Preparation And Characterization Of ITZ Capsules Based On Nanocrystal Technology

Itraconazole(ITZ)belongs to the second generation antifungal triazole.It reaches an antibacterial effect by specifically blocking the demethylation of ergosterol.On clinic,it is mainly used in treating the systemic fungal infection.But as a Biopharmaceutics Classification System class II drug,the absorption and bioavailability of ITZ are influenced or limited due to the poor solubility of drug.In this paper,starting from increasing the solubility of the drug,ITZ nanocrystals were prepared by drug nanocrystal technology,with the expectation of increasing the solubility and dissolution,and improving the drug absorption and bioavailability via reducing particle size of the drug.The UV and HPLC methods were established respectively in this paper for the analysis of the dissolution rate and the assay of ITZ.The results showed that the methods were accurate,reliable,stable.In this paper a media milling method was employed to prepare ITZ nanocrystals,and the technological conditions of this method were also studied with particle size and PI as examining index.The process parameters,such as drug concentrations,types and concentrations of stabilizer,machine rotating speed,grinding time were investigated via single factor tests.Furthermore,the process conditions were optimized in an orthogonal experiment of four factors and three levels,and the results indicated that the optimized process parameters were as follows: the concentration of stabilizer is 20 wt%,the concentration of drug is 200 mg/m L,the amount of milling pearls is 25 g,and the time of grind is 8 h.This paper also studied the pharmaceutical characteristics of ITZ nanocrystals,such as their particle size,morpHology,crystalline state and dissolution rate,etc.The results indicated that the shape of self-made nanocrystals were in a blocky irregular as well as the mean particle size is 300 nm with an equally distributed;and the crystalline state and chemical structure were not changed.Furthermore,compared to bulk drug solubility of ITZ nanocrystals showed obvious increase and dissolution rates also showed significant improvement compared to bulk drug and commercially available capsules.The capsules formulation was composed of ITZ nanocrystals and Talc Powder(0.3%).The contents were filled in NO.2 capsules shell and corresponded to 100 mg ITZ.The quality of self-made capsules met the requirements of capsules in Appendix of Volume ? of Chinese Pharmacopoeia(2010)and the dissolution rates of self-madecapsules showed significant increase compared with the control preparations.The wistar rats were selected as experimental animals and the HPLC method was established to determine plasma concentration of ITZ in the study.Pharmacokinetics of the self-made capsules were studied by single dose tests with bulk drug and commercially available capsules as contorl.The study results were as follows: after oral administration of the self-made capsules,bulk drug and the commercially available capsules,the peak concentration(Cmax)were 1104.25±43.58 ng/mL,258.71±12.37 ng/mL and 460.63±21.26ng/m L,respectively,and the area under plasma drug concentration-time curve(AUC0-?)were 25180±251.13 ng?h/mL,9995±301.22 ng?h/mL and 15060±198.61 ng?h/mL.The study results indicated that the self-made capsules can improve drug absorption and bioavailability and the relative bioavailability were 251.9% and 167.2%,respectively.