Smart nanocrystals of artemether: fabrication, characterization, and comparative in vitro and in vivo antimalarial evaluation

Abstract

Artemether (ARTM) is a very effective antimalarial drug with poor solubility and consequently low bioavailability. Smart nanocrystals of ARTM with particle size of 161±1.5 nm and polydispersity index of 0.172±0.01 were produced in <1 hour using a wet milling technology, Dena^® DM-100. The crystallinity of the processed ARTM was confirmed using differential scanning calorimetry and powder X-ray diffraction. The saturation solubility of the ARTM nanocrystals was substantially increased to 900 µg/mL compared to the raw ARTM in water (145.0±2.3 µg/mL) and stabilizer solution (300.0±2.0 µg/mL). The physical stability studies conducted for 90 days demonstrated that nanocrystals stored at 2°C–8°C and 25°C were very stable compared to the samples stored at 40°C. The nanocrystals were also shown to be stable when processed at acidic pH (2.0). The solubility and dissolution rate of ARTM nanocrystals were significantly increased (P<0.05) compared to those of its bulk powder form. The results of in vitro studies showed significant antimalarial effect (P<0.05) against Plasmodium falciparum and Plasmodium vivax. The IC₅₀ (median lethal oral dose) value of ARTM nanocrystals was 28- and 54-fold lower than the IC₅₀ value of unprocessed drug and 13- and 21-fold lower than the IC₅₀ value of the marketed tablets, respectively. In addition, ARTM nanocrystals at the same dose (2 mg/kg) showed significantly (P<0.05) higher reduction in percent parasitemia (89%) against P. vivax compared to the unprocessed (27%), marketed tablets (45%), and microsuspension (60%). The acute toxicity study demonstrated that the LD₅₀ value of ARTM nanocrystals is between 1,500 mg/kg and 2,000 mg/kg when given orally. This study demonstrated that the wet milling technology (Dena^® DM-100) can produce smart nanocrystals of ARTM with enhanced antimalarial activities.

Keywords:

• artemether
• milling
• smart nanocrystals
• nanosuspension
• in vitro dissolution
• antimalarial activity

Acknowledgments

The authors gratefully acknowledge the Department of Pharmacy, University of Malakand, Chakdara, Dir (L), KPK, Pakistan; Faculty of Pharmacy, Sarhad University Peshawar, Pakistan; Institute of Life Sciences Research, School of Pharmacy, University of Bradford, West Yorkshire, UK; and Universiti Teknologi MARA for support and providing resources to execute this research work. The authors are also thankful to the Deanship of Scientific Research, King Saud University, for funding the work through the research group project no RGP-210.

Disclosure

The authors report no conflicts of interest in this work.