How does the device determine nose-to-brain drug delivery to mice?

Soraia Silva


Owing to the unique anatomical connection between nasal cavity and central nervous system, a great deal of interest has been focused on the exploitation of intranasal route for the delivery of therapeutics directly to the brain by circumventing the blood-brain barrier. Particularly, nose-to-brain delivery of the aerosolized levetiracetam was recently demonstrated in mice, emerging as a new hope for the treatment of epilepsy.

However, it is not yet clear whether the extent of nose-to-brain drug delivery depends (or not) on the device utilized for intranasal administration.

Therefore, a thermorreversible gel (composed of 18% Pluronic F-127 and 0.2% Carbopol 974P) loaded with levetiracetam was intranasally administered to CD-1 male mice using one of the two devices, a micropipette or a polyurethane tube, 1 cm inserted into nasal cavity. At 5 and 15 min post-administration, concentrations were determined in plasma, brain and lungs and plasma-tissue ratios calculated.

Results showed that when administered with the micropipettor, levetiracetam was not detected in the brain, and its concentrations in plasma and lungs were only 17% and 6% of those observed with the polyurethane tube. Moreover, plasma-brain ratio observed with the polyurethane tube was lower than that reported for aerosolized levetiracetam, suggesting that a direct delivery into the brain may occur, but at less extent. Moreover, lung concentrations with polyurethane tube were significantly higher at 5 min (151.36 µg/g).

This study highlights (i) the importance of selecting the adequate device for intranasal administration, that does not compromise the direct passage into the brain, and (ii) proposes the use of an aerosolizer to attain this objective during pre-clinical studies, in order to prompt a correct translation to humans in the future.



Key Message

Direct nose-to-brain drug delivery is not attained when the drug is administered as a pipette nasal gel, in opposition to drug nasal gel instillation with a polyurethane tube inserted 1 cm deep into nasal cavity. This must be considered when designing pre-clinical studies during intranasal central drugs development

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