Study On Purification And Cyclodextrin Inclusion Complexes Of Oridonin

Oridonin is the major antitumor components of Rabdosia rubescences which is traditionally used in China for the treatment of a variety of cancers. Due to the low toxicity of oridonin, abundant resource of Rabdosia rubescences and the obvious pharmacological activity of oridonin, it has attracted special attention and was regarded as a promising anticancer drug. But most research on oridonin is about its pharmacological activity and mechanism, and no systemic research on the dosage form of this drug is reported and no successful product has been put onto the market. This is resulted from the difficulty in the separation and purification of oridonin and from its low aqueous solubility.Based on preliminary study on the physico-chemical properties of oridonin, this paper focuses on the optimization of process of the extraction and purification of oridonin, and mainly on the further purification of oridonin. To increase the aqueous solubility of oridonin, the inclusion complex of oridonin with hydroxypropyl-β-cyclodextrin （HP-β-CD） and sulfobutylether-β-cyclodextrin （SBE-β-CD） were prepared. Furtherly, lyophilized powder for injection of oridonin was prepared based on the inclusion complex, and the quality research was carried out. Lastly, the pharmacokinetics of oridonin/ SBE-β-CD inclusion complex in rats was studied to elucidate the influence of SBE-β-CD on the pharmacokinetic behavior of oridonin.The phyciso-chemical properties of oridonin were studied, especially the equilibrium solubility and stability. As a result, the aqueous solubility of oridonin was quite low, and decreased as the pH increased. The solubility of oridonin in organic solvents such as methanol and alcohol were quite high. Oridonin in solution was unstable to heat and light, and was more unstable in basic solution. In solid phase, the stability of oridonin was good.According to the physicochemical properties of oridonin, the process of extraction and separation of oridonin was improved. The cold extraction method with alcohol was adopted to avoid the degradation of oridonin in heating extraction. The amount of activated carbon for decoloration was decreased to 5% of that of DongLingCao, and the heating time was decreased to 10 mins. The yield of semi-finished oridonin was enhanced. Additionally, method of further purification of oridonin was developed, We adopted silica gel column chromatography, and gradient elution with mixture of chloroform and acetone. As a result, the yield of oridonin with purity over 99.2% was 30.33 %, and that of oridonin with purity over 97.13 % was 76.8 %. It was an effective method of preparation of highly purified oridonin.Solubilization and inclusion complexation of HP-β-CD and SBE-β-CD on oridonin was investigated. The solubility enhancement of oridonin was evaluated by phase solubility method, and the two phase solubility curves displayed typical A_L-type, indicating the formation of 1:1 inclusion complexes. The inclusion stability constants and of the two inclusion complexes were calculated to be 107.7 M^-1 and 84.25 M^-1, respectively, and the complexation efficiencies were 29.8 % and 25.7 %, respectively. There was a nearly 27 fold increase on the solubility of oridonin by inclusion complexation with HP-β-CD. The inclusion complexes of oridonin with HP-β-CD and SBE-β-CD had been produced by lyophilization. The inclusion complexes were characterized by DSC and ROSEY techniques.To solve the unstability of oridonin in solution, the lyophilized powder of oridonin for injection was prepared by lyophilization. The quality study was carried out, and the stability of oridonin was proved to be fine.The pharmacokinetics of lyophilized powder of oridonin/SBE-β-CD in rats was studied to elucidate the influence of SBE-β-CD on the pharmacokinetic behavior of oridonin. As a result, there was no significant difference between the pharmacokinetic parameters of lyophilized powder of oridonin/SBE-β-CD and the reference oridonin solution. This indicated that SBE-β-CD had no significant influence on the pharmacokinetic behavior of oridonin.