DEVELOPMENT OF INHALED VALSARTAN NANOSUSPENSION FOR LOCAL TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

As the third place of cause of death in United States without curative treatment, effective therapeutic treatments for chronic obstructive pulmonary disease (COPD) are urgently needed. Herein, we developed local treatment for COPD using inhalable valsartan mucus penetration nanosuspension (NS). Pluronic F127 coated valsartan nanosuspension (F127/Val-NS) was prepared by using a top-down strategy for long-term storage in the form of powder. All kinds of characterizations revealed that F127/Val-NS possessed desired properties to make them mucus penetrable for pulmonary drug delivery, including uniformed and optimized size distribution, near neutral surface charge, high drug loading capacity (>90%) and sustained drug release profile. Moreover, the in vitro drug activity test indicated the nano formulation of valsartan did not compromise its drug activity. The macrophage uptake studies showed that F127 coating greatly inhibited the uptake of F127/Val-NS by macrophages, which improved their drug delivery efficiency. We also employed hypotonic vehicle solution to facilitate drug delivery by enhancing mucus penetration of F127/Val-NS in murine airway. Then we used the optimized formulation of F127/Val-NS suspended in the best performed hypertonic vehicle to investigate its in vivo osmolarity driven after intratracheal instillation. The inducible transgenic CC10-rtTA-IL-13 mice, with transforming growing factor-β (TGF-β) over expression specifically in the lung post doxycycline treatment were selected as the COPD animal model and their pathology in lung was systematically investigated. After treatment with F127/Val-NS at a dosage of 1 mg/kg and every other day frequency for a month, the TGF-β expression level of the mice was greatly inhibited