A lipid based delivery system for the peroral administration of an orally inactive peptide drug (Myrcludex B)
Final Report Abstract
Aim of this study was the development of an orally applicable liposomal formulation containing tetraether lipids (TELs) for the administration of the hepatotropic hepatitis B peptide drug Myrcludex B. Our previous studies showed that TELs are able to improve both liposomal stability in the GIT as well as to mediate mucosal penetration. TELs were isolated extracted from the extremophilic archaeon Sulfolobulus acidocaldarius and purified in order to obtain glycerylcaldityltetraether lipid (GCTE). Myrcludex B and derivatives were synthesized by solid-phase synthesis and incorporated into the TEL-liposomes. The liposomes containing 5 mol-% of GCTE showed a comparable size, PDI and zeta potential to standard liposomes. Cryo-EM micrographs of both liposomal formulations showed low lamellarity, the prerequisite for high drug loading capacity. Long term storage of the TEL-liposomes was achieved by freeze-drying using 100-500 mM sucrose and trehalose as lyoprotectors. The lyophilized product exhibited a high storage stability with a recovery rate of 82.7 ± 1.6% of intact Myrcludex B after 3 months storage. In animal studies with Wistar rats, the TEL-liposomal formulation led to a substantial enhancement of the uptake of Myrcludex B into the liver. 3 h after oral application a 3.5-fold increase compared to the free peptide and a 2-fold increase when compared to the standard liposomes could be shown. Thus, our studies demonstrated that the TEL-liposomes enabled oral administration of Myrcludex B while also providing long term storage by freezedrying.
Publications
- A liposomal formulation for the oral application of the investigational hepatitis B drug Myrcludex B. Eur J Pharm Biopharm. 2016 Jun;103:159-166
Uhl P, Helm F, Hofhaus G, Brings S, Kaufman C, Leotta K, Urban S, Haberkorn U, Mier W, Fricker G.
(See online at https://doi.org/10.1016/j.ejpb.2016.03.031)
