新型经皮传递胰岛素透明质酸微针制剂的制备及性能考察

目的证明透明质酸微针制剂在药物经皮传递系统方面的应用前景。方法通过皮肤及微针的显微照片考察微针刺入皮肤的性能和在大鼠体内的溶解性能;用皮肤刺激性实验评价透明质酸微针的安全性;以人的离体皮肤为透皮释药模型,通过体外经皮通透实验考察微针对模型药物胰岛素经皮吸收的促进作用。结果微针能够均匀刺穿角质层,在皮肤表面产生与微针一致的阵列形状,在皮肤断面可观察到直至真皮层的通道;在大鼠体内使用1 h后,针体能够完全溶解,皮肤刺激性指数为1.7,属于轻度刺激性;体外经皮实验中,微针中的胰岛素能够以活性形式释放,与同剂量的溶液相比,微针对胰岛素的体外经皮吸收具有显著的促进作用,稳态通透速率达75.33×10-6U.cm-2.h-1。结论以透明质酸为基质制备的微针具有良好的皮肤刺入性、溶解性和轻度的刺激性,对于生物大分子类药物的经皮吸收有明显的促进作用,具有良好的开发前景。

Preparation and characterization of novel hyaluronic acid microneedles for insulin transdermal delivery

Objective To fabricate novel solid microneedle arrays using hyaluronic acid which is naturally found in many tissues of the body and investigate the characteristics and the effect in transdermal delivery. Method Microphotograph was employed to examine the insertion ability and solubility of microneedle arrays. Primary irritation test was used to verify their safety in rat skin. The in vitro transdermal delivery of insulin from microneedle arrays was measured using a Franz diffusion cell fitted with the cadaver human skin. Results Microneedle arrays uniformly pierced the stratum corneum and created pores corresponding to the microneedles in the array. They also inserted deeply into the mid-dermis below with a tapered pathway having the same shape as the microneedle arrays used. Needles can be dissolved absolutely after left in rat skin for 1 h. Primary irritation index was 1.7, which showed microneedle arrays have weak irritation. In the in vitro studies, insulin was released from microneedle arrays in its active form. Compared with insulin solution of the same dose, microneedle arrays showed an outstanding enhancement of insulin permeation, and transdermal flux reached to 75.33×10^-6 U·cm^-2·h^-1. Conclusions Microneedle arrays can be actually fabricated with hyaluronic acid. These microneedle arrays have sufficient insertion ability, suitable solubility and weak irritation. They obviously enhance the transdermal delivery of biologically active protein, which suggests prospect in development.