(260an) Optimization of Aerosol Nanocomposite Microparticles (nCmP) for Deep Lung Delivery of Therapeutics

Pulmonary drug delivery based dry powder aerosols has attracted increasing attention for the treatment of lung diseases, as they are capable of delivering a wide range of therapeutics directly and efficiently to the lungs. Meanwhile, the lungs can also be utilized as a route for systematic drug delivery due to the enormous surface area and plentiful capillary vessels present. In both cases, an intelligent carrier is required to overcome the barriers of pulmonary delivery, which include: (1) dry powder aerosols with aerodynamic diameters smaller than 1 μm will often be exhaled; (2) particles with aerodynamic diameters above 5 μm tend to deposit in the mouth, throat or upper lung mucosa and will then be eliminated due to mucus clearance; (3) particles larger than 260 nm deposited in the deep lung area will undergo macrophage clearance in the alveoli. Our solution to the aforementioned challenges is the use of nanocomposite microparticles (nCmP) for the aerosol delivery of therapeutics. nCmP are microparticles that contain drug-loaded nanoparticles (NP) and an excipient. Upon pulmonary administration, nCmP will deposit on the mucus or surfactant present on the surface of the lungs, decompose into free NP and excipient, and allow the nanoparticles to penetrate the mucus and then release drug to the targeted site at sustained rate.

Many nCmP systems have been developed for various applications, but few comprehensive studies have been done to illustrate how to develop an optimal nCmP system for deep lung delivery of therapeutics. In the present research, we aim to identify the optimal spray drying conditions used to prepare the nCmP with favorable properties including: small aerodynamic diameter, desirable nanoparticle re-dispersity, high drug loading, and low water content. Acetalated dextran was used as the polymer to form nanoparticles due to its biodegradability, biocompatibility and tunable degradation rate. Curcumin was used as model drug and mannitol was applied as excipient of nCmP. The spray drying parameters that were optimized including the nanoparticle-to-total substance ratio, solids feed concentration, and inlet temperature. Boxâ??Behnken design was applied for experimental design using Design-Expert software. The results indicated that the nanoparticle ratio (NP%) and feed concentration (FC) were significant parameters affecting the aerodynamic diameters of the nCmP. NP% was also the significant parameter affecting nCmP drug loading. FC was the only parameter that influenced nCmP water content significantly. All nCmP can be completely re-dispersed, indicating that the spray drying factors have no influence on the re-dispersity of nanoparticles in the design range. Overall, the optimal spray drying condition that can be used to prepare nCmP with a small aerodynamic diameter, complete re-dispersity of nanoparticles, low water content, and high drug loading is a 80% nanoparticle ratio, 0.5% feed concentration, and inlet temperature lower than 130 °C.