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

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 <i>in-vivo</i> 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 <i>in vivo</i> 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.