He Jijun, Yang Jingjing, Liang Zhen, Zhang Zhen, Pu Guojuan, Dong Fudan, Lu Ping, Xia Huiyun, Zhang Junjie
Henan Eye Hospital, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, People's Republic of China.
Int J Nanomedicine. 2025 May 22;20:6447-6462. doi: 10.2147/IJN.S521127. eCollection 2025.
This study aimed to develop itraconazole (ITZ)-loaded polymer micelles using methoxy poly(ethylene glycol)-poly(D, L-lactic acid) (mPEG-PDLLA) as a carrier to improve the ocular bioavailability of ITZ after topical administration.
ITZ-loaded mPEG-PDLLA micelles (ITZ-M) were prepared using the thin-film dispersion method and were characterized by droplet size (DS), zeta potential (ZP), polydispersity index (PDI), morphology, entrapment efficiency (EE%), and critical micelle concentration (CMC). In vitro drug release from ITZ-M, the storage stability and cytotoxicity in human corneal epithelial cells (HCECs) were studied. In vivo transcorneal permeation of micelles labeled with coumarin 6 (C6) was observed using two-photon confocal microscopy, in vivo ocular irritation and pharmacokinetics in rabbit eyes were investigated.
The ITZ-Ms were uniform spherical particles with DS of 18.79 ± 0.16 nm and narrow distribution (PDI of 0.037 ± 0.019), the EE% was nearly 100%, and the CMC of the micelles was 0.083mM. Approximately 60% of the drug was released from the ITZ-M within 72 h, which was significantly higher than that released from the ITZ suspension. The results of the stability study and cytotoxicity assays demonstrated that ITZ-M possessed good physical stability at 4°C and have no toxicity to HCECs. Transcorneal studies indicated that the fluorescence intensity (FI) was mostly enriched in the corneal epithelium, which was reduced in the stroma. The FI in the epithelium and stroma for C6 micelles was much stronger than that in the C6 suspension. Ocular irritation evaluation revealed that ITZ-M was well tolerated. Ocular pharmacokinetic analysis indicated that the area under the curve (AUC) values in the cornea and conjunctiva of rabbit eyes treated with ITZ-M were approximately 410.9- and 2.3-fold higher, respectively, than those treated with ITZ suspension.
This study provides a potential formulation of ITZ for the treatment of fungal keratitis with good tolerability and improved ocular bioavailability.
本研究旨在以甲氧基聚（乙二醇）-聚（D，L-乳酸）（mPEG-PDLLA）为载体开发载伊曲康唑（ITZ）的聚合物胶束，以提高局部给药后ITZ的眼部生物利用度。
采用薄膜分散法制备载ITZ的mPEG-PDLLA胶束（ITZ-M），并通过粒径（DS）、zeta电位（ZP）、多分散指数（PDI）、形态、包封率（EE%）和临界胶束浓度（CMC）对其进行表征。研究了ITZ-M的体外药物释放、在人角膜上皮细胞（HCECs）中的储存稳定性和细胞毒性。使用双光子共聚焦显微镜观察了用香豆素6（C6）标记的胶束的体内角膜渗透情况，研究了兔眼的体内眼部刺激性和药代动力学。
ITZ-M为均匀的球形颗粒，DS为18.79±0.16nm，分布狭窄（PDI为0.037±0.019），EE%接近100%，胶束的CMC为0.083mM。约60%的药物在72小时内从ITZ-M中释放出来，这显著高于从ITZ混悬液中释放的药物。稳定性研究和细胞毒性试验结果表明，ITZ-M在4°C下具有良好的物理稳定性，对HCECs无毒性。角膜渗透研究表明，荧光强度（FI）主要富集在角膜上皮中，在基质中降低。C6胶束在上皮和基质中的FI比C6混悬液中的要强得多。眼部刺激性评估显示ITZ-M耐受性良好。眼部药代动力学分析表明，用ITZ-M治疗的兔眼角膜和结膜中的曲线下面积（AUC）值分别比用ITZ混悬液治疗的高约410.9倍和2.3倍。
本研究为治疗真菌性角膜炎提供了一种潜在剂型的ITZ，具有良好的耐受性和改善的眼部生物利用度。
