| Traditional Chinese medicine Brucea is simaroubaceae plant, It is the dry ripe fruit of Brucea (Brucea javanica (1.) Merr). Brucea javanica oil is the medicinal ingredient of Brucea, with anti-tumor, anti-bacterial, anti-viral, anti-inflammatory and other pharmacological effects. At present, BJO is used as Oral emulsion,injection and soft capsule in the market. Although the pharmacological effect of BJO is clear, the existing formulation of BJO is too less to meet the needs of clinical medicine. Therefore, it is necessary to develop some new formulations, especially the new oral formulation. This study investigated the pharmacokinetic, bioequivalence and tissue distribution of Bmsatol which is the components of BJO after ig administration BJO-CDP. Besides these, this study explored the security of BJO-CDP by acute toxicity test for the formulation development of BJO and effective oral formulations provide the basis for clinical experimental. The study carried out in this paper mainly has the following three aspects:1. Establish the HPLC method to detect the biological samples of Bmsatol. The Column was Symmetry C18 (5 μm,4.6×250 mm). The mobile phase was methanol-water. The proportion of methanol-water is 50:50. The column temperature was 25℃. The flow rate was 0.8 ml·min-1. The detection wavelength was 220 nm and the injection volume was 40μl. The method is accurate, high precision, stable and has good Reproducibility. The average recovery was more than 80% and the day precision RSD were less than 5%. The Bmsatol in the blood plasma, tissue homogenates had a good linear relationship (R2> 0.999) at the concentration range of 19.2～1536 ng/mL.2. Pharmacokinetics and tissue distribution studies of BJO-CDP. We study the effects of different doses of BJO-CDP dynamically change characteristics in rats by pharmacokinetic experiments. The results are as follows:The Pharmacokinetics results in rats were accordance with two-compartment model. The average peak of plasma concentration (Cmax) was (593.869±53.381)ng/ml, (360.244±31.255)ng/ml, (262.293±26.57)ng/ml of three doses (5g/kg, 2g/kg, lg/kg) which is respectively reached the peak at(3.6±0.548), (3.4±0.548)h, (3.8±0.447)h after administration. The absorption half-life (t1/2ka) were (1.151±0.693)h, (1.163±0.338)h, (1.5±0.288)h respectively. The distribution half-life (t1/2a) were (2.649±1.001)h, (5.479±6.298)h, (2.605±1.152)h respectively. The elimination half-life (t1/2β) were (41.057±31.116)h, (46.547±31.322)h, (56.373±28.939)h respectively. The area under Concentration-time curve (AUCO-0 were (5267.556±248.833)ng/ml-h, (3214.986±74.704)ng/ml-h, (2212.106±186.25) ng/ml·h. The total elimination rate (CL) were (916.001 ±67.519)L/h/kg, (572.48±45.724)L/h/kg and (415.256±35.603)L/h/kg respectively.We study the distribution of BJO-CDP in mice through the organization distribution experiments. The Bmsatol have distribution in each group. The distribution in liver, lung, kidney, intestine and stomach is high, and in heart, spleen is low.3. The bioequivalence evaluation of BJO-CDP and commercially available brucea javanica oil. The bioavailability and bioequivalence of BJO-CDP and commercially available brucea javanica oil were evaluated. The bioequivalence of two formulations was evaluated by variance analysis, two-one side t test and (1-2a)% confidential internal to AUC, Cmax and Tmax. The result is that the two formulations don’t have a bioequivalence in rats but BJO-CDP is better than commercially available brucea javanica oil. The relative bioavailability calculated by AUCo-t is 168.609%, and the relative bioavailability calculated by AUCo-∞ is 168.609%.4. The acute toxicity test of BJO-CDP. The result is as follows:The mice which is fed with the maximum volume (0.4 ml/10g) maximum concentration (83mg/ml), after 14 days no death was found in the experimental mice. Mice were sacrificed and dissected after the end of the experiment, no organ abnormalities were found. Also there is no organ pathology in sliced observation which indicates the low toxicity of BJO-CDP and the possibility of clinical use.The results are as follows: ①The results indicated that the HPLC method can be used for the determination of Bmsatol, the operation method is simple which can meet the determination of biological samples of Bmsatol. ②Pharmacokinetics of Bmsatol in rats was fitted to two-compartment model. Bmsatol could be detected in the blood after 0.5 h, and tmax was about 4 h. After 24 h, the concentrations of Bmsatol in high, middle, low dose groups were respectively (53.8±8.91)ng/ml, (34.3±11.75)ng/ml, (25.9±10.90)ng/ml. Cmax and AUC were significantly correlated with the dose. ③The result is that the two formulations don’t have a bioequivalence in rats but BJO-CDP is better than commercially available brucea javanica oil. ④In the acute toxicity test, the dosage of administration equivalent to 12.16 times of the clinical dose, so we explored the security of BJO-CDP. |
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