The Preliminary Pharmaceutical Research On Cerebral Ischemia Protective Diterpene Quinone From Radix Salvia Miltiorrhiza

Danshen,the dried roots and rhizome of Salvia miltiorrhiza(Fam.Labiatea),is one of the commonly used traditional Chinese medicines.Decades of studies have made much achievement on biological features,chemical constitents,pharmacological effects, mechanisms of action,clinical preparation and clinical application.These studies have revealed that liposoluble diterpene quinones and water-soluble phenolic acids are main bioactive components of Danshen,in which the former has showed diverse pharmacological actions,such as antibacterial activity and anti-inflammatory effect,inducing apoptosis, protecting nervous system and the cardia cerebral vessels.Among these diterpene quinones, tanshinoeâ…¡A is paied more attention for its extraordinary curative effect.This work deals with the extraction prosess of the liposoluble tanshinones,the optimization of the purification technology of tanshinoneâ…¡A,and the preliminary preparation studies,such as solid dispersion,dripping pills and aerosol in order to develop suitable anticerebral ischemia preparation for clinical use.This work including the following three parts:1.The maximum extraction yield in the extraction process of the liposoluble tanshinones has been obtained through orthogonal experimentsfor.Then the tanshinones have been enriched through water-precipitation,concentration,etc.To obtain high purity tanshinoneâ…¡A,we have improved the multifunctional apparatus for column chromatography to isolate and purify the tanshinones.This equipment can save the solvents,improve efficiency,reduce the volatilization of solvents,so it can protect the environment.Finally,high purity tanshinoneâ…¡A has been prepared by recrystallization.The cerebral ischemia protectivity of tanshinoneâ…¡A has been studied on the mice model of focal cerebral ischemia.The results show that at the dose of 20mg/kg,10mg/kg,5mg/kg,tanshinoneâ…¡A could significant improve the neurological function of focal cerebral ischemia mice induced by middle cerebral artery occlusion and markedly reduce their infarct size.Tanshinoneâ…¡A could also enhance the SOD activity and remarkably decrease the MDA content in the blood serum.This result suggested that the cerebral protective effect of Tanshinoneâ…¡A may closely related to its antioxydation effect. 2.Solid dispersions of tanshinoneâ…¡A with Poloxamer 188 as a carrier were prepared by hot melting method to improving its dissolubility.The solid dispersions were characterized by scanning electron microscopy(SEM),Powder X-ray diffraction(PXRD),differential scanning calorimetry(DSC),Fourier transform infrared spsectroscopy(FTIR).The results from SEM and PXRD analyses showed tanshinoneâ…¡A existed as a microcrystalline form. The solubility of tanshinoneâ…¡A in solid dispersions was enhanced three times more than its physical mixture with its dissolution rate in fifteen minutes exceeded 50%(That of the physical mixture is below 10%.Solid dispersions were given orally to SD rats and determineed the absolutely bioavailability.The low bioavailability of tanshinoneâ…¡A was relevant with the dissolution rate,but the main factor may be the first pass effect of liver.3.To improve its bioavailability,preliminary preparation studies by other routes of administration on tanshinoneâ…¡A were carried out.On the basis of solid dispersion,dripping pills were prepared using poloxamer 188 as medium.The best parameters for this process were obtained though orthogonal experiments.Aerosol was parepared using HFA 134a as propellent and ethanol as cosolvent.