Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkey.
Department of Pharmaceutical Technology, Faculty of Pharmacy, Erciyes University, 38238, Kayseri, Turkey.
Amino Acids. 2021 Jan;53(1):73-88. doi: 10.1007/s00726-020-02926-0. Epub 2021 Jan 4.
The objective of this study was to prepare a stable self-nanoemulsifying formulation of exendin-4, which is an antidiabetic peptide. As exendin-4 is commercially available only in subcutaneous form, several attempts have been made to discover an effective oral formulation. Self-nanoemulsifying drug delivery systems are known to be suitable carriers for the oral administration of peptide drugs. Various ratios of oil, surfactant, and co-surfactant mixtures were used to determine the area in the pseudoternary phase diagram for clear nanoemulsion. The Design of Experiment approach was used for the optimization of the formulation. Blank self-nanoemulsifying formulations containing ethyl oleate as oil phase, Cremophor EL, and Labrasol as surfactant, absolute ethanol, and propylene glycol as co-solvent in various proportions were approximately 18-50 nm, 0.08-0.204 and - 3 to - 23 mV in droplet size, polydispersity index, and zeta potential, respectively. When all formulations were compared by statistical analysis, five of them with smaller droplet sizes were selected for further studies. The physical stability test was performed for 1 month at 5 °C ± 3 °C and 25 °C ± 2 °C/60% RH ± 5% RH storage conditions. As a result of the characterization and physical stability test results, ethyl oleate: Cremophor EL:absolute ethanol (30:52.5:17.5) formulation and four formulations containing ethyl oleate: Cremophor EL:Labrasol:propylene glycol:absolute ethanol at varying concentrations were considered for peptide encapsulation efficiency. Formulation having the highest encapsulation efficiency of exendin-4 containing ethyl oleate: Cremophor EL:Labrasol:propylene glycole:absolute ethanol (15:42.5:21.25:15.94:5.31) was selected for in vitro Caco-2 intestinal permeability study. The permeabiliy coefficient was increased by 1.5-folds by exendin-4-loaded self-nanoemulsifying formulation as compared to the exendin-4 solution. It can be concluded that intestinal permeability has been improved by self-nanoemulsifying formulation.
本研究的目的是制备一种稳定的艾塞那肽自微乳制剂，艾塞那肽是一种抗糖尿病肽。由于艾塞那肽仅以皮下注射的形式在商业上可用，因此已经进行了多次尝试以发现有效的口服制剂。自微乳给药系统被认为是肽类药物口服给药的合适载体。使用各种油、表面活性剂和助表面活性剂混合物的比例来确定伪三元相图中用于形成澄清微乳的区域。采用实验设计方法对制剂进行优化。空白自微乳制剂含有油相乙基油酸、表面活性剂 Cremophor EL 和 Labrasol、不同比例的绝对乙醇和丙二醇作为助溶剂，其粒径约为 18-50nm，粒径、多分散指数和 Zeta 电位分别为 0.08-0.204mV 和-3 至-23mV。通过统计分析比较所有制剂后，选择了五个粒径较小的制剂进行进一步研究。在 5°C±3°C 和 25°C±2°C/60%RH±5%RH 储存条件下进行了 1 个月的物理稳定性测试。根据表征和物理稳定性测试结果，选择了乙基油酸：Cremophor EL：绝对乙醇（30:52.5:17.5）制剂和四种含有乙基油酸：Cremophor EL：Labrasol：丙二醇：绝对乙醇的制剂，浓度不同，用于包封效率的肽。考虑到艾塞那肽的包封效率最高，含有乙基油酸：Cremophor EL：Labrasol：丙二醇：绝对乙醇（15:42.5:21.25:15.94:5.31）的制剂被选择用于体外 Caco-2 肠通透性研究。与艾塞那肽溶液相比，载有艾塞那肽的自微乳制剂的渗透系数增加了 1.5 倍。可以得出结论，自微乳制剂改善了肠道通透性。
