Subconjunctival injection of microcrystalline prodrug of dexamethasone for long-acting anti-inflammation after phacoemulsification surgery

Xueyan Zhou; Zunkai Xu; Yanliang Dong; Maoyu Cai; Zhixia Chen; Jingqing Mu; Bo Yuan; Xia Hua; Xiaoyong Yuan; Shutao Guo

doi:10.1016/j.jconrel.2024.11.046

Subconjunctival injection of microcrystalline prodrug of dexamethasone for long-acting anti-inflammation after phacoemulsification surgery

J Control Release. 2024 Nov 19:S0168-3659(24)00801-0. doi: 10.1016/j.jconrel.2024.11.046. Online ahead of print.

Authors

Xueyan Zhou¹, Zunkai Xu², Yanliang Dong², Maoyu Cai³, Zhixia Chen², Jingqing Mu⁴, Bo Yuan¹, Xia Hua⁵, Xiaoyong Yuan⁶, Shutao Guo⁷

Affiliations

¹ School of Medicine, Nankai University, Tianjin 300071, China; Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin 300020, China; Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China.
² Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China.
³ Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin 300020, China; Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China; China Clinical College of Ophthalmology, Tianjin Medical University, Tianjin 300020, China.
⁴ Aier Eye Institute, Changsha, Hunan 410009, China.
⁵ Aier Eye Institute, Changsha, Hunan 410009, China; Aier Eye Hospital, Tianjin University, Fukang Road, Tianjin 300110, China. Electronic address: cathayhuaxua@163.com.
⁶ School of Medicine, Nankai University, Tianjin 300071, China; Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin 300020, China; China Clinical College of Ophthalmology, Tianjin Medical University, Tianjin 300020, China. Electronic address: yuanxy_cn@hotmail.com.
⁷ Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China. Electronic address: stguo@nankai.edu.cn.

PMID: 39571655
DOI: 10.1016/j.jconrel.2024.11.046

Abstract

Long-acting injectable formulations of dexamethasone with minimal invasiveness are highly desired to manage chronic ocular inflammatory conditions. Here, we applied microcrystals (MCs) of a hydrophobic acetone-based ketal-linked prodrug of dexamethasone (SKD) to treat postoperative ocular inflammation. We compared the efficacy and safety of SKD MCs through subconjunctival (SC) injection with that of Maxidex (a topical suspension of dexamethasone MCs) through SC injection and eye drops in the phacoemulsification combined with intraocular lens implantation (Phaco-IOL) rabbit model. In Phaco-IOL rabbit eyes, a single SC injection of SKD MCs (0.4 mg dexamethasone equiv.) showed anti-inflammatory effects comparable to Maxidex eye drops and completely alleviated the inflammation within 28 days, while an SC injection of Maxidex at the same dose only provided anti-inflammatory effects for 7 days. The study on the dose-dependent anti-inflammatory effects of SKD MCs showed no significant difference in anti-inflammatory effects for the high dosage (0.8 mg dexamethasone equiv.) and the low dosage (0.4 mg dexamethasone equiv.) in 28 days. Nevertheless, systematic drug distribution of SKD MCs and Maxidex in normal rabbits after SC injection demonstrates that the drug concentration in conjunctiva was higher for the high dosage and that a considerable amount of prodrug and dexamethasone could still be detected in the cornea and iris-ciliary body at least 84 days for SKD MCs at high dosage. Furthermore, no persistent elevated intraocular pressure and abnormality in retinal structure and thickness were observed, confirming the excellent safety of long-acting SKD MCs post-SC injection. Our findings provide valuable insights into using prodrug-based MCs for treating ocular postoperative inflammation, and the detailed drug distribution analysis would promote the clinical translation of these MCs in ocular diseases.

Keywords: Dexamethasone; Drug distribution; Inflammation; Long-acting formulations; Microcrystals; Prodrug.