Efficient design to fabricate smart Lumefantrine nanocrystals using DENA® particle engineering technology: Characterisation, in vitro and in vivo antimalarial evaluation and assessment of acute and sub-acute toxicity

Abstract

Nanocrystalization technologies have a great potential to substantially increase solubility as well as alleviate the erratic bioavailability behaviour of a range of poorly water soluble drugs. The aim of the current study was to fabricate smart nanocrystals of lumefantrine (LF) using wet milling technology (DENA DM-100) with the subsequent in vitro, in vivo evaluation and toxicity screening. This technology successfully produced nanocrystals with an average particle size (214.1 ± 0.2 nm) and PDI (0.201 ± 0.06) in a period of less than 1 h. DSC and PXRD were used to confirm crystallinity of the processed LF. The dissolution rate and saturation solubility of the processed LF was significantly (P < 0.05) increased compared to the raw and marketed tablets. The IC50 value of LF nanocrystals was significantly (P < 0.05) lower than the IC50 value of the raw drug and marketed tablets. In addition, LF nanocrystals at the same dose (30 mg/kg), showed significantly (P < 0.05) the highest reduction in the percentage of parasitemia compared to its other counterparts against P. vivax. The LD50 value of LF nanocrystals in the acute toxicity was between 1000 and 1500 mg/kg and was devoid of any observable sub-acute toxicity. The histopathological investigations and impact of LF nanocrystals on different internal organs of the chosen animal model were found comparable to the saline treated animal group. The results of current study suggested that wet milling can be effectively used to fabricate nanocrystals of LF both in acidic and aqueous media with enhanced antimalarial activities and a similar safety profile.