Thermo-sensitivity and erosion of chitosan crosslinked poly[N-isopropylacrylamide-co-(acrylic acid)-co-(methyl methacrylate)] hydrogels for application to the inferior fornix

Looking to the future of eyedrops

Allergic conjunctivitis (AC) is an inflammation of the conjunctiva that involves immune mechanisms mediated by immunoglobulin E and mast cells. Although it affects up to half of the population in Canada and United States, AC is an often underdiagnosed, non-infectious subset of conjunctivitis. It results from exposure to allergens such as pollen, animal dander, and environmental stimuli. Although AC has always been a predominant form of conjunctivitis, it has increased lately affecting many patients and their quality of life. Because of the high prevalence and the multifactorial causes of AC, a combination of therapies is often necessary to treat the associated signs and symptoms. This also creates a heavy economic burden, necessitating effective and novel treatment approaches, hence the ongoing research for additional therapeutic targets. Its symptoms include itching, tearing and conjunctival hyperemia. This condition is commonly treated using noninvasive eye drops and ointments that are inexpensive and easy to apply. Unfortunately, less than 5% of the applied topical eye drop doses remain bioavailable after administration, attributed to several limiting barriers like drainage and undesirable absorption. Considering the natural eye clearance mechanism, topical eyedrops are deemed ineffective drug delivery methods.

Chitosan-based hydrogels have been extensively studied as ocular therapies owing to their outstanding properties. Several chitosan-based ocular formulations have been developed and tested, including liposomes, in situ gels and nanoparticles. Ocular hydrogel-based in situ forming gels can be largely categorized into thermo-responsive, ion-sensitive and pH-responsive and have been extensively researched for biomedical applications.

Drug delivery systems for anterior eye conditions treatment have been proposed as a promising alternative to conventional eye drops. These systems also apply to the inferior fornix (also referred to as the cul-de-sac). They are sustainable and offer significant advantages over conventional topical eye drops. The main objective of application to the inferior fornix is to create hydrogels that do not obstruct clear vision and do not rapidly deteriorate during blinking. Generally, these systems are either ocular inserts, degradable pre-set films and non-degradable in situ gels.

It has been hypothesized that in-situ thermo-gels capable of degrading over multiple days and safely removing the degradation byproducts via the natural clearance mechanism of the eye can be developed to treat ocular conditions by incorporating chitosan in poly(N-isopropylacrylamide) (pNIPAAM) based hydrogels. To test the hypothesis, PhD student Mitchell Ross, PhD student Emily Anne Hicks, Dr. Talena Rambarran, and led by Dean Heather Sheardown from McMaster University developed thermo-gels based on chitosan crosslinked poly(N-isopropylacrylamide) for sustained release of ketotifen fumarate for treating AC. The work is currently published in the journal, Acta Biomaterialia.

Before crosslinking with chitosan, hydrophobic (methyl methacrylate) and hydrophilic (acrylic acid) comonomers were incorporated to modify the thermo-gelling properties of the base polymer. Furthermore, varying amounts of chitosan were incorporated by carbodiimide chemistry or ionic interaction to produce covalently crosslinked networks or polyelectrolyte complexes, respectively. The research team investigated the effects of chitosan on the properties and performance of the material.

The authors showed that the synthesized chitosan-based thermo-gelling polymers were applicable to the inferior fornix and are an effective alternative for treating surface ocular conditions like AC. The drug-eluting thermo-gels provided sustained therapeutic release over multiple days, eliminating the need for frequent reapplications as with the conventional topical eye drops. For all the chitosan crosslinked thermo-gels, the lower critical solution temperature was less than the surface eye temperature. All these thermo-gels exhibited an equilibrium water content greater than 80% following gelation.

By varying the properties of the base polymer, it was possible to control the lower critical solution temperature after crosslinking. Moreover, incorporating the varying concentration of chitosan improved the mechanical and rheological properties and the final water swollen network pH. Full degradation was tailored over a multiple one-to-four-day period, and it was characterized by tailored release rates of between 40 – 60% of the loaded allergy medication ketotifen fumarate. Physical forces like swelling and subsequent dissolution were the key driving forces behind the hydrogel degradation process. Furthermore, the chitosan crosslinked thermo-gels were nontoxic for both in vivo and in vitro analysis.

In summary, the authors successfully prepared chitosan crosslinked thermo-gels for application to the inferior fornix. The choice of chitosan as the crosslinker for the base polymer was attributed to its outstanding ophthalmic properties and ability to enhance the mechanical properties and provide a degradation means by ionic interaction or covalent conjugation. It allowed the control of the synthesis parameters and the tailoring of the final material properties to impart desirable spreading and retention as well as the rate of drug release and degradation. In a statement to Advances in Engineering, the researchers said “We wanted to create a platform material which can be easily applied through a conventional eyedropper to treat anterior ocular conditions over multiple days”, they continued “We are currently furthering this technology to treat other anterior ocular conditions and also improve the anchoring effect within the inferior fornix by altering the mucoadhesive properties of the thermos-gels” .