title: Development of hot melt co-formulated antimalarial solid dispersion system in fixed dose form (ARLUMELT): Evaluating amorphous state and in vivo performance.
abstract: The aim of this study was to investigate the industrial feasibility of developing a co-formulated solid dispersion (SD) containing two antimalarial drugs artemether (ARTM) and lumefantrine (LUMF). Soluplus(®) (polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer) was used as primary carrier matrices via hot-melt extrusion processing to improve solubility profile and the oral bioavailability of the combination. Based on the preliminary screening, the optimized quantities of PEG 400, Lutrol F127 and Lutrol F68 were incorporated as surfactant with soluplus in different ratios to improve extrudability, increase wettability and the melt viscosity of the HME process. Soluplus(®) was proved to successfully stabilize both the drugs inside its polymeric network during extrusion via forming a stable solid dispersion. Physicochemical properties of the APIs and the SDs characterized by thermo-gravimetric analysis (TGA), differential scanning calorimetry (DSC), MDSC, FTIR spectroscopy and X-ray diffractometry (XRD) revealed the amorphous existence of the drug in all SDs developed. Molecular level morphology of solid dispersion characterized by using advanced physicochemical characterization techniques such as Raman spectroscopy, atomic force microscopy (AFM) and 2D NMR showed the transformation of the crystalline drugs to its stable amorphous state. All manufactured SDs retained their amorphicity even after a stability study conducted in accelerated condition over 6 months. The solubility and in vitro dissolution performance of both drugs in SD formulations was improved significantly when compared with pure drugs and marketed product while the in vivo studies revealed the same.The pharmacokinetic studies in rats revealed that the SD (AL1) shows a 44.12-65.24 folds increase in the AUC(0-72) and 42.87-172.61 folds increase in Cmax compared to that of pure drugs and a better bioavailability than that of commercial product.
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai 400019, Maharashtra, India; H.K College of Pharmacy, Relief Road, Oshiwara, Jogeshwari West, Mumbai 400102, Maharashtra, India. Electronic address: riteshphd.ict@gmail.com.
authors.forename: Ritesh
authors.initials: R
authors.lastname: Fule
authors.affiliation: KLE University's College of Pharmacy, Nehru Nagar, Belagavi 590010, Karnataka, India.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Dhamecha
authors.affiliation: Faculty of Engineering and Science, University of Greenwich, Central Avenue, Chatham Maritime, Chatham, Kent ME4 4TB, United Kingdom.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Maniruzzaman
authors.affiliation: H.K College of Pharmacy, Relief Road, Oshiwara, Jogeshwari West, Mumbai 400102, Maharashtra, India.
authors.forename: Anubha
authors.initials: A
authors.lastname: Khale
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai 400019, Maharashtra, India.
authors.forename: Purnima
authors.initials: P
authors.lastname: Amin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D004337:Drug Carriers / Q000737:chemistry*; D004338:Drug Combinations; D004339:Drug Compounding / Q000379:methods; D004355:Drug Stability; D004356:Drug Storage; D004983:Ethanolamines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D005240:Feasibility Studies; D005449:Fluorenes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry; D014783:Viscosity; D017155:Wettability
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004337:Drug Carriers; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D013501:Surface-Active Agents
keywords: 2D NMR; Artemether; Atomic force microscopy; Bioavailability; Co-formulated solid dispersion; Fixed dose combination; Hot melt extrusion; Lumefantrine; Raman spectroscopy