Skin permeation of d-limonene-based nanoemulsions as a transdermal carrier prepared by ultrasonic emulsification

Abstract

Nanoemulsions can be used for transporting pharmaceutical phytochemicals in skin-care products because of their stability and rapid permeation properties. However, droplet size may be a critical factor aiding permeation through skin and transdermal delivery efficiency. We prepared d-limonene nanoemulsions with various droplet sizes by ultrasonic emulsification using mixed surfactants of sorbitane trioleate and polyoxyethylene (20) oleyl ether under different hydrophilic–lipophilic balance (HLB) values. Droplet size decreased with increasing HLB value. With HLB 12, the droplet size was 23 nm, and the encapsulated ratio peaked at 92.3%. Transmission electron microscopy revealed spherical droplets and the gray parts were d-limonene precipitation incorporated in spherical droplets of the emulsion system. Franz diffusion cell was used to evaluate the permeation of d-limonene nanoemulsion through rat abdominal skin; the permeation rate depended on droplet size. The emulsion with the lowest droplet size (54 nm) achieved the maximum permeation rate. The concentration of d-limonene in the skin was 40.11 μL/cm² at the end of 360 min. Histopathology revealed no distinct voids or empty spaces in the epidermal region of permeated rat skin, so the d-limonene nanoemulsion may be a safe carrier for transdermal drug delivery.

Introduction

Drug delivery through the transdermal route has many advantages over intravenous and oral administration. Transdermal delivery can avoid hepatic metabolism, and the treatment can be immediately withdrawn if necessary [1]. However, the stratum corneum (SC) of the epidermis is a barrier to the passage of molecules and reduces the efficiency of drug delivery through the skin. Many methods have been used to attempt to overcome the SC barrier, the most common being the use of permeation enhancers such as terpenes. Terpenes are not toxic to skin [2], [3]; they can enhance skin permeation by interacting with SC lipids and keratin and increase the solubility of the drug into SC lipids [4]. However, when skin is treated with terpenes, the skin structure is changed because of disruption and extraction of SC lipid bilayers. Distinct voids and empty spaces are often visible in the epidermal region after terpenes treatment, and the extraction of SC lipids may also cause dehydration of the SC, with significant loss of moisture [3], [5].

Nanoemulsions have droplet size between 20 and −200 nm that appear transparent or translucent to the naked eyes [6]. Because of their small droplet size, nanoemulsions can offer high thermodynamic stability against aggregation, flocculation, coalescence and Ostwald ripening. Pharmaceutical phytochemicals can be incorporated into the nanoemulsions and transported through the cell membrane [7]. Nanoemulsions can be used as a vehicle for the transport of pharmaceutical phytochemicals through the SC barrier in skin-care products because of their stability and rapid permeation properties [8]. They have been used as carriers to deliver antifungal drugs, granisetron hydrochloride, ketoprofen, lecithin and meloxicam through the skin [9], [10], [11], [12], [13], [14]. However, the droplet size of these carriers may be a critical factor affecting droplet permeation through skin [15]. As well, no reports have discussed the association of nanoemulsion droplet size and transdermal delivery efficiency.

d-Limonene, a lipophilic terpene obtained from citrus fruits, has been found to effectively enhance skin permeation for delivering tamoxifen [16] and haloperidol [17]. Other compounds for which d-limonene can be used as a transdermal permeation enhancer includes butylparaben, sumatriptan succinate and nicardipine hydrochloride [18], [19], [20]. In our previous study, we used a mixture of the surfactants sorbitane trioleate and polyoxyethylene (20) oleyl ether to form d-limonene in water nanoemulsions with droplet size <100 nm prepared by ultrasonic emulsification [21]. In the current paper, we discuss our results related to permeation of d-limonene nanoemulsions with different hydrophilic–lipophilic balance (HLB) values through the rat abdominal skin by the Franz diffusion cell method. We discuss the possibility of d-limonene nanoemulsions used as transdermal carriers.