| Oleanolic acid (OA) is a pentacyclic triterpenoid drug used for treating acute jaundice hepatitis and chronic hepatitis, which is widely distributed in medicinal plants such as the leaf gall, Ligustrum lucidum and so on. Commercial preparations are now oleanolic acid tablets, capsules, the pharmaceutical products resulted in incomplete absorption in the gastrointestinal tract, low bioavailability, high dose and frequency due to the low solubility of OA (4.61μg/ml). Therefore, it was limited in the clinical. Based on technology of sustained and controlled release solid dispersion system, sustained-release pills are prepared into the form of pills using drops method with the characteristics of increasing drug solubility and control of drug release. In order to tackle the limitations of OA in the clinical application, reduce the dose and frequency, improve patient compliance and expand its usage, OA was prepared sustained-release pills. The sustained-release pills were prepared by melting method based on sustained-release solid dispersion technology, with stearic acid as a sustained-release material, PEG6000, F68 for the immediate-release materials. In this paper, the prescription process, stability and pharmacokinetics of the sustained-release pills was studied.Main experiments and results of this paper are as follows:1. Raw OA from Shanxi Huike Company was a drug extracted from Chinese medicine plants with the content of 96.36%. After purified by recrystallization, the content of raw OA reached to 99.25%, which achieve the Chemical Management Requirements of≥98.5%. Therefore, the "chemicals management" can be used for OA's management.2. In this paper, the UV method was established to direct determinate thecontent of oleanolic acid release pills and its release rate. The method is accurate, reliable, and compared with high-performance liquid chromatography, it is simpler, quicker, save supplies and reduce pollution. In 207 nm wavelength, During the determination of the content, the calibration curves was linear in the concentration range of 20～80μg/ml, r= 0.9995(n =7),The recovery rate was 98.0 %～102%, RSD < 1%(n =3);during determining the dissolution rate, linearity was good within the concentration range of 10～70μg/ml, r= 0.9997(n =7). The recovery rate was 98.0%～102%,RSD≤1%(n =3).3. The ratio of matrix selection, drug content, condensing agent temperature, distance from the drop were selected as four factors, each factor with three level, the L9 (34) orthngonal experiment was used to optimize the prescription; the spherical degree and relative standard deviation of pills weight diferenc, the drug release, the drug loading rate were selected as evaluation index. Optimize prescription obtained as follows: drug content of 5%, matrix ratio of PEG6000: F68: stearic acid = 50%: 30%: 20%, condensation agent temperature of 15±5℃, drops distance 3cm; The sustained-release pills prepared with optimize prescription were good roundness (0.98±0.01), small differences in pills weight (RSD≤1%), Drug release from the dripping pills complied with Higuchi equation and sustained for 12 h in vitro and the cumulative release over 90%,Oleanolic acid existed in the carriers in the form of amorphous and formed solid dispersion from DSC.4. The Influential Factors test results showed that the high temperature (60℃), humidity (25℃, RH90%±5%) are significantly Influential to sustained-release pills oleanolic acid. The stability test confirm the sustained-release dropping pills of Oleanolic acid are stable under high temperature (40℃), light (4500LX±500LX), as well as accelerated test (40℃±2℃, RH75%±5 %) within 3 months. However, the Oleanolic acid release rate and Pill weight are increased, the content of sustained-release pills is reduced under humidity (25℃, RH90%±5%).5. In this paper, the oleanolic acid content in rabbit plasma was determinated by derivating oleanolic acid. The method is simple and fast. Impurities in the plasma samples did not interfere with the determination and obtained a good linear relationship (R = 0.9971) in the scope of the 5μg/ml-70μg/ml, the relative recovery rate was 80% -120%, and extraction recovery rate was 70% -80%. The stability of OA in plasma samples are good neither at room temperature, freeze-thaw conditions nor the long-term conditions, and the precision RSD were less than 5.0%. It was consistent with the requirements of biological samples analysis.6. Self-control cross-administration was used to do pharmacokinetic experiment in six rabbits. As compared with oleanolic acid tablets, the sustained-release dropping pills'Cmax had dropped from 41.3 mg/L to 33.7mg/L, Tmax had been prolonged from 1.5h to 2.0h. The relative bioavailability was 149.8%, and the blood concentration-time curve was sustained decline.
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