Improvement in the variation of inhalation properties of an FK888 dry powder inhaler using an E-haler, by adding coarse lactose in spherical soft agglomerates of fine drug particles, and its absorption in healthy volunteers

FK888 is a candidate selective NK1 receptor antagonist that exhibits poor absorption from the gastro-intestinal tract. In our previous study, it was found that pulmonary application was effective in achieving systemic absorption of the drug in healthy volunteers. In this study inhalation powder formulations, which were carrier-free spherical soft agglomerates of FK888 fine particles, were evaluated using an E-haler. A proportional fine particle dose (FPD defined as the dose deposited less than 4.9 μm) was obtained from 10, 20 and 40-mg formulations (10, 20 and 40 mg as FK888, respectively) after discharging into a cascade impactor using an E-haler. However, poorer reproducibility of FPD was observed when five different lots of active ingredient were used in the 40-mg formulation (14.3 ± 2.7 mg for FPD, 35.8 ± 6.7% for the fine particle fraction; FPF defined as a percentage of FPD compared with the nominal dose defined as the quantity of FK888 loaded in a capsule, and a CV of 18.7%). It was found that the BET surface area of the fine drug particles was closely related to the in vitro aerodynamic properties, and the addition of 25% (w/w) coarse lactose (Pharmatose 325 M) was very effective in improving the variability (17.7 ± 0.9 mg for FPD, 44.2 ± 2.2% for FPF, and a CV of 4.9%, p < 0.05 compared with the carrier-free 40-mg formulation). It was considered that the higher BET surface area reflected a higher amount of finer drug particles, and the 325 M lactose acted as a fixative agent allowing the finer drug particles to adhere to the lactose surface, resulting in a reduced adhesive force between the drug particles. In the formulation containing 325 M lactose using an E-haler, an improvement in systemic absorption was also obtained in healthy volunteers.