目的 基于分析方法质量源于设计（AQbD）理念，建立并优化吡罗昔康凝胶体外释放实验（IVRT）。方法 建立分析目标、确定关键分析属性［体外释放速率（IVRR）、初始采样时间累积释放量（Q₀）、释放度］；基于先前的知识与经验，从分析目标中推导出有影响的方法变量，并利用石川图进行系统总结，对影响的变量进行风险等级评估，筛选出关键方法变量（膜的种类、释放介质的种类、上样量）；对2种上样量（150、300 mg）、3种释放介质（0.9% NaCl溶液、pH 5.5的磷酸盐缓冲液和pH 7.2的磷酸盐缓冲液）和3种膜［混合纤维素膜（MCE）、聚醚砜膜（PES）、聚四氟乙烯膜（PTFE）］进行2×3×3全析因实验设计，采用扩散池法进行IVRT，将各时间点样品进行HPLC定量分析，进一步计算Q₀、释放度和IVRR。利用JMP Pro软件对实验结果进行建模分析，筛选最优参数。参考美国食品药品监督管理局（FDA）、欧洲药品管理局（EMA）要求对建立的IVRT进行膜惰性验证，释放介质验证，线性、精密度和重复性考察，敏感性和特异性考察及耐用性考察。结果 吡罗昔康凝胶 IVRT 采用静态垂直扩散池（扩散面积 1.767 cm²，接收池体积 12 mL），温度 32 ℃，转速 600 r·min^-1，释放介质为 pH7.2磷酸盐缓冲液、膜为 MCE、上样量为 300 mg，取样时间为 0.5、1.0、2.0、3.0、4.0、5.0、6.0 h，取样方式为全部取样。方法学验证均符合要求。结论 所建立的吡罗昔康凝胶IVRT可靠、耐用、具有区分力。

Objective To adapt the analytical quality by design (AQbD) approach to develop an effective in vitro release test (IVRT) method for diclofenac sodium hydrogel.Methods Establish analysis objectives, determine key analysis attributes [in vitro release rate (IVRR), initial sampling time cumulative release (Q₀), release degree]. Based on previous knowledge and experience, influential method variables were derived from the analysis objectives, and a systematic summary was conducted using the Ishikawa diagram. The risk level of the affected variables was evaluated, and key method variables (membrane type, release medium type, sample loading amount) were selected. Two sample loading amounts (150, 300 mg), three release media (0.9% NaCl solution, pH 5.5 phosphate buffer, and pH 7.2 phosphate buffer), and three membranes [mixed cellulose membrane (MCE), polyethersulfone membrane (PES), and polytetrafluoroethylene membrane (PTFE)] were subjected to 2×3×3 full factorial experiment design: diffusion cell method was used for IVRT, samples at each time point were analyzed quantitatively by HPLC, and Q₀, release degree and IVRR were further calculated. Use JMP Pro software to model and analyze the experimental results, and select the optimal parameters. Refer to the requirements of FDA and EMA for membrane inertness verification, release medium verification, linearity, precision, and repeatability testing, sensitivity and specificity testing, and durability testing of the established IVRT.Results Piroxicam gel IVRT adopted a static vertical diffusion cell (diffusion area 1.767 cm², receiving cell volume 12 mL), temperature 32 ℃, rotational speed 600 r·min^-1, release medium pH 7.2 phosphate buffer, mixed cellulose membrane, loading amount 300 mg, sampling time 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0 h, and sampling method was full sampling. The methodological validation met the requirements.Conclusion The IVRT method of piroxicam gel is reliable, robustness and discriminating.

R917

2020年度药品监管科学科研计划（202022）