Preparation Of Pterostilbene Nanosuspensions And Preliminary Study On Its Pharmacokinetics

As one of the active constituents of Dragon’s blood,Pterostilbene has many pharmacological activities,especially in cerebrovascular disease,However,its low solubility in water seriously affects its clinical application.So this study is on pharmacokinetics characteristics in mice and their brains of Pterostilbene,which is the model drug,by adopting nanosuspension technology,to establish foundation for the further research and development.The maximum UV absorption wavelength of Pterostilbene was 306nm which is determined by ultraviolet spectrophotometry.Meanwhile,a stable method of HPLC-UV In vitro analysis was established to measure the lipid water partition coefficient.The balanced aqueous phase and oil phase were measured with HPLC,we can’t detect Pterostilbene in various pH aqueous phase,but we can in oil phase.It shows that the solubility of Pterostilbene in water is very low and almost insoluble.Pterostilbene nanosuspension is prepared by anti-solvent precipitation(HGAP),and the particle size and polydispersity index(PDI)were used as evaluation criteria.It was optimized by Box-Behnken response surface methodology and was checked.The experimental data were simulated by software and optimum prescription was predicted by HGAP.The final prescription is:the concentration of Pterostilbene is 36g/L,pluronic F68 is 2.2g/L and Sodium taurocholate is 3.0g/L.The particle size of Pterostilbene nanosuspension is(134.6±2.5)nm.PDI is 0.097±0.006.The SEM images of Pterostilbene and Pterostilbene nanosuspension shown that Pterostilbene nanosuspension was near-spherical and uniformly distributed.In the preparation process of Pterostilbene nanosuspension,it can be inferred that the crystal type of Pterostilbene has changed and non-crystalline Pterostilbene nanosuspension can speed up the dissolution of the drug by the disappearance of characteristic absorption peak in DSC analysis of nanosuspension.And the structure of Pterostilbene which maintains its biological activities didn’t change by IR.The exoteric results demonstrated that the stripping of Pterostilbene was accelerated by HGAP.This paper established the HPLC analysis method for the determination of pterostilbene mouse plasma and brain homogenate,which is rapid,simple and has good specificity,linearity,precision and high recovery rate.Studying the pharmacokinetics characteristics in mice and their brains after intravenous injection and oral Pterostilbene by this method,and the result is:Nanosuspension made tmax of the drug from 30min to 15min,and the highest plasma concentration of the nano suspension and Pterostilbene are(6.23± 1.28)pg/ml and(1.84±0.82)μg/ml.The results showed that nanocrystallization was beneficial to the absorption of Pterostilebene into blood.Pharmacokinetic parameters showed that oral Pterostilbene improved both Cmax and AUC0-∞ to 3.38 folds and 1.47 folds.The absolute bioavailability calculated by the ratio of AUC0-t of intravenous injection and oral Pterostilbene is 80.41%.In addition,by the contrast the CL of oral Pterostilbene and nanosuspension,change of the form could reduce the clearance rate of Pterostilbene in mice,and prolonged the time of drug action to some degree.Pharmacokinetic parameters in brain showed that oral Pterostilbene nanosuspension advanced the tmax of the drug.And the Cmax of the oral nano suspension in brain is higher than the Cmax of oral Pterostilbene,were(0.99±0.17)μg/ml and(0.35 ±0.08)μg/ml;Pterostilbene nanosuspension improved its targeting rate of brain,and the pharmacokinetic parameters showed that Cmax and AUC0-∞ have improved 2.83 folds and 2.76 folds after oralling Pterostilbene.By the contrast,the CL of oral Pterostilbene is much higher than nanosuspension.The mean residence time(MRT)of nanosuspension was also prolonged,indicating that the drug had a longer duration of action in brain.This paper determinated the Pterostilbene in mouse plasma and brain homogenate after oralling Pterostilbene and drew the drug-time curve.And then we found that Cmax is(0.47±0.05)μg/ml,Tmax is 15min,and its bioavailability is a litte low by the contrast with Pterostilbene,AUC0-∞ is 0.55μg h/ml.The target compounds were not detected in mouse brain homogenate,thus it showed that Pterostilbene is better than Resveratrol in treating vascular disease.In all,this paper prepared Pterostilbene nano suspension by HGAP,and studied the pharmacokinetics characteristics in mice and their brains after intravenous injecting and oralling Pterostilbene.Although Pterostilbene is the derivative of Resveratrol whose 3 and 5 phenolic hydroxyls were replaced by methyls,the bioavailability of Pterostilebene were higher than Resveratrol.This study provided the research routes of the application of Pterostilbene in treating brain disease and established the foundation for the futher research and develpoment.