title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama, 700-8530, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Imada
authors.forename: Takuma
authors.initials: T
authors.lastname: Takahashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuramoto
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Masuda
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Ogawara
authors.forename: Akira
authors.initials: A
authors.lastname: Sato
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Wataya
authors.forename: Hye-Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Higaki
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D005079:Excipients; D005227:Fatty Acids / Q000737:chemistry*; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013141:Spiro Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D045568:Tetraoxanes / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: C571809:6-(1,2,6,7-tetraoxaspiro(7.11)nonadec-4-yl)hexan-1-ol; D000962:Antimalarials; D005079:Excipients; D005227:Fatty Acids; D013141:Spiro Compounds; D045568:Tetraoxanes