Li Yang, Yu Qin, Lu Yi, He Haisheng, Qi Jianping, Tai Zongguang, Chen Zhongjian, Zhu Quangang, Wu Wei
School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China.
School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China; Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, China.
Int J Pharm. 2024 Dec 25;667(Pt B):125006. doi: 10.1016/j.ijpharm.2024.125006. Epub 2024 Nov 26.
Ionic liquids (ILs) show promises as chemical penetration enhancers (CPEs) for transdermal delivery of macromolecular drugs. However, their high viscosity and strong drug-IL affinity may limit drug diffusion and release from the drug-loaded IL (one-step strategy). Herein, a two-step strategy was used by applying choline-based ILs as pretreatment agents followed by insulin solution to improve penetration. Insulin remained stable in the ILs and are released slowly from the IL matrices. In vitro and in vivo studies showed that two-step treatment enhanced insulin penetration compared to one-step treatment, with choline citrate ([Ch][Ci]) and choline geranate ([Ch][Ge]) performing the best. In a diabetic rat model, two-step treatment with [Ch][Ge] reduced blood glucose levels to below 80% within 8 h, while one-step treatment only maintained for 12 h. Trans-epidermal water loss and molecular dynamics simulations suggested that variations in release rates and skin condition accounted for the differences between the two strategies. Physical characterization confirmed that ILs enhanced transdermal delivery of insulin by permeabilizing stratum corneum and opening tight junctions. Preliminary safety assessment indicated mild irritation by [Ch][Ge], whereas [Ch][Ci] showed good biocompatibility. It is concluded that ILs hold potential in enhancing transdermal delivery of insulin.
离子液体（ILs）作为大分子药物经皮给药的化学渗透促进剂（CPEs）显示出应用前景。然而，它们的高粘度和与药物的强亲和力可能会限制药物从载药离子液体中的扩散和释放（一步法策略）。在此，采用两步法策略，先应用胆碱基离子液体作为预处理剂，然后再使用胰岛素溶液来提高渗透率。胰岛素在离子液体中保持稳定，并从离子液体基质中缓慢释放。体外和体内研究表明，与一步法相比，两步法处理可增强胰岛素的渗透，其中柠檬酸胆碱（[Ch][Ci]）和香叶酸胆碱（[Ch][Ge]）效果最佳。在糖尿病大鼠模型中，用[Ch][Ge]进行两步法处理可在8小时内将血糖水平降至80%以下，而一步法处理仅能维持12小时。经皮水分流失和分子动力学模拟表明，释放速率和皮肤状况的差异是两种策略之间差异的原因。物理表征证实，离子液体通过使角质层通透性增加和打开紧密连接来增强胰岛素的经皮递送。初步安全性评估表明，[Ch][Ge]有轻度刺激性，而[Ch][Ci]具有良好的生物相容性。结论是，离子液体在增强胰岛素经皮递送方面具有潜力。
