The Pharmacokinetic Study Of Ferulicacid-co Tetramethylpyrazine And Development Of Tablet

China has rich resource of Chinese medicine, an effective way to search new drugs is searched for active ingredients in traditional Chinese medicine prescriptions, and synthesized by chemical methods. It is also one important way for innovative drug research.According to the treatment of promoting blood circulaton by Chinese medicine, Prof.Tan Zaiyou had separated and extracted a new compound-- ferulic acid-co-tetramethylpyrazine(FATM) from Chinese medicine prescriptions. In addition, Prof.Tan had synthesized FATM by chemical methods, and conducted a preliminary study on pharmacology, that the result showed FATM with antithrombotic effect and low toxicity. In 2000, Pfo.Tan had applied for Chinese patent for FATM, and had received patent licensing in 2005. In 2010, Pfo.Tan had also applied for Chinese patent for crystal of FATM, the application number was 201010562477.0In this thesis,the preformulation had been conducted. The main researches were made and results were as follows:1 The pharmacokinetcs of FATM were determined by HPLC after oral administraion in rabbits.The The blood concentration of FATM were determined in various times.The pharmacokinetic parameters were calculated with 3p97 pharmacokinetic program It was showed that FATM was absorbed rapidly after oral administration and was metabolized quickly.FATM was divided into Ferulic acid (FA) and Tetramethylpyrazine(TMP) in rabbits.The compartmental parameters were as follow: FA was compartment two model.Ka was 4.67h^-1, T_1/2 was0.36h, T_1/2β was 1.68h,T_max wsa 0.38h,C_max was 18.74μg/mL,AUC was36.13μg*h*mL^-1,V/F was 3.87L/kg;TMP was compartment one model.Ka was4.14 h^-1,T_1/2Ka was 0.17 h,T_1/2Ke was 0.36 h,T_max was 0.36h,C_max was 1.86μg/mL,AUC was 1.87μg*h*mL^-1,V/F was 33.07 L/kg。Computing by Kinetica, the Ka of FA was 6.04h^-1, T_1/2α of FA was 0.49h, T_1/2β of FA was 1.84h, T_max of FA was 0.35h, C_max of FA was 18.69μg/mL,AUC of FA was 36.05μg*h*mL^-1,Vc of FA was4.44mL mL/kg;Ka of TMP was 2.59 h^-1,T_1/2Ka of TMP was 0.27 h,T_1/2Ke of TMP was 0.27 h,T_max of TMP was 0.39h,C_max of TMP was 1.81μg/mL. There was no significant difference between the parameters computed by programs 3p97 and Kinetica.The non-compartmental parameters computed by Kinetica were as follow: T_1/2β of FA was 1.69h, T_max of FA was 0.42h, C_max of FA was 17.95μg/mL, AUC of FA was 34.38μg*h*mL^-1, CL of FA was 3.34 L*h*kg^-1, Vss of FA was 6.94 L*kg^-1. T_1/2β of TMP was0.46h, T_max of TMP was 0.33h, C_max of TMP was 2.27μg/mL, AUC ofTMP was 1.83μg*h*mL^-1, CL of TMP was 61.42L*h*kg^-1, Vss of TMP was50.79 L*kg^-1. There was no significant difference between the parameters computed by compartment model and non-compartment model.2. The concentrations of FATM were determined by HPLC after oral administraion in rabbits.The The tissue concentration of FATM were determined in various times.It was showed that FATM was absorbed rapidly after oral administration and was distributed in various organs. The T_max of FA wsa 0.5h in various organs. The AUC of FA in heart,liver, spleen, lung kidney,and brain were 6.68μg*h*mL^-1, 4.19μg*h*mL^-1, 6.04μg*h*mL^-1 , 6.39μg*h*mL^-1 , 31.91μg*h*mL^-1 , 1.27μg*h*mL^-1;The T_max of TMP wsa 0.5h in various organs.The AUC of TMP in heart,liver, spleen, lung kidney,and brain were 0.55μg*h*mL^-1, 0.72μg*h*mL^-1, 0.63μg*h*mL^-1,0μg*h*mL^-1,0.56μg*h*mL^-1,0.41μg*h*mL^-1;The AUC of FA in kidney was highest,which meant that FA was metabolized by kidney. The AUC of TMP in liver was highest,which meant that FA was metabolized by liver. FATM can be detected in brain,which meant that FATM can penetrated into blood brain barrier.The T_1/2 of FA in heart,liver, spleen, lung kidney,and brain were 1.89h, 2.09h, 1.12h,0.95h,1.11h,2.14h;The T_1/2 of TMP in heart,liver, spleen, lung kidney,and brain were 0.26h, 0.28h,0.23h,0h,0.30h,0.35h;The T_1/2 of FA in spleen,lung,kidney were short. The T_1/2 of TMP in heart,liver spleen were short,The MRT of FA in heart,liver, spleen, lung kidney,and brain were 2.08h, 2.52h, 1.59h,1.49h,1.74h,3.04h;The MRT of TMP in heart,liver, spleen, lung kidney,and brain were 0.64h, 0.62h, 0.62h,0h,0.69h,0.78h;The MRT degree of FA was followed by brain, liver heart kidney spleen and lung, while the TMP was brain, kidney, heart, spleen and liver.3 The project was established vitro analytical method of FATM tablet. The content and cumulative dissolution percent of FATM in tablet was determined by UV. The solubility and stability of FATM in various medium was investigated.4. The project was found the preparative method of FATM tablet. The specification of FATM tablet was 100mg/tab. 10%pvp in75%alcohol was used as adhesive. The optimum formulation was designed by the organal method by the following comprsitions:For preparing 10000 FATM tablets,FATM 1000g as the main drug,soluble starch 1000g as filler, Microcrystalline Cellulose 200g as disintegrant.The tablet weigh was 0.22g/tab. Flowability, moisture content and critical humidity of granule were also investigated. The weight variation, friability and dissolution test of FATM tablet were qualified.5. The parameters of degradation kinetics were determined by Kissinger method, the activation energy parameter was 237kJ/mol, the frequency factor is3.02×10^-3. The thero-decomposition kinetics was fist-order kinetics.