Fabrication, Characterization and Bioavailability Studies of Artemisinin, Artemether and Lumefantrine Nanoparticles

Abstract

Poor oral bioavailability is a major challenge affecting the new drugs reaching the market due to its low aqueous solubility. Nanocrystals have the potential and rapidly providing a platform solution to substantially increase dissolution rate, solubility with subsequent enhanced bioavailability and effectiveness via the oral route of administration of a range of poor water soluble drugs. The current study is comprised on two parts utilized antimalarial drugs: the first part was comprised on fabrication of artemether (ARTM) and lumefantrine (LMF) nanoparticles using a novel top down wet milling approach (DENA DM-100) and in the second part: cost effective simplest approach of re-precipitation combined with ultrasonication was utilized for fabrication of artemisinin (ART) nanoparticles with the aims to enhance their dissolution and hence the bioavailability of these antimalarial drugs. Smart nanocrystals of artemether (ARTM) and lumefantrine (LMF) were fabricated in the form of nanosuspensions in shortest milling time (less than 1 hr) in both aqueous and acidic medium using a novel wet milling technology (DENA DM-100). Both high feedstock concentration (10% w/w) and low feedstock concentration (2.5% w/w) of ARTM and LMF yielded nanocrystals with maximum recovery of the active contents. Similarly, we revisited the simplest approach of re-precipitation combined with ultrasonication for fabrication of artemisinin nanoparticles in the form nanosuspensions. Different critical parameters, including the effect of different concentrations of stabilizers, temperature as well as optimum parameters/conditions were identified, which was found to be very critical not only for fabrication as well as for scale up of the batch size, which is critical issue associated with this approach. xii Additionally, the physical stability studies of artemether, lumefantrine and artemisinin were conducted for 90 days at different storage temperatures demonstrated that nanocrystals stored at 2-8°C and 25°C were most stable compared to the samples stored at 40°C. There was not observed any chemical degradation in the APIs during the chemical stability studies which was monitored for 07 days. Similarly artemether, lumefantrine and artemisinin nanocrystals were produced in the size ranges of 161±1.5 nm and 214.1±1.2 nm, 98.77±1.5 nm respectively, where they showed significantly enhanced solubility, dissolution rate and enhanced antimalarial efficacy (in vitro and in vivo) compared to its unprocessed, micronized, microsuspension and their marketed counterparts in relatively low dose. In summary the study demonstrates that both novel top down DENA (DM-100) technology and standard crystallization combined with ultrasonication are effective in producing stable nanocrystals with smallest particle sizes, increased saturation solubility and enhanced dissolution rate with enhanced in vitro and in vivo antimalarial activities while controlling the key experimental and process conditions.