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

• Main Authors: AabdEel-Salam, N.M (Author), Aassi, K.H (Author), de Matas, M. (Author), Hhussain, Z. (Author), Iisreb, M. (Author), Khan, S. (Author), Minhas, M.U (Author), Shah, S.M.H (Author), Shah, S.M.M (Author), Ullah, F. (Author)
• Format: Article
• Language: English
• Published: Dove Medical Press Ltd. 2016
• Subjects: acute toxicity; analysis of variance; Analysis of Variance; animal; animal experiment; animal model; Animals; antimalarial activity; Antimalarial activity; antimalarial agent; Antimalarials; artemether; Artemether; artemisinin derivative; Artemisinins; Article; bioavailability; Biological Availability; biotechnology; chemistry; Chemistry, Pharmaceutical; comparative study; controlled study; drug effects; Drug Liberation; drug release; drug screening; drug stability; Drug Stability; drug synthesis; female; hydroxypropylmethylcellulose; Hypromellose Derivatives; IC50; In vitro dissolution; in vitro study; in vivo study; LD50; Lethal Dose 50; malaria falciparum; Malaria, Vivax; male; Male; medical device; medicinal chemistry; Mice; Milling; mouse; nanocrystal; nanoparticle; Nanoparticles; Nanosuspension; nonhuman; parasitemia; parasitology; particle size; Particle Size; Plasmodium falciparum; Plasmodium vivax; Plasmodium vivax malaria; povidone; Povidone; Smart nanocrystals; solubility; Solubility; suspension; tablet; tablet formulation; Tablets
• Online Access: View Fulltext in Publisher; View in Scopus
• ISBN: 11778881 (ISSN)
• ISSN: 11778881 (ISSN)
• DOI: 10.2147/DDDT.S114962

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. © 2016 Shah et al.