采用确定性筛选设计优化催产素粉末的处方及制备工艺参数

Definitive Screening Design for Optimizing Formulation andProcess Parameters of Oxytocin Powder

采用JMP软件(版本13.0 Pro)的确定性筛选设计(DSD)模块对吸入用催产素粉末的喷雾干燥处方工艺进行了初步筛选。分别设定了6个处方或工艺参数(磷酸盐比例、亮氨酸比例、料液pH、进口温度、进料流速、压缩空气流量),进行13次试验,评价指标为微细粒子分数、产率、玻璃化转变温度、水分含量、几何中位径、催产素含量。结果表明,磷酸盐比例和亮氨酸比例显著影响微细粒子分数,亮氨酸比例显著影响产率,磷酸盐比例和进料流速显著影响水分含量。最后,以微细粒子分数、催产素含量为关键评价指标,通过联合建模获得了优化处方工艺参数。优化处方工艺的验证试验结果显示,所得喷雾干燥粉末的微细粒子分数89.14%、水分含量0.67%、催产素含量94.63%、几何中位径1.36μm、产率68.50%,基本符合催产素干粉吸入剂要求。因此,在多肽类药物干粉吸入剂研发早期,确定性筛选设计可快速衡量各处方或工艺参数对粉末性质的影响。

A definitive screening design(DSD,software JMP 13.0 Pro)was undertaken to preliminarily screen the formulation and process parameters of spray-dried powders of oxytocin for inhalation.Six formulation and process parameters,namely phosphate radio,leucine radio,pH of feed solution,inlet temperature,feed solution flow rate and airflow rate,were set as the influence factors,then 13 batches of oxytocin powder were prepared and characterized in terms of fine particle fraction,yield,glass transition temperature,moisture content,geometric median diameter,oxytocin content.The results showed that fine particle fraction was mainly influenced by phosphate radio and leucine radio,whereas yield was found to be primarily affected by leucine radio,and moisture content was mainly influenced by phosphate radio and feed solution flow rate.Finally,the optimal formulation and process parameters of spray-dried powders of oxytocin was obtained with fine particle fraction and oxytocin content as key indicators through joint modeling.The results of verification test showed that the optimized powders were basically in line with the requirements of oxytocin dry powder for inhalation,with fine particle fraction of 89.14%,moisture content of 0.67%,oxytocin content of 94.63%,geometric median diameter of 1.36μm and yield of 68.50%.In conclusion,DSD can quickly screen and quantify the influence of the formulation or process parameters on powder properties in the early development of peptide dry powder inhalation.