Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.
Department of Applied Chemistry and Chemical Engineering, Noakhali Science and Technology University, Noakhali 3814, Bangladesh.
ACS Appl Bio Mater. 2021 Aug 16;4(8):6256-6267. doi: 10.1021/acsabm.1c00563. Epub 2021 Aug 4.
Lipid-based biocompatible ionic liquids (LBILs) have attracted attention as carriers in transdermal drug delivery systems (TDDSs) because of their lipophilic character. In this study, we report the formulation of a peptide-LBIL complex microencapsulated in an oil phase as a potential carrier for the transdermal delivery of leuprolide acetate as a model hydrophilic peptide. The peptide-LBIL complexes were prepared via a water-in-oil emulsion composed of 1,2-dimyristoyl--glycerol-3-ethyl-phosphatidylcholine (EDMPC), a fatty acid (stearic, oleic, and linoleic acid)-based LBIL, and cyclohexane followed by freeze-drying to remove the water and cyclohexane. Then, the peptide-LBIL complexes were nanodispersed and stabilized in isopropyl myristate (IPM) using sorbitol laurate (Span-20). Ionic-liquid-in-oil nanodispersions (IL/O-NDs) were prepared with varying weight ratios of LBILs and Span-20 as the surfactant and the cosurfactant, respectively. Keeping the overall surfactant constant at 10 wt % in IPM, a 5:5 wt % ratio of surfactant (IL) and cosurfactant (Span-20) in the IL/O-NDs significantly ( < 0.0001) increased the physiochemical stability, drug-loading capacity, and drug encapsulation efficiency. The and peptide delivery across the skin was increased significantly ( < 0.0001) using IL/O-NDs, compared with non-IL-treated groups. Of all of the LBIL-based formulations, [EDMPC][Linoleate]/O-ND was considered the most preferable for a TDDS based on the pharmacokinetic parameters. The transdermal delivery flux with [EDMPC][Linoleate]/O-ND was increased 65-fold compared with the aqueous delivery vehicle. The IL/O-NDs were able to deform the lipid and protein arrangements of the skin layers to enhance the transdermal permeation of the peptide. and cytotoxicity studies of the IL/O-NDs revealed the biocompatibility of the LBIL-based formulations. These results indicated that IL/O-NDs are promising biocompatible carriers for lipid-peptide TDDSs.
脂基生物相容离子液体（LBILs）因其亲脂性而被作为经皮给药系统（TDDSs）的载体受到关注。在这项研究中，我们报告了一种肽-LBIL 复合物的制剂，该复合物被包封在油相中，作为醋酸亮丙瑞林作为模型亲水性肽的经皮递送的潜在载体。肽-LBIL 复合物是通过由 1,2-二肉豆蔻酰基 -3-乙基-磷酸胆碱（EDMPC）、基于脂肪酸（硬脂酸、油酸和亚油酸）的 LBIL 和环己烷组成的油包水乳液制备的，然后通过冷冻干燥除去水和环己烷。然后，将肽-LBIL 复合物在异壬酸异丙酯（IPM）中用失水山梨醇单月桂酸酯（Span-20）纳米分散和稳定。用不同重量比的 LBIL 和 Span-20 作为表面活性剂和助表面活性剂制备离子液体/油纳米分散体（IL/O-ND）。在 IPM 中保持总表面活性剂含量为 10wt%，IL/O-ND 中表面活性剂（IL）和助表面活性剂（Span-20）的 5:5wt%比例显著（<0.0001）增加了物理化学稳定性、载药量和药物包封效率。与非 IL 处理组相比，IL/O-ND 显著（<0.0001）增加了肽的透皮输送。在所有基于 LBIL 的制剂中，基于药代动力学参数，[EDMPC][Linoleate]/O-ND 被认为是最适合 TDDS 的制剂。与水性递送载体相比，[EDMPC][Linoleate]/O-ND 的透皮递送通量增加了 65 倍。IL/O-ND 能够使皮肤层的脂质和蛋白质排列变形，从而增强肽的经皮渗透。IL/O-ND 的 和 细胞毒性研究表明 LBIL 制剂具有生物相容性。这些结果表明，IL/O-ND 是脂质-肽 TDDS 的有前途的生物相容载体。
