Development of a Stimulus Responsive, in-Situ Forming, Nanoparticle-Laden Hydrogel Formulation for Opthalmic Drug Delivery

Glaucoma is a chronic optic neuropathy that ranks as the leading cause of blindness worldwide, affecting as many as 80 million people. Inadequate or obstructed drainage of the aqueous humor through the trabecular mesh within the eye increases intraocular pressure, which subsequently damages the optic nerve situated at the base of the retina. Expectedly, most glaucoma medications exert therapeutic action by lowering the intraocular pressure, and nearly all of these are administered as eye drops. However, since corneal penetration efficiencies of <5% are typical for such dosage forms, which implies that the dosage of drug in these formulations is much higher than required, there is a clear, unmet need for novel transcorneal drug delivery vehicles that achieve higher drug penetration at significantly lower dosages. Such a vehicle would greatly facilitate the formulation of newer, more effective but less bioavailable anti-glaucoma drugs. To this end, we have developed a stimulus-responsive, nanoparticle-laden hydrogel vehicle for spatiotemporal and dosage-controlled release of poorly bioavailable drugs into the aqueous humor of the eye. Our hydrogel matrix is formulated as a composite of two FDA-approved, GRAS polymers that are biocompatible and highly mucoadhesive. Similarly, the physical attributes of the drug-loaded nanoparticles too have been synthetically optimized in order to achieve high transcorneal penetration. Experimental design aided the identification of hydrogel composition and nanoparticle content in the formulation for stimulus-responsive switching between temperature-dependent rheopexy (thickening) and thixotropy (thinning). The liquid formulation has a sol-gel transition temperature of 32°C, which is the temperature of the ocular surface, and its gelation characteristics permit the formulation to form a thin, uniform coating over the cornea through blinking of the eyelid. These properties facilitate its application as an eye drop immediately prior to the patientâ??s bedtime, and also permit easy and scalable manufacturing, which greatly simplifies the path towards development of a regulated industrial-scale manufacturing process. Significantly, our formulation exhibits over a 300% increase over control formulations in whole-eye experiments using Bovine eyeballs, thereby paving the way for the introduction of novel anti-glaucoma products to the market.