title: Role of hydroxypropyl-β-cyclodextrin on freeze-dried and gamma-irradiated PLGA and PLGA-PEG diblock copolymer nanospheres for ophthalmic flurbiprofen delivery.
abstract: Poly(D,L-lactide-co-glycolide) and poly(D,L-lactide-co-glycolide) with poly(ethylene glycol) nanospheres (NSs) incorporating flurbiprofen (FB) were freeze-dried with several cryoprotective agents and sterilized by γ-irradiation. Only when 5.0% (w/v) hydroxypropyl-β-cyclodextrin (HPβCD) was used, a complete resuspension by manual shaking and almost identical particle size of the NSs was obtained after freeze-drying. In vitro drug release and ex vivo corneal permeation of NSs with and without HPβCD were evaluated. The presence of HPβCD resulted in a reduction of burst effect, providing a more sustained release of the drug. A significant decrease in the FB transcorneal permeation of NSs containing HPβCD was obtained, related to the slower diffusion of FB observed in the in vitro results. The uptake mechanism of the NSs was examined by confocal microscopy, suggesting that NSs penetrate corneal epithelium through a transcellular pathway. Ocular tolerance was assessed in vitro and in vivo by the Eytex™ and Draize test, respectively. Long-term stability studies revealed that γ-irradiated NSs stored as freeze-dried powders maintained their initial characteristics. Stability studies of the resuspended NSs after 3 months of storage in the aqueous form showed that NSs were stable at 4°C, while formulations stored at 25°C and 40°C increased their initial particle size.
authors.affiliation: Department of Physical Chemistry, Institute of Nanoscience and Nanotechnology, Faculty of Pharmacy, University of Barcelona, Av Joan XXIII s/n, Barcelona, Spain. evegafre7@far.ub.edu
authors.forename: Estefanía
authors.initials: E
authors.lastname: Vega
authors.forename: M Antònia
authors.initials: MA
authors.lastname: Egea
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Calpena
authors.forename: Marta
authors.initials: M
authors.lastname: Espina
authors.forename: M Luisa
authors.initials: ML
authors.lastname: García
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D060433:Administration, Ophthalmic; D000704:Analysis of Variance; D000818:Animals; D003315:Cornea / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D003451:Cryoprotective Agents / Q000737:chemistry; D004355:Drug Stability; D019573:Epithelium, Corneal / Q000187:drug effects / Q000378:metabolism; D005480:Flurbiprofen / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D005612:Freeze Drying; D005720:Gamma Rays; D019344:Lactic Acid / Q000737:chemistry* / Q000494:pharmacology / Q000528:radiation effects; D008297:Male; D054118:Nanospheres / Q000737:chemistry* / Q000528:radiation effects; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000494:pharmacology / Q000528:radiation effects; D011098:Polyglactin 910 / Q000737:chemistry* / Q000494:pharmacology / Q000528:radiation effects; D011100:Polyglycolic Acid / Q000737:chemistry* / Q000494:pharmacology / Q000528:radiation effects; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011817:Rabbits; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D003451:Cryoprotective Agents; D047392:beta-Cyclodextrins; C102418:poly(lactic-glycolic acid)-poly(ethyleneglycol) copolymer; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011098:Polyglactin 910; D011092:Polyethylene Glycols; D005480:Flurbiprofen