Studies On Submicron Emulsion Of DDP

The method of high performance liquid chromatography （HPLC） was set up to determine the concentration of cisplatin （DDP）. The solubility of DDP in water under different temperature and in different oil were determined respectively. The apparent partition coefficient of DDP in n-octyl alcohol/distilled water was also investigated.The method of high-pressure homogenization was applied to prepare DDP intravenous submicron emulsion. The major composition of the formulation was established on the base of classic fat emulsion and signal factor studies. Appling stability parameters of centrifugation, yield and appearance of emulsion to evaluate the physical and chemical stability of emulsions, the best formulation was screened by orthogonal test. The most optimal formulation was as follows: DDP 0.1%, soybean oil 10%, soybean phospholipids 1.2%, Pluronic F-68 2%, oleic acid 0.2%, vitamin E 0.01%, glycerol 2.25%, EDTA 0.05%. Processing factors were studied based on the best formulation. The most optimal preparation procedures established by signal factor studies were as follows: during homogenization the temperature was 25℃, the pressure was 90MPa, the cycles was 8; the condition of sterilization was 100℃for 30min. The results showed that the mean size was about 150nm and the yield of DDP intravenous submicron emulsion was above 80%, the content was above 90%.The physicochemical properties such as particle size, zeta potential, pH values, and yield of DDP intravenous submicron emulsion were studied. The DDP intravenous submicron emulsion was safe for clinical use within 6 hours protected from light after compatibility test with sodium chloride injection （0.9%）. The influential factor testing indicated that the DDP emulsion was sensitive to light and high temperature. The freeze-thaw testing destroyed the physical stability of emulsion, so it can not be cryopreservation. The long-term stability test showed that the mean particle size, pH values and content had no obvious changes.The pharmaceutical safety test results indicated that DDP intravenous submicron emulsion caused no hemolysis and no stimulation on vein. The acute toxicity of DDP submicron emulsion was studied. The results showed that the acute toxicity of DDP submicron emulsion i.p. in mice (LD5o=41.91 mg·kg^-1)was lower than that of DDP injection.Comparing with control group, the toxicity impairment test indicated that DDP emulsion group and DDP injection group both did damages to the organism, especially renal toxicity and hepatic toxicity. The main impairments about injection group were hepatic cellular necrosis and renal capsule atrophy, which was serious damage and can not be recovered immediately. The main impairments about emulsion group were mild hepatic hydroncus and cyanotic kidney, which can recover quickly. DDP intravenous submicron emulsion toxicity and adverse reaction was reduced compared with DDP injection.