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

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.