Development Of Oleanolic Acid Intravenous Emulsion

We developed intravenous emulsion of Oleanolic Acid(OA-EM) in this study, optimized the emulsion formula and manufacturing parameters,studied the pharmacokinetic experiments in rats.OA-EM was developed by two-step emulsification(high speed stirring-ultrasonic wave).The optimized formula of OA-EM was composed of 0.1%OA,10%admixture of Soybean oil and MCT(25:75) as the lipid phase, 0.3%Pluronic F68 and 1.2%SPC as the emulsifying agent,2.25%glycerol as the isoosmotic adjusting agent.Emulsion formula and manufacturing parameters were optimized by single factor and orthogonal experiment design,and the final product is stream-sterilizable,with an average particle size of 176nm,and mean zeta potential of-17.5mv,pH value of 7.48,sterilized 20min at 121℃.In vitro release behavior of OA-EM was studied by bulk equilibrium dialysis method.Comparing with OA solution,OA-EM exhibited a certain delayed release profile.Stability of OA-EM was systematically evaluated in a series of experiments, including:Centrifugal method,Vibration test,Freeze thawing test(cold-hot circuit test),Accelerating and Long-term stability tests.Results suggest:OA-EM exhibits good tolerance to the influence of centrifugation(4500rpm,15min),Vibration (100shake/min)as well as thermal cycle(4～40℃),and it is stable in the accelerating and long-term stability tests.In the last part,the pharmacokinetic experiments of OA-EM and OA solution were carded.The pharmacokinetic characteristics of a single dose intravenous injection of OA-EM in rats were investigated compared with that of OA solution, and the data were calculated by means of 3p97.According to compartment-model fitting results,OA-EM and OA solution were both fitted with two compartment-model.T_1/2a of OA-EM and OA solution was 7.817±0.753min and 3.513±0.495min respectively.As the results calculated according to statistical moment theory;AUC of OA-EM and OA solution was 164.96±8.63μg·min·mL^-1 and 89.48±8.28μg·min·mL^-1 respectively,and MRT was 239.84±15.41 min and 134.98±10.22 min.The results indicated that compared with OA solution,OA-EM could prolong the circulating time in vivo.