新型小分子化合物ZL-004纳米粒的制备和药动学初步研究  

Preparation of Nanoparticles of ZL-004 and Preliminary Study on Its Pharmacokinetics

作　　者：赵锋[1] 栾瀚森[1] 杨莉[1] 马银玲[2] 张晓红[3] 张淑珍[4] 王浩[1] 

机构地区：[1]药物制剂国家工程研究中心,中国医药工业研究总院,上海201203 [2]河北省人民医院药学部,石家庄050051 [3]上海现代制药股份有限公司嘉定基地,上海201800 [4]内蒙古医科大学第二附属医院科研处,呼和浩特010030

出　　处：《中国药学杂志》2013年第23期2026-2033,共8页Chinese Pharmaceutical Journal

基　　金："十二五重大新药创制"项目资助(2011ZX09401-403-1)

摘　　要：目的制备载ZL-004的PLGA纳米粒(ZL-004-NP),并进行体内外评价。方法采用饱和恒温法、电位法、摇瓶法分别测定ZL-004的溶解度、pK_a及油水分配系数,采用单因素实验结合正交设计优化纳米粒的处方,采用扫描电镜、激光粒度仪及透析法评价优化纳米粒的特征。大鼠灌胃给予ZL-004-NP,采用UpLC-MS/MS检测血药浓度并计算相对生物利用度。结果优化后的ZL-004-NP呈圆球形,表面光滑,平均粒径121.34 nm,分散指数0.16,包封率89.63%,载药量7.65%,体外释放可达216 h,且突释较小。与ZL-004原料药相比,ZL-004-NP的p_(max)提高了1.7倍,可达125μg·L^(-1),t_(max)由(6.47±0.51)h缩短至(4.13±0.48)h,相对生物利用度为200.99%。结论 ZL-004-NP可口服给药改善药物难溶性质提高生物利用度。OBJECTIVE To prepare ZL-004 loaded PLGA nanoparticles（ZL-004-NP） and evaluate its release characteristics in vitro and pharmacokinetics in rats. METHODS In order to determine physico-chemical property of ZL-004, saturation-constant tem- perature method, potentiometrie method and shake flask method were employed to obtain relative parameters, respectively. After inves- tigating single factors, the orthogonal design was used to gain optimal formulation. Then characteristic of ZL-004-NP prepared under condition of best formulation was determined by scanning electromnicroscopy, laser particle size analyzer, dialysis method, respective- ly. Afterward, amounts of ZL-004 in plasma were determined under UPLC-MS/MS and relative bioavailability between ZL-004-NP and its raw material was calculated. RESULTS The feature of ZL-004-NP met aim of experiment, which contained smooth spheres, 121, 34 nm of diameter, 0. 16 of PDI, 89.63% of encapsulation efficiency, 7.65% of loading drug content, sustained release about 216 h in vitro and less burst in initiate stage. In vivo, Cmax of ZL-004-NP was increased robustly 1.7 times, which reached to 125μg· L-1and tmaX was cut down rapidly from （6. 47 ±0. 51 ） h to （4. 13 ±0. 48） h,compared with crude ZL-004. Relative bioavailability be- tween ZL-004-NP and crude ZL-004 was 200. 99%, which greatly improved effect of oral absorption. CONCLUSION ZL-004-NP might be developed to improve water-insolube nature of ZL-004, which could increase oral lative bioavailability.

关 键 词：ZL-004 纳米粒 理化性质 探头超声法 高压均质法 生物if 4用度 

分 类 号：R944[医药卫生—药剂学]