CN115627042A - 一种抗菌肽水凝胶及其制备方法 - Google Patents
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Abstract
本发明公开了一种抗菌肽水凝胶及其制备方法,涉及生物医用技术领域。本发明制备的抗菌肽水凝胶,是以改性聚乙烯醇为载体与抗菌肽共混,在加入自制交联剂,进行辐射交联制得;以聚胍基离子液体聚合物做为交联剂与羧基聚乙烯醇反应,将羧基聚乙烯醇交联纠缠在羧甲基纤维素表面,形成以羧甲基纤维素为网络基体的交联网络结构,在辐照条件下,自制交联剂与改性聚乙烯醇引发单体聚合,形成结构紧密的抗菌肽水凝胶,增强了水凝胶的耐热性、拉伸强度和持水性。
Description
技术领域
本发明涉及生物医用技术领域,具体为一种抗菌肽水凝胶及其制备方法。
背景技术
抗菌肽是一类有望可以替代传统抗生素的生物大分子,其来源广泛,抗菌性能优异且不容易引起细菌耐药性,但抗菌肽具有容易被降解、抗菌性能不稳定等缺陷,在实际应用中需要通过与大分子结合进行改善。
在日常生活中,烧烫伤和割伤造成的皮肤急性损伤时有发生,难以正常愈合且有持续性炎症的慢性伤口也较为常见。有效的伤口敷料不仅可以遮盖与保护伤口,而且能提高伤口愈合的质量;水凝胶具有孔隙率高、含水量高和生物相容性良好等特点,在临床治疗和组织工程等领域具有广阔的应用前景,因此本发明将抗菌肽与水凝胶结合,研究制备一种具有耐热性,并且拉伸强度和持水性好的抗菌肽水凝胶。
发明内容
本发明的目的在于提供一种抗菌肽水凝胶及其制备方法,以解决上述背景技术中提出的问题。
一种抗菌肽水凝胶,所述抗菌肽水凝胶是以改性聚乙烯醇为载体与抗菌肽共混,在加入自制交联剂,进行辐射交联制得。
优选的,所述改性聚乙烯醇是羧基聚乙烯醇、聚胍基离子液体聚合物和羧甲基纤维素共混反应制得。
优选的,所述聚胍基离子液体聚合物是1,1,3,3-四甲基胍、4-乙烯基苄氯和N,N-亚甲基双丙烯酰胺反应制得。
优选的,所述自制交联剂包括聚二甲基二烯丙基氯化铵、2-氨基苯甲酰胺和吡嗪酰胺。
优选的,所述一种抗菌肽水凝胶的制备方法,包括以下具体步骤:
(1)将羧基聚乙烯醇、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和N-羟基虎皮亚酰胺按质量比1:0.1:0.1~1:0.2:0.2混合,搅拌均匀后加入羧基聚乙烯醇质量0.04~0.08倍质量分数为5~8%的硝酸溶液,反应2~3h后,加入羧基聚乙烯醇质量0.1~0.3倍的聚胍基离子液体聚合物和羧基聚乙烯醇质量0.07~0.09倍的没食子酸,继续反应4~8h,制得改性聚乙烯醇;
(2)在氮气氛围下,将质量分数为2~5%的醋酸溶液、聚二甲基二烯丙基氯化铵和2-氨基苯甲酰胺按质量比15:2:4~20:5:9混合并搅拌均匀,加入聚二甲基二烯丙基氯化铵质量0.2~0.4倍的吡嗪酰胺,搅拌均匀,制得自制交联剂;
(3)在氮气氛围下,将改性聚乙烯醇与自制交联剂混合,置于辐照场中进行γ-射线辐照,制得抗菌肽水凝胶。
优选的,上述步骤(1)中:聚胍基离子液体聚合物的制备方法为:将1,1,3,3-四甲基胍与乙腈按质量0.62:1~0.65:1混合,以1~3滴/s的速率滴加1,1,3,3-四甲基胍质量0.85~0.95倍的4-乙烯基苄氯室温反应4~6h,过滤并再次分散在1,1,3,3-四甲基胍质量20~40倍的乙腈中,搅拌均匀后加入1,1,3,3-四甲基胍质量2~4倍的N,N-亚甲基双丙烯酰胺,在50~80kHz下超声脱氧5~8min,转移至氮气氛围下并加入1,1,3,3-四甲基胍质量0.4~0.5倍的偶氮二异丁腈,密封后,在50~80kHz下再进行3~5min的超声处理,升温至55~65℃,反应20~28h后,用去离子水洗涤3~5次,抽滤并干燥,制得聚胍基离子液体聚合物。
优选的,上述步骤(1)中:羧基聚乙烯醇的制备方法为:将聚乙烯醇与二甲基亚砜按质量比1:15~1:20混合,升温至100~120℃,并搅拌溶解,冷却至室温后加入聚乙烯醇质量0.1~0.3倍的三乙醇胺和聚乙烯醇质量0.2~0.3倍的丁二酸酐,继续反应8~10h,制得羧基聚乙烯醇。
优选的,上述步骤(2)中:抗菌肽的制备方法为:将螺旋藻蛋白仅进行酶法水解,加酶量为4000~4500U/g,温度55~58℃,pH为6.8~7.2,时间为160~180min,然后在80~85℃的水浴条件下灭酶15~20min,再用木瓜蛋白进行二次酶解,木瓜蛋白用量为3~5%,温度温度在58~63℃,pH为6.5,时间为200~230min,然后在80~85℃的水浴条件下灭酶15~20min,降温至3~5℃,最后离心并将上清液冻干,制得抗菌肽。
优选的,上述步骤(3)中:改性聚乙烯醇与自制交联剂的质量比为5:1~8:1。
优选的,上述步骤(3)中:辐照剂量为3~5kGy。
与现有技术相比,本发明所达到的有益效果是:
本发明制备的抗菌肽水凝胶,是以改性聚乙烯醇为载体与抗菌肽共混,在加入自制交联剂,进行辐射交联制得;
改性聚乙烯醇是羧基聚乙烯醇、聚胍基离子液体聚合物和羧甲基纤维素共混反应制得;聚胍基离子液体聚合物是1,1,3,3-四甲基胍、4-乙烯基苄氯和N,N-亚甲基双丙烯酰胺反应制得,不仅具有较强的耐热性,还以聚胍基离子液体聚合物做为交联剂与羧基聚乙烯醇反应,胍基能与羧基形成氢键,将羧基聚乙烯醇交联纠缠在羧甲基纤维素表面,形成以羧甲基纤维素为网络基体的交联网络结构,增强了水凝胶的耐热性和拉伸强度;
自制交联剂包括聚二甲基二烯丙基氯化铵、2-氨基苯甲酰胺和吡嗪酰胺;在辐照条件下,自制交联剂与改性聚乙烯醇引发单体聚合,并进行交联成为长链改性聚乙烯醇,再进行链增长聚合,通过接枝共聚使聚二甲基二烯丙基氯化铵、2-氨基苯甲酰胺连接在长链上,同时吡嗪酰胺水解为吡嗪羧酸,与聚胍基离子液体聚合物形成氢键,形成结构紧密的抗菌肽水凝胶,增加含水量的同时,增强持水性。
具体实施方式
下面将结合本发明的实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
为了更清楚的说明本发明提供的方法通过以下实施例进行详细说明,将实施例和对比例中制备的抗菌肽水凝胶的各指标测试方法如下:
耐热性、拉伸强度:将实施例和对比例制备的抗菌肽水凝胶在25℃和50℃下进行拉伸,记录最大拉伸长度。
持水性:将实施例和对比例制备的抗菌肽水凝胶浸泡在25℃的去离子水中,溶胀2小时后取出称重,静置24小时后计算重量变化率。
实施例1
(1)将1,1,3,3-四甲基胍与乙腈按质量0.62:1混合,以1滴/s的速率滴加1,1,3,3-四甲基胍质量0.85倍的4-乙烯基苄氯室温反应4h,过滤并再次分散在1,1,3,3-四甲基胍质量20倍的乙腈中,搅拌均匀后加入1,1,3,3-四甲基胍质量2倍的N,N-亚甲基双丙烯酰胺,在50kHz下超声脱氧5min,转移至氮气氛围下并加入1,1,3,3-四甲基胍质量0.4倍的偶氮二异丁腈,密封后,在50kHz下再进行3min的超声处理,升温至55℃,反应20h后,用去离子水洗涤3次,抽滤并干燥,制得聚胍基离子液体聚合物;
(2)将螺旋藻蛋白仅进行酶法水解,加酶量为4000U/g,温度55℃,pH为6.8,时间为160min,然后在80℃的水浴条件下灭酶15min,再用木瓜蛋白进行二次酶解,木瓜蛋白用量为3%,温度温度在58℃,pH为6.5,时间为200min,然后在80℃的水浴条件下灭酶15min,降温至3℃,最后离心并将上清液冻干,制得抗菌肽;
(3)将聚乙烯醇与二甲基亚砜按质量比1:15混合,升温至100℃,并搅拌溶解,冷却至室温后加入聚乙烯醇质量0.1倍的三乙醇胺和聚乙烯醇质量0.2倍的丁二酸酐,继续反应8h,制得羧基聚乙烯醇;将羧基聚乙烯醇、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和N-羟基虎皮亚酰胺按质量比1:0.1:0.1混合,搅拌均匀后加入羧基聚乙烯醇质量0.04倍质量分数为5%的硝酸溶液,反应2h后,加入羧基聚乙烯醇质量0.1倍的聚胍基离子液体聚合物和羧基聚乙烯醇质量0.07倍的没食子酸,继续反应4h,制得改性聚乙烯醇;
(4)在氮气氛围下,将质量分数为2%的醋酸溶液、聚二甲基二烯丙基氯化铵和2-氨基苯甲酰胺按质量比15:2:4混合并搅拌均匀,加入聚二甲基二烯丙基氯化铵质量0.2倍的吡嗪酰胺,搅拌均匀,制得自制交联剂;
(5)在氮气氛围下,将改性聚乙烯醇与自制交联剂按质量比5:1混合,置于辐照场中进行γ-射线辐照,辐照剂量为3kGy,制得抗菌肽水凝胶。
实施例2
(1)将1,1,3,3-四甲基胍与乙腈按质量0.64:1混合,以2滴/s的速率滴加1,1,3,3-四甲基胍质量0.90倍的4-乙烯基苄氯室温反应5h,过滤并再次分散在1,1,3,3-四甲基胍质量30倍的乙腈中,搅拌均匀后加入1,1,3,3-四甲基胍质量3倍的N,N-亚甲基双丙烯酰胺,在60kHz下超声脱氧6min,转移至氮气氛围下并加入1,1,3,3-四甲基胍质量0.45倍的偶氮二异丁腈,密封后,在50~80kHz下再进行4min的超声处理,升温至60℃,反应24h后,用去离子水洗涤4次,抽滤并干燥,制得聚胍基离子液体聚合物;
(2)将螺旋藻蛋白仅进行酶法水解,加酶量为4300U/g,温度56℃,pH为7.0,时间为170min,然后在83℃的水浴条件下灭酶18min,再用木瓜蛋白进行二次酶解,木瓜蛋白用量为4%,温度温度在60℃,pH为6.5,时间为220min,然后在83℃的水浴条件下灭酶18min,降温至4℃,最后离心并将上清液冻干,制得抗菌肽;
(3)将聚乙烯醇与二甲基亚砜按质量比1:18混合,升温至110℃,并搅拌溶解,冷却至室温后加入聚乙烯醇质量0.2倍的三乙醇胺和聚乙烯醇质量0.25倍的丁二酸酐,继续反应9h,制得羧基聚乙烯醇;将羧基聚乙烯醇、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和N-羟基虎皮亚酰胺按质量比1:0.15:0.15混合,搅拌均匀后加入羧基聚乙烯醇质量0.06倍质量分数为5~8%的硝酸溶液,反应2.5h后,加入羧基聚乙烯醇质量0.2倍的聚胍基离子液体聚合物和羧基聚乙烯醇质量0.08倍的没食子酸,继续反应6h,制得改性聚乙烯醇;
(4)在氮气氛围下,将质量分数为3.5%的醋酸溶液、聚二甲基二烯丙基氯化铵和2-氨基苯甲酰胺按质量比18:4:6混合并搅拌均匀,加入聚二甲基二烯丙基氯化铵质量0.3倍的吡嗪酰胺,搅拌均匀,制得自制交联剂;
(5)在氮气氛围下,将改性聚乙烯醇与自制交联剂按质量比6.5:1混合,置于辐照场中进行γ-射线辐照,辐照剂量为4kGy,制得抗菌肽水凝胶。
实施例3
(1)将1,1,3,3-四甲基胍与乙腈按质量0.65:1混合,以3滴/s的速率滴加1,1,3,3-四甲基胍质量0.95倍的4-乙烯基苄氯室温反应6h,过滤并再次分散在1,1,3,3-四甲基胍质量40倍的乙腈中,搅拌均匀后加入1,1,3,3-四甲基胍质量4倍的N,N-亚甲基双丙烯酰胺,在80kHz下超声脱氧8min,转移至氮气氛围下并加入1,1,3,3-四甲基胍质量0.5倍的偶氮二异丁腈,密封后,在80kHz下再进行5min的超声处理,升温至65℃,反应28h后,用去离子水洗涤5次,抽滤并干燥,制得聚胍基离子液体聚合物;
(2)将螺旋藻蛋白仅进行酶法水解,加酶量为4500U/g,温度58℃,pH为7.2,时间为180min,然后在80~85℃的水浴条件下灭酶20min,再用木瓜蛋白进行二次酶解,木瓜蛋白用量为5%,温度温度在63℃,pH为6.5,时间为230min,然后在85℃的水浴条件下灭酶20min,降温至5℃,最后离心并将上清液冻干,制得抗菌肽;
(3)将聚乙烯醇与二甲基亚砜按质量比1:20混合,升温至120℃,并搅拌溶解,冷却至室温后加入聚乙烯醇质量0.3倍的三乙醇胺和聚乙烯醇质量0.3倍的丁二酸酐,继续反应10h,制得羧基聚乙烯醇;将羧基聚乙烯醇、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和N-羟基虎皮亚酰胺按质量比1:0.2:0.2混合,搅拌均匀后加入羧基聚乙烯醇质量0.08倍质量分数为8%的硝酸溶液,反应2~3h后,加入羧基聚乙烯醇质量0.3倍的聚胍基离子液体聚合物和羧基聚乙烯醇质量0.09倍的没食子酸,继续反应8h,制得改性聚乙烯醇;
(4)在氮气氛围下,将质量分数为5%的醋酸溶液、聚二甲基二烯丙基氯化铵和2-氨基苯甲酰胺按质量比20:5:9混合并搅拌均匀,加入聚二甲基二烯丙基氯化铵质量0.4倍的吡嗪酰胺,搅拌均匀,制得自制交联剂;
(5)在氮气氛围下,将改性聚乙烯醇与自制交联剂按质量比8:1混合,置于辐照场中进行γ-射线辐照,辐照剂量为5kGy,制得抗菌肽水凝胶。
对比例1
对比例1的处方组成同实施例2。该抗菌肽水凝胶及其制备方法与实施例2的区别仅在于不进行步骤(1)的制备,步骤(3)使用1,1,3,3-四甲基胍进行改性聚乙烯醇的制备,其余步骤同实施例2。
对比例2
对比例2的处方组成同实施例2。该抗菌肽水凝胶及其制备方法与实施例2的区别仅在于不进行聚胍基离子液体聚合物的制备,仅使用羧基聚乙烯醇和羧甲基纤维素进行改性聚乙烯醇的制备,其余步骤同实施例2。
对比例3
对比例3的处方组成同实施例2。该抗菌肽水凝胶及其制备方法与实施例2的区别仅在于自制交联剂仅包括聚二甲基二烯丙基氯化铵和2-氨基苯甲酰胺,其余步骤同实施例2。
对比例4
对比例4的处方组成同实施例2。该抗菌肽水凝胶及其制备方法与实施例2的区别仅在于自制交联剂仅包括聚二甲基二烯丙基氯化铵和吡嗪酰胺;其余步骤同实施例2。
效果例
下表1给出了采用本发明实施例1-3与对比例1-4的抗菌肽水凝胶的各性能分析结果:
表1
25℃时拉伸长度(%) | 50℃时拉伸长度(%) | 重量变化率(%) | |
实施例1 | 240 | 220 | 0.36 |
实施例2 | 248 | 219 | 0.48 |
实施例3 | 237 | 226 | 0.33 |
对比例1 | 209 | 162 | 0.45 |
对比例2 | 217 | 176 | 0.49 |
对比例3 | 240 | 209 | 3.59 |
对比例4 | 237 | 211 | 4.16 |
通过表1中实施例与对比例的实验数据比较可以明显发现,实施例1、2、3制备的抗菌肽水凝胶的耐热性、拉伸强度和持水性较好。
对于本领域技术人员而言,显然本发明不限于上述示范性实施例的细节,而且在不背离本发明的精神或基本特征的情况下,能够以其他的具体形式实现本发明。因此,无论从哪一点来看,均应将实施例看作是示范性的,而且是非限制性的,本发明的范围由所附权利要求而不是上述说明限定,因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。不应将权利要求中的任何标记视为限制所涉及的权利要求。
Claims (10)
1.一种抗菌肽水凝胶,其特征在于,所述抗菌肽水凝胶是以改性聚乙烯醇为载体与抗菌肽共混,在加入自制交联剂,进行辐射交联制得。
2.根据权利要求1所述的一种抗菌肽水凝胶,其特征在于,所述改性聚乙烯醇是羧基聚乙烯醇、聚胍基离子液体聚合物和羧甲基纤维素共混反应制得。
3.根据权利要求2所述的一种抗菌肽水凝胶,其特征在于,所述聚胍基离子液体聚合物是1,1,3,3-四甲基胍、4-乙烯基苄氯和N,N-亚甲基双丙烯酰胺反应制得。
4.根据权利要求1所述的一种抗菌肽水凝胶,其特征在于,所述自制交联剂包括聚二甲基二烯丙基氯化铵、2-氨基苯甲酰胺和吡嗪酰胺。
5.一种抗菌肽水凝胶的制备方法,其特征在于,所述抗菌肽水凝胶的制备方法,包括以下具体步骤:
(1)将羧基聚乙烯醇、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和N-羟基虎皮亚酰胺按质量比1:0.1:0.1~1:0.2:0.2混合,搅拌均匀后加入羧基聚乙烯醇质量0.04~0.08倍质量分数为5~8%的硝酸溶液,反应2~3h后,加入羧基聚乙烯醇质量0.1~0.3倍的聚胍基离子液体聚合物和羧基聚乙烯醇质量0.07~0.09倍的没食子酸,继续反应4~8h,制得改性聚乙烯醇;
(2)在氮气氛围下,将质量分数为2~5%的醋酸溶液、聚二甲基二烯丙基氯化铵和2-氨基苯甲酰胺按质量比15:2:4~20:5:9混合并搅拌均匀,加入聚二甲基二烯丙基氯化铵质量0.2~0.4倍的吡嗪酰胺,搅拌均匀,制得自制交联剂;
(3)在氮气氛围下,将改性聚乙烯醇与自制交联剂混合,置于辐照场中进行γ-射线辐照,制得抗菌肽水凝胶。
6.根据权利要求5所述的一种抗菌肽水凝胶的制备方法,其特征在于,上述步骤(1)中:聚胍基离子液体聚合物的制备方法为:将1,1,3,3-四甲基胍与乙腈按质量0.62:1~0.65:1混合,以1~3滴/s的速率滴加1,1,3,3-四甲基胍质量0.85~0.95倍的4-乙烯基苄氯室温反应4~6h,过滤并再次分散在1,1,3,3-四甲基胍质量20~40倍的乙腈中,搅拌均匀后加入1,1,3,3-四甲基胍质量2~4倍的N,N-亚甲基双丙烯酰胺,在50~80kHz下超声脱氧5~8min,转移至氮气氛围下并加入1,1,3,3-四甲基胍质量0.4~0.5倍的偶氮二异丁腈,密封后,在50~80kHz下再进行3~5min的超声处理,升温至55~65℃,反应20~28h后,用去离子水洗涤3~5次,抽滤并干燥,制得聚胍基离子液体聚合物。
7.根据权利要求5所述的一种抗菌肽水凝胶的制备方法,其特征在于,上述步骤(1)中:羧基聚乙烯醇的制备方法为:将聚乙烯醇与二甲基亚砜按质量比1:15~1:20混合,升温至100~120℃,并搅拌溶解,冷却至室温后加入聚乙烯醇质量0.1~0.3倍的三乙醇胺和聚乙烯醇质量0.2~0.3倍的丁二酸酐,继续反应8~10h,制得羧基聚乙烯醇。
8.根据权利要求5所述的一种抗菌肽水凝胶的制备方法,其特征在于,上述步骤(2)中:抗菌肽的制备方法为:将螺旋藻蛋白仅进行酶法水解,加酶量为4000~4500U/g,温度55~58℃,pH为6.8~7.2,时间为160~180min,然后在80~85℃的水浴条件下灭酶15~20min,再用木瓜蛋白进行二次酶解,木瓜蛋白用量为3~5%,温度温度在58~63℃,pH为6.5,时间为200~230min,然后在80~85℃的水浴条件下灭酶15~20min,降温至3~5℃,最后离心并将上清液冻干,制得抗菌肽。
9.根据权利要求5所述的一种抗菌肽水凝胶的制备方法,其特征在于,上述步骤(3)中:改性聚乙烯醇与自制交联剂的质量比为5:1~8:1。
10.根据权利要求5所述的一种抗菌肽水凝胶的制备方法,其特征在于,上述步骤(3)中:辐照剂量为3~5kGy。
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