Novel Strategy for the Systemic Delivery of Furosemide Based on a New Drug Transport Mechanism

• Published in: Biological & pharmaceutical bulletin 2018/12/01, Vol.41(12), pp.1769-1777
• Main Authors: Kimura, Shunsuke, Kiriyama, Akiko, Nishimura, Erika, Sakata, Shiori, Inoue, Daisuke, Furubayashi, Tomoyuki, Yutani, Reiko, Tanaka, Akiko, Kusamori, Kosuke, Katsumi, Hidemasa, Iga, Katsumi, Yamamoto, Akira, Sakane, Toshiyasu
• Format: Article
• Language: English
• Subjects: Absorption; Administration, Oral; amorphous solid particle; Animals; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Membrane Permeability - drug effects; Cell membranes; Chromatography, High Pressure Liquid; Crystals; Curcumin; Dogs; dry powder formulation; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Furosemide; Furosemide - administration & dosage; Furosemide - blood; Furosemide - chemistry; Furosemide - pharmacokinetics; Infusions, Intravenous; Inhalation; Lungs; Madin Darby Canine Kidney Cells; Male; Membranes, Artificial; Powder; Powders; pulmonary absorption; Rats, Wistar; Respiration; Solubility; Surface Properties
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b18-00315

We reported a novel transport mechanism of curcumin, independent of improved solubility, which involved direct contact of amorphous solid particles with the cell membrane. This mechanism has potential as a novel systemic delivery system of poorly water-soluble drugs. In this study, the transport mechanism of furosemide (FUR), which is transported by the same novel mechanism, was examined. In vitro cell permeation studies under air-interface conditions (AICs) revealed that the permeation from powders sprayed on cell monolayers was significantly higher than that under liquid-covered conditions (LCCs) from their solutions. The permeation from amorphous solid particles was faster than that from crystals. Similar results were derived from in vitro studies using an artificial membrane, with which the permeation of FUR could be examined without water. These findings clearly indicated that the transport mechanism of FUR is the same as that of curcumin. For the application of this new transport mechanism, the in vivo absorption of FUR was examined after pulmonary insufflation, which allows the solid particles to make direct contact with the epithelial cells. Pulmonary absorption of FUR from the amorphous powder was almost complete and was faster than that after intragastric administration of the solution, suggesting that FUR was absorbed from the lung by the same mechanism as the in vitro study. This new transport mechanism, which is independent of water dissolution, could be exploited to develop a novel delivery system for poorly water-soluble drugs, using pulmonary powder inhalation.