CN107473964B - 一种有机纳米抗菌剂及其制备方法和应用 - Google Patents
一种有机纳米抗菌剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种有机纳米抗菌剂及其制备方法和应用。所述含三氯生的有机纳米抗菌剂的制备方法包括如下步骤:S1.以水为分散介质,加入有机单体、乳化剂,升温至30~40℃,搅拌溶解;S2.在惰性气体保护下,往步骤S1混合溶液加入水溶性引发剂,并控制搅拌速度为100~200 r/min,升温至70~80℃,聚合反应1~2h;S3.往步骤S2的反应产物中滴加有机单体与含三氯生的单体的混合单体,继续聚合反应1~2h,得到含三氯生的有机纳米抗菌剂乳液。所述抗菌剂比表面巨大,利用率高;有机纳米粒子结构稳定、无毒、不会迁移进入环境与人体、不团聚,易分散,可负载于常规的纤维态医用敷料上,具有较大的应用前景。
Description
技术领域
本发明属于医学材料技术领域。更具体地,涉及一种有机纳米抗菌剂及其制备方法和应用。
背景技术
敷料是一类用以覆盖疮、伤口或其他损伤部位的医用耗材,是重要的医疗器械,它们可替代受损的皮肤起到暂时性屏障作用,避免或控制伤口感染,提供有利于创面愈合的环境。目前,基于棉纱的传统医用敷料约占总量的50%以上(我国市场份额超过80%),以及大多数新型医用敷料,如藻酸盐敷料、水胶体敷料等,都不具有抗感染的性能,它们在防止创面感染以及治疗感染性创伤方面就暴露出本身的不足。
为应对感染问题,现今有为数不多的抗感染敷料获得专利授权,或已应用于临床。这些敷料中都含有抗菌成分,如天然产物壳聚糖及其衍生物、纳米银、甚至一些药物成分。早在1979年,Allan就指出,壳聚糖具有安全广谱的抗菌性能。不过壳聚糖的抗菌性能受pH值、相对分子质量、脱乙酰度的影响,一般pH值5.5~6.5、相对分子质量在104~105范围内时抗菌性较好,随着脱乙酰度的增加而出现极值。由于壳聚糖水溶性较差,限制其应用范围,而且壳聚糖的抑菌性能与溶解以及溶解所呈的阳离子性有关,为了更好的发挥壳聚糖的抗菌活性,研究人员开始对其进行改性,以壳聚糖衍生物制备出抗菌敷料。中国专利CN102552966B公开了一种高吸湿性的海藻酸盐抗菌敷料,该敷料通过海藻酸盐、水溶性壳聚糖衍生物或水溶性甲壳素衍生物混合制得溶液作为纺丝原液;在凝固浴中加入抗菌剂,经湿法纺丝制得海藻酸盐纤维制品,再制得海藻酸盐抗菌敷料。但是该方法在凝固浴中进行,无疑增加了实际操作的复杂性和难度。专利ZL 2011 10082863.4和ZL2011120094847.2也授权了相关的成果。壳聚糖虽然广泛存在于自然界中,但提取还是比较困难,其抗菌性受多种因素影响,并且主要适用于感染程度较低的情况,这大大限制了它在敷料中的应用推广。
另外,含银敷料是一种新型的抗感染敷料,由于其特有的杀菌及抗炎作用,目前临床上广泛应用于各类难治性伤口。基于银特有的抗菌性能,其敷料有阻碍包括细菌、真菌在内的各类微生物与宿主细胞竞争氧气与养分,抑制代谢毒素的产生、下调生长因子表达及局部抗炎作用,有效控制伤口环境中微生物的生长,从而显著改善伤口的愈合。可是,银的毒性及其致色性等副作用,也使得它的应用受到争议与质疑。
临床上也有在纤维型敷料里加入磺胺嘧啶、庆大霉素、青霉素、环丙沙星及头胞他啶等抗生素制得抗菌敷料,并用于治疗烧创伤。由于抗生素抗菌起效迅速,但长期使用易使细菌产生耐药性,时至今日,一些细菌已很难用抗生素杀灭。
三氯生,学名“二氯苯氧氯酚”,化学分子式为C12H7Cl3O2,又名“三氯新”、“三氯沙”等,三氯生常态为白色或灰白色晶状粉末,稍有酚臭味。不溶于水,易溶于碱液和有机溶剂。三氯生是一种广谱抗菌剂,被广泛应用于肥皂、牙膏等日用化学品之中。现有技术中公开了将三氯生添加在医用棉纱敷料中来制备抗菌敷料,由于三氯生不溶于水因此需要经过复杂的前处理才可以有效负载,另外由于敷料种类的不同,三氯生的负载效果往往会呈现巨大差异。同时,三氯生作为一种小分子抗菌剂,具有持效性短,利用率不高等问题,而且容易发生迁移,对细胞造成毒害性。
发明内容
本发明要解决的技术问题是克服现有抗菌剂和抗菌敷料的缺陷和不足,提供一种含三氯生的有机纳米抗菌剂。所述抗菌剂比表面巨大,利用率高;有机纳米粒子结构稳定、无毒、不会迁移进入环境与人体、不团聚,易分散,可负载于常规的纤维态医用敷料上,具有较大的应用前景。
本发明的目的是提供一种含三氯生的有机纳米抗菌剂。
本发明的另一目的是提供上述有机纳米抗菌剂的制备方法。
本发明的再一目的是提供上述有机纳米抗菌剂的应用。
本发明的上述目的是通过以下技术方案给予实现的:
本发明通过先合成含三氯生的有机单体,再通过两步加料的方式乳液聚合得到含三氯生的有机纳米抗菌剂。
本发明首先提供一种含三氯生的单体的制备方法,具体为:往有机溶剂中加入物质量比为1:1~1:1.5的酰氯与三氯生,在惰性气体保护下,40~80℃油浴,搅拌反应12~36h;反应结束后,旋转蒸发40~60 min,用强碱溶液洗涤3~4次,再经干燥、旋转蒸发,得到含三氯生的单体。
优选地,所述酰氯为丙烯酰氯或甲基丙烯酰氯。
优选地,所述有机溶剂为丙酮、丁酮或乙醚。
优选地,所述强碱溶液为5~15%氢氧化钠溶液。
优选地,所述干燥为无水碳酸钾干燥。
同时,由上述方法制备得到的含三氯生的单体及其在制备抗菌剂方面的应用亦在本发明保护范围内。
优选地,所述含三氯生的单体为甲基丙烯酸三氯生酯或丙烯酸三氯生酯。
一种含三氯生的有机纳米抗菌剂的制备方法,首先以水为分散介质,加入有机单体、乳化剂,搅拌混匀后加入适量引发剂引发聚合反应;然后加入有机单体与上述含三氯生的单体的混合单体,再次聚合反应,即得表面带三氯生结构的纳米聚合物抗菌剂乳液。
本发明通过两步加料的方式,首先使常规的有机单体在乳化剂和引发剂的作用下发生乳液聚合,生成的反应产物作为第二次乳液聚合的反应载体。通过往第一次乳液聚合反应产物中加入常规有机单体与含三氯生的单体的混合单体,再次发生乳液聚合,最终得到聚合物分散液;避免了三氯生抗菌基团被包裹在聚合物内,使三氯生抗菌基团暴露在聚合物表面,有效发挥抗菌活性。
具体地,包括如下步骤:
S1.以水为分散介质,加入有机单体、乳化剂,升温至30~40℃,搅拌混匀;
S2.在惰性气体保护下,往步骤S1混合溶液加入引发剂,并控制搅拌速度为100~200r/min,升温至70~80℃,聚合反应1~2h;
S3.往步骤S2的反应产物中滴加有机单体与上述含三氯生的单体的混合单体,继续聚合反应1~2h,得到聚合物分散液;
S4.将聚合物分散液脱气处理得到纳米聚合物抗菌剂乳液;
步骤S1所述有机单体浓度为1%~20%,乳化剂浓度为1%~4%
步骤S3所述有机单体与含三氯生的单体的物质量比为1:1~1:1.5。
本发明所述有机单体在第一次乳液共聚反应中作为共聚单体,其共聚产物作为第二次乳液聚合反应的载体;同时由于制备得到的含三氯生的单体为黄色油状产物无法滴加,因而选择常规的有机单体作为稀释单体与其共混使第二次乳液聚合反应顺利进行;本发明可以选择本领域常规聚合单体,作为一种优选方案,所述有机单体为苯乙烯、丙烯酸甲酯、甲基丙烯酸甲酯或丙烯腈中的一种或多种。
优选地,所述乳化剂为阳离子乳化剂,阳离子乳化剂可使纳米聚合物表面带正电荷;由于细菌表面为负电荷,聚合物可以牢牢吸附在细菌上,发挥抗菌活性。
更优选地,所述阳离子乳化剂为为十二烷基三甲基氯化铵、十六烷基三甲基氯化铵、十八烷基三甲基氯化铵或十二烷基二甲基胺。
优选地,步骤S1所述搅拌速度为400~500 r/min。
优选地,步骤S2所述引发剂用量为单体总质量的0.1%~2%。
优选地,所述引发剂为水溶性引发剂。
更优选地,所述水溶性引发剂为过硫酸钾或过硫酸铵。
优选地,将步骤S3所述聚合物分散液干燥处理即可得到固态的纳米聚合物抗菌剂。
同时,由上述制备方法制备得到的的含三氯生的有机纳米抗菌剂亦在本发明保护范围内。
本发明所述含三氯生的有机纳米抗菌剂由于具有抗菌活性,可用以制备相应的抗菌材料,因此所述含三氯生的有机纳米抗菌剂在制备抗菌材料中的应用也在本发明保护范围内。
优选地,所述抗菌材料为抗菌敷料。
本发明还提供一种抗菌敷料,所述抗菌敷料负载有上述含三氯生的有机纳米抗菌剂。
所述抗菌敷料的制备方法,包括如下步骤:
S1.将上述含三氯生的有机纳米抗菌剂分散到介质中,制成浓度为500~3000 mg/L的分散液;
S2.将纤维态敷料浸没于步骤S1的分散液中,经沥干、烘干,得到负载有含三氯生的有机纳米抗菌剂的抗菌敷料。
优选地,所述介质为水或乙醇与水体积比为3:7~9:1的混合液。
优选地,所述浸没时间为10~60s。
优选地,所述烘干温度为60~95℃。
所述纤维态敷料为医用纱布,医用全棉无纺布,医用水刺无纺布或医用针刺无纺布等。
所述医用水刺无纺布包括全棉无纺布、羧甲基纤维无纺布等;
所述医用针刺无纺布是以藻酸盐纤维或以藻酸盐纤维为主的敷料。
本发明有机纳米抗菌剂通过将具有杀菌功能的三氯生抗菌基团共价结合高分子链上制备而成,产物以纳米形态存在。所述杀菌剂不仅可以解决传统小分子抗菌剂的持效期短的问题,还能降低或消除小分子抗菌剂对细胞的毒性,也可以重复利用。同时,由于杀菌基团在高分子链上的分布与密度可以调控,可以通过结构设计制得性能优异的高分子抗菌剂。
与现有技术相比,本发明具有以下有益效果:
(1)本发明制备得到的抗菌剂对菌液浓度为106cfu/mL的金黄色葡萄球菌、大肠杆菌、白色念珠菌、绿浓杆菌等g-、g+致病菌的杀灭率高于99.9%。
(2)本发明制备得到的该抗菌剂比表面巨大,利用率高;
(3)本发明所述有机纳米抗菌剂粒子结构稳定、无毒、不会迁移进入环境与人体、不团聚,易分散,可负载于常规的纤维态医用敷料上;
(4)本发明所述有机纳米抗菌剂不会使皮肤变色,可以取代银(Ag或Ag+)而制得安全的抗感染敷料,具有较大的应用前景。
(5)本发明所述有机纳米抗菌剂通过改进的乳液聚合方法用有机单体进行制备,相较于其它抗菌剂的制备来说,过程相对简单,成本相对低廉。
具体实施方式
以下结合具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,以下实施例所用试剂和材料均为市购。
实施例1 带三氯生结构的单体制备
在烧瓶中加入甲基丙烯酰氯与三氯生,两者物质量比为1:1.2,并以丁酮作溶剂,在氮气保护及无水环境中,50℃油浴搅拌反应36 h。反应结束后,经旋转蒸发60 min,再用5%氢氧化钠溶液洗涤3次,再经无水碳酸钾干燥、旋蒸,得到油状产物甲基丙烯酸三氯生酯,置入冰箱中备用。
实施例2 带三氯生结构的单体制备
在烧瓶中加入丙烯酰氯与三氯生,两者物质量比为1:1.5,并以丙酮作溶剂,在氮气保护及无水环境中,45℃油浴搅拌反应24 h。反应结束后,经旋转蒸发50 min,再用10%氢氧化钠溶液洗涤3次,再经无水碳酸钾干燥、旋蒸,得到油状产物丙烯酸三氯生酯,置入冰箱中备用。
实施例3 抗菌剂的制备及负载
1、(1)在装有搅拌器、冷凝管和温度计的250 ml四口反应瓶中,加入50 g H20、5 g甲基丙烯酸甲酯和3 g十六烷基三甲基氯化铵,水浴加热,在35℃下,以450 r/min速度搅拌,通入N2 20 min,除氧后加入由0.1 g 过硫酸钾溶于5 mL水的引发剂溶液,将转速降为100 r/min,温度升至70℃,1.5 h后滴加由8 g甲基丙烯酸三氯生酯和2 g甲基丙烯酸甲酯混合的单体,再聚合1.5 h后得到固含量为20%的纳米聚合物分散液,该纳米粒子的平均粒径为68nm,抗菌率为99.92%。
(2)将厚度为0. 35 mm、吸水率为0.05 g/ cm2的医用纱布裁成5 cm × 5cm大小试样,并2层相叠,同时将步骤(1)制得的抗菌剂分散液稀释成1500 mg/L的分散液,随后将纱布在稀释后的分散液中浸10 s,取出、沥干和烘干,得到负载量为0.45 mg/ cm2的抗感染纱布。
2、在内有凝固琼脂的培养皿中涂20μL 105cfu/mL大肠杆菌,随即将该抗感染纱布平铺于琼脂表面,培养24 h,再移去纱布,纱布覆盖区未见菌落。
实施例4 抗菌剂的制备及负载
1、(1)在装有搅拌器、冷凝管和温度计的250 ml四口反应瓶中,加入55 g H20、6 g苯乙烯和3.5 g十二烷基二甲基胺,水浴加热,在35℃下,以400 r/min速度搅拌,通入N2 30min,除氧后加入由0.12 g 过硫酸铵溶于5 mL水的引发剂溶液,将转速降为150 r/min,温度升至75℃,1.2 h后滴加由6 g丙烯酸三氯生酯和4 g丙烯腈混合的单体,再聚合1.2 h后得到固含量为21%的纳米聚合物分散液,该纳米粒子的平均粒径为76 nm,抗菌率为99.96%。
(2)将厚度为0. 35 mm、吸水率为0.05 g/ cm2的医用全棉无纺布裁成3 cm×3 cm大小试样,同时将步骤(1)制得的抗菌剂分散液稀释成1000 mg/L的分散液,随后将全棉无纺布在稀释后的分散液中浸30 s,取出、沥干和烘干,得到负载量为0.05 mg/ cm2的抗感染全棉无纺布敷料。
2、在内有凝固琼脂的培养皿中涂20μL 105cfu/mL金黄色葡萄球菌,随即将该抗感染全棉无纺布平铺于琼脂表面,培养24 h,再移去全棉无纺布,覆盖区未见菌落。
实施例5 抗菌剂的制备及负载
1、(1)在装有搅拌器、冷凝管和温度计的250 ml四口反应瓶中,加入60 g H20、10 g丙烯酸甲酯和5 g十二烷基三甲基氯化铵,水浴加热,在40℃下,以450 r/min速度搅拌,通入N2 30 min,除氧后加入由0.15 g 过硫酸铵溶于5 mL水的引发剂溶液,将转速降为200 r/min,温度升至80℃,1 h后滴加由8 g丙烯酸三氯生酯和4 g丙烯酸甲酯混合的单体,再聚合1 h后得到固含量为25%的纳米聚合物分散液,该纳米粒子的平均粒径为70 nm,抗菌率为99.93%。
(2)将厚度为 0.36 mm、吸水率为0.05g/ cm2的医用羧甲基纤维无纺布裁成3 cm×3 cm大小试样,同时将步骤(1)制得的抗菌剂分散液稀释成1500 mg/L的分散液,随后将水刺无纺布在稀释后的分散液中浸20 s,取出、沥干和烘干,得到负载量为 0.07 mg/ cm2的抗感染水刺无纺布敷料。
2、在内有凝固琼脂的培养皿中涂20μL 105cfu/mL大肠杆菌,随即将该抗感染水刺无纺布平铺于琼脂表面,培养24 h,再移去水刺无纺布,覆盖区未见菌落。
实施例6 抗菌剂的制备及负载
1、(1)在装有搅拌器、冷凝管和温度计的250 ml四口反应瓶中,加入50 g H20、6 g丙烯腈和4 g十八烷基三甲基氯化铵,水浴加热,在30℃下,以500 r/min速度搅拌,通入N2 30min,除氧后加入由0.15 g 过硫酸铵溶于5 mL水的引发剂溶液,将转速降为200 r/min,温度升至75℃,2 h后滴加由7 g甲基丙烯酸三氯生酯和3 g苯乙烯混合的单体,再聚合2 h后得到固含量为23%的纳米聚合物分散液,该纳米粒子的平均粒径为68 nm,抗菌率为99.97%。
(2)将厚度为0.36 mm、吸水率为0.05 g/ cm2的医用羧甲基纤维无纺布裁成3 cm×3cm大小试样,同时将步骤(1)制得的抗菌剂分散液稀释成3000 mg/L的分散液,随后将水刺无纺布在稀释后的分散液中浸20 s,取出、沥干和烘干,得到负载量为0.15 mg/ cm2的抗感染水刺无纺布敷料。
2、在内有凝固琼脂的培养皿中涂20μL 105cfu/mL金黄色葡萄球菌,随即将该抗感染水刺无纺布平铺于琼脂表面,培养24 h,再移去水刺无纺布,覆盖区未见菌落。
实施例7 抗菌剂的制备及负载
1、(1)在装有搅拌器、冷凝管和温度计的250 ml四口反应瓶中,加入50 g H20、4 g苯乙烯和4 g十二烷基三甲基氯化铵,水浴加热,在40℃下,以400 r/min速度搅拌,通入N2 30min,除氧后加入由0.12 g 过硫酸铵溶于5 mL水的引发剂溶液,将转速降为150 r/min,温度升至75℃,1.2 h后滴加由7 g丙烯酸三氯生酯和2 g苯乙烯混合的单体,再聚合1 h后得到固含量为21%的纳米聚合物分散液,该纳米粒子的平均粒径为71 nm,抗菌率为99.95%。
(2)将厚度为1 mm、吸水率为0.2 g/ cm2的医用藻酸盐无纺布裁成3 cm×3cm大小试样,同时将步骤(1)制得的抗菌剂分散液用V(乙醇):V(水)为9:1的混合液稀释成1000mg/L的分散液,随后将针刺无纺布在稀释后的分散液中浸15 s,取出、沥干和烘干,得到负载量为0.15 mg/ cm2的抗感藻酸盐无纺布敷料。
2、在内有凝固琼脂的培养皿中涂20μL 105cfu/mL金黄色葡萄球菌,随即将该抗感染藻酸盐无纺布平铺于琼脂表面,培养24 h,再移去,藻酸盐无纺布覆盖区未见菌落。
实施例8 抗菌剂的制备及负载
1、(1)在装有搅拌器、冷凝管和温度计的250 ml四口反应瓶中,加入50 g H20、5 g丙烯腈和5 g十六烷基三甲基氯化铵,水浴加热,在40℃下,以500 r/min速度搅拌,通入N2 30min,除氧后加入由0.12 g 过硫酸铵溶于5 mL水的引发剂溶液,将转速降为150 r/min,温度升至75℃,1.2 h后滴加由7 g丙烯酸三氯生酯和4 g丙烯腈混合的单体,再聚合2 h后得到固含量为26%的纳米聚合物分散液,该纳米粒子的平均粒径为73 nm,抗菌率为99.91%。
(2)将厚度为1 mm、吸水率为0.2 g/ cm2的医用藻酸盐无纺布裁成3 cm×3cm大小试样,同时将步骤(1)制得的抗菌剂分散液用V(乙醇):V(水)为9:1的混合液稀释成3000mg/L的分散液,随后将针刺无纺布在稀释后的分散液中浸15 s,取出、沥干和烘干,得到负载量为0.55 mg/ cm2的抗感藻酸盐无纺布敷料。
2、在内有凝固琼脂的培养皿中涂20μL 105cfu/mL大肠杆菌,随即将该抗感染藻酸盐无纺布敷料平铺于琼脂表面,培养24 h,再移去,敷料覆盖区未见菌落。
Claims (1)
1.一种抗菌敷料的制备方法,其特征在于,包括如下步骤:
(1)将含三氯生的有机纳米抗菌剂分散到介质中,制成浓度为500~3000mg/L的分散液;
(2)将纤维态敷料浸没于步骤S1的分散液中,经沥干、烘干,得到负载有含三氯生的有机纳米抗菌剂的抗菌敷料;
所述含三氯生的有机纳米抗菌剂的制备方法,包括如下步骤:
S1.以水为分散介质,加入有机单体、乳化剂,升温至30~40℃,搅拌混匀;
S2.在惰性气体保护下,往步骤S1混合溶液加入引发剂,并控制搅拌速度为100~200r/min,升温至70~80℃,聚合反应1~2h;
S3.往步骤S2的反应产物中滴加有机单体与含三氯生的单体的混合单体,继续聚合反应1~2h,得到聚合物分散液;
S4.将聚合物分散液脱气处理得到纳米聚合物抗菌剂乳液;
步骤S1所述有机单体浓度为1%~20%,乳化剂浓度为1%~4%;
步骤S3所述有机单体与含三氯生的单体的物质量比为1:1~1:1.5;
所述乳化剂为十二烷基三甲基氯化铵、十六烷基三甲基氯化铵、十八烷基三甲基氯化铵或十二烷基二甲基胺;
所述引发剂为过硫酸钾或过硫酸铵;
所述含三氯生的单体的制备方法为往有机溶剂中加入物质量比为1:1~1:1.5的酰氯与三氯生,在惰性气体保护下,40~80℃油浴,搅拌反应12~36h;反应结束后,旋转蒸发40~60min,用强碱溶液洗涤3~4次,再经干燥、旋转蒸发,得到含三氯生的单体;所述酰氯为丙烯酰氯或甲基丙烯酰氯;步骤S2所述引发剂用量为单体总质量的0.1%~2%。
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