Influence Of Drug Physicochemical Properties On The Bioavailability Of Water Insoluble Drug Nanosuspensions

Nanosizing of BCS II drugs is an effective way to improve their dissolution rate and bioavailability. Revaprazan hydrochloride nanosuspension was prepared by high pressure homogenization to investigate whether the the nanosuspension strategy is a good way to improve its bioavailability. The influence of homogenization pressure and cycles on particle size were studied as well. Higher pressure and more homogenization cycles favored the decrease of drug particle size, but there were optimal pressure and cycle numbers beyond which the particle size would not decrease. Three different sized revaprazan hydrochloride suspensions were prepared and the in vitro and in vivo evaluations were carried out. The nanosuspensions gained the highest dissolution rate and bioavailability. The results reveal that drug particle size affects the drug absorption and the nanosuspension could improve the bioavailability of revaprazan hydrochloride.In order to investigate the influence of drug physicochemical properties on bioavailability of water insoluble drug nanosuspensions, albendazole, fenofibrate, itraconazole, probucol and revaprazan hydrochloride were selected as model drugs. Due to the poor water solubility the bioavailability of the model drugs are very low. As BSC II drugs their bioavailability could be improved by nanosuspension strategy. The drug nanosuspensions were prepared by high pressure homogenization using the same stabilizer(poloxamer188) and were similar in particle size(around450nm). So the interference from stabilizer and particle size on drug absorption were excluded. DSC and powder X-ray diffraction study showed that the crystalline state of the freeze dried nanoparticles did not change. As a result the interference of crystalline state on drug absorption were excluded either. Based on this the in vitro dissolution in FaSSIF and in vivo bioavailability study in rats were performed. The results showed that the nanosuspensions demonstrated higher dissolution rate and bioavailability compared with the corresponding microsuspensions. Besides, it was found that the dissolvednano/dissolvedmicro in120min was significantly correlated with AUC0-t nano/AUC0-t micro, which revealed that dissolution in FaSSIF could in some extent predict the absorption of the drug nanosuspension. FaSSIF may be a suitable dissolution medium for in vitro-in vivo correlation study of drug nanosuspensions. In order to find the relationship between the bioavailability of the drug nanosuspensions and the drug physicochemical properties (molecular weight, melting point, logP and polar surface area) the statistical analysis were performed. After multi-linear regression analysis and interpolated surface analysis it was found that the drug with smaller melting point, logP value around5and polar surface area value in the range of50-60would gain higher AUC0-t nano and accordingly higher bioavailability.In summary, particle size played an important in drug absorption and melting point, logP and polar surface area were factors that influence the bioavailability of water insoluble drug nanosuspensions in this study. This study gives an excellent resolution in studying the influence of drug physicochemical properties on bioavailability of water insoluble drug nanosuspensions.