复方单硝酸异山梨醇酯缓释片人体生物等效性研究

目的:评价试验制剂复方单硝酸异山梨醇酯缓释片(T) 与参比制剂单硝酸异山梨醇酯缓释片和阿司匹林肠溶片(R) 的生物等效性, 以及缓释制剂释放特点、稳态血浓度和波动度。方法:采用高效液相色谱法分别测定单剂和多剂交叉给药单硝酸异山梨醇酯和阿司匹林代谢物水杨酸经时血浓度, 计算药物动力学参数, 并进行方差分析和双单侧t 检验。结果:单剂给药试验制剂和参比制剂单硝酸异山梨醇酯半衰期(t_1/2) 分别为8.3 ±0.6、8.2 ±0.6 h, 血浓度峰值(C_max) 分别为0.51 ± 0.09、0.53 ±0.09 mg·L^-1, 达峰时间(t_max) 分别为4.8 ±0.4、4.6±0.3 h, 药时曲线下面积(AUC0-t) 分别为4.90 ±0.61、5.2 ±0.8 mg·h^-1·L^-1, 相对生物利用度(F) 为(96.1 ±10.8) %;试验制剂和参比制剂阿司匹林代谢物水杨酸t_1/2分别为2.4 ±0.3、2.5 ±0.3 h, C_max 分别为3.4 ±0.5、3.0 ±0.4 mg·L^-1, t_max 分别为1.7 ±0.2 h 和4.9 ±0.3 h, AUC0-t 分别为13.4 ±2.5 和13.0 ±2.5 mg·h^-1·L^-1, 以水杨酸计阿司匹林F 为(103.6 ±9.6) %。多剂给药试验制剂和参比制剂单硝酸异山梨醇酯C_max 分别为0.68 ±0.14、0.67 ±0.13 mg·L^-1, C_min 分别为0.17 ± 0.03、0.17 ±0.04 mg·L^-1, 波动系数(DF) 分别为(136 ±36) %和(140 ±42) %。结论:单剂和多剂双周期交叉试验,经三因素方差分析和双单侧t 检验, 结果显示试验制剂与参比制剂呈生物等效性;试验制剂中缓释成分单硝酸异山梨醇酯具有明显的缓释特征。

Bioequivalence studies of compound isosorbide-mononitrate sustained release tablets in healthy volunteers

AIM: To compare the bioequivalence of test formulation compound isosorbide-mononitrat sustained release tablets (T) and reference formulation isosorbidemononitrat sustained release tablets and aspirin enteric coated tablets(R), and to evaluate release characteristics and degree of fluctuation of test formulation.METHODS: A high performance liquid chromatography method was used to deter_mine the time-plasma isosorbide-mononitrat and salicylic acid concentrations after a single and multiple oral doses of test and reference formulations in 18 healthy volunteers respectively in an open randomized twoway crossover experimental test.The pharmacokinetic parameters as well as relative bioavailability were calculated with DAS practical pharmacokinetic programme, variance and two one-side t-test were analyzed.RESULTS: The t_1/2, C_max, t_max, AUC0-t for isosorbide-mononitrat after a single oral dose of test and reference were 8.3 ±0.6 and 8.2 ±0.6 h, 0.51 ±0.09 and 0.52 ±0.09 mg·L ^-1, 4.8 ±0.4 and 4.6 ±0.3 h, 4.9 ±0.6 and 5.2 ± 0.8 mg·h ^-1 ·L ^-1, respectively, and the bioavailability of test was (96.1 ±10.8) %, and for salicylic acid, they were 2.4 ±0.3 and 2.5 ±0.3 h, 3.4 ±0.5 and 3.0 ± 0.4 mg·L ^-1, 1.7 ±0.2 and 4.9 ±0.3 h, 13.4 ±2.5 and 13.0 ±2.5 mg·h ^-1·L ^-1, respectively, and the bioavailability of test was (103.6 ±9.6) %.After multiple oral doses of test and reference, the C_max, C_min, DF for isosorbide-mononitrat were 0.68 ±0.14 and 0.67 ± 0.13 mg·L ^-1, 0.17 ±0.03 and 0.17 ±0.04 mg·L ^-1, (136 ±36) % and (140 ±42) %, respectively.CONCLUSION: The compound isosorbide-mononitrat sustained release tablets and isosorbide-mononitrat sustained release tablets and aspirin enteric coated tablets are bioequivalent; the isosorbide-mononitrat of test formulation has sustained release characteristics.