目的 首次使用白及多糖和聚乙烯醇制备载胰岛素（insulin，INS）的可溶性微针柔性贴片（INS-DMNs），并对其理化性质及透皮递送性能进行了初步评价。方法 采用微模塑法制备INS-DMNs，以针体硬度、背衬柔韧性及成型性为指标，考察白及多糖与聚乙烯醇的浓度；扫描电子显微镜（SEM）观察形态特征，考察载药量、溶解性、皮肤刺激性、机械强度及稳定性，共聚焦显微镜评估胰岛素的透皮释放和扩散；采用Franz扩散池考察体外透皮性能；体内药效学评估INS-DMNs对糖尿病大鼠的降血糖作用。结果 INS-DMNs呈金字塔形，针体均匀且机械强度良好，能在2 h内溶解，背衬柔韧平整，每片含药量（0.25±0.02）IU，所诱导的皮肤损伤小且可迅速恢复，稳定性良好，胰岛素可到达皮肤内部220 μm处。体外皮肤渗透结果显示，12 h后，INS-DMNs中胰岛素累积渗透量可达89.63%，证明白及多糖可溶性微针柔性贴片可有效改善胰岛素的透皮渗透。体内药效学结果显示，INS-DMNs表现出明显的降血糖作用，相对于皮下给药，微针给药的持续性更好。结论 INS-DMNs具有足够的机械强度插入皮肤并持续释放药物，同时灵活的背衬提供了更优的皮肤附着力，实现了胰岛素的透皮递送。

Objective The insulin (INS)-loaded dissolving microneedles with flexible patches (INS-DMNs) was prepared by Bletilla striata polysaccharide (BSP) and polyvinyl alcohol (PVA) for the first time, the physicochemical properties and transdermal delivery performance of INS-DMNs were preliminarily evaluated. Methods INS-DMNs were prepared by micro-molding technique. The concentration of BSP and PVA was investigated with the hardness of needle bodies, flexibility of patches and formability of microneedles as the evaluation index. The morphological characteristics was observed by scanning electron microscopy. Drug loading, solubility, skin irritation, mechanical strength and stability were tested. The transdermal release and diffusion of INS were observed by confocal microscopy. In vitro transdermal performance of INS-DMNs was investigated by Franz diffusion cell, and in vivo pharmacodynamics were studied to investigate their hypoglycemic effect on diabetic rats. Results The prepared INS-DMNs were pyramidal in shape with uniform needle bodies and excellent mechanical strength. Meanwhile, the needle bodies of INS-DMNs could dissolve in 2 h, and the patches were flexible and flat. The dosage of INS was (0.25 ±0.02) IU per patch, and the skin damage induced by INS-DMNs was slight and recovered quickly. The stability was excellent and INS could reach 220 μm inside the skin. Moreover, in vitro skin penetration results showed that the cumulative penetration of INS in INs-DMNS reached 89.63% after 12 h, which proved that the Bletilla striata polysaccharide dissolving microneedles with flexible patches could effectively improve the transdermal penetration of INS. The results of in vivo pharmacodynamics showed that INS-DMNs exhibited a significant hypoglycemic effect, and compared with subcutaneous administration, microneedle administration was more sustainable. Conclusion INS-DMNs realized the transdermal delivery of INS, where the needle bodies were mechanically robust enough to insert into the skin and continuously release drugs, while the flexible patches provided better skin adhesion.

R283.6

国家自然科学基金项目（81603309）；国家重点研发计划（2017YFC1700705）；四川省留学人员科技活动项目择优资助经费计划（2018-68）；四川省重点研发计划（2020YFS0330）；四川省重点研发计划（2019YFS0174）