CN112007209B - 一种cs/qcs/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料及其制备方法 - Google Patents
一种cs/qcs/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种CS/QCS/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料及其制备方法，该敷料具有双重抵抗细菌粘附，双重接触杀灭细菌，盐响应释放死菌，从而有效抵抗细菌生物被膜形成的作用；首先通过环氧开环反应制得一定接枝度的季铵化壳聚糖，自由基共聚合反应制得一定共聚比的环氧化两性离子；然后将壳聚糖(CS)在水相中溶解后，再依次加入季铵化壳聚糖、两性离子、AAm、MBAA和APS，离心脱泡后浇筑，一锅法反应制得凝胶；最后将该凝胶浸泡在环氧化两性离子溶液中，并加入TEA，在烘箱中反应一段时间后即可制得一种具有双重抵抗细菌粘附，双重接触杀灭细菌，盐响应释放死菌的抗杀释菌一体化凝胶敷料，有望用于创伤感染的治疗。
Description
技术领域
本发明属于医用凝胶敷料领域，具体涉及一种壳聚糖/季铵化壳聚糖/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料及其制备方法。
背景技术
日常生活中的创伤如划伤、擦伤、烧伤等频繁发生，创伤引发的细菌感染问题困扰着病患的生活。在创伤期间，起临时性皮肤屏障作用的创伤敷料必须具备一定的抗细菌感染功能。而针对细菌，只具有单一抗或杀功能的敷料如今已经愈发不能满足临床使用的要求。抗杀一体化的敷料可以更好的发挥抵抗细菌感染的效用，同时延长敷料的使用时间，降低更换频次，减少感染部位不必要的二次损伤。且即使敷料同时具备抗杀功能，当使用一段时间后，敷料表面的死菌及其分泌的物质极易阻挡敷料和后来细菌的充分接触，从而无法进一步持续发挥敷料抗杀功能，极易逐渐形成难以清除的细菌生物被膜。因此赋予敷料响应性释放死菌的功能，对于现有的敷料极其重要。
发明内容
本发明的目的是解决创伤界面细菌感染问题，提供一种壳聚糖/季铵化壳聚糖/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料及其制备方法，通过两性离子和环氧化两性离子的双重抵抗细菌粘附，壳聚糖和季铵化壳聚糖的双重接触杀灭细菌，盐响应释放死菌，实现凝胶敷料的抗-杀-释一体化。
本发明通过以下技术方案实现：
一种壳聚糖/季铵化壳聚糖/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料，采用如下方法制得：
通过环氧开环反应制得季铵化壳聚糖(QCS)，所述的环氧开环反应功能单体为氯化缩水甘油三甲基胺，所述的季铵化接枝度为2-60％；
通过自由基共聚合反应制得环氧化两性离子(ESBMA)，所述的自由基共聚合反应中功能单体为[2-(甲基丙烯酰基氧基)乙基]二甲基-(3-磺酸丙基)氢氧化铵和甲基丙烯酸缩水甘油酯，共聚混合溶剂为水和其他溶剂，通过调节其他溶剂与水的比例调控共聚比；所述其他溶剂选自二甲基亚砜、乙腈、二甲基甲酰胺、甲醇、乙醇、异丙醇、丙酮、四氢呋喃、乙酸乙酯、***、二氯甲烷、氯仿、甲苯；
将壳聚糖(CS)在水相中溶解后，再依次加入季铵化壳聚糖、两性离子(SBMA)、丙烯酰胺(AAm)、N,N-亚甲基双丙烯酰胺(MBAA)和引发剂过硫酸铵(APS)，离心脱泡后，在模具中浇筑，在烘箱中一锅法反应制得凝胶；
将制得的凝胶浸泡在环氧化两性离子溶液中，并加入三乙胺(TEA)，在烘箱中反应一段时间后即可制得具有良好力学性能和生物相容性，双重抵抗细菌粘附，双重接触杀灭细菌，盐响应释放死菌的抗杀释菌一体化凝胶敷料。
上述技术方案中，进一步的，与常规改变投料比的方法不同，本发明采用调节其他溶剂与水的比例来改变甲基丙烯酸缩水甘油酯和SBMA的共聚比例，可以有效解决单纯改变投料比引起的单体溶解性差、反应效率低的问题，调控所述的共聚比为1:9～9:1，以调整链段的亲疏水性以及ESBMA铆接在凝胶敷料表面的密度、厚度达到合适范围。
进一步的，所述的壳聚糖在水相中溶解制得0.1-10wt％的CS醋酸溶液，依次加入QCS、SBMA、AAm、MBAA和APS，添加量分别为0.1-10wt％、0.25-6.25％、1-25wt％、0.001wt％-0.1wt％、0.01wt％-1wt％。
进一步的，所述的一锅法反应时烘箱温度为40-80℃，反应4-10小时。
进一步的，所述的环氧化两性离子溶液为0.001-0.1wt％ESBMA水溶液。
进一步的，所述的TEA的添加量为环氧化两性离子溶液的0.1-10wt％。
进一步的，加入TEA后转移到烘箱中，设置温度40-80℃，反应12-24小时。
本发明采用CS、QCS、SBMA、ESBMA在水相中一锅法形成的具有优异力学性能且可抗杀释一体的互穿网络，在ESBMA制备时创造性的通过调控共聚混合溶液中其他溶剂与水的比例来调控共聚比例从而影响凝胶敷料的亲疏水性以及ESBMA铆接在凝胶敷料表面的密度和厚度达到合适范围，从而使得制得的抗杀一体凝胶敷料还可具有极佳的释菌性能。可以有效解决如下问题：当使用一段时间后，敷料表面的死菌及其分泌的物质极易阻挡敷料和后来细菌的充分接触，从而无法进一步持续发挥敷料抗杀功能，极易逐渐形成难以清除的细菌生物被膜。因此赋予敷料响应性释放死菌的功能，对于现有的敷料极其重要。
具体实施方式
以下结合实例进一步说明本发明。
实施例1：
1)首先制备ESBMA：配制二甲基甲酰胺、水体积比1：5的二甲基甲酰胺水溶液200mL，依次加入0.1mol甲基丙烯酸缩水甘油酯，0.1molSBMA，各溶解15min，通N2 15min，加入少许引发剂AlBN，60℃加热反应24h后，冰水浴3h终止，旋蒸后，重结晶洗涤三次，冻干即可制得。
并配制如下溶液：0.1wt％CS醋酸溶液，0.001wt％ESBMA水溶液；
2)再向步骤(1)CS醋酸溶液中依次加入10wt％的QCS、0.25wt％的SBMA、1wt％的AAm，0.1wt％MBAA，1wt％的APS充分搅拌均匀，离心脱泡后，在模具中浇筑；
3)再将步骤(2)模具转移到烘箱中，设置温度40℃，反应10小时，制得凝胶；
4)再将步骤(3)凝胶，浸泡在ESBMA水溶液中，并加入10wt％TEA，转移到烘箱中，设置温度40℃，反应24小时即得所需的CS/QCS/SBMA/ESBMA抗杀释菌一体化凝胶敷料。
实施例2：
1)首先配制二甲基亚砜、水体积比1：1的二甲基亚砜水溶液200mL，依次加入0.1mol甲基丙烯酸缩水甘油酯，0.1molSBMA，各溶解15min，通N2 15min，加入少许引发剂AlBN，60℃加热反应24h后，冰水浴3h终止，旋蒸后，重结晶洗涤三次，冻干即可制得。并配制如下溶液：10wt％CS醋酸溶液，0.1wt％ESBMA水溶液；
2)再向步骤(1)CS醋酸溶液中依次加入0.1wt％的QCS、6.25wt％的SBMA、25wt％的AAm，0.05wt％MBAA，0.5wt％的APS充分搅拌均匀，离心脱泡后，在模具中浇筑；
3)再将步骤(2)模具转移到烘箱中，设置温度80℃，反应4小时，制得凝胶；
4)再将步骤(3)凝胶，浸泡在ESBMA水溶液中，并加入0.1wt％TEA，转移到烘箱中，设置温度80℃，反应12小时即得所需的CS/QCS/SBMA/ESBMA抗杀释菌一体化凝胶敷料。
实施例3：
1)首先，配制甲醇、水体积比5：1的甲醇水溶液200mL，依次加入0.1mol甲基丙烯酸缩水甘油酯，0.1molSBMA，各溶解15min，通N2 15min，加入少许引发剂AlBN，60℃加热反应24h后，冰水浴3h终止，旋蒸后，重结晶洗涤三次，冻干即可制得。并配制如下溶液：5wt％CS醋酸溶液，0.5wt％ESBMA水溶液；
2)再向步骤(1)CS醋酸溶液中依次加入5wt％的QCS、3.12wt％的SBMA、12.5wt％的AAm，0.001wt％MBAA，0.01wt％的APS充分搅拌均匀，离心脱泡后，在模具中浇筑；
3)再将步骤(2)模具转移到烘箱中，设置温度60℃，反应8小时，制得凝胶；
4)再将步骤(3)凝胶，浸泡在ESBMA水溶液中，并加入5wt％TEA，转移到烘箱中，设置温度60℃，反应18小时即得所需的CS/QCS/SBMA/ESBMA抗杀释菌一体化凝胶敷料。
Claims (6)
1.一种壳聚糖/季铵化壳聚糖/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料，其特征在于，该敷料采用如下方法制得：
所述的壳聚糖分子量为50w-200w，脱乙酰度为75%-95%；
通过环氧开环反应制得季铵化壳聚糖（QCS），所述的环氧开环反应功能单体为氯化缩水甘油三甲基铵，所述的季铵化接枝度为2-60%；
通过自由基共聚合反应制得环氧化两性离子ESBMA，所述的自由基共聚合反应中功能单体为两性离子[2-(甲基丙烯酰基氧基)乙基]二甲基-(3-磺酸丙基)氢氧化铵（SBMA）和甲基丙烯酸缩水甘油酯，共聚混合溶剂为水和其他溶剂，通过调控其他溶剂与水的体积比例为1：5-5：1，使得共聚比为1：9-9：1；所述其他溶剂选自二甲基亚砜、乙腈、二甲基甲酰胺、甲醇、乙醇、异丙醇、丙酮、四氢呋喃、乙酸乙酯、***、二氯甲烷、氯仿、甲苯；
将壳聚糖（CS）在水相中溶解后，再依次加入QCS、两性离子SBMA、丙烯酰胺（AAm）、N,N-亚甲基双丙烯酰胺（MBAA）和引发剂过硫酸铵（APS），离心脱泡后，在模具中浇筑，在烘箱中一锅法反应制得凝胶；
将制得的凝胶浸泡在环氧化两性离子ESBMA溶液中，并加入三乙胺（TEA），在烘箱中反应一段时间后即可制得抗杀释菌一体化凝胶敷料。
2.如权利要求1所述的壳聚糖/季铵化壳聚糖/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料，其特征在于，所述的壳聚糖在水相中溶解制得0.1-10wt%的CS醋酸溶液，依次加入QCS、SBMA、AAm、MBAA和APS，添加量分别为0.1-10wt%、0.25-6.25wt%、1-25wt%、0.001wt%-0.1wt%、0.01wt%-1wt%。
3.如权利要求1所述的壳聚糖/季铵化壳聚糖/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料，其特征在于，所述的一锅法反应时烘箱温度为40-80℃，反应4-10小时。
4.如权利要求1所述的壳聚糖/季铵化壳聚糖/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料，其特征在于，所述的环氧化两性离子ESBMA溶液为0.001-0.1wt% ESBMA水溶液。
5.如权利要求1所述的壳聚糖/季铵化壳聚糖/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料，其特征在于，所述的TEA的添加量为环氧化两性离子溶液的0.1-10wt%。
6.如权利要求1所述的壳聚糖/季铵化壳聚糖/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料，其特征在于，加入TEA后转移到烘箱中，设置温度40-80℃，反应12-24小时。
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