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. 2016 Jun:103:159-166.
doi: 10.1016/j.ejpb.2016.03.031. Epub 2016 Apr 2.

A liposomal formulation for the oral application of the investigational hepatitis B drug Myrcludex B

P Uhl  1 , F Helm  2 , G Hofhaus  3 , S Brings  4 , C Kaufman  5 , Karin Leotta  4 , S Urban  6 , U Haberkorn  4 , W Mier  7 , G Fricker  2
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A liposomal formulation for the oral application of the investigational hepatitis B drug Myrcludex B

P Uhl et al. Eur J Pharm Biopharm. 2016 Jun.

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.

Keywords: Hepatitis B; Liposome; Myrcludex B; Oral delivery; Peptide drugs; Tetraether lipids.

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