通过手性解析和离子配对协同策略推进氟比洛芬的眼科给药

IF 10.7 1区 医学 Q1 PHARMACOLOGY & PHARMACY Asian Journal of Pharmaceutical Sciences Pub Date : 2024-06-01 DOI:10.1016/j.ajps.2024.100928
Zhining Ma , Yuequan Wang , Huiyang He , Tong Liu , Qikun Jiang , Xiaohong Hou
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摘要

氟比洛芬(FB)是一种非甾体抗炎药,因其显著的抗炎效果而被广泛用于治疗眼部炎症。然而,其商业制剂(Ocufen®)的外消旋性质限制了其治疗活性的全部潜力,因为(S)-对映体负责产生所需的抗炎效果。此外,FB 的角膜渗透性有限,这也大大限制了其生物利用度。在这项研究中,我们成功分离了 FB 的手性异构体,得到了高活性的 (S)-FB。随后,我们利用离子配对技术,将(S)-FB 与各种反离子(如钠、二乙胺、三甲胺 (TMA) 和精氨酸)偶联,以提高其眼部生物利用度。对每种手性异构盐的平衡溶解度、辛醇-水分配系数、角膜渗透性、眼部药代动力学、组织分布和体内眼部抗炎活性进行了全面评估。在各种制剂中,S-FBTMA 的水溶性(约 1-12 mg/ml)、脂溶性(1< lg Pow <3)和角膜渗透性均优于 Ocufen®。与 Ocufen® 相比,S-FBTMA 的体内抗炎活性更高,眼部刺激性(如结膜充血和刺痛)更低。这项研究结果凸显了手性分离和离子对增强渗透技术的潜力,为专注于药物开发的制药企业提供了改善治疗效果的宝贵途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Advancing ophthalmic delivery of flurbiprofen via synergistic chiral resolution and ion-pairing strategies

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 (S)-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 (S)-FB. Subsequently, utilizing ion-pairing technology, we coupled (S)-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 in vivo 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 Pow < 3) and corneal permeability. In comparison to Ocufen®, S-FBTMA demonstrated significantly higher in vivo 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.

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来源期刊
Asian Journal of Pharmaceutical Sciences
Asian Journal of Pharmaceutical Sciences Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
18.30
自引率
2.90%
发文量
11
审稿时长
14 days
期刊介绍: The Asian Journal of Pharmaceutical Sciences (AJPS) serves as the official journal of the Asian Federation for Pharmaceutical Sciences (AFPS). Recognized by the Science Citation Index Expanded (SCIE), AJPS offers a platform for the reporting of advancements, production methodologies, technologies, initiatives, and the practical application of scientific knowledge in the field of pharmaceutics. The journal covers a wide range of topics including but not limited to controlled drug release systems, drug targeting, physical pharmacy, pharmacodynamics, pharmacokinetics, pharmacogenomics, biopharmaceutics, drug and prodrug design, pharmaceutical analysis, drug stability, quality control, pharmaceutical engineering, and material sciences.
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