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

7 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

Fingerprint

Antimalarials
Drug Delivery Systems
Biological Availability
Fatty Acids
Lymphatic System
Liver
Individuality
Powders
Small Intestine
Phase diagrams
Oral Administration
Rats
Lipids

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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

In: Pharmaceutical Research, Vol. 32, No. 8, 01.08.2015, p. 2595-2608.

Research output: Contribution to journalArticle

Imada, Chikako ; Takahashi, Takuma ; Kuramoto, Makoto ; Masuda, Kazufumi ; Ogawara, Ken Ichi ; Sato, Akira ; Wataya, Yusuke ; Kim, Hye-Sook ; Higaki, Kazutaka. / 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. In: Pharmaceutical Research. 2015 ; Vol. 32, No. 8. pp. 2595-2608.
@article{a9694ea6764a4a7d8a7a98bfc1401ce3,
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 = "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.",
author = "Chikako Imada and Takuma Takahashi and Makoto Kuramoto and Kazufumi Masuda and Ogawara, {Ken Ichi} and Akira Sato and Yusuke Wataya and Hye-Sook Kim and Kazutaka Higaki",
year = "2015",
month = "8",
day = "1",
doi = "10.1007/s11095-015-1646-x",
language = "English",
volume = "32",
pages = "2595--2608",
journal = "Pharmaceutical Research",
issn = "0724-8741",
publisher = "Springer New York",
number = "8",

}

TY - JOUR

T1 - 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

AU - Imada, Chikako

AU - Takahashi, Takuma

AU - Kuramoto, Makoto

AU - Masuda, Kazufumi

AU - Ogawara, Ken Ichi

AU - Sato, Akira

AU - Wataya, Yusuke

AU - Kim, Hye-Sook

AU - Higaki, Kazutaka

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84965140368&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84965140368&partnerID=8YFLogxK

U2 - 10.1007/s11095-015-1646-x

DO - 10.1007/s11095-015-1646-x

M3 - Article

VL - 32

SP - 2595

EP - 2608

JO - Pharmaceutical Research

JF - Pharmaceutical Research

SN - 0724-8741

IS - 8

ER -