Engineering Polymer Networks for Enhanced Loading and Extended Release of Therapeutics via Molecular Imprinting

Abstract

Conventional topical ocular therapies such as eye drops and ointments are the current “go to” therapy, and account for over 90% of the market. However, topical drug delivery results in very low drug bioavailability, ranging from 1-7%. Therefore, there is a significant unmet need in the ocular therapeutic market for effective drug delivery mechanism. This study focused on the rational design and engineering of novel contact lenses via molecular imprinting techniques, capable of tailorable loading and extended release of ocular therapeutics. Poly(HEMA-co-DEAEM-co-PEGnDMA) hydrogels imprinted with the non-steroidal anti-inflammatory, diclofenac sodium (DS), were engineered exploiting ionic and hydrogen bonding non-covalent interactions to better understand the effect of various compositional parameters, such as amount and length of crosslinking monomers, template concentration, and functional monomer concentration, on their macromolecular structure and subsequently their binding and transport properties. Varying the compositional parameters had diverse effects on the imprinted hydrogel properties. For example, an increase in the amount of crosslinking resulted in ~3.0 times smaller mesh size, ~1.6 times lower template binding capacity, ~1.3 times lower template binding affinity, and ~1.8 times lower transport diffusion coefficients. When the release studies were performed in artificial lacrimal solution, the presence of salts and ions altered interactions between the anionic template molecule and the cationic functional monomer. A controlled and extended release of diclofenac sodium was achieved for up to 72 hours in artificial lacrimal solution. Moreover, the diffusion coefficients of diclofenac sodium through weakly crosslinked imprinted poly(HEMA-co-DEAEM-co-PEG200DMA) lenses were further controlled by adjusting the functional monomer to template (FM/T) ratio (1, 3.5 and 10.5). There was an inverse correlation between the FM/T ratio and the diffusion coefficient. Extended and controlled release of therapeutically relevant concentrations of diclofenac was achieved for up to 6 days in lacrimal solution at in vitro ocular flowrates. A polyvinyl alcohol (PVA) macromer, Nelfilcon A, which has ~4.4 times larger chain building blocks than poly(HEMA-co-DEAEM-co-PEG200DMA), was used as a backbone monomer to engineer a daily disposable contact lens to tailor the release rate of diclofenac sodium, permitting the study of the imprinting effectiveness in this large network structure. Additionally, silicone hydrogel contact lenses were engineered with varying hydrophobic:hydrophilic ratios as well as including additional crosslinking monomers. As the hydrophobic:hydrophilic ratio increased, the diffusion coefficient of diclofenac decreased up to ~36 times. Release was delayed due to a combination of increased hydrophobic to hydrophilic composition and the inclusion of additional structural constraints, both of which decreased the polymer volume fraction in the swollen state. The study also demonstrated the successful in vivo extended release of an anti-histamine drug, ketotifen fumarate, from molecularly imprinted, therapeutic contact lenses. This is the first time that a steady, effective concentration of drug was maintained in the tear film from a contact lens for an extended period of time for the entire duration of lens wear. The results showed that the imprinted lenses exhibited ~100 times greater bioavailability than eye drops and a dramatic increase in ketotifen mean residence time (MRT). Finally, variations in the release conditions (e.g., volume, mixing rate, and temperature) and their effect on the release of a wide spectrum of both hydrophilic and hydrophobic drugs (ketotifen fumarate, diclofenac sodium, timolol maleate, and dexamethasone) from conventional hydrogel lenses and silicone hydrogel lenses were studied. It was found that volume had the biggest effect on the release profile, which incidentally is the least consistent variable throughout the literature. Faster release rates of up to 12 times were observed when the volume was changed from 2 mL to 200 mL.