Research On The Global Pharmaceutical Properties And Solid Dispersion Micro-pellets Of Salvia Miltiorrhiza Diterpene Quinones Composition

Traditional Chinese medicine component was a complex system. As the material foundation of Traditional Chinese Medicine, there was still no perfect method to characterize or evaluate the diverse properties of TCM component in the past many years, which ultimately hindered the process of modernization and internationalization of TCM preparation. To resolve the key issues faced during the modernization of traditional Chinese medicine, we took salvia miltiorrhiza diterpene quinone composition as the model drug, investigated new ideas of the TCM component preparations based on holistic characteristics, and innovatively put forward a series of key technologies and evaluation methods to characterize the overall nature of traditional Chinese medicine component at the same time. The main contents in the dissertation as follows:1.Determination of the representative components and their structure of salvia miltiorrhiza diterpene quinones composition.To choose the forms of the representative components on the platelet aggregation and coagulation system in vitro, whose pharmacological effects have no significant difference with salvia miltiorrhiza diterpene quinones composition. The different forms had different efficacy, however the main components group A (cryptotanshinone, tanshinone Ⅰ and tanshinone II A) and group B (cryptotanshinone, dihydrotanshinone Ⅰ, tanshinone I and tanshinone II A) had no significant differences with salvia miltiorrhiza diterpene quinones composition on platelet aggregation and coagulation system, they could promote blood circulation, prolongclotting time (TT) and activate partial thromboplastin time (APTT).Rat models of acute myocardial ischemia were induced by hydrochloride isoproterenol. The electrocardiogram(ECG) J point change, cellular enzyme (SOD, MDA, CK, LDH) levels and pathology (myocardial histological changes) of the main components group A, group B and salvia miltiorrhiza diterpene quinones composition were observed. Salvia miltiorrhiza diterpene quinones composition and the main components group B could reduce ECG performance, improve the activity of CK and LDH, significantly increase the activity of SOD and reduce the content of MDA. There was no significant differences between salvia miltiorrhiza diterpene quinones composition and the main components group B on the all aspects. Therefore, the four components including tanshinone II A, tanshinone Ⅰ, cryptotanshinone and dihydrotanshinoneI could be used as the representative components of salvia miltiorrhiza diterpene quinones composition.The four representative components namely tanshinone II A, tanshinone I, cryptotan-shinone and dihydrotanshinone I were determined by HPLC-DAD, and the content were33.6%,20.96%,9.4%and5.8%respectively. 2. The application of the similarity analysis and weight coefficient method in the study of the properties of salvia miltiorrhiza diterpene quinones composition.To evaluate the degree of deviation and dispersion of component by the similarity analysis method based on Cosine and Grubbs. Taking the representative components as the index, equilibrium solubility and apparent oil/water partition coefficient in different pH values solutions were determined, the four representative components exhibited certain similarities and the fluctuate of each value are in a small range of the discrete degree. The weight coefficient method was used to fit the value of each component. The equilibrium solubility of the salvia miltiorrhiza diterpene quinones composition was between2.91-9.96μg·ml-1, which belonged to the very slightly soluble. And the oil/water partition coefficient values LogP ranged from2.24to3.73, that show good fat-soluble, therefor salvia miltiorrhiza diterpene quinones composition mainly had the solubility problems.3. The preparative technology of salvia diterpenoid quinone solid dispersion micro-pellets.Taking the dissolution rate of the representative composition as the index, compare the five kinds of carrier material including PVP K30, PEG4000, PEG6000, P188and P407. The dissolution results showed that PVP K30was better than the others. Solvent method was applied to prepare different drug load ratio of PVP K30solid dispersion separately with1:3,1:6and1:9. Taking the dissolution effects and drug content into account, we took drug load ratio of1:6to prepare salvia diterpene quinone-PVP solid dispersion.The solubility and dissolution of salvia miltiorrhiza diterpene quinones composition and its PVP solid dispersion were investigated in a0.5%aqueous solution of SDS. Using the weight coefficient to fit the solubility and the cumulative dissolution percentages of the respective components. Compared with the bulk drug, the solubility of PVP solid dispersion increased30.84times, the cumulative dissolution percentage within120min was89.35%.Considering the sphericity (planar critical angle φ) and yield(f) to choose the suitable excipients, drug loading, wetting agents and glidant. Taking the cumulative dissolution percentage as the indexes, the proper disintegrant and its appropriate dosage was investigated. Taking planar critical angle φ and yield f weighted composite score (f-2φ) as indicators, the orthogonal test was designed to research the extrusion frequency, spheronization frequency and spheronization time. The optimum preparation process were as follows:Formula was calculated as50g, salvia miltiorrhiza diterpene quinones solid dispersion25g, silica powder2g, CMS Na2g, the wetting agept was appropriate70%ethanol. The optimum conditions for extrusion frequency and pheronization frequency were25Hz and30Hz, spheronization time was6min, the final preparation of salvia miltiorrhiza diterpene quinones composition solid dispersion pellets roundness and good yield, the cumulative dissolution percentages within120min was88.92%.4. The bioavailability evaluation of Salvia miltiorrhiza diterpene quinones composition and its solid dispersion micro-pellets.To investigate the bioavailability of salvia miltiorrhiza diterpene quinones composition and its solid dispersion micro-pellets by UPLC-MS/MS. The statistical moment parameters were calculated by non-compartmental model. Compared with the bulk drug, the bioavailability of four representative components in solid dispersion pellets were increase. The results showed that after oral administration of solid dispersion micro-pellets, Cmax and AUC0～∞, of the four components increased significantly compared with salvia miltiorrhiza diterpene quinones composition. Cmax of dihydrotanshinone I, tanshinone I, cryptotanshinone and tanshinone ⅡA were improved by1.86,1.76,1.90and1.57times and AUC0-∞were improved by1.41,1.60,1.92and1.93times respectively. Based on the approach of self-defined weighting coefficient based on the area under the curve from zero to weight coefficient the holistic pharmacokinetic profiles of salvia miltiorrhiza diterpene quinones composition could be obtain, the relative bioavailability of the composition was162%.