This study was designed to test the feasibility of polymeric microspheres as an inhalable carrier for prostaglandin E(1) (PGE(1)) for treatment of pulmonary arterial hypertension. Poly(lactic-co-glycolic acid) (PLGA) microspheres were prepared by a double emulsion-solvent evaporation method. Six different microspheric formulations were prepared using two different blends of PLGA (50:50 and 85:15) and varying concentrations of polyvinyl alcohol (PVA) in the external aqueous phase (EAP). The particles were characterized for morphology, size, aerodynamic diameter, entrapment efficiency, release patterns, and metabolic stability. Pulmonary absorption was studied in a rat model, and safety of the formulations was evaluated by measuring cytotoxicity in Calu-3 cells and assessing injury markers in bronchoalveolar lavage (BAL) fluid. Both actual particle size and aerodynamic diameter of the formulations decreased with increasing PVA concentration. The mass median aerodynamic diameter of the particles was within the respirable range. Entrapment efficiency increased with increasing PVA concentration; PLGA 85:15 showed better entrapment due to hydrophobic interactions with the drug. Compared to intravenously administered PGE(1), microspheres prepared with PLGA 85:15 produced a 160-fold increase in the half-life of PGE(1) following pulmonary administration. Although plain PGE(1) showed rapid degradation in rat lung homogenate, PGE(1) entrapped in the particles remained intact for about 8 h. Optimized formulations were demonstrated to be safe, based on analysis of cytotoxicity and lung-injury markers in BAL fluid. Overall, the data suggest that microspheric PGE(1) formulations have the potential to be used as a noninvasive and controlled-release alternative to the current medications used for treatment of pulmonary arterial hypertension that are administered by continuous infusion or require multiple inhalations.
2009 Wiley-Liss, Inc. and the American Pharmacists Association