A liposomal formulation for the oral application of the investigational hepatitis B drug Myrcludex B.
A liposomal formulation for the oral application of the investigational hepatitis B drug Myrcludex B.
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DOI：
10.1016/j.ejpb.2016.03.031
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发表时间：
2016-06
期刊：
影响因子：
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通讯作者：
P. Uhl;F. Helm;G. Hofhaus;S. Brings;C. Kaufman;K. Leotta;S. Urban;U. Haberkorn;W. Mier;
中科院分区：
文献类型：
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作者：
P. Uhl;F. Helm;G. Hofhaus;S. Brings;C. Kaufman;K. Leotta;S. Urban;U. Haberkorn;W. Mier;
本研究的目的是开发一种含有特异性四醚脂的脂质体制剂，用于口服研究中的乙肝多肽药物Myrcludex B。为此，从极端嗜热的Sulfolobus acidocaldarius中提取并纯化四醚脂类，以获得所需的甘油二叔丁基四醚脂(GCTE)。采用固相合成法合成了MyrCludex B，并将其包合到含5%GCTE的脂质体中。这些脂质体的大小、多分散性指数和Zeta电位与标准脂质体相当。两种脂质体制剂的冷冻-电子显微镜照片均显示低的片层，这是高载药量的先决条件。用100-500mM蔗糖或海藻糖作为冻干保护剂，实现了GCTE-脂质体的长期保存。冻干产物稳定性好，在−20℃下保存3个月后，其回收率为82.7%±71.6%，而冷冻干燥后的回收率为83.3%±111.3%。口服3小时后，在肝脏中可以检测到大约7%的初始剂量(与游离肽相比增加了3.5倍)。综上所述，GCTE-脂质体能够有效地口服Myrcludex B，并通过冷冻干燥提供长期储存。
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 5 mol% 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 100–500 mM 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 3 months 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. 3 h 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.