Development of novel diolein–niosomes for cutaneous delivery of tretinoin: Influence of formulation and in vitro assessment Maria Letizia Manca a , Maria Manconi a , Amparo Nacher b , Claudia Carbone c , Donatella Valenti a , Anna Maria Maccioni a , Chiara Sinico a , Anna Maria Fadda a, * a Department of Life and Environmental Sciences, CNBS, University of Cagliari, Cagliari, Italy b Department of Pharmacy and Pharmaceutical Technology, University of Valencia, Burjassot, Valencia 46100, Spain c Laboratory of Drug Delivery Technology, Department of Drug Sciences, University of Catania, Italy A R T I C L E I N F O Article history: Received 25 August 2014 Received in revised form 10 October 2014 Accepted 11 October 2014 Available online 16 October 2014 Keywords: Niosomes Labrasol 1 Tretinoin Confocal laser scanning microscopy Skin delivery SAXS A B S T R A C T This work describes innovative niosomes, composed of diolein alone or in association with the hydrophilic penetration enhancer Labrasol 1 , as carriers for cutaneous drug delivery. The model drug was tretinoin and conventional, and Labrasol 1 containing liposomes was used as controls to evaluate the influence of vesicle composition and the role of Labrasol 1 on vesicle physico-chemical properties and performance as skin delivery system. Vesicles, prepared by the thin film hydration technique, were characterized in terms of size distribution, morphology, zeta potential, structure, incorporation efficiency, and rheological properties. The influence of carrier composition on tretinoin delivery to human skin was evaluated by in vitro percutaneous experiments, while formulation distribution on human skin and cellular uptake in human keratinocytes were studied using confocal laser scanning microscopy. Result: showed that tretinoin loaded diolein–niosomes formed unilamellar vesicles very similar in physico-chemical properties to liposomes. The role of Labrasol 1 was similar in niosomes and liposomes. Its addition affected vesicle structure and size, by formation of an interdigitate bilayer with higher curvature and larger vesicle size, and rheological properties. Indeed, the presence of Labrasol 1 allowed both niosomes and liposomes to shift from Newtonian to pseudo-plastic behavior. Confocal laser microscopy highlighted an important contemporaneous deposition of hydrophilic and lipophilic vesicle components in stratum corneum and a high vesicle affinity for skin appendages when Labrasol 1 was added to the diolein–niosomes. Moreover, all samples were internalized in human keratinocytes in vitro. ã 2014 Elsevier B.V. All rights reserved. 1. Introduction Design of new vehicles suitable for dermal delivery represents an important goal of pharmaceutical research, since, therapy of dermatological disorders can benefit from topical application of drugs. Several nanocarriers have been largely studied as drug delivery systems (DDS) for improving treatment of skin patholo- gies. Among these, vesicles, such as liposomes and niosomes provide an alternative for improved drug local efficacy, although, their function as skin DDS is controversial with variable effects being reported in relation to the type of vesicles and their composition. Therefore, in the attempt to improve drug delivery into and through the skin, over the last two decades new classes of lipid vesicles have been developed. These include transfersomes, ethosomes, glycerosomes, and the so called penetration enhancer- containing vesicles (PEVs), i.e., phospholipid vesicles containing in their composition a penetration enhancer (PE) (Ainbinder et al., 2010; Cevc et al., 1998; Chessa et al., 2011; Manca et al., 2013b; Manconi et al., 2012, 2011; Mura et al., 2011, 2009; Sinico and Fadda, 2009). Several PEs were tested as secondary components of phospholipid vesicles and their effect on skin delivery of different drugs was evaluated. Among others, the addition of the well known hydrophilic PE Labrasol 1 (a mixture of hydrophilic surfactants containing caprylocaproyl 104 macrogol 8-glyceride) has shown promising properties in increasing skin deposition of minoxidil, quercetin, and tretinoin (Chessa et al., 2011; Manconi et al., 2011; Mura et al., 2009). Results of ex vivo penetration and permeation studies have shown that the presence of such a PE * Corresponding author at: Department of Life and Environmental Sciences, CNBS, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy. Tel.: +39 706758716; fax: +39 706758710. E-mail address: mfadda@unica.it (A.M. Fadda). http://dx.doi.org/10.1016/j.ijpharm.2014.10.031 0378-5173/ ã 2014 Elsevier B.V. All rights reserved. International Journal of Pharmaceutics 477 (2014) 176–186 Contents lists available at ScienceDirect International Journal of Pharmaceutics journa l home page : www.e lsevier.com/loca te/ijpharm