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Updated: Jun 9, 2025
Intranasal Administration of CNS Therapeutics to Awake Mice
Published on: April 8, 2013
Pharmacokinetic Study of Fingolimod Nasal Films Administered via Nose-to-Brain Route in C57BL/6 J Mice as Potential
Paraskevi Papakyriakopoulou1, Evangelos Balafas2, Nikolaos Kostomitsopoulos2
1Department of Pharmacy, School of Health Sciences Sector of Pharmaceutical Technology, National and Kapodistrian University of Athens, Athens, 15784, Greece.
Background:
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 (Tmax = 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.
Objective:
This study aims to develop and evaluate FH nasal films for enhanced drug delivery.
Methods:
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.
Results:
FH nasal films efficiently delivered the drug to both serum (Cmax(F3) = 0.35 ± 0.021, Cmax(F4) = 0.38 ± 0.029 μg/mL) and brain (Cmax(F3) = 0.39 ± 0.05, Cmax(F4) = 0.44 ± 0.048 μg/mL), achieving higher levels than oral delivery. Brain relative bioavailability (% Frel (0-6 h)) was 519% and 534%, while serum % Frel (0-6 h) was 295% and 343%.
Conclusions:
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).
