他扎罗汀凝胶体外释放度方法开发和释放行为差异分析

Development of an in vitro release method for tazarotene gel and analysis of release behavior differences

摘要

目的: 建立流通池法测定他扎罗汀凝胶释放度,并分析体外释放行为与微观结构特性的相关性。方法: 采用流通池闭环系统,分别考察释放介质、表面活性剂浓度、流速、滤膜孔径、液流类型对他扎罗汀体外释放曲线的影响,并比较市售仿制药与原研产品释放行为的差异;采用激光共聚焦显微拉曼成像仪无损表征仿制药与原研产品中活性药物成分 (active pharmaceutical ingredient,API) 晶型、粒度等微观结构,并分析影响本品体外释放行为差异的关键质量特性。结果: 以含 0.5% 十二烷基硫酸钠的 0.9% 氯化钠溶液为释放介质,温度为 (32±0.5) °C,流速为 8mL⋅min^-1,滤膜孔径为 100μm,可获得既能有效释放又具有一定区分力的释放曲线。国产仿制药中 API 晶型与原研进口产品一致,但仿制药中未溶解的颗粒数量 (54粒∙mm^-2) 明显大于原研产品 (颗粒数量为 25 粒∙mm^-2),导致两者体外释放曲线存在显著差异。结论: 微观结构特性反映处方中关键辅料助溶剂种类的不同,可能影响本品体外释放特性,建议国内生产企业尽快优化处方工艺,提升产品质量。

Abstract

Objective: To establish a flow-through cell method for determining the dissolution of tazarotene gel and analyze the correlation between its in vitro release behavior and microscopic characteristics. Methods: A closed-loop flow-through cell system was employed to systematically investigate the effects of release medium composition, surfactant concentration, flow rate, filter membrane pore size, and fluid flow pattern on the in vitro release profile of tazarotene, while comparing the release behavior differences between commercial generic and originator products.Additionally, confocal laser micro-Raman imaging was utilized for non-destructive characterization of critical microstructure parameters including API polymorphic form and particle size distribution in both formulations, followed by analysis of key quality attributes contributing to the observed in vitro release performance disparities. Results: The dissolution curve with a suitable degree of distinction can be obtained by using 0.9% sodium chloride solution containing 0.5％sodium dodecyl sulfate as dissolution medium, at (32±0.5) °C with a flow rate of 8 mL⋅min^-1 and a 100μm filter membrane.Although the polymorphic form of the active pharmaceutical ingredient (API) in generic formulations was consistent with that of the originator product, the undissolved particle counts (54 particles ⋅ mm^-2) in the generic drugs was significantly higher compared to the originator product (25 particles ⋅ mm^-2), resulting in statistically significant differences in their in vitro release profiles. Conclusion: The microstructural characteristics reflect differences in the types of key solubilizing agents used as excipients in the formulation, which may influence the in vitro release properties of the product.It is recommended that domestic manufacturers promptly optimize formulation processes and improve product quality.

关键词

他扎罗汀凝胶 / 流通池法 / 体外释放 / 微观结构特性 / 助溶剂

Key words

tazarotene gel / flow-through cell method / in vitro release / microstructural characteristics / solubilizers

[1] 国家药典委员会.中华人民共和国药典[S].2025年版.二部.北京:中国医药科技出版社,2025:281-282.
[2] 刘盼盼,邹玉娇,陈星,等.他扎罗汀凝胶对小鼠深部组织损伤的改善作用[J].现代药物与临床,2019,34 (6):1605-1609.
[3] SHAH VP,YACOBI A,RĂDULESCU FŞ,et al.A science based approach to topical drug classification system (TCS)[J].Int J Pharm,2015,491 (1-2):21-25.
[4] 国家药品监督管理局药品审评中心.皮肤外用化学仿制药研究技术指导原则 (试行)[EB/OL].(2023—03—06).https://www.cde.org.cn/main/news/viewInfoCommon/4e790f4ad1cb21091e5a8bf4a107c535.
[5] 沈丹丹,吴群,姜学美,等.他扎罗汀凝胶处方及微观结构特性评价的比较研究5] 沈丹丹,吴群,姜学美,等.他扎罗汀凝胶处方及微观结构特性评价的比较研究[J].中国抗生素杂志,2024,49 (10): 1155-1161.
[6] 国家药品监督管理局药品审评中心.局部起效化学仿制药体外释放 (IVRT) 与体外透皮 (IVPT) 研究技术指导原则 (征求意见稿)[EB/OL].(2025-05-29).https://www.cde.org.cn/main/news/viewInfoCommon/114aa83096de4873146fc035b0f6f747.
[7] 张春晓,彭玉帅,许卉,等.流池法的研究进展及应用[J].药物分析杂志,2021,41 (2):195-202.
[8] 周畅,方瑜,杜青,等.流通池法在药物制剂中的应用进展[J].中国药学杂志,2021,56 (21):1706-1711.
[9] 刘曦,王亚敏,潘阿慧,等.流通池法考察双氯芬酸钠缓释片的体外释放特性[J].中国药学杂志,2013,48 (16):1389-1393.
[10] 谢莉,张亿,朱蓉,等.甲硝唑口颀片的释放度测定及不同测定方法的结果比较[J].中国抗生素杂志,2019,44 (6): 697-700.
[11] 申潜,董海丽,张翕,等.ω-3脂肪酸乙酯90软胶囊溶出度测定方法的建立和溶出曲线相似性评价[J].药物分析杂志,2024,44 (12):2180-2188.
[12] 孙悦,唐素芳.流通池法测定尼古丁缓释贴剂的释放度[J].中国药房,2012,23 (33):3133-3135.
[13] 沈丹丹,张伟,罗立骏,等.流通池法测定曲安奈德益康唑乳膏释放度的方法研究[J].中国抗生素杂志,2023,48 (2):201-208.
[14] 国家药典委员会.中华人民共和国药典[S].2025年版.四部.北京:中国医药科技出版社,2025:632-635.
[15] 吴青宜. 线扫描共聚焦显微拉曼光谱成像系统及其应用方法研究[D].长春:中国科学院大学 (中国科学院长春光学精密机械与物理研究所),2024:1-113.
[16] Allergan Pharmaceuticals Ireland.Summary of productcharacter-istics for ZORAC 0.05％,gel[EB/OL].(2018-08-31).ht-tp://www.mhra.gov.uk.
[17] Allergan Pharmaceuticals Ireland.Summary of productcharacter-istics for ZORAC 0.1％,gel[EB/OL].(2018-08-31).ht-tp://www.mhra.gov.uk.
[18] CHARU PM,CALIF F.Stable gel formulation for topicaltreat-ment of skin conditions:US,5914334[P].1996-03-28.