title: Diclofenac acid nanocrystals as an effective strategy to reduce in vivo skin inflammation by improving dermal drug bioavailability.
abstract: In this work a diclofenac acid nanosuspension formulation was produced as a novel approach for the treatment of skin inflammation. Drug nanocrystals, prepared by the wet media milling technique and stabilized using Poloxamer 188, were characterized by different techniques: scanning electron microscopy, differential scanning calorimetry, X-ray powder diffractometry, Fourier transform infrared spectroscopy and photon correlation spectroscopy. The ability of nanocrystals to improve dermal drug bioavailability was investigated ex vivo by using Franz diffusion vertical cells and mouse skin, in comparison with both diclofenac acid coarse suspensions and a commercial formulation. The topical anti-inflammatory activity of the drug nanosuspension was assessed in vivo by testing its effect compared to common inflammatory endpoints: i.e. the inhibition of chemically induced oedema and leucocyte infiltration (reflected in myeloperoxidase activity). Following the milling procedure, diclofenac nanocrystals exhibited a mean diameter of approximately 279nm, a low polydispersity index (∼0.17) and maintained the same polymorphic form of the starting bulk powder. When the drug nanosuspension was applied on the mouse skin it produced a higher accumulation of diclofenac in the skin compared to both the coarse suspensions and the commercial formulation, as demonstrated by ex vivo transdermal delivery experiments. Moreover, the nanosuspension provided an in vivo oedema inhibition of 50%, which was not statistically different from the commercial formulation. On the contrary, the nanosuspension showed a higher inhibition of myeloperoxidase activity in the damaged tissue (86%) than the commercial formulation (16%).
authors.affiliation: Dept. Scienze della Vita e dell'Ambiente, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Pireddu
authors.affiliation: Dept. Scienze della Vita e dell'Ambiente, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Caddeo
authors.affiliation: Dept. Scienze della Vita e dell'Ambiente, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Valenti
authors.affiliation: Dept. Scienze della Vita e dell'Ambiente, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Marongiu
authors.affiliation: Dept. Scienze Chimiche e Geologiche, Unita di Ricerca del Consorzio Nazionale di Scienze e Tecnologie dei Materiali (INSTM), University of Cagliari, SS 554 Bivio Sestu, 09042 Monserrato (CA), Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Scano
authors.affiliation: Dept. Scienze Chimiche e Geologiche, Unita di Ricerca del Consorzio Nazionale di Scienze e Tecnologie dei Materiali (INSTM), University of Cagliari, SS 554 Bivio Sestu, 09042 Monserrato (CA), Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Ennas
authors.affiliation: Dept. Scienze della Vita e dell'Ambiente, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy. Electronic address: frlai@unica.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lai
authors.affiliation: Dept. Scienze della Vita e dell'Ambiente, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Fadda
authors.affiliation: Dept. Scienze della Vita e dell'Ambiente, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Sinico
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D001692:Biological Transport; D004008:Diclofenac / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004487:Edema / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects*; D010316:Particle Size; D010539:Permeability; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D020442:Poloxamer / Q000737:chemistry; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012995:Solubility; D013535:Suspensions
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D013535:Suspensions; D020442:Poloxamer; D004008:Diclofenac; D009195:Peroxidase
keywords: Dermal delivery; Diclofenac acid; Nanocrystals; Nanosuspension; Poloxamer 188; Skin inflammation