不同β-环糊精衍生物的恩替卡韦包合物的溶解度和溶出度研究  

Study on different β-cyclodextrin and its derivatives for solubilization and dissolution of entecavir

作　　者：王鹛嵩[1] 吴海涛[1] 王敏[1] 陈声文 

机构地区：[1]海南省人民医院药学部,海南海口570311 [2]海南百信药业有限公司制药厂,海南海口570216

出　　处：《中国生化药物杂志》2015年第3期172-175,共4页Chinese Journal of Biochemical Pharmaceutics

摘　　要：目的：研究和制备了不同β－环糊精衍生物的恩替卡韦包合物，探讨不同包合物对恩替卡韦溶解度和溶出度的影响。方法建立标准回归方程，采用磁力搅拌法、研磨法和超声法制备包合物，以包合率为目标，通过考察摩尔比、包合温度、包合时间、搅拌速率等因素对包合的影响，从而得到最佳包合工艺条件；采用高效液相色谱法测定不同包合物的溶解度并用小杯法考察了体外溶出度。结果回归方程为A＝1．026×106C＋4248．8，R2＝0．9999（n＝6），在0．497～4．97μg／mL范围内的线性关系良好；得到的最佳包合方法为磁力搅拌法，最佳包合工艺条件为A摩尔比为1︰1，搅拌速率300 r／min，包合时间为4h，包合温度50℃；恩替卡韦在不同的β－环糊精衍生物包合后得到白色疏松状粉末物质。 ETV、β－CD－ETV、HP－β－CD－ETV、 RM－β－CD－ETV、2，6－DM－β－CD－ETV的溶解度分别为2．51、13．4、18．9、37．6、89．5 g／L，采用不同的环糊精衍生物都具有显著的增溶作用。恩替卡韦的不同环糊精衍生物的包合物的溶出度为ETV＜β－CD－ETV＜HP－β－CD－ETV＜RM－β－CD－ETV＜2，6－DM－β－CD－ETV。结论β－环糊精及其衍生物对疏水性恩替卡韦增溶作用与其亲脂性呈正比，其中2，6－二甲基－β－环糊精的增溶效果和溶出率是最显著的。Objective To prepared inclusion complex of β-cyclodextrin （β-CD） and its derivatives （methyl -β-cyclode-xtrin, 2,6-dimethyl -β-cyclodextrin, hydroxypropyl -β-cyclodextrin ） with entrcavir, and explore effect of different inclusion complex on the solubility and dissolution of entecavir.Methods Regression equation was established,prepared the inclusion complexes by a magnetic stiring method,grinding method and ultrasonic method.While inclusion rate was an index,the effects of reaction process was inquired by mole ratio, inclusion temperature, inclusion time and stirring rate and the most suitable method and technology of inclusion was optimized.Determinated the solubility with HPLC method and investigated in vitro dissolution with a small cup method.Results The regression equation was A=1.026 ×106C＋4248.8, R2 =0.9999 （n=6）, in the range of 0.497~4.97 g/mL, linear relationship was good.The best inclusion method was magnetic stirring, the best process conditions were： mole ratio was 1 ︰1, stirring speed was 300 r/min, inclusion time was 4 hours, inclusion temperature was 50 ℃.The four inclusion complexes all were white loose powder materials.The solubility of ETV,β-CD-ETV,HP-β-CD-ETV,RM-β-CD-ETV,2,6-DM-β-CD-ETV were 2.51, 13.4, 18.9, 37.6 and 89.5 g/L.The dissolution rates was ETV〈β-CD-ETV〈HP-β-CD-ETV〈RM-β-CD-ETV〈2,6-DM-β-CD-ETV.The solubilization effects and dissolution rates of four inclusion complexes ofβ-cyclodextrin with entecavir were both increased significantly.Conclusion β-cyclodextrin and its derivatives on the hydrophobic entecavir solubilization is proportional to its lipophilic, 2,6-β-CD solubilization effect and the dissolution rate is the most significant.

关 键 词：恩替卡韦 Β-环糊精及其衍生物 包合物 溶解度 溶出度 

分 类 号：R944.4[医药卫生—药剂学] R943.3[医药卫生—药学]