Quality-by-design Optimization and Characterization of Artemether–Lumefantrine–Paracetamol Co-loaded Solid Lipid Nanoparticles for Synchronized and Sustained Drug Release

Abstract

Malaria treatment continues to face significant challenges due to emerging drug resistance and pharmacokinetic heterogeneity among artemisinin-based combination therapies. This study reports the development of a triple-drug solid lipid nanoparticle (SLN) system employing Compritol® 888 ATO as the lipid matrix and Labrafil® M 1944 CS as the surfactant, co-loaded with artemether, lumefantrine, and paracetamol to achieve synchronized and sustained drug release. A Quality-by-Design (QbD) approach utilizing a Box–Behnken design was applied to optimize formulation parameters. The optimized formulation, comprising 1,000 mg of lipid, 2.25% surfactant, and a 60-minute homogenization time, yielded stable and monodisperse nanoparticles with a mean size of 131.8 nm, a polydispersity index (PDI) of 0.136, and a zeta potential of −49.4 mV. Encapsulation efficiencies were 91.4% for artemether, 93.0% for lumefantrine, and 91.0% for paracetamol, indicating strong entrapment of the drugs within the solid lipid core. In vitro release studies revealed cumulative drug releases of 90%, 80%, and 85%, respectively, after 72 hours, with mean release times of 18.3 and 24.1 hours demonstrating effective release synchronization. The developed SLN system offers a promising strategy for improving therapeutic efficacy, enhancing patient adherence, and mitigating drug resistance in malaria management.