CN112795030A - 一种载药抗黏附隐形眼镜水凝胶材料及制备方法 - Google Patents
一种载药抗黏附隐形眼镜水凝胶材料及制备方法 Download PDFInfo
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Abstract
本发明涉及高分子水凝胶技术领域,尤其涉及一种载药抗黏附隐形眼镜水凝胶材料及制备方法,所述载药抗黏附隐形眼镜水凝胶材料由甲基丙烯酸羟乙酯、丙烯酸、两性离子单体与疏水单体共聚后负载药物而成。本发明的载药抗黏附隐形眼镜水凝胶材料具有良好的透光度、一定的载药能力并能实现药物的缓释、稳定的脱水‑补液性能、较高的含水量和稳定的保水率、优异的抗蛋白、抗细菌黏附性能;制备方法简洁、高效且环保,对设备无特殊要求,对环境友好,易于产业化。
Description
技术领域
本发明涉及高分子水凝胶技术领域,尤其涉及一种载药抗黏附隐形眼镜水凝胶材料及制备方法。
背景技术
水凝胶是一种由物理相互作用或者化学反应使亲水性聚合物交联形成三维网络结构的材料,能够在水中充分溶胀而不溶解。近年来,水凝胶在各个领域的应用越来越广泛,如隐形眼镜材料、组织工程、伤口敷料、海水淡化等。
在实际应用中,水凝胶在多次脱水-补液循环后依旧能保持稳定的性能具有重要意义。例如,隐形眼镜材料在佩戴使用的过程中,会因水分蒸发导致脱水,重新浸入护理液中则吸收水分,在此过程中可能会发生补液能力下降的情况导致隐形眼镜材料的性能如形状、厚度、曲率等发生变化,影响后续使用。因此,制备具有可控的润湿和溶胀性能的凝胶材料至关重要。
由于眨眼和泪液的清除作用,普通市售眼药水的生物利用率通常不足10%。而将隐形眼镜负载药物后,可作为药物传输系统治疗青光眼等慢性、急性疾病。水凝胶良好的溶胀性能可以吸收药物溶液达到负载药物的作用,药物在角膜表面的接触时间增加,能够提高药物的生物利用度。进一步将药物与隐形眼镜材料之间通过特殊的作用力结合,可以提高药物的负载量和稳定释放能力。
在隐形眼镜佩戴和使用过程中,由于眼部分泌的蛋白以及外界细菌的在材料表面的粘附,是影响隐形眼镜使用期限以及眼部卫生安全的重要因素。两性离子材料因其优异的防污性能而被广泛应用于生物医学和工程应用中。两性离子聚合物分子链上同时带有阴、阳离子基团,可以通过溶剂化作用强烈结合水分子,产生排斥力,能够有效地抵抗蛋白质或者细菌、细胞的黏附。
发明内容
本发明为了克服上述现有技术中存在的问题,提供了一种具有稳定的脱水-补液性能、优异的抗蛋白、抗细菌黏附性能、良好透光度的载药抗黏附隐形眼镜水凝胶材料,该水凝胶具有一定的载药能力并能实现药物的缓释。
本发明还提供了一种载药抗黏附隐形眼镜水凝胶材料的制备方法,该方法简洁、高效且环保,对设备无特殊要求,对环境友好,易于产业化。
为了实现上述目的,本发明采用以下技术方案:
一种载药抗黏附隐形眼镜水凝胶材料,所述载药抗黏附隐形眼镜水凝胶材料由甲基丙烯酸羟乙酯、丙烯酸单体、两性离子单体与疏水单体共聚后负载药物而成。其中甲基丙烯酸羟乙酯中的羟基基团赋予水凝胶较好的亲水性并且与诺氟沙星单体间产生氢键增强载药能力,丙烯酸中的羧基与诺氟沙星单体的氨基之间产生静电作用力赋予水凝胶良好的载药能力,两性离子部分赋予水凝胶优异的抗黏附性能并且改善疏水单体在预液中的溶解性,疏水单体用于调节水凝胶的溶胀性能。
作为优选,所述两性离子单体为磺酸甜菜碱甲基丙烯酸甲酯(SBMA)或者羧酸甜菜碱甲基丙烯酸甲酯(CBMA);优选磺酸甜菜碱甲基丙烯酸甲酯(SBMA)。
所述疏水单体为甲基丙烯酸甲酯(MMA);
所述药物为诺氟沙星或萨马洛尔。
作为优选,所述载药抗黏附隐形眼镜水凝胶材料的最大透光度为95%,具有较高的含水量和稳定的保水率,具有较高的载药能力,具有优异的抗蛋白、抗菌黏附性能。
一种载药抗黏附隐形眼镜水凝胶材料的制备方法,包括以下步骤:
(1)配制甲基丙烯酸羟乙酯、丙烯酸、两性离子单体、疏水单体、交联剂和引发剂混合溶液;
(2)对混合溶液进行除氧,并除去混合溶液中的气泡,得到预液;
(3)将预液密封于透光模具中,紫外光照射反应,得水凝胶;
(4)将水凝胶冻干后再浸入药物溶液中至溶胀平衡,即得载药抗黏附隐形眼镜水凝胶材料。
作为优选,步骤(1)中,所述混合溶液中各组分的质量百分浓度为:甲基丙烯酸羟乙酯5~40wt%,两性离子单体5~40wt%,丙烯酸单体0.5~2.5wt%,疏水单体2~10wt%,交联剂0.2~2wt%,引发剂0.2~1wt%。所述配置过程为将甲基丙烯酸羟乙酯、丙烯酸、两性离子单体、疏水单体、交联剂和引发剂溶解于溶剂中随后搅拌均匀;所述溶剂包括水。
作为优选,步骤(1)中,所述引发剂为2-羟基-4-(2-羟乙氧基)-2-甲基苯丙酮(I2959),I2959赋予水凝胶单体较高的引发速率。
作为优选,步骤(1)中,所述交联剂为分子量为550或750的聚乙二醇二甲基丙烯酸酯;优选分子量为550的聚乙二醇二甲基丙烯酸酯。
作为优选,步骤(2)中,所述除氧通过通入氮气或惰性气体降低氧气溶解性的方式进行;所述去除混合溶液中气泡的方法为超声。
作为优选,步骤(3)中:所述透光模具包括玻璃模具;所述紫外光照射反应时选用波长为365nm的紫外光;所述紫外光照射反应时长为3~4h,优选为3h。
作为优选,步骤(4)中,所述药物为诺氟沙星或萨马洛尔,所述药物溶液的浓度为240~260μg/mL,更优选为250μg/mL。
因此,本发明具有如下有益效果:
(1)本发明的载药抗黏附隐形眼镜水凝胶材料具有良好的透光度、一定的载药能力并能实现药物的缓释、稳定的脱水-补液性能、较高的含水量和稳定的保水率、优异的抗蛋白、抗细菌黏附性能;
(2)制备方法简洁、高效且环保,对设备无特殊要求,对环境友好,易于产业化。
附图说明
图1为本发明实施例4~7所制得的水凝胶的透光度;
图2为本发明实施例4~7所制得的水凝胶的溶胀性能;
图3为本发明实施例4~7所制得的水凝胶反复脱水-溶胀(在去离子水中溶胀)质量变化率曲线图;
图4为本发明实施例4~7所制得的水凝胶含水率及保水率曲线(A为室温下实施例4~7所制得的水凝胶的含水量(去离子水中溶胀);B为室温下实施例4~7所制得的水凝胶的保水率(去离子水中溶胀);C为室温下实施例4~7所制得的水凝胶的含水量(市售护理液中溶胀);D为室温下实施例4~7所制得的水凝胶的保水率(市售护理液中溶胀);
图5为本发明实施例4所制得的水凝胶的细胞相容性;
图6为本发明实施例4~7所制得的水凝胶的载药量;
图7为本发明实施例4~7所制得的水凝胶的释药曲线;
图8为本发明实施例4~7所制得的水凝胶与市售隐形眼镜的抗蛋白黏附情况;
图9为本发明实施例4~7所制得的水凝胶与市售隐形眼镜的抗大肠杆菌黏附情况。
具体实施方式
下面通过具体实施例,并结合附图,对本发明的技术方案作进一步具体的说明。
在本发明中,若非特指,所有设备和原料均可从市场购得或是本行业常用的,下述实施例中的方法,如无特别说明,均为本领域常规方法。
实施例1~9
一种新型可用作隐形眼镜的载药抗黏附水凝胶的制备方法,所述制备方法包括以下制备步骤:
1)配制甲基丙烯酸羟乙酯、丙烯酸、两性离子单体、疏水单体、交联剂和引发剂混合溶液;
2)对混合溶液进行除氧,并超声除去混合溶液中的气泡,得到预液;
3)将预液密封于透光玻璃模具中,波长为365nm的紫外光照射反应5h制备水凝胶;
4)将水凝胶冻干后再浸入药物溶液中至溶胀平衡,即得到所述新型载药抗黏附水凝胶。
其中,步骤1)所述引发剂为I2959,所述交联剂为PEGDMA(Mn=550),混合溶液的溶剂均为去离子水;所述两性离子单体为SBMA,所述疏水单体为MMA,所述药物为诺氟沙星。
步骤1)配料如下表表1所示。
表1.实施例1-9的配料表。
依照表1配料、表2的制备参数进行制备,并在制备结束后对实施例1~9步骤(3)所制得的水凝胶进行性能测试。
所述性能测试包括以下几个方面:
(1)透光度测试:制备直径为2.5cm的圆形水凝胶样品,用紫外/可见/近红外分光光度计测定样品的透光率。
(2)脱水-补液测试:将水凝胶片状样品放置于50℃烘箱内1h,称重记为W1;随后将称重后的水凝胶样品放入去离子水中至溶胀平衡,称重记为W2。上述步骤重复七次循环。原始水凝胶样品的质量为W0。每种样品重复测试三次取平均值。根据以下公式求水凝胶质量变化率。
(3)含水量及保水率测试:将水凝胶样品放置于室温下,放置不同时间的水凝胶样品称重记为Wt,完全烘干的水凝胶样品称重记为Wd。将溶胀平衡时的水凝胶质量记为Ws。根据以下公式求得水凝胶含水量及保水率。
(4)载药及释药测试:将冻干的水凝胶浸泡入250μg/mL的诺氟沙星溶液中,避光过夜。用酶标仪(DG5033A)测量273nm处浸泡前后药物溶液的吸光度,求得水凝胶的载药量。将负载诺氟沙星后的水凝胶浸泡入10mL磷酸缓冲液中,放置于37℃水浴锅中,隔一段时间取出1mL液体,用酶标仪测量273nm处的吸光度,得到水凝胶的释药曲线。
(5)抗蛋白黏附性能测试:将溶胀、杀菌后的水凝胶片状样品置于24孔板中,向每个孔中加入1mL以辣根过氧化物酶标记的羊抗人球蛋白(HRP-IgG),在37℃培养箱中放置12h后,取出一部分样品在PBS缓冲液中超声1min。将处理过的样品放入新的24孔板中,将含有1μg/mL邻苯二胺和0.03%过氧化氢的1mL 0.1M柠檬酸盐-磷酸盐缓冲液(pH=5)加入孔中,15min后加入2mL 2M H2SO4终止反应。取上清液用酶标仪在492nm处测定光密度(OD)值,实验结果为三次实验的平均值。另一部分样品在市售隐形眼镜护理液中超声1min后,重新加入新鲜蛋白质溶液,重复上述步骤,循环五次。
(6)抗菌性能测试:将溶胀、杀菌后的水凝胶片状样品置于12孔板中,向每个孔中加入1mL光密度(OD)为0.1的大肠杆菌菌液,然后将12孔板放置于摇床中,设置温度为37℃,转速为120rpm,使样品与菌液共培养24h。共培养结束后,将样品从菌液中取出,在PBS缓冲液中超声1min后,在无光环境中用染料染色10min,用倒置荧光显微镜观察细菌在样品表面的黏附情况。
(7)体外细胞毒性实验:将L929细胞接种在96孔板中,每孔密度为5×104,在37℃下培养24h。然后,用200μL具有不同浓度的水凝胶渗滤液替换细胞培养基,并继续培养细胞24h。随后,除去培养基并加入200μL MTT溶液(0.5mg/mL)。反应4h后,用150μL二甲基亚砜代替培养基。最后,将孔板置于酶标仪(DG5033A)中,在492nm处测量孔中溶液的吸光度。将结果定义为相对于未处理的细胞的细胞活力的平均百分比,计算如下
在水凝胶渗滤液存在下获得ODtreated,在不存在水凝胶渗滤液的情况下获得ODcontrol,并且在不存在水凝胶渗透物和细胞的情况下获得ODblank。在独立的平行样品上测量OD值四次。
实施例4~7所制得的水凝胶的透光度如图1所示,其中实施例7所述配方制备的水凝胶具有最高的透光度,在可见光波长内大于95%。
实施例4~7所制得的水凝胶的溶胀曲线如图2所示,实施例4~7所述配方制备的水凝胶的溶胀率分别为19.95%,58.76%,87.42%,121.24%。
实施例4~7所制得的水凝胶在去离子水中重复脱水-补液的质量变化率如图3所示,实施例4~7所述配方制备的水凝胶均具有稳定的脱水-补液能力。
实施例4~7所制得的水凝胶的含水量及保水率如图4所示,随着SBMA含量的增加,水凝胶的含水量和保水率增大,实施例7所述配方制得的水凝胶具有最高的含水量和最强的保水能力。
实施例4所制得的水凝胶的细胞相容性如图5所示,在与不同浓度的水凝胶浸出液培养不同时间后,细胞存活率均高于85%。
实施例4~7所制得的水凝胶的载药量如图6所示,其中实施例7所制得的水凝胶具有最高的载药能力,为11.66mg/mL。
实施例4~7所制得的水凝胶的释药曲线如图7所示,实施例4~7所制得的水凝胶均具有稳定的释药能力。
实施例4~7所制得的水凝胶的抗蛋白黏附情况如图8所示,实施例7所制得的水凝胶具有最低的蛋白吸附率,在7个循环实验中均低于市售隐形眼镜表面的蛋白吸附率。
实施例4~7所制得的水凝胶的抗大肠杆菌黏附情况如图9所示,实施例4~7所制得的水凝胶均具有优异的抗大肠杆菌黏附性能。
通过上述大量的实验结果表明,本发明技术方案所制得的载药抗黏附水凝胶确实具有良好的透光度、一定的载药能力并能实现药物的缓释、稳定的脱水-补液性能、较高的含水量和稳定的保水率、优异的抗蛋白、抗细菌黏附性能,可用作制备隐形眼镜的理想材料。
以上所述仅为本发明的较佳实施例,并非对本发明作任何形式上的限制,在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。
Claims (10)
1.一种载药抗黏附隐形眼镜水凝胶材料,其特征在于,所述载药抗黏附隐形眼镜水凝胶材料由甲基丙烯酸羟乙酯、丙烯酸单体、两性离子单体与疏水单体共聚后负载药物而成。
2.根据权利要求1所述的一种载药抗黏附隐形眼镜水凝胶材料,其特征在于,
所述两性离子单体包括磺酸甜菜碱甲基丙烯酸甲酯或羧酸甜菜碱甲基丙烯酸甲酯;
所述疏水单体包括甲基丙烯酸甲酯;
所述药物为诺氟沙星或萨马洛尔。
3.根据权利要求1所述的一种载药抗黏附隐形眼镜水凝胶材料,其特征在于,所述载药抗黏附隐形眼镜水凝胶材料的最大透光度为95%。
4.一种如权利要求1-3任一所述的载药抗黏附隐形眼镜水凝胶材料的制备方法,其特征在于,包括以下步骤:
(1)配制甲基丙烯酸羟乙酯、丙烯酸、两性离子单体、疏水单体、交联剂和引发剂混合溶液;
(2)对混合溶液进行除氧,并除去混合溶液中的气泡,得到预液;
(3)将预液密封于透光模具中,紫外光照射反应,得水凝胶;
(4)将水凝胶冻干后再浸入药物溶液中至溶胀平衡,即得载药抗黏附隐形眼镜水凝胶材料。
5.根据权利要求4所述的制备方法,其特征在于,步骤(1)中,所述混合溶液中各组分的质量百分浓度为:甲基丙烯酸羟乙酯5~40wt%,两性离子单体5~40wt%,丙烯酸单体0.5~2.5wt%,疏水单体2~10wt%,交联剂0.2~2wt%,引发剂0.2~1wt%。
6.根据权利要求4所述的制备方法,其特征在于,步骤(1)中,所述引发剂为2-羟基-4-(2-羟乙氧基)-2-甲基苯丙酮。
7.根据权利要求4所述的制备方法,其特征在于,步骤(1)中,所述交联剂为分子量为550或750的聚乙二醇二甲基丙烯酸酯。
8.根据权利要求4所述的制备方法,其特征在于,步骤(2)中,所述除氧通过通入氮气或惰性气体降低氧气溶解性的方式进行;所述去除混合溶液中气泡的方法为超声。
9.根据权利要求4所述的制备方法,其特征在于,步骤(3)中:所述透光模具包括玻璃模具;所述紫外光照射反应时选用波长为365 nm的紫外光;所述紫外光照射反应时长为3~4h。
10.根据权利要求4所述的制备方法,其特征在于,步骤(4)中,所述药物为诺氟沙星或萨马洛尔,所述药物溶液的浓度为240~260μg/mL。
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