title: 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.
abstract: 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 5mg because the fine particle fraction (FPF) was reduced at doses over 5mg. 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 ngh/ml as AUCs for 10, 20 and 40 mg FK888, respectively; R(2)=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.
authors.affiliation: Fujisawa Pharmaceutical Co., Ltd, Kashima, Yodogawa-ku, Osaka, Japan. toshiomi_nakate@po.fujisawa.co.jp <toshiomi_nakate@po.fujisawa.co.jp>
authors.forename: Toshiomi
authors.initials: T
authors.lastname: Nakate
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Yoshida
authors.forename: Atsuo
authors.initials: A
authors.lastname: Ohike
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tokunaga
authors.forename: Rinta
authors.initials: R
authors.lastname: Ibuki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kawashima
mesh_terms: D000042:Absorption / Q000187:drug effects / Q000502:physiology; D000280:Administration, Inhalation; D000328:Adult; D002626:Chemistry, Pharmaceutical; D004151:Dipeptides / Q000008:administration & dosage* / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000737:chemistry*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D036501:Metered Dose Inhalers / Q000592:standards*; D011208:Powders
chemical_list: D004151:Dipeptides; D007211:Indoles; D011208:Powders; C078949:FK 888