title: Enhancing and sustaining the topical ocular delivery of fluconazole using chitosan solution and poloxamer/chitosan in situ forming gel.
abstract: Fungal keratitis is a serious disease that can lead to loss of vision. Unfortunately, current therapeutic options often result in poor bioavailability of antifungal agents due to protective mechanisms of the eye. The aim of this work was to evaluate the potential of a chitosan solution as well as an in situ gel-forming system comprised of poloxamer/chitosan as vehicles for enhanced corneal permeation and sustained release of fluconazole (FLU). For this, in vitro release and ex vivo corneal permeation experiments were carried out as a function of chitosan concentration from formulation containing the chitosan alone and combined with the thermosensitive polymer, poloxamer. Microdialysis was employed in a rabbit model to evaluate the in vivo performance of the formulations. The in vitro release studies showed the sustained release of FLU from the poloxamer/chitosan formulation. Ex vivo permeation studies across porcine cornea demonstrated that the formulations studied have a permeation-enhancing effect that is independent of chitosan concentration in the range from 0.5 to 1.5% w/w. The chitosan solutions alone showed the greatest ex vivo drug permeation; however, the poloxamer/chitosan formulation presented similar in vivo performance than the chitosan solution at 1.0%; both formulations showed sustained release and about 3.5-fold greater total amount of FLU permeated when compared to simple aqueous solutions of the drug. In conclusion, it was demonstrated that both the in situ gelling formulation evaluated and the chitosan solution are viable alternatives to enhance ocular bioavailability in the treatment of fungal keratitis.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Taís
authors.initials: T
authors.lastname: Gratieri
authors.forename: Guilherme Martins
authors.initials: GM
authors.lastname: Gelfuso
authors.forename: Osvaldo
authors.initials: O
authors.lastname: de Freitas
authors.forename: Eduardo Melani
authors.initials: EM
authors.lastname: Rocha
authors.forename: Renata F V
authors.initials: RF
authors.lastname: Lopez
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D048271:Chitosan / Q000008:administration & dosage* / Q000737:chemistry; D003315:Cornea / Q000187:drug effects / Q000378:metabolism; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems / Q000379:methods; D005079:Excipients / Q000008:administration & dosage / Q000737:chemistry; D015821:Eye Infections, Fungal / Q000188:drug therapy / Q000378:metabolism; D015725:Fluconazole / Q000008:administration & dosage* / Q000737:chemistry; D005782:Gels / Q000008:administration & dosage* / Q000737:chemistry; D017551:Microdialysis / Q000379:methods; D009883:Ophthalmic Solutions / Q000008:administration & dosage* / Q000737:chemistry; D010539:Permeability / Q000187:drug effects; D020442:Poloxamer / Q000008:administration & dosage* / Q000737:chemistry; D011817:Rabbits; D013552:Swine; D013696:Temperature
chemical_list: D000935:Antifungal Agents; D003692:Delayed-Action Preparations; D005079:Excipients; D005782:Gels; D009883:Ophthalmic Solutions; D020442:Poloxamer; D015725:Fluconazole; D048271:Chitosan