依非韦伦固体分散体的制备及其体内外评价  

Preparation of Efavirenz Solid Dispersion and Its in vitro and in vivo Evaluation

作　　者：李金丰 陆振举 顾王文 刘怡 孙考祥[1] LI Jinfeng;LU Zhenju;GU Wangwen;LIU Yi;SUN Kaoxiang(School of Pharmacy, Yantai University, Yantai 264000;Center for Formulations System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203;Ashland {China) Holding Co., Ltd., Shanghai 200233;Yantai Institute of Materia Medica, Yantai 264003)

机构地区：[1]烟台大学药学院,山东烟台264000 [2]中国科学院上海药物研究所药物制剂研究中心,上海201203 [3]亚什兰(中国)投资有限公司,上海200233 [4]烟台药物研究所,山东烟台264003

出　　处：《中国医药工业杂志》2019年第5期530-538,共9页Chinese Journal of Pharmaceuticals

摘　　要：分别以聚维酮K29/32、共聚维酮S-630、聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)以及3个规格的醋酸羟丙甲纤维素琥珀酸酯(HPMCAS,规格L、M和H)为载体材料,采用喷雾干燥技术制备依非韦伦固体分散体。以120 min 的动力溶解度为指标考察,筛选出增溶效果和抑晶效果较优的载体材料,并用全因子设计优化喷雾干燥的工艺参数。通过差示扫描量热(DSC)法、X射线粉末衍射(XRPD)法和红外光谱(FT-IR)法对优化所得的固体分散体进行物相鉴别。结果表明,L规格的HPMCAS 增溶效果最好;依非韦伦与HPMCAS L 的质量比为1∶3时制得的固体分散体在pH6.8 磷酸盐缓冲溶液中120min 的动力溶解度达到(955.97±5.13)μg/ml,比原料药提高了约66.7 倍;喷雾干燥工艺参数中泵的流速越慢、氮气流量越大,制得的固体分散体动力溶解度越高。DSC 和XRPD 结果表明依非韦伦以无定形分散在载体材料中,FT-IR 显示依非韦伦与载体材料分子之间以氢键结合。加速试验[40℃、相对湿度75%]结果表明HPMCAS L 固体分散体在6个月内较稳定;大鼠体内药动学试验表明,该固体分散体的cmax 和AUC0→t分别为原料药的1.98 和1.79 倍。本试验表明以HPMCAS L为载体制备的依非韦伦固体分散体可显著提高药物的溶解度和口服生物利用度。Efavirenz solid dispersions were respectively prepared by spray drying method with different carriers, such as povidone K29/32, copovidone S-630, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) and hypromellose acetate succinate HPMCAS (grades L, M and H). The optimal carrier with prior solubility and crystal growth inhibition was selected with dynamic solubility at 120 min as the index, and the process parameters of spray drying were also optimized by full factorial design experiment. The final solid dispersion was characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and infrared spectroscopy (FT-IR). The results showed that the solid dispersion with drug-HPMCAS L ratio of 1∶3 exhibited dynamic solubility of (955.97±5.13)μg/ml in pH 6.8 phosphate buffer solution, which was 67.7 times higher than that of bulk drug. Both pump flow rate and nitrogen flow rate significantly influenced the dynamic solubility of the solid dispersions. The pump flow rate was negatively related while the nitrogen flow rate was positively related to the dynamic solubility. The results of DSC and XRPD showed that efavirenz existed in an amorphous state form in solid dispersion. The infrared spectra showed that there was hydrogen bonding between efavirenz and the carrier polymer. And the product was rather stable under the accelerated condition (40 ℃/RH75%) for six months. The pharmacokinetic behaviors of efavirenz and its solid dispersion in SD rats were investigated by HPLC method. The cmax and AUC0→t of the solid dispersion with drug HPMCAS L ratio of 1∶3 were 1.98 and 1.79 times higher than those of the bulk drug, indicating the oral bioavailability of efavirenz solid dispersion was significantly improved.

关 键 词：依非韦伦 醋酸羟丙甲纤维素琥珀酸酯 固体分散体 喷雾干燥 动力溶解度 生物利用度 

分 类 号：R944.9[医药卫生—药剂学]