Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India.
AAPS PharmSciTech. 2020 Aug 3;21(6):219. doi: 10.1208/s12249-020-01729-6.
Diclofenac sodium is a potent NSAID, classified under BCS class II category having a poor aqueous solubility. Recently, its injectable formulation got banned and withdrawn from the market due to its severe nephrotoxicity caused by the use of synthetic surfactant, i.e. Transcutol-P as solubilizer. Therefore, the present study was aimed to prepare Transcutol-P free injectable using Vitamin E TPGS as a biosurfactant which is in list of inactive ingredients by US-FDA. Various cost effective aqueous injectable formulations were prepared by mixed solvency method that were characterized and optimized for different in vitro quality control parameters. Further, ex vivo hemolytic study showed the increased safety (23.4 ± 1.6%) of optimized formulation as compared with its commercial counterpart (100 ± 4.2%) at 75 mg/ml. Furthermore, in vivo acute and sub-acute toxicity study demonstrated an increase in LD to 123.75 ± 6.2 mg/kg to that of a commercial counterpart (109.96 ± 5.5 mg/kg). In addition, optimized formulation demonstrated better mean residence time and area under curve when compared with commercial test group, respectively. Moreover, optimized formulation was also evaluated for its therapeutic efficacy. The results obtained from acetic acid-induced writhing test in albino mice showed 78 ± 2.1% protection from writhes after 120 min, whereas the commercial formulation had only 48.3 ± 1.9% protection. Additionally, carrageenan-induced rat paw edema model also confirmed the better anti-inflammatory activity of optimized aqueous injectable formulation than its commercial counterpart. Thus, the developed aqueous injectable formulation of diclofenac is free from toxic Transcutol-P with enhanced safety and therapeutic efficacy.
双氯芬酸钠是一种强效的非甾体抗炎药，属于 BCS 分类 II 类，其水溶性较差。最近，由于使用合成表面活性剂即 Transcutol-P 作为增溶剂而导致严重的肾毒性，其注射剂已被禁用并从市场上撤出。因此，本研究旨在制备不含 Transcutol-P 的注射用制剂，使用维生素 E TPGS 作为生物表面活性剂，该物质已被美国 FDA 列入非活性成分清单。通过混合溶解度法制备了各种具有成本效益的水性注射剂配方，并对不同的体外质量控制参数进行了特征描述和优化。此外，离体溶血研究表明，与市售对照剂（100±4.2%）相比，优化配方在 75mg/ml 时的安全性更高（23.4±1.6%）。此外，急性和亚急性毒性研究表明，LD 增加至 123.75±6.2mg/kg，而市售对照剂为 109.96±5.5mg/kg。此外，与市售对照组相比，优化配方的平均滞留时间和曲线下面积也有所提高。此外，还对优化配方进行了治疗效果评估。在醋酸诱导的扭体试验中，在白化小鼠中获得的结果表明，在 120 分钟后，扭体的保护率为 78±2.1%，而市售制剂仅为 48.3±1.9%。此外，角叉菜胶诱导的大鼠足肿胀模型也证实了优化的水性注射用制剂比市售对照剂具有更好的抗炎活性。因此，开发的双氯芬酸钠水性注射用制剂不含有毒的 Transcutol-P，具有更高的安全性和治疗效果。
