Incorporation of drug particles for extended release of Cyclosporine A from poly-hydroxyethyl methacrylate hydrogels

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Cyclosporine A is prescribed for a number of ophthalmic applications such as dry eyes, uveitis in children and adolescents, vernal keratoconjunctivitis, and peripheral ulcerative keratitis. Extended release of cyclosporine from contact lenses has been explored due to the significant benefits of increased bioavailability in comparison with eye drops. Incorporation of drug loaded particles is considered to be a promising approach for increasing the drug release duration. Here we explore the feasibility of extended release of cyclosporine and possibly other hydrophobic drugs by dispersing particles that are 100% drug rather than drug loaded particles. The expected benefits are high drug loading and extended release. Specifically, we explore transport of cyclosporine in hydroxyethyl methacrylate gels for the case when the gel is loaded with high concentration of drug leading to in situ formation of particles. We explore whether we can increase the release duration from the gels by incorporation of the particles, without sacrificing light transmission which is a critical property for contact lenses. Hydrogels were prepared by free radical UV initiated polymerization with drug dissolved in the monomer solution at varying loadings. Drug release kinetics were measured from the particle loaded lenses and fitted to the Higuchi model to determine the diffusivity. The measured diffusivity is two orders of magnitude lower than estimates from Brinkman model. The differences were attributed to the high partition coefficient of about 150, which implies that a majority of the drug in the gel is bound to the polymer. The bound drug can diffuse along the surface or desorb and diffuse. The diffusivity estimates match the measured values after binding is taken into consideration. Light transmittance was measured to determine whether particle incorporation reduces the transparency. Results showed that the drug release duration could be controlled by increasing the drug loading but the transmittance was significantly reduce particularly at high drug loadings, which suggest that this approach may have limited applicability for contact lenses, but could be useful in other applications where light transmission is not critical.

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