State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China; Key Laboratory of Biopharmaceutical Preparation and Delivery, Chinese Academy of Sciences, Beijing 100190, PR China; University of the Chinese Academy of Sciences, Beijing 100049, PR China.
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China; Key Laboratory of Biopharmaceutical Preparation and Delivery, Chinese Academy of Sciences, Beijing 100190, PR China.
J Control Release. 2024 Nov;375:745-757. doi: 10.1016/j.jconrel.2024.09.043. Epub 2024 Oct 1.
Sustained release microspheres loaded with goserelin are regarded as a promising candidate for treating prostate cancer and other sex hormone diseases. However, their widespread adoption has been hindered by issues such as wide particle size distribution and unstable release characteristics. To address these challenges, we employed a combination of the solid-in-oil-in-water microspheres preparation approach (S/O/W) and innovative premix membrane emulsification technology and deeply investigated the effects of four key parameters on the loaded performance of microspheres and the microscopic mechanisms behind them. With this approach, we successfully produced goserelin-loaded sustained release microspheres of narrow particle size distribution (Span 0.642), remarkable encapsulation efficiency (DL = 4.23 %, EE = 93.98 %), low initial burst release (about 0.50 % within 2 h), and compatibility with small injection needles (23-G, inner diameter 0.33 mm, outer diameter 0.64 mm, maximal force 59 N). In the animal model(administered dose, 2.4 mg·Kg), goserelin long-acting sustained release microspheres sustained release for over 32 days, maintaining effective concentrations above 2 ng·mL, and effectively reduced serum testosterone concentrations to castration levels (<1.0 ng·mL) by day 4, maintaining this inhibition for up to 21 days, exhibiting comparable efficacy to the positive control group. In vivo release kinetics analysis revealed that goserelin-loaded sustained release microspheres exhibited a release pattern dominated by diffusion with corrosion assistance in vivo. In summary, the systematic and comprehensive evaluation of uniform-sized goserelin-loaded sustained release microspheres has highlighted their excellent translational potential, and the study herein may provide new strategies and ideas for the development of microsphere dosage forms.
载有戈舍瑞林的缓释微球被认为是治疗前列腺癌和其他性激素疾病的有前途的候选药物。然而，其广泛应用受到粒径分布较宽和释放特性不稳定等问题的阻碍。为了解决这些挑战，我们采用了固体油包水微球制备方法（S/O/W）和创新的预混膜乳化技术相结合的方法，并深入研究了四个关键参数对微球载药性能的影响及其背后的微观机制。通过这种方法，我们成功地制备了粒径分布较窄（Span 0.642）、包封效率高（DL=4.23%，EE=93.98%）、初始突释率低（约 0.50%在 2 小时内）、与小注射针兼容（23-G，内径 0.33mm，外径 0.64mm，最大力 59N）的载有戈舍瑞林的缓释微球。在动物模型（给药剂量 2.4mg·kg）中，戈舍瑞林长效缓释微球持续释放超过 32 天，有效浓度保持在 2ng·mL 以上，并且在第 4 天有效地将血清睾酮浓度降低至去势水平（<1.0ng·mL），持续抑制长达 21 天，与阳性对照组的疗效相当。体内释放动力学分析表明，载有戈舍瑞林的缓释微球在体内表现出以扩散为主、腐蚀为辅的释放模式。综上所述，对均匀粒径载有戈舍瑞林的缓释微球的系统全面评价突出了其优异的转化潜力，本研究可能为微球剂型的开发提供新的策略和思路。
