Vitamin C (l-ascorbic acid, VC), a water soluble antioxidant [1], is an essential nutrient with the maintenance of various physiological functions [2]. And it is available as an additive in commercial cosmetics for its effect on the skin is particularly outstanding. It exerts several functions on the skin such as collagen synthesis, depigmentation and antioxidant activity [3], [4]. As an antioxidant, it protects the skin by sequentially donating electrons to neutralize reactive oxygen species (ROS) generated on exposure to sunlight [5]. In biological systems, it reduces both oxygen and nitrogen-based free radicals [6] and thus delays the aging process. Due to its antioxidant properties, VC can interact with copper ions in the inactive part of tyrosine to inhibit the activity of tyrosinase and facilitate the reduction of dopamine (the intermediate of tyrosine conversion into melanin). Thereby VC can reduce and inhibit the formation of melanin [7], [8], melanin mainly exists at the basal layer of the junction of epidermis and dermis. VC is also essential for collagen biosynthesis. It acts as a co‑factor for the enzymes prolysyl and lysyl hydroxylase, the enzymes that are responsible for stabilizing and cross‑linking the collagen molecules [9]. Moreover, VC has a potential anti‑inflammatory activity [10]. It can promote wound healing and prevent post‑inflammatory hyperpigmentation [11].

However, cutaneous application of VC is limited by its hydrophilic property, the relative poor stability and the barrier properties of skin [12], [13]. The transport of hydrophilic molecules is highly challenging due to the complex morphology of human skin [14]. The main reason for this is the barrier function of the stratum corneum (SC), a structure constituted by keratinocytes embedded in a lipid matrix, which acts as a strong barrier against chemical compounds and pathogens, thus hindering the penetration of hydrophilic molecules [15], [16]. This represents a major challenge toward utilization of VC which suffers severe stability problems as well as difficulty in delivery to the targeted site [17]. Several strategies have been developed to solve these problems, among them: reduction of water content through the use of anhydrous/nonaqueous formulations, development of VC derivatives and application of VC loaded nanocarriers [18], [19]. Nevertheless, these derivatives do not have direct antioxidant activity and must be converted by enzymatic reaction into VC in vivo [11]. The problem with using the derivatives is that the molecules get trapped within the lipophilic stratum corneum and do not penetrate the other parts of the skin layers well [20]. For this issue, nanocarriers drug delivery systems can increase the solubility and diffusion coefficient of molecules in the stratum corneum and also increase molecule stability [21], [22]. Research focused on VC delivery includes incorporating compounds into nanocarriers, such as spanlastics [23], liposomes [24], [25], nanogel system [26], hydrogels [27], double emulsions [28]. However, it was found that formulations were unable to display long-time stability and high encapsulation efficiency. Therefore, the aim of this study was to investigate the ability of a nanosize carriers system to incorporate and deliver VC into the skin, especial the basal layer of epidermis. For this purpose, solid-in-oil nanodispersions (SONDs) were prepared.

Solid-in-oil nanodispersion is typical reverse micellar systems, which is an oil-based nanodispersion of the solid powder of a hydrophilic molecule coated with hydrophobic surfactant molecules [29]. Compared with conventional water-in-oil (W/O) microemulsions, the solid-in-oil nanodispersions have a better dispersibility (particle size of 50–300 nm) and excellent stability. In addition, the solid-in-oil nanodispersions are capable of maintaining a better primary pharmacological activity for hydrophilic drugs than emulsions and liposome carriers, because they do not contain an aqueous medium and this anhydrous environment can decrease the risk of oxidation and biochemical degradation [30]. Since the SONDs contain permeation enhancers and have a submicron size, they are considered good candidates for the administration of hydrophilic drugs through the skin [31]. A previous work reported the SONDs for the transdermal release of diclofenac sodium, in order to avoid the adverse effects that arise when administered orally. The authors found a 3.8-fold increase in the flux of the drug formulated in a SONDs, in relation to a control, suggesting the potential of this system to increase the permeability of hydrophilic drugs when administered transdermally [32]. Moreover, our previous study showed the SONDs, a unique preparation, which show promising pharmacokinetic parameters and allow effective drug accumulation in vivo may be able to successfully induce anti-cancer immune activity through the oral delivery of nitrogen containing bisphosphonates [33].

In the current study the potential of transdermal delivery using SONDs loaded with the model hydrophilic molecule VC was investigated. SONDs were prepared using different oils, and formulation optimization was attempted. The system was characterized by average size, polydispersity index and encapsulation efficiency, selecting from a series of formulations, those with the best technological qualities to proceed to evaluate the in vitro release, permeation and retention profiles and in vivo pharmacodynamic. We demonstrate its suitability in increasing skin permeation and retention, and promoting the effectiveness and stability of VC to achieve best clinical results.