| Itraconazole belongs to the second class in the biopharmaceutics classification system（BCS）,is a highly effective synthetic triazole broad-spectrum antifungal drug.It is mainly used in clinical treatment such as gynecological vulvovaginal candidiasis,fungal keratitis,onychomycosis and othesr fungal infections,has exact effect and good tolerance.However,the drug is difficult to dissolve in water,it has a poor oral absorption,and low bioavailability,which affects the efficacy.In this thesis,itraconazole was nanonized and made into pellet capsules using method of coating active ingredients.Under the premise of ensuring the dissolution and absorption of the drug,there was no organic solvent in the preparation,which made the production process safer and more environmentally friendly,which was in line with modern green pharmaceutical concepts.Itraconazole nanosuspension was preparated using media grinding method.Through the screening and optimizing of the formulation and process parameters,the formulation was determined:the main drug concentration was 200 mg/m L,the stabilizer was a mixture of SDS and PVPK30 in a ratio of 1:5.The process was determined:First,the pretreatment of initial suspention was performed using zirconium beads with a diameter of 0.8 mm,and then the suspention was grinded at a speed of 230 r/min for 8 hours using the beads with a diameter of 0.1 mm.After nanocrystallization,the average particle size of itraconazole was（124.6±2.24）nm,the average PDI was 0.184±0.003,the zeta potential was+31 m V.The results showed that the itraconazole nanosuspension prepared by this method has a small particle size,a narrow particle size distribution,a stable process,and good reproducibility.The formulation of the nanosuspension coating solution and the process parameters of the fluidized bed were optimized.The blank sucrose pellet cores were coated with the active ingredient,and the drug concentration of the coating liquid was 2%,the concentration of the coating materials was 2%,the frequency of the fan was 25 Hz,the atomizing pressure was 1.2 kg/cm2,and the inlet air temperature was 40°C.Multiple batches of pellets were prepared,the product was white,the surface was smooth,and the size was uniform.Finally,a No.0 capsule was used to filling,and the filling amount was0.5 g.Quality of homemade capsules was researched.The capsule appearance,loading difference and moisture were consistent with Chinese Pharmacopoeia.The dissolution analysis method and content analysis method were established,and the method was verified.The results showed that the method was stable,reliable and suitable for the dissolution and content to the analysis of itraconazole.Experiments with the established method,the results showed that the cumulative dissolution rate of the homemade itraconazole capsules was significantly improved compared with the physical mixtures;Compared with the commercial capsules,there was a significant improvement in acetate buffer at p H 4.5,phosphate buffer at p H 6.8 and distilled water.Wistar rats were used as experimental animals,and the pharmacokinetics of homemade capsules,commercial capsules,and physical mixtures were studied on the basis of HPLC method for blood concentration analysis.The results showed that the Cmaxof the nanocapsules,commercial capsules,and physical mixtures was（517.17±14.58）ng/m L,（911.87±25.37）ng/m L,and（341.64±6.34）ng/m L respectively,and the t1/2 was（15.00±1.59）h,（4.44±2.03）h,and（6.89±2.40）h respectively.The AUC0-∞was（13471.58±207.24）ng?h/m L,（13935.39±224.52）ng?h/m L,and（7742.77±192.02）ng?h/m L respectively.The results showed that compared with the physical mixtures,the absorption of the homemade nanocapsules had been significantly improved,and the relative bioavailability was 173.99%;compared with the commercial capsules,the drug action time may be prolonged,the toxicity and side effects may be reduced,the relative bioavailability was 96.67%,which had no significant difference in durg absorption. |
