Design and characterization of a resveratrol spray-dried inhalable formulation for pulmonary delivery with <i>in vivo</i> pharmacokinetic and toxicological evaluation

Resveratrol is a polyphenolic compound with therapeutic potential for pulmonary diseases, yet its use is limited mostly due to low oral bioavailability. Inhalable powder formulations are a promising strategy to help overcome those challenges. Here, we report the development and physicochemical characterization of a spray-dried resveratrol formulation suitable for pulmonary delivery. The pharmacokinetic profile and in vivo toxicity were then assessed. Particle size, interparticle cohesion, morphology, uptake, and stability of the formulation were evaluated. Intratracheal administration was then performed in A/J mice and pulmonary distribution was compared to a micronized resveratrol formulation. Lung and plasma concentrations were quantified by LC-MS/MS at 5–70 min postadministration, followed by long-term toxicity evaluation. The spray-drying process produced resveratrol with improved lung exposure while preserving properties essential for pulmonary delivery. In vivo, the spray-dried formulation achieved improved pulmonary and lower systemic distribution compared to the micronized form, increasing the lung to plasma AUC ratio from 77 to 282. Moreover, a greater number of mice had detectable concentrations of resveratrol in the lungs following spray-dried administration (62.5% vs 37.5% for micronized). The long-term intratracheal administration of spray-dried resveratrol (1 mg, 3× per week for 12 weeks) was well tolerated, with no clinical, biochemical, or histopathological signs of toxicity. Altogether, the spray-dried formulation of resveratrol could be efficiently delivered to the lungs and displayed an excellent safety profile, supporting its future investigation in respiratory disease models.