CN103182086B - 超顺磁性氧化铁纳米粒在经皮给药系统中的应用 - Google Patents
超顺磁性氧化铁纳米粒在经皮给药系统中的应用 Download PDFInfo
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Abstract
本发明提供一种超顺磁性氧化铁纳米粒在制备经皮给药系统中的应用,所述的超顺磁性氧化铁纳米粒是为作为表柔比星的药物载体,制备表柔比星-超顺磁性氧化铁纳米粒经皮给药系统。所述的超顺磁性氧化铁纳米粒表面具有伯胺基团(-NH2)。本发明提供的超顺磁性氧化铁纳米粒能实现透皮吸收,并对皮肤无毒、无刺激、无过敏反应,克服了超顺磁性氧化铁纳米粒给药方式单一、磁场实施受限的缺陷。
Description
技术领域
本发明属制药领域,涉及超顺磁性氧化铁纳米粒在制备经皮给药系统中的应用。
背景技术
超顺磁性氧化铁纳米粒(Superparamagnetic Iron Oxide Nanoparticles,SPION)是指具有磁响应性的纳米级粒子,当磁性纳米粒子的粒径小于其超顺磁性临界尺寸时,粒子进入超顺磁性状态,它比细胞、病毒、蛋白质、基因等的大小更小或者接近,这样有利于其之间发生相互作用,生物分子在其表面的覆盖也更容易达到。磁性纳米粒子能在外加磁场作用下定向快速运动,从而可进一步缩短药物定向富集的时间,并且在交变磁场作用下,可以产生热效应,可以更好地控制靶向药物的释放,被认为是一种比较理想的药物载体。超顺磁性纳米粒子的粒径可在几纳米到几百纳米之间,除了具有一般磁性载药粒子的优点外,还具有以下优点:1、比表面积大,载药率高,更易于在靶向部位浓集,实现低毒性;2、链接或载带的功能基团或活性中心多,易于药物的载带和控制释放;3、操作和贮存过程中不易产生磁性团聚;4、不易被网状内皮系统的吞噬细胞迅速吞噬清除。此外,超顺磁体与一般铁磁体不同,前者不存在磁滞现象,当去除外磁场后,剩磁立即消失,这一特性使得SPION成为一种堪称理想的靶向药物纳米载体,但是目前SPION主要用于注射剂载药系统,给药方式较为单一,且也为给药过程中的磁场实施带来了较大限制。
经皮给药系统(transdermal drug delivery system,TDDS)是一种将药物通过非侵入方式传递到体内的常用方法,是药物治疗学研究的热门领域之一。TDDS的迅速发展是由于经皮给药具有它独特的优点,如避免肝首过效应、吸收不受胃肠道因素的影响、个体差异小、避免其它给药方法引起的血药浓度峰谷现象及可随时中断给药。目前,在TDDS领域,包括采用经皮吸收促进剂、制备包合物、脂质体及新型囊泡、纳米粒等制剂学技术,都被用于促进药物的经皮吸收;同时,离子导入、超声波、电穿孔、微针技术等物理学电学的方法也被用来克服药物经皮吸收时角质层的屏障作用,这些都给TDDS的研究带来勃勃生机。而目前并没有关于超顺磁性氧化铁纳米粒在经皮给药中的应用报导,如果能够应用TDDS的方法进行SPION的经皮载药,将可以有效地解决SPION现有的给药方式及磁场实施的限制。
发明内容
为了解决上述问题,本发明的目的是克服现有超顺磁性氧化铁纳米粒应用技术的不足,提供一种超顺磁性氧化铁纳米粒在制备经皮给药系统中的应用。
本发明是通过以下技术方案实现的,所述的超顺磁性氧化铁纳米粒是为作为一种经皮给药的药物载体,所述的超顺磁性氧化铁纳米粒是作为表柔比星的药物载体,在制备经皮给药中的应用,所述的超顺磁性纳米粒表面具有伯胺基团(-NH2) 。
所述的超顺磁性氧化铁纳米粒是通过以下步骤制得:
(1)称取10mg二氯化铁(FeCl2·4H2O)和28mg偏硅酸钠(Na2SiO3·9H2O)溶解在30ml已脱气的超纯水中得到混合铁盐溶液,用盐酸溶液调整PH值为3.0,升高温度至30℃后,逐滴加入碱液至反应液PH值为9~10,停止加入碱液,然后水浴加热,使反应混悬液在80℃下熟化1小时,8000rpm离心5分钟,分离沉淀物,沉淀物用超纯水和无水乙醇各洗三遍后,于70℃真空干燥、备用。
(2)将步骤(1)所得到的沉淀物,超声分散在10ml PH为5.0的硼酸溶液中,加入2mg碳二亚胺的催化剂及2ml三乙氧基硅烷,80℃水浴,磁力搅拌12小时,反应结束后,用超纯水和无水乙醇依次洗涤三次,真空干燥,即得表面伯胺基(-NH2)修饰的超顺磁性氧化铁纳米粒。
所述的表柔比星-超顺磁性氧化铁纳米粒是通过以下步骤制得:
上述步骤制得的超顺磁性氧化铁纳米粒(SPION)溶解在硼酸溶液中,依次加入26mg 表柔比星、2mg EDC·HCl、2mg NHS 进行酰胺化交联反应,反应时间48小时,反应温度25℃,离心,8000rpm,分离沉淀物并用渗透膜截留分子量3000道尔顿的反应产物,最终得到棕红色Epi-SPION混悬液,真空干燥后,得到表柔比星-超顺磁性氧化铁纳米粒(Epi-SPION)。
本发明的有益效果是:本发明所应用的超顺磁性氧化铁纳米粒能实现透皮吸收,并对皮肤无毒、无刺激、无过敏反应,克服了超顺磁性氧化铁纳米粒给药方式单一、磁场实施受限的缺陷。
附图说明
图1是本发明所制得的EPI-SPION在激光粒度分布仪中测定的粒径大小分布图。
图2是本发明所制得的EPI-SPION和SPION的磁滞回线。
图3是本发明所制得的FITC-SPION和SPION在不同浓度下对HaCaT细胞的细胞毒性。
图4是EPI-SPION、SPION进行皮肤渗透实验之后的皮肤组织在透射电镜下的观察结果。
具体实施方式
下面结合实施例及附图对本发明所述的表柔比星超顺磁性氧化铁纳米粒及其制备方法进行详细说明。
实施例一:
(1)共沉淀法合成超顺磁性氧化铁纳米粒
称取10mg二氯化铁(FeCl2·4H2O)和28mg偏硅酸钠(Na2SiO3·9H2O)溶解在30ml已脱气的超纯水中得到混合铁盐溶液,用盐酸溶液调整PH值为3.0,升高温度至30℃后,逐滴加入碱液至反应液PH值为9~10,停止加入碱液,然后水浴加热,使反应混悬液在80℃下熟化1小时,8000rpm离心5分钟,分离沉淀物,沉淀物用超纯水和无水乙醇各洗三遍后,于70℃真空干燥、备用。
(2)表面氨基修饰
将步骤(1)所得到的沉淀物,超声分散在100ml PH为5.0的硼酸溶液中,加入2mg碳二亚胺的催化作用及2ml三乙氧基硅烷,80℃水浴,磁力搅拌5小时,反应结束后,用超纯水和无水乙醇依次洗涤三次,真空干燥,即得表面伯胺基(-NH2)修饰的SPION。
(3)偶联表柔比星,制备EPI-SPION
将步骤(2)所得表面伯胺基(-NH2)修饰的超顺磁性氧化铁纳米粒超声溶解在10ml硼酸溶液中,依次加入26mg 表柔比星、2mg EDC·HCl、2mg NHS 进行酰胺化交联反应,反应时间48小时,反应温度25℃,离心,8000rpm,分离沉淀物并用渗透膜截留分子量3000道尔顿的反应产物,最终得到棕红色Epi-SPION混悬液,真空干燥后,得到Epi-SPION。
实施例二
(1)磁流体粒径及电位测定
用透射电镜专用的200目铜网支撑膜蘸取适量实施例一中所制得的Epi-SPION混悬液,常温干燥后置JEM-1200EX型透射电镜下观察纳米粒的大小及形状,结果参见图1,Epi-SPION纳米粒的粒径为8~10nm,颗粒规则,呈近似圆球形,分散性较好,未见有明显团聚现象发生;另取适量(约0.5ml)纳米粒混悬液,超声分散处理后稀释至3~5倍,用Zetasizer Nano S90高灵敏纳米粒度分析仪测定纳米粒的粒径大小及Zeta电位,测定结果参见图1:EPI-SPION粒径主要分布在28.1nm,呈正态分布,多分散系数0.181,表明制备得到的Epi-SPION粒子大小均匀性良好。在pH为5.0的硼酸缓冲液中Zeta电位28.4mV,具有利于稳定的荷电性质。采用激光散射采用动态激光散射法测得是水合动力半径,由于SPION经表面修饰后具有较好的亲水性,所以测得的结果要比TEM实际测得的粒径大了2~3倍。
(2)磁力学性质测定
精密称取实施列一种所制得的SPION、EPI-SPION各 2mg,放置于JDM-13D磁性测定仪中,测定温度为300K,随着外磁场从-5000~5000 kA · m-1的变化,测定纳米粒磁矩的变化情况,并绘制对应的磁性曲线,结果参见图2:曲线为过原点的单一曲线,即当外加磁场为0时,SPN没有剩磁;当有外加磁场存在时,产生剩磁,从而说明该纳米粒具有超顺磁性。
实施例三
(1)细胞培养
将HaCaT细胞(正常人皮肤细胞系,凯基生物)复苏后,用含10%胎牛血清的RPM1640培养基, 37℃,5%CO2的环境下培养,每隔一天换液一次,用EDTA-胰蛋白酶消化传代。
(2)细胞毒性考察
将上述细胞传代培养,达到80-90%汇合,用0.25%胰蛋白酶-EDTA溶液消化后,用含10%胎牛血清的RPM1640培养液配成单细胞悬液,以每孔5×103/孔接种于96孔板;在37℃、5% CO2条件下培养24h;弃去上清液,用PBS液洗涤2遍,分别依次加入含EPI-SPION、SPION的培养基,培养基中含纳米粒浓度分别为50μg/ml、100μg/ml、200μg/ml、400μg/ml、600μg/ml、800μg/ml、1000μg/ml的上述纳米粒混悬液和10%胎牛血清培养液200μl,每组设计3个复孔,其中以未加入细胞、只加入纳米粒溶液的孔作为样品对照;未加入纳米粒、只有细胞的孔作为控制;只加培养基溶液的孔作为空白对照,培养24h后,加入浓度为5μg/ml的MTT溶液,每孔20μl,于37℃、5%CO2培养箱中继续孵化4h,弃去上清液,每孔加入200μl的二甲亚砜,于平板震荡仪上震荡10分钟,酶标仪中在490nm波长处测定吸收度。根据公式:细胞存活率=(实验组OD-空白组OD)/(对照组OD-空白组OD),计算分析样品的细胞毒性,并进行比较,结果参见图3:不同浓度的EPI-SPION、SPION与HaCaT细胞孵化24h后,随着培养液中纳米粒浓度的增加,细胞活力也随之下降,但是是高浓度1000μgFe/ml,细胞活力也在70%以上,说明EPI-SPION、SPION细胞毒性很低。
(3)SPION的经皮给药能力考察
1)体外经皮渗透试验
试验分为:SPION渗透组、EPI-SPION渗透组、及空白对照组,试验所用透皮装置采用天津市正通科技有限公司的TT-6透皮吸收仪,具体方法为:取去除皮下组织的裸鼠皮肤,用生理盐水洗净后,剪取合适大小,将皮肤夹在扩散池(供给体)与扩散池(接受体)之间,继续用生理盐水冲洗皮肤上下表面,每30min更换一次生理盐水,洗清3次后,用滤纸吸干皮肤角质层面的液体,在扩散池(接受体)内放置一块永磁铁,在扩散池(供给体)内加入适量实施例一中制备的SPION样品或者EPI-SPION样品或者生理盐水,持续24 小时,用于考察SPION样品或者EPI-SPION在外加磁场的作用下渗透进皮肤的能力。
2)切片TEM观察
上述1)中的步骤结束后,将进行扩散实验的皮肤投入10%福尔马林溶液中固定48小时,按照2)中的相关步骤进行脱水,石蜡包埋后,切片,然后进行荧光监测及透射电镜观察,结果参见图4,可见SPION颗粒能在外加磁场的作用下进入皮肤真皮层(箭头标示为SPION颗粒)。
综上所述仅为本发明的较佳实施例,并非用来限定本发明的实施范围。即凡依照本发明申请专利范围的内容所做的等效变化及修饰,皆应属于本发明的技术范畴。
Claims (1)
1.一种超顺磁性氧化铁纳米粒在制备经皮给药系统中的应用,其特征在于,所述的超顺磁性氧化铁纳米粒是作为表柔比星的药物载体,在制备表柔比星-超顺磁性氧化铁纳米粒经皮给药中的应用,所述的超顺磁性纳米粒表面具有伯胺基团,所述的表柔比星-超顺磁性氧化铁纳米粒通过以下步骤制得:
(1)称取10mg二氯化铁和28mg偏硅酸钠溶解在30ml已脱气的超纯水中得到混合铁盐溶液,用盐酸溶液调整PH值为3.0,升高温度至30℃后,逐滴加入碱液至反应液PH值为9~10,停止加入碱液,然后水浴加热,使反应混悬液在80℃下熟化1小时,8000rpm离心5分钟,分离沉淀物,沉淀物用超纯水和无水乙醇各洗三遍后,于70℃真空干燥、备用;
(2)将步骤(1)所得到的沉淀物,超声分散在10ml PH为5.0的硼酸溶液中,加入2mg碳二亚胺的催化剂及2ml三乙氧基硅烷,80℃水浴,磁力搅拌12小时,反应结束后,用超纯水和无水乙醇依次洗涤三次,真空干燥,即得表面伯胺基修饰的超顺磁性氧化铁纳米粒;
(3)将步骤(2)制得的超顺磁性氧化铁纳米粒溶解在硼酸溶液中,依次加入26mg 表柔比星、2mg EDC·HCl、2mg NHS 进行酰胺化交联反应,反应时间48小时,反应温度25℃,离心,8000rpm,分离沉淀物并用渗透膜截留分子量3000道尔顿的反应产物,最终得到棕红色混悬液,真空干燥后,得到表柔比星-超顺磁性氧化铁纳米粒。
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