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 beta-cyclodextrin, HP beta-cyclodextrin and HP-gamma-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 C-max was increased from 0.22 mu g/mL to 0.85 mu g/mL, 0.7 mu g/mL and 0.72 mu g/mL, the AUC(0 similar to 40) was increased from 2.35 mu g*h/mL to 3.94 mu g*h/mL, 5.06 mu g*h/mL and 6.73 mu g*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 beta-cyclodextrin, HP beta-cyclodextrin and HP-gamma-cyclodextrin respectively. After combination with sulfamethoxazole cyclodextrin complex, the antibacterial activity of the complex of trimethoprim with methyl beta-cyclodextrin was increased significantly compared with the pure drug alone, indicated that this complex can be used as new potent antibacterial agent.