Preferential nose-to-brain delivery of phenytoin via an intranasal phenytoin-arginine co-amorphous system.

This study aimed to design a co-amorphous (CA) formulation of poorly water-soluble phenytoin (PHT) to improve its brain delivery after intranasal administration. To screen a coformer required for novel CA system, PHT was ground with 20 amino acids at equimolar ratios, and L-arginine (ARG) was selected as a coformer for CA. Further investigation revealed that PHT and ARG at a molar ratio of 1:1 exhibited the highest glass transition temperature, suggesting superior amorphous stability, as well as high PHT loading of 59.2 %. In solubility studies using simulated nasal fluid, CA showed a maximum concentration of dissolved PHT immediately after the start of the test, which was 38-fold and 4-fold higher than that of PHT alone and physical mixture, respectively. Evaluation of the molecular state after CA dissolution by 1H NMR spectroscopy suggested the presence of ionic interactions between PHT and ARG. This enhancement was attributed to supersaturation induced by amorphization and ionization resulting from the addition of ARG. Following intranasal administration to mice, CA suspension showed a significant increase in the amount of PHT delivered to the brain and olfactory bulb (3.2- and 3.3-fold, respectively), compared with PHT alone, whereas no significant differences were observed in plasma exposure. These results suggest that CA formation improves the solubility of PHT and induces ionization, which may reduce membrane permeability, and thereby preferentially promote brain delivery via the nose-to-brain pathway without enhancing systemic exposure. These findings suggest that PHT-ARG CA system is an effective formulation strategy for achieving preferential intranasal delivery to the brain.