Preparation of trimethoprim/methyl β-cyclodextrin complexes, in vitro and in vivo pharmacokinetic study, and evaluation of antibacterial activity in combination with the complex of sulfamethoxazole/methyl β-cyclodextrin

Through cyclodextrin selection from phase solubility study, complexation method screening, and complexation condition optimization by using single and orthogonal strategy, the complexes of trimethoprim with methyl β-cyclodextrin, HP β-cyclodextrin and HP-γ-cyclodextrin with the best solubility increasing so far were prepared and confirmed by FTIR, DSC and proton NMR spectra. The in vitro pharmacokinetic study showed that trimethoprim was 80 %–90 % released in three complexes in 20 min., and in their dog's in vivo pharmacokinetic study, the Cmax was increased from 0.22 µg/mL to 0.85 µg/mL, 0.7 µg/mL and 0.72 µg/mL, the AUC0∼40 was increased from 2.35 µg*h/mL to 3.94 µg*h/mL, 5.06 µg*h/mL and 6.73 µg*h/mL, the LC was shorten from 2.17 L/kg/h to 0.89 L/kg/h, 0.56 L/kg/h and 1.07 L/kg/h for the complexes with methyl β-cyclodextrin, HP β-cyclodextrin and HP-γ-cyclodextrin respectively. After combination with sulfamethoxazole cyclodextrin complex, the antibacterial activity of the complex of trimethoprim with methyl β-cyclodextrin was increased significantly compared with the pure drug alone, indicated that this complex can be used as new potent antibacterial agent. © 2024