评估药物负载和聚合物类型对GDC-6893无形固体分散物的溶解行为和扩散流的影响
Nivedita Shetty1, Jonathan Hau1, Shijia Tang1
1Department of Synthetic Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Journal of pharmaceutical sciences
|January 29, 2025
概括
开发高药载无形固体分散 (ASD) 是一个挑战. 这项研究表明,使用HPMCAS或PVPVA聚合物的ASD保持物理稳定性并增强药物吸收,无论药物负载如何,促进合理的配方设计.
科学领域:
- 制药科学 制药科学
- 材料科学 材料科学 材料科学
背景情况:
- 开发高药载无形固体分散剂 (ASD) 对于改善药物的生物可用性至关重要,但在维持质量和性能方面面临挑战.
- 无形固体分散 (ASDs) 是一种有前途的策略,可以提高难溶性药物的可溶性和生物利用性.
研究的目的:
- 研究药物载荷 (DL) 和聚合物类型对GDC-6893 ASDs溶解,扩散流和体外药物吸收的影响.
- 为了评估与HPMCAS和PVPVA聚合物配制的ASD在各种药物负载下混合性,物理稳定性和生物性能.
主要方法:
- 使用喷雾干燥,使用HPMCAS和PVPVA聚合物生产具有不同DL (20-80%) 的ASD.
- 固态核磁共振 (ssNMR) 评估了药物-聚合物混合性.
- μFLUXTM 仪器评估了溶解和药物膜传输.
- 高性能液体色谱 (HPLC) 使用充电的气溶探测器 (CAD) 监控聚合物释放.
- 在体外生物可访问性 (%BioA) 评估的Tiny-TIM模拟胃肠道过境.
主要成果:
- ASDs表现出良好的混合性和物理稳定性,即使在80%的DL,与HPMCAS和PVPVA.
- 所有GDC-6893ASD显示溶解超过无形溶解度 (20μg/mL),无论DL或聚合物.
- 发生了玻璃液相分离 (GLPS),导致纳米化体物种的形成和最大的扩散流量.
- 与晶体GDC-6893相比,Tiny-TIM显示了ASD的改善%BioA,DL或聚合物类型没有显著影响.
结论:
- 高药载ASD (高达80%) 可以通过HPMCAS和PVPVA成功开发,保持物理稳定性并增强溶解.
- 从ASD中迅速溶解药物和聚合物,其次是GLPS,有助于改善体外药物吸收.
- 了解药物聚合物相互作用,溶解行为和体外吸收是合理的ASD配方设计的关键.
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