Formulation and evaluation of epinephrine-loaded poly(acrylic acid-co-N-isopropylacrylamide) gel for sustained ophthalmic drug delivery

Abstract

Conventional eyedrops commonly used to deliver ophthalmologic treatments do not provide a sustained delivery of the drug, since a large portion of the intended dose is lost through eye drainage immediately following application. Micrometric sized crosslink gel based on copolymers incorporating thermal-sensitive copolymers were proposed for use in ophthalmic drug delivery. Eyedrops based on a thermoresponsive polymer were developed by mixing poly(acrylic acid-graft-N-isopropylacrylamide) (PAAc-graft-PNIPAAm) with PAAc-co-PNIPAAm gel and incorporating [3H]-epinephrine for in vitro evaluation of ophthalmic drug release. Polymeric eyedrops are clear solutions at room temperature but undergo partial solidification to a soft thin film on coming into contact with the corneal surface. On evaluation of the in vitro release kinetics of the embedded [3H]-epinephrine, PAAc-graft-PNIPAAm was found to exhibit faster drug release, while the mixture of PAAc-graft-PNIPAAm and PAAc-co-PNIPAAm gel showed a more sustained release profile and identifying the anomalous transport mechanism as a key factor. Intraocular pressure (IOP) was monitored by administration of epinephrine in polymeric eyedrops effectively reduced IOP for 36h, which is a considerable prolongation of the effect compared to the 8-h IOP decrease observed following administration via traditional eyedrops. Overall, our results indicate that the kinetics of drug release from the polymeric eyedrops are determined by crosslinking density, which affects the formation of capillary networks in the polymer matrix and thereby regulates drug diffusion into the polymeric network, hence considered as feasible approach to controlled drug release in ophthalmic drug delivery.