| 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, this drug 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 to our knowledge, no systemic research on the dosage form of this drug is reported and no successful product has been put onto the market.This paper systemically studied the drug as viewed from dosage from. We mastered the in vitro and in vivo behavior of oridonin through preformulation study, and designed the proper dosage forms for it. We studied the possibity of preparing oridonin-hydroxypropyl-β-cyclodextrin (HP-β-CD) complex, submicron emulsion, liposome and solid lipid nanoparticles, and found HP-β-CD complex and liposome are suitable drug delivery systems for oridonin. Oridonin-HP-β-CD complex and liposome were prepared and evaluated by us.Firstly, this paper determined the physical-chemical property of oridonin, especially for its equilibrium solubility, partition coefficients for the n-octanol—water/buffer solution systems and stability.The equilibrium solubility of oridonin in water is 0.725 mg·mL-1 at 25℃and has lower values in basic buffer solutions. The equilibrium solubility of oridonin in organic media was also detected and oridonin has high solubility in high polarity organic media such as methanol and ethanol, while the solubility is poor in low polarity organic media such as petroleum ether and n-hexane. The partition coefficients for the n-octanol—water(lgPapp) of oridonin is 1.66, which showed oridonin has moderate hydrophobicity. The partition coefficients for the n-octanol—buffer solution systems varied little with the pH values of phosphorate buffer solution. The stability of oridonin in solution is poor. Light and high temperature can reduce the stability of oridonin in solution. Oridonin was less stable along with the increase of pH values at the interval of 4～10 and was most stable at pH4. According to the physico-chemical properties of oridonin, we improved the process of the extraction and purification of oridonin, and by the new process more oridonin was got and the purity of oridonin was also enhanced.Secondly, this paper studied the pharmaeokineties of oriodnin in rats and its distribution in mice.After intravenous administration, the plasma concentration of oridonin first decreased rapidly and then more slowly, that is to say, the plasma concentration of oridonin after intravenous administration decreased bi-exponentially and the terminal elimination half-life was relatively long (about 10 h). After intravenous administration, the pharmacokinetic parameters of oridonin were dose-independent at three doses, 5, 10 and 15 mg/kg. These results show that oridonin exhibits linear kinetics following intravenous administration over the dose range studied. The enterohepatic circulation may pay contribution to the plateau in the plasma concentration-time curves.The oral absolute bioavailability of oridonin was rather low (4.32-10.85％) and appeared to be dose-dependent. Considering the amount of unchanged oridonin recovered from the gastrointestinal tract and feces 48 h after oral administration (the mean value was approximately 6.52％), the low oral absolute bioavailability values are most likely due to hepatic, gastric, and/or intestinal first-pass effects. While the dose-dependent phenomenon may be resulted from the saturation of first-pass metabolism.After intraperitoneal administration of oridonin solution to rats at a single dose of 10 mg/kg, the bioavailability of oridonin was 12.64％. This result shows that hepatic first-pass effect may be the main reason for the low oral bioavailability of oridonin.The distribution of oridonin after intravenous administration of oridonin at a dose of 20 mg/kg to mice was detected. After oridonin was administrated, it distributed widely and quickly except brain. The concentration of oridonin in heart, lung and kidney was high, but the concentration of oridonin in heart and lung decreased quickly while the concentration of oridonin in spleen decreased slowly. On the contrary, the concentration of oridonin in liver was low soon after drug administration and increased until it reached a maximum value at the time of 0.5 h after drug administration.Lastly, this paper studied the dosage form design of oridonin. Considering the poor water solubility and oral bioavailability of oridonin and severe side effect of organic medium, we planned to develop organic medium free colloidal drug delivery system including HP-β-CD complex, submicron emulsion, liposome and solid lipid nanoparticles. This paper studied the solubilizing effect of HP-β-CD on oridonin and the action between oddoain and HP-β-CD. Though the action between oridonin and HP-β-CD was poor, HP-β- CD was a good solubilizing agent for oridonin and the concentration of oridonin in HP-β-CD solution can fit clinical requirement.Using DSC and X-ray diffraction, we confirmed the formation of oridonin-HP-β-CD complex. And with the help of UV, IR and 1H-NMR, we got that the active radical of ofidonin(α-methylene-cyclopentanone) was not in the cavity of HP-β-CD, so it can not be protected by HP-β-CD. Though HP-β-CD can not protect oridonin for degradation, the solid state of oddonin-HP-β-CD complex is rather stable. Furthermore, powder of the complex can form clear solution when water is added, and the solution keeps clear when dilution.Pharmacokinetics behavior of oridonin-HP-β-CD complex in rat is similar with oddonin solution solubilized with organic medium. Only the distribution rate of oddonin after intravenous administration of oridonin-HP-β-CD complex increased slighty which induced a smaller AUC value.Distributioin of ofidonin after intravenous administration of oridonin-HP-β-CD complex is different from that of oridonin solution. Less distribution in heart and more in lung was got after intravenous administration of oddonin-HP-β-CD complex. Safety experiment showed the oddonin-HP-β-CD complex did not induce hemolysis or irritation and fit for parenteral drug delivery.Considering the stability and entrapment efficiency of the dosage forms as well as the chemical stability of ofidonin, we considered that liposome prepared by "freeze-drying of monophase solutions" method is for fit for the delivery of oridonin.Preparing with the optimized method mentioned above, we will get liposome with entrapment efficiency of 63％or so. The average particle size of the liposome is 119 and its distribution is narrow. After stored for 12 h, entrapment efficiency did not decreased significantly and no precipitation was found.Safety experiment showed the oridonin loaded liposome did not induce hemolysis or irritation and fit for parenteral ues.Pharmacokinetics behavior of oridonin loaded lipsome in rat was different from that of oridonin solution solubilized with'organic medium. The distribution rate of oridonin increased slighty while the terminate rate decreased significantly. The apparent elimination half-life extended to about 2 folds of that after intravenous administration of oridonin solution. The longer apparent elimination half-life induced a bigger AUC value. Distributioin of oridonin after intravenous administration of oridonin loaded liposome wass different from that of oridonin solution. Compared with oridonin solution, oridonin loaded liposome enhanced the liver distribution and reduced the distribution in heart significantly. While the distribution in spleen and lung was slightly reduced and the drug distribution in brain was increased.
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