Formulation development of inhalation powders for FK888 using the E-haler® to improve the inhalation performance at a high dose, and its absorption in healthy volunteers

FK888 is a candidate selective NK1 receptor antagonist, and it exhibits poor absorption from the gastrointestinal tract in healthy volunteers. In a previous study, the optimized dry powder inhaler (DPI) formulation with carrier lactose using the Spinhaler® was developed, although the maximum dose per capsule was only 5 mg because the fine particle fraction (FPF) was reduced at doses over 5 mg. The objective of this study was to develop an optimized DPI formulation for higher doses, such as 40 mg, with proportional systemic absorption. The Spinhaler® and E-haler® were used as the inhalation devices, and the in vitro deposition was evaluated using a multistage cascade impactor at different flow rates (28.3 and 60 l/min). When hydroxypropyl methylcellulose (HPMC) capsules were used as the container, and spherical soft agglomerates of fine FK888 particles (soft pellets) and the E-haler® were used, the fraction of particles emitted from the inhalation system (Em) was significantly improved, to over 80% of the nominal dose, and no significant difference was found between the airflow rates (84.3±2.3% for 28.3 l/min, 88.1±3.6% for 60 l/min). It was also found that the E-haler® was an extremely suitable device for obtaining the higher respirable particle percentage of emitted particles (RP) in the 40 mg formulation with the soft pellets contained in HPMC capsules (35.0±1.8% for 28.3 l/min and 42.5±3.5% for 60 l/min), compared with the Spinhaler® (13.8±3.0% for 28.3 l/min and 28.9±1.0% for 60 l/min). Using the formulations with the E-haler®, proportional systemic absorption was achieved up to 40 mg FK888 in healthy volunteers (62.91±27.58, 103.70±40.19 and 254.79±85.01 ng h/ml as AUCs for 10, 20 and 40 mg FK888, respectively; R2=0.9641). It is also expected that the E-haler® will act as an efficient device when a higher dose, such as 40 mg, is required in clinical situations.