Zhou Deliang, Law Devalina, Reynolds Judie, Davis Lynn, Smith Clifford, Torres Jose L, Dave Viraj, Gopinathan Nishanth, Hernandez Daniel T, Springman Mary Kay, Zhou Casey Chun
AbbVie Inc, North Chicago, Illinois, 60064.
J Pharm Sci. 2014 Jun;103(6):1664-72. doi: 10.1002/jps.23953. Epub 2014 Mar 20.
The purpose of this study is to identify critical physicochemical properties of hydroxypxropyl methylcellulose (HPMC) that impact the dissolution of a controlled release tablet and develop a strategy to mitigate the HPMC lot-to-lot and vendor-to-vendor variability. A screening experiment was performed to evaluate the impacts of methoxy/hydroxypropyl substitutions, and viscosity on drug release. The chemical diversity of HPMC was explored by nuclear magnetic resonance (NMR), and the erosion rate of HPMC was investigated using various dissolution apparatuses. Statistical evaluation suggested that the hydroxypropyl content was the primary factor impacting the drug release. However, the statistical model prediction was not robust. NMR experiments suggested the existence of structural diversity of HPMC between lots and more significantly between vendors. Review of drug release from hydrophilic matrices indicated that erosion is a key aspect for both poorly soluble and soluble drugs. An erosion rate method was then developed, which enabled the establishment of a robust model and a meaningful HPMC specification. The study revealed that the overall substitution level is not the unique parameter that dictates its release-controlling properties. Fundamental principles of polymer chemistry and dissolution mechanisms are important in the development and manufacturing of hydrophilic matrices with consistent dissolution performance.
本研究的目的是确定影响控释片溶出度的羟丙基甲基纤维素(HPMC)的关键物理化学性质,并制定一项策略来减轻HPMC批次间和供应商间的差异。进行了一项筛选实验,以评估甲氧基/羟丙基取代度和粘度对药物释放的影响。通过核磁共振(NMR)探索了HPMC的化学多样性,并使用各种溶出装置研究了HPMC的侵蚀速率。统计评估表明,羟丙基含量是影响药物释放的主要因素。然而,统计模型预测并不稳健。NMR实验表明,批次间以及供应商间的HPMC存在结构多样性。对亲水性基质药物释放的综述表明,侵蚀是难溶性药物和可溶性药物的关键方面。随后开发了一种侵蚀速率方法,该方法能够建立一个稳健的模型和有意义的HPMC规格。该研究表明,总体取代水平不是决定其控释性能的唯一参数。高分子化学的基本原理和溶解机制在开发和制造具有一致溶出性能的亲水性基质中很重要。