Currently, nanosizing is becoming increasingly prevalent as an efficient way for the improvement of oral drug absorption. This study mainly focuses on two points, namely the crystal properties, and the in vitro and in vivo characterizations of drug crystals during the nanosizing process. We used glyburide, an oral type 2 diabetes (T2D) medication, as our model drug. We sought to reduce the crystalline size of this drug and evaluate its absorption properties by comparing it with the original coarse drug because of previous reports about its gastrointestinal absorption insufficiency. Glyburide crystals, ranging from 237.6 to 4473 nm were prepared successfully by jet milling and media milling. The particle sizes and the crystal morphology were analyzed by characterization of the solid states, equilibrium solubility, and dissolution behavior. Additionally, pharmacokinetic study was performed in SD rats. The solid state results indicated a loss in crystallinity, amide-imidic acid interconversion, and partial amorphization during nanosizing. Further, in in vitro tests, nanocrystal formulations remarkably increased the solubility and dissolution of the drug (compared to microcrystals). In the in vivo test, reducing the particle size from 601.3 to 312.5 nm showed no improvement on the C max and AUC (0-36 h) values, while a profound slowing of the drug elimination occurred with reduction of particle size. Further reduction from 312.5 to 237.6 nm lead to a significant increase (p < 0.001) of the AUC (0-36 h) from 6857.8 ± 369.3 ng mL-1 h to 12,928.3 ± 1591.4 ng mL-1 h, respectively, in rats. Our present study confirmed that nanosizing has a tremendous impact on promoting the oral absorption of glyburide.
Keywords: Crystalline; Glyburide; Nanocrystal; Nanosizing; Oral bioavailability.