Development of lipid matrix tablets containing a double-fixed dose combination of artemether and lumefantrine

Abstract

Malaria remains one of the most serious vector-borne and prominent life-threatening diseases in sub-Saharan Africa. Africa has the heaviest malarial disease burden in the world, accounting for 91% of the estimated 445 000 deaths globally in 2016. Despite numerous efforts to minimise the morbidity and mortality of malaria, it was deliberated the fourth most prevalent cause of death, responsible for 10% of child deaths in sub-Saharan Africa in 2017. In order to combat this disease, the World Health Organisation (WHO) encourages the development of artemisinin-based combination therapy (ACT) and has recommended the use of ACT as first-line treatment for uncomplicated P. falciparum in malaria endemic countries. However, one of the main complications in the development of ACT, is that most of the antimalarial drugs are poorly aqueous soluble and therefore, are poorly biopharmaceutically available for absorption into the systemic circulation. Thus, the primary challenge is to design a dosage form that is able to enhance the solubility of both drugs. For this reason, this study investigated the incorporation of a double-fixed dose combination of 20 mg artemether and 120 mg lumefantrine into lipid matrix tablets as lipid-based formulations are proposed to enhance the solubility of highly lipophilic drugs by providing a microenvironment into which they can partition. Pre-formulation studies characterised the physical properties of the active ingredients as well as the solid lipid dispersions prepared by means of the hot fusion method. Moreover, their powder flow properties were scrutinised. Thereafter, lipid matrix tablets were directly compressed in accordance with a full factorial design of experiments. The physical tablet properties (mass variation, friability, disintegration, hardness and tensile strength) were subsequently evaluated and only viable formulations progressed for further analysis regarding swelling, erosion and drug release. Reviewing the physical characteristics of the manufactured lipid matrix tablets, it could clearly be seen that only the formulations comprising either MicroceLac® 100 or CombiLac® as fillers were viable. These resulting 18 formulations underwent dissolution profile characterisation and were compared to the commercially available product, Coartem®. Overall, formulation SA0.5C1 was identified as the optimal formulation (regarding physical and dissolution properties), fitting the Korsmeyer-Peppas with Tlag dissolution model capable of releasing 97.21% artemether whilst Coartem® fitted the Peppas-Sahlin 2 with Tlag drug release profile and displayed only 86.12% artemether drug release over a period of 12 h in the tested dissolution media. In vitro permeability studies were conducted as a proof of concept for the lipid based formulations utilising the study’s optimised formulation, which rendered 3.35% artemether and 4.88% lumefantrine drug transport, respectively. Therefore, in conclusion, preliminary evaluation of the formulated lipid matrix tablets containing a double-fixed dose combination of artemether and lumefantrine proved capable of increasing the active ingredients solubility whilst demonstrating modified drug release. The optimal lipid matrix tablet formulation, SA0.5C1, requires further in vivo analysis to comment on the formulations potential to increase the biopharmaceutical availability of the two incorporated highly lipophilic active ingredients.