| Isoliquiritigenin(ISL)is a flavonoid compound isolated from the traditional Chinese medicinal material Glycyrrhiza uralensis.Its low solubility in water and poor bioavailability in the body limited its further clinical application.Therefore,in this subject,a thin film dispersion method was used to load ISL onto different amphiphilic polymer materials(F127 and P123)to form micellar solution.The differences in dissolution ability and improvement in bioavailability were explored by in vitro and in vivo experiments.DPPH free radical was used to examine the antioxidant activity of ISL and ISL-loaded preparations.Furthermore,pathological mouse models were employed to investigate the hepatoprotective effect of the drug and preparations.Altogether,this study was conducted to increase the theoretical basis for the further clinical application of ISL.Chapter? ReviewThis chapter first introduces the research overview of ISL and its related preparations,including the physicochemical properties,pharmacological activities,and preparations of ISL;then it describes the formation mechanism,mode of action,and classification of micelles as one of the nanometer drug delivery carriers.The application and prospect of polymer micelles are also analyzed.The review of ISL and micelles in this section provides a theoretical basis and direction guidance for subsequent experiments.Chapter? Preformulation StudiesIn this chapter,by determining the maximum UV absorption wavelength of ISL,a method for the determination of ISL by high performance liquid chromatography was established.The standard curve of drug concentration and peak area(n=3,R~2=0.9999)has a good linear relationship in the range of 0.1-200?g/mL,with a limit of detection of 0.7 ng and a limit of quantification of 2 ng.The solubility experiments of ISL in three solutions with different pH value found that the solubility of the drug in pH 1.2 hydrochloric acid solution,neutral deionized water,and pH 7.4 buffered saline solution were 2.52±0.11?g/mL,3.74±0.33?g/mL,4.95±0.76?g/mL,respectively.From the above data,it can be determined that ISL is a poorly soluble compound,which provides a theoretical basis for improving its solubility by using pharmaceutical methods.Chapter? Preparation and in vitro Evaluation of ISL-F127 MicellesIn this chapter,the ISL-loaded F127 micelles(ISL-F127)were prepared by the thin-film dispersion method.The measured particle diameter was 24.97±0.70 nm,the polydispersity index was 0.199±0.009,and the zeta potential was-38.52±0.27mV.In addition,the encapsulation efficiency of this preparation was 91.65%and the drug loading rate was 5.73%.The in vitro release behavior of ISL-F127 investigated by dialysis method showed that its cumulative release in media of pH 7.4,pH 7.0 and pH 1.2 was about 50%,which was only a small increase compared to the free drug.This result suggested that the release effect was not good enough and needed further improvement.However,preliminary stability experiments showed that the ISL-F127had little sedimentation at extremely high speed of centrifugation and had good storage stability within 30 days.In addition,the DPPH free radical scavenging experiment showed that the ISL-F127 could achieve the same clearance effect as free ISL.This chapter demonstrates that triblock copolymer F127 can successfully encapsulate ISL to form micelles.This formulation has a small particle size,uniform distribution,good stability and similar scavenging effect on free DPPH radical to free ISL.However,its release performance in aqueous media is not ideal,which needs to be improved.Chapter? Preparation and in vitro Evaluation of Mixed ISL-loaded MicellesIn this chapter,the ISL-loaded mixed micelles(ISL-F127/P123)were screened and prepared.The ratio of polymer excipient to drug in the formulation was determined to be 15:1,and the ratio of F127 percentage was 35%.The particle size of the prepared ISL-F127/P123 was 20.12±0.72 nm,the polydispersity index was 0.183±0.046,the potential was-38.31±0.33 mV,the encapsulation efficiency was 93.76%,the drug loading was 5.86%.The in vitro release test showed that the cumulative release rate within 12 h in pH 1.2 hydrochloric acid,water,and pH 7.4 phosphate buffer solution were 77.66±1.51%,82.06±2.01%,and 85.48±3.42%,respectively.Centrifugation acceleration test and storage test showed that ISL-F127/P123 has good stability.In vitro antioxidant data showed that at the same concentration,ISL-F127/P123 achieved a clearance effect comparable to that of the free ISL.Chapter? Studies on Pharmacokinetics Parameters and Hepatoprotective Activity of ISL-loaded micellesIn this chapter,the method for in vivo analysis of ISL using acetanilide as an internal standard substance was established,and a standard equation based on the ratio of peak area of??free ISL and internal standard against concentration of ISL was established,which laid the foundation for study on the in vivo characteristics of ISL.The pharmacokinetic parameters of ISL and its drug-loaded micelle preparations were studied by intragastric administration of rats.It could be seen from the results that the peak concentrations of ISL-F127 micelles and ISL-loaded mixed micelles had been increased by 3.90 and 6.20 times compared to free drug;the half-life had been extended from 1.85 h to 3.99 h and 4.71 h;the AUC of ISL-F127 and ISL-F127/P123was XX h??g?mL~-11 and 28.13±5.7 h??g?mL~-11 respectively,which is 162.17%and223.08%of free drug,indicating that both preparations had successfully improved the oral bioavailability of ISL and the ISL-F127/P123 micelle preparation worked better than ISL-F127.By measuring the levels of ALT and AST in the liver in mice with acute liver injury,the hepatoprotective effect of the ISL was studied.The results showed that both ISL-loaded micellar preparations could successfully reduce the levels of ALT and AST in serum,and also could reduce the concentration of MDA in damaged liver.In addition,the mixed micelles of ISL performed better than ISL-F127micelles in reducing ALT and AST,indicating that the mixed micelle formulation not only had good in vitro characteristics,but also could be effectively used in vivo. |
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