Polymer-free electrospun hydroxypropyl-β-cyclodextrin inserts for sustained ocular delivery of fenofibrate: a novel approach for management of posterior segment ocular disease.

The ocular delivery of hydrophobic small-molecule anti-angiogenic agents remains challenging due to poor aqueous solubility, limited bioavailability, and inadequate drug retention at the target site. Polymer-free electrospun hydroxypropyl-β-cyclodextrin (HPβCD) inserts loaded with fenofibrate were developed for sustained episcleral drug delivery. Fenofibrate-HPβCD inclusion complexes were characterized using 1H NMR, FTIR, and DSC. Phase solubility studies were conducted at temperatures ranging from 4 to 50°C to determine complexation parameters. Electrospun inserts were prepared from solutions containing 25-150% w/v HPβCD with fenofibrate loadings of 2.5-10% w/w and processed under optimized conditions. Fiber morphology was evaluated using scanning electron microscopy. Drug content, complexation efficiency, in vitro release, and ex vivo transscleral permeation were assessed using validated HPLC methods. Biocompatibility was evaluated using ARPE-19 retinal pigment epithelial cells and HET-CAM irritation assays. Anti-angiogenic efficacy was determined through wound-healing, and fibrin bead sprouting assays. Spectroscopic analysis confirmed inclusion complex formation through characteristic peak shifts and intensity changes. Electrospinning produced uniform fibers with diameters ranging from 2.04-2.75 μm and drug loadings up to 8.56% (w/w). Higher drug loadings resulted in decreased complexed drug fractions (74% at 2.5% loading vs. 23% at 10% loading). In vitro release profiles showed sustained drug release over 168 h with minimal burst effect (<2%), achieving 19-35% cumulative release. Ex vivo transscleral permeation studies demonstrated 0.35-0.5% drug penetration within 24 h, compared to undetectable levels for free fenofibrate. All formulations-maintained cell viability above 85%, with minimal irritation observed in HET-CAM assays. Anti-angiogenic studies revealed dose-dependent activity: wound closure decreased from 45.13% (control) to 8% (10% w/w), Fibrin bead sprouting was reduced by approximately 44% in length (276 ± 140 µm vs 493 ± 142 µm for media only) and 49% in number (3.4 ± 1.6 vs 6.6 ± 2.6 for media only) for the 10% w/w formulation. The polymer-free HPβCD electrospinning approach successfully addresses fenofibrate's solubility limitations while providing sustained drug release and preserved biological activity. The excellent biocompatibility profile and significant anti-angiogenic efficacy demonstrate the potential for clinical translation in treating ocular neovascular diseases.