头孢丙烯国产口服制剂质量评价与生物等效性初步预测的研究

Quality assessment and bioequivalence primary prediction of domestic oral dosage forms of cefprozil

目的:评价头孢丙烯国产口服制剂质量并初步预测生物等效性。方法:采用HPLC法分析原料及制剂的杂质谱变化,采用光纤探头与流通池法结合,模拟胃肠环境下,研究头孢丙烯片、分散片和胶囊的溶出曲线及溶出行为差异。HPLC法:采用Alltima-C_(18)色谱柱(4.6 mm×250 mm,3.5μm),柱温25℃,流速1.0 mL·min^(-1);有关物质测定时以0.23%磷酸二氢铵溶液—甲醇的为流动相,梯度洗脱,检测波长为225 nm;溶出曲线实验时,以磷酸二氢铵溶液(称取磷酸二氢铵20.7 g.加水1 800 mL使溶解,用磷酸调节pH至4.4)-乙腈(90∶10)为流动相,检测波长为280 nm。光纤溶出法:分别以水、介质1、介质2为溶出介质,溶出体积900 m ,采用转篮法,转速为100 r·min^(-1),分别在4、8、10、30 min时取样。流通池法:以水、介质1、介质2为溶出介质,温度37.0℃,流速4 mL·min^(-1),分别在3、6、10、15、30 min时取样。结果:国产头孢丙烯制剂中主要杂质为头孢羟氨苄,属工艺杂质;各剂型中头孢羟氨苄与总杂质控制较好,分别约含0.3%和0.4%左右;与专利药相比,无明显差异;国产头孢丙烯片具有与专利药相同的体外溶出行为;分散片和胶囊的体外溶出行为与片剂相似,无明显差异,表现为快速释放。结论:头孢丙烯国产口服制剂质量较好,工艺较稳定;国产头孢丙烯片与专利药相比,药品质量无差异,体外溶出实验初步预测二者生物等效;而分散片和胶囊的快速溶出,对保证头孢丙烯的临床抗菌效果是有利因素。

Objective： To evaluate the quality and preliminarily predict bioequivalence of domestic oral dosage form of cefprozil ; Methods： To analyze the changes of impurity profile between API and dosage form by using HPLC, and study the difference in dissolution behaviors of cefprozil tablet, dispersible tablet and capsule in vitro simulated gastrointestinal environment by using fiber-optic dissolution and flow-through cell method. The HPLC method was carried out on a Alltima-C18 column （4.6 mm×250 mm,3.5μm） with mobile phase at a flow rate of 1.0 mL· min^-1, and the column temperature was 25 ℃ The mobile phase of related substance detection consisted of 0. 23% ammonium biphosphate-methanol with gradient elution, and the detection wavelength was 225 nm; the mobile phase of dissolution profile detection consisted of ammonium biphosphate （ 20. 7 g ammonium biphosphate, dissolved in 1 800 mL water, pH was adjusted by phosphoric acid to 4. 4 ） -acetonitrile （ 90 ： 10 ）, and the detection wavelength was 280 nm. The fiber-optic dissolution method was carried out using dissolution medium （ water, medium 1, medium 2 ）, the dissolution volume is 900 mL; the basket method was adopted with a rotating speed of 100 r· min^-1, and was sampled at 4, 8, 10, 30 min, respectively. The flow-through cell method was carried out using dissolution medium （water, medium 1, medium 2 ） with the medium temperature at 37.0 ℃, the flow rate was 4 mL· min^-1, and was sampled at 3,6, 10, 15, 30 rain, respectively. Results： The main impurity was cefadroxil, which existed in dosage forms and belonged to a process impurity. The control limits of single and total impurity was better, which were approximately 0.3% and 0.4%. Compared with the brand-name drug, the domestic tablet of cefprozil exhibited the same behavior of in vitro dissolution, and no significant difference of dissolution behavior was found in dispersible tablets and capsules in vitro environment, and all oral dosage forms showed the quick release. Conclusion： The quality of domestic oral dosage form of cefprozil is good and the preparation process is stable. Bioequivalence is found between the brand-name drugs and domestic tablet of cefprozil according the experimental results of the primary prediction. Rapidly dissolving is more favorable to guarantee the clinical antibacterial effect for dispersible tablet and capsule of cefprozil.