非诺洛芬钙缓释片的制备及其人体药动学初步研究

Preliminary Studies on the Preparation and Pharmacokinetics of the Fenoprofen Calcium Sustained-Release Tablets

目的研制非诺洛芬钙(fenoprofencalcium,FC)亲水凝胶缓释骨架片,并评价其人体药动学特性及生物利用度。方法以羟丙基甲基纤维素(HPMC)和羧甲基纤维素钠(CMCNa)为二元骨架系统,采用均匀设计法优化FC缓释片。以RP-HPLC测定FC血药浓度,并将优化处方对4名健康志愿者进行药动学和生物利用度初步研究。结果FC缓释片优化处方中骨架材料为HPMCK4M20%,CMCNa15%,体外释放特性呈零级动力学过程;单剂量po300mgFC缓释片与参比制剂(非诺克片)的AUC分别为(134·85±25·96)和(131·14±29·89)mg·h·L-1;tmax为(2·75±0·96)和(0·88±0·5)h;ρmax为(17·52±6·84)和(32·13±6·46)mg·L-1;MRT为(7·72±0·72)和(4·32±0·39)h;缓释片的相对生物利用度为(105·36±23·48)%。结论采用二元骨架系统来控制非诺洛芬钙等水难溶性药物的释放是可行的。

OBJECTIVE To prepare the fenoprofen ealeium（FC）sustained release tablets and study the pharmaeokineties and bioavailability. METItOD A binary polymer matrix was developed. Optimization of the release rate of FC from matrices tablet containing HPMC and CMCNa was made using uniform design. Contour plots were formed based on a quadratic model to assess the release rate of FC in order to select the optimum area. Optimization of formulation was performed applying overlap on the cumulative amounts of FC released after 1,6 and 12 h release time intervals. Plasma concentration of FC was detected by RP-HPLC. The pharmacokinetics and relative bioavailability of FC sustained release tablets and control tablets（300 mg）were investigated in 4 healthy volunteers after oral administration in random 2-way crossover design. RESULTS Optimized formulation contain 20% HMPC K4M and 15% CMCNa presented release rates that were close to the predicted values and its releasing profile fitted the Zero-order equation well. Single dose test showed that relative bioavailability of FC sustained release tablets was （ 105.36 ± 23.48） % ; AUC of sustained release and control tablets were （ 134.85 ± 25.96） and （ 131.14 ± 29.89）μg. ·L^- 1 ; tmax were（2.75 ± 0.96） and （0.88 ± 0.5） h; pmax were （ 17.52 ± 6.84） and （32.13 ± 6.46） mg· L^-1 ; MRT were（7.72 ± 0.72） and（4.32 ± 0.39） h, respectively. The tmax, Pmax and MRT for the two preparations were significantly different, while the AUC for them was equal. CONCLUSION A binary polymer system might be used to control the release rate of slightly soluble drug, such as FC.