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.
摘要：
吡罗昔康（PX）是一种非甾体抗炎药（NSAID），通常与胃肠道（GI）损伤有关。包括消化不良,胃灼热,炎症,出血,溃疡,和危及生命的穿孔。基于β-环糊精(β-CD)的PX制剂(PX@CD)已显示通过改善PX的溶解度和溶出速率来减少胃副作用。然而,β-CD只能在有限的程度上增加PX的溶解度，由于PX和β-CD之间的结合常数较低(~100M-1)。因此,不良反应如上腹痛和发热仍是常见的报道。葫芦[7]脲（CB[7]）是一种合成的大环主体化合物，与各种药物强烈结合。在这项研究中,我们证明了CB[7]在胃酸环境中与PX形成复合物，其结合常数比β-CD和PX之间的结合常数高约70倍。PX@CB[7]包合物在胃环境中表现出快速的溶解速率。此外,与PX和PX@CD（1:2.5）相比，PX@CB[7]显示出明显更高的口服生物利用度和最大浓度（Cmax），改善小鼠和大鼠模型的抗炎作用。此外，与PX相比，PX@CB[7]（1：2.5）与胃粘膜的粘附最小，并且在大鼠模型中引起最温和的胃副作用，PX@CD(1:2.5),和PX@CB[7]（1：1）。最后,CB[7]在亚急性毒性评估研究中表现出良好的口服生物相容性。这些发现表明，CB[7]可以用作赋形剂，以提高口服制剂的治疗效果和减少不良反应，具有良好的安全性。
