title: Flurbiprofen PLGA-PEG nanospheres: role of hydroxy-β-cyclodextrin on ex vivo human skin permeation and in vivo topical anti-inflammatory efficacy.
abstract: In this study, flurbiprofen (FB) loaded poly(d,l-lactide-co-glycolide) (PLGA) and PLGA with poly(ethylene glycol) (PLGA-PEG) nanospheres (NSs) with and without hydroxypropyl-β-cyclodextrin (HPβCD) were developed as skin controlled delivery systems. X-ray diffraction was used to determine the physical state of the entrapped drug. Results showed that the drug in PLGA NSs was present in the form of a molecular dispersion (dissolved state) in the polymers, whereas in PLGA-PEG NSs, the drug was present in both molecular dispersion and crystalline forms. Furthermore, HPβCD provided solubilization of the free FB present on the surface of the PLGA-PEG NSs and a complete amorphosization of the drug was obtained. Optical analyses using TurbiscanLab(®) demonstrated that HPβCD provided an efficient steric stability of the NSs, preventing particle aggregation. The ex vivo permeation profiles of the NSs and conventional FB solution were evaluated using human skin. Results demonstrated that only PLGA-PEG NSs showed slight permeation improvement. However, after 24h, the FB retained in the skin was about 9-fold higher with NSs compared with the control solution, attributed to the reservoir effect of NSs acting as a depot, sustaining the drug and limiting its systemic absorption. In vivo performance of NSs was evaluated by assessing anti-inflammatory efficacy in TPA-induced mouse ear edema. Topically applied NSs significantly decreased in vivo inflammation compared to the control solution and the anti-inflammatory efficacy of HPβCD NSs was stronger than NSs without HPβCD. In vivo skin irritation evaluated by the in vivo Draize test showed no irritation of the formulations tested.
authors.affiliation: Department of Physical Chemistry, Institute of Nanoscience and Nanotechnology, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 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: M Luisa
authors.initials: ML
authors.lastname: Garduño-Ramírez
authors.forename: M Luisa
authors.initials: ML
authors.lastname: García
authors.forename: Elena
authors.initials: E
authors.lastname: Sánchez
authors.forename: Marta
authors.initials: M
authors.lastname: Espina
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Calpena
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005480:Flurbiprofen / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry / Q000494:pharmacology; D054118:Nanospheres / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D011100:Polyglycolic Acid / Q000737:chemistry / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D005480:Flurbiprofen