Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Int J Pharm. 2020 Jun 30;584:119469. doi: 10.1016/j.ijpharm.2020.119469. Epub 2020 May 26.
Non-injectable delivery of peptides and proteins is not feasible due to the limitations of large molecular mass, high hydrophilic properties, and gastrointestinal degradation. Therefore, proposing a new method to solve this problem is a burning issue. The objective of this study was to propose a novel protein delivery strategy to overcome the poor efficacy and irritation of buccal insulin delivery. In this study, we applied a conjugate of cell-penetrating peptides (LMWP) and insulin (INS-PEG-LMWP) for buccal delivery. INS-PEG-LMWP was prepared using insulin solution and mixture as references. The transport behaviour, in vivo bioactivity, hypoglycaemic effect, and safety of INS-PEG-LMWP were systematically characterised. An in vitro study demonstrated that the uptake and transportation of INS-PEG-LMWP across buccal mucosal multilayers significantly increased. By comparing the effects of different endocytic inhibitors on INS-PEG-LMWP uptake, the conjugate might be delivered via an energy independent, electrostatically adsorbed pathway. INS-PEG-LMWP's relative pharmacological bioavailability was high and its relative bioavailability was up to 26.86%, demonstrating no visible mucosal irritation. Cell-penetrating peptides are likely to become a reliable and safe tool for overcoming insulin's low permeability through the epithelial multilayers, the major barrier to buccal delivery.
由于大分子量、高亲水性和胃肠道降解等限制，非注射性肽和蛋白质给药是不可行的。因此，提出一种新的方法来解决这个问题是当务之急。本研究旨在提出一种新的蛋白质递药策略，以克服口腔胰岛素传递的疗效差和刺激性问题。在本研究中，我们应用了穿透肽（LMWP）和胰岛素（INS-PEG-LMWP）的缀合物用于口腔给药。INS-PEG-LMWP 是使用胰岛素溶液和混合物作为参考制备的。系统地研究了 INS-PEG-LMWP 的转运行为、体内生物活性、降血糖作用和安全性。体外研究表明，INS-PEG-LMWP 穿过口腔黏膜多层的摄取和转运显著增加。通过比较不同内吞抑制剂对 INS-PEG-LMWP 摄取的影响，该缀合物可能通过能量非依赖性、静电吸附途径进行传递。INS-PEG-LMWP 的相对药效生物利用度较高，其相对生物利用度高达 26.86%，没有明显的黏膜刺激性。穿透肽有可能成为一种可靠和安全的工具，用于克服胰岛素通过上皮多层的低渗透性，这是口腔传递的主要障碍。
