CN106581851A - 一种具有磁热效应的药物控释透皮微针系统及制备方法和应用 - Google Patents
一种具有磁热效应的药物控释透皮微针系统及制备方法和应用 Download PDFInfo
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Abstract
本发明一种具有磁热效应的药物控释透皮微针系统,包括一个基层,基层上设置有复数个微针,任意一个微针的高度在400μm‑600μm之间,微针的尖段宽度在10μm‑30μm之间,微针的底部宽度在200μm‑400μm之间,基层和微针中嵌入有纳米磁性颗粒、或者三亚甲基碳酸酯中的任意一种或者两种的组合。本发明还提供了上述药物控释透皮微针系统的制备方法和在透皮药物输送中的应用。本发明的透皮载药微针的载药量高,能够负载的药物种类多,同时本发明制备的透皮载药微针系统能够通过改变内嵌的纳米磁性颗粒和TMC的含量来调节释放速度,并且具有良好的磁热效应,能实现药物治疗协同磁热治疗的双重功效。
Description
技术领域
本发明属于医药技术领域,涉及一种医疗器械,具体来说是一种具有磁热效应的药物控释透皮微针系统及制备方法和应用。
背景技术
目前,全世界的各种疾病发病率呈急剧上升趋势,国内外临床治疗手段中一个重要的方法是药物疗法,而通常的给药方式有口服用药、注射用药等。然而口服用药有以下几个缺点:首先一些药物会对胃肠道有副作用,而且其容易受饮食的影响;其次对大分子药物的吸收困难,更重要的是对于老人和小孩口服方式有一定的局限性;另一方面,注射用药会由于起始的高浓度引起副作用,而且还会引起感染导致安全问题,并且需要医护人员的专门培训,还会引起患者产生疼痛感。
为了提高药物的输送效果,国内外的研究人员正在积极的研究透皮载药微针系统,即药物以一定的速率通过皮肤,经毛细血管吸收进入体循环而产生药效的一类制剂。透皮给药与传统的给药方式相比有许多优点:避免肝脏的“首过效应”;减少人体血药浓度出现峰谷的变化;通过维持恒定的血药浓度增加疗效;容易使用;适于半衰期短的药物;避免了胃肠道的副作用。然而,由于皮肤(特别是角质层,角质层一般介乎 10μm至 40μm不等)对药物透皮吸收起屏障作用,大多数药物,即便是剂量低、疗效高的一些药物,透皮渗透速度也难以满足治疗的需要,成为开发透皮给药制剂的重大障碍。但是,皮肤能够通过各种物理方法打开给药通路。微针透皮的给药机理是在一个很小的面积上(传统的透皮贴片的尺寸),同时覆盖数百根微针刺穿皮肤角质层,允许药物通过这个重要的屏障实现对药物的导入。因此,微针透皮给药系统可以实现高效的药物输送。现在有许多研究的可溶微针都是基于有机高分子材料制备而成,其释放是基于高分子材料在体内的降解而实现,这种降解过程和所用材料的生物降解性密切相关,导致药物的释放行为很难控制。因此,如何设计一种可控的药物释放微针成为了透皮载药微针系统研发的关键。
发明内容
针对现有技术中的上述技术问题,本发明提供了一种具有磁热效应的药物控释透皮微针系统及制备方法和应用,所述的这种具有磁热效应的药物控释透皮微针系统及制备方法和应用要解决现有技术中的可溶微针难以控制药物释放的技术问题。
本发明提供了一种具有磁热效应的药物控释透皮微针系统,包括一个基层,所述的基层上设置有复数个微针,任意一个微针的高度在400μm-600μm之间,所述的微针的尖段宽度在10μm-30μm之间,所述的微针的底部宽度在200μm-400μm之间,所述的基层和微针中嵌入有纳米磁性颗粒或者具有光热效应的纳米颗粒、或者三亚甲基碳酸酯中的任意一种或者两种的组合。
进一步的,所述的纳米磁性颗粒为磁性纳米颗粒Fe3O4。
进一步的,所述的基层和微针的基材为生物高分子材料聚己内酯。
本发明还提供了上述的一种具有磁热效应的药物控释透皮微针系统的制备方法,其特征在于包括以下步骤:
1)一个配置浆料的步骤,称取聚己内酯,加入氯仿中,在室温下密封静置使其完全溶入氯仿,在上述溶液中加入三亚甲基碳酸酯、纳米Fe3O4颗粒和药物,所述的三亚甲基碳酸酯的质量为上述聚己内酯、三亚甲基碳酸酯、纳米Fe3O4颗粒质量之和的0~30%,所述的纳米Fe3O4颗粒的质量为上述聚己内酯、三亚甲基碳酸酯、纳米Fe3O4颗粒质量之和0~30%,所述的药物的质量为上述聚己内酯、三亚甲基碳酸酯、纳米Fe3O4颗粒质量之和1‰~10%;在通风厨里搅拌,使三亚甲基碳酸酯和纳米Fe3O4颗粒充分的分散在氯仿溶液中,并且调制溶液至5000~8000mPa.s之间的粘度;
2)一个离心浇注成型的步骤,将上述步骤中的浆料加入至PDMS模具中,所述的浆料的体积为所有微针体积的二分之一,在离心机中以3000~5000rpm的转速离心10~20min,取出;接着再次加入所有微针体积的二分之一的浆料至模具中继续以相同的转速离心10~20min,取出;然后加纯聚己内酯浆料至两次离心后的模具中,使其完全填充衬底空间,为成型的微针提供基座;
3)还包括一个脱模的步骤,将步骤2)中制备的样品置于37℃烘箱干燥20~30h,小心脱模,即得到具有磁热效应的药物控释透皮微针系统.
进一步的,步骤1)中,所述的三亚甲基碳酸酯的质量为上述聚己内酯、三亚甲基碳酸酯、纳米Fe3O4颗粒质量之和的10~30%,所述的纳米Fe3O4颗粒的质量为上述聚己内酯、三亚甲基碳酸酯、纳米Fe3O4颗粒质量之和10~30%。
本发明还提供了上述的具有磁热效应的药物控释透皮微针系统在透皮药物输送中的应用。
本发明的优点和积极效果如下:
1. 能够显著提高药物的透皮输送效率
药物释放实验结果显示,本发明所提供的装载模拟药物磁热控释透皮微针系统能够通过外界磁场的刺激提高微针的温度从而提高药物输送和释放效率。
2. 药物储藏量高
本发明所提供的药物控释透皮微针系统微针尺寸可以包埋高含量药物,并且储存的药物也易释放。
3. 药物储藏量高
本发明所提供的具有磁热效应的药物控释透皮微针系统适合药物在微针中储藏,与背景技术相比,药物储藏量高且可控,并且,储藏的药物易于控制释放。
4. 使治疗的疗效显著增加
本发明所提供的具有磁热效应的药物控释透皮微针系统兼具有磁热疗的功能,能够促使药物进入病发部位并诱发病变细胞凋亡,明显提高药物疗效果。并且,该微针系统在外界交变磁场作用下能在较短时间内控制其升温范围在43~50℃,还可以通过控制该药物控释透皮微针系统本身的磁性颗粒的含量以及交变磁场的加热参数,增加病变细胞或组织与周围正常细胞或组织的温差,诱发病变细胞凋零,同时减轻治疗过程中因正常细胞或组织过热而引起并发症。
5. 能够实现药物治疗协同磁热治疗的双重治疗
本发明通过以PCL为基材,同时嵌入具有磁热效应的Fe3O4纳米颗粒和低熔点以改善释放性能的TMC单体(三亚甲基碳酸酯)以及药物,通过离心浇注的方法制备了兼具高效率输送药物和磁热效应的药物控释透皮微针系统,可实现药物治疗协同磁热治疗的双重治疗。
本发明和已有技术相比,其技术进步是显著的。本发明制备的透皮载药微针的载药量高,能够负载的药物种类多,同时本发明制备的透皮载药微针系统能够通过改变内嵌的纳米磁性颗粒和TMC的含量来调节释放速度,并且微针系统具有良好的磁热效应,能够实现药物治疗协同磁热治疗的双重功效。
附图说明
图1为实施例1制备的具有磁热效应的药物控释透皮微针系统的扫描电镜(SEM)图。
图2为实施例1制备的具有磁热效应的药物控释透皮微针系统的力学性能曲线。
图3为实施例1制备的具有磁热效应的药物控释透皮微针系统的磁热升温曲线。
图4为实施例2制备的储藏模拟药物罗丹明B的具有磁热效应的药物控释透皮微针系统在pH7.4在不同温度下的释放曲线。
具体实施方式
以下结合附图,对本发明所涉及的一种具有磁热效应的药物控释透皮微针系统、制备方法及其应用做进一步说明。
实施例1
本实施例所提供的药物控释透皮微针系统为包括嵌入在PCL内部的Fe3O4纳米颗粒和模拟药物罗丹明B。该药物控释透皮微针系统制备方法包括以下步骤:
步骤一,配置浆料:取0.4g的PCL(生物高分子材料聚己内酯)加入适量的氯仿中,并在室温下密封静置4h使其完全溶入氯仿,在上述溶液加入0.1gFe3O4纳米颗粒,在通风厨里搅拌1-2h,使Fe3O4纳米颗粒充分的分散在氯仿溶液中,并且调制溶液至适当的粘度(5000~8000mPa.s)。
步骤二,离心浇注成型:将步骤一中的浆料加0.2mL至PDMS模具中,在离心机中以4000rpm的转速离心15min,取出,然后再次加入0.2mL浆料至模具中继续以相同的转速离心15min,取出;加过量的纯PCL浆料至两次离心后的模具,使其完全填充衬底空间并小心除掉多余浆料,为成型的微针提供一个坚实的基座;
步骤三,脱模:将步骤二中制备的样品置于37℃烘箱干燥24h,小心脱模,即得到具有磁热效应的药物控释透皮微针系统;
图1为实施例1制备的具有磁热效应的药物控释透皮微针系统的扫描电镜(SEM)图。
取本实施例制备的药物控释透皮微针系统置于扫描电镜(SEM)下观察,结果如图1所示,本实施例制备的药物控释透皮微针系统包含100根微针,微针尖端大约20微米,底部大约250微米,高度大约450微米,微针的形貌完整。
图2为实施例1制备的具有磁热效应的药物控释透皮微针系统的力学性能测试曲线。
将本实施例制备的药物控释透皮微针系统进行抗压性能测试,结果如图2所示,表明该药物控释透皮微针系统具有较好的力学性能,满足刺透人体体肤的要求,能够进行透皮药物输送。
图3为实施例1制备的具有磁热效应的药物控释透皮微针系统磁热升温曲线。
将制备的具有磁热效应的药物控释透皮微针系统置于1mL离子水,采用在DM100磁热疗效应分析仪(西班牙nanoscale biomagnetics公司)测定该药物控释透皮微针系统磁热效应。当设置磁场强度为180Gauss,磁场频率409kHz,交变磁场作用570秒使得溶液温度从37oC升温至50℃。
结果如图3所示,在交变磁场(磁场强度180Gauss, 磁场频率409kHz)作用下,制备的具有磁热效应的药物控释透皮微针系统快速升温,能够在570秒内从37℃升至50℃。说明实施例1制备的具有磁热效应的药物控释透皮微针系统有很好的磁热效应,能够在较短时间内达到磁热疗的温度(磁热疗温度一般在43~48oC),有利于实际应用。
实施例2
本实施例所提供的药物控释透皮微针系统为在实例1的基础上加入了调节释放性能的低熔点单体TMC的药物控释透皮微针系统,其制备方法为:
步骤一,配置浆料:取适量的0.3gPCL加入适量的氯仿中,并在室温下密封静置4h使其完全溶入氯仿,在上述溶液加入0.1g的TMC(三亚甲基碳酸酯)和0.1g的Fe3O4纳米颗粒和药物罗丹明B(2.5mg),在通风厨里搅拌1-2h,使TMC和Fe3O4纳米颗粒充分的分散在氯仿溶液中,并且调制溶液至适当的粘度(5000~8000mPa.s);
步骤二,离心浇注成型:将步骤一中的浆料加0.2mL至PDMS模具中,在离心机中以4000rpm的转速离心15min,取出;然后再次加入0.2mL浆料至模具中继续以相同的转速离心15min,取出;加过量的纯PCL浆料至两次离心后的模具,使其完全填充衬底空间并小心除掉多余浆料,为成型的微针提供一个坚实的基座;
步骤三,脱模:将步骤二中制备的样品置于37℃烘箱干燥24h,小心脱模,即得到具有磁热效应的药物控释透皮微针系统;
图4为实施例2制备的具有磁热效应的药物控释透皮微针系统的体外药物释放曲线。
将实例2制备的具有磁热效应的药物控释透皮微针系统在37℃、43℃和50℃的PBS溶液(pH=7.4)中进行体外模拟药物罗丹明B的释放实验。释放药物浓度在NanoDrop 2000C超微量分光光度计上测定,实验测定前先测定罗丹明B在溶液中浓度与吸光度的标准曲线。
结果如图4所示,在37℃时,24小时内只有36%的罗丹明B从微针中释放出来;而在43℃和50℃分别有45%和48%的罗丹明B释放出来说明输送系统在对温度是敏感的,可以通过温度来控制药物的释放。
当然,本发明所涉及的具有磁热效应的药物控释透皮微针系统、制备方法及其应用并不仅仅限定于上述两个实例中的内容。以上内容仅为本发明构思下的基本说明,而依据本发明的技术方案所作的任何等效变换,均属于本发明的保护范围。
Claims (6)
1.一种具有磁热效应的药物控释透皮微针系统,其特征在于:包括一个基层,所述的基层上设置有复数个微针,任意一个微针的高度在400μm-600μm之间,所述的微针的尖段宽度在10μm-30μm之间,所述的微针的底部宽度在200μm-400μm之间,所述的基层和微针中嵌入有纳米磁性颗粒、或者三亚甲基碳酸酯中的任意一种或者两种的组合。
2.根据权利要求1所述的一种具有磁热效应的药物控释透皮微针系统,其特征在于:所述的纳米磁性颗粒为磁性纳米颗粒Fe3O4。
3.根据权利要求1所述的一种具有磁热效应的药物控释透皮微针系统,其特征在于:所述的基层和微针的基材为生物高分子材料聚己内酯。
4.权利要求1所述的一种具有磁热效应的药物控释透皮微针系统的制备方法,其特征在于包括以下步骤:
1)一个配置浆料的步骤,称取聚己内酯,加入氯仿中,在室温下密封静置使其完全溶入氯仿,在上述溶液中加入三亚甲基碳酸酯、纳米Fe3O4颗粒和药物,所述的三亚甲基碳酸酯的质量为上述聚己内酯、三亚甲基碳酸酯、纳米Fe3O4颗粒质量之和的0~30%,所述的纳米Fe3O4颗粒的质量为上述聚己内酯、三亚甲基碳酸酯、纳米Fe3O4颗粒质量之和0~30%,所述的药物的质量为上述聚己内酯、三亚甲基碳酸酯、纳米Fe3O4颗粒质量之和1‰~10%;在通风厨里搅拌,使三亚甲基碳酸酯和纳米Fe3O4颗粒充分的分散在氯仿溶液中,并且调制溶液至5000~8000mPa.s之间的粘度;
2)一个离心浇注成型的步骤,将上述步骤中的浆料加入至PDMS模具中,所述的浆料的体积为所有微针体积的二分之一,在离心机中以3000~5000rpm的转速离心10~20min,取出;接着再次加入所有微针体积的二分之一的浆料至模具中继续以相同的转速离心10~20min,取出;然后加纯聚己内酯浆料至两次离心后的模具中,使其完全填充衬底空间,为成型的微针提供基座;
3)还包括一个脱模的步骤,将步骤2)中制备的样品置于37℃烘箱干燥20~30h,小心脱模,即得到具有磁热效应的药物控释透皮微针系统。
5.根据权利要求4所述的一种具有磁热效应的药物控释透皮微针系统的制备方法,其特征在于:步骤1)中,所述的三亚甲基碳酸酯的质量为上述聚己内酯、三亚甲基碳酸酯、纳米Fe3O4颗粒质量之和的10~30%,所述的纳米Fe3O4颗粒的质量为上述聚己内酯、三亚甲基碳酸酯、纳米Fe3O4颗粒质量之和10~30%。
6.权利要求1、2或者3所述的具有磁热效应的药物控释透皮微针系统在透皮药物输送中的应用。
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