通过流变学和区分性溶出优化制剂热熔挤出的工艺处方设计  

Optimization of Formulation Drug Design for Hot Melt Extrusion with Aid of Rheology and Discriminatory Dissolution

作　　者：张丽君 赵周明 卢金萍 刘东昊 张津州 ZHANG Lijun;ZHAO Zhouming;LU Jinping;LIU Donghao;ZHANG Jinzhou(Zhejiang Huahai Pharmaceutical Co.,Ltd.,Linhai 317000,China)

机构地区：[1]浙江华海药业股份有限公司,浙江临海317000

出　　处：《中国药学杂志》2025年第5期488-496,共9页Chinese Pharmaceutical Journal

基　　金：浙江省领军型创新创业团队建设项目资助(2019R01009)。

摘　　要：目的本研究旨在通过流变学和区分性溶出来助推难溶性药物泊沙康唑的热熔挤出制剂的工艺处方设计。方法通过旋转平行板流变仪对聚合物的黏弹性在温度140~180℃和角频率100~0.1 rads·s^(-1)的范围内进行了振荡剪切评估。溶出:通过桨法与开环流池法分别筛选确立了关键工艺质量属性。结果所选载体在实验温度范围内的储存模量(G′)>损耗模量(G″),损耗因子Tan(delta)<1,具有较好的可加工性。振幅-频率实验进一步揭示模量G′和G″在140℃时随着角应变提高要比在150、160℃时更趋于稳定。根据质量源于设计借助区分性溶出,明确了片剂中辅料羟丙基纤维素的处方设计并确定了用于片剂的热熔挤出物混颗粒的尺寸。通过差示扫描量热法、X射线衍射技术、拉曼、偏光显微镜对挤出件的表征显示原料药的型态已从其原先的多晶态变成了挤出后的无定型分子分散体。结论泊沙康唑的热熔挤出自研制剂T的体内外药物释放与参比制剂一致。OBJECTIVE To develop appropriate formulation and process design for hot melt extrusion(HME)of poorly soluble drug posaconazole with aid of rheology and discriminatory dissolution.METHODS The viscoelastic properties of polymer matrices were assessed for oscillation shear strain on a rotation disc rheometer within temperature of 14-180℃and angular frequency of 100-0.1 rads·s^(-1),respectively.A paddle method and an open flow cell method were developed alternatively to screen key critical quality attributes.RESULTS The selected polymer carrier showed storage modulus(G′)>loss modulus(G″)with loss factor Tan(delta)<1 within the assessed temperature range,for better HME processability.Oscillation-frequency assessments further demonstrated that G′and G″were more shear stable with angular strain at 140℃compared with the increasing modulus trends at 150 and 160℃.Based on quality by design,discriminatory dissolution helped in defining if need to add excipient hydroxypropylcellulose in the process,as well as in designing HME granule size for formulation drug T.DSC,XRPD,Raman and optical microscopy characterization showed that the morphology of API changed from multicrystalline state to amorphous molecule dispersion after extrusion.CONCLUSION The drug release in vitro and in vivo of formulation drug posaconazole T is in bioequivalence with that of reference listing drug.

关 键 词：流变学 热熔挤出 黏度 模量 溶出 

分 类 号：R944[医药卫生—药剂学]