472751 Engineering Polymeric Nanostructures in Silicone Hydrogel Contact Lens Biomaterials for Controlled Release to Treat Glaucoma
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. Engineering macromolecular memory involves molecular imprinting of flexible polymer chains. Functional monomers are selected to have high affinity to the drug via non-covalent interactions. Molecular complexes comprised of the functional monomers and drug molecules are crosslinked into the hydrogel matrix during polymerization. These nanostructures remain after removal of the drug and provide interaction points throughout the polymer that delay release. Lenses are specifically designed for the selected drug because the chemistry and structure of the drug molecule dictate which types of non-covalent interactions are utilized. This study highlights a selected combination of functional monomers interacting with two forms of latanoprost, a prominent glaucoma medication prescribed today.
Silicone hydrogel and hydroxyethyl methacrylate (HEMA) contact lens formulations were developed to release the prostaglandin analogue, latanoprost, in both its active form (LPA) and prodrug form (LP). The major components of our silicone hydrogel lenses were methacryloxypropyl-tris-(trimethylsiloxy) silane (TRIS), dimethyl acrylamide (DMA), and methacryloxypropyl terminated polydimethylsiloxane (DMS-R11). HEMA was the main constituent of the HEMA 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 both forms of latanoprost. For LP, 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-DMS-R11-co-DMA-co-EGDMA-co-PEG200DMA) network and poly(AA-co-MAA-co-HEMA-co- PEG200DMA) network. For LPA, 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-DMS-R11-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).
One of the most significant variables to consider in these formulations is the molar ratio of the functional monomers (M) to the template drug molecule (T)—the M/T ratio. In this study, various combinations of the M/T ratio were tested for both drug types (20/1, 50/1, 100/1) in the silicone hydrogel and HEMA lenses. Ratios between the monomers varied between 1 and 3 to show how the monomer content and proportions directly impact the nature of the memory sites formed and the resultant release properties from the lenses. Previous studies have shown that the release rate and overall release profile can be controlled through the adjustment of the M/T ratio and 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. Both LP and LPA were successfully released for over a week under in vitrophysiological 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 an improved, more efficient and effective method of topical drug delivery to the eye. Macromolecular memory has the potential to revolutionize ocular therapeutics for a wide range of ocular conditions and diseases through the incorporation of nanostructured memory sites specifically catering to 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 is applied for the first time to the global issue of glaucoma as a possible remedy for current drug delivery methods. Improved treatment via macromolecular memory could ultimately reduce incidence of glaucomatous blindness and greatly improve patients’ quality of life.