title: A liposomal formulation for the oral application of the investigational hepatitis B drug Myrcludex B.
abstract: The aim of this study was the development of a liposomal formulation containing specific tetraether lipids for the oral administration of the investigational hepatitis B peptide drug Myrcludex B. For this purpose, tetraether lipids were extracted from the extremophilic archaeon Sulfolobus acidocaldarius and purified in order to obtain the desired glycerylcaldityltetraether lipids (GCTE). Myrcludex B was synthesized by solid-phase synthesis and incorporated into liposomes containing 5mol% of GCTE. These liposomes showed a size, polydispersity index and zeta potential comparable to the standard liposomes. Cryo-EM micrographs of both liposomal formulations displayed low lamellarity, the prerequisite for high drug loading capacity. Long term storage of the GCTE-liposomes was achieved by freeze-drying using 100-500mM sucrose or trehalose as lyoprotectors. The lyophilized product showed high stability with a recovery rate of 82.7±1.6% of intact Myrcludex B observed after storage for 3months at -20°C as compared to a recovery rate of 83.3±1.3% directly after the freeze-drying process. In vivo, the GCTE-liposomal formulation led to substantial enhancement of the liver uptake of iodine-131-labeled Myrcludex B in Wistar rats. 3h after oral application, approximately 7% of the initial dose (corresponding to a 3.5-fold increase compared to the free peptide) could be detected in the liver. In summary, the GCTE-liposomes enabled efficient oral administration of Myrcludex B and provided long term storage by freeze-drying.
authors.affiliation: Department of Pharmaceutical Technology and Biopharmacy, University of Heidelberg, Heidelberg, Germany; Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Uhl
authors.affiliation: Department of Pharmaceutical Technology and Biopharmacy, University of Heidelberg, Heidelberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Helm
authors.affiliation: Bioquant, CellNetWorks, University of Heidelberg, Heidelberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Hofhaus
authors.affiliation: Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Brings
authors.affiliation: Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany; Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kaufman
authors.affiliation: Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Leotta
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Urban
authors.affiliation: Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Haberkorn
authors.affiliation: Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany. Electronic address: walter.mier@med.uni-heidelberg.de.
authors.forename: W
authors.initials: W
authors.lastname: Mier
authors.affiliation: Department of Pharmaceutical Technology and Biopharmacy, University of Heidelberg, Heidelberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Fricker
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D004339:Drug Compounding; D006509:Hepatitis B / Q000188:drug therapy*; D055666:Lipopeptides / Q000627:therapeutic use*; D008081:Liposomes; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000998:Antiviral Agents; D055666:Lipopeptides; D008081:Liposomes; C571888:myrcludex-B
keywords: Hepatitis B; Liposome; Myrcludex B; Oral delivery; Peptide drugs; Tetraether lipids