Effect of molecular interaction on the antiplasmodial efficacy of lumefantrine in amorphous polymethacrylate-urea solid solution

Abstract

Malaria, a leading cause of mortality and morbidity in the developing world, with children aged under 5 years, accounts for 61% of all the global malaria deaths. The World Health Organization approved fixed-dose first-line artemisinin-based combination therapy (ACT) – artemether-lumefantrine for effective malaria treatment, is challenged by poor aqueous solubility and inadequate bioavailability leading to treatment failures and emergence of resistant strains. This study focuses on evaluating novel lumefantrine (LF) polymethacrylate-urea solid solutions comprising of a retarding polymer for enhanced anti-plasmodial efficacy comparable with existing artemether-lumefantrine combination therapy. Lumefantrine polymethacrylate-urea solid solutions were prepared by solvent evaporation and characterized by differential scanning calorimetry (DSC), and dissolution studies. In vivo anti-plasmodial activity was determined by measuring the schizonticidal activity of Plasmodium berghei-infected mice using the Peter’s 4-day curative test and the safety of the solid solutions was tested in major organs implicated in malaria. The solid state characterizations confirmed the formation of amorphous lumefantrine polymethacrylate-urea solid solutions. There was greater drug release from the matrix polymer in acidic than basic biorelevant media, with release kinetics following the Higuchi order. Interestingly, the reduction in parasitaemia caused by the lumefantrine polymethacrylate-urea formulations (72.3 and 81.27 %) for ternary and quaternary systems, batches SDA3 and SDB3, respectively) were significantly higher (p < 0.05) and more sustained than lumefantrine pure powder, but with comparable efficacy to the commercial brand-Coartem®. The formulation was stable over a period of 6 months. Thus, this study provides useful information on developing sustained lumefantrine formulation with improved solubility and antiplasmodial efficacy.
 Keywords: Solid dispersion, lumefantrine, solubility, parasitaemia reduction, eudragit polymer, Urea.