title: 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) againstPlasmodium falciparumandPlasmodium vivax. The IC50(median lethal oral dose) value of ARTM nanocrystals was 28- and 54-fold lower than the IC50value of unprocessed drug and 13- and 21-fold lower than the IC50value 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%) againstP. vivaxcompared to the unprocessed (27%), marketed tablets (45%), and microsuspension (60%). The acute toxicity study demonstrated that the LD50value 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.
authors.affiliation: Department of Pharmacy, Sarhad University of Science & Information Technology, Peshawar.
authors.forename: Syed Muhammad Hassan
authors.initials: SM
authors.lastname: Shah
authors.affiliation: Department of Pharmacy, University of Malakand, Chakdara, Pakistan.
authors.forename: Farhat
authors.initials: F
authors.lastname: Ullah
authors.affiliation: Department of Pharmacy, University of Malakand, Chakdara, Pakistan; Institute of Life Sciences Research, School of Pharmacy, University of Bradford, West Yorkshire.
authors.forename: Shahzeb
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Pharmacy, University of Swabi, KPK, Pakistan.
authors.forename: Syed Muhammad Mukarram
authors.initials: SM
authors.lastname: Shah
authors.affiliation: SEDA Pharmaceutical Development Services, The BioHub at Alderley Park, Cheshire, UK.
authors.forename: Marcel
authors.initials: M
authors.lastname: de Matas
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutics, Universiti Teknologi MARA, Selangor, Malaysia.
authors.forename: Zahid
authors.initials: Z
authors.lastname: Hussain
authors.affiliation: Faculty of Pharmacy & Alternative Medicine, The Islamia University of Bahawalpur Pakistan, Bahawalpur, Pakistan.
authors.forename: Muhammad Usman
authors.initials: MU
authors.lastname: Minhas
authors.affiliation: Riyadh Community College, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Naser M
authors.initials: NM
authors.lastname: AbdEl-Salam
authors.affiliation: Institute of Life Sciences Research, School of Pharmacy, University of Bradford, West Yorkshire.
authors.forename: Khaled Hafez
authors.initials: KH
authors.lastname: Assi
authors.affiliation: Institute of Life Sciences Research, School of Pharmacy, University of Bradford, West Yorkshire.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Isreb
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D000077549:Artemether; D037621:Artemisinins / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D065546:Drug Liberation; D004355:Drug Stability; D065347:Hypromellose Derivatives / Q000737:chemistry; D007928:Lethal Dose 50; D016780:Malaria, Vivax / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010963:Plasmodium falciparum / Q000187:drug effects; D010966:Plasmodium vivax / Q000187:drug effects; D011205:Povidone / Q000737:chemistry; D012995:Solubility; D013607:Tablets
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D013607:Tablets; D065347:Hypromellose Derivatives; D000077549:Artemether; D011205:Povidone
keywords: antimalarial activity; artemether; in vitro dissolution; milling; nanosuspension; smart nanocrystals