热流变特性对牛蒡苷元固体分散体制备工艺的作用

Role of Thermo-rheological Properties of Formulation in Instructing the Preparation of Arctigenin Solid Dispersion

关键词:  热流变玻璃化温度  热熔挤出  牛蒡苷元  固体分散体  醋酸羟丙甲纤维素琥珀酸酯

Key words:  thermo-rheological glass transition temperature  hot melt extrusion  arctigenin  solid dispersion  hydroxypropyl methylcellulose succinate acetate(HPMCAS-MG)

摘要:

目的 考察制剂处方的热流变特性与热熔挤出(hot melt extrusion，HME)固体分散体工艺的相关性。方法 以牛蒡苷元为模型药，考察载体辅料、药辅混合物在一定的应力应变作用下黏弹性随温度的变化，及在一定的温度下，剪切频率扫描下的处方热流变特性。以体外溶出率为考察指标，辅以扫描电镜及X射线衍射法，考察HME的处方参数和工艺参数，评价热流变特性参数对HME工艺的指导作用。结果 制剂处方在高于热流变玻璃化转变温度(thermo-rheological glass transition temperature，Tgrheo)20 ℃(Tgrheo+20 ℃)，复数黏度均<10⁴Pa·s，说明在该温度时物料可以顺利挤出。以体外溶出率为考察指标，扫描电镜和X射线衍射法对固体分散体进行物相鉴别，优化得到牛蒡苷元HME最优的处方和工艺：聚合物HPMCAS-MG为载体，药辅比为1∶6，螺杆设计为0对或1对捏合块，挤出温度为155 ℃，螺杆转速30~70 r·min^-1。该条件下获得的固体分散体，在pH 6.8的缓冲液中牛蒡苷元表观溶解度提高了近13倍，在60 min内溶出度可达到90%左右，且3 h内溶出稳定，未发生重结晶。结论 HME制剂处方的Tgrheo温度对HME具有重要的参考价值，Tgrheo+20 ℃是HME物料适宜的操作温度，本实验考察的所有处方均符合该规律，这一规律对提高HME的制剂处方优化研究效率具有重要意义。

Abstract:

OBJECTIVE To investigate the correlation between the thermo-rheological properties of the formulations and the hot melt extrusion(HME) process conditions for the preparation of solid dispersion. METHODS Arctigenin was adopted as the model drug, the carriers and drug-carrier mixtures were subjected to thermo-rheology study. Under certain stress and strain, the change of viscoelasticity with temperature was explored, thermo-rheological properties under shear frequency sweeping at a certain temperature was investigated too. The in vitro dissolution rate was employed as the index to investigate the formulation and processing parameters of HME with the results of scanning electron microscopy and X-ray diffraction to evaluate the effect of thermo-rheological properties on directing HME process conditions. RESULTS At the temperature 20 ℃ higher than the thermo-rheological glass transition temperature(Tgrheo), that was, Tgrheo+20 ℃, for all the formulations studied, the complex viscosity was <10⁴ Pa·s, which was the appropriate viscosity. Under the guidance of the results of thermo-rheological properties, the optimized formulation and process of arctigenin HME were obtained: HPMCAS-MG was used as the carrier, the arctigenin HPMCAS-MG ratio was 1︰6, the number of kneading blocks was none or a pair, the extrusion temperature was 155 ℃, and screw speed was at 30-70 r·min^-1. The solid dispersion obtained under these conditions enhanced the apparent solubility of arctigenin in the pH 6.8 buffer by nearly 13-fold. The dissolution rate reached 90% within 60 min, and the dissolution was stable within 3 h without precipitation. CONCLUSION The Tgrheo of formulation has important reference value for HME. Tgrheo+20 ℃ is suitable for HME and all the formulations studied in this experiment meet the rule. It is of great significance to improve the research efficiency of HME prescription optimization.