Abstract
This study describes the properties of an amphotericin B-containing mucoadhesive nanostructured lipid carrier (NLC), with the intent to maximize uptake within the gastrointestinal tract. We have reported previously that lipid nanoparticles can significantly improve the oral bioavailability of amphotericin B (AmpB). On the other hand, the aggregation state of AmpB within the NLC has been ascribed to some of the side effects resulting from IV administration. In the undissolved state, AmpB (UAmpB) exhibited the safer monomeric conformation in contrast to AmpB in the dissolved state (DAmpB), which was aggregated. Chitosan-coated NLC (ChiAmpB NLC) presented a slightly slower AmpB release profile as compared to the uncoated formulation, achieving 26.1% release in 5 hours. Furthermore, the ChiAmpB NLC formulation appeared to prevent the expulsion of AmpB upon exposure to simulated gastrointestinal pH media, whereby up to 63.9% of AmpB was retained in the NLC compared to 56.1% in the uncoated formulation. The ChiAmpB NLC demonstrated mucoadhesive properties in pH 5.8 and 6.8. Thus, the ChiAmpB NLC formulation is well-primed for pharmacokinetic studies to investigate whether delayed gastrointestinal transit may be exploited to improve the systemic bioavailability of AmpB, whilst simultaneously addressing the side-effect concerns of AmpB.
Highlights
Amphotericin B (AmpB) is a broad spectrum antifungal agent commonly used to treat invasive systemic fungal infections and visceral leishmaniasis (Legrand et al 1992)
amphotericin B (AmpB) exerts its antifungal properties by binding to ergosterol within fungal membranes, forming transmembrane pores that allow depletion of intracellular ions, which eventually lead to the cell death
The oral bioavailability of AmpB can be boosted through formulation intervention as we have recently shown using solid lipid nanoparticles (SLNs)
Summary
Amphotericin B (AmpB) is a broad spectrum antifungal agent commonly used to treat invasive systemic fungal infections and visceral leishmaniasis (Legrand et al 1992). AmpB binds to mammalian cholesterol within the plasma membrane, which lead to severe side effects, notably nephrotoxicity (Butani et al 2016). This is the hallmark of the toxic effects of the dimers mentioned above (Radwan et al 2017). The NLC protect against possible enzymatic degradation and can accommodate relatively higher levels of cargoes than the SLNs (Yoon et al 2013; Yostawonkul et al.2017; Liu et al 2017)
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