Novel Nano-Composite Particles For Controlled Release Drugs Via Inhalation: Liposomal Nanocrystalline Ciprofloxacin

This thesis evaluates the feasibility of developing inhalable dry powders of ciprofloxacin nanocrystals inside liposomes (CNL) by spray drying for controlled drug release. Spray drying was optimized for the production of CNL powder using an experimental design methodology followed by testing the storage stability of the optimized formulations. Dry powders of CNL were successfully produced either by freeze-thaw liposomal liquid formulations followed by spray drying or by a simple one-step process of spray drying. Regardless of the production pathway, sucrose to lipids at 2:1 w/w ratio was an excellent lyoprotectant for liposomes during processing. Drug encapsulation efficiency (EE) was above 79% with mostly a single drug nanocrystal residing inside each liposomal vesicle. The powders composed of spherical particles with a median diameter of ~ 1 µm and a respirable fraction (% wt. < 5 µm) above 58%. A prolonged drug release over 12 hours was achieved in vitro by CNL powders. The optimization of spray drying was performed using the Box–Behnken design. The study independent variables were the protectant type (sucrose, trehalose or lactose), protectant amount, drying temperature, and spray gas flow. Liposomal particle size, drug EE, liposomal zeta potential, and nanocrystal dimensions were the dependant variables. Sucrose and lactose were superior protectants to liposomes during spray drying compared to trehalose. The protectant amount significantly affected the characteristics of CNL powders. The optimized powders were stored for six months at room temperature (RT) and either 4 or 20% relative humidity (RH) for the stability study. Sucrose CNL powder exhibited consistent liposomal integrity, aerosol performance, and controlled release of ciprofloxacin over six months of storage at 4 %RH. However, storage of the powder at 20 %RH for the same period caused sucrose crystallization and consequently a significant change in the physicochemical properties. Lactose CNL maintained superior aerosol performance irrespective of the storage RH. However, liposomal instability occurred at both RHs within the first month of storage. In conclusion, the CNL powders were suitable for aerosol delivery and amenable to a once-daily treatment regimen. The optimum processing conditions utilized 57% w/w sucrose, 80°C inlet temperature, and atomization rate of 742 L/hr. This research suggests that CNL powder formulation with sucrose as a stabilizing excipient must be stored under a relatively low humidity environment of 4 %RH and controlled RT storage to achieve at least a six-month shelf-life