Screen and Evaluation of Ternary Co-Amorphous System of Repaglinide-p-Aminobenzoic Acid-Gallic Acid

OBJECTIVE To construct a ternary supramolecular system using repaglinide and gallic acid as a model of dual active pharmaceutical ingredients(APIs) and using p-aminobenzoic acid as a bridging molecule in order to improve the bioavailability of repaglinide, so as to provide new ideas for the combined treatment of diabetes with natural bioactive and chemical drugs.

METHODS The ternary supramolecular system was prepared by solvent evaporation. The supramolecular complex was characterized by powder X-ray diffraction, thermal analysis and infrared spectroscopy. The equilibrium solubility and dissolution rate of the complex were determined by saturated solubility and paddle method, respectively. The pharmacokinetics of repaglinide and its ternary supramolecular complex were evaluated through determining the concentration of repaglinide in SD rat plasma using LC-MS/MS.

RESULTS The repaglinide-p-aminobenzoic acid-gallic acid ternary co-amorphous supramolecular system was successfully constructed. The solubility of repaglinide in the ternary co-amorphous complex was 1.2 times of the pure drug monomer, and its dissolution rate was significantly improved compared with the monomer. In vivo pharmacokinetic results showed that the peak concentration(C_max) of the complex group was 1.9 times of the monomer group(P<0.05), while AUC_0-t and AUC_0-∞ both exhibited an upward trend.

CONCLUSION The ternary co-amorphous supramolecular system constructed in this study remarkably improves the bioavailability of repaglinide. On the other hand, p-aminobenzoic acid is used as a bridging molecule to co-assemble gallic acid, a natural active component with hypoglycemic activity, into the system. This system accordingly provides a molecular-level delivery strategy for the combined treatment of diabetes mellitus with natural active components and chemical drugs.