Shanghai Dermatology Hospital, Shanghai 200443, China.
Key Laboratory of Smart Drug Delivery of MOE, School of Pharmacy, Fudan University, Shanghai 201203, China.
Int J Pharm. 2019 Mar 10;558:380-387. doi: 10.1016/j.ijpharm.2019.01.021. Epub 2019 Jan 18.
The aim of this work was to develop biocompatible ionic liquids (ILs) for enhancement of dermal delivery of hydrophilic macromolecules. The ILs were prepared from malic acid and choline, which are commonly used as food additives and generally regarded as safe. The choline malate IL (CM-IL) was formed via ionic interactions, which has been validated by Fourier transform infrared spectroscopy and nuclear magnetic resonance. Analysis by differential scanning calorimetry confirmed a melting point of -65.2 °C for CM-IL. In skin penetration study, CM-IL was proved to be able to deliver a model hydrophilic macromolecule dextran into deep skin. The amount of dextran delivered to epidermis and dermis by CM-IL is approximately two folds that of by dextran solution. Enhanced in vivo skin penetration by CM-IL was proved as well. The fluorescence of FITC-dextran could be observed permeating pervasively throughout the skin from 4 h to 24 h, while in the control groups it was mainly concentrated in stratum cornea (SC) and hair follicles. In addition, CM-IL did not shown any irritation to mice skin within 7 days of successive treatment and any toxicity to human epidermal cells (HEK-A) within 24 h. In conclusion, CM-IL could be potentially used as enhancers or vehicles for dermal delivery of hydrophilic macromolecules.
本工作旨在开发用于增强亲水性大分子经皮传递的生物相容性离子液体（ILs）。ILs 由常用于食品添加剂且通常被认为是安全的苹果酸和胆碱制备而成。通过离子相互作用形成了胆碱苹果酸盐 IL（CM-IL），这已通过傅里叶变换红外光谱和核磁共振得到验证。差示扫描量热法分析证实 CM-IL 的熔点为-65.2°C。在皮肤渗透研究中，CM-IL 被证明能够将模型亲水性大分子葡聚糖递送至真皮深部。CM-IL 递送至表皮和真皮的葡聚糖量约为葡聚糖溶液的两倍。还证明了 CM-IL 增强了体内皮肤渗透。从 4 小时到 24 小时，可以观察到 FITC-葡聚糖的荧光遍及整个皮肤渗透，而在对照组中，它主要集中在角质层（SC）和毛囊中。此外，CM-IL 在连续治疗 7 天内对小鼠皮肤没有任何刺激作用，在 24 小时内对人表皮细胞（HEK-A）也没有任何毒性。总之，CM-IL 可能被用作亲水性大分子经皮传递的增强剂或载体。
