Development and evaluation of fixed dose bilayer dispersible tablet formulations of artemether, lumefantrine and paracetamol for the treatment of malaria in children

Abstract

The World Health Organization estimated that there were 249 million cases of malaria in 2022 compared to 244 million cases in 2021, in sub-Saharan Africa. From these, infants less than 5 years or who were malnourished, made up a greater number of the cases and deaths. Developing antimalarial drugs specifically suited to the needs of these children is essential to malaria control and elimination.

The aim of the study was to develop and evaluate a dispersible bilayer formulation of artemether, lumefantrine and paracetamol tablet (ALPT). The specific objectives of the study were to: (i) develop a bilayer dispersible oral formulation of ALPT; (ii) evaluate post-compression physical characteristics of the ALPT; and (iii) comparatively study the in vitro dissolution profile of ALPT with innovator brands. The study adopted the experimental design where the artemether- lumefantrine layer was formulated with other additives.  Compression of bilayer ALPT was done having pale yellow color on one side, and off-white color on the other side. The uniformity of weight, hardness, disintegration, friability, active ingredient assay and palatability studies followed standard procedures. Comparative dissolution studies with the innovator products were done. Similarity factor (f2) was calculated using one-way analysis of variance and Tukey post hoc test. The ALPT passed the British Pharmacopoeia (BP) standards for visual appearance. The weight of 20 tablets did not deviate (+ 2% variance), the average tablet disintegration time was 105 sec, the friability test was not more than 1% and the breaking force/hardness was not less than 5 kiloponds. The mean dissolution profile of ALPT and Coartem^®, in HCl (pH 1.2), acetate buffer (pH 4.5) and phosphate buffer (pH 6.8) dissolution media respectively, were comparable, with a similarity factor (f2) of above 50 in all three media. The dissolution profile of artemether and lumefantrine in both ALPT and the innovator product showed maximal response in HCl (pH 1.2). For the paracetamol component of ALPT, the dissolution profiles for the samples of ALPT and the innovator product showed that they released more than 85% within 15 min in all the physiological pH dissolution media tested. The microbial limits and stability results complied with BP specifications. ALPT, a fixed dose combination of more than one antimalarial drug will simplify the treatment of malaria in children, resulting in improved medication compliance and clinical outcomes, and ultimately reduce mortality and morbidity.