School of Pharmaceutical Sciences, Guangzhou Higher Education Mega Center, Sun Yat-sen University, No. 132, Waihuan East Road, 510006, Guangzhou, People's Republic of China.
College of Pharmacy, University of Texas at Austin, 2409 West University Avenue, PHR 1.108, Austin, Texas, 78712, USA.
AAPS PharmSciTech. 2018 Aug;19(6):2499-2508. doi: 10.1208/s12249-018-1026-z. Epub 2018 Jun 11.
The dispersibility and stability issues of peptide drugs during preparation and storage hinder the widespread adoption of pressurized metered-dose inhaler (pMDI). This study aimed to develop a reverse microemulsion (RM) of exenatide (EXE) pMDI through a liquid-based bottom-up method, thus to overcome the stability issue of peptide drugs encountered in traditional top-down methods, such as milling down and high-pressure homogenization. In this study, Pluronic® L64 (L64) was chosen as a surfactant to prepare the EXE-RM pMDI formulations with the assistance of ethanol. The results showed RM possessed a particle size of 123.80 ± 2.91 nm with 0.121 ± 0.024 PdI and a satisfied fine-particle fraction of 41.30 ± 3.73% measured by a next-generation impactor. In addition, the dispersion stability of RM pMDI was maintained after storage at 4 °C for 50 days. The secondary structure of EXE was maintained during the preparation process. Moreover, the results indicated that L64 was compatible with cells and could improve the penetration of EXE through cell monolayers. Through the liquid-based bottom-up method, EXE-RM pMDI was successfully prepared and exhibited favorable stability and aerodynamic performance. This study offers a preparation strategy to enhance the stability of peptides in pMDIs.
肽类药物在制备和储存过程中的分散性和稳定性问题阻碍了其在加压定量吸入器（pMDI）中的广泛应用。本研究旨在通过基于液体的自下而上的方法开发一种艾塞那肽（EXE）pMDI 的反胶束（RM），从而克服传统自上而下方法（如研磨和高压匀浆）中遇到的肽类药物稳定性问题。在本研究中，选择 Pluronic® L64（L64）作为表面活性剂，在乙醇的辅助下制备 EXE-RM pMDI 制剂。结果表明，RM 的粒径为 123.80±2.91nm，多分散指数（PdI）为 0.121±0.024，下一代撞击器测量的细颗粒分数为 41.30±3.73%。此外，RM pMDI 在 4°C 储存 50 天后仍能保持分散稳定性。EXE 的二级结构在制备过程中得以保持。此外，结果表明 L64 与细胞相容，并能提高 EXE 通过细胞单层的渗透。通过基于液体的自下而上的方法，成功制备了 EXE-RM pMDI，表现出良好的稳定性和空气动力学性能。本研究为提高 pMDI 中肽类药物的稳定性提供了一种制备策略。
