PROJECT SUMMARY Among the estimated 165 million worldwide contact lens wearers one third experience itchy eyes from seasonal or perennial allergic conjunctivitis. Prevalence of ocular allergy has also risen in part due to environmental changes related to increased carbon emissions and the contributory role of air pollution in conjunctival immunological response. Topical anti-allergic agents with multiple mechanisms of action such as ketotifen and olopatadine are currently recommended as the first-line agents. Olopatadine drops have proven to be more effective than ketotifen to relieve the symptoms and signs of allergic conjunctivitis] and to provide more ocular comfort at application. Contact lens wearers are frustrated that ocular allergy interferes with normal wear and often rely on eye drops to manage symptoms which they find frustrating. The recent and first approval in the U.S. of a medicated contact lens that addresses this market is Johnson & Johnson's ACUVUE® Theravision™ with ketotifen medicated daily disposable hydrogel lens. We propose to further develop a next-generation, 1-day drug delivery contact lens (DDCL) platform for olopatadine using boundary charge modifiers to extend and control drug release. The work will build on our previous accomplishments in the field—enabling the use of both the most efficacious allergy drug and the most breathable lenses. The recent Johnson & Johnson product requires compromises in both areas to accomplish just a few hours (~2 h) duration of release. Lynthera's technology enables a boundary surface modification scheme to directly incorporate anionic long-chain fatty acids in silicone hydrogel contact lens' internal nanodomains to house nearly 80% of cationic charged drugs in the polymer- aqueous pore interfaces of a lens. Our modification scheme will substantially raise olopatadine retention at these interfaces due to electrostatic interactions between fatty acid anions with olopatadine cations, thereby raising the precision, duration, and resultant efficacy of olopatadine drug delivery, as well as prolonging comfortable wear time due to the silicone hydrogel lenses oxygen transmission. With the key aims of Phase I substantially completed, Phase II will focus on pre-clinical development of its technology platform for a daily disposable, drug delivery contact lens with olopatadine. Our specific aims are: (1) to optimize a 1-day silicone hydrogel DDCL that delivers 5 to 22 µg olopatadine with a sustained in vitro release profile for at least 12 hours, while maintaining requisite commercial standards for optical transmission, oxygen transmissibility and shelf-life; (2) the DDCL prototype will be evaluated by two in vivo studies of New Zealand rabbits including a small-scale, pilot pharmacokinetics and one-month toxicology, the latter of which is required to support the IND filing; (3) regulatory development of the DDCL for an Investigational New Drug (IND) filing with key activities to include pre-IND me...