Hate Siddhi S, Thompson Stephen A, Singaraju Aditya B
Synthetic Molecule Design and Development, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Division of Molecular Pharmaceutics and Drug Delivery, The University of Texas at Austin, Austin, TX 78712, USA.
J Pharm Sci. 2025 Jan;114(1):520-529. doi: 10.1016/j.xphs.2024.10.032. Epub 2024 Oct 30.
Developing a controlled release (CR) formulations is a complex and iterative process, often requiring preclinical or clinical studies to establish in vitro-in vivo correlations. This can be particularly challenging for poorly soluble drugs due to the non-sink conditions encountered in vitro. Although compendial dissolution methods (e.g., USP II, IV) have historically been used to understand the dissolution performance of CR formulations, there is increasing interest in more physiologically relevant experimental techniques to improve the predictive ability. In this study, traditional USP apparatus as well as the biorelevant absorptive dissolution apparatus were employed to understand the impact of apparatus type and sink condition on the release mechanisms of CR formulations and in turn evaluate the application of absorptive dissolution apparatus for dissolution testing of CR formulations. Release mechanisms were further analyzed using the Peppas equations, providing additional mechanistic insights. The release behavior showed a strong dependence on sink conditions for drugs with low intrinsic solubility, while highly soluble drugs were unaffected by dissolution conditions. Interestingly, the dissolution mechanism was found to be independent of the apparatus type. The study clearly underscores the importance of considering the sink conditions in developing more predictive and biorelevant dissolution testing methods for CR formulations. Furthermore, the study highlights the potential impact on the sink and resultant differences in the drug release mechanisms as a function of the dose.
开发控释（CR）制剂是一个复杂且反复的过程，通常需要进行临床前或临床研究以建立体外-体内相关性。对于难溶性药物而言，由于体外会遇到非漏槽条件，这可能极具挑战性。尽管药典溶出方法（如美国药典II法、IV法）一直以来被用于了解CR制剂的溶出性能，但人们对采用更具生理相关性的实验技术以提高预测能力的兴趣与日俱增。在本研究中，使用了传统的美国药典装置以及生物相关性吸收溶出装置，以了解装置类型和漏槽条件对CR制剂释放机制的影响，进而评估吸收溶出装置在CR制剂溶出度测试中的应用。使用Peppas方程进一步分析释放机制，提供了更多的机理见解。对于固有溶解度低的药物，释放行为对漏槽条件有很强的依赖性，而高溶解度药物不受溶出条件的影响。有趣的是，发现溶出机制与装置类型无关。该研究清楚地强调了在开发更具预测性和生物相关性的CR制剂溶出度测试方法时考虑漏槽条件的重要性。此外，该研究突出了漏槽条件的潜在影响以及药物释放机制因剂量而异的情况。
