Thermo-sensitivity and erosion of chitosan crosslinked poly[N-isopropylacrylamide-co-(acrylic acid)-co-(methyl methacrylate)] hydrogels for application to the inferior fornix

Thermo-gels based on chitosan crosslinked poly(N-isopropylacrylamide) were developed as alternatives to conventional eye drops for the sustained release of ketotifen fumarate in the treatment of allergic conjunctivitis. The thermo-gelling properties of the base polymer were altered prior to crosslinking with chitosan by incorporation of the hydrophilic and hydrophobic comonomers acrylic acid and methyl methacrylate respectively. Varying amounts of chitosan were incorporated by ionic interaction to produce polyelectrolyte complexes or by carbodiimide chemistry to produce covalently crosslinked networks. The lower critical solution temperature of all the chitosan crosslinked thermo-gels produced was below the surface temperature of the eye. All the chitosan crosslinked thermo-gels were found to have greater than 80% equilibrium water contents following gelation. The method and amount of chitosan incorporation allowed for tailor-ability of material rheologic properties, with full degradation occurring over a one-to-four-day period, and tailorable rates of release of 40-60% of the loaded allergy medication ketotifen fumarate. The chitosan crosslinked thermo-gels were demonstrated to be nontoxic both in vitro and in vivo. It was demonstrated that the synthesized materials could be applied to the inferior fornix of eye, sustaining a multiple day release of ketotifen fumarate, as an alternative to conventional eyedrops. STATEMENT OF SIGNIFICANCE: Topical eyedrops are the main treatment modality for anterior ocular conditions. However, due to the natural clearance mechanisms of the eye, topical eyedrops are well established to be largely ineffective as a method of drug delivery. Herein, we investigate a method of altering thermo-gel properties of an n-isopropylacrylamide based polymer to enable the incorporation of greater amounts of chitosan by different methods of crosslinking. By controlling the synthesis parameters, final material properties can be tailored to impart ideal spreading, retention on the eye, and the rate of degradation and drug release over several days. This work also focuses on studying the rheological properties of the chitosan crosslinked thermo-gels which has not been investigated previously.