An inhalable composite particulate system for targeted delivery of therapeutics deep into small airways: in vitro and in vivo evaluation.

Chronic obstructive pulmonary disease (COPD) is characterized by the airflow limitation due to chronic inflammation and excessive airway mucus secretion. Targeted delivery of therapeutics deep into small airways is the key step in treatment of COPD. In this study, we designed an inhalable composite particulate system with nano in micro structure for targeted delivery of therapeutics deep into small airways. Curcumin was incorporated into solid lipid nanoparticles modified with PEG₂₀₀₀ to improve the retention time and reduce the immune recognition and clearance in small airways. Then, flower-like lactose with rapid dissolution rate was used as an inhalable carrier to deliver the nanoparticles deep into the small airways. The inhalable composite particles showed a mass median aerodynamic diameter suitable for deep lung deposition (approximately 2.5 μm), high fine particle fraction (approximately 58 %) and rapid dissolution rate in simulated lung fluid. The in vivo pharmacokinetic study indicated that intratracheal administration of the inhalable composite particles significantly improved the concentration and retention time of curcumin in the lung and decreased the systemic exposure of the therapeutics. The inhalable composite particles also showed good safety in the in vitro cell viability study and the in vivo acute inhalation toxicity study. In the in vivo pharmacodynamic study, intratracheal administration of the inhalable composite particles delayed the progression of COPD by reducing the inflammation and inhibiting the excessive collagen production in the lung. The inhalable composite particulate system demonstrated a great potential for targeting delivery of therapeutics into small airways.