得有机层，再用硫酸镁干燥过滤，减压干燥得到的微黄色固体；
第二步：将上步产物溶于四氢呋喃甲醇混合溶剂中，加入硼氢化钠，冰浴下搅拌3h，将反应液旋蒸浓缩后，加盐酸水溶液溶解，用三氯甲烷萃取3次，得有机层，再用硫酸镁干燥过滤，减压干燥得到的微黄色固体；
第三步：将上步产物溶于无水乙腈中，加入N,N'-二琥珀酰亚胺基碳酸酯，并在反应液中加入三乙胺，氮气氛围下室温搅拌5h；将反应液旋蒸浓缩后，加盐酸水溶液溶解，用三氯甲烷萃取3次，得有机层，再用饱和碳酸氢钠清洗三次，硫酸镁干燥，过滤，减压干燥得到所需的紫外光可断裂的苄硝基分子。
4.根据权利要求1所述的一种光敏性聚乙二醇基抗菌水凝胶敷料，其特征在于，所用的交联剂为聚乙二醇双丙烯酸酯（DAPEGDA），分子量 2000，所用的引发剂为过硫酸铵（APS）和四甲基乙二胺（TEMED）。
5.根据权利要求1所述的一种光敏性聚乙二醇基抗菌水凝胶敷料，其特征在于，热引发的温度为90℃，交联时间为30min。
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