沙拉沙星/β-环糊精包合物微囊的特性分析

Characterization and Analysis of SAR/β-CD Inclusion Complex Microcapsules

旨在制备并表征沙拉沙星/β-环糊精(SAR/β-CD)包合物微囊新制剂,测定增溶倍数和包封率,进行SAR/β-CD包合物微囊的体外溶出与体内药代动力学研究。采用搅拌法制备包合物微胶囊,用透射电镜、扫描电镜和粉末X光衍射技术进行物态表征。采用液相色谱法测定SAR/β-CD包合物微囊的增溶倍数和包封率,通过溶出试验研究SAR/β-CD包合物微囊在磷酸盐缓冲液(pH6.8)中的释放规律。最后,进行了环糊精包合物微囊在鸡体内的药代动力学评价。理化表征试验证明,药物进入β-环糊精空腔,成功获得了SAR/β-CD包合物微囊。3个试验批次的SAR/β-CD包合物微囊的平均增溶倍数和平均包封率分别为(25.3±1.15)倍和90.3%±0.15%。在磷酸盐缓冲液(pH6.8)中SAR/β-CD包合物微囊的溶出率为95.6%,而普通粉剂的溶出率仅为72.2%,包合反应后的制剂溶解度和溶出度均有显著提高。药代动力学试验中血药浓度检测的标准曲线为y=1.5632 x-0.1896,R 2=0.9993,在0.25~10.00μg·mL-1内呈良好的线性关系。分析方法的精密度RSD值小于10%,分析方法的准确度大于90%,同时小于110%;回收率试验表明,低浓度(0.50μg·mL-1)回收率为90.55%±3.81%,中浓度(1.00μg·mL-1)回收率为93.85%±3.14%,高浓度(2.50μg·mL-1)回收率为98.19%±5.41%。冻融试验表明冻融稳定性(n=3)符合《中华人民共和国兽药典》(2015版)规定。鸡口服药代动力学试验表明,SAR/β-CD包合物微囊和沙拉沙星粉的AUC(mg·h-1·L-1)、T max(h)、C max(μg·mL-1)分别为43.59±0.50、2.18±0.09、5.99±0.30和17.27±0.30、0.98±0.07、1.19±0.10。成功制备沙拉沙星/β-环糊精包合物微囊新剂型,明显提高了药物的溶出率和生物利用度,对喹诺酮类药物的推广应用具有重要意义。

A new formulation of sarafloxacin/β-cyclodextrin(SAR/β-CD)inclusion complex microcapsules was prepared and characterized,and its solubilization ratio and entrapment efficiency were determined.The dissolution and pharmacokinetics of SAR/β-CD inclusion complex microcapsules were studied in vitro and in vivo.The inclusion complex microcapsules were prepared by the stirring method.The characterization was carried out by transmission electron microscope(TEM),scanning electron microscope(SEM)and powder X-ray diffraction(PXRD).The solubilization ratio and entrapment efficiency of SAR/β-CD inclusion complex microcapsules were determined by liquid chromatography,and the release of SAR/β-CD cyclodextrin inclusion complex microcapsules in phosphate buffer(pH6.8)was studied by dissolution experiment.Finally,the pharmacokinetics of inclusion complex microcapsules was evaluated in chicken with oral administration.Physical and chemical characterization showed that the drug entered theβ-cyclodextrin cavity and SAR/β-CD inclusion complex microcapsules were successfully obtained.The average solubilization ratio and entrapment efficiency of the three batches of SAR/β-CD inclusion complex microcapsules were 25.3 times and 90.3%,respectively.The dissolution rate of SAR/β-CD inclusion complex microcapsules in phosphate buffer(pH6.8)was 95.6%,while that of common powder was only 72.2%.The solubility and dissolution of the preparation were significantly improved after the inclusion reaction.In pharmacokinetic experiments,the standard curve of pharmacokinetic determination of plasma concentration was y=1.5632 x-0.1896,R 2=0.9993,which showed a good linear relationship in the range of 0.25-10.00μg·mL-1.The precision RSD of the analytical method is less than 10%,and the accuracy of the analytical method is more than 90%and less than 110%.The recovery experiments showed that the recovery rates of low concentration(0.50μg·mL-1),medium concentration(1.00μg·mL-1)and high concentration(2.50μg·mL-1)were 90.55%±3.81%,93.85%±3.14%and 98.19%±5.41%,respectively.The freeze-thaw experiment shows that the freeze-thaw stability(n=3)accords with the regulations of China Veterinary Pharmacopoeia(2015 edition).The pharmacokinetic tests showed that the AUC(mg·h-1·L-1),T max(h)and C max(μg·mL-1)of SAR/β-CD inclusion complex microcapsules and sarafloxacin powder were 43.59±0.50,2.18±0.09,5.99±0.30 and 17.27±0.30,0.98±0.07,1.19±0.10,respectively.A new dosage form of SAR/β-cyclodextrin inclusion complex microcapsule was obtained,which can significantly improve the drug dissolution rate and bioavailability.It is of great significance to the popularization and application of quinolones.