School of Pharmacy, Key Laboratory of Smart Drug Delivery of MOE, Fudan University, Shanghai 201203, China.
College of Chemical Engineering, North China University of Science and Technology, Tangshan 063210, PR China.
J Control Release. 2024 Nov;375:812-828. doi: 10.1016/j.jconrel.2024.09.035. Epub 2024 Oct 9.
Proteins and peptides have been increasingly developed as pharmaceuticals owing to their high potency and low side effects. However, their administration routes are confined to injections, such as intra-muscular and intra-venous injections, making patient compliance a challenge. Hence, non-injectable delivery systems are crucial to expanding the clinical use of proteins and peptides. In this context, two choline-based ionic liquids (ILs), namely, choline geranic acid ([Ch][Ger]) and choline citric acid ([Ch][Cit]), have been identified as promising agents for enhancing the permeation and prolonging the retention time of glucagon (GC) after intra-nasal administration. Notably, intra-nasal delivery of GC via ILs (GC/ILs) elicited rapid and smooth reversal of acute hypoglycaemia without leading to rebound hyperglycaemia in type 1 diabetic rats subjected to insulin induction. In addition, ILs could improve the transcellular transport of GC through electrostatic interaction. ILs could also transiently open inter-cellular tight junctions transiently to facilitate the paracellular transport of GC. Safety tests indicated that continuous intra-nasal delivery of ILs led to reversible changes, such as epithelial cell inflammation, goblet cell overgrowth, and impacts on the distribution of nasal cilia. However, these changes could be alleviated by the innate self-repair ability of mucosal epithelial cells. This study highlights the considerable potential of ILs for long-term nasal delivery of biomacromolecules.
由于蛋白质和肽具有高效力和低副作用的特点，它们已越来越多地被开发为药物。然而，它们的给药途径仅限于注射，如肌肉内和静脉内注射，这使得患者的依从性成为一个挑战。因此，非注射性的给药系统对于扩大蛋白质和肽的临床应用至关重要。在这方面，两种基于胆碱的离子液体（ILs），即胆甾酸胆碱([Ch][Ger])和柠檬酸胆碱([Ch][Cit])，已被确定为增强胰高血糖素（GC）经鼻内给药时的渗透和延长保留时间的有前途的试剂。值得注意的是，通过 ILs（GC/ILs）经鼻内给予 GC 可迅速、平稳地逆转 1 型糖尿病大鼠胰岛素诱导后的急性低血糖，而不会导致反弹性高血糖。此外，ILs 可以通过静电相互作用改善 GC 的跨细胞转运。ILs 还可以瞬时打开细胞间紧密连接，促进 GC 的旁细胞转运。安全性测试表明，连续经鼻内给予 ILs 会导致上皮细胞炎症、杯状细胞过度生长以及对鼻纤毛分布的影响等可逆变化。然而，这些变化可以通过黏膜上皮细胞的固有自我修复能力得到缓解。本研究强调了 ILs 用于生物大分子长期经鼻给药的巨大潜力。
