Preparation Of Oleanolic Acid-loaded Nanosuspensions And Its Lyophilized Powders

Oleanolic acid is a triterpene compound and commonly used in the therapy of acute and chronic hepatitis. Because of its poorly solubility and low rate of dissolution in water, the oral administration of oleanolic acid often results in low bioavailability, which limits its therapeutic application. The aim of the study is to increase its solubility and drug dissolution velocity. For poorly soluble drugs, nanosuspensions are reported to be a promising approach in pharmaceutical research. They have numerous advantages such as increased saturation solubility and drug dissolution velocity, which result in improved bioavailability. In this paper, the nanosuspensions of oleanolic acid were prepared. The main results are as follows:(1) Oleanolic acid-loaded nanosuspensions were prepared by nanoprecipitation method in ethanol-water system. With the increase of the ratio of organic to water, the particle size of nanoparticles was fastly decreased, then followed by the increase. Nanosuspensions with different particle size, different polydispersity and zeta potentials could be prepared using various surfactants with different concentrations.(2) Oleanolic acid-loaded nanosuspensions were also prepared by high-pressure homogenization. In this process, the pressure of homogenization played a key factor on the particle size. The increased pressure and homogenization cycles could decrease the particle size of nanosuspensions. Surfactants showed no influence on particle size, but contributed to the stability of nanosuspensions.(3) Oleanolic acid-loaded nanosuspensions obtained using nanoprecipitation had spherical shape, while those obtained using high-pressure homogenization are short stick-like shape. X-ray diffraction (XRD) and differential scanning calorimeters (DSC) indicated that oleanolic acid existed in amorphous state in nanosuspensions obtained from nanoprecipitation, while the crystalline structure of coarse oleanolic acid was kept in nanosuspensions prepared by high-pressure homogenization. The solubility and the dissolution rate of nanosuspensions were both increased.(4) The lyophilized powders of oleanolic acid-loaded nanosuspensions were obtained in order to enhance the stability of nanosuspensions. Glucose, sucrose, lactose, fucose and mannitol were used as cryoprotectants in the lyophilized process. Sucrose was selected as the optimum cryoprotectant due to the minimum change of the average particle sizes before and after freeze-drying process.(5) The method for measuring plasma concentration of oleanolic acid was investigated by HPLC. Methanol was used to denature plasma proteins. The mobile phase was a mixture of acetonitrile, water, glacial acetic acid and triethylamine (90:10:0.06:0.03, v/v/v/v). Oleanolic acid and the impurity could be well separated, but the low detection limit limited the application of the method. The ramification of oleanolic acid with p-toluidine was prepared to increase its UV absord and improve its detection limit, but its stability should be further improved before practical application..