Drug delivery to the brain: In situ gelling formulation enhances carbamazepine diffusion through nasal mucosa models with mucin

Abstract

The objective of this work was to optimize a thermosensitive in situ gelling formulation to improve intranasal and nose-to-brain delivery of the antiepileptic drug carbamazepine (CBZ). A preliminary procedure of vehicles obtained just mixing different fractions of poloxamer 407 (P407) and poloxamer 188 (P188) revealed preparations with phase transition temperatures, times to gelation and pH values suitable for nasal delivery. Subsequently, the mucoadhesive properties of the most promising formulations were tuned by adding hydroxypropylmethylcellulose types of different viscosity grades, and the effect of the adhesive polymers was evaluated by testing in vitro time and strength of mucoadhesion on specimens of sheep nasal mucosa. The formulation that showed the greatest mucoadhesive potential in vitro, with a time and force of mucoadhesion equal to 1746,75 s and 3.66 × 10-4 N, respectively, was that composed of 22% P407, 5% P188 and 0.8% HPMC low-viscous and it was further investigated for its ability to increase drug solubility and to control the release of the drug. Lastly, the capability of the candidate vehicle to ensure drug permeation across the biomimetic membrane Permeapad®, an artificial phospholipid-based barrier with a stratified architecture, and the same barrier enriched with a mucin layer was verified. The final formulation was characterized by a pH value of 6.0, underwent gelation at 32.33°C in 37.85 s, thus showing all the features required by in situ gelling thermosensitive preparations designed for nasal delivery and, more notably, it conserved the ability to favor drug permeation in the presence of mucin. These findings suggest that the optimized gelling system could be a promising and easy to realize strategy to improve CBZ delivery to the brain exploiting both a direct and indirect pathway.