title: Surfactants from itaconic acid: Toxicity to HaCaT keratinocytes in vitro, micellar solubilization, and skin permeation enhancement of hydrocortisone.
abstract: One of the most widely used approaches for improving drug permeation across the stratum corneum barrier of the skin is the use of chemical penetration enhancers, such as surfactants. In this study, two anionic surfactants, named C12-OPK and C18-OPK, were synthesized via condensation of itaconic acid and fatty amines, with C12 and C18 alkyl chains, respectively. Assessment of impacts on HaCaT keratinocyte cell viability was used as indicator of their potential to cause skin irritation 24h post exposure (Alamar Blue assay). The LC50values of C12-OPK and C18-OPK (144 and 85mg/L, respectively) were lower than LC50values of the most used commercial surfactants (e.g. SDS). The effect of different surfactant concentrations (up to ten times the critical micellar concentration, CMC) on hydrocortisone (HC) solubility and permeation through porcine skin was also evaluated. Results showed that drug solubility increased linearly with increasing concentrations of both surfactants, as a consequence of the association between drug and micelles. In vitro permeation results showed that the permeability coefficient increased at surfactant concentrations lower than the CMC. In particular, a higher enhancement effect on drug permeation was obtained with C18-OPK, due to its hydrophobic properties that ensured a more effective HC permeation in comparison to C12-OPK.
authors.affiliation: Department of Pharmacy and Biotechnology, Via San Donato 19/2, University of Bologna, 40127 Bologna, Italy. Electronic address: angela.abruzzo2@unibo.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Abruzzo
authors.affiliation: Department of Chemistry "G. Ciamician", University of Bologna, CIRI EA (Interdepartmental Center of Industrial Research Energy and Environment), Via Selmi 2, 40126 Bologna, Italy. Electronic address: nicola.armenise2@unibo.it.
authors.forename: Nicola
authors.initials: N
authors.lastname: Armenise
authors.affiliation: Department of Pharmacy and Biotechnology, Via San Donato 19/2, University of Bologna, 40127 Bologna, Italy. Electronic address: federica.bigucci@unibo.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Bigucci
authors.affiliation: Department of Pharmacy and Biotechnology, Via San Donato 19/2, University of Bologna, 40127 Bologna, Italy. Electronic address: teresa.cerchiara2@unibo.it.
authors.forename: Teresa
authors.initials: T
authors.lastname: Cerchiara
authors.affiliation: Department of Chemistry "G. Ciamician", University of Bologna, CIRI EA (Interdepartmental Center of Industrial Research Energy and Environment), Via Selmi 2, 40126 Bologna, Italy; Nano Safety Research Group, Heriot-Watt University, Edinburgh EH14 4AS, United Kingdom. Electronic address: mirbroch@yahoo.com.
authors.forename: Mireia Broch
authors.initials: MB
authors.lastname: Gösser
authors.affiliation: Department of Chemistry "G. Ciamician", University of Bologna, CIRI EA (Interdepartmental Center of Industrial Research Energy and Environment), Via Selmi 2, 40126 Bologna, Italy. Electronic address: chiara.samori3@unibo.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Samorì
authors.affiliation: Department of Chemistry "G. Ciamician", University of Bologna, CIRI EA (Interdepartmental Center of Industrial Research Energy and Environment), Via Selmi 2, 40126 Bologna, Italy. Electronic address: paola.galletti@unibo.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Galletti
authors.affiliation: Department of Chemistry "G. Ciamician", University of Bologna, CIRI EA (Interdepartmental Center of Industrial Research Energy and Environment), Via Selmi 2, 40126 Bologna, Italy. Electronic address: emilio.tagliavini@unibo.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Tagliavini
authors.affiliation: Nano Safety Research Group, Heriot-Watt University, Edinburgh EH14 4AS, United Kingdom. Electronic address: d.brown@hw.ac.uk.
authors.forename: David M
authors.initials: DM
authors.lastname: Brown
authors.affiliation: Nano Safety Research Group, Heriot-Watt University, Edinburgh EH14 4AS, United Kingdom. Electronic address: h.johnston@hw.ac.uk.
authors.forename: Helinor J
authors.initials: HJ
authors.lastname: Johnston
authors.affiliation: Nano Safety Research Group, Heriot-Watt University, Edinburgh EH14 4AS, United Kingdom. Electronic address: t.fernandes@hw.ac.uk.
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Fernandes
authors.affiliation: Department of Pharmacy and Biotechnology, Via San Donato 19/2, University of Bologna, 40127 Bologna, Italy. Electronic address: barbara.luppi@unibo.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Luppi
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D006854:Hydrocortisone / Q000737:chemistry*; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000187:drug effects*; D008823:Micelles; D012867:Skin / Q000187:drug effects; D012869:Skin Absorption; D012995:Solubility; D013386:Succinates / Q000737:chemistry*; D013501:Surface-Active Agents / Q000737:chemistry*; D013552:Swine
chemical_list: D008823:Micelles; D013386:Succinates; D013501:Surface-Active Agents; C005229:itaconic acid; D006854:Hydrocortisone
keywords: Cytotoxicity; Hydrocortisone; Keratinocyte; Micellar solubilization; Skin permeation enhancement; Surfactants