Formulation and Optimization of Artemether and Lumefantrine Calcium Alginate Capsules Using Inverse Gelation Technique

ABSTRACT Poorly water-soluble drug candidates are associated with dissolution, absorption and bioavailability challenges. Consequently, poor solubility and non-reproducible absorption from the gastrointestinal tract following oral administration constitute a biopharmaceutical concern to dosage form design and formulation. The use of lipid-based formulations to address this concern has been the choice of many scientists in the drug delivery domain. Artemether and Lumefantrine the drugs investigated in the work are poorly soluble with unpredictable absorption and bioavailability problems. In addition they may be prone to acid hydrolysis and precipitation respectively in gastric environment of the stomach. To date there is no published work on alginate capsules geared towards solving bioavailability problems and inactivation of Artemether and Lumefantrine in the stomach. In this work we aimed at employing optimized lipid-based formulation capable of solubilizing artemether and lumefantrine, and protecting artemether from possible stomach acid degradation using alginate capsules, for ultimate avoidance of resistance and improved antimalarial performance. A 33 full factorial experimental design was employed to optimize excipient compositions using JMP Discovery V10 Statistical Software. The software generated 27 formulae, which was transformed into formulations using inverse gelation technique and subsequently evaluated. The resulting responses were fed back to the software which was exclusively re-run. Five, out of the 125 formulae with the best predicted responses were chosen as the optimal batches. In vitro studies carried out on the optimized batches include quantity of oil encapsulated, percentage capsule yield, mean capsule diameter, percentage encapsulation, swelling index, mucoadhesivity, differential scanning calorimetry (DSC) and drug release / kinetic properties. In vivo antimalarial studies were carried out in mice against virulent rodent malaria parasite plasmodium berghei using Peter’s 4 days protocol. The percentages of drugs encapsulated were high for all the batches, 64.60 ±0.10% - 88.50 ±0.07%. The percentage of Artemether and Lumefantrine released in SGF pH 1.2 were in the range of 0.75± 0.01 to 23.86 ± 0.53% after 320 minutes while, in SIF pH 6.8 and pH 7.2, the percentage of Artemether and Lumenfantrine released were in the range of 13.79±0.75 to 99.43 ± 0.12%. The optimized batches exhibited higher antimalarial activities. DSC revealed that the oil-dissolved drugs did not crystallize out of the formulations. Optimized alginate capsules improved aqueous solubility of artemether and Lumenfantrine with increased in vivo antimalarial activity.