Hydrophobically-modified poly(vinyl pyrrolidone) as a physically-associative, shear-responsive ophthalmic hydrogel.

ABSTRACT

The potential of hydrophobically-modified poly(vinyl pyrrolidone) as a shear-responsive, self-associative hydrogel for ophthalmic applications is demonstrated. Hydrophobic modification was achieved via random copolymerization of N-vinylpyrrolidone with N-vinylformamide, the latter of which can be hydrolyzed to expose a desired degree of reactive amine groups permitting grafting of alkyl chlorides of varying alkyl chain lengths. The resulting materials formed highly shear-responsive physical hydrogels, exhibiting tunable shear thinning over 4-5 decades of viscosity from infinite shear to zero shear conditions that facilitates lubrication upon blinking and/or facile injection or drop-based delivery to the anterior or posterior segments of the eye. Viscosity changes due to self-association over time can also be tuned by changing the length of the hydrophobe, with C18-grafted materials exhibiting prolonged thickening over several weeks to form extremely stiff hydrogels and shorter grafts equilibrating significantly faster but forming weaker gels. The hydrogels remained transparent even at very high polymer concentrations (20 wt%) and are demonstrated to facilitate controlled release of a model drug (doxorubicin). The polymers exhibit minimal cytotoxicity in vitro to human corneal epithelial cells and retinal pigment epithelial cells, particularly when lower molecular weight backbone polymers were used. In vivo assessments in rabbits indicated no significant conjunctival edema or redness, secretion, corneal opacity, or iris involvement upon anterior application. Following intravitreal injection in rat eyes, no opacification of the lens, cornea or vitreous, nor any morphological or functional change to the posterior segment was observed. Examination of wholemount tissues and histology demonstrated no adverse effect from the injection or deposition of material. As such, these shear-thinning materials offer potential for drug delivery in both the anterior and posterior segments or as a vitreal replacement that can be easily administered or removed.