Preparation And Evaluation Of Curcumin-Glycyrrhizin Solid Dispersion

Objective To clarify the feasibility of glycyrrhizin as a solid dispersion carrier to improve the solubility and oral bioavailability of curcumin,and to investigate the interaction between glycyrrhizin and curcumin in vitro and in vivo.The present study will lay foundation for the development of new preparations.It will also provide reference for elucidating the combination mechanism of turmeric and licorice.Methods1.The micelle morphology of glycyrrhizin was observed by transmission electron microscope,the critical micelle concentration of glycyrrhizin solution was determined by pyrene fluorescence probe method.The reversibility and retentiveness of glycyrrhizin hydrogel were investigated,and the effects of temperature and concentration on gel viscosity were studied.The effects of gel formation and lyophilized process on the molecular structure of glycyrrhizin were evaluated by FTIR.2.The formulation were optimized according to curcumin solubility of solid dispersion.The solubility of curcumin and glycyrrhizin in three different media of purified water,0.1 N HCl and p H 6.8 PBS were determined.The dissolution of curcumin and glycyrrhizin in 0.1 N HCl,p H 6.8 PBS were also determined.3.The interaction between curcumin and glycyrrhizin was studied by FTIR and 2D NMR spectra.The existing state of drug was investigated by XRD and DSC.The initial stability test was carried out for 3 months at 40℃and 75%relative humidity.4.HPLC method for in vivo samples was established to determine the concentration of curcumin and glycyrrhizin,respectively.The solid dispersion solution was given orally to rats at a dose of 30 mg/kg（curcumin）for pharmacokinetic study.The tissue distribution was evaluated by oral administration to mice at a dose of 50 mg/kg of curcumin.Results1.Glycyrrhizin forms 20～30 nm spherical micelles in aqueous solution.The critical micelle concentration is 0.2 mg/m L.A hydrogel with good reversibility could be formed when drug concentration reaches 19 mg/m L.The viscosity and strength of the gel were influenced by temperature and concentration.The molecular structure of glycyrrhizin remained unchanged in the process of gel formation and freeze-drying.2.Curcumin was dissolved in acetone and lyophilized with glycyrrhizin solution（1:6,w/w）,the solubility of curcumin was improved by 1.03×10⁴times.The results of dissolution test showed that solid dispersion could significantly improve the dissolution of curcumin in p H 6.8 PBS.3.The results of DSC and XRD showed that curcumin in the solid dispersion was amorphous.The results of FTIR and roesy showed that there was a weak hydrogen bond interaction between the curcumin and glycyrrhizin,which was helpful to improve the stability of the amorphous system.The stability of curcumin in solid dispersion was confirmed by the experimental results.4.The HPLC method for curcumin and glycyrrhizin analysis showed good specificity and stability.The pharmacokinetic tests in rats showed that T_max,C_max,AUC and t_1/2of curcumin in solid dispersions were 0.02,2.70,1.54 and 1.86 times in comparison to that in suspension,respectively.The results showed that oral absorption rate and degree of curcumin were significantly increased whereas the metabolic rate was slowed down.The AUC of glycyrrhizin in solid dispersion was significantly increased and the absorption was slower than that in aqueous solution group.The results of tissue distribution in mice showed that the distribution of curcumin were increased in all tissues.And drug distribution in the lung was improved the most（AUC was 2.31 times of suspension group）.Glycyrrhizin in solid dispersion was mainly distributed in heart,liver and kidney.Its metabolite,glycyrrhetinic acid,was mainly distributed in heart,liver and spleen.Conclusion The Curcumin-glycyrrhizin solid dispersion prepared by solvent method was able to improve the solubility and dissolution of curcumin,and curcumin bioavailability and distribution in lung were also increased.The combination of curcumin and glycyrrhizin in the form of solid dispersion is expected to significantly improve pharmaceutical efficacy and showed promising clinical value.