Studies On Preparation Of Compound Suan Zao Ren Granules And Pharmacokinetics Of Its Main Components

Suanzaoren Decoction(SZR)is derived from the Synopsis of Golden Chamber written by the eastern han dynasty physician Jing Zhong Zhang.It is composed of Semen Ziziphi Spinosae,Poria cocos,Rhizoma Anemarrhenae,Rhizoma Chuanxiong,Radix and Glycyrrhizae Uralensis.It has the functions of nourishing blood and regulating liver,clearing away heat and removing blood stasis,nourishing heart and tranquilizing the mind and so on.It has played an important role in sedative,hypnotic,anti depression,anti anxiety,anti convulsion,anti neurasthenia and protection of cardiovascular and cerebrovascular diseases.The clinical efficacy of Suanzaoren Decoction(SZR)decoction in the treatment of intractable insomnia due to deficiency of yin and yang.However,due to the unclear mechanism of action,and the material basis of efficacy is not clear,it has not been developed as an effective traditional Chinese medicine preparation.Effective material system ourprevious screened Suanzaoren Decoction play a sedative and hypnotic based on the effective fractions + total polysaccharides,the effective ingredients of Suanzaoren granules as the research object,carries on the preparation process,quality standard,plasma protein binding rate and pharmacokinetic studies will provide a scientific basis for the as a new dosage form of Suanzaoren Decoction and guide clinical medication safety.(1)Study on preparation technology of particlesConsidering Semen Ziziphi Spinoase granules as a whole,the preparation process was investigated.By the method of Uniform design and orthogonal experiment,the extraction technology was studied,aobtaining reliable technical parameters;types and dosage of Supplementary material and the critical relative humidity were studied systematicly by using Modern preparation technology.then the reasonable preparation process was established;Pilot verification was carried on and it can be stepped into industrialization.(2)Quality standard studyBy using modern Analysis methods,Semen Ziziphi Spinoase granules' s characteristics,TLC,Content determination of a variety of effective composition,the size of the granules,melting of granules,heavy metals,arsenic salt,and water examination were systematically investigated and developed the preparation quality standard and perfect,can effectively control intrinsic quality of Semen Ziziphi Spinoase granules.(3)The determination of plasma protein bindingTo establish a UPLC-MS/MS assay for seven five parts from Semen Ziziphi Spinoase granules,determination of the five kinds of components protein binding rate in plasma of rat,and to and to provide the reference for security of drug usage in clinical practice.Ultrafiltratio-UPLC-MS/MS method is adopted to simultaneous determine mangiferin,ferulic acid,liquiritin,spinosin and timosaponin B? five effective components plasma protein binding situations.The ultrafiltration membrane can adsorb each test object,which adsorbs spinosin glycosides strongest.The content detection in high,medium and low concentration of plasma protein combined rate was(27.29% ~ 91.08%),the concentration of plasma protein binding rate of no concentration dependent and from high to low: spinosin,timosaponin B?,mangiferin,liquiritin,ferulic acid.The combination of these five components with the rat plasma protein binding,The experiment for clinical safe medication to provide a reference.(4)Pharmacokinetic studyTo establish a method for the simultaneous determination of mangiferin,ferulic acid,liquiritin,spinosin and timosaponin B?by UPLC-MS / MS for the first time,puerarin as internal standard,using ESI source in negative ion mode,multiple reaction monitoring(MRM)analysis.The recoveries of the analytes were between 78%~114%,and the relative recoveries of the analytes were between 74%~118%,and the specificity,matrix effect,precision,accuracy and stability of the method were in accordance with the requirements of biological sample analysis.The plasma concentration of rats were given different doses of Semen Ziziphi Spinoase granules after 5 kinds of components were determined by the established method,All five constituents in rat plasma showed good dose-exposure relationship with plasma concentrations.Five compounds fitted well to a two-compartment model with first-order absorption except liquiritin in low dose group,and so are mangiferin and liquiritin in hige dose group.Conclusion The UPLC-MS assay was successfully applied for the pharmacokinetic study of multi-constituents of Semen Ziziphi Spinoase granules with different doses.Except for mangiferin,there were significant differences in the pharmacokinetic models of the 4 compounds in high and low dose groups.