Developing Self-Nanoemulsifying Drug Delivery Systems Comprising an Artemether-Lumefantrine Fixed-Dose Combination to Treat Malaria.

Abstract

Background: Despite attempts to control malaria, poor drug bioavailability means malaria still places enormous pressure on health globally. It has been found that the solubility of highly lipophilic compounds can be enhanced through lipid formulations, e.g., self-emulsifying drug delivery systems (SEDDSs). Thus, quality-by-design and characterization were used to justify the development and determine the feasibility of oral oil-in-water SEDDSs comprising a fixed-dose combination (FDC) of artemether-lumefantrine to treat malaria more effectively without the aid of a fatty meal. These formulations were compared to a commercial product containing the same active compounds.

Methods: Excipient compatibility and spontaneous emulsification capacity of different FDC-excipient combinations were identified by employing isothermal microcalorimetry, solubility, and water titration tests. Pseudoternary phase diagrams were constructed, and checkpoint formulations were selected within the self-emulsification region by reviewing formulation properties essential for optimized drug delivery. SEDDSs capable of enduring phase separation within 24 h were subjected to characterization experiments, i.e., drug concentration determination, cloud point, droplet size, size distribution, self-emulsification time, self-emulsification efficacy, viscosity, zeta potential, and thermodynamic stability analysis. SEDDSs with favorable characteristics were identified in the micro or nano range (SNEDDSs) before being subjected to drug release studies.

Results: All final formulations depicted enhanced artemether and lumefantrine release compared to the commercial product, which could not release lumefantrine at a quantifiable concentration in this study. The avocado oil (AVO)4:6 and olive oil (OLV)3:7 SNEDDSs overall portrayed the ideal characteristics and depicted the highest percentage of drug release.

Conclusions: This study offers evidence that SNEDDSs from selected natural oils comprising an artemether-lumefantrine FDC can potentially enhance the bioavailability of these lipophilic drugs.