Development And Pharmacokinetic Study On Liquiritigenin Injection

As a monomer component of flavanone extracted from licorice,liquiritigenin has a variety of pharmacological activities like anti-inflammation,antibiosis,liver protection,anti-tumor,and so on.Among them,study on anti-tumor effect in vivo and in vitro suggested that liquiritigenin showed prominent effect on anti-tumor and was expected to become next effective drugs of anti-tumor.According to basic technical guidelines of drug preparation research,liquiritigenin was enzymolyzed and purified from liquiritin as object,this research studied on several aspects as preformulation study,preparation process,quality and stability study,and preliminary studies on pharmacokinetics of drug preparation in vivo,in order to provide a reference for the preparation development and utilization of liquiritigenin.The specific topics of this thesis are as follows:1.Preparation and structure identification of liquiritigenin materialsCrude liquiritigenin was obtained by hydrolyzing liquiritin using aglycone as enzyme and liquiritin as raw materials,and the high-purity liquiritigenin(purity>97%)was purified with Sephedex LH-20 column.Then structure was identified by UV,IR,HPLC spectra,in order to provide qualified materials for subsequent preparation study.2.Preformulation studiesAn HPLC method for determination of liquiritigenin was established.Equilibrium solubility and apparent partition coefficient of liquiritigenin was measured in different solvents and different pH conditions by classic shake-flask method,and the influence of factors were examined such as effects of acid,alkali,light,temperature and oxidation on the stability of the main drug liquiritigenin.The results showed that liquiritigenin had poor water solubility,moderate apparent partition coefficient and was unstable under alkaline conditions.These results may lay foundation for the next prescription and technology research.3.Prescription and technology research on liquiritigenin injectionWe determined liquiritigenin injection as the dosage form of drug based on clinical needs and physicochemical property,and then determined the formulation solvents,excipients dosage,pH,pyrogen removal methods and sterilization process through single factor,ultimately filtered out the best prescription formulations and processes conditions.4.Quality research on liquiritigenin injection and study on preliminary stabilityFirstly,we did the qualitative research on liquiritigenin raw material for injection,from four aspects including character,identification,inspection(loss on drying,residue on ignition,heavy metals,related substances)and content determination to control quality;then according to requirements of injections in "Chinese Pharmacopoeia" 2010 appendix,we studied on quality of three batches of preparations;Finally,based on the quality of research preparations,three batches of preparation samples were studied on accelerated stability,the results showed that three batches of samples were stable under accelerated stability conditions within three months.5.Pharmacokinetic studies on liquiritigenin injectionA method of liquiritigenin determination in biological samples was established using UHPLC-MS/MS analytical techniques.Then this method was applied to study on the pharmacokinetics of liquiritigenin injection in rats,its linear kinetics characteristic of absorption process in vivo over the dose range was clarified and major pharmacokinetic parameters and plasma concentration-time curve were obtained,in order to provide a scientific basis for the evaluation of preparation and in-depth research.