CN111840209B - 可程序化释放银屑病治疗药物的微针贴片及其制备方法 - Google Patents
可程序化释放银屑病治疗药物的微针贴片及其制备方法 Download PDFInfo
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Abstract
本发明属于生物医用高分子材料领域,公开了一种可程序化释放银屑病治疗药物的微针贴片及其制备方法,该微针贴片上的微针包括能快速溶解释放银屑病药物的生物相容性基质,以及位于该生物相容性基质表面和/或内部的能缓慢释放银屑病药物的聚合物粒子;其中,所述生物相容性基质所采用的基质材料为易溶物或可溶物,该生物相容性基质内具有独立存在的银屑病药物成分,以便快速溶解释放;所述聚合物粒子是掺有银屑病药物成分的难溶聚合物粒子,利用难溶聚合物的作用能够使该聚合物粒子内的银屑病药物成分被缓慢释放。本发明紧密围绕银屑病治疗的用药需求,通过对微针的内部结构和组成进行改进,能有效实现银屑病治疗药物的程序化释放。
Description
技术领域
本发明属于生物医用高分子材料领域,更具体地,涉及一种可程序化释放银屑病治疗药物的微针贴片及其制备方法,该微针扎入皮肤后可先快速释放银屑病药物缓解银屑病皮损,同时将缓释性粒子留在皮内保持长时间有效的药物治疗效果。
背景技术
银屑病是一种常见的慢性炎症性皮肤病,典型症状是皮肤出现红斑且覆盖银白色鳞屑,该病反复发作,严重影响患者的生活和心理状况。目前还未发现有效根治银屑病的方法,只能应用对症支持疗法缓解病情。
甲氨蝶呤(MTX)、环孢素、维A酸类、硫唑嘌呤、羟基脲、来氟米特、麦考酚酯、糖皮质激素和抗肿瘤坏死因子-α(抗TNF-α)等是银屑病临床治疗指南中的常用系统药物,IL12/23抗体、IL17A抗体、IL23p19抗体是治疗银屑病的新型药物,但以上药物系统给药效率低,并且往往带来严重的副作用,比如:胃肠道毒性、肝脏损害、骨髓抑制、免疫力低下导致感染等。因此,局部经皮给药成为近年来治疗银屑病的研究热点,但是皮肤的最外层是人体最重要的屏障—角质层,将药物直接涂于皮肤表面是很难完全透过的,这就导致经皮给药治疗银屑病总是效果不佳。
中国专利(申请号:201910231045.2)公开了一种银屑病治疗微针贴片,该贴片可有效穿过皮肤角质层,将药物递送至皮内。由于银屑病治疗药物在皮内会被快速代谢,不能满足中重度患者的长时间治疗需求。
本发明发明人在前研究得到了一种可程序性释放药物的聚合物复合微针及其制备(可参见中国专利文献CN108245482A),尽管其也公开了一种可程序性释放药物的聚合物复合微针,但由于其针尖部分作为整体留在皮内用于缓释,因此其释放出的药物浓度从靠近针尖部分向边缘部分逐渐降低,药物分布不均一。
发明内容
针对现有技术的以上缺陷或改进需求,本发明的目的在于提供一种可程序化释放银屑病治疗药物的微针贴片及其制备方法,紧密围绕银屑病治疗的用药需求,通过对微针的内部结构和组成进行改进,能有效实现银屑病治疗药物的程序化释放。该微针扎入皮肤后可先快速释放银屑病药物缓解银屑病皮损,同时将缓释性粒子留在皮内保持长时间有效的药物治疗效果,并且,由于采用聚合物粒子,能够提高局部药物释放浓度的均一性。
为实现上述目的,按照本发明的一个方面,提供了一种可程序化释放银屑病治疗药物的微针贴片,其特征在于,该微针贴片上的微针包括能快速溶解释放银屑病药物的生物相容性基质,以及位于该生物相容性基质表面和/或内部的能缓慢释放银屑病药物的聚合物粒子;其中,所述生物相容性基质所采用的基质材料为易溶物或可溶物,该生物相容性基质内具有独立存在的银屑病药物成分,以便快速溶解释放;所述聚合物粒子是掺有银屑病药物成分的难溶聚合物粒子,利用难溶聚合物的作用能够使该聚合物粒子内的银屑病药物成分被缓慢释放。
作为本发明的进一步优选,所述生物相容性基质所采用的基质材料为透明质酸、海藻酸钠、胶原蛋白、明胶、硫酸软骨素、聚赖氨酸、羧甲基纤维素、聚乙烯吡咯烷酮、聚乙二醇、羟丙基纤维素、环糊精、聚丙烯酸钠中的至少一种。
作为本发明的进一步优选,所述聚合物粒子所采用的难溶聚合物材料为聚(对二氧环己酮)、聚(丙交酯-共-乙交酯)、聚己内酯、聚乳酸、聚醚酯、聚酯酰胺中的至少一种。
作为本发明的进一步优选,所述聚合物粒子的大小为0.01~50μm。
作为本发明的进一步优选,所述银屑病治疗药物为甲氨蝶呤(MTX)、环孢素、阿维A、硫唑嘌呤、羟基脲、来氟米特、麦考酚酯、糖皮质激素、抗肿瘤坏死因子-α(抗TNF-α)、IL12/23抗体、IL17A抗体、IL23p19抗体中的至少一种。
作为本发明的进一步优选,任意一个所述微针中,任意一个所述微针中,所述聚合物粒子内含有的银屑病药物成分与所述生物相容性基质内含有的独立存在的银屑病药物成分两者的质量比为1:99~99:1。
按照本发明的另一方面,本发明提供了上述可程序化释放银屑病治疗药物的微针贴片的制备方法,其特征在于,包括以下步骤:
(1)将银屑病治疗药物包裹于难溶聚合物材料内部,形成聚合物粒子;
(2)将所述聚合物粒子与银屑病治疗药物、可溶或易溶的生物相容性基质材料混合,注入模具中,干燥得到微针针尖;
(3)将可溶或易溶的生物相容性基质材料铺在所述步骤(2)的形成有微针针尖的模具表面;
(4)干燥,成形,脱模即可得到可程序化释放银屑病治疗药物的微针。
通过本发明所构思的以上技术方案,与现有技术相比,快速释药基质(即,能快速溶解释放银屑病药物的生物相容性基质)和缓释性粒子(即,能缓慢释放银屑病药物的聚合物粒子)中都负载有银屑病治疗药物,缓释性粒子药物释放速率比基质材料更慢,可达到快速释药缓解疾病和缓慢释放持续有效的治疗效果;基于本发明,通过调控缓释粒子的降解周期,可以调控药物的释放速度,满足不同患者的治疗需求。
本申请中可程序化释放银屑病治疗药物的微针贴片,能够快速释药缓解银屑病皮损,而通过采用难溶聚合物粒子可达到缓释效果,并且,由于使用聚合物粒子(粒子大小可控制在0.01~50μm),能够提高局部药物释放浓度的均一性。本发明通过调节聚合物粒子内药物与快速释放药物的比例,可同时实现快速和长效的银屑病治疗。
本发明中的可程序化释放银屑病治疗药物的微针贴片,通过调节快速释放药物基质和缓释性粒子的载药量之比,缓释粒子的降解周期,可以满足不同病程银屑病患者的初始缓解治疗和长时间有效的治疗需求。
本发明中的微针贴片负载银屑病治疗药物后可用于制备治疗不同病程银屑病的制剂。例如,对于重度患者,可制备0.01μm大小的纳米缓释性粒子,可调节快速释放药物与缓释药物质量比为8:2;对于轻度患者,可制备30μm的缓释性粒子,调节快速释放药物与缓释药物之比为2:8。
本发明主要针对银屑病患者的具体治疗需求设计相应的兼顾快速释放和缓慢释放的银屑病治疗微针,同时为了使药物分布更均匀,选择聚合物粒子作为缓释药物的载体。根据不同患者的不同病程,基于本发明可通过调节缓释性粒子的尺寸(0.01~50μm),快速释放药物与缓释药物的比例(1:99~99:1)来调整得到最佳的治疗效果。
综上,本发明的微针及微针贴片,可有效地将银屑病药物递送至皮内,并满足不同病程银屑病患者快速起效、且长时间有效的银屑病药物治疗需求。本发明得到的微针,能够有效满足银屑病治疗快速起效和长时间给药这2种治疗需求,该微针扎入皮肤后可先快速释放银屑病药物缓解银屑病皮损,同时将缓释性粒子留在皮内保持长时间有效的药物治疗效果。
附图说明
图1是本发明程序化释放银屑病治疗药物微针的结构示意图。
图2是本发明实施例1微针的显微镜照片。
图3是本发明实施例6治疗银屑病小鼠后耳部皮损的抑制情况(Control—对照组,即,正常组;Model—疾病组;HD MTX MN—本发明微针组)。
图4是实施例6肝脏里两种酶的活性值(丙氨酸转氨酶ALT、天冬氨酸转氨酶AST);其中,对照—正常小鼠;疾病—银屑病小鼠;微针—本发明微针组。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。此外,下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
总体来说,本发明中可程序化释放银屑病治疗药物的微针贴片,包括快速释放银屑病药物的基质材料和位于针尖部分能缓释药物的粒子。这些能缓释药物的粒子,既可以基质材料的表面,也可以位于基质材料的内部。
下面就以缓释药物的粒子位于基质材料的内部为例,进行详细介绍。
实施例1
包括以下步骤:
1.用激光雕刻机刻蚀出底边直径200μm,高度850μm,相邻微针中心间距600μm的10*10聚二甲基硅氧烷(PDMS)阴模板备用;
2.配制10mg/mL甲氨蝶呤和5mg/mL聚(丙交酯-共-乙交酯)的氯仿混合溶液,然后用0.45μm的滤膜过膜,得到尺寸为0.45μm的包覆了甲氨蝶呤的纳米粒子(这些纳米粒子中,聚(丙交酯-共-乙交酯)成分在外,甲氨蝶呤成分被包裹在里面);纳米粒子的尺寸受滤膜孔径大小直接影响,可根据粒子粒径大小的实际需求,调整滤膜孔径;本步骤中所采用的甲氨蝶呤,对应的是后续应用时能够被缓慢释放的银屑病药物,所采用的甲氨蝶呤溶液的具体浓度和体积,可根据不同需求来调整;
3.将上述步骤2所述的粒子与含有50mg/mL甲氨蝶呤的200mg/mL聚乙烯吡咯烷酮(PVP)溶液按照纳米粒子内药物:快速释放药物=2:8混合并搅拌均匀;本步骤中所采用的甲氨蝶呤,对应的是后续应用时能够被快速释放的银屑病药物,所采用的甲氨蝶呤溶液的具体浓度和体积,可根据不同需求来调整;
4.取适量步骤3中溶液通过抽真空法填入PDMS模具尖端并用刮抄刮去多余溶液,置于干燥器中常温干燥8h后取出。在干燥后的PDMS模具上铺一层纯200mg/mL PVP溶液,真空除去气泡,继续干燥24h后脱模即可得到可程序性释放甲氨蝶呤的微针阵列。
实施例2-5与实施例1制备步骤大体相同,只是在一些细节参数的设计上与实施例1存在区别,如下表所示:
实施例6
将上述实施例1制备得到的微针用于重度银屑病模型小鼠上,隔3天使用一片10*10阵列的微针贴片,3周后观察其治疗效果肝脏毒性(丙氨酸转氨酶、天冬氨酸转氨酶水平)。图3中组织切片(H&E染色)和皮损增厚表达因子的结果(Ki67)表明本发明对治疗银屑病小鼠的耳部皮损有明显的疗效;图4中肝脏内两种酶(丙氨酸转氨酶ALT、天冬氨酸转氨酶AST)的水平相对于无疾病正常小鼠没有明显变化,说明本发明没有明显的肝脏毒性。
本发明中出现的“难溶”、“可溶”、“易溶”,满足常规定义。
本领域的技术人员容易理解,以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (5)
1.一种可程序化释放银屑病治疗药物的微针贴片,其特征在于,该微针贴片上的微针包括能快速溶解释放银屑病药物的生物相容性基质,以及位于该生物相容性基质内部的能缓慢释放银屑病药物的聚合物粒子;其中,所述生物相容性基质所采用的基质材料为易溶物或可溶物,该生物相容性基质内具有独立存在的银屑病药物成分,以便快速溶解释放;所述聚合物粒子是掺有银屑病药物成分的难溶聚合物粒子,利用难溶聚合物的作用能够使该聚合物粒子内的银屑病药物成分被缓慢释放;
并且,所述聚合物粒子所采用的难溶聚合物材料为聚(对二氧环己酮)、聚(丙交酯-共-乙交酯)、聚己内酯、聚乳酸、聚醚酯、聚酯酰胺中的至少一种;所述难溶聚合物粒子中,所述银屑病药物成分被包裹于难溶聚合物材料的内部;
所述银屑病治疗药物为甲氨蝶呤(MTX)、环孢素、阿维A、硫唑嘌呤、羟基脲、来氟米特、麦考酚酯中的至少一种。
2.如权利要求1所述微针贴片,其特征在于,所述生物相容性基质所采用的基质材料为透明质酸、海藻酸钠、胶原蛋白、明胶、硫酸软骨素、聚赖氨酸、羧甲基纤维素、聚乙烯吡咯烷酮、聚乙二醇、羟丙基纤维素、环糊精、聚丙烯酸钠中的至少一种。
3. 如权利要求1所述微针贴片,其特征在于,所述聚合物粒子的大小为0.01~50 μm。
4.如权利要求1-3任意一项所述微针贴片,其特征在于,任意一个所述微针中,所述聚合物粒子内含有的银屑病药物成分与所述生物相容性基质内含有的独立存在的银屑病药物成分两者的质量比为1:99~99:1。
5.如权利要求1-4任意一项所述可程序化释放银屑病治疗药物的微针贴片的制备方法,其特征在于,包括以下步骤:
(1)将银屑病治疗药物包裹于难溶聚合物材料内部,形成聚合物粒子;
(2)将所述聚合物粒子与银屑病治疗药物、可溶或易溶的生物相容性基质材料混合,注入模具中,干燥得到微针针尖;
(3)将可溶或易溶的生物相容性基质材料铺在所述步骤(2)的形成有微针针尖的模具表面;
(4)干燥,成形,脱模即可得到可程序化释放银屑病治疗药物的微针。
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