Improvement of oral bioavailability of n-251, a novel antimalarial drug, by increasing lymphatic transport with long-chain fatty acid-based self-nanoemulsifying drug delivery system

Chikako Imada, Takuma Takahashi, Makoto Kuramoto, Kazufumi Masuda, Ken Ichi Ogawara, Akira Sato, Yusuke Wataya, Hye Sook Kim, Kazutaka Higaki

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Purpose The objective of this study was to improve the absorption behavior of N-251, a novel antimalarial drug, by preparing an appropriate self-nanoemulsifying drug delivery system (SNEDDS). Methods Two different types of SNEDDS formulations, medium-chain fatty acid-based SNEDDS (MC-SNEDDS) and long-chain fatty acid-based SNEDDS (LC-SNEDDS), were prepared based on pseudo-ternary phase diagram, and examined for their in vivo oral absorption behavior in rats. Results Oral dosing of MC-SNEDDS formulations significantly improved the bioavailability (BA) of N-251 compared with N-251 powders. However, its high hepatic extraction limited the BA of N-251 to only 0.49 for MC-SNEDDS B, the best formulation of MC-SNEDDS. LC-SNEDDS formulations, especially LC-SNEDDS F provided the highest BA, 0.65, and successfully attenuated the inter-individual difference in the absorption behavior. Furthermore, it was confirmed that lymphatic transport of N-251 for LC-SNEDDS F was significantly increased up to around 3.19 times larger than that for MC-SNEDDS B. Simulation study suggested that 20 to 39% of N-251 uptaken by the small intestine would be delivered to lymphatic system after oral administration of LC-SNEDDS F. Conclusions SNEDDS formulations significantly improved the absorption behavior of N-251 and long-chain fatty acid-based lipid further improved it by avoiding the hepatic first-pass elimination.

Original languageEnglish
Pages (from-to)2595-2608
Number of pages14
JournalPharmaceutical research
Volume32
Issue number8
DOIs
Publication statusPublished - Aug 1 2015

Keywords

  • Antimalarial drug
  • Bioavailability
  • Hepatic first-pass elimination
  • Long-chain fatty acid
  • Lymphatic transport
  • Medium-chain fatty acid
  • Self-nanoemulsifying drug delivery system (SNEDDS)

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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