Mucoadhesive thermogel platform for treating anterior ocular conditions.

A platform mucoadhesive and thermogelling eyedrop was developed for application to the inferior fornix for the treatment of various anterior segment ocular conditions. The poly(n-isopropylacrylamide) polymers (pNIPAAm), containing a disulfide bridging monomer, were crosslinked with chitosan to yield a modifiable, mucoadhesive, and natively degradable thermogelling system. Three different conjugates were studied including a small molecule for treating dry eye, an adhesion peptide for modeling delivery of peptides/proteins to the anterior eye, and a material property modifier to create gels with different rheologic characteristics. Based on the conjugate used, different material properties such as solution viscosity and lower critical solution temperature (LCST) were produced. In addition to releasing the conjugates through disulfide bridging with ocular mucin, the thermogels were shown to deliver atropine, with 70%-90% being released over 24-h, depending on the formulation studied. The results illustrate that these materials can deliver multiple therapeutic payloads at one time and release them through various mechanisms. Finally, the safety and tolerability of the thermogels was demonstrated both in vitro and in vivo. The gels were instilled into the inferior fornix of rabbits and were shown to not produce any adverse effects over 4 days. These materials were demonstrated to be highly tunable, creating a platform that could be easily modified to deliver various therapeutic agents to treat a multitude of ocular diseases and have the potential to be an alternative to conventional eyedrops.

Thermo-responsive and mucoadhesive gels for the treatment of cystinosis.

Mucoadhesive thermogels were developed by crosslinking poly(n-isopropylacrylamide) based polymers with chitosan and incorporating disulfide bridges, capable of releasing cysteamine upon interaction with mucin, for the treatment of cystinosis. Through crosslinking with chitosan and incorporating varying concentrations of the disulfide monomer into the polymer backbone, the extent of how mucoadhesive the developed thermogels were could be controlled. Through disulfide bridging with mucin, the thermogels released 6 to 10 µg of the conjugate model 2-mercaptopyridine over five days. Utilizing chitosan as the crosslinker, the developed thermogels were shown to degrade to a statistically higher extent following incubation with lysozyme, the highest concentration tear enzyme, by gravimetric and rheologic analysis. The developed thermogels were extensively tested in vivo utilizing a rat model in which materials were applied directly to the corneal surface and a rabbit model in which thermogels were applied to the inferior fornix. With the developed models, there was no adverse reactions or visual discomfort incurred following application of the thermogels. It has been demonstrated that the thermogels produced can be applied to the inferior fornix and release the stable conjugated payload over several days. The developed thermogel was designed to improve upon the current clinical treatment options for ocular cystinosis which are acidic topical formulations that require reapplication multiple times a day.