Carrier screening of baicalin/polysaccharide complex based on molecular simulation and its preparation and evaluation
Objective To improve the water solubility,dissolution and bioavailability of baicalin and explore the solubilization mechanism,molecular simulation combined with a solubilization experiment was applied to screen the carrier material of baicalin/polysaccharide complex,and the baicalin/hyaluronic acid complex(Bai/HA Co)was prepared.Methods Firstly,the binding free energies of baicalin with different polysaccharides were calculated by molecular docking and simulation,and the solubilization effect of these polysaccharides on baicalin was evaluated by solubilization experiment to screen proper polysaccharide as carrier material of the complex.Secondly,Bai/HA Co was prepared by stirring under heating combined with the freeze-drying method.Using solubilization ratio of baicalin and drug loading as indicators,the process was optimized by single factor experiments combined with Box-Behnken design-response surface methodology.Thirdly,the in vitro dissolution of Bai/HA Co in different media and in vivo pharmacokinetics in SD rats were investigated.Finally,the solubilization mechanism of Bai/HA Co was explored by Fourier transform infrared spectrometry(FT-IR),differential scanning calorimetry(DSC),powder X-ray diffraction(PXRD)and molecular dynamics(MD)simulation.Results The results of molecular docking,molecular simulation and solubilization experiment showed that hyaluronic acid could improve the water solubility of baicalin and exhibited the best solubilization effect.The solubilization ratio and drug loading of Bai/HA Co were greatly affected by the heating temperature and the concentration of hyaluronic acid.The results showed that the optimal process for preparing Bai/HA Co was as follows:hyaluronic acid concentration of 2 mg/mL,heating temperature of 65℃,stirring speed of 900 r/min and stirring time of 1 h.The Bai/HA Co prepared showed a great solubilization effect on baicalin,which was 23.37 times higher than that of baicalin,and its drug loading was 17.09%.The results of in vitro dissolution indicated that Bai/HA Co could significantly improve the dissolution of baicalin in pH 1.2,4.5 media and deionized water,and the bioavailability of baicalin.The results of FT-IR,DSC,PXRD and MD simulations revealed that the H-bond interaction between baicalin and hyaluronic acid enabled baicalin to disperse into the hyaluronic acid molecular chain in an amorphous state.Conclusion Molecular simulation combined with solubilization experiment provides a more accurate method for screening polysaccharides as carrier materials for complex.The Bai/HA Co prepared by the method of stirring under heating combined with freeze-drying can improve the water solubility,dissolution of baicalin and bioavailability of baicalin.
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