不同工艺制得蒿甲醚pH依赖型固体分散体的比较研究(1)
摘要：目的应用不同工艺制备蒿甲醚/HPMCAS(HF)固体分散体，通过含量、溶出度、收率的测定，阐明蒿甲醚pH依赖型固体分散体的最优制备工艺。方法以醋酸羟丙甲纤维素琥珀酸酯HPMCAS(HF)为固体分散体载体，通过3种工艺(共沉淀法、溶剂蒸发法及喷雾干燥法)制备蒿甲醚/HPMCAS(HF)固体分散体。考察其含量、收率以及在PH68和PH76环境下溶出度。结果原型药物及物理混合物溶出度均较低，喷雾干燥法制备的药物含量测定和收率都符合要求，在PH76的环境下能在2 h内完全溶出，明显高于另外两种方法。结论喷雾干燥技术制备的固体分散体显著改善蒿甲醚的溶出，而且有较好的pH依赖性，更适合用以蒿甲醚pH依赖型固体分散体的制备及工业生产。
关键词：蒿甲醚;固体分散体;制备工艺;溶出度
中图分类号：R2842 文献标志码：B 文章编号：1007-2349(2018)06-0065-03
Comparative Study of Artemether pH-dependent Solid Dispersions Prepared by Different Techniques
LI Wen-ting1，2，ZHANG Guo-li2，ZHANG Rui-wu2，DUAN Guo-lei2，YANG Zhao-xiang2
(1. Dali University，Dali 671000，China;
2. Kunming Pharmaceutical Group Co ，Ltd ，Kunming 650106，China)
【Abstract】Objective：To prepare artemether/HPMCAS(HF)solid dispersions by different techniques and to expound optimal preparation process of artemether pH-dependent solid dispersions by the determination of contents，dissolution and yield Methods：Hypromellose acetate HPMCAS(HF)was used as solid dispersion carrier to prepare artemether/HPMCAS(HF)solid dispersion by three types of processes(co-precipitation，solvent evaporation and spray drying) The content，yield，and dissolution under pH 68 and pH 76 were examined Results：The dissolution of the drug prototype and physical mixture was low The drug content and yield by spray drying method were all in line with the requirements The dissolution could be completely finished within 2 hours under pH 7 6，which significantly had higher rate than the other two methods Conclusion：The solid dispersion prepared by spray drying technique can significantly improve the dissolution of artemether，and has better pH dependence It is more suitable for the preparation and industrial production of artemether pH-dependent solid dispersions
【Key words】artemether，solid dispersions，preparation techniques，dissolution rate
蒿甲醚(Artemethere，Art)為来自青蒿素的衍生物，在临床上治疗恶性疟和脑型疟有显著疗效，近年的研究发现，青蒿素及其衍生物有明确的抗肿瘤作用，有研究证实蒿甲醚能使小鼠结直肠癌移植瘤的生长减缓[1]。目前已证实青蒿素类衍生物对结肠癌细胞SW480、SW602有杀灭活性[2]。该药物为基于生物药剂学分类系统(BCS)Ⅱ类药物，水中溶解度极低[3]。故提高该药物的溶解度和溶出速度能改善其在肠道吸收，利用pH依赖型给药系统能实现其口服结直肠定位释放的目的。
本研究设计的蒿甲醚pH依赖型固体分散体是一种pH依赖型给药系统，正常生理条件下，人体小肠pH值大致在68左右，结直肠pH值大致在76左右[4]。本研究运用醋酸羟丙甲纤维素琥珀酸酯(hydroxypropyl methylcellulose acetate succinate，HPMCAS)为载体，挑选其中的型号HF，该型号在pH68以上环境才能溶解。运用这种pH 依赖型的纤维素类衍生物作为固体分散体(Solid dispersions，SD)的载体，可以使药物在胃和小肠部位不释放或少量释放，而当到达结肠部位后，由于pH 升高，载体材料溶解而大量释放药物[5]。
近年来，已尝试使用共沉淀法、溶剂蒸发法、喷雾干燥等方法制备蒿甲醚固体分散体。但现在关于蒿甲醚固体分散体的研究基本上仍以一种制备方法为主，缺少对不同固体分散技术制备蒿甲醚固体分散体的性质比较。本研究以HPMCAS(HF)为载体，分别采用共沉淀法、溶剂蒸发和喷雾干燥的方法来制备了蒿甲醚结直肠定位固体分散体，并从溶出度、含量、收率几个方面比较不同工艺的适用性和产业化应用。, http://www.100md.com(李文婷 张国丽 张锐武 段国蕾 杨兆祥)
关键词：蒿甲醚;固体分散体;制备工艺;溶出度
中图分类号：R2842 文献标志码：B 文章编号：1007-2349(2018)06-0065-03
Comparative Study of Artemether pH-dependent Solid Dispersions Prepared by Different Techniques
LI Wen-ting1，2，ZHANG Guo-li2，ZHANG Rui-wu2，DUAN Guo-lei2，YANG Zhao-xiang2
(1. Dali University，Dali 671000，China;
2. Kunming Pharmaceutical Group Co ，Ltd ，Kunming 650106，China)
【Abstract】Objective：To prepare artemether/HPMCAS(HF)solid dispersions by different techniques and to expound optimal preparation process of artemether pH-dependent solid dispersions by the determination of contents，dissolution and yield Methods：Hypromellose acetate HPMCAS(HF)was used as solid dispersion carrier to prepare artemether/HPMCAS(HF)solid dispersion by three types of processes(co-precipitation，solvent evaporation and spray drying) The content，yield，and dissolution under pH 68 and pH 76 were examined Results：The dissolution of the drug prototype and physical mixture was low The drug content and yield by spray drying method were all in line with the requirements The dissolution could be completely finished within 2 hours under pH 7 6，which significantly had higher rate than the other two methods Conclusion：The solid dispersion prepared by spray drying technique can significantly improve the dissolution of artemether，and has better pH dependence It is more suitable for the preparation and industrial production of artemether pH-dependent solid dispersions
【Key words】artemether，solid dispersions，preparation techniques，dissolution rate
蒿甲醚(Artemethere，Art)為来自青蒿素的衍生物，在临床上治疗恶性疟和脑型疟有显著疗效，近年的研究发现，青蒿素及其衍生物有明确的抗肿瘤作用，有研究证实蒿甲醚能使小鼠结直肠癌移植瘤的生长减缓[1]。目前已证实青蒿素类衍生物对结肠癌细胞SW480、SW602有杀灭活性[2]。该药物为基于生物药剂学分类系统(BCS)Ⅱ类药物，水中溶解度极低[3]。故提高该药物的溶解度和溶出速度能改善其在肠道吸收，利用pH依赖型给药系统能实现其口服结直肠定位释放的目的。
本研究设计的蒿甲醚pH依赖型固体分散体是一种pH依赖型给药系统，正常生理条件下，人体小肠pH值大致在68左右，结直肠pH值大致在76左右[4]。本研究运用醋酸羟丙甲纤维素琥珀酸酯(hydroxypropyl methylcellulose acetate succinate，HPMCAS)为载体，挑选其中的型号HF，该型号在pH68以上环境才能溶解。运用这种pH 依赖型的纤维素类衍生物作为固体分散体(Solid dispersions，SD)的载体，可以使药物在胃和小肠部位不释放或少量释放，而当到达结肠部位后，由于pH 升高，载体材料溶解而大量释放药物[5]。
近年来，已尝试使用共沉淀法、溶剂蒸发法、喷雾干燥等方法制备蒿甲醚固体分散体。但现在关于蒿甲醚固体分散体的研究基本上仍以一种制备方法为主，缺少对不同固体分散技术制备蒿甲醚固体分散体的性质比较。本研究以HPMCAS(HF)为载体，分别采用共沉淀法、溶剂蒸发和喷雾干燥的方法来制备了蒿甲醚结直肠定位固体分散体，并从溶出度、含量、收率几个方面比较不同工艺的适用性和产业化应用。, http://www.100md.com(李文婷 张国丽 张锐武 段国蕾 杨兆祥)