| The method of high performance liquid chromatography (HPLC) was set up to determine the concentration of docetaxel (DOC). The total solubility of DOC in different medium and the apparent partition coefficients of DOC were determined. The stability of DOC in different conditions such as strong acid, strong base, high temperature, oxidation, strong light was studied.DOC is an nonwater-solubility and bad lipo-solubility molecule. There are many disadvantages such as low drug-loading and bad stability in DOC liposome prepared by conventional method. Good liposomal mode is that drug is packed inner liposome as microcrystal or other nonsoluble states, thereby to carry out to improve the drug loading. But there is another problem that DOC can be easily separated from liposome. So in order to raise DOC liposome’s stability, we should improve membrane material, which can increase the affinity between drug and membrane, and interrupt medicine through meanwhile. Because of this, in the designing of formula we add new membrane stable reagents such as Sodium cholesteryl sulfate, sodium dodecylsulphate et al amphoteric material. Also, we firstly suggest emulsifying-volatilizing method to prepare DOC liposome in the designing of technique. The specific process is that, solve drug, liposomal material and membrane stable reagent in organic solvent such as dichlormethane, and then put it into water phase. The mixture is processed by emulsifying device, forming O/W emulsion. For membrane materials are mostly amphoteric, so they exist in the interfacial film mainly. When organic solvent is volatilized, the concentration of drug in organic solvent becomes thicker, and at last microcrystal appears in lipid membrane. Through optimizing of prescription and craft, successfully prepared DOC liposome with drug loading 96.9%, mean size 111.9 nm, size distribution 50～200 nm and good stability.The impacts of lyophilization process and lyo-protectant on the freeze-dried product were studied. The optimized freeze-drying process was as follows: freezing temperature was -40℃, freezing time was 4 h, drying time was 36 h and lactose was chosen as its lyo-protectant at 10% of total volume. Also particle size, encapsulation efficiency and so on before and after freeze-drying were studied. The result suggested docetaxel liposome can keep its characteristic after freeze-drying.The physico-chemical properties such as morphous, particle size, zeta potential, pH value and so on of DOC liposome for injection were studied. So did the releasing efficiency of DOC liposome for injection in 5% glucose injection and Tris-HCl buffer solution. Simultaneously, accelerated and long-term test for 3 months were conducted, results showed there was no significant change of the appearance, content and other parameters of free-drying product.The pharmaceutical safety test results indicated that DOC liposome for injection caused no hemolysis in vitro, and irritation of it was less than DOC injection. A reliable analysis method by HPLC was established to determine the concentration of DOC in rat plasma. The results of the drug pharmacokinetics in vivo showed that DOC liposome for injection had a half-life, bioavailability compared to DOC injection. |
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