Vinorelbine Liposomes

Objective:To study physicochemical properties of Vinorelbine and provide a theoretical basis. To determine the formulation and preparation of Vinorelbine Liposomes. To study physicochemical properties of Vinorelbine liposomes. To evaluate the acute toxicity of Vinorelbine liposomes in mice. To study tissue distribution of Vinorelbine liposomes in mice.Methods:l.Experiment was carried out on ELITE C18 (4.6mm×250mm,5um)column with mobile phase consisted of acetonitrile-0.06mol-L-1 KDP buffer (35:65)at a flow rate of 1.0 ml-min-1. The detection wavelength was at 215nm and the column temperature was at 30℃.The injection volume was 10μL. Oil water partition coefficient of Vinorelbine was determined by shake flask method. Solubility of Vinorelbine in different solvents was determined by HPLC. The encapsulation of liposome was investigated.2. The preparation of liposomes was filtered with the parameter of entrapment efficiency and particle size. Using single factor and design-response surface, the formulation of Vinorelbine liposomes was optimized.3.Application of dissolution tester study was used in vitro drug release. Morphology of the liposomes was detected by transmission electron microscopy. The measurement of particle size was using Malvern laser. The stability of Vinorelbine liposomes was investigated with the parameter of the appearance of color, size, encapsulation efficiency, pH value, leakage efficiency and peroxide value.4.Blood vessels irritation of vinorelbine was investigated with the ordinary observation and histopathology. Through the hemolytic experiment, Vinorelbine liposome for in vitro hemolytic was investigated. Vinorelbine injection was taken as the control, and LD50, the vein irritation and hemolysis of these two medicines were compared.5.Vinorelbine liposomes were injected at lOmgkg-1 compared with control group, using Lewis lung carcinoma models. Sampling was scheduled at 0.5,2.0 and 12.Oh, and HPLC method was performed to determine the drug concentration in plasma and several tissues. The drug targeting index was computed finally. Results:1.HPLC method was established for the determination of content of Vinorelbine. The solubility of the oil phase is much larger than the aqueous phase and with the increase of pH value the maximum solubility of drugs was in the ether. Encapsulation efficiency of liposomes was determined by Gel-filtra.tion.2.Liposomes were prepared by thin-film ultrasonication method. The best formulation and process:Vinorelbine was 0.0100g, lecithin was 0.0795g, cholesterol 0.0389g dissolved in lOmL chloroform. The temperature was 40℃. Rotary evaporation under vacuum removed chloroform within 60min. It will form a uniform white film by adding 25mL pH7.6 phosphate buffer solution, hydrating 30min and ultrasonic 20min (50KHz). The last was through 0.45μm pore membrane.3.With transmission electron microscopy, the appearance of Vinorelbine liposomes were complete spherical or oval pellets, uniform size, and obviously bilayer structure of liposomes was observed. The mean particle size was 149.2nm. Oxidation index was less than 0.2. The appearance of Vinorelbine liposomes, pH, particle size and content changed little. The leakage efficiency was less than 9% within nine months (<4℃)4.The LD50 of Vinorelbine liposoms and Vinorelbine injection in mice was 16.02 and 4.16 mg-kg-1 respectively. Through Vinorelbine liposomes group compared with injection, infiltration, congestion and edema of inflammatory cell of rabbits vascular were significantly reduced. Vinorelbine liposomes had no hemolytic effect.5.Vinorelbine liposomes were distributed mainly in liver, spleen and tumor in rats compared with control group(P<0.05). At 0.5,2.0 and 12.Oh, the drug targeting index in tumor was 2.6393,4.8027and 4.3223 respectively.Conclusion:1.The experiment determined the nature of Vinorelbine and provides a theoretical basis for further preparation.2.The best method to preparing Vinorelbine Liposome is high encapsulation efficiency, the preparation of Vinorelbine liposomes was feasible.3.The Vinorelbine liposomes with uniform partical size, fine-looking, high entrapment efficiency, have sustained releasing effect. The results of leakage efficiency was consistent with the requirements of "Chinese Pharmacopoeia" 2010 edition.4.The experiment showed Vinorelbine liposomes was security.5.The Vinorelbine liposomes with fine-looking could increase the delivery to the tumor in rats and reduce the toxicity.