盐酸多西环素微囊制备及其在家兔体内的药动学研究

Preparation of Doxycycline Hyclate Microcapsule and Its Pharmacokinetic in Rabbit

以可生物降解材料壳聚糖为囊材,采用乳化交联法制备盐酸多西环素壳聚糖微囊,考查其形态学特征、载药量、及体外释药情况等;将12只小鼠随机分为2组,每组6只,分别按药物剂量20mg.kg-1灌胃,采用HPLC法,以C18为固定相,流动相为乙腈∶甲醇∶0.01mol.L-1草酸溶液(2∶1∶7),在346nm处对不同时间点的血药浓度进行检测,研究其在家兔体内药动学特征。结果成功制得外观较均一、光滑,平均粒径约10μm,药物含量为20.60%,平均包封率为85.54%且具有明显缓释作用的盐酸多西环素微囊;家兔口服给药盐酸多西环素原药和微囊后主要药动学参数Cmax分别为(1.74±0.00)和(1.10±0.00)mg.L-1,Tmax分别为3和12h,AUC(0-t)分别为(11.71±0.17)和(32.51±0.20)mg.L-1.h,T1/2α分别为(1.16±0.53)和(7.51±2.87)h,T1/2β分别为(2.19±0.38)和(9.00±1.60)h,相对生物利用度为289.4%,药时数据符合一级吸收二室模型。说明微囊化后的盐酸多西环素吸收、分布缓慢,生物利用度有了很大提高。

The objective of this study was to prepare the chitosan-microcapsule of doxycycline hyclate by emulsifying cross-linking method,and evaluate its surface morphology,particle size,drug encapsulation efficiency,in vitro-release et al.Doxycycline hyclate solution and microcapsule suspension were orally administrated on health rabbits to study the pharmacokinetic of doxycycline hyclate microcapsule.Six rabbits received single doses of doxycycline hyclate solution at 20 mg·kg-1,and the other six rabbits received doxycycline hyclate suspension at the same doses.The plasma concentration of doxycycline hyclate was determined by HPLC.The stationary phase was C18,and acetonitrile-methanol-0.01 mol·L-1 oxalic acid solution（2：1：7） was taken as the mobile phase,AUV detector was used at 346 nm.Using doxycycline hyclate solution as a reference,their pharmacokinetic differences were compared.The results indicated that the microcapsule was successfully prepared.SEM observation showed the drug-loaded microparticles exhibited sphere-like shape and small particle size was about 10 μm.The mean content and encapsulation efficiency were 20.60% and 85.54%,respectively;In vitro release studies revealed that the drug-loaded microparticles substantially enhanced the release property.The pharmacokinetic data of two groups was in line with a two-compartment model.The main pharmacokinetic parameters were shown as Cmax of（1.74±0.00） vs.（1.10±0.00） mg·L-1,Tmax of 3 vs.12 h,T1/2α of（1.16±0.53） vs.（7.51±2.87） h,T1/2β of（2.19±0.38） vs.（9.00±1.60） h,and AUC（0-t） of（11.71±0.17） vs.（32.51±0.20） mg·L-1·h,respectively.The relative bioavailability of the microcapsule was 289.4%.It resulted that doxycycline hyclate microcapsule exhibited high bioavailability and was slowly absorbed and distributed after administration in the healthy rabbit.