Abstract
The pulmonary administration of cannabidiol (CBD) in dry powder form provides an effective strategy to bypass first-pass metabolism and achieve therapeutic concentrations in both the lungs and the systemic circulation. Formulating a stable CBD dry powder remains challenging and requires appropriate excipients to achieve the desired physicochemical and performance characteristics. Although excipients can improve aerosolization performance, their excessive use may compromise drug loading and introduce potential adverse effects. An alternative strategy involves assessing co-active compounds that could offer additional pharmacological benefits and potentially support formulation properties. In this study, kaempferol (KAM), a non-toxic flavonoid with antioxidant and anti-inflammatory properties, was co-formulated with CBD into an inhalable dry powder via spray drying. A 32-factorial design was employed to evaluate the effects of feed concentration and L-leucine (LEC) concentration on aerosolization performance of the CBD-KAM combination dry powder. The formulation with 0.8% (w/v) feed concentration and 10% (w/w) LEC showed the highest fine particle fraction (FPF), attaining 60.3 ± 1.0% for CBD and 66.3 ± 0.4% for KAM. The cytotoxicity studies on A549 cells confirmed the non-toxic nature of KAM. The CBD-KAM combination exhibited reduced cytotoxicity compared with CBD alone. The anti-inflammatory activity of the CBD-KAM combination was comparable to raw CBD. These findings suggest that the CBD-KAM combination powder formulations exhibit improved aerosolization, reduced cytotoxicity, and maintained efficacy, representing a promising approach for inhaled combination therapy in pulmonary diseases.