Size-dependent interfacial retention of vaterite particles under tear flow: Linking hydrodynamic detachment to ocular pharmacodynamics.

Rapid precorneal clearance remains a major limitation of topical ocular therapy, yet the fundamental physical mechanisms governing particle retention under tear flow are poorly understood. Current delivery strategies primarily rely on empirical optimization of surface chemistry, while the role of particle size in interfacial stability under dynamic conditions remains largely unexplored. Here, we establish a mechanistic size-retention-pharmacodynamic framework for porous vaterite particles designed as mucoadhesive ocular drug carriers. Two structurally equivalent particle fractions were engineered: micron-sized (3.8 ± 0.5 µm) and submicron (0.65 ± 0.15 µm) particles with preserved vaterite phase stability in simulated tear fluid, porous architecture, comparable surface physicochemical properties, matched enalaprilat loading (∼5 wt%), and diffusion-controlled release kinetics. This design enabled isolation of particle size as the primary variable governing interfacial behavior. Under tear-mimicking flow on mucin-coated substrates, submicron particles exhibited ∼1.8-fold slower washout compared to micron-sized counterparts. This difference is consistent with a size-dependent balance between hydrodynamic torque and adhesive stabilization, where detachment propensity increases with particle diameter. Ex vivo corneal experiments under ∼100 × accelerated physiological tear flow revealed convergence of retention (∼10% surface coverage after 2 h), indicating a transition from physics-dominated to biology-dominated interfacial behavior on native tissue. Most importantly, these interfacial effects were associated with improved therapeutic performance in vivo. Submicron enalaprilat-loaded particles produced a more sustained intraocular pressure reduction and an approximately 2.1-fold increase in cumulative intraocular pressure-lowering effect compared to free drug, whereas micron-sized particles showed no clear improvement. Developed formulations demonstrated good cytocompatibility and excellent ocular tolerability in vitro and in vivo. Overall, this work identifies particle size as a key parameter of interfacial retention under flow and suggests that reducing hydrodynamic detachment at mucosal interfaces can enhance ocular pharmacodynamic performance without increasing the administered drug dose. The presented framework provides a basis for rational design of interface-controlled drug delivery systems beyond empirical formulation approaches.