Preparation, formation mechanism and preliminary evaluation of oral absorption of a Bicyclol-phospholipid complex / 药学学报

ABSTRACT

Bicyclol with benzyl alcohol structure, is a poorly water-soluble drug, used for the treatment of chronic hepatitis B. To increase the drug solubility and oral bioavailability, a Bicyclol-phospholipid complex was studied on its preparation, formation mechanism, and the influence on drug physicochemical properties and oral absorption. The complex was prepared by a solvent evaporation method. The optimal formulation was selected by orthogonal experimental design, and a reasonable evaluating method of the complexation rate was established. Various methods, such as differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and 31P nuclear magnetic resonance (31P-NMR), were used to explore the phase state and formation mechanism of the complex. The solubility of drug in complex was investigated in water/n-octanol. Preliminary study of its absorption and liver tissue distribution in rats was also carried out. The results showed that Bicyclol and phosphatidylcholine can be complexed entirely in the molar ratio 1 : 2. Bicyclol was dispersed in phospholipids as amorphous state. They were combined by intermolecular hydrogen bond due to charge transfer effect which occurred between the two polarities of the double bond between phosphorus and oxygen (P=O) of phosphatidylcholine and benzalcohol group of Bicyclol. The solubility of the complex compared to the active pharmaceutical ingredient (API) was effectively enhanced 5.75 times in water and 7.72 times in n-octanol, separately. In addition, drug concentrations were also enhanced 43 times in plasma and 13 times in liver with one hour after administering the complex to rats via oral gavage. All of these indicated that Bicyclol with benzalcohol group can interact with phospholipids to form complex, improving drug's physicochemical properties, thus further increasing its absorption and target tissue distribution. This study also provided theoretical reference for the research of other benzalcohol derivatives complexed with phospholipids.