Cyclosporine A (CsA) is a calcineurin-inhibiting immunomodulator that suppresses T cell-mediated inflammation, a central mechanism in the pathogenesis of many ocular surface diseases. Following the systemic use of CsA in ophthalmology, topical formulations were developed to provide local immunomodulation at the ocular surface while keeping systemic absorption negligible. Since the approval of the first commercial ophthalmic emulsion in 2002, topical CsA has become a cornerstone disease-modifying therapy. Unlike corticosteroids, topical CsA provides sustained anti-inflammatory control without the long-term risks of glaucoma and cataract. Its highly lipophilic and poorly water-soluble nature, however, has posed a persistent formulation challenge, driving the development of diverse delivery platforms, including anionic and cationic oil-in-water emulsions, aqueous nanomicellar and nanoemulsion solutions, and water-free semifluorinated alkane vehicles. Despite sharing the same active molecule, these formulations differ in concentration, ocular surface retention, bioavailability, and tolerability. This review comprehensively evaluates these formulations in terms of their pharmaceutical delivery systems, concentrations, and clinical applications, together with comparative data on efficacy and safety across dry eye disease, vernal and atopic keratoconjunctivitis, Sjögren’s-associated dry eye, ocular graft-versus-host disease, and high-risk keratoplasty. Topical CsA demonstrates a consistently favorable systemic safety profile, with ocular tolerability and a slow onset of action remaining its principal practical limitations. Individualized formulation selection, together with standardized head-to-head trials and biomarker-based approaches, will be key to optimizing the clinical use of topical CsA.
Purpose: This study aimed to investigate the safety and effectiveness of 5% diquafosol eye drops for treating dry eye disease (DED) in a double-blind, multicenter, phase 3 noninferiority clinical trial. Methods: Of the 271 participants randomized to receive either 5% diquafosol (TJO-083) 3 times per day or an active control [3% sodium diquafosol; Diquas-S (DQS)] 6 times per day for 12 weeks, 268 were included in the full analysis set. The outcome measures included corneal fluorescein staining score (CFS), conjunctival staining score, tear break-up time (TBUT), the Schirmer test, Ocular Surface Disease Index (OSDI), and adverse events (AEs). Results: Baseline demographic and clinical characteristics related to DED did not differ significantly between the 2 groups. At 4 weeks after treatment, mean CFS (95% CI: −0.316, 0.199), TBUT, OSDI scores, and Schirmer test values improved significantly from baseline and were maintained through 12 weeks of treatment in both groups. In between-group analysis, no statistically significant differences were observed in the CFS ( P = 0.6548), TBUT, OSDI scores, and Schirmer values. Regarding tolerability evaluation scores, blurred vision was more frequent in the TJO-083 group ( P = 0.0022). In contrast, photophobia occurred more frequently in the DQS group ( P = 0.0323). Conclusions: This study found that 5% diquafosol demonstrated clinical efficacy and AE rates equivalent to those of 3% diquafosol, despite a halved dosing frequency. Therefore, 5% diquafosol may offer a more convenient treatment option for DED patients by reducing frequency. Clinical Trial Registration: The trial was registered with the U.S. National Library of Medicine at ClinicalTrials.gov (identifier: NCT06427031).
This narrative review evaluates the role of mineralocorticoid receptor (MR) signaling in diabetic retinopathy (DR) and the therapeutic potential and translational limitations of MR antagonists (MRAs). PubMed and ClinicalTrials.gov were searched through August 10, 2026, with priority given to original mechanistic, pharmacokinetic, animal, and human studies. Available evidence indicates that MR activation contributes to retinal inflammation, oxidative stress, vascular leakage, angiogenesis, and Müller-cell ion and water dysregulation. In experimental models, spironolactone and finerenone reduced several pathological retinal endpoints. Finerenone was administered orally at 10 mg/kg/day for 12 weeks in diabetic hypertensive rats and intraperitoneally at 5 mg/kg/day in a mouse model of oxygen-induced retinopathy. In the exploratory ReFineDR/DeFineDR analysis involving 244 participants, the 2-year incidence of vision-threatening complications was 3.7% with finerenone and 6.4% with placebo (difference, −2.6%; 95% confidence interval, −8.2% to 2.9%), while ocular interventions occurred in 3.0% and 15.5% of participants, respectively. However, the ocular subgroup was not separately randomized or powered to evaluate ocular efficacy, and retinal or vitreous concentration–time data following oral finerenone have not been published. MRAs therefore have a biologically plausible and experimentally supported role in retinal disease, but their efficacy for DR in humans remains unproven. Dedicated randomized trials incorporating standardized retinal outcomes, exposure–response assessment, and potassium and kidney function monitoring are warranted.
Purpose: Infectious keratitis remains a leading cause of corneal blindness worldwide despite effective antimicrobial agents. Conventional topical therapy is limited by rapid precorneal clearance, restricted corneal penetration, and inadequate stromal drug exposure, resulting in subtherapeutic drug concentrations. These pharmacokinetic barriers are particularly important in fungal, protozoal, deep stromal, and antimicrobial-resistant keratitis, where prolonged or targeted exposure is essential for successful treatment. This review evaluates emerging ocular antimicrobial delivery strategies through a pharmacokinetic framework, emphasizing the relationship among delivery platform, depth of corneal involvement, pathogen-specific requirements, and clinical feasibility. Methods: We searched PubMed and Scopus for literature published from 2017 through August 31, 2026, including preclinical studies, clinical trials, and regulatory records. Platforms covered include polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, dendrimers, hybrid nanocarriers, mucoadhesive formulations, hydrogels, drug-eluting contact lenses, ocular inserts, microneedles, intrastromal delivery, photoactivated chromophore for keratitis corneal cross-linking (PACK-CXL), and amniotic membrane. Quantitative pharmacokinetic outcomes were compared with those of conventional formulations. Results: Each platform addresses a distinct pharmacokinetic challenges, so platforms function as complementary options. Quantitative pharmacokinetic data are compared to assess improvements in ocular residence, corneal exposure, and sustained drug delivery relative to conventional formulations. A decision-tree framework is proposed to guide platform selection by drug lipophilicity, corneal permeability, and dosing requirements. Newer systemic anti-infective agents with potential for ocular reformulation are also identified. Hybrid systems increasingly target multiple limitations simultaneously, but most evidence remains preclinical, and human corneal pharmacokinetic data are limited. Conclusions: Future studies should prioritize direct comparisons of novel platforms with standard therapy and establish whether improved delivery maintains concentrations above pathogen-specific inhibitory thresholds and translates into superior clinical outcomes.
Background: Pexidartinib (PLX3397), a small-molecule kinase inhibitor, has shown therapeutic potential in experimental ocular inflammatory and retinal degenerative disease models following oral administration; however, its intravitreal (IVT) safety remains unknown. As IVT delivery enables direct retinal targeting, this study aims to evaluate the IVT safety profile of pexidartinib using in vitro and in vivo models. Methods: In vitro safety of pexidartinib was evaluated in adult retinal pigment epithelial cells (ARPE-19), 661W, human corneal epithelial (HCE), and N9 cell lines using the MTT assay. In vivo safety was assessed in rats following IVT administration of pexidartinib at 100 n M , 10 μ M , and 100 μ M . Ocular safety was evaluated using slit-lamp biomicroscopy, intraocular pressure (IOP) measurements, RT-qPCR, histology, and immunofluorescence. Results: Pexidartinib was well tolerated in ARPE-19, 661W, HCE, and N9cells up to 10 μ M , while higher concentrations (50–100 μ M ) reduced cell viability in all cell lines except in 661W cells. In vivo , slit-lamp examination and IOP measurements showed no detectable changes postinjection across all tested concentrations. Histological and immunofluorescence evaluation demonstrated preserved retinal and corneal layers, with no significant increase in retinal Caspase-3 expression. Furthermore, RT-qPCR analysis showed minor alterations, predominantly at the low dose (100 n M ), compared with the higher doses (10 and 100 μ M ); however, these changes were not associated with structural or apoptotic degeneration, possibly indicating nonmonotonic dose responses for various kinase inhibitors. Conclusion: IVT pexidartinib was well tolerated in both in vitro (10 μ M ) and in vivo (100 μ M ). These findings support the potential development of pexidartinib as a localized therapy for treating posterior segment eye diseases. However, further long-term studies on ocular safety, pharmacokinetics, and efficacy are warranted.
