Preparation And Evaluation Of Tetrandrine Submicro-emulsion

This study aimed to investigate the preparation and stability of tetrandrine submicro-emulsion, furthermore, to evaluate its pharmacokinetics,tissue distribution,administration safety and pharmacodynamics. The study may provid some useful data for developing a new tetrandrine preparation for injection.Objective:Tetrandrine is a alkaloid extracted from the root of fourstamen, has activity of dephlogisticate,analgesia,underpressure,anti-silicosis and anti-tumor. The preparation of tetradrine injection on sale will cause some adverse such as pain and phlebitis. To improve these adverses, this study prepared tetrandrine submicro-emulsion for injection, through packaging drug into oil phase, reduced the direct contact with injection site, so reduced the irritation of drug. The study aimed to gain a new preparation of tetradrine which can be made successfully in industrial scale and has stable qulity.Methods:①Preformulation study of tetrandrine. HPLC method was established to detect the content of tetrandrine.The influence of severe condition to detecting tetrandrine was investigated. The dissolubility and oil-water equilibrium coefficient of tetrandrine were investigated.②Formulation and preparation study of tetrandrine. The formulation of tetrandrine submicro-emulsion was optimized by orthogonal-design, and the emulsifier and pH value of the preparation were also optimized. Then the method of preparation was studied, such as preparative method of oil phase,times and pressure of homogen and the sterilization method.③Studies for qulity and stability of tetrandrine submicro-emulsion. The assay methods of particle diameter,Zeta electric potential,envelopment rate,content and relative substance were studied. The compatibility with infusion solution used in clinic was also studied. And the stability of the submicro-emulsion was investigated.④Parmacokinetics and tissue distribution of tetrandrine submicro-emulsion. HPLC method was established to detect the tetrandrine in vivo, the blood plasma sample was processed by liquid-liquid extraction. Then the pharmacokinetics and tissue distribution of tetrandrine in rat were investigated.⑤Safety evaluation of tetrandrine submicro-emulsion. The irritation of submicro-emulsion and injection were investigated by using rabbits. The LD50 of submicro-emulsion and injection in mice were studied.⑥Pharmacodynamics of tetrandrine submicro-emulsion. The antitumous effect of tetrandrine submicro-emulsion was evaluated by tumor-bearing mice model.Results:①The HPLC method can effectively segregate tetrandrine and demethyltetrandrine, and it is sensitive,shortcut and has good specificity. Tetrandrine dissolved in oil was more than that in water. It can dissolve much more in oleic acid. It dissolve well in acidic solution, but dissolve little in alkaline solution.②The best oil phase of tetrandrine submirco-emulsion was composed by 10%MCT,5%LCT,3%phospholipid and 0.5%oleic acid. The emulsifier included phospholipid in oil phase and poloxamer188 in water phase. The pH value was adjusted to 7-7.5. The emulsion was homogened 2-4 times at 1000bar, then sterilized for 15min at 121℃。The submicro-emulsion can be made successfully in industrial scale through this preparation method.③The assay method for detecting tetrandrine submicro-emulsion was reliable and sensitive. This submicro-emulsion can keep stable in 5% glucose solusion, the state doesn't change after being diluted. The stability experiments showed this submicro-emulsion can stay stablely at low temperature.④The study of pharmacokinetics and tissue distribution in rat showed that the AUC,T1/2 and tissue distribution of tetrandrine submicro-emulsion were similar with tetrandrine injection's.⑤The irritative study showed that tetrandrine submirco-emulsion diminished irritation.⑥The antitumor study showed that the depressant effect of tetrandrine submirco-emulsion on Lewis lung cancer cell was similar with tetrandrine injection's.Conclusion:This formulation and preparation method of tetrandrine submirco-emulsion were reliable. Sterilizing the preparation under thermocompression condition was suitable for industrial produce. The depressant effect of tetrandrine submirco-emulsion on Lewis lung cancer cell was similar with tetrandrine injection's. And submirco-emulsion didn't change the characters of drug in vivo, but had slighter irritation. So it maybe apply well in clinic.