| We had studied on the formulation and processing factors of Cyclosporine（CsA） intravenous submicron emulsion and evaluated its physicochemical properties,stabilities, safety and Pharmacokinetics in rats.The method of high performance liquid chromatography（HPLC）was set up to determine the concentration of CsA.The solubility of CsA in water and in different oil were determined respectively.The apparent partition coefficient of CsA in n-octyl alcohol/distilled water was investigated.CsA in different conditions（60℃,strong light of 4500Lx±500Lx,25℃and RH 92.5%）and its stabilities in solution was also evaluated.The method of high-pressure homogenization was applied to prepare CsA intravenous submicron emulsion.The major composition of the formulation was established on the base of classic fat emulsion and single factor analysis was employed to evaluate the influence of the concentration of Phosphatidyl choline,Pluronic F-68,oleic acid and oil phase on the relevant properties of the submicron emulsion,respectively.Then based on the results of the single factor analysis,the formulation was optimized by orthogonal design.The stability parameter and entrapment efficiency was taken as the response.The effect of variable factors in preparing process such as emulsifying temperature,pressure and frequency of the homogenizing process were investigated.The optimal formulation and preparation condition of CsA submicron emulsion were as follows:MCT 10%,egg phospholipids E-80 1.5%,CsA 1.0%,oleic acid 0.1%were dissolve in the absolute ethanol,solvent evaporation.Its solution was completed by warming up the mixture（70℃）.Under ultraturax,the aqueous solution of 2.25%glycerol and 0.3%Pluronic F-68 was added to emulsifier-oil.After emulsified at 22000 r.mim-1for 8min,the pH of the pre-emulsion was adjusted to about 8.5,then passing the emulsion through homogenizer six times at a pressure of 600 bar.The final emulsion was sealed after nitrogen was added.The condition of sterilization was 100℃for 30 min. The physicochemical properties of CsA submicron emulsion such as particle size,Zetapotential, pH and entrapment efficiency were studied.The stabilities of CsA submicron emulsion such as vibration test,centrifugal acceleration test,freeze-thaw and affecting factors testing cycles were also evaluated.It was safe within 10 hours after dilution experiments with glucose injection（5%）and sodium chloride injection（0.9%）.The pharmaceutical safety test results indicated that CsA intravenous submicron emulsion caused no hemolysis.Pharmacokinetics of CsA intravenous submicron emulsion in rats was studied.A reliable analysis method by HPLC was established to determine the concentration of CsA in rats blood.After iv administration at a single dosage of 25 mg.kg-1in rats,the concentration-time curve of rats fitted two-compartment model.The results of the drug pharmacokinetics in vivo showed that the CsA intravenous submicron emulsion had a higher AUC,AUMC,MRT compared to CsA injection.The data of experiment were treated by Statistic Quadrature. |
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