PROJECT SUMMARY Among the estimated 165 million worldwide contact lens wearers many suffer from allergies but face a challenge as the application of eye drops is generally incompatible with lens wearing. It has been estimated one third contact lens wearers experience itchy eyes; and a majority of these are frustrated that allergy interferes with their normal wear and often they rely on allergy eye drops to manage their symptoms. The first approval of a medicated contact lens that addresses this need occurred only recently (2021) when Johnson & Johnson's Acuvue Theravision with ketotifen drug eluting daily disposable hydrogel lens received marketing authorization in Japan. We propose to develop a next-generation drug delivery contact lens (DDCL) platform for allergy drugs 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 drugs and the most breathable lenses. The new Johnson & Johnson product requires compromises in both areas to accomplish just a few hours duration of release. Many commercial contact lenses intended for both for extended wear and increasingly for daily disposable wear consist of hydrophilic poly (2-hydroxyethyl methacrylate), hydrophobic silicone macromer phase and remainder aqueous pores to simultaneously achieve high transparency, tear affinity, and oxygen transmission. This nanodomain structure naturally has a very high pore surface area to volume ratio, which we will utilize to control drug release with designed surface modifications. For delivering a charged drug molecule, the incorporation of an oppositely charged ligand group at the polymer-aqueous pore interfaces will enhance the molecule's partition and retention at the interfaces. Thus, due to the exceptionally large surface areas of the nanodomains, effectively and precisely control its release kinetics from a DDCL. Lynthera's technology enables a boundary surface modification scheme to directly incorporate long-chain fatty acids, amines, or quaternary ammonium salts onto either hydrophilic poly (2-hydroxyethyl methacrylate) or silicone polymer surfaces to house nearly 80% of ionic drugs in a lens. The retention occurs within the charged boundary double layers formed at the large area of polymer-pore interfaces. Our modification scheme will substantially raise the charge density at the lens-pore interfaces – especially for silicone hydrogel lenses – thereby raising the precision, duration, and resultant efficacy of ketotifen drug delivery, as well as prolonging comfortable wear time due to the silicone hydrogel lenses' higher oxygen transmission. Specific Aim 1 is to develop a better (longer duration, higher precision, and more comfort) Ketotifen eluting DDCL to compete in the daily disposable contact lens market. Specific Aim 2 is to develop a sustainable and high-precision delivery of Olopatadine from a daily disposable contact lens by desig...