Engineering large porous microparticles with tailored porosity and sustained drug release behavior for inhalation.

Sustained drug delivery is considered as an effective strategy to improve the treatment of local lung diseases. In this context, inhalation administration of large porous microparticles (LPPs) represents promising prospects. However, one major challenge with said delivery technology is to control the drug release pattern (especially to decrease the burst release) while maintaining a low mass density/high porosity, which is of high significance for the aerodynamic behavior of LPP systems. Here, we show how to engineer drug-loaded, biodegradable LPPs with varying microstructure by means of a premix membrane emulsification-solvent evaporation (PME-SE) method using poly(vinyl pyrrolidone) (PVP) as the pore former. The influence of PVP concentration on the physicochemical properties, in-vitro drug release behavior and in-vitro aerodynamic performance of the drug-loaded microparticles was tested. We demonstrated that the PME-SE technique led to LPPs with favorable pore distribution characteristics (i.e., low external but high internal porosity) as a function of the PVP concentration. In general, more PVP conditioned a larger discrepancy of the internal vs. external porosity. When the external porosity of the LPP formulation (15% of PVP during the manufacturing process) was less than 3%, the burst release of the embedded drug was significantly reduced compared to LPPs prepared by a "conventional" emulsification solvent evaporation method. All the formulations prepared by the PME-SE method had aerodynamic properties suitable for inhalation. This is the first report indicating that the microstructure of LPPs can be tailored using the PME-SE technology with PVP as a suitable pore former. Doing so, we designed LPP formulations having full control over the drug release kinetics and aerodynamic behavior.