Department of Pharmacy, School of Health Sciences Sector of Pharmaceutical Technology, National and Kapodistrian University of Athens, Athens, 15784, Greece.
Laboratory Animal Facility, Centre of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, 11527, Greece.
Pharm Res. 2024 Oct;41(10):1951-1963. doi: 10.1007/s11095-024-03745-8. Epub 2024 Oct 29.
Fingolimod hydrochloride (FH) has emerged as a vital medication for managing Multiple Sclerosis (MS). Despite its high oral bioavailability of 93%, it is plagued by slow oral absorption (T = 8-12 h) and extensive hepatic metabolism. Intranasal administration has emerged as an alternative to address these limitations, ensuring efficient central nervous system delivery and minimizing peripheral exposure and first-pass metabolism.
This study aims to develop and evaluate FH nasal films for enhanced drug delivery.
A Design of Experiments approach was employed to formulate FH nasal films, utilizing HPMC E50 as a film-forming polymer, PEG 400 as a plasticizer, and Me-β-CD as a permeation enhancer. Two formulations with superior in vitro and ex vivo performance were selected for in vivo evaluation. A comparative pharmacokinetic study was conducted in C57BL/6 J mice in the brain and serum after administration of nasal films and oral FH solution, respectively. Sparse sampling and non-compartmental analysis were used.
FH nasal films efficiently delivered the drug to both serum (C = 0.35 ± 0.021, C = 0.38 ± 0.029 μg/mL) and brain (C = 0.39 ± 0.05, C = 0.44 ± 0.048 μg/mL), achieving higher levels than oral delivery. Brain relative bioavailability (% F) was 519% and 534%, while serum % F was 295% and 343%.
The rapid nose-to-brain delivery within 30 min, in contrast to 10-h Tmax of the oral solution, indicates the potential of a combined IN and oral treatment regimen. This approach could expedite the attainment of steady-state concentrations, offering a promising method for managing multiple sclerosis (MS).
盐酸芬戈莫德（FH）已成为治疗多发性硬化症（MS）的重要药物。尽管其口服生物利用度高达 93%，但它存在口服吸收缓慢（T=8-12 小时）和广泛的肝脏代谢等问题。鼻腔给药已成为解决这些局限性的一种替代方法，可确保高效的中枢神经系统递送，同时最小化外周暴露和首过代谢。
本研究旨在开发和评估 FH 鼻用薄膜以增强药物递送。
采用实验设计方法来制备 FH 鼻用薄膜，使用 HPMC E50 作为成膜聚合物，PEG 400 作为增塑剂，Me-β-CD 作为渗透增强剂。选择具有优越体外和离体性能的两种配方进行体内评价。分别给予鼻腔薄膜和口服 FH 溶液后，在 C57BL/6J 小鼠的脑和血清中进行比较药代动力学研究。采用稀疏采样和非房室分析。
FH 鼻用薄膜可有效将药物递送到血清（C=0.35±0.021，C=0.38±0.029μg/mL）和大脑（C=0.39±0.05，C=0.44±0.048μg/mL），达到高于口服给药的水平。脑相对生物利用度（%F）为 519%和 534%，而血清%F 为 295%和 343%。
与口服溶液 10 小时的 Tmax 相比，30 分钟内快速的鼻内到脑递送表明联合 IN 和口服治疗方案的潜力。这种方法可以加快达到稳态浓度，为管理多发性硬化症（MS）提供了一种有前途的方法。
