Abstract
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Background and Aims: To address the limitations of conventional postoperative eye drop regimens following cataract surgery, we developed an acid-sensitive prodrug-based Microcrystals (MCs) of Dexamethasone (SKD) for sustained anti-inflammatory therapy via Subconjunctival (SC) injection. We evaluated the therapeutic efficacy of the formulation in a rabbit Phacoemulsification–IOL Implantation (Phaco-IOL) model, and assessed drug distribution and long-term ocular safety in healthy rabbits, aiming to support its clinical translation for the management of ocular inflammation.
Methods: SKD MCs were prepared using an anti-solvent process combined with grinding. The morphology and particle size of SKD and MAX were evaluated. Therapeutic effects were assessed in rabbits Phaco-IOL inflammation model through slit-lamp and AS-OCT imaging, IF staining, H&E staining and ELISA kit, etc. HPLC-MS/MS was employed to evaluate the tissue distribution of drugs following SC injection of SKD MCs and MAX. In addition, polarized light microscopy and H&E staining were employed to investigate the subconjunctival drug depot.
Results: In Phaco-IOL rabbit eyes, a single SC injection of SKD MCs (0.4 mg Dex equiv.) showed anti-inflammatory efficacy comparable to MAX eye drops, completely resolving inflammation within 28 days, whereas MAX SC injection at the same dose was effective for only 7 days. SC injection of SKD MCs effectively reduced levels of inflammatory factors (e.g., TNF-α, IL-6, NCAM-1) in anterior segment tissues within 28 days post-surgery. Drug distribution analysis in normal rabbits revealed that SKD MCs achieved higher conjunctival drug concentrations at increased doses, with both prodrug and dexamethasone remaining detectable in the cornea and iris-ciliary body for at least 84 days. In contrast, MAX was rapidly cleared within 7 days, accounting for its limited duration of action. No sustained elevation in IOP was observed, supporting the favorable safety profile of long-acting SKD MCs. Following SC injection, SKD MCs formed a dense drug depot enabling sustained dexamethasone release. Initially encapsulated by a fibroblast-rich zone with minimal inflammatory cell infiltration, the depot gradually resolved during drug release without inducing fibrosis or tissue damage.
Conclusions: This study showed that a single SC injection of SKD (0.4 or 0.8 mg Dex equiv.) effectively controlled inflammation in Phaco-IOL rabbit eyes, similar to MAX eye drops, whereas MAX SC injection lacked long-term efficacy. In contrast, the SC injection of high-dose SKD MCs formed a more prolonged drug depot compared to the low-dose, with prodrug and dexamethasone detectable in the cornea and iris-ciliary body for at least 84 days. Our findings provide valuable insights into the use of prodrug-based MCs for ocular postoperative inflammation, with drug distribution analysis supporting their clinical translation in ocular diseases.
Keywords: Inflammation, Dexamethasone, Prodrug, Microcrystals, Long-Acting Formulations, Drug Distribution.
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