Copolymerized Polymers Based on Cyclodextrins and Cationic Groups Enhance Therapeutic Effect of Rebamipide in the N-Acetylcysteine-Treated Dry Eye Model.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-09-27 eCollection Date: 2024-01-01 DOI:10.2147/DDDT.S469445

Hiroko Otake, Ko Kobayashi, Reita Kadowaki, Taiyo Kosaka, Mizuki Itahashi, Masanobu Tsubaki, Masaru Matsuda, Norio Iwakiri, Eiji Harata, Noriaki Nagai

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引用次数: 0

Abstract

Purpose: We aimed to prepare a β-cyclodextrin (β-CD) polymer using radical polymerization with co-monomers, 6-deoxy-6-(2-methacryloyloxyethylsuccinamide)-β-cyclodextrin (CD-MSAm) and N,N,N-trimethyl-N-(2-hydroxy-3-metacryloyloxopropyl)-ammonium chloride (QA) to design cyclodextrins suitable for use in ophthalmology. In addition, we evaluated their solubility and inclusion properties with rebamipide (REB), a poorly soluble drug, and investigated the usefulness of the β-CD polymer and REB (REB@CDQA) combination in treating dry eye.

Methods: The β-CD polymer (CD-MSAm-co-QA, CDQA) based on CD-MSAm/QA was prepared via radical polymerization, and the usefulness of REB@CDQA in treating dry eye was evaluated using a rabbit treated with N-acetylcysteine (dry eye model).

Results: The solubility of the CDQA powder was higher than that of the β-CD powder, and 80 nm colloids were observed in the CDQA solution. No corneal toxicity was observed in human corneal epithelial cells or rat corneas treated with 0.2% CDQA solution. The levels of REB dissolved in the CDQA solution were higher than those of the β-CD solution. Moreover, the application of the CDQA solution enhanced REB retention in the cornea and attenuated the transcorneal penetration of REB. In addition, instillation of REB@CDQA enhanced the volume of the lacrimal fluid and normalized the reduced mucin levels in the dry eye model. The extent of tear film breakup was attenuated by REB@CDQA instillation.

Conclusion: The CDQA solution enhanced the solubility of REB, and the combination of CDQA and REB enhanced the drug content in the corneal tissue. Moreover, the therapeutic effect on dry eye was higher than that of REB suspensions without CDQA.

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基于环糊精和阳离子基团的共聚聚合物可增强雷巴米特在 N-乙酰半胱氨酸治疗的干眼症模型中的治疗效果

目的：我们的目标是利用自由基聚合法制备β-环糊精（β-CD）聚合物，并加入共聚单体--6-脱氧-6-（2-甲基丙烯酰氧基乙基琥珀酰胺）-β-环糊精（CD-MSAm）和N,N,N-三甲基-N-（2-羟基-3-甲基丙烯酰氧基丙基）-氯化铵（QA），从而设计出适用于眼科的环糊精。此外，我们还评估了它们与难溶性药物雷巴米特（REB）的溶解性和包合特性，并研究了 β-CD 聚合物和 REB（REB@CDQA）组合在治疗干眼症方面的作用：方法：通过自由基聚合法制备了基于CD-MSAm/QA的β-CD聚合物（CD-MSAm-co-QA，CDQA），并用N-乙酰半胱氨酸治疗兔（干眼症模型）评估了REB@CDQA在治疗干眼症中的作用：CDQA粉末的溶解度高于β-CD粉末，在CDQA溶液中观察到80纳米的胶体。用 0.2% CDQA 溶液处理人角膜上皮细胞或大鼠角膜时，未观察到角膜毒性。溶解于 CDQA 溶液中的 REB 含量高于溶解于 β-CD 溶液中的 REB 含量。此外，使用 CDQA 溶液可增强 REB 在角膜中的滞留，并减弱 REB 的角膜穿透力。此外，在干眼症模型中，REB@CDQA 还能增加泪液量，并使减少的粘蛋白水平恢复正常。REB@CDQA的灌注减轻了泪膜破裂的程度：结论：CDQA溶液提高了REB的溶解度，CDQA和REB的组合提高了角膜组织中的药物含量。此外，与不含 CDQA 的 REB 悬浮液相比，CDQA 对干眼症的治疗效果更高。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.