目的 基于分析方法質(zhì)量源于設(shè)計(jì)（AQbD）理念，建立并優(yōu)化吡羅昔康凝膠體外釋放實(shí)驗(yàn)（IVRT）。方法 建立分析目標(biāo)、確定關(guān)鍵分析屬性［體外釋放速率（IVRR）、初始采樣時(shí)間累積釋放量（Q₀）、釋放度］；基于先前的知識(shí)與經(jīng)驗(yàn)，從分析目標(biāo)中推導(dǎo)出有影響的方法變量，并利用石川圖進(jìn)行系統(tǒng)總結(jié)，對(duì)影響的變量進(jìn)行風(fēng)險(xiǎn)等級(jí)評(píng)估，篩選出關(guān)鍵方法變量（膜的種類(lèi)、釋放介質(zhì)的種類(lèi)、上樣量）；對(duì)2種上樣量（150、300 mg）、3種釋放介質(zhì)（0.9% NaCl溶液、pH 5.5的磷酸鹽緩沖液和pH 7.2的磷酸鹽緩沖液）和3種膜［混合纖維素膜（MCE）、聚醚砜膜（PES）、聚四氟乙烯膜（PTFE）］進(jìn)行2×3×3全析因?qū)嶒?yàn)設(shè)計(jì)，采用擴(kuò)散池法進(jìn)行IVRT，將各時(shí)間點(diǎn)樣品進(jìn)行HPLC定量分析，進(jìn)一步計(jì)算Q₀、釋放度和IVRR。利用JMP Pro軟件對(duì)實(shí)驗(yàn)結(jié)果進(jìn)行建模分析，篩選最優(yōu)參數(shù)。參考美國(guó)食品藥品監(jiān)督管理局（FDA）、歐洲藥品管理局（EMA）要求對(duì)建立的IVRT進(jìn)行膜惰性驗(yàn)證，釋放介質(zhì)驗(yàn)證，線(xiàn)性、精密度和重復(fù)性考察，敏感性和特異性考察及耐用性考察。結(jié)果 吡羅昔康凝膠 IVRT 采用靜態(tài)垂直擴(kuò)散池（擴(kuò)散面積 1.767 cm²，接收池體積 12 mL），溫度 32 ℃，轉(zhuǎn)速 600 r·min^-1，釋放介質(zhì)為 pH7.2磷酸鹽緩沖液、膜為 MCE、上樣量為 300 mg，取樣時(shí)間為 0.5、1.0、2.0、3.0、4.0、5.0、6.0 h，取樣方式為全部取樣。方法學(xué)驗(yàn)證均符合要求。結(jié)論 所建立的吡羅昔康凝膠IVRT可靠、耐用、具有區(qū)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年度藥品監(jiān)管科學(xué)科研計(jì)劃（202022）