Intranasal delivery of phenytoin-loaded nanoparticles to the brain suppresses pentylenetetrazol-induced generalized tonic clonic seizures in an epilepsy mouse model

Abstract

In this work we describe the preparation and characterization of lecithin-chitosan nanoparticles (L₁₀C_i⁺), and investigate their ability to deliver the anti-epileptic drug phenytoin (PHT) to mouse brain following intranasal (IN) administration. L₁₀C_i⁺ were retained in the nasal cavity compared to PHT in PEG200 solution (PHT/PEG), which suffered immediate nasal drainage. PHT was detected in the brain after 5 min of IN administration reaching a maximum of 11.84 ± 2.31 %ID g^-1 after 48 hours. L₁₀C_i⁺ were associated with a higher brain/plasma ratio (<i>C</i>_b/p) compared to the experimental control comprising free PHT injected <i>via</i> the intraperitoneal route (PHT-IP) across all tested time points. Additionally, L₁₀C_i⁺ led to lower PHT accumulation in the liver and spleen compared to PHT-IP, which is vital for lowering the systemic side effects of PHT. The relatively high drug targeting efficiency (DTE%) of 315.46% and the drug targeting percentage (DTP%) of 68.29%, combined with the increasing anterior-to-posterior gradient of PHT in the brain confirmed the direct nose-to-brain transport of PHT from L₁₀C_i⁺. Electroencephalogram (EEG) analysis was used to monitor seizure progression. L₁₀C_i⁺ resulted in a complete seizure suppression after 4 hours of administration, and this inhibition persisted even with an 8-fold reduction of the encapsulated dose compared to the required PHT-IP dose to achieve a similar inhibitory effect due to systemic loss. The presented findings confirm the possibility of using L₁₀C_i⁺ as a non-invasive delivery system of PHT for the management of epilepsy using reduced doses of PHT.