Study On Itraconazole-Loaded Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLN) were solid colloidal systems with natural or synthetic lipid as drug carrier. They were novel and promising drug delivery systems, which could be used for topical, oral and parenteral administration and had the advantages of ideal targeting effects, low speed of drug leakage, good physical stability and low toxicity, etc. The objective of thesis was to investegate itraconazole-loaded solid lipid nanoparticles (ITZ-SLN) for intravenous administration.First, a high speed centrifugalization method was established to determine the entrapment efficiency. The method of emulsion evaporation-solidification at low temperature was employed to prepare ITZ-SLN, with stearic acid and soybean lecithin as lipid carrier. The optimal formulation was obtained by uniform design method, with the entrapment efficiency of ITZ-SLN as the criterion, and the type and dosage of the surfactant, stearic acid-to-soybean lecithin ratio,drug-to-lipid ratio, emulsifying temperature, as influence factors. The highest entrapment efficiency of 93.6% was acquired. We prepared ITZ-SLN for the first time, without any report both at home and abroad.The physicochemical proprieties of ITZ-SLN were studied as well. The results showed that ITZ-SLN prepared in our research was regular and well distributed with a mean diameter of (118.2±15.00) nm, a zeta potential of (-37.06±0.53) mv, a pH close to 7.0, and a drug-loaded capacity of 10%. Result of the preliminary stability experiments indicated that the ITZ-SLN suspension could keep stable at 4℃for at least one month, and there were no remarkable changes on the particle size and entrapment efficiency. In addition, the in vitro drug release of ITZ-SLN was investi-gated and the result tally with weibull equation. The formation of ITZ-SLN was validated by DSC, which indicated that it was absolutely different from the simple mixture of its components.The method of HPLC was established to determine itroconzoe in serum and tissues of mice with steady recovery, high sensitivity, accurateness and good reproducibility, which was suitable for the analysis of bio-samples in batches. After iv administration of itroconzoe solution and ITZ-SLN to mice, the drug concentrations in serum and different tissues were determined by HPLC, and the pharmacokinetic progresses in the mice for two preparations were brought into comparison, which showed they were both best fitted to two-compartment open model. AUCwere 4.4and 9.8 h(mg/l); Vd were 3.287 and 41.122; Cl were 3.409 and 1.513L/h/kg; MRT were 3.980 and 12.657h; Eliminative half-life were 45.511 and 69.315h, respectively. The levels of itroconzoe of serum were much higher when itroconzoe was administrated in SLN, and decreased in tissues. The pharmacokinetic parameters and tissues distribution of ITZ-SLN were different from itraconazole solution, which provided theoretical basis for treating systemic fungous infection and scientific basis for improving the therapeutic efficacy and reducing the adverse reactions.