米唑斯汀-固体脂质纳米粒载眼部水凝胶的制剂及组织病理学研究。

BACKGROUND: Mizolastine (MZL) is a dual-action nonsedating topical antihistamine anti-inflammatory agent that is used to relieve allergic conditions, such as rhinitis and conjunctivitis. Solid lipid nanoparticles (SLNs) are advanced delivery system in ophthalmology, with the merits of increasing the corneal drug absorption and hence improved bioavailability with the objective of ocular drug targeting. METHODS: First, MZL was formulated as MZL-SLNs by hot homogenization/ultrasonication adopting a 3 full factorial design. Solid-state characterization, in vitro release, and stability studies have been performed. Then, the optimized MZL-SLNs formula has been incorporated into ocular hydrogels using 1.5% w/v Na alginate and 5% w/v polyvinylpyrrolidone K. The gels were evaluated via in vitro release as well as in vivo studies by applying allergic conjunctivitis congestion in a rabbit-eye model. RESULTS: The optimized formula (F4) was characterized by the highest entrapment efficiency (86.5±1.47%), the smallest mean particle size (202.3±13.59 nm), and reasonable zeta potential (-22.03±3.65 mV). Solid-state characterization of the encapsulation of MZL in SLNs was undertaken. In vitro results showed a sustained release profile from MZL-SLNs up to 30 hours with a non-Fickian Higuchi kinetic model. Stability studies confirmed immutability of freeze-dried MZL-SLNs (F4) upon storage for 6 months. Finally, hydrogel formulations containing MZL-SLNs, proved ocular congestion disappearance with completely repaired conjunctiva after 24 hours. Moreover, pretreatment with MZL-SLNs-loaded hydrogel imparted markedly decreased TNF-α and VEGF-expression levels in rabbits conjunctivae compared with post-treatment with the same formula. CONCLUSION: MZL-SLNs could be considered a promising stable sustained-release nanoparticulate system for preparing ocular hydrogel as effective antiallergy ocular delivery systems.

背景：米唑斯汀（MZL）是一种具有双重作用的非镇静性局部抗组胺抗炎药物，用于缓解过敏症状，如鼻炎和结膜炎。固体脂质纳米粒（SLNs）是眼科领域的先进给药系统，具有增加角膜药物吸收的优点，从而提高生物利用度，实现眼部药物靶向。

方法：首先，通过采用 3 因素完全实验设计的热熔匀化/超声法将 MZL 制成 MZL-SLNs。进行了固态特征描述、体外释放和稳定性研究。然后，将优化的 MZL-SLNs 配方纳入含有 1.5%w/v 海藻酸钠和 5%w/v 聚乙烯吡咯烷酮 K 的眼部水凝胶中。通过在兔眼模型中应用过敏性结膜炎充血，评估凝胶的体外释放和体内研究。

结果：优化配方（F4）的特点是包封效率最高（86.5±1.47%）、平均粒径最小（202.3±13.59nm）和合理的 ζ 电位（-22.03±3.65mV）。进行了 MZL 在 SLNs 中的包封的固态特征描述。体外结果表明，MZL-SLNs 具有长达 30 小时的持续释放曲线，符合非 Fickian Higuchi 动力学模型。稳定性研究证实，冻干的 MZL-SLNs（F4）在储存 6 个月后保持不变。最后，含有 MZL-SLNs 的水凝胶配方证明，在 24 小时后可使眼部充血消失，完全修复结膜。此外，与相同配方的后处理相比，用载有 MZL-SLNs 的水凝胶预处理可显著降低兔结膜中的 TNF-α 和 VEGF 表达水平。