Improving ocular bioavailability of hydrophilic drugs through dynamic covalent complexation.
Improving ocular bioavailability of hydrophilic drugs through dynamic covalent complexation.
复制标题
DOI：
10.1016/j.jconrel.2023.01.081
复制
发表时间：
2023-02
期刊：
影响因子：
--
通讯作者：
Jing-Jie Wang;Xin-Xin Liu-Xin;Chenchen Zhu;Tian-zuo Wang;Siyao Wang;Yan Liu;Xin-Yang Pan;Minhong Liu;Di Chen;Ling-Li Li-Ling-Li-Li-2204573503;Zhimin Zhou;Kai-hui Nan
中科院分区：
文献类型：
--
作者：
Jing-Jie Wang;Xin-Xin Liu-Xin;Chenchen Zhu;Tian-zuo Wang;Siyao Wang;Yan Liu;Xin-Yang Pan;Minhong Liu;Di Chen;Ling-Li Li-Ling-Li-Li-2204573503;Zhimin Zhou;Kai-hui Nan
地夸磷索四钠 (DQS) 是一种亲水性 P2Y2 受体激动剂，用于治疗干眼症，其临床疗效因严格的给药方案而受到阻碍。然而，传统的药物递送载体主要针对疏水性小分子药物，要实现 DQS 的持续释放具有挑战性。为了解决这个问题，我们利用硼酸盐介导的 DQS 和羟丙基瓜尔胶之间的动态共价络合，开发了一种 DQS 亲和水凝胶。所得制剂（3% DQS 凝胶）的特点是持续释放、低角膜渗透性和延长眼内滞留时间，这些都是眼表药物递送的理想特性。进行了体外和体内研究来验证3% DQS Gel的生物相容性。使用角膜荧光素染色、Schirmer 试验、PAS 染色、定量 PCR 和免疫组织学分析作为结果测量，在小鼠干眼模型中证明了 3% DQS 凝胶优于 PBS、水凝胶载体和游离 DQS 的治疗效果。我们本文报道的 DQS 递送策略很容易适用于其他具有顺式二醇部分的亲水性小分子药物，从而提供了改善多种疾病临床结果的通用解决方案。
The clinical benefits of diquafosol tetrasodium (DQS), a hydrophilic P2Y2 receptor agonist for dry eye, have been hindered by a demanding dosing regimen. Nevertheless, it is challenging to achieve sustained release of DQS with conventional drug delivery vehicles which are mainly designed for hydrophobic small molecule drugs. To address this, we developed an affinity hydrogel for DQS by taking advantage of borate-mediated dynamic covalent complexation between DQS and hydroxypropyl guar. The resultant formulation (3% DQS Gel) was characterized by sustained release, low corneal permeation, and extended ocular retention, which were desirable attributes for ocular surface drug delivery. Bothin vitroandin vivostudies had been carried out to verify the biocompatibility of 3% DQS Gel. Using corneal fluorescein staining, the Schirmer's test, PAS staining, quantitative PCR and immunohistological analyses as outcome measures, the superior therapeutic effects of 3% DQS Gel over PBS, the hydrogel vehicle and free DQS were demonstrated in a mouse dry eye model. Our DQS delivery strategy reported herein is readily applicable to other hydrophilic small molecule drugs withcis-diol moieties, thus providing a general solution to improve clinical outcomes of numerous diseases.