Impact of using amorphous solid dispersions on brain and systemic delivery of intranasally administered phenytoin

This study aimed to design an amorphous solid dispersion (ASD) of poorly water-soluble phenytoin (PHT) to improve brain distribution and systemic delivery after intranasal administration. ASDs were prepared using PHT and seven types of polymers at various weight ratios using the solvent evaporation method to select polymers that formed physically stable ASDs with a high PHT content. The results showed that ASDs made with polyvinylpyrrolidone K30 (K30) and copolyvidone (VA64) maintained their amorphous state for 56 days under humid high-temperature conditions (40 °C, 75 % relative humidity) at a high PHT content weight ratio (PHT:polymer 1:2). In the solubility test, the amount of dissolved PHT in VA64-ASD at 3 min was 10-fold higher than that in PHT alone, and 2-fold higher than that in K30-ASD. This solubility-enhancing effect due to amorphization led to VA64-ASD showing a significant 5-fold increase in PHT permeability through a nasal mucosal model monolayer compared to PHT. Additionally, the increased viscosity of the VA64-ASD suspension, attributed to the addition of VA64, increased the residual amount of PHT in the nasal mucosa 2.3 fold after intranasal administration compared with the PHT suspension. Furthermore, the amount of PHT delivered to the brain and plasma significantly increased 2.5 and 3.5 fold, respectively. These findings suggest that ASD formation by PHT is an effective strategy to enhance both brain and systemic delivery via intranasal administration.