Desenvolvimento de implantes intraoculares constituídos de poliuretanos biodegradáveis e acetato de dexametasona

Abstract

The treatment of diseases of the posterior segment of the eye is limited by the difficulty in delivering effective doses of the drug to the vitreous, retina and choroid. Despite of systemic drug administration reaches the posterior segment of the eye, the natural ocular barriers makedifficult the absorption, and high doses of the drug are required to maintain the therapeutic range of the drug. Intravitreal injection can deliver drugs to the posterior segment of the eye, but it is an invasive technique and shows risk of infections and damages in ocular tissues.Aiming to reach adequate therapeutic range of the drugs in the posterior segment of the eye for long periods, controlled drug release systems implanted in the vitreous have been investigated for the treatment of several ocular diseases. In this study, polyurethanes, PUD5and PUD6, derived from poly(e-caprolactone) and poly(ethylene glycol), were synthesized based on aqueous dispersion of these polymers, and dexamethasone acetate was incorporated into the aqueous dispersion of the polyurethanes. Implants constituted by biodegradable polyurethanes and dexamethasone acetate were developed and explored as intraocular devices for controlled drug delivery for the treatment of posterior segment diseases of the eye. The implants were characterized by FTIR, XRD and SAXS and were submitted to the in vitro drug release study. Additionally, the pure polyurethane films were submitted to in vitro biodegradation and in vitro and in vivo biocompatibility studies. The different techniques ofcharacterization revealed that dexamethasone acetate preserved its chemical integrity after incorporation into the polymeric matrices, and the drug leaded to the new morphology of PUD5, while alterations were not detected in the nanostructure of PUD6. The polymeric systems provided controlled dexamethasone acetate release for a long period, and it was not observed liberation burst of the drug, which represented an advantage of these systems. The biodegradation process of the polyurethanes leaded to the mass loss and formation ofcrystallites, due to the hydrolysis of ester bonds present in poly(caprolactone) segments. The hard segments, based on urethane bonds, were preserved during the biodegradation. Moreover, APRE-19 cells cultured with medium containing the degradation products from thepolyurethanes showed viability, indicating their non-cytotoxic effect. The polyurethanes showed in vitro biocompatibility, since ARPE-19 cells were able to adhere, migrate, proliferate and form an organized and functional layer onto the polymeric surfaces. The polyurethanes showed also in vivo biocompatibility, since no inflammatory response and disorganization of the ocular tissues were observed after implantation of PUD5 and PUD6 in 19 the subretinal space and vitreous of mices eyes. Therefore, PUD5 and PUD6, biodegradable and biocompatible polyurethanes, provided the development of intraocular implants for the controlled release of dexamethasone acetate, applied to the treatment of diseases of theposterior segment of the eye.