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, Tatsuhiro; Kuramoto, Makoto; Masuda, Kazufumi; Ogawara, Ken Ichi; Sato, Akira; Wataya, Yusuke; Kim, Hye Sook; Higaki, Kazutaka

doi:10.1007/s11095-015-1646-x

Cited by 18 publications

(20 citation statements)

References 35 publications

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“…This study suggested that co-administration with LCT promotes transport via the lymphatic pathway relative to co-administration with MCT or LCT. Other researchers have also observed increased bioavailability of PWS drugs using LCT due to enhanced lymphatic transport [115]. The solubility of the drug in lipid is also a factor in lymphatic transport.…”

Section: Key Processes Governing Lipid Impact On Overall Oral Absomentioning

confidence: 98%

Lipid-associated oral delivery: Mechanisms and analysis of oral absorption enhancement

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2016

Journal of Controlled Release

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The majority of newly discovered oral drugs are poorly water soluble, and co-administration with lipids has proven effective in significantly enhancing bioavailability of some compounds with low aqueous solubility. Yet, lipid-based delivery technologies have not been widely employed in commercial oral products. Lipids can impact drug transport and fate in the gastrointestinal (GI) tract through multiple mechanisms including enhancement of solubility and dissolution kinetics, enhancement of permeation through the intestinal mucosa, and triggering drug precipitation upon lipid emulsion depletion (e.g., by digestion). The effect of lipids on drug absorption is currently not quantitatively predictable, in part due to the multiple complex dynamic processes that can be impacted by lipids. Quantitative mechanistic analysis of the processes significant to lipid system function and overall impact on drug absorption can aid understanding of drug-lipid interactions in the GI tract and exploitation of such interactions to achieve optimal lipid-based drug delivery. In this review, we discuss the impact of co-delivered lipids and lipid digestion on drug dissolution, partitioning, and absorption in the context of the experimental tools and associated kinetic expressions used to study and model these processes. The potential benefit of a systems-based consideration of the concurrent multiple dynamic processes occurring upon co-dosing lipids and drugs to predict the impact of lipids on drug absorption and enable rational design of lipid-based delivery systems is presented.

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Section: Key Processes Governing Lipid Impact On Overall Oral Absomentioning

confidence: 98%

Lipid-associated oral delivery: Mechanisms and analysis of oral absorption enhancement

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Speciner

Carrier

2016

Journal of Controlled Release

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“…Literature reveals that the nanoparticles are being explored for drug delivery of antimalarial drugs which include pheroids, 84 lipososmes, 85 solid lipid nanoparticles, 86 polymer-lipid nanoparticles, 87 dendrimers, 88 polymeric nanoparticles, 89 self-emulsifying drug delivery systems 90 for antimalarial drugs. In recent years, hydrogels based systems for antimalarial drugs are also being explored which have shown decent results.…”

Section: Hydrogel Based Systems For Malariamentioning

confidence: 99%

Recent trends on hydrogel based drug delivery systems for infectious diseases

et al. 2016

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For centuries, the rapid spread and cure of infectious diseases have been a major concern to the progress and survival of humans. These diseases are the global burden and the prominent cause for the worldwide deaths and disability. Nanomedicine has emerged as the most excellent tool to eradicate and halt their spread. Various nanoformulations (NFs) using advanced nanotechnology are in demand. Recently, hydrogel and nanogel based drug delivery devices poses new prospects to simulate the natural intelligence of various biological systems. Owing to their unique porous interpenetrating network design, hydrophobic drug incorporation and stimulus sensitivity hydrogels owe excellent potential as targeted drug delivery system. Present review is an attempt to highlight the recent trends of hydrogel based drug delivery systems for the delivery of therapeutic agents and diagnostics for the major infectious diseases including Acquired immune deficiency syndrome (AIDS), Malaria, Tuberculosis, Influenza and Ebola. Future prospective and challenges are also briefed.

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“…Pharmacokinetics in animal studies is required to forward the development of N-251, which is a drug that can be of practical use. Although we have already started the additional study about the improvement of the bioavailability ( F ) of N-251 in non-infected rats [16], a pharmacokinetic (PK) analysis was performed under various conditions in mice, which included dose dependency, influence of diet, parasite infection, and number of administrations. In addition, the appropriate administration schedule for achieving the complete curative effect of N-251 against P. berghei in mice has already been determined [12].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic analysis of new synthetic antimalarial N-251

et al. 2019

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Background With the emergence and growing number of drug-resistant Plasmodium falciparum , a new drug for malaria control must be urgently developed. The new antimalarial synthetic compound N-251 was recently discovered. As an endoperoxide structure in the body, the compound shows high antimalarial activity and curative effects. We performed a pharmacokinetic (PK) analysis of N-251 under various conditions using mice to understand the inhibitory effect of N-251 in parasite-infected mice. Results PK study of N-251 after intravenous and oral administration in mice showed plasma concentration of N-251 was decreased drastically by intravenous route. C max was reached in 2 h after oral administration of N-251, and the level decreased to a level similar to that obtained after intravenous administration. The area under the curves (AUCs) of the plasma concentration of N-251 increased dose-proportionally in both administrations, and bioavailability ( F ) was approximately 23%. Additionally, T max , C max , AUC, and F increased in fasted mice compared to normal-fed mice after the administration of N-251, indicating the influence of diet on the absorption kinetics of N-251. Furthermore, in parasite-infected fasted mice, the plasma concentration-time profile of N-251 was similar to that in normal-fasted mice. Based on the PK parameters of single oral administration of N-251, we investigated the effect of multiple oral doses of N-251 (68 mg/kg three times per day for 2 days) in normal-fed mice. The plasma concentration of N-251 was between 10 and 1000 ng/mL. The simulation curve calculated based on the PK parameters obtained from the single-dose study well described the plasma concentrations after multiple oral dosing, indicating that N-251 did not accumulate in the mice. Multiple oral administrations of N-251 in mice were required to completely eliminate parasites without accumulation of N-251. Conclusions N-251 has been selected as a potent antimalarial candidate. We found that N-251 showed short half-life in plasma, and AUCs increased proportionally to dose. With multiple doses of N-251, the plasma level of N-251 was greater than 10 ng/mL in normal-fed mice, and accumulation of N-251 was not observed; however, multiple treatments with N-251 are required for the complete cure of parasite-infected mice. Determining the appropriate dosage was an important step in the clinical applications of N-251.

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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: 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.

Cited by 18 publications

References 35 publications

Lipid-associated oral delivery: Mechanisms and analysis of oral absorption enhancement

Lipid-associated oral delivery: Mechanisms and analysis of oral absorption enhancement

Recent trends on hydrogel based drug delivery systems for infectious diseases

Pharmacokinetic analysis of new synthetic antimalarial N-251

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