Pulmonary targeted inhalational therapy for neutrophillic asthma using a novel simvastatin-rapamycin dry powder...

Neutrophillic asthma, characterized by persistent airway inflammation and poor corticosteroid responsiveness, presents a significant therapeutic challenge. Repurposing rapamycin, an mTOR inhibitor, and simvastatin, a statin with anti-inflammatory effects, through targeted pulmonary delivery may provide a novel therapeutic strategy. A combinatorial dry powder inhalation formulation was developed by blending rapamycin and simvastatin with lactose carriers, and a Box-Behnken design was employed to optimize blending time, fine lactose content, and leucine content. Analytical characterization using FTIR, P-XRD, DSC, and SEM confirmed effective adsorption of actives onto lactose carriers with no significant drug-excipient incompatibilities. Aerodynamic evaluation demonstrated a fine particle fraction of 53.35% and 58.67% and a mass median aerodynamic diameter 2.037 µm and 4.307 µm, for simvastatin and rapamycin respectively indicating efficient pulmonary deposition. Stability studies showed acceptable stability for 6 months and in-vivo inhalational toxicity in healthy C57BL/6 mice confirmed safety. This preclinical proof-of-concept highlights the potential of localized pulmonary delivery to reduce systemic exposure while targeting inflammatory pathways in neutrophillic asthma. Further in vivo and translational studies are warranted to establish therapeutic efficacy. This approach provides a platform for repurposing simvastatin and rapamycin as an asthma treatment and addresses the unmet need in managing steroid-resistant asthma endotypes.