A lipid based delivery system for the peroral administration of an orally inactive peptide drug (Myrcludex B)

用于口服无活性肽药物 (Myrlucex B) 口服给药的脂质递送系统

• 批准号: 267260074
• 负责人: Professor Dr. Gert Fricker
• 金额: --
• 依托单位: Abteilung für Nuklearmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/267260074?language=en
• 关键词: lipid; based; delivery; system; peroral

The oral delivery of of peptides/proteins gernerally fails due to instability and low absorption in the gastrointestinal tract (GI-tract) . In this project we will study a liposomal carrier system containing tetraether lipids (TELs) from Archaeae. Preliminary studies show an extremely increased stability of such liposomes in the GI-tract compared to conventional liposomes. By dual asymmetric centrifugation peptides can be incorparated into these liposomes to a very high extent. First studies in rats show a significantly increased bioavailability of incorporated peptides in rats compared to dissolved drugs (26-fold for octreotide (MW 1,17 kDa), ca 360-fold for human growth hormone MW ca 23,5 kDa). This system should now enable the oral administration of the hepatitis B virus (HBV) therapeuticum Myrcludex B. This drug, being in phase 2- clinical tests, is derived from an enevelope protein of the virus. It exhibits an extreme hepatotropism and inhibits hepatitis B and D infection at pricomolar concentrations. However its bioavailability after oral administration is zero. This peptide will be incroporated into TEL-liposomes. Thereby, loading capacity, liposomes size, stability under various conditions, release properties and development of a formaulation, which is applicable to humans will be studied. Then, a bioavailability study in rats as well as a proof-of-concept study in a rodent hepatitis model (HBV-positive mice) will be performed in collaboration with Prof. Urban, Heidelberg, in order to demonstrate the efficiency of this liposomal peptide system after oral administration.

由于不稳定和胃肠道（GI-tract）的低吸收，肽/蛋白质的口服递送通常失败。在本项目中，我们将研究含有古菌四醚脂质的脂质体载体系统。初步研究表明，与传统脂质体相比，这种脂质体在胃肠道中的稳定性大大提高。通过双不对称离心，多肽可以被高度地结合到脂质体中。首先在大鼠身上进行的研究表明，与溶解药物相比，合并肽在大鼠体内的生物利用度显著提高(奥曲肽为26倍（分子量为1,17 kDa），人类生长激素为360倍（分子量为23,5 kDa）。该系统现在应该能够口服乙型肝炎病毒（HBV）治疗药物Myrcludex B。这种药物是从病毒的一种包膜蛋白中提取的，目前正处于2期临床试验。它表现出极端的嗜肝性，并在pricomolar浓度下抑制乙型和丁型肝炎感染。然而口服后的生物利用度为零。该肽将被纳入tel脂质体。因此，将研究载药量、脂质体大小、各种条件下的稳定性、释放特性以及适用于人类的制剂的开发。然后，将与Heidelberg教授Urban合作进行大鼠生物利用度研究以及啮齿动物肝炎模型（hbv阳性小鼠）的概念验证研究，以证明口服给药后脂质体肽系统的效率。

项目成果

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

• DOI: 10.1016/j.ejpb.2016.03.031
• 发表时间: 2016-06
• 期刊: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
• 作者: P. Uhl;F. Helm;G. Hofhaus;S. Brings;C. Kaufman;K. Leotta;S. Urban;U. Haberkorn;W. Mier