渗透促进剂对大鼠舌下黏膜及胰岛素舌下给药的影响

Effects of various penetration enhancers on the sublingual absorption of insulin in rats

目的 研究不同渗透促进剂对蛋白多肽药物舌下吸收的影响及作用机制。方法 以胰岛素为模型药,考察各种渗透促进剂经正常大鼠舌下给药后降血糖的效果,以皮下注射为对照,计算胰岛素舌下给药的药理相对生物利用度(PA％);采用拉曼光谱、圆二色谱和荧光偏振实验技术考察渗透促进剂对大鼠舌下黏膜的膜脂流动性及膜蛋白构象的影响。结果 一般情况下,胰岛素溶液经舌下给药后的生物利用度较低,渗透促进剂苄泽35、蛋黄卵磷脂和壳聚糖均能显著增加胰岛素溶液的降血糖作用;渗透促进剂能够影响膜脂的微观结构和膜蛋白的构象,不同渗透促进剂的影响差别较大。苄泽35、蛋黄卵磷脂和壳聚糖能够增加膜脂的流动性,并使蛋白构象趋于松散,从而提高黏膜的通透性,促进胰岛素的舌下吸收,并表现为降糖作用的增加。结论 渗透促进剂可以不同程度地影响膜脂流动性和膜蛋白构象,提高胰岛素经舌下给药后的降糖效果。

OBJECTIVE: To study the effects of various penetration enhancers on the sublingual absorption of insulin in rats. METHODS: Several absorption enhancers were selected to be co-administered with insulin sublingually in rats. The sublingual absorption of insulin was calculated by its pharmacological bioavailability (PA%) compared to subcutaneously administered insulin solution. The effects of penetration enhancers on the structural properties of the sublingual membrane of rats were investigated by Fourier Transform Raman Spectroscopy, Circular Dichroism and Fluorescence Polarization in vitro. RESULTS: The permeability of insulin significantly increased compared to control after coadministration with Brij35, chitosan and egg lecithin. After being treated with Brij35, egg lecithin and chitosan, not only the fluidity of sublingual lipid membrane increased but also the conformation of the membrane protein loosed. The investigated penetration enhancers produced different effects. CONCLUSION: Penetration enhancers can change the fluidity of membrane lipid and the conformation of membrane protein in certain degrees, and increase the sublingual absorption of insulin.