摘要
目的 研制结合雌激素(conjugated estrogens, CE)亲水凝胶骨架缓释片,进行试验制剂与参比制剂倍美力■体外释放的相似性考察。方法 参照质量源于设计(QbD)理念,采用高效液相色谱法(HPLC)与差示扫描量热法(DSC)结合评价原辅料相容性。采用粉末直接压片工艺研制结合雌激素缓释片。对物料属性和工艺参数进行风险评估,通过Plackett-Burman(P-B)设计筛选影响CE片关键质量属性(CQAs)的关键物料属性(CMAs)和关键工艺参数(CPPs)。建立释放曲线的测定方法,并使用非模型依赖相似因子(f_(2))法评价试验制剂与参比制剂的体外释放一致性。结果 CE原料药(API)加速条件(40±2)℃,相对湿度(75±5)%存放30 d,马烯雌酮硫酸钠降解22.04%,雌酮硫酸钠降解9.53%,提示CE API对湿热敏感。CE API与各辅料的混合样品与平行对照相比热力学行为相似,提示原辅料相容性良好。粉末直接压片法制备的CE缓释片的硬度、释放度等均符合规定。在pH 1.2释放介质中羟丙甲纤维素的处方比例显著影响试验制剂与参比制剂释药行为的相似性。照最优处方生产的三批试验制剂批间释放均一性良好,试验制剂与参比制剂在4种介质(pH 1.2盐酸介质、pH 4.5醋酸盐介质、pH 6.8磷酸盐介质和水介质)中f_(2)值均>50,提示二者在体外具有相似的释放行为。结论 粉末直接压片法制备CE片的工艺稳定可靠,具备工业生产的可行性。
OBJECTIVE To study conjugated estrogens(CE)hydrophilic gel skeleton sustained release tablets and investigate the similarity ofin vitrorelease between the test drug and the reference listed drug(RLD)PremarinⓇ.METHODS Refer to the quality by design(QbD)concept,the compatibility of active pharmaceutical ingredient(API)and excipients were evaluated by high perform⁃ance liquid chromatography(HPLC)and differential scanning calorimetry(DSC).CE sustained release tablets was prepared by divect powder compression method.The risk assessment was applied to material attributes and process parameters,Plackett⁃burman(P⁃B)design was used to screen critical material attributes(CMAs)and critical process parameters(CPPs)that affected critical quality attrib⁃utes(CQAs)of CE tablets.A method for the determination of release curve was established,and thein vitrorelease consistency of the test drug and the RLD was evaluated by the model independent similarity factor(f_(2))method.RESULTS The CE API was stored under accelerated conditions(40±2)℃,(75±5)%RH for 30 days,the content of sodium equilin sulfate and sodium estrone sulfate degraded by 22.04%and 9.53%,respectively.It demonstrated that CE was susceptible to high-humidity and high⁃temperature.The thermodynamic behavior of the mixed samples of CE API and excipients was similar to the parallel control,indicating good compatibility of API and excipients.The hardness and the releasing degree of CE sustained⁃release tablets produced by the powder direct compres⁃sion method were in compliance with the regulations.The formulation proportion of HPMC significantly affected the similarity between the test drug and the RLD in pH 1.2 release medium.The release homogeneity of three batches of test drug produced according to the optimal formulation was good,thef_(2)values of the test drug and the RLD in four medams(pH 1.2 hydrochloric acid medium,pH 4.5 acetate medium,pH 6.8 phosphate medium and water medium)were all greater than 50,suggesting that they had similar release be⁃havior in vitro.CONCLUSION The process of prepared CE tablets by direct powder compression method was stable and reliable,and had the feasibility for industrial production.
作者
刘运霄
李盼盼
谢湘云
高晓黎
LIU Yun-xiao;LI Pan-pan;XIE Xiang-yun;GAO Xiao-li(College of Pharmacy,Xinjiang Medical University,Urumuqi830017,China;Xinjiang Key Laboratory of Active Components and Drug Release Technology for Natural Medi-cines,Urumuqi830017,China;Engineering Research Center of the Ministry of Education of Xinjiang and Central Asia Characteristic Medical Resources,Urumuqi830017,China)
出处
《中国药学杂志》
CAS
CSCD
北大核心
2023年第9期807-817,共11页
Chinese Pharmaceutical Journal
基金
新疆维吾尔自治区2022年重大科技专项资助(2022A02013)。
关键词
质量源于设计
结合雌激素
原辅料相容性
粉末直接压片法
亲水凝胶骨架片
相似因子f_(2)
quality by design
conjugated estrogens
drug⁃excipients compatibility
direct powder compression method
hydrophil⁃ic gel skeleton tablet
similarity factor f_(2)
