Key Laboratory of Smart Drug Delivery of MOE, School of Pharmacy, Fudan University, Shanghai 201203, PR China.
Shanghai Dermatology Hospital, Shanghai 200443, PR China.
Int J Pharm. 2019 Oct 5;569:118584. doi: 10.1016/j.ijpharm.2019.118584. Epub 2019 Jul 31.
This study aimed to develop biocompatible deep eutectic solvents (DESs) as carriers for improving the nasal delivery of insulin. The DES was prepared from malic acid and choline chloride broadly used in foods, drugs, or cosmetics as biocompatible additives. The DES of choline chloride and malic acid (CM-DES) demonstrated lower melting point (-59.1 °C) and higher viscosity (120,000 cP) compared with hydrogels based on sodium carboxyl methyl cellulose (CMC-Na). The conformational structure of insulin does not change in CM-DES as characterized by circular dichroism. The in vitro results showed that CM-DES dissociated gradually but did not disintegrate immediately upon contact with water. CM-DES was able to improve the hypoglycemic effect of insulin significantly at different doses compared with hydrogels or solutions of insulin, which could be ascribed to facilitated penetration of insulin across the nasal epithelia by CM-DES. The hypoglycemic effect of CM-DES loading insulin at a dose of 25 IU/kg was similar to that of subcutaneous insulin at 1 IU/kg. In addition, no evident toxicity to nasal epithelia was observed after nasal administration to rats for seven consecutive days. In conclusion, CM-DES showed promising potential in enhancing the hypoglycemic effect of insulin via the nasal route.
本研究旨在开发生物相容性深共晶溶剂（DES）作为载体，以提高胰岛素的鼻腔给药。DES 由广泛用于食品、药物或化妆品的生物相容性添加剂马来酸和氯化胆碱制备。与基于羧甲基纤维素钠的水凝胶（CMC-Na）相比，胆碱和马来酸的 DES（CM-DES）具有更低的熔点（-59.1°C）和更高的粘度（120,000 cP）。圆二色性表明，CM-DES 中胰岛素的构象结构没有变化。体外结果表明，CM-DES 与水接触时逐渐解离但不会立即崩解。与胰岛素水凝胶或溶液相比，CM-DES 能够以不同剂量显著提高胰岛素的降血糖作用，这可以归因于 CM-DES 促进胰岛素穿过鼻上皮的渗透。在 25 IU/kg 剂量下，CM-DES 负载胰岛素的降血糖作用与 1 IU/kg 剂量的皮下胰岛素相似。此外，连续七天经鼻给予大鼠后，未见对鼻上皮有明显毒性。总之，CM-DES 通过鼻腔给药显示出增强胰岛素降血糖作用的巨大潜力。
