1. Cucurbit[7]uril-based host-guest complexes for improving bioavailability and reducing side effects of piroxicam.
- Author
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Wang Y, Yang X, Luo J, Yi S, Guo T, Liao Y, Yu C, and Zhang X
- Subjects
- Animals, Male, Mice, Rats, Sprague-Dawley, Rats, Drug Liberation, Administration, Oral, Heterocyclic Compounds, 2-Ring, Macrocyclic Compounds, Imidazolidines, Piroxicam administration & dosage, Piroxicam chemistry, Piroxicam pharmacokinetics, Piroxicam adverse effects, Biological Availability, Imidazoles chemistry, Imidazoles administration & dosage, Imidazoles pharmacokinetics, Imidazoles adverse effects, Bridged-Ring Compounds chemistry, Bridged-Ring Compounds administration & dosage, Bridged-Ring Compounds pharmacokinetics, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Anti-Inflammatory Agents, Non-Steroidal chemistry, Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics, Anti-Inflammatory Agents, Non-Steroidal adverse effects, beta-Cyclodextrins chemistry, beta-Cyclodextrins administration & dosage, Solubility
- Abstract
Piroxicam (PX) is a nonsteroidal anti-inflammatory drug (NSAID) commonly associated with gastrointestinal (GI) injuries, including dyspepsia, heartburn, inflammation, bleeding, ulceration, and life-threatening perforation. The β-cyclodextrin (β-CD)-based PX formulation (PX@CD) has been shown to reduce gastric side effects by improving PX's solubility and dissolution rates. However, the solubility of PX can only be increased to a limited extent by β-CD, due to the low binding constant between PX and β-CD (∼100 M
-1 ). As a result, adverse reactions such as epigastric pain and pyrosis are still commonly reported. Cucurbit[7]uril (CB[7]) is a synthetic macrocyclic host compound that binds strongly to various drugs. In this study, we demonstrated that CB[7] forms complexes with PX in the gastric acid environment with a binding constant approximately 70 times higher than that between β-CD and PX. The PX@CB[7] inclusion complexes exhibited rapid dissolution rates in the gastric environment. In addition, PX@CB[7] showed significantly higher oral bioavailability and maximum concentration (Cmax ) compared to PX and PX@CD (1:2.5), resulting in improved anti-inflammatory effects in both mouse and rat models. Moreover, PX@CB[7] (1:2.5) had the least adhesion to the gastric mucosa and caused the mildest gastric side effects in rat models when compared to PX, PX@CD (1:2.5), and PX@CB[7] (1:1). Lastly, CB[7] demonstrated good oral biocompatibility in a subacute toxicity evaluation study. These findings indicate that CB[7] could be used as an excipient to improve treatment effectiveness and decrease adverse reactions in orally administered formulations with a favorable safety profile., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xiangjun Zhang reports financial support was provided by Natural Science Foundation Project of Chongqing. Xiangjun Zhang reports financial support was provided by Chongqing Municipal Education Commission Foundation. Yan Wang, Chao Yu and Xiangjun Zhang has patent pending to National Intellectual Property Administration,PRC. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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