Study On Preparation And Pharmacokinetics Of Quercetin-loaded Mixed Micelles Composed Of Pluronic P123/F68

The polymer micelle is a kind of new nanometer drug delivery system formed by amphiphilic block copolymers,and it composed spontaneously through hydrophobic interaction in aqueous solution.The polymer micelle is consist of core and shell structure with different functions:the core as a carrier can solubilize poorly water soluble drugs,meanwhile,the shell not only can help micelle escape recognizing and uptaking by the reticuloendothelial system?RES?,but also can prolong the circulation time and maintain the drug stability in the body.Unlike the surfactant,the amphiphilic block copolymers are more safer.Also polymeric micelle is the carrier of anti-cancer,anti-inflammatory and gene therapy medicine.In this research,to prepared the Quercetin loaded mixed micelles composed of Pluronic P123 and Pluronic F68,we used quercetin as the model drug,Pluronic P123 and Pluronic F68 as the ingredients to improve the disadvantage of low water solubility of quercetin.We also investigated the characters of mixed micelles,according to physicochemical properties,drug release behavior in vitro,and pharmacokinetics of rats.The methods and results are as follows.1.Preparation of the Quercetin loaded mixed micellesUltraviolet spectrophotometry was used to determine the content of medicine,and the thin-film hydration method was used to prepared the mixed micelles.By using entrapment efficiency and loading efficiency as criteria,evaluated the effects of amount of quercetin,P123 mass fraction,temperature of rotary evaporation,temperature of water bath,amount of water on the characteristics of micelle.The mixed micelles formulation was optimized by orthogonal design.The optimized prescription was 20 mg of quercetin,50%of P123 mass fraction,40?of water bath,5 mL of water phase.The entrapment efficiency and loading efficiency of mixed micelle were?94.25±2.13?%,?8.61±0.18?%respectively.2.Physicochemical properties and drug release behavior in vitro of Quercetin loaded mixed micellesTransmission electron microscopy was used to observed the morphology of mixed micelles.Particle size and zeta potential were measured by the Malvern Instruments.And pyrene fluorescent probe method and DSC?Differential Scanning Calorimeter,DSC?was carried out of evaluated the CMC?Critical Micelle Concentration,CMC?and the physicochemical properties of the micelles.The optimized micelle were spherical and the mean particle size and zeta potential were?77.88±1.07?nm,?-17.12±1.29?m V respectively.The CMC value was 0.338 mg·mL^-1The result of DSC indicated that quercetin encapsuled into micelles successlly.We also choose 4%mannitol as the protective agent to prepared the lyophilized micelles and tested the stability at the same time.The test showed that the leakage rate of quercetin mixed micelles reached 20.04%at ambient temperature after 4 days.However the leakage rate of lyophilized quercetin loaded micelles were 2.67%at 4?after 1 month.The stability of lyophilized micelles was preliminarily shown.The dynamic membrane dialysis technique was used to investigate the vitro release behaviors of mixed micelles compared with free quercetin solution:physiological saline contained 1%Tween-80 as the release medium,release temperature was 37?,and the rotation rate was 100r·min^-1.The results indicated that the quercetin mixed micelles could described by Higuchi model and expressed by the equation:F=6.735·t^0.5?Rsqr_adj=0.9604,AIC=75.5840?.The free quercetin solution could described by First-order model and expressed by the equation:F=100·[1-Exp?-0.379·t?]?Rsqr_adj=0.9555,AIC=46.7969?.So mixed micelles had the effect of made quercetin release slowly.3.Pharmacokinetic studies of Quercetin loaded mixed micelles in rats in vivoThe research established UPLC?Ultra Performance Liquid Chrom-atography?method to measure the plasma concentration of quercetin in rats.We also used self-made quercetin solution as control preparat ion to studied the pharmacokinetics after tail intravenous quercetin lo aded mixed micelles in rats.The pharmacokinetic parameters were ca lculated with PK Solver.The results showed that internal process of quercetin solution and mixed micelles fitted two compartment model.The elimination half-lives of quercetin mixed micelles and solution were 34.88 min and 30.47 min,plasma clearance were 0.026 mL·min^-11 and0.037 mL·min^-1.This manifested that quercetin micelles could reduce the process of drug elimination in rats plasma.The pharmacokinetic parameters were calculated on the basis of non-compartment model indicated that the AUC_0-inf-inf of quercetin mixed micelles and solution were289.52?g·mL^-1·min and 192.86?g·mL^-1·min,MRT were 27.06 min and11.22 min.Pharmacokinetic parameters of quercetin mixed micelles and solution had statistically significant difference?P<0.05?,and even very significantly difference?P<0.01?.It can be proven that the Quercetin loaded mixed micelles composed of Pluronic P123 and Pluronic F68 could raise the water solubility of it and make quercetin release slowly.It also could reduce the clearace rate,prolong the elimination half life and improve the area under the curve of quercetin through intravenous injection.So this mixed micelles had a broad application prospect.