CN112516449A - 一种可溶性微针阵列及其制备方法 - Google Patents
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Abstract
本发明公开一种可溶性微针阵列及其制备方法,包括针尖、背衬层,针尖由水溶性三七多糖制成,背衬层由水溶性高分子材料形成,水溶性高分子材料为透明质酸,透明质酸的分子量为10kDa;本发明制作的可溶性微针阵列,其可溶性微针针尖具有足够的硬度,能有效刺穿皮肤角质层,直接作用于活性表皮层和真皮层,实现快速溶解并释放出存储在针尖中的目标药物,本发明的可溶性微针阵列以具有免疫佐剂活性的三七多糖针尖作为载体,将药物装载于针尖中,作用于皮肤后,药物能够随可溶性针尖的溶解而释放,同时,三七多糖自身的强免疫活性,能够作为免疫增生剂,协同药物更好地发挥免疫治疗作用。
Description
技术领域
本发明涉及医药技术领域。更具体地,涉及一种可溶性微针及其制备方法。
背景技术
经皮免疫是近年来兴起的极具有前景的新型免疫方法。人体皮肤角质层下的活性表皮层中存在着一类树突状细胞(DCs)--郎格汉斯细胞(Langerhans cells,LCs)。LCs是活性表皮内的未成熟的DCs,当它捕捉到抗原,产生剌激后,形成成熟的DCs,可离开皮肤表皮向局部淋巴结游走,产生很强的免疫效应,所以活性表皮层被认为是疫苗接种的最佳部位。根据皮肤在免疫、生理和生物方面的特性,将皮肤作为给药部位有其独特的优势,但经皮免疫最大的阻力来源于皮肤外层的角质层。
微针(microneedle,MN)阵列技术作为一种新兴的物理经皮促透方法,具有精确、无痛、高效、便利等诸多优势,是替代传统经皮给药系统的一种有效治疗方式,它能在角质层产生数微米级的空洞,从而形成能使微粒到达活性表皮层的药物通道,部分或完全溶解并释放药物。其优点主要为原料来源广泛,制备方法相对简单,适于产业化生产等,同时由于微针尺寸微小,不触及或较少触及痛觉神经,可实现无痛给药,从而增加了给药方面的优势。大分子和小分子化合物都可以作为微针的负载物。与传统的不可溶性微针给药途径相比,可溶性微针给药的成本低、安全性好、载药效率高、释药速率可控,是一种具有广阔应用前景的透皮给药方式。
为了最大程度的提高微针的治疗效果,需要提供一种工艺简单、安全性能高,具有药物协同作用的可溶性微针。
发明内容
为了解决背景技术中存在的问题,本发明将具有免疫佐剂活性的三七多糖作为基质材料并制备适用于经皮给药的可溶性微针阵列,本发明的可溶性微针阵列以具有免疫佐剂活性的三七多糖针尖作为载体,将药物装载于针尖中,作用于皮肤后,药物能够随可溶性针尖的溶解而释放,同时,三七多糖自身的强免疫活性,能够作为免疫增生剂,协同药物更好地发挥免疫治疗作用。
本发明提供一种可溶性微针阵列,包括针尖和背衬层;所述针尖由中国专利(CN111533820A)中具有强免疫活性的水溶性三七多糖组分(PNPS)形成,所述PNPS能够促进小鼠骨髓来源树突状细胞成熟,增强T细胞功能,调控肿瘤相关巨噬细胞,可以作为免疫佐剂,增强自身免疫系统,杀伤或抑制肿瘤细胞;所述背衬层由水溶性高分子材料形成,所述水溶性高分子材料为透明质酸(HA);优选的,所述HA分子量为10kDa。
所述针尖高度为800μm;针尖间距为800μm;微针底部尺寸为410μm×410μm,背衬层尺寸为12.4mm×12.4mm;微针阵列数量为11×11。
本发明还提供所述三七多糖可溶性微针的制备方法,包括以下步骤;
S1、将水溶性三七多糖溶于去离子水中,配制成浓度为10mg/mL的水溶液,12000rpm离心5min,取上清,备用;
S2、将透明质酸溶于去离子水中,配制成浓度为10mg/mL的HA凝胶,20℃超声10min,使透明质酸完全溶解于去离子水,静置120min,排出所有气泡,备用;
S3、将S1得到上清液注入聚二甲基硅氧烷微针模具中,4000rpm离心10mim,旋转180°,再次4000rpm离心10mim,吸出多余液体;
S4、将S2静置好的HA凝胶溶液填满进微针模具凹槽,干燥24h,脱模,即可。
所述凹槽深度为1.5mm。
本发明还提供所述的微针阵列机械性能评价方法,包括硬度测试、皮肤刺入能力测试、溶解性能测试、药物渗透性测试以及药物传递时效性测试。
本发明的有益效果为:
通过本发明的微针能够有效提高给药部位的药物递送浓度,最大程度实现大分子经皮递送,同时便于患者自主给药,依从性提高。此外,微针的基质材料PNPS自身具有免疫调节活性及高分子聚合物特性,能够以免疫增生剂的方式,协同药物更好地发挥免疫治疗作用。
附图说明
图1为实施例1制备得到的实体微针及其SEM扫描电镜图;
图2为实施例1制备得到的可溶性微针针尖承重力测试图;
图3为实施例1制备得到的可溶性微针作用皮肤后的皮肤角质层切片CLSM图;
图4为实施例1制备得到的可溶性微针作用皮肤后的皮肤表面水分散失曲线;
图5为实施例1制备得到的可溶性微针针尖溶解性能图;
图6为实施例1制备得到的可溶性微针药物渗透性能测试图;
图7为实施例1制备得到的可溶性微针药物传递药物时荧光在皮肤内的滞留量;
图8为实施例1制备得到的可溶性微针药物传递药物时透过皮肤的荧光强度。
具体实施方式
以下结合附图与具体实施例,对本发明进行更加详细的说明,但本发明的保护范围绝非仅局限于实施例。
实施例1
一种三七多糖可溶性微针阵列的制备方法,具体步骤如下:
(1)基质溶液配制:
按照中国专利(CN111533820A一种三七多糖及其制备方法与应用)中的方法制备得到的水溶性三七多糖(PNPS),PNPS能够促进小鼠骨髓来源树突状细胞成熟,增强T细胞功能,调控肿瘤相关巨噬细胞,可以作为免疫佐剂,增强自身免疫系统,杀伤或抑制肿瘤细胞;将PNPS溶于去离子水中,配制成浓度为10mg/mL的水溶液,12000rpm离心5min,取上清,备用;
将透明质酸溶于去离子水中,配制成浓度为10mg/mL的HA凝胶,20℃超声10min,使透明质酸完全溶解于去离子水,静置120min,排出所有气泡,备用;
(2)基质溶液离心入模:
将步骤(1)得到的上清液注入针长800μm,11×11阵列的聚二甲基硅氧烷(PDMS)微针模具中,4000rpm离心10mim,旋转180°,再次4000rpm离心10mim,吸出多余液体;将静置好的HA凝胶溶液填满进微针模具凹槽,凹槽深度为1.5mm,放入干燥器,室温干燥24h,脱模,即可,得到微针阵列针尖高度为800μm;针尖间距为800μm;微针底部尺寸为410μm×410μm,微针贴片尺寸即背衬层尺寸为12.4mm×12.4mm;微针阵列数量为11×11。
如图1所示,制备出的三七多糖可溶性微针阵列针尖大小一致,分布均匀。
三七多糖可溶性微针阵列的性能评价:
(1)微针承重性能测试:
微针贴片针尖朝上置于试验台,放置不同重量的砝码于针尖,通过皮肤测试仪观察不同作用力下的针尖形态变化。
如图2所示,当负载100g砝码时,可见PNPS针尖有一定破损;当负载500g砝码时,针尖出现明显弯曲;当负载1000g砝码时,针尖严重弯曲,尖锐消失,证明了PNPS微针良好的硬度与承重性能,足以穿刺皮肤。
(2)皮肤穿刺能力测试:
在活体的昆明大鼠上,将11×11针长800μm的三七多糖微针快速压入大鼠皮肤脱毛位置,按压30s后,移除微针,并迅速将此块皮肤剥离,进行石蜡包埋,切片,通过激光共聚焦(CLSM)拍摄,如图3所示,能够明显的看出,皮肤角质层出现明显的断裂;同时将多糖微针分别作用于活体大鼠背部皮肤1min、5min、10min、15min、30min、45min、60min,通过经皮水分测定仪,测定出微针作用不同时间点的情况下,皮肤表面的水分散失率(TWEL)情况,如图4所示,多糖微针作用后的皮肤,其TWEL显著高于空白对照组,表明皮肤角质层已经破损,上述试验证实了多糖微针具有良好的皮肤刺入能力,为后续药物的经皮有效递送奠定了基础。
(3)溶解性能测试:
将透明质酸微针(HA)与三七多糖微针(PNPS)刺入离体的大鼠皮肤后,置于Franz透皮仪上,分别于0min、5min、15min、30min后取下微针,通过扫描电镜SEM拍摄针尖变化情况,结果如图5所示,在作用相同时间下,PNPS微针的溶解性明显优于HA微针,并且PNPS微针在30min时,针尖几乎完全溶解,这些结果表明,PNPS微针具有良好的溶解性能,可在短时间内释放药物,为后期的药物快速释放提供依据。
(4)药物渗透性测试:
为了验证三七多糖微针的皮肤渗透性,对三七多糖进行了FTSC荧光标记,得到PNPS-FTSC微针,取离体猪皮置于玻片上,使用微针注射器将PNPS-FTSC微针分别刺入皮肤30s、1min、3min、5min、15min、30min后,移除微针,其荧光渗透深度如图6所示,通过CLSM拍摄得出,随着微针作用时间的不断延长,PNPS-FTSC荧光渗透越来越深,当作用30min时,荧光渗透深度可达到380μm,据相关文献报道,皮肤角质层到达真皮层的深度约在220μm左右,因此PNPS微针能够使药物递送至皮肤的真皮层。
(5)药物传递性能时效性测试:
为了验证PNPS微针对不同特性药物的载药性能,分别将脂溶性荧光(尼罗红)和水溶性荧光(荧光素钠)装载入PNPS微针中,将两种微针分别作用于离体的大鼠皮肤,与水溶液给药组做对照,将给药后的皮肤置于Franz透皮仪,分别在不同时间点取样,测定荧光在皮肤内的滞留量(如图7(a)(b)(c)(d))以及透过皮肤的荧光强度(如图8(a)(b)),结果显示,两组微针给药组皮肤内荧光强度明显高于水溶液组,证明了微针具有良好的载药性能,同时载水溶性荧光的微针与载脂溶性荧光的微针相比,荧光透过皮肤的量更多,证明PNPS微针能够更好的携带水溶性药物透过皮肤。
Claims (5)
1.一种可溶性微针阵列,其特征在于,包括针尖、背衬层,针尖由水溶性三七多糖制成,背衬层由水溶性高分子材料制成。
2.根据权利要求1所述可溶性微针阵列,其特征在于,水溶性高分子材料为透明质酸,透明质酸的分子量为10kDa。
3.根据权利要求1所述可溶性微针阵列,其特征在于,针尖高度为800μm;针尖间距为800μm;微针底部尺寸为410μm×410μm,背衬层尺寸为12.4mm×12.4mm;微针阵列数量为11×11。
4.权利要求1所述可溶性微针阵列的制备方法,其特征在于,包括以下步骤:
S1、将水溶性三七多糖溶于去离子水中,配制成浓度为10mg/mL的水溶液,12000rpm离心5min,取上清,备用;
S2、将透明质酸溶于去离子水中,配制成浓度为10mg/mL的HA凝胶,20℃超声10min,使透明质酸完全溶解于去离子水,静置120min,排出所有气泡,备用;
S3、将S1所得的上清液注入聚二甲基硅氧烷微针模具中,4000rpm离心10mim,旋转180°,再次4000rpm离心10mim,吸出多余液体;
S4、将S2静置好的HA凝胶溶液填满进微针模具凹槽,干燥24h,脱模,即得到微针阵列。
5.根据权利要求4所述可溶性微针阵列的制备方法,其特征在于,凹槽深度为1.5mm。
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