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

肽/蛋白质的口服递送由于在胃肠道（GI-道）中的不稳定性和低吸收而通常失败。在这个项目中，我们将研究一个脂质体载体系统包含四醚脂质（TELs）从兰科植物。初步研究表明，与常规脂质体相比，这种脂质体在胃肠道中的稳定性大大增加。通过双重不对称离心，肽可以很高程度地掺入这些脂质体中。在大鼠中的第一项研究显示，与溶解的药物相比，掺入的肽在大鼠中的生物利用度显著增加（奥曲肽（MW 1.17 kDa）为26倍，人生长激素MW约23.5 kDa为约360倍）。该系统现在应该能够口服施用治疗B型肝炎病毒（HBV）的Myrcludex B。这种药物正处于第二阶段的临床试验中，它是从病毒的一种包膜蛋白中提取的。它表现出极端的嗜肝性，并在一摩尔浓度下抑制B和D型肝炎感染。然而，口服给药后的生物利用度为零。 该肽将被掺入到TEL-脂质体中。因此，将研究负载能力、脂质体大小、在各种条件下的稳定性、释放性质和适用于人类的制剂的开发。然后，将与Urban教授（海德堡）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）概念验证研究，以证明该脂质体肽系统经口给药后的有效性。

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.