Study On Preparation Of ITZ Nanocrystals Based On Porous Colloidal Silicon Dioxide

Itraconazole is a triazole broad-spectrum high-efficiency antifungal drug,which is weakly alkaline,poorly soluble,and highly permeable,and it is a typical BCSII drug.Its poor solubility in water limits the clinical oral bioavailability of itraconazole.At present,a variety of solubilization technologies have been applied to the field of BCSII drug formulations,which has improved the dissolution rate of drugs.Among them,the application of nano-crystallization technology is becoming more and more extensive.The dissolution of itraconazole strongly depends on stomach acid and is absorbed in the small intestine.Generally,itraconazole nanocrystals with polymer compounds as stabilizers have poor stability,and after rapid dissolution in the stomach and during emptying to the small intestine,the environmental p H will change,which may cause itraconazole supersaturates and crystallizes out.And it will reduce the bioavailability of itraconazole.To solve this problem,this study used inorganic nano-material porous colloidal silicon dioxide as a stabilizer to prepare itraconazole nanocrystals with high dissolution rate and suitable dissolution rate,thereby improving the oral bioavailability of itraconazoleScreen porous colloidal silicon dioxide suitable as a stabilizer.According to the monodispersity and particle size uniformity of porous colloidal silicon dioxide,the modified St(?)eber method was used to synthesize material.By adjusting the formulation,MSN2-2,MSN4-4 and MSN6 with average particle diameters of about 100 nm,450 nm,and 1 μm were screened.And hollow porous colloidal silicon dioxide HMSN with an average particle diameter of about 420 nm was synthesized by a hard template method as a stabilizer.The commercially available colloidal silicon dioxide with a particle size of about 50 nm was selected as a reference stabilizer.Determine the nanocrystalline preparation process.Stabilizer was represented by MSN2-2.The solvent deposition method,equal volume impregnation method andco-milling method were used to prepare ITZ nanocrystals.According to the amorphous state of itraconazole in the preparation,the solvent deposition method has the best effect.Study on the loading capacity of porous colloidal silicon dioxide.According to the amorphous degree of itraconazole in nanocrystals with different dosages,the loading capacity of porous colloidal silicon dioxide was studied to obtain the most suitable drug loading.And under the condition of the same dosage,the loading capacity of porous colloidal silicon dioxide with different particle sizes was studied.The results showed that the larger the average particle size and the smaller the specific surface area of the porous colloidal silicon dioxide,the weaker the loading capacity.In order to determine the content of itraconazole in the process of quality research,two determination methods of ultraviolet spectrophotometry and high performance liquid chromatography were established,and the methodologies validation was carried out respectively.The results showed that the method had strong specificity and high feasibility.The linear relationship in the measured concentration range was good,and the precision was high,which met the quantitative analysis requirements of this study.The nanocrystalline preparations were evaluated through in vitro dissolution and pharmacokinetic experiments.Comparing the dissolution of itraconazole nanocrystals prepared with porous colloidal silicon dioxide with different particle sizes as the carrier,it was found that when MSN2-2 with a particle size of 100 nm was used as the carrier,100%dissolution occurred within two hours.As the particle size increased,the dissolution rate became slower and slower,and the dissolution rate became smaller and smaller.When the particle size was too small,the dissolution effect was not good because ITZ cannot completely exist in an amorphous state.However,compared with the commercially available Sporanox as a reference preparation,the dissolution rate was more gentle.Comparing the dissolution results of MSN4-4 and hollow HMSN with similar particle sizes,the hollow structure of porous colloidal silicon dioxide was not conducive to the dissolution of poorly soluble drugs.When the p H of the dissolution medium increased,thedissolution of ITZ significantly decreased,indicating that the dissolution of ITZ dissolved in gastric juice during the transfer to the small intestine may result in supersaturated crystal precipitation due to the increase in p H.However,the dissolution rate of the MSN2-2 @ ITZ group was higher than that of the reference preparation Sporanox,indicating that the nanocrystals prepared with porous colloidal silicon dioxide as a stabilizer are beneficial to improve the dissolution of itraconazole in the small intestine.The pharmacokinetics of itraconazole nanocrystals prepared from porous colloidal silicon dioxide MSN2-2 as a stabilizer were tested using commercially available Sporanox as a reference formulation.The results showed that the area under the drug-time curve within48 h was 1.5 times more than Sporanox,indicating that the bioavailability of itraconazole nanocrystals prepared with porous colloidal silicon dioxide as a stabilizer had been improved.In this study,porous colloidal silicon dioxide of inorganic materials was used as a stabilizer for nanocrystals.The porous colloidal silicon dioxide nanocrystal drug system with simple preparation process,high drug loading,suitable dissolution rate,high dissolution rate and high relative bioavailability was obtained,which improved the solubility of the poorly soluble drug itraconazole.