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
•The inclusion complexes of trimethoprim/cyclodextrin were prepared and confirmed by NMR, DSC and FTIR.•The solubility of trimethoprim was increased 1500-2600 times through complexation which are the highest results so far.•The in vitro and in vivo PK study of this complex was conducted, through com...
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| Published in: | Journal of molecular structure Vol. 1321; p. 140105 |
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| Main Authors: | , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Elsevier B.V
05-02-2025
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | •The inclusion complexes of trimethoprim/cyclodextrin were prepared and confirmed by NMR, DSC and FTIR.•The solubility of trimethoprim was increased 1500-2600 times through complexation which are the highest results so far.•The in vitro and in vivo PK study of this complex was conducted, through complexation, the AUC, Cmax of trimethoprim were increased significantly.•After combination with sulfamethoxazole cyclodextrin complex, the antibacterial activity of the complex of trimethoprim with methyl β-cyclodextrin was increased significantly.
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.
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| ISSN: | 0022-2860 |
| DOI: | 10.1016/j.molstruc.2024.140105 |