Design of mucoadhesive PLGA microparticles for ocular drug delivery

Topically administered ocular drug delivery systems typically face severe bioavailability challenges because of the natural protective mechanisms of eyes. The rational design of drug delivery systems that are able to persist on corneal surfaces for sustained drug release is critical to tackle this problem. In this study, we fabricated monodisperse chitosan-coated PLGA microparticles with tailored diameters from 5 to 120 μm by capillary microfluidic techniques and conducted detailed investigations of their mucoadhesion to artificial mucin-coated substrates. AFM force spectroscopy revealed strong instant adhesion to mucins, whereas the adhesion force, rupture length, and adhesion energy were positively correlated to the particle diameter and contact time. Particle detachment tests under shear flow in a microfluidic mucin-coated flow cell were in accord with the AFM measurements and revealed that microparticles smaller than 25 μm exhibited strong persistence in the flow cell, withstanding high shear rates up to 28,750 s^-1 which are equivalent to the harshest in vivo ocular conditions. A simple scaling analysis connects the AFM and detachment tests, and reveals the existence of a threshold diameter below which mucoadhesion performance essentially saturates?an important insight in managing the opposing design criteria of enhanced mucoadhesion and slow, sustained drug delivery. Our findings thus pave the way for the rational design of mucoadhesive microparticulate ocular drug delivery systems that are capable of enhancing the bioavailability of topically applied drugs to eyes, as well as to other tissues whose epithelial surfaces contain mucosae.