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ABSTRACTBackgroundLumefantrine (LMF) is first-line antimalarial drug, possesses activity against almost all human malarial parasites, but the in vivoactivity of this molecule gets thwarted due to its low and inconsistent oral bioavailability (i.e. 4–12%) owing to poor biopharmaceutical attributes.MethodsLumefantrine phospholipid complex (LMF-PC) was prepared by rota-evaporation method following job’s plot technique for the selection of apt stoichiometric ratios. Docking studies were carried out to determine the possible interaction(s) of LMF with phosphatidylcholine analogue. Comparative in vitrophysiochemical, solid-state characterization, MTT assay, dose-response on P. falciparum, in vivoefficacy studies including pharmacokinetic and chemosuppression on NK-65 P. bergheiinfected mice were carried out.ResultsAqueous solubility was distinctly improved (i.e. 345 times) with phospholipid complex of LMF. Cytotoxicity studies on Hela and fibroblast cell lines demonstrated safety of LMF-PC with selectivity indices of 4395 and 5139, respectively. IC50value was reduced almost 2.5 folds. Significant enhancement in Cmax(3.3-folds) and AUC (2.7-folds) of rat plasma levels indicated notable pharmacokinetic superiority of LMF-PC over LMF suspension. Differential leukocytic count and cytokine assay delineated plausible immunoregulatory role of LMF-PC with nearly 98% chemosuppression and over 30 days of post-survival.ConclusionSuperior antimalarial efficacy and survival time with full recovery of infected mice revealed through histopathological studies.

Cerebral malaria is a serious plasmodial infection that calls for immediate treatment for parasitic clearance from brain. Oral regimen of cerebral malaria is an impracticable option, it being often associated with problems like impaired consciousness, nausea and anorexia. The current research studies were, accordingly, undertaken to develop a patient-friendly non-invasive and rapid therapy via intranasal delivery of artemether (AM) and lumefantrine (LMF) employing their surface-modified lipidic nanocarriers (LNCs) using N, N, N trimethyl chitosan (TMC) as the polymer. Systematically developed employing Quality-by-Design (QbD) principles, LNCs and TMC-LNCs exhibited particle size of 63.7 and 80.8 nm, polydispersity of 0.19 and 0.28, respectively, along with modulated drug release profile for a period of 48 h. TMC-LNCs indicated nearly 2- and 7-folds enhancement in the mucoadhesive strength and nasal mucosal permeation vis-à-visconventional LNCs and pure drug(s) suspension, respectively. In vitro nitric oxide assay unraveled the potential of both TMC-LNCs and LNCs to trigger macrophages for stimulating innate immune response against the parasites. Brain biodistribution studies in female C57BL/6 mice indicated higher drug concentrations in mice brain with intranasally delivered TMC-LNCs over intranasal and peroral AM-LMF suspension. Further, the speed and effectiveness of TMC-LNCs and LNCs in eradicating Plasmodium bergheiANKA strain in the murine model was also evaluated. Intranasal TMC-LNC demonstrated considerable in vivoanti-plasmodial efficacy with over 95% parasite suppression on day 7, followed by intranasal LNCs (82.5%), intranasal AM-LMF (79.1%) and peroral AM-LMF (46.3%). Overall, the surface-modified formulation, i.e.,intranasal TMC-LNCs demonstrated markedly superior efficacy and parasitic suppression in brain.