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目的:研制吲哚美辛(IMC)缓释栓,以期为临床提供一种维持时间长、用药方便和不良反应小的吲哚美辛制剂,并考察其释放度、药动学及其相对生物利用度。方法:以PEG400、PEG6000为主要基质,阻滞剂EudragitRL100及黏附剂泊洛沙姆188,采用正交设计法,以体外释放度为指标,优化吲哚美辛缓释栓处方。体外释放度测定采用中国药典2005年版二部转篮法,体内血药浓度用高效液相色谱法测定和3P97程序计算药动学参数。结果:当PEG400-PEG6000为40∶60,EudragitRL100及泊洛沙姆188含量分别为1.0%,6.0%时,体外释药行为符合零级动力学;体内过程为一室模型,药动学参数为t1/2=(2.3±0.5)h,tpeak=(1.9±0.4)h,Cmax=(9.8±2.7)mg·L-1,AUC0→∞=(97.5±18.6)μg·L-1.h,相对生物利用度为(101.7±15.8)%。结论:该制剂与普通栓相比,达峰浓度降低,达峰时间延长,缓释特征明显。
OBJECTIVE: To develop indomethacin (IMC) sustained-release suppository with a view to providing an indomethacin preparation with long-term maintenance, convenient administration and little adverse reaction for clinical use and to investigate its release, pharmacokinetics and its relative bioavailability Utilization. Methods: PEG400, PEG6000 as the main matrix, blocker EudragitRL100 and adhesive poloxamer 188, using orthogonal design method, in vitro release as an index to optimize indometacin sustained release suppository prescription. In vitro release was determined using the Chinese Pharmacopoeia 2005 edition of the two spin-basket method, in vivo plasma concentration using high performance liquid chromatography and 3P97 program to calculate pharmacokinetic parameters. RESULTS: The in vitro release behavior of PEG400-PEG6000 was consistent with the zero-order kinetics when the PEG400-PEG6000 was 40:60, Eudragit RL100 and poloxamer 188 were 1.0% and 6.0%, respectively. The in vivo process was a one-compartment model and the pharmacokinetic parameters were t1 / 2 = (2.3 ± 0.5) h, tpeak = (1.9 ± 0.4) h, Cmax = 9.8 ± 2.7 mg · L-1 and AUC0 → ∞ = 97.5 ± 18.6 μg · L-1.h, The relative bioavailability was (101.7 ± 15.8)%. Conclusion: Compared with ordinary suppository, the peak concentration of the preparation is reduced, the peak time is prolonged, and the sustained-release characteristics are obvious.