Preparation Of Isoliquiritigenin Self-microemulsion And Its Pharmacodynamics

Isoliquiritigenin?ISL?is a flavonoid containing chalcone structure,which mainly exists in the roots of Glycyrrhiza,astragalus,Dalbergia,soybean,etc.it has a wide range of pharmacological activities,such as antioxidant,anti-inflammatory,anti-tumor,cell protection,etc.,but ISL has the disadvantages of low solubility in water,poor oral absorption,low bioavailability,etc.However,its clinical application is limited.In this paper,the self-microemulsifying drug delivery system?SMEDDS?of ISL was prepared to solve the problems of low water solubility and poor oral absorption of ISL,so as to increase its bioavailability in-vivo and improve its anti-hyperuricemia?HUA?.The paper is divided into the following five parts:Chapter one:ReviewsThis chapter mainly introduces the physical and chemical properties,pharmacological activities and research progress of ISL,then introduces the characteristics,prescription composition and research status of SMEDDS,finally summarizes the research progress of HUA,including the mechanism of action,therapeutic drugs,etc.It provides a theoretical basis for the follow-up study.Chapter two:Pre prescription study of ISL-SMEDDSIn this chapter,the in-vitro HPLC analysis method of ISL was established,the in vitro standard curve was established,and the methodology was investigated.The equilibrium solubility and oil-water partition coefficient of ISL in the medium of pH1.2 HCl solution,pH 6.8 PBS solution and double distilled water solution were investigated.The results showed that the solubility of ISL in water was the highest,which was 6.09±0.55?g/mL,and the solubility of ISL in pH 6.8 PBS was the lowest,which was 3.85±0.31?g/mL,indicating the poor water solubility of ISL.The oil-water partition coefficients of ISL in pH 1.2 HCl,pH 6.8 PBS and double distilled water were 2.57,2.49 and 2.51,respectively,indicating that ISL has strong hydrophobicity.Chapter three:Preparation and in-vitro evaluation of ISL-SMEDDSFirstly,the solubility of ISL in different oil phase,emulsifier and co emulsifier was investigated.The compatibility of the primary screened oil phase with the emulsifier was investigated.The pseudo ternary phase diagram was used to screen the oil phase,emulsifier and co emulsifier,which were ethyl oleate,Tween-80 and PEG-400 respectively.The optimal formulation of ISL-SMEDDS was selected by combining the star point design response surface method,which was 21.17%for oil phase and emulsifier 62.09%,CO emulsifier 16.7%.At last,the best preparation process was determined by single factor experiment:the preparation temperature was37?,the stirring speed was 300 rpm,and the stirring time was 20 min.In-vitro characterization of ISL-SMEDDS was carried out.The type of microemulsion formed by ISL-SMEDDS was identified as O/W microemulsion by staining method.The microemulsion formed by ISL-SMEDDS after self emulsification was spherical and smooth by transmission electron microscopy.The average particle size of ISL-SMEDDS was 44.78±0.35 nm,the polydispersity index?PDI?was 0.20±0.01,the zeta potential was-10.67±0.86 mV,the encapsulation rate was 98.17±0.24%,and it had good stability.The results of in-vitro release showed that the cumulative drug release rate of ISL-SMEDDS was significantly higher than that of ISL,and it could prolong the action time of ISL in-vivo.Chapter four:Pharmacokinetics of ISL-SMEDDS in ratsIn this chapter,the HPLC method for the determination of ISL concentration in rat plasma was first established,and the methodology was investigated.The pharmacokinetics of ISL and ISL-SMEDDS were studied in rats.The non-compartment kinetic model was used to calculate the pharmacokinetic parameters and evaluate ISL-SMEDDS in-vivo.The results showed that the plasma concentration of ISL-SMEDDS was significantly higher than that of ISL.The half-life T_1/2/2 of ISL and ISL-SMEDDS were 8.14 h and 24.07 h,respectively,and the MRT was 7.04 h and 9.73 h,respectively,which indicated that ISL-SMEDDS had sustained-release effect.In addition,AUC_{0-24 h}-24 h of ISL and ISL-SMEDDS were 2.72±0.26?g/mL and12.81±1.40?g/mL,respectively.AUC_{0-24 h}-24 h of ISL-SMEDDS was significantly higher than that of ISL.The bioavailability of ISL-SMEDDS is 4.71 times higher than that of ISL.The results showed that the oral bioavailability of ISL-SMEDDS was significantly improved.Chapter five:Study on the anti-HUA and gouty arthritis activity of ISL-SMEDDSIn this chapter,the in-vivo analytical method for the determination of UA in blood was established and the methodology was investigated.A rat model of acute Hua was established by intraperitoneal injection of potassium oxyzinate and intragastric administration of hypoxanthine.The results showed that both ISL and ISL-SMEDDS could significantly reduce the UA and XOD activities in the blood of rats with HUA.The difference was statistically significant?p<0.01?.The histopathological sections showed that ISL and ISL-SMEDDS had better organ protective effects on rats with HUA.The gouty arthritis model was successfully established by injecting sodium urate?MSU?solution into the articular cavity of rats.The results showed that both ISL and ISL-SMEDDS could significantly reduce the degree of joint swelling in the model rats,and the difference was statistically significant?p<0.01?,also could reduce the levels of IL-1?,TNF-?and IL-6.And the effect of ISL-SMEDDS is better than that of ISL,which shows that SMEDDS can improve the efficacy.