脂质体制剂的研究性乙肝药物Myrcludex乙的口头应用

StephenW

Eur J Pharm Biopharm. 2016 Apr 2. pii: S0939-6411(16)30121-7. doi: 10.1016/j.ejpb.2016.03.031. [Epub ahead of print]
A liposomal formulation for the oral application of the investigational hepatitis B drug Myrcludex B.Uhl P1, Helm F2, Hofhaus G3, Brings S4, Kaufman C5, Leotta K4, Urban S6, Haberkorn U4, Mier W7, Fricker G2.
Author information

• 1Department of Pharmaceutical Technology and Biopharmacy, University of Heidelberg, Heidelberg, Germany; Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.
• 2Department of Pharmaceutical Technology and Biopharmacy, University of Heidelberg, Heidelberg, Germany.
• 3Bioquant, CellNetWorks, University of Heidelberg, Heidelberg, Germany.
• 4Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.
• 5Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany; Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Germany.
• 6Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Germany.
• 7Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany. Electronic address: [email protected].
  

AbstractThe 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.
Copyright © 2016. Published by Elsevier B.V.


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

StephenW

欧元J医药生物制药。 2016年2月PII：S0939-6411（16）30121-7。 DOI：10.1016 / j.ejpb.2016.03.031。 [打印EPUB提前]
脂质体制剂的研究性乙肝药物Myrcludex B的口头申请
乌尔P1，头盔F2，Hofhaus G3，带来S4，考夫曼C5，Leotta K4，城市​​S6，Haberkorn U4，迷尔W7，弗里克G2。
制药技术和生物制药，海德堡，德国海德堡大学的作者信息教研室;核医学，海德堡大学医院，德国海德堡系。制药技术和生物制药，海德堡大学，德国海德堡教研室。 3 Bioquant，CellNetWorks，海德堡大学，德国海德堡。核医学，海德堡大学医院，德国海德堡4Department。核医学，海德堡大学医院，德国海德堡5Department;传染科，分子病毒学，海德堡大学医院，德国。传染病6Department，分子病毒学，海德堡大学医院，德国。核医学，海德堡大学医院，德国海德堡7Department。电子地址：[email protected]。
抽象
本研究的目的是包含特定四醚脂质的研究性乙型肝炎肽药物Myrcludex B.为了这个目的，四醚脂质从极端型古细菌硫化酸杆菌和纯化提取的口服给药的脂质体制剂的开发中，以获得所需glycerylcaldityltetraether脂类（GCTE）。 Myrcludex B在通过固相合成法合成并掺入含有GCTE的5摩尔％的脂质体。这些脂质体显示出尺寸，多分散指数和zeta电位媲美的标准的脂质体。这两个脂质体制剂冷冻电镜显微照片显示低层数，对于高载药量的前提。的500mM蔗糖或海藻糖作为lyoprotectors - 所述GCTE脂质体的长期储存，通过使用100冷冻干燥来实现的。相比，冷冻干燥过程后直接83.3±1.3％的回收率的冻干产品显示出高稳定性的储存后观察到3个月-20℃完好Myrcludex的B 82.7±1.6％的回收率。在体内，GCTE-脂质体制剂导致碘-131标记的Myrcludex B在Wistar大鼠的肝摄取的大幅提升。 3小时后口服应用，初始剂量（对应于相对于游离肽的3.5倍）的约7％可在肝脏进行检测。总之，GCTE脂质体启用Myrcludex的B有效口服给药和通过冷冻干燥提供长期存储。
版权所有©2016年出版由Elsevier B.V.
关键词：
乙型肝炎;脂质体; Myrcludex B：口服给药;多肽药物;四醚脂