Investigations on skin permeation of hyaluronic acid based nanoemulsion as transdermal carrier

Abstract

An alcohol-free oil/water hyaluronic acid nanoemulsion was developed to be applied as transdermal carrier for active lipophilic ingredient. In vitro hemolysis, skin penetration and histological examinations were carried out using α-tocopherol as model ingredient to assess skin permeability and bioavailability. Without any chemical enhancers, nanoemuslion performed desirable skin permeable capacity, being able to penetrate across stratum corneum and diffuse deeper into dermis compared with the control group (ethanol solution) via follicular and intercellular pathway. Penetration mechanism was preliminarily studied and suggested to be closely concerned with transmembrane concentration gradient, carrier characteristics and penetration enhancers. No irritation has been found in dermis and skin surface indicated hyaluronic acid nanoemulsions could be successfully used as purcutaneous delivery carrier of active lipophilic ingredient and favorable for drug and cosmetic applications.

Introduction

Skin is the largest organ in the body whose major function is to protect the body from dehydration and unwanted effects from the external environment (Schäfer & Redelmeier, 1996). Although the protective and impermeable qualities of the skin protect the organism from losing water, minerals and dissolved proteins, percutaneous delivery system has been taken advantage as a topical delivery system in pharmaceutical or cosmetic industries. In contrast to traditional drug administration pathway, transdermal administration is featured by its noninvasive procedure, which eliminates side effects, increases patient compliance and possibility for continuous and controlled drug absorption (Lee, Lee, Kim, Yoon & Choi, 2005). Besides, being a vital organ, the skin must be nourished as the other organs of the body by means of cosmetic formulations (Souto & Müller, 2008).

The stratum corneum (SC), the outermost nonviable layer of the epidermis, comprises flattened, stacked, hexagonal, and cornified cells (corneocytes or horny cells) anchored in a mortar of highly organized intercellular lipids, which is described as brick and mortar model (Contreras & Elizabeth, 2007). The corneocytes are surrounded by hydrophobic lipid bilayers which aligned approximately parallel to the surface of corneocytes, while intercellular spaces are abundant in SC lipids (Bouwstra, Pilgram, Gooris, Körten & Ponec, 2001). The particular structure is considered as the rate controlling barrier in the transdermal absorption of substances, which directly relate to lipophilicity of substances (Mahmoud, 2010). However, lipophilic molecule does not favorably partition out of the SC into the more aqueous viable epidermis (Potts, Bommannan & Guy, 1992), hindering deeper diffusion and further capillary uptake into circulation. In comparison, hydrophilic substances penetrate across the skin harder than lipophilic penetrants and as low as 10⁻⁴-fold differences in flux can be noted (Sznitowska, Janicki & Williams, 1998).

In order to overcome the epidermal barrier as to increase transdermal transport, various transdermal carrier systems have been developed. Due to the permeability of a substance through the skin is inversely related to its size under certain conditions (Mahmoud, 2010), nanoparticulate systems investigations are promising, such as solid lipid nanoparticle (SLN), nanostructured lipid carrier (NLC), liposomes, microemulsions, and hexagonal phase nanodispersion (Küchler et al., 2009). In addition, as a good transdermal delivery system, beyond allowing desirable amounts of active ingredient to overcome the skin barrier, the material has to be biocompatible, preferentially biodegradable, or at least should be able to be excreted (Vauthier, Dubernet, Fattal, Pinto-Alphandary & Couvreur, 2003), ensuring non-irritancy to skin and sustain ingredients be active on the skin's surface or during the permeation process (Langer, 2004). Among those transdermal carrier systems, nanoemulsions appear to be attractive and competitive.

Nano-sized emulsions are a class of stable emulsions composed of surfactant and oil suspended in water with a particle diameter ranging 50–200 nm (Kong & Park, 2011). Nanoemulsions seem to be ideal liquid vehicles for drug delivery since they provide all the possible requirements of a liquid system including easy formation, low viscosity with Newtonian behavior, high solubilization capacity for both lipophilic and hydrophilic ingredients, and very small droplet size (Kogan & Garti, 2006). The small droplets confer nanoemulsions large surface to volume ratio, favoring to close contact with the skin providing high concentration gradient and improved substance permeation. Moreover, low surface tension ensures better adherence to the skin. Also, the dispersed phase can act as a reservoir making it possible to transport bioactive molecules in a more controlled fashion (Elena, Paola & Maria, 2001).

Hyaluronan (hyaluronic acid, HA) is a sort of naturally occurring polymer, composed of unbranched repeating units of glucuronic acid and N-acetyl glucosamine linked by β1–3 and β1–4 glycosidic bonds (Ambrosio, Borzacchiello, Netti & Nicolais, 1999). Properties of HA including specific viscoelasticity, biocompatibility, hydration and lubrication (Garg & Hales, 2004) make this polysaccharide potentially very useful in the food, medical and cosmetic industries. By means of HA based nanoemulsion, a promising transdermal carrier was developed in previous study, whose transdermal capacity and bioavailability were investigated in this article. In-vitro percutaneous penetration was studied quantitatively and qualitatively using α-tocopherol as model lipophilic ingredient.