ABSTRACT
Rho-kinase (ROCK) inhibitors represent a new category of anti-glaucoma medications. Among them, Fasudil hydrochloride, a selective ROCK inhibitor, has demonstrated promising outcomes in glaucoma treatment. It works by inhibiting the ROCK pathway, which plays a crucial role in regulating the trabecular meshwork and canal of Schlemm's aqueous humor outflow. This study aims to investigate the ocular absorption pathway of Fasudil hydrochloride and, subsequently, develop a nanoparticle-based delivery system for enhanced corneal absorption. Employing the ionic gelation method and statistical experimental design, the factors influencing chitosan nanoparticle (Cs NP) characteristics and performance were explored. Fasudil in vitro release and ex vivo permeation studies were performed, and Cs NP ocular tolerability and cytotoxicity on human lens epithelial cells were evaluated. Permeation studies on excised bovine eyes revealed significantly higher Fasudil permeation through the sclera compared to the cornea (370.0 µg/cm2 vs. 96.8 µg/cm2, respectively). The nanoparticle size (144.0 ± 15.6 nm to 835.9 ± 23.4 nm) and entrapment efficiency range achieved (17.2% to 41.4%) were predominantly influenced by chitosan quantity. Cs NPs showed a substantial improvement in the permeation of Fasudil via the cornea, along with slower release compared to the Fasudil aqueous solution. The results from the Hen's Egg Test Chorioallantoic Membrane (HET-CAM) and Bovine Corneal Opacity and Permeability (BCOP) tests indicated good conjunctival and corneal biocompatibility of the formulated chitosan nanoparticles, respectively. Lens epithelial cells displayed excellent tolerance to low concentrations of these nanoparticles (>94% cell viability). To the best of our knowledge, this is the first report on the ocular absorption pathway of topically applied Fasudil hydrochloride where the cornea has been identified as a potential barrier that could be overcome using Cs NPs.
ABSTRACT
INTRODUCTION: Glaucoma is a group of progressive optic neuropathies resulting in irreversible blindness. It is associated with an elevation of intraocular pressure (>21 mm Hg) and optic nerve damage. Reduction of the intraocular pressure (IOP) through the administration of ocular hypotensive eye drops is one of the most common therapeutic strategies. Patient adherence to conventional eye drops remains a major obstacle in preventing glaucoma progression. Additional problems emerge from inadequate patient education as well as local and systemic side effects associated with adminstering ocular hypotensive drugs. AREAS COVERED: Sustained-release drug delivery systems for glaucoma treatment are classified into extraocular systems including wearable ocular surface devices or multi-use (immediate-release) eye formulations (such as aqueous solutions, gels; ocular inserts, contact lenses, periocular rings, or punctual plugs) and intraocular drug delivery systems (such as intraocular implants, and microspheres for supraciliary drug delivery). EXPERT OPINION: Sustained release platforms for the delivery of ocular hypotensive drugs (small molecules and biologics) may improve patient adherence and prevent vision loss. Such innovations will only be widely adopted when efficacy and safety has been established through large-scale trials. Sustained release drug delivery can improve glaucoma treatment adherence and reverse/prevent vision deterioration. It is expected that these approaches will improve clinical management and prognosis of glaucoma.
