热熔挤出技术制备艾拉莫德固体分散体及体外溶出度的影响因素研究  

Preparation of Iguratimod Solid Dispersion via Hot-melt Extrusion and Investigation of Factors Affecting Dissolution Profile

作　　者：陈玉红[1] 王青松[1,2] 平其能[1] 张灿[1] 

机构地区：[1]中国药科大学药剂学教研室,南京210009 [2]江苏先声药业有限公司,南京210042

出　　处：《中国药学杂志》2013年第17期1464-1470,共7页Chinese Pharmaceutical Journal

基　　金：国家重大新药创制科技重大专项(2009ZX09310-004)

摘　　要：目的采用热熔挤出(hot-melt extrusion,HME)技术制备高熔点难溶性药物艾拉莫德(iguratimod,T-614)的固体分散体(solid dispersion,SD),提高其体外溶出度。方法以艾拉莫德的体外溶出度为指标,运用熔融法和吸附法筛选载体材料。采用热熔挤出技术在低于药物熔点的温度下制备艾拉莫德固体分散体,考察不同载体、操作温度和增塑剂对溶出度和物理状态的影响。评价影响固体分散体稳定性的因素及大鼠口服后药动学行为。结果以PVP/VA 64为载体制备的热熔挤出固体分散体的体外溶出最快,其过饱和溶液可在至少2 h内不发生重结晶。提高操作温度对溶出度的影响较小,10%的PEG1500增塑作用好。X射线粉末衍射(XRPD)分析显示艾拉莫德在固体分散体中以无定形态存在。固体分散体片对高温和强光稳定,在高湿条件下重结晶,体外溶出度下降。药动学研究表明,固体分散体片的t max缩短,生物利用度与市售片相同。结论载体可影响固体分散体中药物的溶出行为和物理状态。以PVP/VA 64为载体,采用热熔挤出技术制备固体分散体能够显著提高高熔点难溶性药物的体外溶出度。OBJECTIVE To identify a suitable polymer system for iguratimod （T-614）, a poorly water-soluble compound with high melting point, and prepare a chemically stable single phase solid dispersion （SD） of T-614 by hot-inch extrusion （HME） tech- nique to enhance its dissolution rate. METHODS Mehing method and adsorption based screening techniques were utilized to screen hydrophilic polymers suitable for immediate release formulations. T-614 SDs were prepared with polymer carriers such as PVP/VA 64, Soluplus, HPMC AS-LF and HPC-SL via HME below the drug melting point, and suitable temperature and plasticizer for HME were chosen. The dissolution behaviors of SD powder and SD tablets were compared with those of T-614 powder and commercial T-614 tab- lets, respectively. State of T-614 in HME SDs was characterized by X-ray powder diffraction. The homogenous SD tablets were analyzed further for physical stability in an influencing factors test. The bioavailability of SD tablets was assessed in rats. RESULTS Results of the screening studies demonstrated that PVP/VA 64, Soluplus, HPMC AS-LF and HPC-SL provided higher degree of miscibility and dissolution enhancement. The HWE SD tablets showed significantly enhanced dissolution. The supersaturation state of HME SD powder in water was maintained for at least 120 min, suggesting that PVP/VA 64 had an inhibitory effect on recrystallization of T-614 from a supersaturated solution. Samples prepared via HME at 160 ~C were substantially amorphous ,which were unchanged in the influencing factors test at high temperature and strong light, but recrystallization occurred at high humidity. PEG1500 appeared to be a promising plasticizer. Same bioavailability was achieved when compared with commercial T-614 tablets. CONCLUSION The polymersas carri- ers for T-614 SD have significant impact on the dissolution behavior and state of T-614. Using PVP/VA 64 as the carrier, hot-melt ex- trusion is an effective technology for improving the in vitro dissolution of T-614.

关 键 词：热熔挤出 固体分散体 高熔点药物 难溶性 艾拉莫德 无定形 溶出度 

分 类 号：R944[医药卫生—药剂学]