Abstract Betulin, a kind of small molecular compound, was reported that has hypoglycemic effect. Due to its low aqueous solubility and high permeability, betulin has low and variable oral bioavailability. In this work, betulin nanoparticles were thus prepared by antisolvent precipitation for accelerating dissolution of this kind of poorly water-soluble drugs. Ethanol was used as solvent and deionized water was used as antisolvent. The effects of various experimental parameters on the mean particle size (MPS) of nanocrystallization betulin were investigated. The MPS of betulin nanoparticles suspension basically remain unchanged when precipitation time was within 60 min and then increased from 304 nm to 505 nm later. However, the MPS of betulin nanoparticles suspension decreased with increased betulin solution concentration. On the contrary, the MPS of betulin nanoparticles suspension decreased along with the increase of temperature. Stirring intensity and the speed ratio of solvent adding into antisolvent had no significant influences on the MPS of betulin nanoparticles suspension. Betulin nanoparticles suspension with a MPS of approximately 110 nm was achieved under the optimal precipitation conditions. FTIR, Liquid chromatography coupled with tandem mass spectrometry (LC-MS), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used to analyze the characteristic of betulin nanoparticles powder. These results show that betulin nanoparticles powder has the same chemical structure as raw drug, but a smaller size and lower crystallinity. The dissolution rate and solubility of betulin nanoparticles powder were separately 3.12 and 1.54 times of raw drug. The bioavailability of betulin nanoparticles powder increased 1.21 times compared with raw betulin. The result of in vivo evaluation on diabetic animals demonstrates that the betulin nanoparticles powder show an excellent hypoglycemic effect compared with raw betulin. In addition, the residual ethanol is less than the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human) limit for class 3 solvents of 5000 ppm or 0.5% for solvents.
Keywords: Absorption enhancer; bioavailability; in vitro/in vivo correlations; nanotechnology; oral absorption.