College of Pharmacy, Keimyung University, Daegu, Republic of Korea; Center for Forensic Pharmaceutical Science, Keimyung University, Daegu, Republic of Korea.
College of Pharmacy, Keimyung University, Daegu, Republic of Korea.
J Control Release. 2021 Oct 10;338:644-661. doi: 10.1016/j.jconrel.2021.08.060. Epub 2021 Sep 2.
Despite many ongoing and innovative approaches, there are still formidable challenges in the clinical translation of oral peptide drugs into marketable products due to their low absorption and poor bioavailability. Herein, a novel nanocarrier platform was developed that employs a hydrophobic ion-pairing (HIP) of model peptide (insulin) and the anionic bile salt (sodium glycodeoxycholate, SGDC), and markedly improves intestinal absorption via the bile acid pathway. The developed HIP-nanocomplexes (C1 and C2) were optimized, characterized, and in vitro and in vivo evaluation were performed to assess oral efficacy of these system. The optimal molar ratios of C1 and C2-nanocomplexes were 30:1 and 6:1 (SGDC:insulin), respectively. Compared to the insulin solution, the C1 and C2 nanocomplexes significantly enhanced the permeation of insulin across the Caco-2 cell monolayers, with 6.36- and 4.05-fold increases in apparent permeability, respectively. Uptake mechanism studies were conducted using different endocytosis inhibitors and apical sodium-dependent bile acid transporter (ASBT)-transfected MDCK cells, which demonstrated the involvement of the energy-dependent ASBT-mediated active transport. Furthermore, the intrajejunal administration of C1 and C2 resulted in their pharmacological availabilities (PA) being 6.44% and 0.10%, respectively, indicating increased potential for C1, when compared to C2. Similarly, the PA and the relative bioavailability with intrajejunal administration of the C1 were 17.89-fold and 16.82-fold greater than those with intracolonic administration, respectively, confirming better jejunal absorption of C1. Overall, these findings indicate that the HIP-nanocomplexes could be a prominent platform for the effective delivery of peptides with improved intestinal absorption.
尽管有许多正在进行的创新方法，但由于口服肽类药物的吸收率低和生物利用度差，其向市场化产品的临床转化仍然面临巨大挑战。在此，开发了一种新型纳米载体平台，该平台采用模型肽（胰岛素）与阴离子胆汁盐（甘氨脱氧胆酸钠，SGDC）的疏水离子对（HIP），并通过胆汁酸途径显着提高肠道吸收。对开发的 HIP-纳米复合物（C1 和 C2）进行了优化、表征，并进行了体外和体内评估，以评估这些系统的口服疗效。C1 和 C2 纳米复合物的最佳摩尔比分别为 30:1 和 6:1（SGDC:胰岛素）。与胰岛素溶液相比，C1 和 C2 纳米复合物显着提高了胰岛素在 Caco-2 细胞单层中的渗透，表观渗透分别增加了 6.36 倍和 4.05 倍。使用不同的内吞抑制剂和顶端钠依赖性胆汁酸转运体（ASBT）转染的 MDCK 细胞进行了摄取机制研究，表明涉及能量依赖性 ASBT 介导的主动转运。此外，C1 和 C2 的空肠内给药导致其药代动力学可用性（PA）分别为 6.44%和 0.10%，表明与 C2 相比，C1 具有更大的潜力。同样，C1 的空肠内给药的 PA 和相对生物利用度分别比结肠内给药高 17.89 倍和 16.82 倍，证实了 C1 更好的空肠吸收。总之，这些发现表明，HIP-纳米复合物可能是提高肠道吸收的肽类有效传递的突出平台。
