Ma Zhining, Wang Yuequan, He Huiyang, Liu Tong, Jiang Qikun, Hou Xiaohong
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
Asian J Pharm Sci. 2024 Jun;19(3):100928. doi: 10.1016/j.ajps.2024.100928. Epub 2024 May 22.
Flurbiprofen (FB), a nonsteroidal anti-inflammatory drug, is widely employed in treating ocular inflammation owing to its remarkable anti-inflammatory effects. However, the racemic nature of its commercially available formulation (Ocufen®) limits the full potential of its therapeutic activity, as the ()-enantiomer is responsible for the desired anti-inflammatory effects. Additionally, the limited corneal permeability of FB significantly restricts its bioavailability. In this study, we successfully separated the chiral isomers of FB to obtain the highly active ()-FB. Subsequently, utilizing ion-pairing technology, we coupled ()-FB with various counter-ions, such as sodium, diethylamine, trimethamine (TMA), and l-arginine, to enhance its ocular bioavailability. A comprehensive evaluation encompassed balanced solubility, octanol-water partition coefficient, corneal permeability, ocular pharmacokinetics, tissue distribution, and ocular anti-inflammatory activity of each chiral isomer salt. Among the various formulations, S-FBTMA exhibited superior water solubility (about 1-12 mg/ml), lipid solubility (1< lg P < 3) and corneal permeability. In comparison to Ocufen®, S-FBTMA demonstrated significantly higher anti-inflammatory activity and lower ocular irritability (such as conjunctival congestion and tingling). The findings from this research highlight the potential of chiral separation and ion-pair enhanced permeation techniques in providing pharmaceutical enterprises focused on drug development with a valuable avenue for improving therapeutic outcomes.
氟比洛芬（FB）是一种非甾体抗炎药，因其显著的抗炎作用而被广泛用于治疗眼部炎症。然而，其市售制剂（Ocufen®）的外消旋性质限制了其治疗活性的全部潜力，因为（）-对映体具有所需的抗炎作用。此外，FB有限的角膜通透性显著限制了其生物利用度。在本研究中，我们成功分离了FB的手性异构体，得到了高活性的（）-FB。随后，利用离子对技术，我们将（）-FB与各种抗衡离子（如钠、二乙胺、三甲胺（TMA）和L-精氨酸）偶联，以提高其眼部生物利用度。对每种手性异构体盐的平衡溶解度、正辛醇-水分配系数、角膜通透性、眼部药代动力学、组织分布和眼部抗炎活性进行了全面评估。在各种制剂中，S-FBTMA表现出优异的水溶性（约1-12mg/ml）、脂溶性（1<lg P<3）和角膜通透性。与Ocufen®相比，S-FBTMA表现出显著更高的抗炎活性和更低的眼部刺激性（如结膜充血和刺痛）。本研究结果突出了手性分离和离子对增强渗透技术在为专注于药物开发的制药企业提供改善治疗效果的宝贵途径方面的潜力。
