Micelle-nanogel platform for ferulic acid ocular delivery

Corneal wound healing after a trauma or a chemical injury has been shown to correlate with antioxidant levels at the ocular surface. However, ocular bioavailability of efficient antioxidants (e.g. ferulic acid) after topical administration is limited by their poor solubility, low stability and short residence time. The aim of this work was to formulate ferulic acid in a nanocomposite platform composed of nanogels and micelles for efficient delivery to cornea. Solubility enhancement factor of ferulic acid was found to be equal to 1.9 +/- 0.3 and 3.4 +/- 0.3 for 50 and 100 mg/ml Pluronic (R) F68 micellar solutions. Hyaluronan was added to blank and ferulic acid loaded micelles, and then cross-linked with epsilon-polylysine. Hyaluronan nanogels showed dimensions of similar to 300 nm with positive zeta potential values. The formulations were characterized in terms of rheological behavior, biocompatibility, wound healing properties, ferulic acid release pattern and penetration into excised bovine corneas. In comparison to Pluronic (R) micelles that released ferulic acid rapidly, micelle-nanogel composites sustained the release up to 2 days. Furthermore, the micelle-nanogel formulation favored in vitro wound closure promoting fibroblasts growth and ex vivo accumulation of ferulic acid into both healthy and damaged corneas ( > 100 mu g/cm(2)).