Fein Katherine C, Gleeson John P, Newby Alexandra N, Whitehead Kathryn A
Department of Chemical Engineering, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA 15213, United States.
Department of Chemical Engineering, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA 15213, United States; Department of Biomedical Engineering, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA 15213, United States.
Eur J Pharm Biopharm. 2022 Jan;170:70-76. doi: 10.1016/j.ejpb.2021.11.010. Epub 2021 Dec 5.
The decades-long effort to deliver peptide drugs orally has resulted in several clinically successful formulations. These formulations are enabled by the inclusion of permeation enhancers that facilitate the intestinal absorption of peptides. Thus far, these oral peptide drugs have been limited to peptides less than 5 kDa, and it is unclear whether there is an upper bound of protein size that can be delivered with permeation enhancers. In this work, we examined two permeation enhancers, 1-phenylpiperazine (PPZ) and sodium deoxycholate (SDC), for their ability to increase intestinal transport of a model macromolecule (FITC-Dextran) as a function of its size. Specifically, the permeability of dextrans with molecular weights of 4, 10, 40, and 70 kDa was assessed in an in vitro and in vivo model of the intestine. In Caco-2 monolayers, both PPZ and SDC significantly increased the permeability of only FD4 and FD10. However, in mice, PPZ and SDC behaved differently. While SDC improved the absorption of all tested sizes of dextrans, PPZ was effective only for FD4 and FD10. This work is the first report of PPZ as a permeation enhancer in vivo, and it highlights the ability of permeation enhancers to improve the absorption of macromolecules across a broad range of sizes relevant for protein drugs.
数十年来口服肽类药物的努力已产生了几种临床成功的制剂。这些制剂通过加入促进肽类肠道吸收的渗透促进剂得以实现。到目前为止，这些口服肽类药物仅限于小于5 kDa的肽，并且尚不清楚使用渗透促进剂递送的蛋白质大小是否存在上限。在这项工作中，我们研究了两种渗透促进剂，1-苯基哌嗪（PPZ）和脱氧胆酸钠（SDC），考察它们促进一种模型大分子（异硫氰酸荧光素标记的葡聚糖）肠道转运的能力与其大小的关系。具体而言，在肠道的体外和体内模型中评估了分子量为4、10、40和70 kDa的葡聚糖的渗透性。在Caco-2单层细胞中，PPZ和SDC均仅显著提高了FD4和FD10的渗透性。然而，在小鼠中，PPZ和SDC表现不同。虽然SDC改善了所有测试大小葡聚糖的吸收，但PPZ仅对FD4和FD10有效。这项工作是关于PPZ作为体内渗透促进剂的首次报道，它突出了渗透促进剂改善与蛋白质药物相关的广泛大小的大分子吸收的能力。
