Office of Pharmaceutical Quality Research, CDER, U.S. FDA, 10903 New Hampshire Avenue, WO64-Rm1032, Silver Spring, MD, 20993, USA.
Division of Bioequivalence III, Office of Bioequivalence, Office of Generic Drugs, CDER, U.S. FDA, Silver Spring, MD, USA.
AAPS PharmSciTech. 2024 Aug 13;25(6):186. doi: 10.1208/s12249-024-02887-7.
Winlevi (clascoterone) topical cream (1%, w/w) was approved by the U.S. FDA for the treatment of acne vulgaris in patients 12 years of age and older. The active ingredient, clascoterone, is not stable in physiological solutions and can hydrolyze to cortexolone at body temperature. Instability of clascoterone poses a significant challenge in accurately assessing the rate and extent of clascoterone permeation in vitro. Therefore, the purpose of this study was to develop an in vitro skin permeation test (IVPT) method, and a robust analytical method, that can minimize hydrolyzation of clascoterone during the study for quantification of clascoterone. Two IVPT methods, using either vertical diffusion cells or flow-through cells, were developed and compared to evaluate in vitro permeation of clascoterone from Winlevi. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed to monitor the level of clascoterone and cortexolone in the IVPT samples. The analytical method features a 2-min high-throughput analysis with good linearity, selectivity, and showed a lower limit of quantitation (LLOQ) of 0.5 ng/mL for both clascoterone and cortexolone. The in vitro skin permeation of clascoterone and cortexolone was observed as early as 2 h in both IVPT methods. A substantive amount of clascoterone was found to hydrolyze to cortexolone when using the vertical static diffusion cells with aliquot sampling. Conversely, degradation of clascoterone was significantly minimized when using the flow-through diffusion cells with fractional sampling. The data enhanced our understanding of in vitro permeation of clascoterone following topical application of the Winlevi topical cream, 1% and underscores the importance of IVPT method development and optimization during product development.
Winlevi（clascoterone）乳膏（1%，w/w）获美国 FDA 批准用于治疗 12 岁及以上痤疮患者。活性成分 clascoterone 在生理溶液中不稳定，可在体温下水解为皮质酮。clascoterone 的不稳定性给准确评估体外 clascoterone 渗透的速率和程度带来了重大挑战。因此，本研究旨在开发一种体外皮肤渗透测试（IVPT）方法和一种强大的分析方法，以最大限度地减少研究过程中 clascoterone 的水解，从而对 clascoterone 进行定量分析。建立了两种 IVPT 方法，分别使用垂直扩散池或流动池，以评估 Winlevi 中 clascoterone 的体外渗透。建立了液相色谱-串联质谱（LC-MS/MS）方法来监测 IVPT 样品中 clascoterone 和皮质酮的水平。该分析方法具有 2 分钟的高通量分析，具有良好的线性、选择性，对于 clascoterone 和皮质酮的定量下限（LLOQ）均为 0.5ng/mL。两种 IVPT 方法均可在 2 小时内观察到 clascoterone 和皮质酮的体外皮肤渗透。当使用等分采样的垂直静态扩散池时，发现大量的 clascoterone 会水解为皮质酮。相反，当使用分数采样的流动扩散池时，clascoterone 的降解显著减少。这些数据增强了我们对 Winlevi 乳膏 1%外用后 clascoterone 体外渗透的理解，强调了在产品开发过程中 IVPT 方法开发和优化的重要性。
