Feasibility Study Of Glycyrrhizin Acid As An Active ’Pharmaceutical Excipient’

Objective:1.The naringenin nanosuspension was constructed by the solubilization and biological surface activity of glycyrrhizin acid,and the nanosuspension was fixed by the characteristics of glycyrrhizin acid hydrogel to improve the stability of nano-preparation.2.The new dosage of glycyrrhizin acid hydrogel loaded with naringenin nanosuspension was constructed.The role of glycyrrhizin acid’solubilization,biological surface activity,hydrogel properties and the advantages of this new dosage form in pharmacokinetics and pharmacodynamics experiments were evaluated by in vitro and vivo experiments.To evaluate the feasibility of glycyrrhizin acid as an active’pharmaceutical excipient’and expand the application field of glycyrrhizin acid.Methods:1.Preparation of naringenin nanosuspension.The effects of medium,concentration and p H on the formation conditions of glycyrrhizin acid hydrogel were optimized.The rheological characteristics of the hydrogel,the morphological characteristics of the freeze-dried powder and the infrared and X-ray diffraction patterns were characterized.The safety and the drug release behavior of hydrogel drug delivery system were evaluated.2.The change process of drug in vivo and the variation of blood concentration with time under the influence of hydrogel drug loading system were studied.3.A mouse model of cholestasis was established byα-naphthyl isothiocyanate.The appearance of the liver and the serum were observed.The serum of ALT（glutamic pyruvic transaminase）,AST(glutamic oxalacetic transaminase,ALP（alkaline phosphatase）,TBA（total bile acid）,TBIL（total bilirubin）,DBIL（direct bilirubin）,IBIL（indirect bilirubin）were analyzed.The liver and the spleen index were calculated.The oxidative stress and inflammatory factors in the liver of mice were determined.The H&E staining was performed to investigate the pathological changes of the liver.Results:1.The 30 mg/m L of glycyrrhizin acid in water had better stability,and the preparations were safety,no hemolysis and vascular irritation.The cumulative release of naringenin in 24 hours of naringenin solution,naringenin nanosuspension,glycyrrhizin acid hydrogel loaded with naringenin solution,glycyrrhizin acid hydrogel loaded with naringenin nanosuspension in gastro-intestinal were 24.54±0.78%,61.70±0.68%,47.78±1.35%,95.50±4.07%,respectively.The cumulative release of naringenin in 24 hours of naringenin solution,naringenin nanosuspension,glycyrrhizin acid hydrogel loaded with naringenin solution,glycyrrhizin acid hydrogel loaded with naringenin nanosuspension in PBS were 29.15±1.80%,67.07±6.20%,35.81±3.25%,90.58±4.40%,respectively.2.After a single oral administration of 90 mg/kg naringenin,the pharmacokinetic curves and pharmacokinetic parameters of naringenin solution,naringenin nanosuspension,glycyrrhizin acid hydrogel loaded with naringenin solution,glycyrrhizin acid hydrogel loaded with naringenin nanosuspension were significantly different,C_max were 1076.2,3119.3,2305.1,3460.3 ng/m L,AUC_0→t were 6307.2,8941.5,14492,22934 ng/m L.h,respectively.3.The model of cholestasis was established successfully byα-naphthyl isothiocyanate.Different drug treatment groups had different therapeutic effects.The glycyrrhizin acid hydrogel loaded with naringenin nanosuspension had the best therapeutic effect.The indexes of serum and liver could be restored to normal levels.Conclusion:Glycyrrhizin acid hydrogel was uniform,safe and non-toxic in aqueous solution.In vivo and in vitro experiments indicated the superiority of glycyrrhizin acid hydrogel and its drug-loading system.Glycyrrhizin acid hydrogel not only has strong pharmacological activity,but also conforms to the characteristics of pharmaceutical excipients.Therefore,glycyrrhizin acid will be expected to become a new active’pharmaceutical excipient’and will expand the application field of glycyrrhizin acid.