Engineered hyalurosomal gel co-delivering citicoline sodium and nifedipine for potential glaucoma management: formulation and pharmacodynamic evaluation

Abstract

Introduction Glaucoma is a neurodegenerative ocular disorder that requires multi-targeted therapeutic strategies to counteract intraocular pressure (IOP) elevation and oxidative stress–mediated retinal ganglion cells (RGCs) loss. This study developed an innovative hyalurosomal hydrogel platform co-delivering Nifedipine (NFD, a calcium channel blocker that promotes ocular vasodilation and IOP reduction) and Citicoline sodium (CTC, a potent neuroprotective and antioxidant agent) as a potential topical therapeutic approach for glaucoma. Methods NFD-loaded hyalurosomes (NFD-HAs) were prepared using thin-film hydration and statistically optimized via a D-Optimal design. The optimized formulation (NFD-OF) was probe-sonicated, combined with CTC, and incorporated into an HPMC hydrogel. Results and discussion Sonicated NFD-OF displayed nanosized spherical vesicles (198.6 ± 23.1 nm), high entrapment efficiency (70.7 ± 1.8%), and stable zeta potential (–39.1 ± 1.3 mV). Transmission electron microscopy (TEM) analysis confirmed the distinct spherical morphology, non-aggregated state, and structural integrity of NFD-OF. The final CTC/NFD-OF gel exhibited pseudoplastic shear-thinning flow, an optimal ocular pH (6.9 ± 0.02), and sustained release over 24 h (65.5% for NFD and 99.5% for CTC). The dual gel demonstrated superior free radical scavenging capability (IC 50 = 16.44±0.7 μg/mL) compared to free NFD (219.43 μg/mL) and CTC (234.62 μg/mL). Confocal microscopy confirmed a 2.2-fold enhancement in transcorneal penetration depth (110 μm) compared with the control solution (50 μm). In vivo pharmacodynamic evaluation revealed a significantly higher maximum IOP decrease (51.85 ± 8.2%), extended mean residence time (8.9 ± 2.7 h), and increased relative exposure (AUC 0 –∞ = 494.1 ± 191.9) compared to commercial Xola™ eye drops (36.4 ± 5.9% max IOP decrease, AUC 0 –∞ = 182.8 ± 33.7). Terminal gamma sterilization preserved physicochemical characteristics and release profiles. Draize and histopathological assays confirmed excellent ocular tolerability. Overall, the CTC/NFD-OF gel demonstrated promising ocular hypotensive activity and safety, supporting its potential as a multifunctional topical therapeutic approach for glaucoma.

The authors' abstract, as published at the source. Frontiers in Pharmacology, 2026 · DOI ↗