Studies On Itraconzole Nanocrystal Dry Suspension

Itraconazole (ITZ) is highly concerned as a kind of broadspectrum antifungal triazole with reliable efficacy and good safety. Because of its low water solubility, poor oral absorption, and high risk of renal toxicity by injection, ITZ is limited used in clinic. The purpose of this study is to enhance ITZ's bioavailability and to improve its conformability. Combining nanocrystallization and dry suspension technique, the dry suspension of ITZ was prepared, and its quality standards and stability were also studied. The main results are as follow:1. Comprehensive study of ITZ nanocrystal's physic-chemical property indicated that it was white powder with small bulk density and poor fluidity. To determinate ITZ loaded in or dissolute from nanocrystal powder, UV spectra was adopted and proved to be a convenience and confidence method. The results of influencing factors test suggested that high temperature, high humidity and illumination could affect ITZ nanocrystal's properties in different ways. ITZ nanocrystal was stable at room temperature for 6 months.2. According to dispersion, ratio of subsided volume and re-dispersion, by single factor experiment and response surface optimization method,the best prescription was checked out which consists of xanthan gum 20mg, mannitol 500mg and proper amount of other excipients. The characteristics of ITZ nanocrystal were not changed after solidification. The fluidity of the suspension was better. Its dissolution curve showed the suspension could release more than 90% drugs in 45min with little batch difference and without abrupt-release.3. Related substance was determined by HPLC method, with varying degree increased between each destructive test, but can be controlled within 1.5%. The method has good linearity of when the concentration of ITZ in 29.88～149.40μg.mL-1. The content of ITZ in powder was between 98% to 102%, with good homogeneity and little loaded difference.4. According to the standards, influencing factors test, accelerated test and 6-months long term stability test were finished,focused on property, ratio of subsided volume, loss on drying, dissolution and content altered of related substance. The results of influencing factors test suggested that the dry suspension should be stored in sealed, cool and dry conditions. The results of accelerated test demonstrated that the quality of dry suspension was stable in aluminium foil bags, and the final term of validity should be based on the results of long term stability test.