Influence Of Freeze-Drying And Gamma- Irradiation In Preclinical Studies Of Flurbiprofen Polymeric Nanoparticles For Ocular Delivery Using D-(+)-Trehalose And Polyethylene Glycol

This study investigated the suspension of poly(e-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-P epsilon CL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-P epsilon CL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and gamma-irradiation with polyethylene glycol 3350 (PEG3350) and D-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PeCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after gamma-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen's egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PeCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PeCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over >30 days. This study concludes that both formulations meet the Goldman's criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials.