艾司奥美拉唑镁肠溶微丸片的制备及体内外评价  

Preparation and in vitro/in vivo Evaluation of Esomeprazole Magnesium Enteric-coated Pellet-based Tablets

作　　者：冯中 魏瑞霞 贾俊伟 陈梦钰 燕继永 张贵民 FENG Zhong;WEI Ruixia;JIA Junwei;CHEN Mengyu;YAN Jiyong;ZHANG Guimin(School of Pharmaceutical Sciences(Shenzhen),Sun Yat-sen University,Shenzhen 518107;Shandong Pharmaceutical Internationalization Engineering Lab.,Lunan Pharmaceutical Group Co.,Ltd.,Linyi 276006)

机构地区：[1]中山大学药学院(深圳),广东深圳518107 [2]鲁南制药集团股份有限公司,山东省药物国际化工程实验室,山东临沂276006

出　　处：《中国医药工业杂志》2021年第10期1337-1346,共10页Chinese Journal of Pharmaceuticals

基　　金：国家手性制药工程技术研究中心(2016GGH4528)给予资助

摘　　要：采用流化床底喷上药包衣技术,依次对蔗糖丸芯包衣制备艾司奥美拉唑镁肠溶微丸:以2%的羟丙甲纤维素E5 LV、0.3%的滑石粉和原料药制备固含量为15%的浆液进行上药层包衣;然后以羟丙纤维素LF和滑石粉(1∶2)制备固含量为10%的浆液进行隔离层包衣,增重范围为(23±2)%;以肠溶材料Eudragit L30D-55、枸橼酸三乙酯和Tween-80(28∶4∶5)制备固含量为15%的浆液对隔离层微丸进行肠溶层包衣,增重范围为45%~50%。最后,加入微晶纤维素(MCC 101∶MCC 102为40∶60)、交联聚维酮和硬脂富马酸钠,混匀后压片、包薄膜衣制得肠溶微丸片。结果显示,自制肠溶微丸片的含量均匀度、耐酸力、释放度符合《中华人民共和国药典》2020年版要求。建立了LC-MS法测定Beagle犬血浆中艾司奥美拉唑浓度。体内试验表明,犬空腹给予自制肠溶微丸片和参比制剂后,c_(max)为(287.16±13.37)和(290.34±12.42)ng/ml,t_(max)为(1.34±1.37)和(1.41±2.37)h,自制肠溶微丸片的口服相对生物利用度为(98.5±6.7)%。进食状态下给药,参比制剂和自制肠溶微丸片的AUC和c_(max)均下降。该工艺可解决艾司奥美拉唑镁对酸不稳定的问题。Enteric-coated pellets of esomeprazole magnesium were prepared by bottom spray fluid bed process.First,the blank sugar pellets were coated with a 15%-solid-content liquid containing 2%hydroxypropyl methylcellulose E5 LV,0.3% talc and the bulk drug.Then,the drug-coated pellets were coated with a 10%-solid-content liquid containing the mixture of hydroxypropyl cellulose LF and talc(1∶2),and the weight gain of this isolation layer was(23±2)%.After that,the above pellets were coated with a 15%-solid-content liquid containing Eudragit L30D-55,triethyl citrate and Tween-80(28∶4∶5).The final enteric pellets were obtained when the weight gain of enteric layer reached 45%-50%.Finally,the title tablets were obtained by blending with microcrystalline cellulose(with ratio of MCC 101 to MCC 102 of 40∶60),crospovidone and sodium stearyl fumarate,compression and coating with a film layer.The results showed that the content uniformity,acid resistance and release of the coated tablets met the requirements of Chinese pharmacopoeia 2020.A method for determination of esomeprazole in Beagle dog plasma by LC-MS was established.Under fasting condition,c_(max) of the self-made pellet-based tablets and reference preparation were(287.16±13.37)and(290.34±12.42)ng/ml,t_(max) were(1.34±1.37)and(1.41±2.37)h,respectively.The oral relative bioavailability of the selfmade preparation was(98.5±6.7)%.Under feeding condition,AUC and c_(max) obviously decreased for both self-made and reference preparations.This process could solve the acid instability problem of esomeprazole magnesium.

关 键 词：艾司奥美拉唑镁 肠溶微丸 微丸片 流化床包衣 体外释放 药动学 

分 类 号：R944.4[医药卫生—药剂学]