Development and characterization of a polymeric film for the ocular controlled release of micelles

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 that contains micelles and is able to control their release. Loaded micelles, once released from the platform, can take advantage of the nanometric size, solubilization capability and tissue penetration. D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), capable of self-assembling into micelles of approximately 13 nm, was chosen as a nanocarrier for the potential loading of hydrophobic drugs and as permeation enhancer on ocular tissues [2]. Micelles were then loaded into a polymeric film consisting of polyvinyl alcohol (hydrolysis degree 87%, MW 83400 Da) and xanthan gum. Crosslinking 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 crosslinking conditions were selected: 121°C for 19 minutes and 130°C for 90 minutes. The crosslinking effects were investigated by swelling studies and determination of the release kinetics of the micelles. Swelling studies have shown that more drastic crosslinking, in terms of time and temperature, is responsible for less significant swelling. At the same time, the studies of TPGS release from crosslinked films confirmed the diffusion ability of the micelles through the crosslinked polymer platform and, unexpectedly, they identified the milder crosslinking (121°C-19’) as the most efficient strategy in controlling micelles release over time. The significant swelling of the crosslinked film under milder conditions corresponded to a more controlled release of TPGS over time. The obtained images (SEM analysis) of the film section after swelling and freeze-drying showed how the sample subjected to more drastic crosslinking had larger and fewer meshes compared to the film crosslinked in milder conditions. These features could help to explain the release kinetics of TPGS: although the mesh size was in both cases larger than that of the micelles, the slower release recorded for the mildest crosslinked system could be due to the more tortuous path that micelles face during their diffusion. The applicability of the platform was then confirmed through retention and permeation studies across different porcine ocular tissues (conjunctiva, sclera, choroid), mounted on Franz-type diffusion cells. These data were strengthened by images collected by two-photon microscopy, using a film loaded with micelles carrying Nile Red as fluorescent probe. The swelling and release data, the ex-vivo studies on ocular tissues, the microscopic investigations and the loading with hydrophobic drugs (ongoing studies) suggest that the developed polymer platform can become an effective and versatile ocular drug delivery system. [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)