Technological Advances in a Therapy of Primary Open-Angle Glaucoma: Insights into Current Nanotechnologies

**Background:** Glaucoma is the second-leading cause of irreversible blindness worldwide, with primary open-angle glaucoma accounting for up to 90% of cases and a global prevalence of 3.1%. The main modifiable risk factor is intraocular pressure (IOP), and reducing IOP by 30–50% from baseline can effectively slow disease progression. Current pharmacotherapy relies on topical eye drops, but these have low bioavailability (only 1–10% reaches the aqueous humor), require frequent dosing (1–3 times daily), and suffer from poor patient adherence. This narrative review explores novel nanotechnologies that may overcome these limitations.

**Methods:** The authors conducted a narrative review of literature from PubMed, Web of Science, and Scopus up to May 2023. The initial search used the terms (glaucoma) AND (nanotechnology OR nanomedicine), yielding 129,819 results from 1961 to 2023. After focusing on the last 10 years and applying a second search string including specific nanocarrier types (inserts, contact lenses, hydrogels, liposomes, niosomes, nanoemulsions, nanosuspensions, nanocrystals, nanomicelles, polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, dendrimers, cubosomes, olaminosomes, bilosomes), 103 articles were included in the qualitative synthesis. Only English-language articles were selected.

**Key Results:** The review describes multiple nanotechnology platforms: - **Ocular inserts:** A ring insert containing 13 mg of bimatoprost showed no significant difference in IOP reduction compared to eye drops in clinical trials. Side effects include mucoid discharge, conjunctival hyperemia, and punctate keratitis. - **Contact lenses:** Various drug-loaded contact lenses have been developed. For example, PLGA-latanoprost film lenses provided sustained release for 1 month. Vitamin E-loaded lenses extended timolol and dorzolamide release to 2 days. Cellulose nanoparticle lenses reduced IOP for 8 days in a rabbit model. - **Hydrogels:** Ion-activated polysaccharide hydrogels increase viscosity upon instillation, prolonging drug retention and allowing once-daily administration. - **Liposomes:** Latanoprost-loaded liposomes (EggPC) showed 60% drug release over 14 days and a greater IOP reduction (approximately 4.8 mmHg) compared to daily latanoprost (2.5 mmHg) for over 90 days. iRGD-modified liposomes loaded with brinzolamide demonstrated enhanced corneal penetration and prolonged therapeutic effect. Brimonidine and travoprost liposomes achieved encapsulation efficiencies of 24.78% and ≥99.01%, respectively, and produced faster, longer-lasting IOP reduction in rabbits. - **Niosomes:** Acetazolamide-loaded niosomes showed sustained release following the Higuchi kinetic model, with IOP reduction lasting up to 5 hours. Latanoprost niosome-in-gel systems achieved 88% encapsulation efficiency. Timolol-loaded niosomes prolonged IOP reduction to 8 hours versus 2 hours with solution. - **Nanoemulsions:** Catioprost (0.005% latanoprost cationic emulsion) is FDA-approved and showed similar IOP-lowering efficacy to Xalatan but with better tolerability. Acetazolamide nanoemulsion in situ gels achieved AUC of 189.15 ± 10.18% h versus 82.51 ± 7.53% h for Azopt. - **Nanosuspensions/nanocrystals:** Forskolin-loaded nanosuspension reduced IOP by 31% for 12 hours. Brinzolamide nanocrystals achieved 75% IOP reduction versus 49% for conventional brinzolamide. Travoprost nanocrystals showed three-times higher bioavailability than Travatan in rabbits. - **Nanomicelles:** Pilocarpine-loaded poloxamer 407 micelles extended miotic response to approximately 225 minutes versus control. Dorzolamide-loaded micelles showed sustained IOP reduction in rabbits. - **Polymeric nanoparticles:** PLGA nanoparticles loaded with brimonidine and timolol provided sustained release for 28–35 days and reduced IOP for 4 days in rabbits. Chitosan-coated PLGA nanoparticles with forskolin released 90% over 72 hours versus 96.6% in 12 hours for conventional suspension. - **Solid lipid nanoparticles (SLNs):** Cationic SLNs loaded with melatonin reduced IOP in rabbits for over 24 hours. - **Nanostructured lipid carriers (NLCs):** Brinzolamide and latanoprost NLCs (<200 nm, 97.5% entrapment) showed 81.4% and 84.2% corneal permeation at 24 hours. Brimonidine NLCs achieved IOP reduction of −13.14 ± 1.28 mmHg. - **Dendrimers:** DenTimol (0.5% timolol dendrimer) reduced IOP by approximately 30% (7.3 mmHg) in rats within 30 minutes. - **Cubosomes:** Latanoprost cubosomes (~200 nm, ~90% encapsulation) showed sustained release. Acetazolamide cubosomes achieved 38.22% IOP reduction versus 31.14% for Azopt and 21.99% for Cidamex. - **Olaminosomes:** Agomelatine-loaded olaminosomes with chitosan showed promising IOP reduction in rabbits with no histopathological changes. - **Bilosomes:** Betaxolol-loaded bilosomes showed 2.2-fold enhanced corneal permeation and 57.81% IOP reduction versus 35.27% for Epitaxol. Acetazolamide bilosomes improved and extended IOP lowering.

**Clinical Implications:** Nanotechnology-based drug delivery systems offer significant advantages over conventional eye drops, including sustained drug release, improved bioavailability, reduced dosing frequency, and potential for better patient compliance. Many systems have demonstrated superior IOP reduction in preclinical models. However, most technologies are still in preclinical or early clinical stages, with only a few (e.g., Catioprost nanoemulsion, Betoptic S nanosuspension) having received regulatory approval. Challenges remain in large-scale production, long-term stability, and clinical translation. Further research is needed to optimize formulations and evaluate safety and efficacy in human trials.