Enhancement of solubility, antioxidant ability and bioavailability of taxifolin nanoparticles by liquid antisolvent precipitation technique.

Taxifolin is a kind of flavanonol, whose antioxidant ability is superior to that of ordinary flavonoids compounds owing to its special structure. However, its low bioavailability is a major obstacle for biomedical applications, so the experiment is designed to prepare taxifolin nanoparticles by liquid antisolvent precipitation (LAP) to improve its bioavailability. We selected ethanol as solvent, deionized water as antisolvent, and investigated primarily the type of surfactant and adding amount, drug concentration, volume ratio of antisolvent to solvent, precipitation temperature, dropping speed, stirring speed, stirring time factors affecting drug particles size. Results showed that the poloxamer 188 was selected as the surfactant and the particle size of taxifolin obviously reduced with the increase of the poloxamer 188 concentration, the drug concentration and the dropping speed from 0.08% to 0.45%, from 0.04 g/ml to 0.12 g/ml, from 1 ml/min to 5 ml/min, respectively, when the volume ratio of antisolvent to solvent increased from 2.5 to 20, the particle size of taxifolin first increased and then decreased, the influence of precipitation temperature, stirring speed, stirring time on particle size were not obvious, but along with the increase of mixing time, the drug solution would separate out crystallization. The optimum conditions were: the poloxamer 188 concentration was 0.25%, the drug concentration was 0.08 g/ml, the volume ratio of antisolvent to solvent was 10, the precipitation temperature was 25 °C, the dropping speed was 4 ml/min, the stirring speed was 800 r/min, the stirring time was 5 min. Taxifolin nanosuspension with a MPS of 24.6 nm was obtained under the optimum conditions. For getting taxifolin nanoparticles, the lyophilization method was chosen and correspondingly γ-cyclodextrin was selected as cryoprotectant from γ-cyclodextrin, mannitol, lactose, glucose. Then the properties of raw taxifolin and taxifolin nanoparticles were characterized by scanning electron microscopy (SEM), fourier-transform infrared spectroscopy (FTIR), high performance liquid chromatography-mass spectrometry (LC-MS), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermo gravimetric (TG), and the conclusion was drawn that taxifolin nanoparticles can be converted into an amorphous form but its chemical construction cannot been changed. Furthermore, dissolving capability test, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity and reducing power assay, solvent residue test were also carried out. The experimental data showed that the solubility and the dissolution rate of taxifolin nanoparticles were about 1.72 times and 3 times of raw taxifolin, the bioavailability of taxifolin nanoparticles increased 7 times compared with raw taxifolin, and the antioxidant capacity of taxifolin nanoparticles was also superior to raw taxifolin. Furthermore, the residual ethanol of the taxifolin nanoparticles was less than the ICH limit for class 3 solvents of 5000 ppm or 0.5% for solvents and could be used for pharmaceutical. These results suggested that taxifolin nanoparticles might have potential value to become a new oral taxifolin formulation with high bioavailability.

Zu Y ，Wu W ，Zhao X ，Li Y ，Wang W ，Zhong C ，Zhang Y ，Zhao X ... -  《-》

The high water solubility of inclusion complex of taxifolin-γ-CD prepared and characterized by the emulsion solvent evaporation and the freeze drying combination method.

This study selected γ-cyclodextrin (γ-CD) as the inclusion material and prepared inclusion complex of taxifolin-γ-CD by the emulsion solvent evaporation and the freeze drying combination method to achieve the improvement of the solubility and oral bioavailability of taxifolin. We selected ethyl acetate as the oil phase, deionized water as the water phase. The taxifolin emulsion was prepared using adjustable speed homogenate machine in the process of this experiment, whose particle size was related to the concentration of taxifolin solution, the volume ratio of water phase to oil phase, the speed and time of homogenate. We knew through the single-factor test that, the optimum conditions were: the concentration of taxifolin solution was 40 mg/ml, the volume ratio of water phase to oil phase was 1.5, the speed of homogenate was 5,000 rpm, the homogenate time was 11 min. Taxifolin emulsion with a MPS of 142.5 nm was obtained under the optimum conditions, then the high-concentration taxifolin solution (3mg/ml) was obtained by the rotary evaporation process. Finally, the inclusion complex of taxifolin-γ-CD was prepared by vacuum freeze-dry. The characteristics of the inclusion complex of taxifolin-γ-CD were analyzed using SEM, FTIR, XRD, DSC, and TG. The FTIR results analyzed the interaction of taxifolin and γ-CD and determined the molecular structure of the inclusion complex of taxifolin-γ-CD. The analysis results of XRD, DSC and TG indicated that the inclusion complex of taxifolin-γ-CD was obtained and showed significantly different characteristics with taxifolin. In addition, dissolving capability test, antioxidant capacity test, solvent residue test were also carried out. The experimental datas showed that the solubility of inclusion complex of taxifolin-γ-CD at 25°C and 37°C were about 18.5 times and 19.8 times of raw taxifolin, the dissolution rate of inclusion complex of taxifolin-γ-CD were about 2.84 times of raw taxifolin, the bioavailability of inclusion complex of taxifolin-γ-CD increased 3.72 times compared with raw taxifolin, and the antioxidant capacity of inclusion complex of taxifolin-γ-CD was also superior to raw taxifolin. Furthermore, the amounts of residual solvent of the inclusion complex of taxifolin-γ-CD were suitable for pharmaceutical use. These results suggested that inclusion complex of taxifolin-γ-CD may have potential value to become a new oral taxifolin formulation with high solubility.

Zu Y ，Wu W ，Zhao X ，Li Y ，Zhong C ，Zhang Y ... -  《-》

Preparation and characterization of amorphous amphotericin B nanoparticles for oral administration through liquid antisolvent precipitation.

We prepared amphotericin B (AmB) nanoparticles through liquid antisolvent precipitation (LAP) and by freeze-drying to improve the solubility of AmB for oral administration. The LAP was optimized through a single-factor experiment. We determined the effects of surfactants and their concentration, the stirring time, the precipitation temperature, the stirring intensity, the drug concentration and the volume ratio of antisolvent to solvent on the mean particle size (MPS) of the AmB nanoparticles. Increased stirring intensity and precipitation time favored AmB nanoparticles with smaller MPS, but precipitation times exceeding 30 min did not further reduce the MPS. Increased Tween-80 concentration and the drug concentration decreased the MPS of the AmB nanoparticles. Increased precipitation temperature and antisolvent to solvent volume ratio initially decreased the MPS of the AmB nanoparticles, which increased thereafter. Optimum conditions produced AmB nanoparticles with an MPS of 135.1 nm. The AmB nanoparticles were characterized through scanning electron microscopy (SEM), mass spectrometry (MS), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TG), solvent residue, drug purity test, and dissolution testing. The analyses indicated that the chemical structure of AmB remained unchanged in the nanoparticles, but the structure was changed from crystalline to amorphous. The residual DMSO in the nanoparticles was 0.24% less than the standard set by the International Conference on Harmonization limit for class III solvents. The AmB nanoparticles exhibited 2.1 times faster dissolution rates and 13 times equilibrium solubility compared with the raw drug. The detection results indicate that the AmB nanoparticles potentially improved the oral absorption of AmB.

Zu Y ，Sun W ，Zhao X ，Wang W ，Li Y ，Ge Y ，Liu Y ，Wang K ... -  《-》

Preparation and characterization of betulin nanoparticles for oral hypoglycemic drug by antisolvent precipitation.

Zhao X ，Wang W ，Zu Y ，Zhang Y ，Li Y ，Sun W ，Shan C ，Ge Y ... -  《-》

In vitro dissolution enhancement of micronized l-nimodipine by antisolvent re-crystallization from its crystal form H.

In order to enhance solubility and dissolution rate in water, micronized l-nimodipine (NMD) has been successfully prepared by antisolvent re-crystallization process using acetone as solvent and deionized water as antisolvent. The effects of five experimental parameters on the mean particle size (MPS) of NMD nanosuspension were investigated. It was found that the MPS of NMD nanosuspension decreased significantly when the concentration of NMD-acetone solution increased from 50 to 150 mg/mL along with the increase of volume ratio of antisolvent to solvent from 1 to 3, and then increased slightly with the following increase of them. By contrast, the MPS decreased with the increased feed rate of NMD-acetone solution and the amount of surfactant, from 1 to 3 mL/min and 0.025% to 0.2%, respectively. Thereafter, the MPS did not show any obvious change. The precipitation temperature had no significant effects on MPS. The optimum micronization conditions were determined as follows: NMD-acetone solution concentration of 150 mg/mL, the volume ratio of antisolvent to solvent of 3, the flow rate of NMD-acetone solution of 9 mL/min, the preparation temperature of 15°C and the amount of the surfactant of 0.2%. Under optimum conditions, micronized NMD with a MPS of 708.3 nm was obtained. The micronized product was characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), high performance liquid chromatography-mass spectrometry (LC-MS), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermo gravimetric (TG), to verify the influences of micronization process on the final product. The results showed that the chemical structure of micronized NMD was not changed, but the crystalline structure had undergone transition during precipitation, which changed from form H into L. The dissolution test showed that micronized NMD exhibited enhanced dissolution rate and solubility of 5.22 folds compared to raw H-NMD. These results suggested that micronized NMD may have potential value to become a new oral NMD formulation with high bioavailability.

Zu Y ，Li N ，Zhao X ，Li Y ，Ge Y ，Wang W ，Wang K ，Liu Y ... -  《-》