Enhanced in vitro permeability of curcuminoids and ar-turmerone using microemulsions of menthol-based hydrophobic deep eutectic solvents

Abstract

Curcumin has considerable therapeutic potential; however, its poor solubility and permeability limit its clinical applications. We evaluated menthol-based hydrophobic deep eutectic solvents (HDES) as oil phases in microemulsions to address these challenges. HDES were formulated by combining l-menthol with acids (lactic, decanoic, dodecanoic, and oleic acids) and incorporating them into microemulsions using surfactant mixtures of Cremophor RH40 (CrRH40) and diethylene glycol monoethyl ether or CrRH40 and Labrasol, with a 3 : 7 oil-to surfactant ratio. Oleic acid, coconut oil, and medium chain triglyceride were used as the conventional oil phase. Physical properties, curcumin solubility in microemulsion, and their effects on in vitro permeability using synthetic membranes were assessed. Although oleic acid-based microemulsions (CLO) demonstrated higher curcumin solubility (54.5 mg mL⁻¹) than HDES-based microemulsions (14.6–24.0 mg mL⁻¹), curcumin permeation in oleic acid-based microemulsions was modest. In contrast, optimized HDES systems, particularly CL2MDO (menthol : dodecanoic acid, 2 : 1, as oil phase), achieved 116 µg cm⁻² cumulative curcumin permeation over 12 h, significantly surpassing conventional formulations (CLO, achieving 20.0 µg cm⁻² curcumin permeation) (p < 0.05). In oleic acid–menthol (HDES)-based formulations, increasing the menthol-to-oleic acid proportion enhanced permeation. CL2MO (menthol : oleic acid, 2 : 1) achieved 64.5 µg cm⁻² cumulative curcumin permeation at 12 h, compared to 40.0 µg cm⁻² in CLMO (menthol : oleic acid, 1 : 1) and lower at 37.2 µg cm⁻² in CLM2O (menthol : oleic acid, 1 : 2). Enhanced permeability was correlated with a 2 : 1 menthol-to-acid ratio using CrRH40 and Labrasol as surfactant mixtures. The menthol-to-acid ratio critically influenced permeation efficiency. The combination of HDES with microemulsion technology provides a strategy for the transdermal delivery of hydrophobic compounds, outperforming conventional oils in permeation.

Introduction

Curcumin (Cur), a bioactive compound extensively used in foodand medicinal applications, has limited bioavailability andpermeability owing to its poor aqueous solubility and lowabsorption through the intestines and skin.1,2Therefore, the development of advanced delivery systems to overcome these challenges is critical to fully obtain the therapeutic potential of Cur.

The low bioavailability of Cur poses a signifficant challenge in its formulation and achievement of desired clinical outcomes. Various methods have been used to improve Cur solubility, bioavailability, and skin penetration, including the use of nanoparticles, liposomes, micelles, micro/nano-emulsions, and solid dispersions.3,4 The small droplet size (20–200 nm) of nanoemulsions allows enhanced skin penetration and bioavailability.5 Liposomal Cur formulations have shown improved stability, skin permeation, and therapeutic effects upon topical delivery.3 Cur-loaded self-nanoemulsifying drug delivery systems (SNEDDS) enhance the efficacy of topical preparations for treating inflammatory conditions.6 SNEDDS gels demonstrate superior drug release an permeation compared with non-SNEDDS formulations.6 A Cur nanoemulsion gel demonstrated signifficantly higher antifungal efficacy against Candida albicans than a gel formulation.7

A nanoemulsion (NE) containing D-limonene, sorbitan trioleate, polyoxyethylene (20) oleyl ether, and ethylene glycol enhances Cur skin permeation by increasing its diffusion rate.8 A high surface concentration of Cur promotes deeper skin penetration, while the NE may interact with epidermal lipids, further facilitating permeation.8 In another study, Cur-loaded microemulsions (MEs) were optimized for topical application using geranium oil, Tween 80, and propylene glycol with a particle size of 199 nm.9 Ex vivo studies demonstrated substantial Cur permeation through rat skin over 24 h, which was attributed to the small particle size of MEs and the penetration-enhancing effects of geranium oil and propylene glycol.9 Overall, micro/ nanoemulsions are advantageous for topical delivery due to their small particle size, stability, and enhanced skin permeation.

The oil phases in emulsion systems include oleic acid, isopropyl myristate, geranium oil, and D-limonene.8–11 Hydrophobic deep eutectic solvents (HDESs) can serve as the oil phase in microemulsion systems.12,13 HDES based microemulsions exhibit small, uniform particle sizes and improved solubility of curcuminoids.12,13 Notably, the anti-inflammatory effects of Curcuma longa L. (CL) extract in these microemulsions were signifficantly more potent than those in the DMSO vehicle, while maintaining comparable cytotoxicity profiles.12,13 HDESs not only function as an oil phase for solubilized active pharmaceutical ingredients but also provide bioactive effects, such as anti-inflammatory properties, wound healing through the migration of HaCaT cells, and antimicrobial activity.12–14 Combining HDES with microemulsion technology may yield synergistic results for Cur delivery. In addition, menthol and HDES have been previously used as skin permeation enhancers.15,16

HDESs have shown promise as functional oil phases in microemulsions with enhanced solubility and bioactivity. However, menthol-based HDES, which combine the penetration-enhancing properties of menthol with HDES, have not yet been explored for improving the permeability of Cur. This lack of exploration represents a critical gap in formulation strategies to overcome the poor permeability barriers of Cur. Therefore, the aim of this study was to investigate mentholbased HDES as the oil phase in microemulsion systems to enhance the in vitro skin permeation of curcuminoids and arturmerone.

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Materials

All reagents and materials used in this investigation were of analytical grade, unless otherwise specied. PEG-40 hydrogenated castor oil (Cremophor RH40, CrRH40) was procured from BASF Co., Ltd (Germany). Diethylene glycol monoethyl ether (DGME), L-menthol (purity $99%), lactic acid (90% w/v), and oleic acid (purity $99%) were acquired from Chanjao Longevity Co., Ltd (Bangkok, Thailand). Caprylocaproyl polyoxyl-8 glyceride (Labrasol) was obtained from Gattefosse (France). Absolute ethanol (analytical reagent grade), methanol (analytical reagent grade), and HPLC-grade acetonitrile were obtained from RCI LabScan (Bangkok, Thailand). Commercial foodgrade coconut oil was obtained from a local supplier in Thailand. Phosphate-buffered saline (PBS, pH 7.4) was supplied by Thermo Fisher Scientific (Waltham, MA,USA).Synthetic Strat-M membrane was obtained from Merck KGaA (Darmstadt, Germany).

Reference standards of curcuminoids, including demethoxycurcumin (Dem, purity $98%) and curcumin (Cur, purity $99.5%), were supplied by Sigma-Aldrich (Missouri, USA), while bisdemethoxycurcumin (Bis, purity $98%) was purchased from Tokyo Chemical Industry Co., Ltd (Tokyo, Japan). Additional reagents included lactic acid (88% w/v) from Loba Chemie Pvt. Ltd (Mumbai, India), and aromatic turmerone (arTur, purity $90%) from Toronto Research Chemicals, Inc. (Ontario, Canada). Curcuma longa L. (CL) rhizomes were sourced from the Surat Thani Province, Thailand. The rhizomes were subsequently fragmented and desiccated in a hot-air oven at 50 °C. CL extract was prepared by maceration of the powdered dried rhizomes using absolute ethanol as the solvent at a 1:10 solvent-to-solid ratio for 72 h. The resulting extract was altered and concentrated using a rotary vacuum evaporator at 45°C. Thesemi-solid extract was desiccated in a vacuum oven for 24h. Thefinaldried extract was stored at −20 °C in a light-resistant container to preserve its integrity.

Nuntika Wangpradit, Fonthip Makkliang, Arpa Petchsomrit, Gorawit Yusakul, Enhanced in vitro permeability of curcuminoids ar-turmerone microemulsions of menthol-based hydrophobic deep eutectic solvents, RSC Advances, Published on 21 September 2026, Licensed under CC-BY-NC 4.0, Received 9th May 2026, Accepted 12th September 2026, DOI: 10.1039/d6ra03993f, rsc.li/rsc-advances