Walenga Ross L, Babiskin Andrew H, Boyce Heather J, Feng Xin, Zidan Ahmed, Kamal Nahid S, Xu Xiaoming, Kim Myong-Jin, Zhao Liang
Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
J Control Release. 2025 Feb 10;378:982-996. doi: 10.1016/j.jconrel.2024.12.049. Epub 2025 Jan 2.
Oxycodone hydrochloride (HCl) extended release (ER) tablet is an abuse-deterrent formulation that uses a physical barrier to make it more difficult to crush tablets prior to abuse via various routes. A previously conducted in vivo pharmacokinetics (PK) study showed that particle size exhibited significant effects on PK. Here, a computational modeling study using a novel combined computational fluid dynamics and physiologically based PK model was applied to better understand the mechanisms that produce differences in PK according to particle size and formulation type for nasally insufflated oxycodone HCl immediate release (IR) and ER tablets. Dissolution data were collected using a United States Pharmacopeia (USP) Apparatus 4 to support model parameterization. The in vitro dissolution data showed that the number of powder layers in the bead-based system impacted the observed dissolution pattern for the finely milled (106-500 μm) ER formulations, but not the finely milled IR (106-500 μm) or coarsely milled ER (500-1000 μm) formulations. The model was validated via comparison of PK predictions with available in vivo PK data for finely milled (106-500 μm) IR and ER formulations in the 30 mg strength, a coarsely milled (500-1000 μm) ER formulation in the 30 mg strength, and a finely milled ER formulation in the 80 mg strength. Model predictions showed relative differences no greater than 3.3 % for maximum plasma concentration (C) and 14.9 % for area under the plasma concentration time curve from time zero to the last time point, as well as absolute differences no greater than 0.8 h for time to C. The residence time in the nasal cavity was predicted to be 1 h for finely milled ER formulations as compared with approximately 20 min for the finely milled IR and coarsely milled ER formulations. When differences in dissolution input data were considered, there were noticeable changes in PK predictions observed for the finely milled ER formulations, according to the different number of powder layers in the USP Apparatus 4. Overall, the results of this study suggest that biopredictive in vitro characterization of abuse deterrence via the nasal route for an oxycodone HCl ER tablet drug product may include methods to characterize dissolution and impacts of formulation on residence time in the nasal cavity.
盐酸羟考酮缓释片是一种具有抗滥用设计的制剂，它采用物理屏障，使得通过各种途径滥用前更难碾碎片剂。之前进行的一项体内药代动力学（PK）研究表明，粒径对药代动力学有显著影响。在此，应用一项使用新型计算流体动力学和基于生理学的PK模型相结合的计算建模研究，以更好地理解对于经鼻吸入的盐酸羟考酮速释（IR）片和缓释片，根据粒径和制剂类型产生药代动力学差异的机制。使用美国药典（USP）装置4收集溶出数据以支持模型参数化。体外溶出数据表明，基于微丸的系统中粉末层的数量影响了细磨（106 - 500μm）缓释制剂的观察到的溶出模式，但不影响细磨（106 - 500μm）速释制剂或粗磨（500 - 1000μm）缓释制剂。通过将PK预测与30mg规格的细磨（106 - 500μm）IR和缓释制剂、30mg规格的粗磨（500 - 1000μm）缓释制剂以及80mg规格的细磨缓释制剂的现有体内PK数据进行比较，对模型进行了验证。模型预测显示，最大血浆浓度（Cmax）的相对差异不超过3.3%，从时间零至最后时间点的血浆浓度 - 时间曲线下面积的相对差异不超过14.9%，达峰时间（tmax）的绝对差异不超过0.8小时。预测细磨缓释制剂在鼻腔中的停留时间为1小时，而细磨速释制剂和粗磨缓释制剂约为20分钟。当考虑溶出输入数据的差异时，根据USP装置4中不同的粉末层数，观察到细磨缓释制剂的PK预测有明显变化。总体而言，本研究结果表明，对于盐酸羟考酮缓释片药物产品，通过鼻腔途径进行抗滥用的生物预测性体外表征可能包括表征溶出以及制剂对鼻腔停留时间影响的方法。
