Optimized Molecular Weight of Hydroxypropyl Cellulose in Inhaled Spray-Freeze-Dried Powders for High Deagglomeration...

Mucociliary clearance is a unique defense mechanism that forcibly transfers micron-sized substances deposited on the airway epithelium from the lungs, but may interfere with inhalation therapy. The application of mucoadhesive agents to inhaled formulations is expected to improve their efficacy by prolonging the drug residence time in the lungs through inhibited mucociliary clearance. In the present study, we attempted to develop new inhaled spray-freeze-dried (SFD) powders with high deagglomeration and pulmonary retention abilities by combining hydroxypropyl cellulose (HPC) of different molecular weights as a mucoadhesive agent and dileucine (diLeu) as a dispersion enhancer. The incorporation of diLeu into SFD powders resulted in a rough surface structure with large cavities and improved their deagglomeration abilities. In addition, the incorporation of HPC of lower molecular weights resulted in SFD powders with higher deagglomeration abilities. On the other hand, SFD powders with HPC and diLeu showed similar particle size distributions to that with trehalose (Tre) and diLeu after emission from a device regardless of the molecular weight of HPC incorporated. A biodistribution study through intratracheal administration to mice revealed that pulmonary drug retention was longer with SFD powders with HPC and diLeu than with a drug solution or SFD powder with Tre and diLeu, and also that HPC of a high molecular weight (approx.100000) provided the highest pulmonary retention ability of the SFD powder. These results strongly indicate that the molecular weight of HPC incorporated is a critical factor that markedly affects both the deagglomeration and pulmonary retention abilities of SFD powders.