(604a) Developing Novel Therapeutic Contact Lenses for the Treatment of Glaucoma Via Macromolecular Memory

Eye drops are the current standard of care for general ocular therapeutics, representing over 90% of the ophthalmic drug market today. Despite this dominance, eye drops are only marginally effective with typically less than 1-7% of the applied drug being productively absorbed. Although easily accessible for treatment, the eye presents highly effective physiological barriers that make topical treatment extremely challenging. To combat low bioavailability and short residence time, a rigorous eye drop regimen is prescribed. This makes topical ocular therapies highly susceptible to patient compliance issues. A vast number of ocular conditions rely heavily on topical treatment, which can lead to devastating consequences when treatment is inadequate. This is the case for glaucoma, the world’s leading cause of irreversible blindness which is estimated to affect over 60 million worldwide and currently has no cure. The dominant treatment method prescribed for glaucoma patients is daily eye drops. If untreated or poorly treated, individuals experience progressive, permanent vision loss due to an increase in intraocular pressure that damages the optic nerve.

Our solution to replace eye drops for ocular therapeutics is the therapeutic contact lens. Macromolecular memory is one of the most promising concepts for therapeutic lens design, and our lab has shown (both in vivo and in vitro) this technology is capable of delivering drug at a controlled rate for a wide range of drug classes and molecules, lens types, lens modalities, and lens wear schedules. Macromolecular memory uses nature as a guide, mimicking protein-ligand combinatorial chemistry. Like protein-ligand interactions, macromolecular memory is centered around the creation of highly specific sites within the polymer, tailored for a selected therapeutic to be delivered. Memory sites are developed within the flexible polymer architecture and are capable of binding, releasing, and rebinding with the template molecule. To successfully incorporate macromolecular memory, functional monomers are carefully chosen to make up the memory sites; these functional monomers must have high affinity to the drug via non-covalent interactions. Molecular complexes comprised of the functional monomers and drug molecules self-assemble in solution and are crosslinked into the hydrogel matrix during polymerization. These memory sites remain after removal of the drug and provide points of interaction for drug diffusing throughout the polymer, which delays release into the eye. Due to the highly specific nature of macromolecular memory design, lenses are made only for the drug chosen to be released; the chemistry and structure of the drug molecule serve as a very specific template (or analyte) and dictate which types of non-covalent interactions are utilized. This study highlights a selected combination of functional monomers interacting with latanoprost, a prominent glaucoma medication prescribed today.

Silicone hydrogel and hydrogel contact lens formulations were developed to release prostaglandin analogues used to treat glaucoma. The major components of our silicone hydrogel lenses were methacryloxypropyl-tris-(trimethylsiloxy) silane (TRIS), dimethyl acrylamide (DMA), and silicone macromer. Hydroxyethyl methacrylate (HEMA) was the main constituent of the hydrogel lenses. Poly(ethylene glycol) 200 (PEG200) and ethylene glycol dimethacrylate (EGDMA) served as crosslinkers. Functional monomers were selected to specifically cater to the chemistry of the prostaglandin analogues. For the prostaglandin analogue, latanoprost, hydrogen bonding was the focus with acrylic acid (AA) and methacrylic acid (MAA) to form variations of a poly(AA-co-MAA-co-TRIS-co-macromer-co-DMA-co-EGDMA-co-PEG200DMA) network and poly(AA-co-MAA-co-HEMA-co- PEG200DMA) network. For the active form of latanoprost, ionic bonding potential was taken advantage of with 2-(diethylamino)ethyl methacrylate (DEAEM) and diallyldimethylammonium chloride (DADMAC) for the development of poly(DEAEM-co-DADMAC-co-TRIS-co-macromer-co-DMA-co-EGDMA-co-PEG200DMA) network and poly(DEAEM-co-DADMAC-co-HEMA-co- PEG200DMA) network. UV free-radical photopolymerization was used to form the contact lenses from solution. Drug binding studies were performed to show successful incorporation of macromolecular memory. Dynamic release studies were done in two ways: a large volume release system (200 mL at 34˚C) and microfluidic devices designed to mimic physiological volumes and flow rates (3µL/min).

The most significant variables to consider in these formulations are the number of interactions and the functional monomer diversity. The number of interactions can be described by the molar ratio of the imprinting functional monomers (M) to the template drug (T)—the M/T ratio. In this study, various combinations of the M/T ratio were tested for both drug types (between 1.5 to 50 M/T) in the silicone hydrogel and HEMA lenses. The M/T ratio was shown to directly affect the release rate of the therapeutic from the lens, as a result of impacting the nature of the memory sites formed. Previous studies have shown that the release rate and overall release profile can be controlled through the adjustment of the M/T ratio as well the diversity of functional monomers used. For both HEMA and silicone hydrogel lenses produced, higher M/T ratios resulted in a slower release of drug over time. Functional monomer diversity has also been shown to have a significant effect on macromolecular memory, contributing to the degree of specificity incorporated into the memory sites (therefore contributing to the effectiveness of the memory sites being created). Both LP and LPA were successfully released for over a week under in vitro physiological conditions in both lens types. Optical clarity and mechanical properties were also tested to show that the polymers had appropriate physical properties for use as contact lenses.

There exists a great need for a more efficient and effective method of drug delivery to the eye. Macromolecular memory could revolutionize ocular therapeutics for a wide range of ocular conditions and diseases by using nature as a guide—mimicking protein-ligand interactions through the incorporation of memory sites specifically designed for the chosen drug molecule. This technology has been proven to provide tailorable release rates with versatility in application, while also being capable of fitting seamlessly into current manufacturing schemes. Our study shows how this technology being successfully applied for the first time to the global issue of glaucoma as a possible remedy for current drug delivery methods through extended-wear therapeutic contact lenses. Ultimately, improving treatment via macromolecular memory could reduce glaucomatous blindness and greatly improve the quality of life for patients worldwide.