Influence of freeze-drying and γ-irradiation in preclinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using d-(+)-trehalose and polyethylene glycol.
This study investigated the suspension of poly(ε-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-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-PεCL-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 γ-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-PεCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-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.
Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, University of Barcelona, Barcelona, Spain.
Gladys Rosario
GR
Ramos Yacasi
Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, University of Barcelona, Barcelona, Spain.
María Luisa
ML
García López
Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, University of Barcelona, Barcelona, Spain.
Marta
M
Espina García
Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, University of Barcelona, Barcelona, Spain.
Alexander
A
Parra Coca
Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, University of Barcelona, Barcelona, Spain.
Ana Cristina
AC
Calpena Campmany
D060433:Administration, Ophthalmic; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D002645:Chickens; D003315:Cornea / Q000187:drug effects; D005123:Eye / Q000187:drug effects; D005480:Flurbiprofen / Q000008:administration & dosage*; D005612:Freeze Drying / Q000379:methods*; D005720:Gamma Rays; D007249:Inflammation; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000494:pharmacology; D012212:Rheology; D013552:Swine; D014199:Trehalose / Q000008:administration & dosage*
D000893:Anti-Inflammatory Agents; D011108:Polymers; D011092:Polyethylene Glycols; D005480:Flurbiprofen; D014199:Trehalose; C000595212:polyethylene glycol 3350
d-(+)-trehalose; flurbiprofen; freeze-drying; nanoparticles; polyethylene glycol 3350; γ-irradiation