Delicaflavone Injectable:Preparation And Its In Vivo Pharmacokinetics In Rats

Delicaflavone is a biflavonoid compound existing in the Selaginella doederleinii Hieron and other herbals or plants.It has good antitumor activity and excellent safety profiles.It is worth further research and development.Previous studies have found that Delicaflavone is insoluble in water and is not conducive to oral or injectable administration.Therefore,it is necessary to carry out Delicaflavone dosage form studies to improve its water solubility.In this paper,we carried out Delicaflavone injectable preparations,its in vitro antitumor activity and in vivo pharmacokinetic in rats.The main contents and results of this paper are as follows:First,a high-performance liquid chromatography?HPLC?method for the determination of Delicaflavone was established.Then,we studied the physical and chemical properties of Delicaflavone and the method to improve the solubility of Delicaflavone to make it into injectables.The solubility of Delicaflavone was investigated in different pH solutions,using a mixed solvent or cyclodextrin inclusion compound.The results show that the solubility of Delicaflavone can be improved by using a mixed solvent of ethanol:propylene glycol:water=25%:30%:45%.Further study found that Delicaflavone was instable in aqueous solution.It was made into freeze-dried powder for injection and using 25%ethanol and 30%propylene glycol to reconstitute before use.The bulking agents and antioxidants were screened.The experiment showed that when using the sucrose as a bulking agent,the appearance of Delicaflavone powder was good,and the stability of Delicaflavone was improved by using Na₂S₂O₃ as antioxidant.The results showed that Delicaflavone injection was stable in injection water,glucose injection and sodium chloride solution within 8hours.MTT assay was used to detect the inhibitory effect of different doses of Delicaflavone injection on the proliferation of human lung cancer cell A549,human colon cancer cell HCT116,human hepatoma cell line HepG2 and human pancreatic cancer cell line PANC-1.The results showed that Delicaflavone injectable had inhibitory effect on the growth of four kinds of cancer cells,the IC50 was 18.41±0.33?g/mL,44.19±3.76?g/mL,33.02±0.77?g/mL and 67.79±5.51?g/mL respectively.The results were consistent with our previous study on Delicaflavone.Indicating that Delicaflavone is made into an injection without affecting its antitumor activity,while increasing its solubility,and its druggability may be improved.A LC/MS method for the determination of Delicaflavone in rat plasma was established and used in the study of plasma pharmacokinetic of rats.SD rats were injected with Delicaflavone injection at a dose of 1 mg/kg,2 mg/kg and 4 mg/kg.The venous blood was collected at 2.5,5,10,15,30,45,60,90,120,240,360 min after administration.The plasma drug concentration was detected,the pharmacokinetic parameters were calculated and the elimination process of Delicaflavone in rat plasma was analyzed.The results showed that Delicaflavone injection had a short biological half-life(t_1/2=41.735±10.186⁴4.763±11.776 min),it removed rapidly in the plasma?CL=0.015±0.003⁰.017±0.002 L/min/kg?,and the AUC were positively correlated with the dose,indicating that Delicaflavone was linear pharmacokinetic process in rats.