Preparation, In-vitro, Ex-vivo, and Pharmacokinetic Study of Lasmiditan as Intranasal Nanoemulsion-based In Situ Gel
Authors: Jabir Saba Abdulhadi , Rajab Nawal A. 
Published: January 2024

Background:

Lasmiditan (LAS) is a recently developed antimigraine drug and was approved
in October, 2019 for the treatment of acute migraines; however, it suffers from low oral bioavailability,
which is around 40%.

Objective:

This study aimed to improve the LAS bioavailability via formulation as nanoemulsionbased
in situ gel (NEIG) given intranasally and then compare the traditional aqueous-LASsuspension
(AQS) with the two successful intranasal prepared formulations (NEIG 2 and NEIG 5) in
order to determine its relative bioavailability (F-relative) via using rabbits.

Methods:

Two successfully prepared nanoemulsion (NE) formulas, a and b, were selected for the incorporation
of different percentages of pH-sensitive in situ gelling polymer (Carbopol 934) to prepare
NEIGs 1, 2, 3, 4, 5, and 6. The pH, gelation capacity, gel strength, and viscosity were predicted for
the prepared NEIGs. The release (in vitro) and the nasal permeation (ex vivo) were determined for
NEIG 2 and 5, and then both were subjected to pharmacokinetics in vivo studies. Eighteen male rabbits
weighing 2.0 to 2.5 kg were employed in the parallel design study. The body surface area (BSA)
normalization method was applied for LAS dose calculation. Serial blood samples were taken out and
subjected to drug analysis using the HPLC method previously developed and validated by Kumar et
al. Primary pharmacokinetics parameters, including maximum drug concentration in plasma (Cmax),
time to reach C-max (T-max), and area under the concentration-time curve from time zero to
affinity (AUCt0-∞) were calculated. Both NE (a and b), together with NEIG (2 and 5) formulas, were
subjected to the stability study. Finally, a nasal ciliotoxicity study was carried out to evaluate the nasal
toxicity of developed NEIGs 2 and 5.

Results:

The results showed that NEIGs 2 and 5 could be selected as the optimized NEIGs as both
achieved 100% permeation within 20 min and then released within 25 and 35 min, respectively, thus
achieving 3.3 folds with higher permeation percentages as compared to the AQS. Both NEIGs 2 and
5 exerted comparable release and permeation values as the corresponding NE a and b with more residence
time in order to overcome the normal nasal physiological clearance. The values of C-max, Tmax,
and AUC0- ∞ for NEIG 2 and NEIG 5 were 8066 ± 242 ng/ml, 0.75 ± 0.05 h, 19616.86 ± 589
ng. h/ml, and 7975.67 ± 239 ng/ml, 1.0 ± 0.05 h, 17912.36 ± 537 ng. h/ml, respectively, compared to
the traditional AQS, which is equal to 4181.09 ± 125 ng/ml, 2 ± 0.2 h, and 8852.27 ± 266 ng. h/ml,
respectively.

:

It was discovered that NEIGs 2 and 5 had better intranasal delivery of LAS and could significantly (p
< 0.05) achieve a higher value of permeability coefficient (3.3 folds) and 2.5 folds improvement in
bioavailability when compared to AQS. The NE a, NE b, NEIG2, and NEIG5 formulations showed
good stability at various temperatures. According to the nasal ciliotoxicity study, the nasal mucosal
membrane, which was treated with NEIG 5, showed irritation with a bit of damage. However, damage
was not observed when it was treated with NEIG 2, indicating the biocompatibility of the last one
to be selected as the optimum formula.

Conclusion:

NEIG 2 and NEIG 5 are promising new intranasal formulas with a faster onset of action
and greater bioavailability than the oral dosage form (AQS). Finally, the selected optimum gold formula
that will be ready for further clinical study is NEIG 2.