Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Key Laboratory of New Material Research Institute, Department of Pharmaceutical Research Institute, Shandong University of Traditional Chinese Medicine, No. 4655, Daxue Road, Jinan 250355, China.
Int J Pharm. 2023 Apr 5;636:122863. doi: 10.1016/j.ijpharm.2023.122863. Epub 2023 Mar 18.
As low-temperature storage and transportation of peptides require high costs, improving the dosage form of peptides can reduce costs. We developed a thermostable and fast-releasing stratified dissolving microneedle (SDMN) system for delivering exenatide (EXT) to patients with type 2 diabetes. Among the tested polymers, dextran and polyvinyl alcohol (PVA) were the best at stabilizing EXT under high-temperature storage for 9 weeks. The two polymers possess a relatively high glass transition temperature (T) and weak hydrogen bonding between PVA and EXT. Additionally, zinc sulfate (ZnSO) had a stabilizing effect on EXT among the selected stabilizers, suggesting that EXT formed a dimer after coordination with zinc ions (Zn). In addition, the denaturation temperature (T) of EXT was increased by adding ZnSO, thus stabilizing EXT. Accordingly, SDMNs consisting of a tip layer (dextran encapsulating the Zn-EXT complex) and a base layer (PVA) were fabricated. Within 2 min of implantation, the EXT loaded on the patch was quickly released into the skin. Transdermal pharmacokinetics studies showed that manufactured SDMNs generated comparable efficacy to subcutaneous injection. Significantly, the remaining EXT amount was not significantly different under storage at 40 °C and -20 °C for 3 months, supporting that the SDMN system had excellent delivery efficiency and stability, thus reducing the dependence on the cold chain.
由于肽类的低温储存和运输成本较高，因此改善肽类的剂型可以降低成本。我们开发了一种热稳定且快速释放的分层溶解微针（SDMN）系统，用于向 2 型糖尿病患者递送艾塞那肽（EXT）。在测试的聚合物中，葡聚糖和聚乙烯醇（PVA）在高温储存 9 周的条件下最能稳定 EXT。这两种聚合物具有相对较高的玻璃化转变温度（T）和 PVA 与 EXT 之间较弱的氢键。此外，在所选择的稳定剂中，硫酸锌（ZnSO）对 EXT 具有稳定作用，表明 EXT 在与锌离子（Zn）配位后形成二聚体。此外，添加 ZnSO 会增加 EXT 的变性温度（T），从而稳定 EXT。因此，制备了由尖端层（包封 Zn-EXT 复合物的葡聚糖）和基底层（PVA）组成的 SDMN。在植入后 2 分钟内，贴剂上装载的 EXT 迅速释放到皮肤中。经皮药代动力学研究表明，所制 SDMN 产生的疗效与皮下注射相当。值得注意的是，在 40°C 和 -20°C 下储存 3 个月后，剩余的 EXT 量没有显著差异，这表明 SDMN 系统具有出色的递送效率和稳定性，从而降低了对冷链的依赖。
