Prolonged Ocular Retention of Mucoadhesive Nanoparticle Eye Drop Formulation Enables Treatment of Eye Diseases Using Significantly Reduced Dosage

Abstract

Eye diseases, such as dry eye syndrome, are commonly treated with eye drop formulations. However, eye drop formulations require frequent dosing with high drug concentrations due to poor ocular surface retention, which leads to poor patient compliance and high risks of side effects. We developed a mucoadhesive nanoparticle eye drop delivery platform to prolong the ocular retention of topical drugs, thus enabling treatment of eye diseases using reduced dosage. Using fluorescent imaging on rabbit eyes, we showed ocular retention of the fluorescent dye delivered through these nanoparticles beyond 24 h while free dyes were mostly cleared from the ocular surface within 3 h after administration. Utilizing the prolonged retention of the nanoparticles, we demonstrated effective treatment of experimentally induced dry eye in mice by delivering cyclosporin A (CsA) bound to this delivery system. The once a week dosing of 0.005 to 0.01% CsA in NP eye drop formulation demonstrated both the elimination of the inflammation signs and the recovery of ocular surface goblet cells after a month. Thrice daily administration of RESTASIS on mice only showed elimination without recovering the ocular surface goblet cells. The mucoadhesive nanoparticle eye drop platform demonstrated prolonged ocular surface retention and effective treatment of dry eye conditions with up to 50- to 100-fold reduction in overall dosage of CsA compared to RESTASIS, which may significantly reduce side effects and, by extending the interdosing interval, improve patient compliance.

Gelatin–epigallocatechin gallate nanoparticles with hyaluronic acid decoration as eye drops can treat rabbit dry-eye syndrome effectively via inflammatory relief

“…Fluorescence images taken from rabbit eyes treated with free indocyanine green revealed a dramatic decrease after 3 hours, but the mucoadhesive NPs in eye drops made of poly(d,l-lactic acid) with dextran NPs prolonged retention of drug at the ocular surface, enabling the successful treatment of DES. 58 The fluorescence signal of GE or GEH on the ocular surface was traced within 2 hours and was much higher than the dye solution in this study. Considering the rapid clearance of drugs from the ocular surface within the first 20 minutes of the administration of eye drops, 58,59 this study demonstrates that GEH NPs can significantly prolong the ocular retention of loaded therapeutics by attachment to the ocular surface.…”

Matrix metalloproteinase-9 in the pathophysiology and diagnosis of dry eye syndrome

“…CsA not only strikingly increases conjunctival goblet cell (GC) numbers in humans and animal models of dry eye, but also decreases epithelial apoptosis. 118,[120][121][122][123][124][125][126] By doing so, it has an indirect effect on the ocular surface by increasing the production of immunomodulatory factors by conjunctival goblet cells. 127,128 CsA has been shown to decrease MMP-2, -3, -9 and -13 production and activity in cultured human gingival and pterygium fibroblasts.…”

Nanomicelle‐Assisted Targeted Ocular Delivery with Enhanced Antiinflammatory Efficacy In Vivo

“…To further strengthen the mucoadhesive properties of nanosystems, one strategy is the use of a covalent binding reaction between specific ligands and the corneal surface. For example, phenylboronic acid (PBA)‐modified nanoparticles could adhere to the ocular mucous membrane through covalent linkage between PBA and sialic acid 40. Another optimal strategy is locating a receptor that is distributed on the ocular surface and developing a corresponding ligand that could be linked with drugs.…”