星点设计-响应面法优化盐酸氮卓斯汀温敏型原位凝胶滴眼液处方

Optimization of azelastine hydrochloride thermosensitive in situ gel eye drops by central composite design-response surface methodology

目的:制备盐酸氮卓斯汀温敏型原位凝胶滴眼液。方法:以泊洛沙姆407、泊洛沙姆188和羟丙基甲基纤维素为辅料,冷溶法制备盐酸氮卓斯汀温敏型原位凝胶滴眼液;试管倒转法测定胶凝温度,星点设计-响应面法设计试验,泊洛沙姆407、188和羟丙甲纤维素为自变量,凝胶被模拟泪液稀释前后的胶凝温度(T_1,T_2)为因变量,拟合方程及方差分析,优化处方,预测值和实测值比较分析。结果:泊洛沙姆407和188的浓度显著影响胶凝温度,泊洛沙姆407浓度和胶凝温度呈负相关,泊洛沙姆188浓度和胶凝温度正相关,羟丙甲纤维素降低胶凝温度较小,模拟泪液稀释使胶凝温度升高较大。T1和T2二元多项式方程代表性较好,模型方差分析差异显著,而自变量交叉方差分析不显著。P407 22.00%-P188 4.50%-HPMC 0.25%,P407 21.44%-P188 3.35%-HPMC 0.20%,P407 21.07%-P188 3.00%-HPMC 0.20%3个优选处方胶凝温度(T_1,T_2)预测值和实测值的偏差在±1%以内,满足室温下呈流动态、经模拟泪液稀释后32℃实现胶凝的基本要求。处方中盐酸氮卓斯汀含量为0.05%。结论:通过星点设计-响应面法实现了盐酸氮卓斯汀温敏型原位凝胶滴眼液处方优化,制备了盐酸氮卓斯汀温敏型原位凝胶滴眼剂,为盐酸氮卓斯汀的临床应用提供了一种新的制剂研究。

Objective： To prepare azelastine hydrochloride thermosensitive in situ gel eye drops. Methods： Poloxamer 407,poloxamer 188 and hydroxypropyl methylcellulose were selected as pharmaceutical excipients.The gelation temperature was measured by tube inversion method and optimized by the central composite design-response surface methodology（ CCD-RSM）. T1 was decided as gelation temperature before simulated tear fluid dilution,and T2 as gelation temperature after simulated tear fluid dilution. Binomial expressions were fitted by defining the gelation temperatures（ T1,T2） as responses,and poloxamer407,poloxamer188 and hydroxypropyl methylcellulose as independent variables. The predicted and measured values were compared. Results： Poloxamer407 significantly dominated gelation temperature with negative correlation; however,poloxamer188 significantly dominated the parameter with positive correlation. Hydroxypropyl methylcellulose slightly lowered gelation temperature. Dilution of simulated tear fluid significantly highlighted gelation temperature. Binomial expressions about T1 and T2were suitable to the central composite design experiments with statistically significant analysis of variance（ ANOVA） values.P407 22. 00%-P188 4. 50%-HPMC 0. 25%,P407 21. 44%-P188 3. 35%-HPMC 0. 20%,and P407 21. 07%-P188 3. 00%-HPMC 0. 20% were measured with deviation within ± 1%. The content of azelastine hydrochloride in the optimized formulations was 0. 05%. Conclusion： Azelastine hydrochloride thermosensitive in situ gel eyedrops were successfully optimized by the central composite design-response surface methodology. The azelastine hydrochloride thermosensitive in situ gel eye drops provided useful new pharmaceutical preparation of azelastine hydrochloride for clinical use.