Research On The Multiple Drug Delivery System Of Ginkgo Flavone And Ginkgolide Based On Composition Properties

Traditional Chinese medicines are mostly prepared into pill, powder, paste, elixir, and decoction, but with such drawbacks as high administration dose and poor efficay. With the process of modernization of traditional Chinese medicines, new-type preparations have been developed and made outstanding achievements. However, they fail to make an organic intergration between traditional Chinese medicine theories and modern preparation theories. Traditional Chinese medicines are multiple complex, their dosage forms are required to be designed in line with their characteristics, in order to improve the bioavailability of traditional Chinese medicines. Characteristics of traditional Chinese medicines are required to be taken into account during the development of traditional Chinese medicines.Traditional Chinese medicine is composed of several compositions, and there is a certain rario structure between composition and composition. Based on the overall concept of Chinese medicine, we took ginkgo flavone and ginkgolide compositions as the model drug, confined and selected the best structure between ginkgo flavone and ginkgolide compositions initially, investigated the biopharmaceutical properties, including solubility and permeability, and attempted to built the biopharmaceutics classification system of traditional Chinese medicine composition. In the research, on the basis of multiple composition and clear nature of composition, modern multi formulation technologies were taken to improve the property defects of traditional Chinese medicines multiple composition. And a multi-drug release system of traditional Chinese medicines was established, ultimately to achieve the purpose of strengthening the nature of composition and improving the bioavailability. The details are as follows:1. The preliminary research of structure optimization between the ginkgo flavone and ginkgolide compositionsThis part is mainly based on pharmacological experiments of anti-platelet aggregation in vitro, coagulation system and the protect effect on the injury of vascular endothelial cells induced by hydrogen peroxide. Comparing the efficacy strength of the different stucture proportions between ginkgo flavone and ginkgolide compositions on the above three models to select and confine the structure of ginkgo flavone and ginkgolide compositions initially. From the experiment results of this chapter, it could conclude that the ginkgo flavone and ginkgolide compositions of ratio between2:1and4:1had better pharmacological effects, and the ratio was similar to that reported in Chinese Pharmacopoeia. Therefore, the compositions within the ratio scope could be considered as the structure optimizated composition, which provided the basis and object for the subsequent experiments. 2. The research about the biological properties of ginkgo flavone and ginkgolide compositions.To establish a method for the determination of the ginkgo flavone and ginkgolide compositions by UPLC, and the established method was simple and convenient, which provided a reliable, fast and applicable way for the analysis in the further research.The experiment was conducted to measure the equilibrium solubility, apparent oil/water partition coefficient in different pH solutions and the permeability. Using the weight coefficient method to characterize the overall nature of traditional Chinese medicine composition and trying to classify ginkgo flavone and ginkgolide compositions. The results showed that the equilibrium solubility and apparent oil/water partition coefficient in different pH buffer solutions were different. The equilibrium solubility of ginkgo flavone and ginkgolide compositions were373.06～688.61μg·mL-1and20.21～54.27μg·mL-1respectively, and the oil/water partition coefficient values LogP of ginkgo flavone and ginkgolide compositions were0.416～0.602and2.068～2.693, besides, the permeability of ginkgo flavone and ginkgolide compositions from apical side to basal side were0.5545×10-6cm·s-1and3.0252×10-6cm·s-1respectively. Therefore, it could conclude that ginkgo flavone composition had low solubility and poor permeability, while ginkgolide composition had low solubility and general permeability. The determination of biopharmaceutics nature of composition provided a basis for the design of composition formulation.3. Construction of multiple drug release system of ginkgo flavone and ginkgolide compositions by using multiple preparation technologiesIn order to improve the property defects of composition, we use technology of phospholipid complex to solve the problem of poor permeability of ginkgo flavone composition, and using solid dispersion technology to solve the low solubility of ginkgolide composition. Finally, with the help of extruding and rolling technique to prepare micro-pellets delivery units and build multiple drug release system to increase the clinical efficacy of traditional Chinese medicine.4. The evaluation of multiple drug release system of ginkgo flavone and ginkgolide compositionsThis chapter combined release studies in vitro and pharmacodynamics experiment in vivo to evaluate multiple drug release system of ginkgo flavone and ginkgolide compositions and investigate the scientificalness and rationality of multiple drug release system. Firstly, we used the similarity factor method to evaluate each delivery unit and multi-drug release system separately. More than80%ginkgo flavone components and ginkgolide components were released from each delivery unit, which indicated the two delivery units had good release in vitro. The similarity of dissolution profile for ginkgo flavone components and ginkgolide components in the multi-drug delivery system after integrated was compared, and the similarity factor between both compositions indicated that ginkgo flavone and ginkgolide compositions could achieve simultaneous release in the multiple drug release system. Secondly, the pharmacodynamics experiment in vivo of the acute myocardial ischemia model induced by intraperitoneal injection of isoproterenol hydrochloride (ISO) was conducted. And the ECG ST-elevation, heart weight index, myocardial water loss percentage and pathology (myocardial histological changes) were observed to compare the ability of anti-myocardial ischemia of each experimental group. The multiple drug release system of ginkgo flavone and ginkgolide compositions had a stronger inhibitory effect on myocardial ischemic ST-elevation and decrease the heart weight index and reduce the percentage of cardiac. It indicated that the multi-drug release system of ginkgo flavone and ginkgolide compositions had better anti-ischemic ability.