Formulation development of inhalation powders for FK888 with carrier lactose using Spinhaler and its absorption in healthy volunteers.

Abstract (4 R )-4-Hydroxy-l-[(l-methyl-l H -indol-3-yl)carbonyl]- l -prolyl- N -benzyl- N -methyl-3-(2-naphthyl)- l -alaninamide (FK888) is a candidate selective NK1 receptor antagonist, and it exhibits poor absorption from the gastrointestinal (GI) tract in healthy volunteers. The objective of this study was to develop an optimized DPI formulation with carrier lactose using a Spinhaler®, and thereby improve the systemic absorption of FK888. The fine particles of FK888 were blended with various carrier lactoses, and in vitro deposition properties were investigated using a twin impinger. The mixture using 100M and 325M lactoses [Sieved lactoses (SLs)] exhibited a higher emitted dose (Em) than 200M, 450M and micronized lactoses [Milled lactoses (MLs)]. The flowability of carrier lactose had an influence on the Em. On the other hand, the respirable particle (RP) fraction in the formulations with MLs was much higher than that of SLs, in spite of the blended ratios of lactose. It was also observed that the mixture of 325M with the micronized lactose particles had the same RP as 200M, although the 325M alone had a low RP. Considering the Em and RP obtained, we chose 200M for FK888 dry powder inhaler (DPI). The proportional absorption was found up to the 12.5% of the FK888 ratio (5 mg as unit dose) for the C max and AUC in healthy volunteers. In conclusion, 200M, which has fine lactose particles and a better flowability than other MLs, is an extremely suitable carrier for maximizing the fine particle dose as far as FK888 is concerned. Furthermore, an improvement in the systemic absorption of FK888 was achieved using the dry powder formulations.