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使用PBPK模型开发和评估瑞卢的无形固体分散,以模拟药理动力学特征

Kanchan Bharti¹, Deepika Deepika^2,3, Manish Kumar¹

¹Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India.

AAPS PharmSciTech

|October 27, 2023

概括

这项研究使用聚烯酸 (PAA) 开发了瑞卢 (RLZ) 的稳定无形固体分散 (ASD). RLZ:PAA ASD显著增强了药物溶解,并改善了大鼠的药物动力学概况,并预测了人类的暴露.

科学领域:

制药科学制药科学
药物输送系统药物输送系统
药理动力学药理动力学

背景情况:

像瑞卢 (RLZ) 这样的水溶性较差的药物通常具有有限的生物可用性.
无形固体分散 (ASD) 是一种有前途的策略,可以提高这种药物的可溶性和溶解性.
确定适合ASD配方的聚合物对于药物的性能至关重要.

研究的目的:

选聚合物开发一个稳定的无形固体分散 (ASD) 的riluzole (RLZ).
评估优化的RLZ ASD配方的体外和体内性能.
开发和验证一种基于生理学的药理动力学 (PBPK) 模型,用于预测大鼠和人类的药物暴露.

主要方法:

聚合物选 (聚烯酸,聚烯酸烯酸乙烯酸,基甲基纤维素酸) 基于药物-聚合物相互作用和湿.
无形固体分散的固态特征.
在实验室溶解研究和在老鼠体内药理动力学研究.
从大鼠到人类的生理学基础药理动力学 (PBPK) 模型的开发和推断.

主要成果:

聚烯酸 (PAA) 证明了最佳的药物聚合物相互作用和湿性质,导致稳定的RLZ ASD.
与市场上销售的产品相比,RLZ:PAA ASD显著提高了和溶解度和溶解率.
在老鼠体内研究显示,ASD配方的血和大脑中Cmax和AUC增加.
PBPK模型准确地预测了老鼠和人类的RLZ暴露,模拟的Cmax和AUC是实验数据的两倍之内.
预测的人类数据表明ASD的脑Cmax和AUC增强,表明治疗潜力有所改善.

结论:

聚烯酸是一种有效的聚合物,可以创建稳定的无形固体分散的riluzole.
开发的RLZ:PAA ASD显著改善了Riluzole的生物制药性能.
PBPK建模为预测药物暴露和优化不同物种中ASD的剂量方案提供了宝贵的工具.
这些发现表明,RLZ ASD有潜力提高治疗效果,因为大脑的传递得到了改善.

关键词:

无形固体分散的无形固体分散溶解溶解是一种肝毒性肝毒性肝毒性基于生理学的药物动力学模型.瑞卢 (riluzole) 是一种药物.

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