title: Freeze-drying of HI-6-loaded recombinant human serum albumin nanoparticles for improved storage stability.
abstract: Severe intoxications with organophosphates require the immediate administration of atropine in combination with acetyl cholinesterase (AChE) reactivators such as HI-6. Although this therapy regimen enables the treatment of peripheral symptoms, the blood-brain barrier (BBB) restricts the access of the hydrophilic antidotes to the central nervous system which could lead to a fatal respiratory arrest. Therefore, HI-6-loaded albumin nanoparticles were previously developed to enhance the transport across this barrier and were able to reactivate organophosphate-(OP)-inhibited AChE in an in vitro BBB model. Since HI-6 is known to be moisture-sensitive, the feasibility of freeze-drying of the HI-6-loaded nanoparticles was investigated in the present study using different cryo- and lyoprotectants at different concentrations. Trehalose and sucrose (3%, w/v)-containing formulations were superior to mannitol concerning the physicochemical parameters of the nanoparticles whereas trehalose-containing samples were subject of a prolonged storage stability study at temperatures between -20°C and +40°C for predetermined time intervals. Shelf-life computations of the freeze-dried HI-6 nanoparticle formulations revealed a shelf-life time of 18 months when stored at -20°C. The formulations' efficacy was proven in vitro by reactivation of OP-inhibited AChE after transport over a porcine brain capillary endothelial cell layer model.
authors.affiliation: Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Dadparvar
authors.affiliation: Department of Cell Biology & Applied Virology, Fraunhofer Institute for Biomedical Engineering, St. Ingbert, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Department of Cell Biology & Applied Virology, Fraunhofer Institute for Biomedical Engineering, St. Ingbert, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Wien
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.affiliation: Department of Cell Biology & Applied Virology, Fraunhofer Institute for Biomedical Engineering, St. Ingbert, Germany.
authors.forename: Hagen
authors.initials: H
authors.lastname: von Briesen
authors.affiliation: Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. Electronic address: kreuter@em.uni-frankfurt.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kreuter
mesh_terms: D001812:Blood-Brain Barrier; D004355:Drug Stability; D005240:Feasibility Studies; D005612:Freeze Drying; D006801:Humans; D066298:In Vitro Techniques; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles; D011994:Recombinant Proteins / Q000737:chemistry; D012709:Serum Albumin / Q000737:chemistry*
chemical_list: D011994:Recombinant Proteins; D012709:Serum Albumin
keywords: Blood–brain barrier (BBB); Drug delivery; Freeze-drying; HI-6; Nanoparticles; Organophosphate intoxication; Oximes; Recombinant human serum albumin; Storage stability