Abou-Taleb Heba A, Shoman Mai E, Makram Tarek Saad, Abdel-Aleem Jelan A, Abdelkader Hamdy
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Merit University (MUE), Sohag 82755, Egypt.
Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
Pharmaceutics. 2023 Feb 20;15(2):713. doi: 10.3390/pharmaceutics15020713.
Since its introduction to the market in the 1970s, ketoprofen has been widely used due to its high efficacy in moderate pain management. However, its poor solubility and ulcer side effects have diminished its popularity. This study prepared forms of ketoprofen modified with three basic excipients: tris, L-lysine, and L-arginine, and investigated their ability to improve water solubility and reduce ulcerogenic potential. The complexation/salt formation of ketoprofen and the basic excipients was prepared using physical mixing and coprecipitation methods. The prepared mixtures were studied for solubility, docking, dissolution, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), in vivo evaluation for efficacy (the writhing test), and safety (ulcerogenic liability). Phase solubility diagrams were constructed, and a linear solubility (AL type) curve was obtained with tris. Docking studies suggested a possible salt formation with L-arginine using Hirshfeld surface analysis. The order of enhancement of solubility and dissolution rates was as follows: L-arginine > L-lysine > tris. In vivo analgesic evaluation indicated a significant enhancement of the onset of action of analgesic activities for the three basic excipients. However, safety and gastric protection indicated that both ketoprofen arginine and ketoprofen lysine salts were more favorable than ketoprofen tris.
自20世纪70年代上市以来，酮洛芬因其在中度疼痛管理方面的高效性而被广泛使用。然而，其溶解性差和溃疡副作用降低了它的受欢迎程度。本研究制备了用三种碱性辅料（三羟甲基氨基甲烷、L-赖氨酸和L-精氨酸）修饰的酮洛芬剂型，并研究了它们改善水溶性和降低致溃疡潜力的能力。酮洛芬与碱性辅料的络合/盐形成采用物理混合和共沉淀法制备。对所制备的混合物进行了溶解度、对接、溶出度、差示扫描量热法（DSC）、傅里叶变换红外光谱法（FTIR）、体内药效评价（扭体试验）和安全性（致溃疡倾向）研究。构建了相溶解度图，并用三羟甲基氨基甲烷得到了线性溶解度（AL型）曲线。对接研究表明，使用 Hirshfeld 表面分析可能与L-精氨酸形成盐。溶解度和溶出速率增强的顺序如下：L-精氨酸>L-赖氨酸>三羟甲基氨基甲烷。体内镇痛评价表明，三种碱性辅料的镇痛活性起效时间显著延长。然而，安全性和胃保护作用表明，酮洛芬精氨酸盐和酮洛芬赖氨酸盐均比酮洛芬三羟甲基氨基甲烷盐更具优势。
