The Human Pharmacokenetic Study Of Two Sustained-release Preparations

Two specific, sensitive and simple HPLC-UV method were developed to determine roxithromycin and metformin hydrochloride levels in human plasma. The methods were successfully used in pharmacokinetic studies of metformin hydrochloride sustained-release tablet and roxithromycin sustained-release granule in human.1. Study on the Pharmacokinetics of roxithromycin sustained-release granule in human A sensitive and rapid HPLC-UV method was developed to determine roxithromycin levels in human plasma. The sustained-release granules (T) and regular granules (R) of single and repeated dose were orally administrated to healthy volunteers in randomized crossover design. The analytes were extracted from plasma samples by liquid-liquid extraction, separated on a Diamonsil C₁₈ column and detected by a UV detector. Clarithromycin was used as the internal standard. The mobile phase was acetonitrile-methanol-0.05mol/L phosphoric acid (pH 7.0) (30:35:60, v/v) , at a flow rate of 1.4 mL/min. The UV detector was set at 220nm. The linear calibration curve was obtained in the concentration range of 0.25-32μg/mL. The lower limit of quantification (LLOQ) was 0.25μg/mL. The intra-day and inter-day precision, expressed as the relative standard deviation (RSD), were less than 3.0% and 5.2%, determined from QC sample for roxithromycin. The accuracy was within±5.3% in terms of relative error. The C_max (7.82±1.23μg/mL) of regular granules after single oral dose of 300mg roxithromycin in 18 healthy volunteers was higher than that of sustained-release granules(7.07±1.53μg/mL). The T_max(3.78±0.88h) and t_1/2 (17.23±3.50h) of T was significantly longer than those (T_max : 1.75±0.77h, t_1/2 14.38±3.26h) of R (PO.05). No significant difference in main pharmacokinetic parameters was found between the two preparations by analysis of variance (ANVOA) and 90% confidence intervals of AUC_0-t and C_max fell within the acceptable range for bioequivalence. The sustained-release granules of roxithromycin was bioequivalent to its regular granules.The relative bioavailability of sustained-release granules was found to be 109.6±6.9%. After repeated oral dose of roxithromycin the T_max (3.61±0.61h) of T was significantly longer than that (1.81±0.82h) of R (P<0.05). No significant difference in AUC^ss was found between the two preparations by analysis of variance (ANVOA) and 90% confidence intervals of A UC^ss fell within the acceptable range for bioequivalence. The relative bioavailability of sustained-release granules was calculated to be 106.6±13.4%.The sustained-release granules exhibited a sustained- release property with a significantly longer T_max and a lower C_max.2. Study on the pharmacokinetics of metformin hydrochloride sustained-release tablet in humanA sensitive and rapid HPLC-UV method was developed to determine the metformin hydrochloride concentration in human plasma. The sustained-release tablets (T) and regular tablets (R) of single and repeated dose were orally administrated to healthy male volunteers in randomized crossover design. The metformin hydrochloride and the internal standard, atenolol, were separated on a Diamonsil C₁₈ column after precipitation of protein with acetonitrile. The mobile phase was a mixture of 40% acetonitrile, 0.01 mol/L sodium dodecyl sulphate and 0.02 mol/L potassium dihydrogen phosphate (pH 3.7). The flow rate was set at 1.0 mL/min. The UV detector was set at 233nm. The linear calibration curve was obtained in the concentration range of 10～5000ng/mL. The lower limit of quantification (LLOQ) was 10ng/mL. The intra-day and inter-day precision, expressed as the relative standard deviation (RSD), were less than 4.3% and 11.7%, determined from QC sample for metformin hydrochloride. The accuracy was within±4.5% in terms of relative error. The average C_max (2126±487ng/mL) of regular tablets after single oral dose of 1000mg metformin hydrochloride in 20 healthy volunteers was significantly higher than that of sustained-release tablets(1660±439ng/mL). The T_max (4.15±1.09h) of T was significantly longer than that of R(2.53±1.03h)(P＜0.05). No significant difference in main pharmacokinetic parameters was found between the two preparations after the analysis of variance (ANVOA) and 90% confidence intervals of AUC_0-t and C_max fell within the acceptable range for bioequivalence. The sustained-release tablet of metformin hydrochloride was bioequivalent to its R. The relative bioavailability of T was calculated to be 97.0±10.2%. After repeated oral dose of metformin hydrochloride, the T_max (3.64±0.85h) of ST was significantly longer than that (2.14±0.70h) of R (P＜0.05). T exhibited a sustained-release property with a significantly longer T_max and a lower C_max.