CN116603076B - 一种具有超疏水性能的药物结构涂层及其制备方法 - Google Patents
一种具有超疏水性能的药物结构涂层及其制备方法 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
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Abstract
本发明属于生物医用功能材料技术领域,具体涉及一种具有超疏水性能的药物结构涂层及其制备方法。本发明的制备方法利用酚胺化合物在氧化剂的作用下发生氧化、交联和聚合反应,在载药纳米颗粒外生成一层多酚纳米颗粒膜层,该多酚纳米膜层既充载药纳米颗粒的“保护层”及其之间的交联物质,也可将载药纳米颗粒固定在基底材料表面,经过反应和沉积后,可在基底材料表面形成一层具有微纳拓扑结构的药物纳米多级结构涂层。紫外交联仪在辐照过程中会产生大量的活性氧自由基,通过紫外辐照样品,活性氧自由基与药物涂层中的胶束保护层充分反应,使酚胺中的亲水性酚羟基转变为疏水性的醌基,微纳拓扑结构与疏水基团协同作用赋予了材料表面的超疏水性能。
Description
技术领域
本发明属于生物医用功能材料技术领域,具体涉及一种具有超疏水性能的药物结构涂层及其制备方法。
背景技术
通过研究自然界中具有超浸润现象的表面,发现超亲水和超疏水表面是由微/纳拓扑结构和化学基团协同实现的。据研究发现,在抗污材料中,超疏水表面比超亲水表面具有更为优异的阻抗粘附性能。超疏水材料也被广泛应用于除抗污领域以外的自清洁、防腐、降低流阻等领域,故受到科研工作者和工程技术人员的关注。然而目前阶段的研究从在如下缺点:
1、现阶段研究人员基于润湿模型理论,采用模板法、溶胶-凝胶法、化学修饰法、自组装法、热裂解法、化学沉积法、光刻蚀法等工艺方法,仿生制备具有不同水粘附力的超疏水材料表面,虽能达到所需应用性能,但仍存在仪器设备与反应原料价格昂贵、制备步骤繁琐、分层粗糙结构稳固度较低、反应参数较剧烈、损伤基底、难以在复杂结构材料表面实现等问题,并且所制备的微纳拓扑结构都是由惰性物质构建。
2、具体到实际应用,对于医用抗污材料(特别是长期血液接触材料,如血液接触导管、人工血管、血管支架、心脏瓣膜等),在与人体接触后,体内的蛋白质(特别是血浆蛋白)将快速的在材料表面粘附和变性,引发急性血栓和急性炎症反应,对植入材料的服役带来不良影响。因此材料植入初期的抗蛋白粘附性能对阻止急性血栓和急性炎症反应具有重要作用。然而,随着器械体内服役时间延长,超疏水与体液中的空气层终将被破坏,在超疏水性能失功后暴露出的疏水表面具有强粘附性能,体液中的蛋白质将在材料表面非特异性粘附和变性,并造成严重的血栓和炎症反应。另外,对于诸如动/静脉血管支架、人工血管、心脏瓣膜等器械,其材料表面虽在初期具有一定的抗污性能,但是长期使用时亦会产生抗凝、抗炎、抗菌和抗增生不佳的问题。
故基于现阶段上述问题,提出本发明技术方案。
发明内容
为了解决现有技术存在的问题,本发明提供了一种具有超疏水性能的药物结构涂层的制备方法,所述制备方法包括如下步骤:
(1)将载药纳米颗粒分散在溶剂中,得到载药纳米颗粒悬浊液;
(2)将所述载药纳米颗粒悬浊液与酚胺类化合物酸性缓冲液、氧化剂酸性缓冲液混合,得到混合液;
(3)在基底材料表面加入所述混合液进行反应,完成后清洗、干燥,得到改性基底材料;
(4)将所述改性基底材料进行紫外光辐照,即得到所述具有超疏水性能的药物结构涂层。
为便于理解本发明,对本发明的反应过程进行说明:
本发明首先将载药纳米颗粒均匀分散在溶剂中,在酸性环境下,再通过酚胺类化合物在氧化剂的作用下氧化、交联、聚合生成酚胺纳米颗粒(十纳米级)膜层,纳米膜层将载药纳米颗粒(百纳米级)均匀包裹的同时将其牢固固定在基底材料表面;通过多次反应进行反复沉积,从而获得均匀、致密的具有微纳拓扑结构的药物纳米多级结构表面。然后利用紫外辐照过程产生的活性氧自由基与涂层中的酚羟基发生氧化反应,将亲水性的酚羟基氧化为疏水性的醌基,改变涂层的润湿性,最终形成一个以药物为涂层主体成分的具有超疏水性能的药物结构涂层。该技术可用于如导管、血管支架、人工血管、心脏瓣膜、防腐蚀、水/油分离等材料及器械的表面改性处理。
优选地,步骤(1)中,所述载药纳米颗粒为载药高分子纳米颗粒(高分子纳米球和纳米囊)、载药纳米脂质体、载药聚合物胶束、载药树枝状大分子或载药无机纳米粒子中的一种。
优选地,步骤(1)中,所述溶剂为水溶液、乙醇溶液或水与乙醇的混合溶液;所述水与乙醇的混合溶液中,乙醇与水的体积比为0.1~5:0.1~5。
优选地,步骤(2)中,所述酚胺类化合物酸性缓冲液由酚胺类化合物和酸性缓冲液混合而成;所述酚胺类化合物为单宁酸、没食子酸、多巴胺、丹酚酸B、表没食子儿茶素没食子酸酯、表儿茶素没食子酸酯、表儿茶素、去甲肾上腺素、胺多酚、表没食子儿茶素、邻苯二酚、邻苯三酚中的一种或两种以上的组合。
优选地,步骤(2)中,所述氧化剂酸性缓冲液由氧化剂和酸性缓冲液混合而成;所述氧化剂为过氧化氢、过硫酸铵、氯化铜、浓硝酸、高碘酸钠、氯化铁,高锰酸钾、硝酸银、重铬酸钾中的一种或两种以上的组合。
优选地,步骤(2)中,所述酸性缓冲液的pH为3~7;所述酸性缓冲液为乙酸-乙酸盐缓冲液、2-(N-吗啡啉)乙磺酸缓冲液、甘氨酸-盐酸缓冲液、邻苯二甲酸-盐酸缓冲液、邻苯二甲酸氢钾-氢氧化钠缓冲液、磷酸氢二钠-柠檬酸缓冲液、柠檬酸-氢氧化钠-盐酸缓冲液或柠檬酸-柠檬酸钠缓冲液中的一种。
优选地,步骤(2)中,所述混合液中,载药纳米颗粒的浓度为0.5~10 mg/mL,酚胺类化合物的浓度为0.5~20 mg/mL,氧化剂的浓度为0.1~10 mg/mL。
优选地,步骤(3)中,所述基底材料为金属基生物材料、陶瓷基生物材料、高分子基生物材料或复合生物材料中的一种;所述反应的温度为10~40℃,反应的时间为0.1~10h,反应的次数为1~10次。
优选地,步骤(4)中,所述紫外光辐照的波长为365nm(UVA)、302nm(UVB)或254nm(UVC),所述紫外光辐照的时间为1~48h。
基于相同的技术构思,本发明的再一方案是提供一种上述制备方法得到的具有超疏水性能的药物结构涂层。
本发明的有益效果为:
1、本发明所述的制备方法,基于酚胺类化合物在氧化剂的作用下发生氧化、交联、聚合和沉积,只需要简单的“one-pot”法即可在载药纳米颗粒表面形成一层均匀的多酚纳米颗粒膜层,该多酚纳米颗粒膜层不但增加了载药纳米颗粒的稳定性,同时将载药纳米颗粒牢固固定在基底材料表面,开拓了载药纳米颗粒在超疏水表面的应用。且该多酚纳米颗粒膜层具有非材料依赖性,可以在不同形状和性能的基底材料表面进行修饰、改性,具有广泛的适用性。
2、传统方法制备的超疏水表面都不具有生物活性(惰性物质构建),单纯依赖超疏水性能实现被动抗污。本发明所述药物结构涂层实现了以药物为涂层构建的本体材料,只要涂层存在就有药物存在并长效发挥生物学功能的性能;由超疏水平台(被动抗污)与药物(主动抗污)协同维持材料微环境稳定性,为实现由人造抗污表面向天然抗污表面转化提供可能。
3、区别于通过物理浸涂和化学接枝在涂层中负载药物,本发明所述制备方法是将药物装载在纳米颗粒中(如聚合物胶束),极大的提高了涂层中药物的负载量。同时,所制备的载药纳米颗粒外表面有一层酚胺纳米膜保护层,在紫外辐照过程中可以有效保护药物的生物活性不被破坏,维持药物原有的生物学性能。
4、本发明操作简单,反应高效、条件温和,具有广谱实用性,可以将不同的载药纳米颗粒修饰在不同材料和形状的基底表面,制备出只要涂层存在就有药物存在并长效发挥生物学功能的超疏水药物纳米多级结构涂层。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为实施例1制得的具有超疏水性能的药物结构涂层的表面形貌扫描电子显微镜(SEM)图;
图2为实施例1制得的具有超疏水性能的药物结构涂层的动态水接触角图(a)和滚动角图(b);
图3为实施例1制得的具有超疏水性能的药物结构涂层长效抗菌的荧光染色图。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将对本发明的技术方案进行详细的描述。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的前提下所得到的所有其它实施方式,都属于本发明所保护的范围。
实施例1
本实施例提供一种具有超疏水性能的药物结构涂层的制备方法,所述制备方法包括如下步骤:
(1)将载药吐温-80(聚合物胶束)分散在乙醇/水的混合溶剂中,得到载药纳米颗粒悬浊液;其中,乙醇与水的体积比为1:4;
(2)将单宁酸、氯化铜分别用pH=5的乙酸钠缓冲液溶解,得到单宁酸缓冲液、氯化铜缓冲液;
(3)将所述载药纳米颗粒悬浊液、所述单宁酸缓冲液、所述氯化铜缓冲液混合,得到混合液;其中,载药纳米颗粒、单宁酸、氯化铜的浓度分别为2 mg/mL、1 mg/mL和0.5 mg/mL;
(4)在洁净的金属基生物材料表面加入混合液,在25℃下反应3 h后,用RO水充分清洗并再重复反应沉积2次,再氮气干燥,得到改性基底材料;
(5)将所述改性基底材料放入波长为254 nm的紫外交联仪(紫外交联仪在辐照过程中会产生大量的活性氧自由基)中充分辐照5 h,即得到具有超疏水性能的药物结构涂层。
实施例2
本实施例提供一种具有超疏水性能的药物结构涂层的制备方法,所述制备方法包括如下步骤:
(1)将载药聚乳酸纳米球(高分子纳米粒)分散在水中,得到载药纳米颗粒悬浊液;
(2)将多巴胺、高锰酸钾分别用pH=4的乙酸-乙酸盐缓冲液溶解,得到多巴胺缓冲液、高锰酸钾缓冲液;
(3)将所述载药纳米颗粒悬浊液、所述多巴胺缓冲液、所述高锰酸钾缓冲液混合,得到混合液;其中,载药纳米颗粒、多巴胺、高锰酸钾的浓度分别为5 mg/mL、2 mg/mL和2mg/mL;
(4)在洁净的高分子基生物材料表面加入混合液,在20℃下反应5h后,用RO水充分清洗并再重复反应沉积3次,再氮气干燥,得到改性基底材料;
(5)将所述改性基底材料放入波长为254 nm的紫外交联仪中充分辐照6 h,即得到具有超疏水性能的药物结构涂层。
实施例3
本实施例提供一种具有超疏水性能的药物结构涂层的制备方法,所述制备方法包括如下步骤:
(1)将载药卵磷脂(固体脂质纳米粒)分散在水中,得到载药纳米颗粒悬浊液;
(2)将表儿茶素没食子酸酯、氯化铁分别用pH=3.5的邻苯二甲酸-盐酸缓冲液溶解,得到表儿茶素没食子酸酯缓冲液、氯化铁缓冲液;
(3)将所述载药纳米颗粒悬浊液、所述表儿茶素没食子酸酯缓冲液、所述氯化铁缓冲液混合,得到混合液;其中,载药纳米颗粒、表儿茶素没食子酸酯、氯化铁的浓度分别为6mg/mL、3 mg/mL和3 mg/mL;
(4)在洁净的陶瓷基生物材料表面加入混合液,在15℃下反应10h后,用RO水充分清洗并再重复反应沉积5次,再氮气干燥,得到改性基底材料;
(5)将所述改性基底材料放入波长为365 nm的紫外交联仪中充分辐照8 h,即得到具有超疏水性能的药物结构涂层。
实施例4
本实施例提供一种具有超疏水性能的药物结构涂层的制备方法,所述制备方法包括如下步骤:
(1)将载药纳米脂质体分散在水中,得到载药纳米颗粒悬浊液;
(2)将去甲肾上腺素、过硫酸铵分别用pH=4的柠檬酸-柠檬酸钠缓冲液溶解,得到去甲肾上腺素缓冲液、过硫酸铵缓冲液;
(3)将所述载药纳米颗粒悬浊液、所述去甲肾上腺素缓冲液、所述过硫酸铵缓冲液混合,得到混合液;其中,载药纳米颗粒、去甲肾上腺素、过硫酸铵的浓度分别为2 mg/mL、1mg/mL和1 mg/mL;
(4)在洁净的金属基生物材料表面加入混合液,在35℃下反应1.5h后,用RO水充分清洗并再重复反应沉积1次,再氮气干燥,得到改性基底材料;
(5)将所述改性基底材料放入波长为302 nm的紫外交联仪中充分辐照2 h,即得到具有超疏水性能的药物结构涂层。
实施例5
本实施例提供一种具有超疏水性能的药物结构涂层的制备方法,所述制备方法包括如下步骤:
(1)将载药多孔二氧化硅纳米粒子(无机纳米粒子)分散在水中,得到载药纳米颗粒悬浊液;
(2)将表没食子儿茶素没食子酸酯、硝酸银分别用pH=6的甘氨酸-盐酸缓冲液溶解,得到表没食子儿茶素没食子酸酯缓冲液、硝酸银缓冲液;
(3)将所述载药纳米颗粒悬浊液、所述表没食子儿茶素没食子酸酯缓冲液、所述硝酸银缓冲液混合,得到混合液;其中,载药纳米颗粒、表没食子儿茶素没食子酸酯、硝酸银的浓度分别为6 mg/mL、2mg/mL和2 mg/mL;
(4)在洁净的高分子基生物材料表面加入混合液,在35℃下反应1h后,用RO水充分清洗并再重复反应沉积3次,再氮气干燥,得到改性基底材料;
(5)将所述改性基底材料放入波长为254 nm的紫外交联仪中充分辐照4 h,即得到具有超疏水性能的药物结构涂层。
实施例6
本实施例提供一种具有超疏水性能的药物结构涂层的制备方法,所述制备方法包括如下步骤:
(1)将载药泊洛沙姆载药纳米颗粒分散在水中,得到载药纳米颗粒悬浊液;
(2)将多巴胺、氯化铜分别用pH=6.5的乙酸-乙酸盐缓冲液溶解,得到多巴胺缓冲液、氯化铜缓冲液;
(3)将所述载药纳米颗粒悬浊液、所述多巴胺缓冲液、所述氯化铜缓冲液混合,得到混合液;其中,载药纳米颗粒、多巴胺、氯化铜的浓度分别为8 mg/mL、4mg/mL和4 mg/mL;
(4)在洁净的高分子基生物材料表面加入混合液,在25℃下反应2h后,用RO水充分清洗并再重复反应沉积3次,再氮气干燥,得到改性基底材料;
(5)将所述改性基底材料放入波长为302 nm的紫外交联仪中充分辐照5 h,即得到具有超疏水性能的药物结构涂层。
实验例
实施例1所得产品的具有超疏水性能的药物纳米多级结构涂层形貌SEM如图1所示,从图中可以看出在基底材料表面生成了一层由载药纳米颗粒为主体的纳米多级结构涂层,该涂层中载药纳米颗粒外表面由粒径为10~20 nm的酚胺纳米颗粒均匀覆盖,且该反应过程并未对载药纳米颗粒形态造成改变,具有为纳米多级结构。
从图2的涂层的水接触角(a)和水滴滚动角测试(b)可以看出,所制备的涂层具有仿荷叶结构的超疏水性能。具体的:
用动态水接触角仪检测涂层表面的水接触角,图2中的a为水滴与样品表面的接触的状态:在第2秒(t=2s)时,为水滴与样品表面接触瞬间;从2秒~5秒(t=2s~5s)为水滴与表面充分接触;从第6秒(t=6s)开始,水滴离开样品表面。从结果发现,水滴无法停留在样品表面,证明涂层具有超疏水性能。
图2中的b为将超疏水涂层直接沉积在直径为9厘米的培养皿后,检测涂层滚动角小于5度的模拟装置。在第1.25秒(t=1.25s)时,两滴水滴与表面接触;在第1.69秒(t=1.69s)时,水滴在涂层表面滚动;在2.88~3.97秒(t=2.88s~3.97s),水滴在表面混合并滚动。
进一步地,图3中的基底材料即为实施例1中步骤(4)所述的金属基生物材料,将基地材料经过无水乙醇和水充分清洗后,直接与金黄色葡萄球菌培养,作为对照;再将实施例1所得产品的具有超疏水性能的药物纳米多级结构涂层直接与金黄色葡萄球菌培养(0D),再将实施例1所得产品的具有超疏水性能的药物纳米多级结构涂层分别浸泡在碱性磷酸盐溶液稀释的浓度为1 mg/mL的牛血清白蛋白溶液中7天(7D)和14天(14D)。待充分清洗后分别与金黄色葡萄球菌培养6小时,通过DAPI染色后,用激光共聚焦观察表面细菌粘附情况。
从图3可以发现,在基底材料的表面粘附了大量的细菌;然而,在按照实施例1所述方法处理的所有的超疏水表面基本没有细菌粘附。说明具有超疏水性能的药物纳米多级结构涂层可以长效的阻抗蛋白质及细菌的粘附和生长。
以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应以所述权利要求的保护范围为准。
Claims (7)
1.一种具有超疏水性能的药物结构涂层的制备方法,其特征在于,所述制备方法包括如下步骤:
(1)将载药吐温-80聚合物胶束分散在溶剂中,得到载药吐温-80聚合物胶束悬浊液;
(2)将所述载药吐温-80聚合物胶束悬浊液与单宁酸的酸性缓冲液、氯化铜的酸性缓冲液混合,得到混合液;
(3)在金属基生物材料表面加入所述混合液进行反应,完成后清洗、干燥,得到改性基底材料;
(4)将所述改性基底材料进行紫外光辐照,即得到所述具有超疏水性能的药物结构涂层。
2.根据权利要求1所述具有超疏水性能的药物结构涂层的制备方法,其特征在于,步骤(1)中,所述溶剂为水、乙醇或水与乙醇的混合溶液;所述水与乙醇的混合溶液中,乙醇与水的体积比为0.1~5:0.1~5。
3.根据权利要求1所述具有超疏水性能的药物结构涂层的制备方法,其特征在于,所述酸性缓冲液的pH为3~7;所述酸性缓冲液为乙酸-乙酸盐缓冲液、2-(N-吗啡啉)乙磺酸缓冲液、甘氨酸-盐酸缓冲液、邻苯二甲酸-盐酸缓冲液、邻苯二甲酸氢钾-氢氧化钠缓冲液、磷酸氢二钠-柠檬酸缓冲液、柠檬酸-氢氧化钠-盐酸缓冲液或柠檬酸-柠檬酸钠缓冲液中的一种。
4.根据权利要求1所述具有超疏水性能的药物结构涂层的制备方法,其特征在于,步骤(2)中,所述混合液中,载药吐温-80聚合物胶束的浓度为0.5~10mg/mL,单宁酸的浓度为0.5~20mg/mL,氯化铜的浓度为0.1~10mg/mL。
5.根据权利要求1所述具有超疏水性能的药物结构涂层的制备方法,其特征在于,步骤(3)中,所述反应的温度为10~40℃,反应的时间为0.1~10h,反应的次数为1~10次。
6.根据权利要求1所述具有超疏水性能的药物结构涂层的制备方法,其特征在于,步骤(4)中,所述紫外光辐照的波长为365nm、302nm或254nm,所述紫外光辐照的时间为1~48h。
7.权利要求1~6任一项所述制备方法得到的具有超疏水性能的药物结构涂层。
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