Background: Celecoxib is generally used for the treatment of rheumatoid arthritis, however its poor bioavailability and cytotoxicity in pure form have reduced its therapeutic efficacy. This study aims to develop celecoxib liquid suppositories with improved bioavailability and reduced toxicity. Methods: The celecoxib liquid suppositories were prepared by thoroughly mixing celecoxib, poloxamer 188 and poloxamer 407, and tween-20, respectively used as drug, polymers and surfactant, in triple distilled water using cold technique. The developed liquid suppositories were characterized in terms of their gelation temperature, gelation time, and gel strength. Moreover, the muco-adhesive force was determined for the suppositories. The release behavior of the liquid suppositories was investigated in distilled water and compared with drug suspension. Furthermore, pharmacokinetics and morphological studies were carried out in rats after rectal administration of the celecoxib liquid suppository compared with drug suspension. Results: Poloxamer 188 and Tween-20 concentrations have significantly reduced the gelation temperature and time; however, the gel strength and bio-adhesive force were significantly enhanced. The concentration of celecoxib has no significant effect on the properties of liquid suppositories. A significantly enhanced and potentially sustained drug release was observed from the celecoxib liquid suppositories as compared with the drug suspension. The optimized formulation was easy to administer rectally because it quickly forms gel upon insertion into the body due to a suitable gelation temperature of about 31.7 °C. After rectal administration in rats, the celecoxib liquid suppository gave a significantly increased pharmacokinetic profile including enhanced plasma concentration and 9.7 fold improved area under the curve (AUC) compared to the drug suspension. Additionally, the morphology study exhibited no toxicity to the rectal tissue, no signs of irritation, or injury after the application of suppository. However, severe rectal tissue toxicity and irritation was observed in the suspension treated rectum. Conclusions: It can be concluded that the liquid suppository system may significantly enhance the solubilization and bio-availability of sparingly water-soluble drugs as evident in the case of celecoxib with no toxicity at the site of application.

中文翻译：

---

塞来昔布液体栓剂直肠给药在大鼠中具有增强的生物利用度和安全性

背景：塞来昔布通常用于治疗类风湿性关节炎，但其较差的生物利用度和纯净形式的细胞毒性降低了其治疗效果。本研究旨在开发生物利用度更高、毒性更低的塞来昔布液体栓剂。方法：将塞来昔布、泊洛沙姆188和泊洛沙姆407、吐温20分别作为药物、聚合物和表面活性剂在三次蒸馏水中用冷法充分混合制备塞来昔布液体栓剂。开发的液体栓剂的特征在于它们的胶凝温度、胶凝时间和凝胶强度。此外，测定了栓剂的粘膜粘附力。研究了液体栓剂在蒸馏水中的释放行为，并与药物悬浮液进行了比较。此外，与药物悬浮液相比，塞来昔布液体栓剂直肠给药后的大鼠进行了药代动力学和形态学研究。结果：泊洛沙姆188和Tween-20浓度显着降低了胶凝温度和时间；然而，凝胶强度和生物粘附力显着增强。塞来昔布的浓度对液体栓剂的性质没有显着影响。与药物悬浮液相比，从塞来昔布液体栓剂中观察到显着增强且可能持续的药物释放。优化后的制剂易于直肠给药，因为由于约 31.7 °C 的合适凝胶温度，它在插入体内后迅速形成凝胶。大鼠直肠给药后，与药物悬浮液相比，塞来昔布液体栓剂的药代动力学特征显着增加，包括血浆浓度增加和曲线下面积 (AUC) 增加 9.7 倍。此外，形态学研究表明在使用栓剂后对直肠组织没有毒性，没有刺激或损伤迹象。然而，在悬浮液处理的直肠中观察到严重的直肠组织毒性和刺激。结论：可以得出结论，液体栓剂系统可以显着提高微水溶性药物的溶解度和生物利用度，这在塞来昔布的情况下很明显，并且在应用部位没有毒性。与药物悬浮液相比，曲线下面积 (AUC) 提高了 7 倍。此外，形态学研究表明在使用栓剂后对直肠组织没有毒性，没有刺激或损伤迹象。然而，在悬浮液处理的直肠中观察到严重的直肠组织毒性和刺激。结论：可以得出结论，液体栓剂系统可以显着提高微水溶性药物的溶解度和生物利用度，这在塞来昔布的情况下很明显，并且在应用部位没有毒性。与药物悬浮液相比，曲线下面积 (AUC) 提高了 7 倍。此外，形态学研究表明在使用栓剂后对直肠组织没有毒性，没有刺激或损伤迹象。然而，在悬浮液处理的直肠中观察到严重的直肠组织毒性和刺激。结论：可以得出结论，液体栓剂系统可以显着提高微水溶性药物的溶解度和生物利用度，这在塞来昔布的情况下很明显，并且在应用部位没有毒性。