Original Article
Nanoemulsion strategy of pioglitazone for the treatment of skin inflammatory diseases

https://doi.org/10.1016/j.nano.2019.03.017Get rights and content

Abstract

Pioglitazone (PGZ) is a peroxisome proliferator-activated receptor agonist. Its role in the inflammatory response modulation paves the way for additional therapeutic applications. The purpose of this study was to develop a pioglitazone nanoemulsion (PGZ-NE) in order to investigate its anti-inflammatory efficacy on the skin. To that end, an NE vehicle developed for skin delivery was optimized and characterized. The resulting PGZ-NE showed good anti-inflammatory efficacy by decreasing the expression of inflammatory cytokines IL-6, IL-1β and TNF-α. The properties of the developed nanocarrier allowed achievement of a high permeation flux of PGZ through the skin as well as a high retained amount in the skin, likely due to the depot effect of ingredients, which assured a prolonged local action, with good skin tolerability among participating individuals. Consequently, these results suggest that PGZ-NE may be used as an alternative treatment for inflammatory skin diseases such as rosacea, atopic dermatitis or psoriasis.

Graphical Abstract

The reported anti-inflammatory efficacy of pioglitazone, a peroxisome proliferator-activated receptor agonist was exploited for the elaboration of a therapeutic agent aimed for the treatment of skin inflammatory diseases. A nanoemulsion system was specifically developed and characterized for the skin delivery of pioglitazone. This nanoemulsion provided enhanced flux of the drug through the skin and its retention. This fact promoted a decrease of the expression of adipose inflammatory cytokines IL-6, IL-1β and TNF-α, which reinforced the anti-inflammatory efficacy of the drug. The tolerance study in humans guaranteed its safety maintaining biomechanical skin properties in the site of action.

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Section snippets

Materials

The PGZ was purchased from Capot Chemical (Hangzhou, China). Labrasol®, transcutol® P, plurol® oleique CC 497, labrafil® M1944 CS, lauroglycol® 90 were gift samples from Gattefossé (Saint-Priest, France). Macrogolglycerol ricinoleate (cremophor® EL) was purchased from Fagron Iberica (Barcelona, Spain). Tween 80, castor oil, polyethylene glycol and propylene glycol were obtained from Sigma-Aldrich (Madrid, Spain). Components for histological assays were purchased from Sigma and Thermo Fisher

Pseudo-ternary phase diagrams and preparation of PGZ-NE

Results of PGZ solubility in different ingredients are reported in supporting information 2. The components that exhibited the greatest solubilizing potential were selected as constituents of PGZ-NE. Thus, castor oil was used as oil phase, labrasol® as surfactant, transcutol® P and propylene glycol as co-surfactants. Six pseudo-ternary phase diagrams were performed in order to establish which exhibited the largest area of NE formation (Figure 1). Several ratios labrasol®:transcutol® P were

Discussion

In recent years, studies of the therapeutic potential of PGZ have gone far beyond its primary use as an antidiabetic drug. The anti-inflammatory effect of this drug has made it a compelling candidate for the treatment of dermatological disorders via topical application.9 However, its low aqueous solubility and the limited permeability of SC to external substances could hinder its penetration through the target area. NEs improve solubility, absorption and diffusion of drugs. Therefore it can

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    Financial Disclosure: The authors have no financial, personal or other relationships with other people or organizations within five years of the beginning of the submitted work that could inappropriately influence, or be perceived to influence, their work. The authors declared that no competing interests exist.

    Acknowledgements: This work was supported by the Generalitat de Catalunya (grant number 2017 SGR 1477), the Secretaría de Educación Superior, Ciencia, Tecnología e Innovación (SENESCYT – Ecuador) (grant number 073-CIBAE-2015), the Coordination for the Improvement of Higher Education Personnel (CAPES)—Brazil (grant number 0869/14-7) and the Universidad Técnica Particular de Loja, Ecuador (grant number 20-VI-UTPL). The authors also acknowledge Jonathan Proctor (M.Ed) for his help in the language review.

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