Sistemi nanocompositi termosensibili per la somministrazione intravitreale di cefuroxima

Postoperative endophthalmitis, a possible complication of cataract surgery, is an eye infection that can lead to serious eye damage. Currently, it is treated with an intravitreal injection of 1 mg cefuroxime (CEF) at the end of surgery, followed by a home-based therapy consisting in administering antibiotic eye drops thrice a day. The effectiveness of this procedure is often reduced by low compliance of the patient [1]. The present research is based on the collaboration among different departments and hospitals with the general aim of developing new sustained-release dosage forms of ophthalmic antibiotics for post-operative infections. Novel injectable drug delivery systems, defined as “nanocomposite hydrogels”, for intravitreal admin-istration of CEF are proposed, based on nanoformulations, such as solid lipid nanoparticles (SLN) and microemulsions (μE), vehicled in thermoresponsive in situ forming gels, whose viscosity increases at body temperature. Trilaurin SLNs are prepared with the innovative method called "cold microemulsion dilution", an evolution of a method previously developed by the research group where this thesis was carried out [2]. To allow the incorporation of CEF, being highly hydrophilic, in the internal lipid phases it was necessary to synthesize a prodrug, obtained by esterification of CEF with a dodecyl chain (dodecyl-CEF). Both nanosystems (SLN or μE) were then dispersed in a Pluronic®F127 hydrogel, in order to obtain an injectable system gelling at body temperature, allowing a prolonged in situ permanence of the drug. The preparation of the μE initially involved a formulation step, aimed to identify the appropriate surfac-tant/co-surfactant system and biocompatible ingredients allowed for intraocular administration. The ob-tained SLNs were characterized by optical and scanning electron microscopy, in order to exclude the presence of crystals and/or aggregates and to evaluate their morphology; moreover, with the dynamic light scattering technique, Zeta potential and mean diameter were measured, resulting around -20 mV and 300 nm respectively; finally, pH and osmolarity were assessed. The results of entrapment efficiency showed that the esterification of the drug is an excellent approach to optimize the inclusion of CEF with-in SLN. In vitro CEF release studies carried out in thermostatic incubator at two different temperatures, below and above the transition temperature of the thermoresponsive polymer, clearly showed significant dif-ference in drug release profile. Preliminary studies of cytotoxicity, performed following the cell growth inhibition in ARPE-19 retinal cell line over 72 hours, showed a moderate biocompatibility of the tested systems. Therefore, in collabora-tion with the Department of Chemistry, a series of cross-linked polymers of PNIPAM [3] are under eval-uation with the aim to further increase their biocompatibility. A detailed physico-chemical characteriza-tion of these systems are currently underway in order to identify the best derivative of PNIPAM. However, based on the preliminary results, these innovative nanocomposite hydrogels can be consid-ered as a promising and strategic approach to control the intravitreal delivery of antibiotics and possibly also of other ophthalmic drugs.