**1. Introduction**

Nanoparticles are pharmaceutical forms that are used to improve the efficacy and bioavailability of different poorly water-soluble active ingredients. The physicochemical properties of nanoparticles, such as their high surface-to-volume ratio, the ability to increase permeability through different cell tissues, the possibility of increasing the solubility of active ingredients, or the ability to modulate the release kinetics to achieve depot formulations, make nanoparticles a very attractive approach to improve the therapeutical indices of active ingredients through different routes of administration.

In recent decades, there has been a great deal of research related to modulated targeting and localized release in different parts of the body. The stratum corneum, comprised of a group of low water content corneocytes and a lipid matrix made of ceramides and cholesterol as the main components, acts as a barrier for topical products in a very efficient way [1]. In the past few years, different nanoencapsulation platforms have been developed to transport drugs to the inner layers of the skin. Regarding the transdermal route, it is well-known that flexible particles, such as transfersomes, or micellar systems are capable of increasing permeation [2,3]; however, the loading capacity of these systems is usually low. In recent years, the transfollicular route has gained more attention, as it has been suggested to increase dermal absorption, probably due to accumulation in the pilosebaceous unit.

**Citation:** Pena-Rodríguez, E.; Lajarin-Reinares, M.; Mata-Ventosa, A.; Pérez-Torras, S.; Fernández-Campos, F. Dexamethasone-Loaded Lipomers: Development, Characterization, and Skin Biodistribution Studies. *Pharmaceutics* **2021**, *13* , 533 . https:// doi.org/10.3390/pharmaceutics13040533

Academic Editor: Ana Catarina Silva

Received: 29 March 2021 Accepted: 8 April 2021 Published: 11 April 2021

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For example, Lademann et al. demonstrated that, by using nanoparticles made of poly (lactic-co-glycolic acid) (PLGA), it was possible to obtain a depot effect for 10 days in porcine hair follicles, whereas nanoparticles on the skin surface were only detectable for 24 h [4]. Furthermore, nanosystems, such as polymeric nanoparticles or nanostructured lipid carriers, have higher loading capacities [5]. However, there is still a lack of information regarding the accumulation of these systems in the anatomy of the hair follicle.

Lipomers, or lipid core polymeric nanocapsules (LPNCs), are oily vesicles surrounded by a polymeric wall [6]. In polymeric nanospheres, the active is trapped both on the surface of the particle and in its core. They usually have a burst release effect, due to the desorption of the active from the surface, followed by a plateau based on diffusion/erosion mechanisms. Urzula Bazylinska et al. compared the release of a lipophilic active encapsulated in nanospheres and lipid polymer hybrid nanocapsules and verified that the presence of the lipid nucleus increased the encapsulation efficiency and decreased the burst release effect, obtaining a more sustained release [7].

Topical corticosteroids are the most frequently used drugs for the treatment of inflammatory diseases. Dexamethasone (DEX) has been used topically to treat ocular inflammation [8], atopic dermatitis [9], and alopecia areata (AA) [10], among other diseases, with a high benefit-to-risk ratio. In the case of AA, topical corticoids are frequently ineffective and oral or intralesional therapy is required; furthermore, the potential adverse effects and patient discomfort caused by scalp injections must be considered [11]. Some authors have used solutions with a high proportion of ethanol (70%), as a permeation enhancer, to deliver DEX [9]. They found drug accumulation exclusively in the lipid interspaces and did not observe efficient penetration into corneocytes. There exist other topical corticoids in the market, such as mometasone or methylprednisolone, which are also formulated in hydroalcoholic vehicles with a high content of ethanol. Ethanol has been associated with skin irritation or contact dermatitis [12], it could alter the stratum corneum structure [13], and modify the skin microbiota [14], which could be related to skin diseases and inflammatory status. Thus, it is preferable to minimize its use in topical formulations. Other authors encapsulated DEX (hemisuccinate) in liposomes by microfluidics and film hydration techniques [15]. Even though liposomes are very attractive drug delivery systems, the loading capacity is usually low and could be an issue for specific indications that require higher doses. Considering the above, the improvement of topical treatment is still required, to increase patient quality of life and to minimize adverse effects. Lipomers are a promising drug delivery system to improve the therapeutical balance of DEX in AA treatment, due to possible accumulation in the pilosebaceous unit, where the disease takes place, and under the hypothesis that the lipid nucleus increases the loading capacity. This fact leads to a higher drug concentration in the LPNCs, compared with similar particles without the lipidic core, for which the DEX loading capacity was about 1–2% [16].

For this study, DEX-LPNCs were developed and characterized, in terms of their physicochemical properties and drug release. A description of the skin biodistribution and its accumulation on hair follicles is given. Additionally, information about the associated in vitro cytotoxicity and efficacy is shown. It was found that the proposed DEX-loaded LPNCs have potential as a tool for the topical treatment of AA and other inflammatory skin diseases.
