Preparation And Characterization Of Spray-dried ITZ Nanosuspensions And The Study On The Adsorption Of ITZ In Rat Gastrointestinal Tract

Recently, more and more attention has been paid to nanocrystals (nanosuspensions), which is being widely used in pharmaceutical field. Nanocrystals could enhance the dissolution rate and oral bioavailability of poorly soluble drugs, generally a reduction in the variability of fed-fasted state and individual bioavailability accompanies with this formulation. Although there has been drug nanosuspensions as the commercial product, nanosuspensions are thermodynamic unstable and often associated with stability issues including Ostwald ripening, aggregation and crystalline transformation. Therefore, the drying process of nanosuspensions is a necessary step for developing new drug formulation. However, the drying process is often accompanied by the irreversible aggregation of drug nanoparticles, which then decreases the dissolution rate of drugs. Therefore, developing dried drug nanosuspensions that preserve the high dissolution rate for the enhancement of oral bioavailability of poorly water soluble drugs is an important research goal. In this study, itraconazole (ITZ) was used as the model drug. ITZ nanosuspensions were prepared by utilizing acid-base neutralization reaction. Dried ITZ nanosuspensions were prepared by spray drying. The effects of stabilizers and matrix formers on the dissolution rate of spray-dried ITZ nanosuspensions were also studied. The mechanism of dried ITZ nanosuspensions enhancing the biaoavailability and reducing the effect of food intake was also studied. The main results of this study are as follows:(1) The effects of various stabilizers including HPMC, PVP, poloxamer, Tween 80, and preparation parameters on the size and dissolution rate of ITZ nanosuspensions were studied. The mechanisms of stabilizers influencing the formation of ITZ nanosuspensions were studied by the method of SEM and TEM. The results demonstrated that HPMC and HPC-L were suitable stabilizers for preparing ITZ nanosuspensions:the size of ITZ nanocrystals was approximately 250 nm, the dissolution rate was more than 90% in 10 min. In addition, we demonstrated that 0.22μm filter could exclude undissolved ITZ nanocrystals using methods of UV and fluorescence curves.(2) The effects of stabilizers and matrix formers on the dissolution rates of spray dried ITZ nanosuspensions were studied. Various methods including XRD, TEM, SEM. XPS were used to investigate properties of spray-dried ITZ nanosuspensions. The results demonstrated that dried ITZ nanosuspensions ITZ:HPMC 50cp:mannitol 1:0.5:2 maintained the high dissolution rate:the dissolution rate of dried ITZ nanosuspensions was approximately 93.5% during the initial 20 min and was 2.1-fold higher than that of sporanox pellets (control). In addition, spray-dried ITZ nanosuspensions have a good stability.(3) The effects of pH value of dissolution media on dissolution rates of spray-dried ITZ nanosuspensions were studied. The results demonstrated that the dissolution rate of spray-dried ITZ nanosuspensions was significantly decreased when the pH value of dissolution media was enhanced, which implied that supersaturation could easily occur when dissolved ITZ was transported from the stomach to small intestine. After oral administration in rats, the AUC0-36 from dried ITZ nanosuspensions was 1.5-fold and 1.8-fold higher than the AUC0-36 from sporanox pellets (control) in the led and fasted states respectively. More importantly, the AUC0-36 from dried ITZ nanosuspensions showed no difference between fed/fasted states (spray-dried ITZ nanosuspensions AUC0-36.fed/AUC0-36.fasted≈1,sporanox pellets AUC0-36.fed/AUC0-36.fasted≈1.2).(4) The AUC0-36 of dried ITZ nanosuspensions from small intestine perfusion was slightly higher than that from oral administration. The AUC0-36 of sporanox pellets from small intestine perfusion was significantly higher than that from oral administration and similar to that of dried ITZ nanosuspensions from small intestine perfusion. In addition, the results demonstrated that crystalline ITZ could not be adsorbed when the drug was directly injected to small intestine. The results demonstrated that the adsorption of ITZ in vivo mainly originated from the dissolution of ITZ in small intestine rather than in the stomach, ITZ nanosuspensions could be more easily transported from the stomach to the small intestine compared to sporanox pellets which enhanced the chance of ITZ being adsorbed in small intestine and reduced the effect of food intake on the adsorption of the drug.In general, this study demonstrated that ITZ nanocrystals have the advantages of enhanceing the bioavailability and eliminating the food intake on the adsorption of ITZ, which supplies a promising strategy for developing the new ITZ formulation.