Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Campus Vida, 15782, Santiago de Compostela, Spain.
Department of Pharmaceutics and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, Campus Vida, 15782, Santiago de Compostela, Spain.
Drug Deliv Transl Res. 2021 Apr;11(2):524-545. doi: 10.1007/s13346-021-00920-x. Epub 2021 Feb 11.
The potential of nanoemulsions for the oral administration of peptides is still in its early stage. The aim of the present work was to rationally design, develop, and fully characterize a new nanoemulsion (NE) intended for the oral administration of hydrophobically modified insulin (HM-insulin). Specific components of the NE were selected based on their enhancing permeation properties as well as their ability to improve insulin association efficiency (Miglyol 812, sodium taurocholate), stability in the intestinal fluids, and mucodiffusion (PEGylated phospholipids and poloxamer 407). The results showed that the NE co-existed with a population of micelles, forming a mixed system that exhibited a 100% of HM-insulin association efficiency. The nanosystem showed good stability and miscibility in different bio-relevant media and displayed an acceptable mucodiffusive behavior in porcine mucus. In addition, it exhibited a high interaction with cell mono-cultures (Caco -2 and C2BBe1 human colon carcinoma Caco-2 clone cells) and co-cultures (C2BBe1 human colon carcinoma Caco-2 clone/HT29-MTX cells). The internalization in Caco-2 monolayers was also confirmed by confocal microscopy. Finally, the promising in vitro behavior of the nanosystem in terms of overcoming the biological barriers of the intestinal tract was translated into a moderate, although significant, hypoglycemic response (≈ 20-30%), following intestinal administration to both healthy and diabetic rat models. Overall, this information underlines the crucial steps to address when designing peptide-based nanoformulations to successfully overcome the intestinal barriers associated to the oral modality of administration.
纳米乳剂在肽类口服给药中的应用潜力仍处于初级阶段。本工作的目的是合理设计、开发和全面表征一种新型纳米乳剂（NE），用于口服给予疏水性修饰胰岛素（HM-insulin）。根据其增强渗透性能以及提高胰岛素结合效率的能力（Migl yol 812、牛磺胆酸钠）、在肠液中的稳定性和黏膜扩散性（PEG 化磷脂和泊洛沙姆 407）选择 NE 的特定成分。结果表明，NE 与胶束共存，形成混合体系，表现出 100%的 HM-insulin 结合效率。纳米系统在不同的生物相关介质中表现出良好的稳定性和混溶性，并在猪黏液中表现出可接受的黏膜扩散行为。此外，它与细胞单层（Caco-2 和 C2BBe1 人结肠癌细胞 Caco-2 克隆细胞）和共培养物（C2BBe1 人结肠癌细胞 Caco-2 克隆/HT29-MTX 细胞）表现出高相互作用。通过共聚焦显微镜也证实了在 Caco-2 单层中的内化。最后，纳米系统在克服肠道生物学屏障方面具有有希望的体外行为，这转化为适度但显著的降血糖反应（≈20-30%），在健康和糖尿病大鼠模型中经肠道给药后观察到。总的来说，这些信息强调了在设计基于肽的纳米制剂时需要解决的关键步骤，以成功克服与口服给药方式相关的肠道屏障。
