| Objective: The aim of this research was to study the pharmacokinetics and relative bioavailabilty of isosorbide 5-mononitrate and aspirin from compound isosorbide mononitrate sustained released tablets in healthy volunteers and to evaluate the bioequivalence.Methods: In a randomized two-crossover design, the test formulation and reference formulation in a single dose or muiltiple doses were given to 20 and 18 healthy male volunteers. The plasma samples, added theophylline as internal standard, were extracted with ethyl acetate. Zorbax DB-C18 (5 μm,2.1 mm×150 mm) analytical column was used, and the mobile phase consisted of A-3 mmol·mL-1 ammonnium acetate(including 0.022% acetic acid) and B-methanol-acetonitrile(85:15), at flow rate 0.17mL·min-1 (A) and 0.03mL·min-1 (B). Isosorbide 5-mononitrate (IS-5-MN) and aspirin (acetylsalicylic acid, ASA) was measured by ESI-MSD, salicylic acid (SA) by DAD. Excel 2000 (Microsoft) was used for calculations, statistics, and graphic interfaces. Measured plasma concentrations of IS-5-MN and SA were used to derive the pharmacokintic parameters. All pharmacokintic parameters, other than Cmax and Tmax, which were directly mesured, were derived by noncompartmental methods. For Isosorbide 5-mononitrate, the relative bioavailability(F) was calculated according to the formula: F=AUC0-t,T/ AUC0-t,R×100%, For Aspirin, the relative bioavailability (F) was calculated according to the formulation: F=AUCm,0-∞,T/ AUCm,0-∞,R×100%. All pharmacokintic parameters, except Tmax, were natural log transformed prior to ANOVA. The bioequivalence of the two formulations was evaluated by two one-sided t test and [1-2α] confidential interval. The analysis of non-transformed Tmax was based on non-parametric Wilcoxon signed rank test.Results: The linear ranges of IS-5-MN , ASA and SA were 6.25～1200μg·L-1(n=9, r=0.9998), 25～1200μg·L-1 (n=7, r=0.9993) and 0.0625～12mg·L-1 (n=9, r= 0.9994) respectively. All method recoveries approached 100%. The extraction recoveries were more than 80%. The RSD values of intra-day and inter-day were less than 6%After a single oral administration of test formulation and reference formulation, the main pharmacokintic parameters of isosorbide 5-mononitrate were obtained as following: AUC0-36h(10025.1±1336.9) and (9472.0±1139.3) μg·L-1·h；Tmax (4.7±1.0) and (4.5±0.8) h；Cmax (661.9±76.5) and (658.0±83.2)μg·L-1, respectively. There was no statistical significant difference between the two formulations on Cmax, Tmax, t1/2, Vd, TBCL values (P>0.05),but significant difference on AUC(P<0.05). The natural log-transformed AUC0-36h and Cmax of the two formulations were analyzed by two one-sided t test. The result showed that the two formulations were bioequivalent. Although the mean AUC0-36h value of test formulation was higher than that of reference formulation, the standard 90% confidential interval for the ratios of the mean values was 103.3%-108.3% and thus within the bioequivalence range of 80%-125%. The standard 90% confidential intervals for Cmax was 103.3%-108.3% and also within the bioequivalence range of 70%-143%. For salicylic acid, the main pharmacokintic parameters were AUC0-∞ (21.86±6.33) and (18.87±5.38) mg·L-1·h；Tmax (0.8±0.4) and (4.7±1.0) h；Cmax (605±1.13) and (3.80±0.87)mg·L-1, respectively. The result of the statistical analysis showed all pharmacokintic parameters of the two formulations had significant difference(P<0.05). The natural log-transformed AUC0-∞ and Cmax of the two formulations were analyzed by two one-sided t test. The result showed that AUC of the two formulations were bioequivalent, but Cmax weren't bioequivalent. The 90% confidential interval for the ratios of the mean AUC0-∞ were 104.5%-115.7%, which was within the bioequivalence range of 80%-125%, but the 90% confidential intervals for Cmax was 147.6%-175.9%, which was outside the acceptable the range of 70%-143%. The result of the statistical analysis showed that the two formulations were of bioequivalence in extent of... |
