CN115337447A - 一种用于伤口快速愈合的磺胺嘧啶银水凝胶及其制备方法与应用 - Google Patents
一种用于伤口快速愈合的磺胺嘧啶银水凝胶及其制备方法与应用 Download PDFInfo
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Abstract
本发明涉及一种用于伤口快速愈合的磺胺嘧啶银水凝胶及其制备方法与应用，所述水凝胶包含如下质量百分比的组分：0.5wt％～2wt％的磺胺嘧啶银、10wt％～20wt％的聚(N‑异丙基丙烯酰胺)、3wt％～5wt％的明胶、2wt％～10wt％的PEG400，余量为水。其制备方法包括以下步骤：(1)将磺胺嘧啶银、PEG400加入超纯水中，超声得到分散液；将N‑异丙基丙烯酰胺、明胶溶于超纯水中，得到混合溶液；(2)将上述分散液与混合溶液混合均匀，在惰性气氛下加入引发剂和促进剂进行聚合反应，制备得到所述磺胺嘧啶银水凝胶。本发明制备的磺胺嘧啶银水凝胶具有良好的粘附性、生物相容性以及力学性能，且具有温敏特性，接触人体皮肤时发生相变收缩，结合磺胺嘧啶银的缓释抗菌效果，可有效促进伤口愈合。
Description
技术领域
本发明涉及医用材料领域，具体涉及一种用于伤口快速愈合的磺胺嘧啶银水凝胶及其制备方法与应用。
背景技术
皮肤覆盖于人体表面，易于受到损伤，例如：烧伤、创伤、感染、手术等。而皮肤损伤的修复过程是一个非常复杂的过程，其机制涉及到血液凝固、炎症的发生与进展、基质合成、血管再生、纤维组织增生、再上皮化、创口收缩及组织重构等过程。一般愈合过程可分为以下三个阶段：止血和炎性反应阶段、增殖及肉芽组织形成阶段以及成熟和重塑阶段，在该过程中，不合理的治疗方案往往会引发细菌感染、组织脱水、严重的二次创伤等。因此，研发可防治创面感染以及促进伤口快速愈合的新型伤口敷料在现代医学中具有重要的临床意义。
近年来，水凝胶敷料因具有吸收创面渗出液、促进伤口愈合的作用，且适用于真皮浅层及其以上的浅表性创面及手术缝合后切口护理，从而备受关注。但传统的水凝胶敷料因缺乏固有抗菌性能且粘合性能与机械性能较差，从而限制了其实际应用的推广。目前市售的用于创面治疗的抗菌药物主要为磺胺嘧啶银软膏，磺胺嘧啶银对创面感染常见的革兰氏阳性菌及革兰氏阴性菌均具有抑制作用，且还具有较好的促伤口收敛闭合作用，是局部抗感染的常用药物。由于磺胺嘧啶银溶解度较低，这类软膏在使用过程中普遍存在突释效应，为达到有效的需要浓度，需要增加给药次数，但多次给药又会造成银离子的蓄积，从而带来血管毒性、角蛋白以及成纤维细胞毒性等问题，同时多次给药还存在患者顺应性差的问题。
为提高水凝胶敷料的抗菌性能以及避免磺胺嘧啶银软膏的局限性，近年来有研究将二者结合制备磺胺嘧啶银水凝胶，例如专利CN 108126237B公开了一种磺胺嘧啶银温敏凝胶及其制备方法粘合应用，该凝胶以泊洛沙姆作为凝胶基质，利用其温敏凝胶热性实现对伤口的贴合和去除，同时实现抗菌药物的缓释，但水凝胶本身粘合性及其机械性能较差的问题没有得到改善，且该凝胶在低温条件下会转为液体，该特性也限制了以泊洛沙姆作为凝胶基质的水凝胶在低温条件下的治疗效果。
发明内容
本发明要解决的技术问题是提供一种用于伤口快速愈合的磺胺嘧啶银水凝胶及其制备方法与应用，利用水凝胶基质的热响应收缩能力，从而对伤口起到机械收缩作用，在抗菌药物的协同作用下，促进伤口快速愈合。
为解决上述技术问题，本发明提供以下技术方案：
本发明第一方面提供了一种磺胺嘧啶银水凝胶，所述磺胺嘧啶银水凝胶包含如下质量百分比的组分：0.5wt％～2wt％的磺胺嘧啶银、10wt％～20wt％的聚(N-异丙基丙烯酰胺)、3wt％～5wt％的明胶、2wt％～10wt％的PEG400，余量为水。
进一步地，所述磺胺嘧啶银的平均粒径为200nm～500nm，例如300～400nm。
进一步地，所述聚(N-异丙基丙烯酰胺)与明胶的质量比为1～4：1。
本发明第二方面提供了第一方面所述的磺胺嘧啶银水凝胶的制备方法，包括以下步骤：
(1)将磺胺嘧啶银、PEG400加入超纯水中，球磨分散得到分散液；将N-异丙基丙烯酰胺、明胶溶于超纯水中，得到混合溶液；
(2)将步骤(1)制备的分散液、混合溶液混合均匀，在惰性气氛下加入引发剂和促进剂进行聚合反应，制备得到所述磺胺嘧啶银水凝胶。
本发明采用纳米级磺胺嘧啶银，由于粒径小、比表面积大，表面能高易发生自聚合以降低体系的能量，因此本发明先将磺胺嘧啶银与PEG400加入超纯水中充分分散，使纳米级磺胺嘧啶银在PEG400的作用下可均匀分散于水中，形成稳定的分散体系，再与水凝胶基质溶液混合均匀后反应，制备得到磺胺嘧啶银均匀分散的水凝胶。PEG400的引入作为磺胺嘧啶银的分散剂的同时，还起到保湿的作用，减少水凝胶水分的流失。
进一步地，步骤(2)中，所述引发剂为过硫酸铵、过硫酸钠或过硫酸钾。
进一步地，步骤(2)中，所述促进剂为四甲基乙二胺。
进一步地，步骤(2)中，所述聚合反应在密封条件下进行。
进一步地，步骤(2)中，所述聚合反应的反应温度为0～10℃，反应时间为5～10h。
进一步地，所述反应温度优选在5℃以下。
本发明第三方面提供了第一方面所述的磺胺嘧啶银水凝胶在制备抗菌敷料、促伤口愈合敷料中的应用。
进一步地，所述磺胺嘧啶银水凝胶可冻干储存。
进一步地，将冻干的磺胺嘧啶水凝胶与无菌盐溶液混合后敷于伤口处进行治疗。
与现有技术相比，本发明的有益效果在于：
1.本发明以聚(N-异丙基丙烯酰胺)和明胶作为水凝胶基质形成互穿网络，两亲性的聚(N-异丙基丙烯酰胺)具有亲水基团酰胺基，可与皮肤产生共价胶料从而牢固的粘附在皮肤表面，化学交联的聚(N-异丙基丙烯酰胺)水凝胶在接近人体皮肤温度32℃左右时发生体积收缩，从而具有机械收缩伤口的热响应收缩能力，同时具有与胶原相同组分和生物性质的明胶可促进血管的形成，有利于伤口的快速愈合；此外协同抗炎药物磺胺嘧啶银，通过水凝胶基质实现抗炎药物的缓释，有效避免药物突释造成银离子的蓄积引起血管毒性等问题，延长抗炎药物的抑菌效果。
2.本发明利用高温溶解低温凝胶的明胶以及低温溶解高温凝胶的聚(N-异丙基丙烯酰胺)作为凝胶基质，制备得到磺胺嘧啶银水凝胶在较低温度条件仍保持凝胶状态，较之现有技术中以泊洛沙姆为凝胶基质制备的水凝胶，本发明制备的水凝胶不易发生凝胶状态向液体状态的改变，因此不易发生磺胺嘧啶银的突释现象，可有效控制抗炎药物的缓释，结合聚(N-异丙基丙烯酰胺)的热响应收缩能力对伤口进行机械收缩，以及明胶对血管的促进作用，可促进伤口快速愈合；此外，本发明制备的水凝胶可冻干保存，方便携带，使用时与无菌盐溶液混合即可对伤口进行治疗。
具体实施方式
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。本文所使用的术语“及/或”包括一个或多个相关的所列项目的任意的和所有的组合。
下面结合具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
实施例1
本实施例涉及一种磺胺嘧啶银水凝胶的制备，具体的制备过程如下：
(1)将100mg磺胺嘧啶银(平均粒径为321.5nm，多分散系数为0.261)与0.5g PEG400加入5mL超纯水中，球磨分散得到20mg/mL的磺胺嘧啶银分散液；将1.5g N-异丙基丙烯酰胺溶于超纯水中制备100mg/mL的N-异丙基丙烯酰胺溶液，将0.5g明胶溶于超纯水中制备25mg/mL的明胶溶液。
(2)将步骤(1)制备的N-异丙基丙烯酰胺溶液与明胶溶液混合均匀，边搅拌边加入磺胺嘧啶银分散液，然后于氮气保护下加入过硫酸铵和四甲基乙二胺，并于冰水浴中密闭反应8h，凝胶后得到所述磺胺嘧啶银水凝胶。
实施例2
本实施例涉及一种磺胺嘧啶银水凝胶的制备，具体的制备过程如下：
(1)将50mg磺胺嘧啶银(平均粒径为321.5nm，多分散系数为0.261)与0.2g PEG400加入5mL超纯水中，球磨分散得到10mg/mL的磺胺嘧啶银分散液；将1g N-异丙基丙烯酰胺溶于超纯水中制备80mg/mL的N-异丙基丙烯酰胺溶液，将0.3g明胶溶于超纯水中制备20mg/mL的明胶溶液。
(2)将步骤(1)制备的N-异丙基丙烯酰胺溶液与明胶溶液混合均匀，边搅拌边加入磺胺嘧啶银分散液，然后于氮气保护下加入过硫酸铵和四甲基乙二胺，并于冰水浴中密闭反应8h，凝胶后得到所述磺胺嘧啶银水凝胶。
实施例3
本实施例涉及一种磺胺嘧啶银水凝胶的制备，具体的制备过程如下：
(1)将200mg磺胺嘧啶银(平均粒径为321.5nm，多分散系数为0.261)与1g PEG 400加入5mL超纯水中，球磨分散得到40mg/mL的磺胺嘧啶银分散液；将2.0g N-异丙基丙烯酰胺溶于超纯水中制备100mg/mL的N-异丙基丙烯酰胺溶液，将1g明胶溶于超纯水中制备25mg/mL的明胶溶液。
(2)将步骤(1)制备的N-异丙基丙烯酰胺溶液与明胶溶液混合均匀，边搅拌边加入磺胺嘧啶银分散液，然后于氮气保护下加入过硫酸铵和四甲基乙二胺，并于4℃下密闭反应6h，凝胶后得到所述磺胺嘧啶银水凝胶。
对比例1
本对比例涉及一种聚(N-异丙基丙烯酰胺)水凝胶的制备，具体的制备过程如下：
(1)将1.5g N-异丙基丙烯酰胺溶于超纯水中制备100mg/mL的N-异丙基丙烯酰胺溶液，将0.5g明胶溶于超纯水中制备25mg/mL的明胶溶液。
(2)将步骤(1)制备的N-异丙基丙烯酰胺溶液与明胶溶液混合均匀，然后于氮气保护下加入过硫酸铵和四甲基乙二胺，并于冰水浴中密闭反应8h，凝胶后得到所述聚(N-异丙基丙烯酰胺)水凝胶。
对比例2
本对比例涉及一种磺胺嘧啶银水凝胶的制备，具体的制备过程如下：
(1)将100mg磺胺嘧啶银(平均粒径为321.5nm，多分散系数为0.261)与0.5g PEG400加入5mL超纯水中，球磨分散得到20mg/mL的磺胺嘧啶银分散液；将0.5g N-异丙基丙烯酰胺溶于超纯水中制备100mg/mL的N-异丙基丙烯酰胺溶液，将0.5g明胶溶于超纯水中制备25mg/mL的明胶溶液。
(2)将步骤(1)制备的N-异丙基丙烯酰胺溶液与明胶溶液混合均匀，边搅拌边加入磺胺嘧啶银分散液，然后于氮气保护下加入过硫酸铵和四甲基乙二胺，并于冰水浴中密闭反应8h，凝胶后得到所述磺胺嘧啶银水凝胶。
对比例3
本对比例涉及一种磺胺嘧啶银水凝胶的制备，具体的制备过程如下：
(1)将100mg磺胺嘧啶银(平均粒径为321.5nm，多分散系数为0.261)与0.5g PEG400加入5mL超纯水中，球磨分散得到20mg/mL的磺胺嘧啶银分散液；将1.5g N-异丙基丙烯酰胺溶于超纯水中制备100mg/mL的N-异丙基丙烯酰胺溶液。
(2)将步骤(1)制备的N-异丙基丙烯酰胺溶液与明胶溶液混合均匀，边搅拌边加入磺胺嘧啶银分散液，然后于氮气保护下加入过硫酸铵和四甲基乙二胺，并于冰水浴中密闭反应8h，凝胶后得到所述磺胺嘧啶银水凝胶。
对比例4
本对比例涉及一种磺胺嘧啶银水凝胶的制备，具体的制备过程如下：
(1)将100mg磺胺嘧啶银(平均粒径为321.5nm，多分散系数为0.261)与0.5g丙三醇加入5mL超纯水中，球磨分散得到20mg/mL的磺胺嘧啶银分散液；将1.5g N-异丙基丙烯酰胺溶于超纯水中制备100mg/mL的N-异丙基丙烯酰胺溶液，将0.5g明胶溶于超纯水中制备25mg/mL的明胶溶液。
(2)将步骤(1)制备的N-异丙基丙烯酰胺溶液与明胶溶液混合均匀，边搅拌边加入磺胺嘧啶银分散液，然后于氮气保护下加入过硫酸铵和四甲基乙二胺，并于冰水浴中密闭反应8h，凝胶后得到所述磺胺嘧啶银水凝胶。
性能研究
1.可压缩性研究
通过TMS-Pro万能试验机测试上述实施例及对比例制备的水凝胶的压缩性能，取底面积均为4cm2、体积相同的圆柱形水凝胶试样，以10mm/min的速度进行压缩，记录压缩率为50％，各水凝胶对应的压缩应力大小，测试结果如下表1所示：
表1为各实施例及对比例制备的水凝胶的压缩应力
由表1可知，较之单一凝胶基质明胶或聚(N-异丙基丙烯酰胺)制备的水凝胶，包含以上两种凝胶基质的是凝胶具有较高的可压缩性，这是由于明胶与聚(N-异丙基丙烯酰胺)形成互穿网络，二者之间的非共价相互作用使水凝胶在形变作用下能量耗散，从而提高水凝胶的力学性能。对比例4制备的水凝胶在压缩过程中出现局部破损的现象，推测是由于内部磺胺嘧啶银局部聚集导致应力集中。
2.温敏性研究
对上述实施例及对比例制备的水凝胶的温敏性进行研究，取底面积均为6cm2、体积相同的圆柱形水凝胶试样，将试样置于37℃下，恒温放置30min，记录各水凝胶试样的面积收缩率，测试结果如下表2所示：
表2为各实施例及对比例制备的水凝胶在37℃放置30min后的面积收缩率
由表2可知，包含聚(N-异丙基丙烯酰胺)的水凝胶试样在37℃下放置30min后，发生明显收缩，其中实施例1～3制备的水凝胶收缩率均超出50％，该现象也说明本发明制备的水凝胶在体温附近具有显著的温敏效应，该收缩行为可用于机械收缩伤口，促进伤口愈合。
3.抗菌性研究
对实施例1及对比例1～4制备的水凝胶的抗菌性进行研究，取底面积均为1cm2、体积相同的圆柱形水凝胶试样，将各试样分别放入一个培养皿中，各加入10mL磷酸缓冲溶液及2mL菌悬液(包含耐甲氧西林金黄色葡萄球菌、铜绿假单胞菌中的一种)，置于37℃培养箱中培养24h，置换培养液和菌液继续培养24h，测试不同试样对两种菌的抑菌效果。测试结果如下所示：
表3为各实施例及对比例制备的水凝胶的抑菌效果
由抗菌试验结果表面，本发明制备磺胺嘧啶银水凝胶具有良好的抗菌效果以及良好的缓释效果，实施例1制备的水凝胶在置换培养液和菌液后仍具有良好的抗菌效果，其中对比例4制备的水凝胶在前期具有优异的抗菌效果，但置换培养液和菌液后，其抑菌效果达到下降，该现象说明对比例4制备的水凝胶存在抗菌药物突释现象，进而说明本发明采用PEG 400对磺胺嘧啶银进行预处理分散，可改善药物突释问题。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例，本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换，均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。
Claims (10)
1.一种磺胺嘧啶银水凝胶，其特征在于，所述磺胺嘧啶银水凝胶包含如下质量百分比的组分：0.5wt％～2wt％的磺胺嘧啶银、10wt％～20wt％的聚(N-异丙基丙烯酰胺)、3wt％～5wt％的明胶、2wt％～10wt％的PEG400，余量为水。
2.根据权利要求1所述的磺胺嘧啶银水凝胶，其特征在于，所述磺胺嘧啶银的平均粒径为200nm～500nm。
3.根据权利要求1所述的磺胺嘧啶银水凝胶，其特征在于，所述聚(N-异丙基丙烯酰胺)与明胶的质量比为1～4：1。
4.一种权利要求1～3任一所述的磺胺嘧啶银水凝胶的制备方法，其特征在于，包括以下步骤：
(1)将磺胺嘧啶银、PEG400加入超纯水中，球磨分散得到分散液；将N-异丙基丙烯酰胺、明胶溶于超纯水中，得到混合溶液；
(2)将步骤(1)制备的分散液、混合溶液混合均匀，在惰性气氛下加入引发剂和促进剂进行聚合反应，制备得到所述磺胺嘧啶银水凝胶。
5.根据权利要求4所述的制备方法，其特征在于，步骤(2)中，所述引发剂为过硫酸铵、过硫酸钠或过硫酸钾。
6.根据权利要求4所述的制备方法，其特征在于，步骤(2)中，所述促进剂为四甲基乙二胺。
7.根据权利要求4所述的制备方法，其特征在于，步骤(2)中，所述聚合反应在密封条件下进行。
8.根据权利要求4所述的制备方法，其特征在于，步骤(2)中，所述聚合反应的反应温度为0～10℃，反应时间为5～10h。
9.一种权利要求1～3任一项所述的磺胺嘧啶银水凝胶在制备抗菌敷料、促伤口愈合敷料中的应用。
10.根据权利要求9所述的应用，其特征在于，所述磺胺嘧啶银水凝胶冻干存储，将冻干的磺胺嘧啶银水凝胶与无菌盐溶液混合后敷于伤口处进行治疗。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6180132B1 (en) * | 1997-09-18 | 2001-01-30 | Sherwood Services, Ag | Hydrogel wound dressing and the method of making and using the same |
| CN108126237A (zh) * | 2018-01-10 | 2018-06-08 | 中国人民解放军军事科学院军事医学研究院 | 一种磺胺嘧啶银温敏凝胶及其制备方法和应用 |
| CN112999412A (zh) * | 2021-03-10 | 2021-06-22 | 苏州大学 | 用于伤口愈合的水凝胶敷料及其制备方法 |
| CN114470313A (zh) * | 2022-01-28 | 2022-05-13 | 华南理工大学 | 一种仿生机械活性水凝胶粘合剂及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6180132B1 (en) * | 1997-09-18 | 2001-01-30 | Sherwood Services, Ag | Hydrogel wound dressing and the method of making and using the same |
| CN108126237A (zh) * | 2018-01-10 | 2018-06-08 | 中国人民解放军军事科学院军事医学研究院 | 一种磺胺嘧啶银温敏凝胶及其制备方法和应用 |
| CN112999412A (zh) * | 2021-03-10 | 2021-06-22 | 苏州大学 | 用于伤口愈合的水凝胶敷料及其制备方法 |
| CN114470313A (zh) * | 2022-01-28 | 2022-05-13 | 华南理工大学 | 一种仿生机械活性水凝胶粘合剂及其制备方法 |
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