Reformulating lumefantrine as Flash NanoPrecipitated particles and the impact of incorporation into milk-based formulations on drug solubilisation during digestion

Abstract

Lumefantrine and artemether are currently used as one of the first line therapies for treatment of uncomplicated malaria. However, commercially-available lumefantrine/artemether tablets often result in poor and variable oral bioavailability due to low aqueous solubility of the drugs. To circumvent these issues, consumption of food containing lipids with the lumefantrine/artemether tablet(s) is recommended to increase exposure of the drugs, which brings high variability to the systemic drug exposure. In this study, we investigated the potential use of infant formula as a milk-based lipid formulation to improve the solubilisation of lumefantrine/artemether with controlled fat content, both as a formulation for the two drug substances as well as when co-dosed with lumefantrine after re-formulation into nanoparticles. Time-resolved synchrotron small angle X-ray scattering (SAXS) was used to probe the solubilisation behaviour of the drugs and high-performance liquid chromatography (HPLC) was used to quantify the amount of drugs dissolved during digestion. Findings from these studies suggest that the solubility of artemether in undigested and digested infant formula was greater than 5 fold relative to lumefantrine and that 5 g of fat was not sufficient to completely solubilise a 120 mg lumefantrine dose. When formulated as nanoparticles, there was evidence of slight lumefantrine crystallisation when the highly amorphous drug powder was added to infant formula but digestion did not appear to significantly affect the presence of crystalline lumefantrine. These findings suggest a potential reduced food effect for lumefantrine nanoparticles compared to the crystalline counterpart, further highlighting that lumefantrine nanoparticles may be orally administered in both fasted and fed conditions.