A water-soluble drug nanoparticle-loaded in situ gel for enhanced precorneal retention and its transduction mechanism of pharmacodynamic effects

Timolol maleate (TM), a hydrophilic small molecule, is widely used in the clinical management of glaucoma. However, the complex physiological barriers of the eyes result in suboptimal bioavailability for traditional ophthalmic formulations. To address these challenges, we have developed an innovative pharmaceutical formulation. The nanoparticles (NPs) were formulated by a multi-step optimization process involving a Plackett-Burman design (PBD), steepest ascent design (SAD), and Box-Behnken design (BBD) to obtain TM-HA/CS@ED NPs. It was then encapsulated in an in situ gel (ISG) system consisting of deacetylated gellan gum (DGG) and xanthan gum (XG) to yield the TM-HA/CS@ED NPs ISG. The formulation demonstrated favorable safety in a series of ocular irritation assays and was characterized as a pseudoplastic fluid by rheological analyses, enhancing spreadability on the ocular surface and prolonging the retention time. Moreover, the NPs exposed after ISG dissolution exhibited strong mucosal adhesion and hydrophobicity, facilitating the hydrophilic TM to penetrate the corneal barrier. In vitro and in vivo retention evaluations and tear elimination pharmacokinetic study confirmed that TM-HA/CS@ED NPs ISG showed superior precorneal retention ability, and favorable sustained drug concentrations, resulting in sustained and stable transcorneal permeation into the eyes and significant intraocular pressure (IOP) lowering efficacy with a duration of 12 h. These results provide valuable insights into the design of ophthalmic drug delivery systems for water-soluble drugs and therapeutic interventions for glaucoma.