Studies On Pharmacikinetics Of Diclofenic Sodium And Bioequivalenca Of Its Sustained Release Tablets

Diclofenac Sodium is a traditional non-steroidal anti-inflammatory drug.The pharmacokinetics,bioequivalence of Diclofenac Sodium sustained release tablets in vivo as well as its in vitro protein binding ability were investigated in the present studies.A method based on cloud-point extraction(CPE)and high performance liquid chromatography-ultraviolet detection(HPLC-UV)was firstly developed to determine Diclofenac Sodium in rat plasma.The non-ionic surfactant Triton X-114(5%,v/v)was chosen as the extraction solvent.The incubation was carried at 50℃for 20 min.The surfactant-rich phases were separated,and then analyzed by HPLC-UV.The mobile phase was a mixture of sodium acetic buffer(0.02 mol·mL^-1)-acetonitrile(35∶65 v/v)at a flow rate of 1.0 mL/min with detection wavelength at 225 nm.Variable parameters affecting the CPE efficiency were evaluated and optimized.Under the optimum conditions,the method was proved to be reproducible and reliable with intra-day precision below 7.8%,inter-day precision below 11.5%,and accuracy within±5.8%and mean extraction recovery more than 80%,which were all calculated using spiked samples at three concentrations of 0.50,25.0 and 160.0μg/ml for Diclofenac Sodium in plasma.The linear range was from 0.25 to 200.0μg/ml.After strict validation,the method was successfully applied to the pharmacokinetic study of Diclofenac Sodium in rats after intravenous and intragastric administration,respectively.The bioavailability in rats is about 43.4%.Another method was developed and successfully applied to determine Diclofenac Sodium concentrations in human plasma with relatively high extraction efficiency and good separation selectivity.The accuracy,precision,sensitivity,specificity and linearity of this method satisfied the requirement of pharmaceutical analysis in human samples.The equilibrium dialysis combined with HPLC to determine the protein binding rates of Diclofenac Sodium at low,middle and high concentration(100.0,200.0 and 400.0 ng·mL^-1), which were all above 99%.The method was used to evaluate the bioequivalence of Diclofenac Sodium sustained release tablets in 20 healthy volunteers.Diclofenac Sodium concentration in plasma was detected by HPLC after single dose and multiple doses of Diclofenac Sodium sustained release tablet was given to 20 healthy male volunteers in an randomized cross-over design. The main pharmacokinetic parameters of the test preparation and the reference preparation were as follows,single dose:AUC_0-t,were(2103±651.7)and(2265±731.9)ng·h·mL^-1, respectively.The relative bioavailability of the test to reference preparation was 95.4%±21.8%calculated by AUC_0-t.Multiple doses:AUC_SSwere(2923±398.6)and(2844±429.4) ng·h·mL^-1,respectively.The DF/τvalue of reference preparation is 102.9%±18.0%of test preparation,and the relative bioavailability of test to reference preparation was 103.5%±10.3%calculated by AUC_SS.The results of statistic analysis show that the reference preparation and the test preparation are bioequivalent.