title: Enhanced intra-cutaneous delivery of a Mn-containing antioxidant drug by high-frequency ultrasounds.
abstract: This study was carried out to evaluate whether high-frequency ultrasounds, a commonly used aesthetic medicine treatment for skin rejuvenation, may enhance the penetration of the Mn-containing compound Mn(II)(Me2DO2A) (manganese(II) 4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetate) biologically active as a superoxide anion scavenger, in the cutaneous layers of ex vivo human skin explants. Although its antioxidant properties are well known and the compound is basically not toxic in animal models, its trans-cutaneous permeation and its toxicological profile at a systemic level have not yet fully analyzed. Therefore, its possible penetration in the deep cutaneous layers was also evaluated. To this purpose, Mn(II)(Me2DO2A) was formulated as emulsion-gel, lipogel and hydrogel. These different formulations were also tested in combination with high-frequency ultrasounds (10-3500 Hz frequency modulation on a 5 MHz main frequency) used as physical permeation enhancers, delivered by a MedVisage™ device (General Project, Montespertoli, Italy) currently used for aesthetic medicine purposes. The permeation of the Mn-containing compound from the formulations was evaluated by inductively coupled plasma atomic emission spectrometry (ICP-AES) measurements of Mn in horizontal cryosections of the skin samples cut at different depths to separate the epidermis, papillary and reticular dermis, as well as by vertical Franz diffusion cells. The results show that the hydrogel formulation yielded the highest transepidermal delivery of Mn(II)(Me2DO2A) and that the application of ultrasounds (3 W, FM 100 Hz, 2×10 s) significantly enhanced its penetration into the epidermis and upper dermal layers. Of note, nearly undetectable amounts of Mn(II)(Me2DO2A) were detected in the reticular dermis and the Franz cell fluid. Although an in vivo confirmation of these results will be necessary, this method may allow to minimize undesired drug passage to the bloodstream and undesired delivery to non-target internal organs and avoiding its renal excretion and release into the environment.
authors.affiliation: Department of Clinical and Experimental Medicine, Research Unit of Histology & Embryology, University of Florence, Viale Pieraccini, 6, 50139 Firenze, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Bani
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia, 3, 50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bencini
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia, 3, 50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Maria Camilla
authors.initials: MC
authors.lastname: Bergonzi
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia, 3, 50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Bilia
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia, 3, 50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Clizia
authors.initials: C
authors.lastname: Guccione
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia, 3, 50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Severi
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia, 3, 50019 Sesto Fiorentino, Firenze, Italy. Electronic address: roberto.udisti@unifi.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Udisti
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia, 3, 50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Valtancoli
mesh_terms: D000279:Administration, Cutaneous; D000975:Antioxidants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004655:Emulsions; D005782:Gels; D006801:Humans; D020100:Hydrogels; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012869:Skin Absorption; D013054:Spectrophotometry, Atomic; D014465:Ultrasonics / Q000379:methods*
chemical_list: D000975:Antioxidants; D004655:Emulsions; D005782:Gels; D020100:Hydrogels; D009942:Organometallic Compounds; C551155:manganese(II) 4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetate
keywords: Antioxidant agent; Hydrogel formulation; Manganese complex; Skin penetration; Ultrasound application