Development of an Anti-inflammatory Drug Eluting Ocular Adhesive

Abstract

Purpose : Local drug delivery, such as topical eye drops, suffers from low drug bioavailability due to structural barriers of the cornea and rapid tear turnover. Micelle (MC) based drug delivery systems (DDS) allow for targeted and controlled release of drugs to tissues. Here, we demonstrate a DDS using drug-laden MCs within our previously described photopolymerizable hydrogel to allow for sustained elution of anti-inflammatories.

Methods : mPEG-b-p(HPMAm-Lac_n) block copolymers were synthesized via free radical polymerization, and anti-inflammatories (loteprednol etabonate (LE), prednisolone acetate (PA), and dexamethasone (DEX)), were encapsulated in the polymeric MCs. MCs were characterized via dynamic light scattering (DLS). Encapsulation and drug loading efficiency were measured using LCMS, and drug release was assessed via dialysis method under sink conditions. Biocompatibility was assessed by studying the metabolic activity and viability of human corneal epithelial cells (hTCEpi) with MC-loaded hydrogels. Additionally, hydrogels were studied in vivo in a rat subcutaneous implantation model.

Results : Average size of drug-loaded MCs were measured at 117.30±0.03 nm (LE), 111.40±0.94 nm (PA), and 84.30±0.34 nm (DEX). The polydispersity index of MCs were 0.02±0.01 (LE), 0.02±0.01 (PA), and 0.03±0.02 (DEX). Encapsulation and drug loading efficiency showed values of 25.5±2.8% & 2.5±0.3% (LE), 57.8%±2.1% & 74.6±6.0% (PA), and 5.5±0.2% & 6.9±0.5% (DEX). Burst release was observed in all drug-loaded MCs with 53.1% (LE), 57.3% (PA), and 83.1% (DEX) of drug released within 24 h, and complete drug release over ten days. LIVE/DEAD staining showed high cell viability (>90%) and adherence over the MC-loaded hydrogel surface. Cells demonstrated a consistent increase in fluorescence over the study period (7 days). Subcutaneous MC-loaded hydrogels were explanted (day 28) and showed a small amount of cell infiltration with no significant fibrosis detected. The presence of CD68⁺ cells was detected on day 7, which was significantly reduced on day 28.

Conclusions : Drug-loaded MCs demonstrated successful release of anti-inflammatories over ten days. MC-loaded hydrogels exhibited biocompatibility, stability, and retention after 28 days in vivo. This highlights the potential of utilizing drug-loaded MCs in a hydrogel adhesive as a DDS that would allow for the sustained release of drugs and increased drug bioavailability, without a complicated drug regimen.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.