Studies On Solid Lipid Nanoparticles Loaded Oridonin

Solid lipid nanoparticles （SLN） is a promising drug delivery system with solid lipid as drug carriers, diameter ranging between 50 and 1000 nanometer, which has the advantages of high physical stability, slow speed of drug leakage and low toxicity etc. The objective of this thesis was to study the preparation, characterization, in vitro release of SLN with oridonin （ORI） as a model drug.An HPLC method with methanol-water（50/50, v/v） as mobile phase was developed for the assay of ORI in formulation, solubility and oil/water partition coefficient of ORI. The analysis method was precise, simple and reliable. The results of solubility and partition coefficient showed that ORI was almost insoluble in water and oil.Base on the physico-chemical properties of oridonin, we improved the process of the extraction and purification of oridonin, and more oridonin was got and the purity of oridonin was also enhanced with the new process.According to the results of the pre-formulation study, high shear homogenization -ultrasonic method was developed to prepare ORI -SLN dispersion. Homogenization time, ultrasonic time and intensity were key factors for the preparation of SLN. A high drug loading SLN could be acquired with glyceryl monostearate as lipid carrier, Soybean lecithin/Pluronic F₆₈ as emulsifiers. Base on the study above, with the index of encapsulation efficiency and long-term stability, orthogonal design experiments were performed to optimize the process parameters.Many physico-chemical characteristics of ORI-SLN were investigated. The appearance and particle size distributions of the ORI-SLN were examined by transmission electron microscopy. The dynamic dialysis was performed to investigate the in vitro release; The drug entrapment efficiency （EE%） was determined with the sephadex gel chromatogram and highperformance liquid chromatogram （HPLC）. The long-term stability was also evaluated.The appearance of SLN was spheric with mean particle size of （123±16） nm. Theζ, potential and pH of the ORI-SLN were detected to be -20- -25 mV and 5.8-5.9 respectively. The encapsulation efficiency was above 80 %. Results of the release experiments indicated that the release rate of ORI from ORI-SLN accorded with Weibull equation with an initial burst effect followed by a slower rate stage. Some drug might be adsorbed in the surface and some embeded in the SLN. Stability experiments results indicated that ORI-SLN could be kept stable at 4℃.SLN were successfully lyophilized in order to increase their stability, the parameters of freeze-drying process of ORI-SLN were optimized. The protective effect of various types andconcentrations of cryoprotective agents were screened by shape,color and redispersibility. ORI-SLN was freeze-dried with the mixture of 3% sucrose and 3% mannitol as cryoprotectant, as a result, the problem that colloidal solution was not stable and difficult to disperse in water was resolved. The optimal freeze-drying process followed as : precooled at -45℃for 12hr; primary drying at -35℃for 1hr; secondary drying at -20℃for 12hr; Finally drying at 10℃for 3hr. The quality of the ORI-SLN lyophilization was evaluated and the results achieved the requirement of injection. The in vitro release kinetics of ORI-SLN lyophilization in PBS（pH=7.4） was investigated and the results showed that the release of ORI-SLN lyophilization powder and dispersion could be well characterized by Weibull equation.