(730e) Extended Delivery of Ophthalmic Drugs through Highly Crosslinked Nanoparticles

Ophthalmic drug delivery through eye drops has a low bioavailability of less than 5% due to rapid clearance from tears through drainage and conjunctival absorption. Additionally, eye drop based drug delivery suffers from low compliance because of the need of frequent administration. Several approaches are currently being explored for extended delivery of ophthalmic drugs to overcome the limitations of eye drops. This talk will focus on extended delivery of timolol, a beta blocker used for glaucoma therapy by devices such as conjunctival inserts, puncta plugs and contact lenses comprising of nanoparticles dispersed in hydrogels. To retain transparency of the devices, it is important to ensure that the nanoparticles are smaller than about 100 nm to avoid any scattering of the visible light. It is a major challenge to prepare sub 100 nm particles that can release small molecule drugs such as timolol for extended durations. This talk will focus on development of ultra small nanoparticles that can be dispersed in devices to create transparent devices for extended ophthalmic drug delivery. The basic approach is to prepare the nanoparticles by polymerization of an emulsion of a monomer with multi-vinyl functionalities in presence of diluents such as the drug. The drops of the emulsion serve as microsize reactors in which several nanogels form and grow. The concentration of the diluent in the unpolymerized liquid increased with time and eventually terminates the nanogel growth leading to formation of nanosized highly crosslinked particles containing drug. The specific crosslinker that will be discussed in this talk is PGT (propoxylated glyceryl triacylate). The particles are about 4-5 nm in size and relatively monodisperse. The drug containing particles are then dispersed in polymeric hydrogels such as p-hydroxyl ethyl methacrylate (HEMA) or silicone hydrogels to form contact lenses, conjunctival inserts and puncta plugs. The specific dimensions of the devices vary but the drug release profiles from all the devices are similar as the rate limiting step is transport of the drug from the nanoparticles, with the subsequent step of diffusion in the gel being very rapid. Each device releases drug for about a month in in vitro drug release tests under perfect sink conditions and the amount of the drug release could be controlled by the particle loadings in the devices to achieve therapeutic doses. The release profiles are non-diffusive likely because the pore size of the particles is much less than the drug size, and so the drug transport is an activated process. The release time from the devices is temperature sensitive suggesting the validity of the hypothesis that the release is an activated process, and so the particle laden gels can be used as thermally responsive gels. For instance, the release duration decreases from a month to an hour on increasing the temperature from about 22 to 100 oC. The temperature dependence is utilized to compute the energy barrier for the activation. The results of this study are useful for ophthalmic extended drug delivery. Also, highly crosslinked nanoparticles could find use in other drug delivery applications. Furthermore, the results of the study are useful in understanding the mechanisms of transport in highly crosslinked gels.