title: Sustained-release liquisolid compact tablets containing artemether-lumefantrine as alternate-day regimen for malaria treatment to improve patient compliance.
abstract: The present study aimed to develop low-dose liquisolid tablets of two antimalarial drugs artemether-lumefantrine (AL) from a nanostructured lipid carrier (NLC) of lumefantrine (LUM) and estimate the potential of AL as an oral delivery system in malariogenic Wistar mice. LUM-NLCs were prepared by hot homogenization using Precirol®ATO 5/Transcutol®HP and tallow fat/Transcutol®HP optimized systems containing 3:1 ratios of the lipids, respectively, as the matrices. LUM-NLC characteristics, including morphology, particle size, zeta potential, encapsulation efficiency, yield, pH-dependent stability, and interaction studies, were investigated. Optimized LUM-NLCs were mixed with artemether powder and other dry ingredients and the resultant powder evaluated for micromeritics. Subsequent AL liquisolid tablets were tested for in vitro drug release and in vivo antiplasmodial activity in mice infected withPlasmodium berghei berghei(NK 65). Results showed that optimized LUM-NLC were stable, spherical, polydispersed but nanometric. Percentage yield and encapsulation efficiency were ~92% and 93% for Precirol®ATO 5/Transcutol®HP batch, then 81% and 95% for tallow fat/Transcutol®HP batch while LUM was amorphous in NLC matrix. In vitro AL release from liquisolid compacts revealed initial burst release and subsequent sustained release. Liquisolid tablet compacts formulated with Precirol®ATO 5/Transcutol®HP-AL4 achieved higher LUM release in simulated intestinal fluid (84.32%) than tallow fat/Transcutol®HP-BL3 (77.9%). Non-Fickian (anomalous) diffusion and super case II transport were the predominant mechanisms of drug release. Equal parasitemia reduction was observed for both batches of tablet compacts (~92%), superior to the reduction obtained with commercial antimalarial formulations: Coartem®tablets (86%) and chloroquine phosphate tablets (66%). No significant difference (P<0.05) in parasite reduction between double (4/24 mg/kg) and single (2/12 mg/kg) strength doses of AL compacts was observed. Our result highlights that AL could be formulated in much lower doses (4/24 mg/kg), for once-in-two days oral administration to improve patient compliance, which is currently not obtainable with conventional AL dosage forms.
authors.affiliation: Drug Delivery and Nanomedicines Research Group, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria; Department of Drug Delivery, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University, Saarbrücken, Germany.
authors.forename: Petra Obioma
authors.initials: PO
authors.lastname: Nnamani
authors.affiliation: Drug Delivery and Nanomedicines Research Group, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria.
authors.forename: Agatha Adaora
authors.initials: AA
authors.lastname: Ugwu
authors.affiliation: Drug Delivery and Nanomedicines Research Group, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria.
authors.forename: Emmanuel Chinedu
authors.initials: EC
authors.lastname: Ibezim
authors.affiliation: Drug Delivery and Nanomedicines Research Group, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria.
authors.forename: Franklin Chimaobi
authors.initials: FC
authors.lastname: Kenechukwu
authors.affiliation: Drug Delivery and Nanomedicines Research Group, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria.
authors.forename: Paul Achile
authors.initials: PA
authors.lastname: Akpa
authors.affiliation: Drug Delivery and Nanomedicines Research Group, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria.
authors.forename: John-Dike Nwabueze
authors.initials: JN
authors.lastname: Ogbonna
authors.affiliation: Department of Pharmaceutical Technology and Industrial Pharmacy, Faculty of Pharmaceutical Sciences.
authors.forename: Nicholas Chinedu
authors.initials: NC
authors.lastname: Obitte
authors.affiliation: Department of Human Kinetics and Health Education, University of Nigeria, Nsukka, Nigeria.
authors.forename: Amelia Ngozi
authors.initials: AN
authors.lastname: Odo
authors.affiliation: Department of Drug Delivery, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University, Saarbrücken, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Windbergs
authors.affiliation: Department of Drug Delivery, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University, Saarbrücken, Germany; PharmBioTec GmbH; Department of Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbrücken, Germany.
authors.forename: Claus-Michael
authors.initials: CM
authors.lastname: Lehr
authors.affiliation: Drug Delivery and Nanomedicines Research Group, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria.
authors.forename: Anthony Amaechi
authors.initials: AA
authors.lastname: Attama
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002152:Calorimetry, Differential Scanning; D003692:Delayed-Action Preparations / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry; D004338:Drug Combinations; D065546:Drug Liberation; D004983:Ethanolamines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005449:Fluorenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008055:Lipids / Q000737:chemistry; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D049329:Nanostructures / Q000737:chemistry; D010316:Particle Size; D010349:Patient Compliance; D010962:Plasmodium berghei / Q000187:drug effects; D017550:Spectroscopy, Fourier Transform Infrared; D013607:Tablets
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D008055:Lipids; D013607:Tablets
keywords: antiplasmodial activity; artemisinin-based combination therapy; liquisolid compacts; malaria; nanostructured lipid carriers