Daptomycin delivery into the eye by encapsulation into chitosan coated alginate nanoparticles

Abstract

Bacterial endophthalmitis is an ocular inflammation resultant from the introduction of an infectious agent into the posterior segment of the eye. Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis are the main cause of majority of endophthalmitis cases. Currently, treatment of bacterial infections and inflammation in the eye poses the dilemma of anatomic barriers and the delicate nature of the interior of the eye. Local drug applied to the eye represents a non-invasive, safe and less painful solution than surgery, laser treatments or eye injections. Daptomycin is a novel acidic cyclic lipopeptide antimicrobial agent with activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus, becoming a powerful agent for treatment of bacterial endophthalmitis, though, topical administration of daptomycin directly into the eye is limited due to the rapid ocular fluid turn-over, requiring formulations with mucoadhesive properties. In spite of the existence of chitosan nanoparticles as daptomycin carrier, it is required an efficient alternative that may improve their biological and pharmaceutical properties. In the present project, mucoadhesive chitosan-coated alginate nanoparticles are proposed as effective delivery systems for daptomycin through ocular epithelium, taking advantage of the favourable biological properties of alginate and chitosan to prolong precorneal residence time of the antibiotic, enhancing drug accumulation and permeation. Nanoparticles were prepared by ionotropic pre-gelation of an alginate core followed by chitosan polyelectrolyte complexation, characterized regarding particle size, polydispersity and zeta potential, encapsulation efficiency was determined, and antimicrobial activity was also tested after encapsulation of the antibiotic. Also, in vitro ocular permeability of daptomycin-loaded nanoparticles was tested using cell culture models. Formulated daptomycin-loaded chitosan coated alginate nanoparticles were negatively charged and sized between 380-420 nm, suitable for ocular application. Encapsulation efficiencies were between 79 and 92%. Antibacterial activity of daptomycin against major microorganisms responsible for bacterial endophthalmitis was not affected by encapsulation into nanoparticles. In vitro permeability was up to 6% for corneal cells and 5% for retinal cells after 4 hours. In conclusion, obtained nanoparticles are suitable for daptomycin delivery in the eye and seem to be a promising vehicle for bacterial endophthalmitis

Date of Award	2014
Original language	English
Awarding Institution	Universidade Católica Portuguesa
Supervisor	Maria Manuela Pintado (Supervisor) & Bruno Sarmento (Supervisor)