Study On The Pharmacokinetics Of Brucea Javanica Oil Emulsion And Development Of Its Rectal Formulation

Brucea javanica oil (BJO), a kind of fatty acid extracted from the nucleoli of Bruceajavanica (L.) Merr.(Simaroubaceae), has been used in treatment of various ailmentsincluding cancer, amoebic dysentery, and malaria. BJO has been used widely to treatcarcinomas because of its broad anti-tumor spectra which had been proved in clinical. Themost common formulation of BJO is emulsion, including oral emulsion and intravenousemulsion, which has been widely applied in clinical for the treatment of lung cancer, brainmetastasis and gastrointestinal cancer. However, such the formulations also have somedisadvantages in production and clinical practices. As to the pharmacokinetic studies, BJOemulsion has seldom reported. Rectal administration may not only undergo hepaticfirst-pass effect, also reduce the stimulus to digestive tract, which is an essential way for thedevelopment of BJO formulations. Therefore, the pharmacokinetics and tissues distributionof BJO emulsion via oral and rectal administration were studied, expecting to provide basisfor clinical use of the emulsion. Rectal administration formulations were preliminarystudied and provided experimental basis for the further development of new BJOformulations.Firstly, the gas chromatography method was established for the determination of oleicacid and linoleic acid in rat plasma and rat tissues. The method was specific, linearity foroleic acid was tested ranging from15.35μg·mL-1to1535μg·mL-1(r=0.9984) in plasma and3.88μg·mL-1to248.05μg·mL-1in tissues (r＞0.99). Linearity for linoleic acid was testedranging from16.91μg·mL-1to1691μg·mL-1(r=0.9992) in plasma and3.77μg·mL-1to241.00μg·mL-1in tissues (r＞0.99). The method recoveries were between80.0%and120.0%and the intra-and inter-day RSD were less than10%. The method was suitable for determination of oleic acid and linoleic acid in rat plasma and tissues.Pharmacokinetics of BJO emulsion after oral administration in rats: six rats were oraladministrated with BJO emulsion, plasma sample was obtained before administration andwhen0.5,1,2,3,4,5,6,8,10,12,18,24,30,36,48hour after administration, theconcentrations of drugs in plasma were determined. Distribution of BJO emulsion in rats:21male SD rats were divided into7groups, and oral administrated with BJO emulsion, thetissues of heart, liver, spleen, lung, kidney, brain, prostate and rectum were obtained beforeadministration and when2,4,6,8,12,24after administration. The concentrations of drugwere detected by GC. Then pharmacokinetic software DAS3.1.1was used to calculate thepharmacokinetic parameters. The results showed that the parameters of AUC of oleic acidand linoleic acid were3367.54±331.53μg·h·mL-1and4065.35±827.15μg·h·mL-1, Cmaxwere124.06±10.05μg·mL-1and158.43±11.96μg·mL-1, respectively. And tmaxboth were18h. The distribution results indicated that drugs were determined in various tissues in ratsafter oral administration of BJO emulsion and the concentration in prostate was the highest.Plasma and animal tissues were obtained at different time after rectal administration ofBJO emulsion, then the concentrations were detected and the pharmacokinetic parameterswere calculated. Results showed that the AUC of oleic acid after rectal administration was1252.85±475.57μg·h·mL-1, which was37%of oral administration; Cmaxwas38.86±4.04μg·mL-1,31%of oral administration, tmaxwas8h. AUC of linoleic acid was2824.66±830.33μg·h·mL-1,69%of oral administration, Cmaxwas105.10±8.29μg·mL-1,66%of oraladministration, tmaxwas12h. The distribution results showed that drug concentration canbe detected in various tissues in rats after rectal administration of BJO emulsion. Itindicated that rectal administration could transfer BJO to organs in vivo and may becomeanother method of administration of BJO.The hot melting method was used to prepare the BJO suppository. The outward, melttime limit, weight difference and drug content were as the indexes, various emulsifiers andproportions were optimized to be the best prescription. The release experiments showedthat90%of the ingredients of BJO release from suppository in30min, providing a basisfor further pharmacokinetic study. Plasma and animal tissues were obtained at different time after rectal administration ofBJO suppository, then the concentrations were detected and the pharmacokineticparameters were calculated. Results showed that the AUC of oleic acid after rectaladministration was1959.87±234.36μg·h·mL-1,1.56times as much as that of oraladministration; Cmaxwas245.60±73.88μg·mL-1,6.32times as much as that of oraladministration, tmaxwas4h. AUC of linoleic acid was1766.40±654.37μg·h·mL-1,62%oforal administration, Cmaxwas414.72±54.71μg·mL-1,3.95times as much as that of oraladministration, tmaxwas4h. The distribution results showed that drug concentration couldbe detected in various tissues in rats after rectal administration of BJO suppository and theAUC of oleic acid in prostate was higher than emulsion.In conclusion, tissue distribution of BJO emulsion after oral administration showedthat drugs could be determined in various tissues. The concentration was the highest inprostate which indicated that drug could accumulate in prostate. Thus it providedexperimental basis of adding new clinical indications (prostate cancer) for the emulsion.The prepared BJO suppository not only can increase Cmaxof oleic acid, but also short thetmax. Thus the suppository formulation could be considered as rapid and could be usedeffectively in the treatment of diseases which providing a new concept for the developmentof new product of BJO.