Development and characterization of a polymeric film for ocular controlled release of micelles loaded with neuroprotective drugs

The growing incidence of ophthalmic diseases and the difficulties in the administration of drugs to the eye make the ocular drug delivery a research area of great interest. The anatomical, physiological and metabolic barriers of the eye, together with the physico- chemical properties of the active compounds, represent significant challenges for the administration of drugs, especially to the posterior segment [1]. All these aspects are responsible for the use of high concentrations, frequent administrations, poor therapeutic adherence and, overall, low bioavailability. The aim of the work was the formulation of a biocompatible polymeric ocular platform capable of overcoming these issues: ensuring the controlled release of hydrophobic drugs, controlling their release kinetics over time and promoting their transport through the ocular tissues. Therefore, melatonin (MEL), cyclosporine A (CYC) and coenzyme Q10 (Q10) were selected based on their neuroprotective properties on the retinal tissue. Due to their low solubility, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was used as solubilizer: TPGS self-assembles in micelles having a size of about 13 nm and acts as a permeation enhancer on ocular tissues [2]. Micelles were then loaded into a polymeric film consisting of polyvinyl alcohol (hydrolysis degree 87%) and xanthan gum. Cross-linking at high temperatures (dry heat, in presence of 0.03% w/v citric acid) was used as a strategy to guarantee controlled micelles release over time. After a preliminary evaluation, two cross-linking conditions were selected: 121°C for 19 minutes and 130°C for 90 minutes. The cross-linking effects were investigated by swelling studies and determination of the release kinetics of the micelles and the drugs loaded. Swelling studies have shown that more drastic cross-linking, in terms of time and temperature, is responsible for less significant swelling. At the same time, the studies of TPGS release from cross-linked films in the two different conditions confirmed the diffusion ability of the micelles through the cross-linked polymer platform and, unexpectedly, they identified the milder cross-linking (121°C, 19’) as the most efficient strategy in controlling micelles release over time. The significant swelling of the cross-linked film under milder conditions corresponded to a more controlled release of TPGS over time. Finally, MEL, CYC or Q10 release from cross-linked films was studied. The results confirmed cross-linking at 121°C for 19 minutes as the best strategy to obtain a controlled release and identified the physico-chemical properties of the molecules and their loading capabilities into the micelles as further crucial factors influencing the release. [1] Gaudana, R., et al. Recent Perspectives in Ocular Drug Delivery. Pharm Res 26, 1197– 1216 (2009) [2] Ghezzi, M., et al. Cyclosporine-loaded micelles for ocular delivery: Investigating the penetration mechanisms, Journal of Controlled Release 349, 744–755 (2022)