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Review

Plant Essential Oil Nanoemulgel as a Cosmeceutical Ingredient: A Review

by
Xing Fui Yap
1,
Seow Hoon Saw
1,
Vuanghao Lim
2 and
Chin Xuan Tan
1,*
1
Department of Allied Health Sciences, Faculty of Science, Universiti Tunku Abdul Rahman, Jalan Universiti Bandar Barat, Kampar 31900, Perak, Malaysia
2
Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Kepala Batas 13200, Pulau Pinang, Malaysia
*
Author to whom correspondence should be addressed.
Cosmetics 2024, 11(4), 116; https://doi.org/10.3390/cosmetics11040116
Submission received: 27 April 2024 / Revised: 15 June 2024 / Accepted: 26 June 2024 / Published: 10 July 2024
(This article belongs to the Collection Editorial Board Members' Collection Series: "Novel Delivery Systems for Dermocosmetic Applications")
Browse Figures
Figure 1
<p>Fabrication of nanoemulgel for topical delivery of EO.</p> "> Figure 2
<p>Rationales of developing EO nanoemulgel.</p> "> Figure 3
<p>Nanoemulgel preparation.</p> "> Figure 4
<p>Continuous and dispersed phases in (<b>A</b>) W/O emulsion and (<b>B</b>) O/W emulsion.</p> ">
Versions Notes

Abstract

:
Essential oils (EOs) are concentrated, hydrophobic volatile compounds derived from different parts of plants. They are recognized for their diverse and versatile functional properties. Approximately 90% of EOs are administered via topical or transdermal routes. However, EOs are susceptible to oxidation, and their high volatility often poses a challenge to the transdermal delivery of their bioactive constituents. Additionally, the direct application of pure EOs on the skin may result in irritating effects. Hence, various novel carrier systems have been explored for the topical application of EOs. Among these, nanoemulgel has received particular attention from the cosmeceutical industry. It is a hybrid technology combining nanoemulsion and a gelling phase, which can enhance the bioadhesivity of EOs, at the same time minimizing their irritating effects. This review summarizes the methods of EO extraction, steps and factors influencing the preparation of EO nanoemulgel, and characterization parameters for nanoemulgel studies. The potential cosmeceutical applications of EO nanoemulgels as an anti-inflammatory, antimicrobial, antioxidant, and penetration enhancer are also compiled and discussed.

1. Introduction

Essential oils (EOs) are complex mixtures of lipophilic, volatile compounds derived from the roots, stems, leaves, flowers, fruits, and seeds of plants [1]. They have been utilized across diverse industries, including food and beverage (35%), cosmetics, fragrances, and aromatherapy (29%), household (16%), and pharmaceutical (15%) [2]. Aligned with contemporary consumption trends and market preferences, EOs are increasingly favored as green alternatives to synthetic chemicals due to their superior eco-sustainability and safety profiles [1]. In 2022, the global EOs market was valued at USD 10.5 billion, with projections indicating growth to USD 27.5 billion by 2032; this could be driven by the continuous expansion of the cosmeceutical industry, specifically in managing dermatological conditions, such as acne, burn, and eczema [3]. To date, up to 3000 EOs have been extracted, with 300 of them being commercially significant [4]. In terms of administration, EOs can be delivered via topical or transdermal, oral, and pulmonary routes [5,6,7]. Notably, 90% of EOs are administered via topical or transdermal routes, primarily due to their non-invasive nature, lower incidence of adverse events, and higher patient compliance [5]. However, the topical application of EOs is confronted with challenges due to their high volatility, low chemical stability, poor water solubility, and skin permeability, thereby diminishing the bioavailability of EOs at their intended sites of action [8]. Additionally, the direct application of pure EOs onto the skin, especially in high concentrations, could result in irritating effects such as allergic contact dermatitis and phytophotodermatitis [9].
Conventional emulsion or coarse emulsion, with a droplet diameter ranging from 0.3 μm to 100 μm, have been explored to facilitate the topical delivery of EOs [10]. However, conventional emulsion systems are prone to gravitational separation and coalescence, particularly over time or in response to environmental changes such as fluctuations in temperature; these characteristics diminish their appeal in contemporary delivery systems [11]. Novel carrier systems, characterized by smaller droplet size and higher permeability, such as liposomes, niosomes, and microspheres, are emerging as promising candidates for the effective topical delivery of EOs [12]. However, these methods were typically constrained due to stability issues or high production costs. A nanoemulsion, on the other hand, is a heterogeneous, colloidal dispersion system composed of an oil phase and an aqueous phase, where one phase is dispersed within the other in the form of tiny droplets (ranging from 20 to 500 nm), usually stabilized via a surfactant or in conjunction with a co-surfactant, forming an oil-in-water (O/W) or a water-in-oil (W/O) nanoemulsion system [13]. Nanoemulsions stand out as an excellent candidate for the topical delivery of EOs, owing to their smaller droplet size relative to the conventional emulsion system, which offers higher kinetic stability and shielding of the volatile EO compounds from oxidation, thereby augmenting their bioavailability and chemical reactivity when encapsulated [13]. Histopathology studies using animal models also showed that the dermal irritant properties of pure EOs can be mitigated by encapsulating them in nanoemulsion droplets [14].
However, the transdermal delivery of EOs via a nanoemulsion system is poor due to its low viscosity, resulting in a low retention time and poor spreadability [15]. To address these concerns, a hybrid technology known as a nanoemulgel was developed (Figure 1). A nanoemulgel is prepared by adding a gelling agent to a nanoemulsion, thereby enhancing its bioadhesivity and retention time on the skin [15]. Moreover, nanoemulgels demonstrate improvements in thixotropic properties, they are easily spreadable, water-soluble, non-greasy, and easy to remove, they have a longer shelf life, and they provide an emollient effect [16].
The fabrication of EO nanoemulgels is influenced by several key factors, as shown in Figure 2. Firstly, nanoemulgels enable the efficient delivery of EOs and their native constituents, thereby offering specific therapeutic benefits. Secondly, EOs can be co-delivered with lipophilic drugs, potentially resulting in synergistic effects for disease treatment. Thirdly, EOs may solely serve as carrier media for drugs, without contributing synergistically to the drugs’ functional properties in treatment. A wide range of drugs, including non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, antifungal agents, retinoids, plant extracts, and other active ingredients, have been successfully loaded into EOs and fabricated into nanoemulgels. This article provides an overview of EO extraction methods and the steps and factors influencing the preparation of plant EO nanoemulgels. The potential cosmeceutical applications of EO nanoemulgels are also compiled and discussed.

2. Methodology

Research articles published from January 2015 to May 2024 were identified through several search engines and scientific databases, including Google Scholar, PubMed, Web of Science, Scopus, and ScienceDirect. The search was restricted to specific keywords, including “essential oil”, “volatile oil”, “nanoemulgel”, “nanoemulsion gel”, “nanoemulsion hydrogel”, and “cosmeceutical”. Furthermore, these keywords were linked using the AND operator to enhance the retrieval of relevant results. Articles lacking full-text availability, redundant publications, personal opinions, studies irrelevant to the research focus, letters to editors, unpublished data, and non-English literature were excluded.

3. Essential Oils

Plants synthesize essential and fixed oils. Essential oils, also known as volatile oils, are complex mixtures of volatile, odoriferous, and lipophilic compounds commonly isolated from different parts of plants. They are typically liquid at room temperature, colorless or pale yellow, with a low molecular weight (below 300 Daltons), and they are soluble in most organic solvents (alcohol, ether, and acetone) and poorly soluble in water [17]. The physical and chemical properties of EOs are remarkably different from those of fixed oils. Fixed oils, also known as fatty oils, are esters of a glycerol molecule attached to three fatty acids [17]. They are a non-volatile oil fraction containing components such as fats, waxes, and resins.
EOs are intricate mixtures of more than 20 chemical classes, including alcohols, ethers, aldehydes, ketones, esters, oxides, amines, amides, phenols, sulfur, and nitrogen compounds present at diverse concentrations [17]. Gas chromatography–mass spectrometry, gas-chromatography–olfactometry, high-performance liquid chromatography–mass spectrometry, and nuclear magnetic resonance spectroscopy are commonly utilized techniques for the physicochemical characterization and authenticity assessment of EOs [2]. The chemical profiles of EOs vary across different plant species or even within identical species, with these variations arising from a range of biotic factors such as symbiotic microbes and insects, as well as abiotic factors, including soil hydrology, pH, and salinity; differences in extraction methods also contribute to these variations [18].

3.1. Extraction Methods for Essential Oils

The choice of EO extraction methods is greatly influenced by the characteristics of the plant material and its active constituents. Opting for an unsuitable extraction method may result in the degradation or hydrolysis of specific bioactive components, consequently diminishing their bioactivity. In certain instances, discoloration, odor deterioration, and physical alterations such as increased viscosity may occur in EOs because of these factors [19]. Steam distillation, hydrodistillation, and cold pressing are among the common extraction methods for obtaining EOs [20].

3.1.1. Steam Distillation

Steam distillation stands as the predominant method for EO extraction, representing approximately 93% of the global production volume of EOs [21]. In operational procedures, steam is generated and introduced into a vessel containing plant materials under controlled pressure conditions [20]. Through the application of heat, volatile compounds are released from cellular cavities and condensed along with water vapor. Subsequent separation is achieved via decantation, relying on the immiscibility or density of EO and aqueous phases. This method also prevents the chemical transformation or hydrolysis of water-sensitive compounds, such as esters, as there is no direct contact between the plant material and water [18].

3.1.2. Hydrodistillation

Hydrodistillation is considered the simplest and standard method for extracting EOs [19]. In this method, the plant material is submerged in water and heated to boiling under atmospheric pressure. The resultant mixture of steam and volatile compounds is then condensed using the Clevenger apparatus and separated based on density disparities. Anhydrous sodium sulfate can be utilized to effectively remove residual water content from the collected EO [20,22]. Hydrodistillation generally results in a higher yield of EO compared to steam distillation, possibly due to the enhanced penetration of heat into the plant materials.

3.1.3. Cold Pressing

Cold pressing is a renowned method for extracting EOs, and it is known for yielding products with exceptional purity of up to 100% while concurrently preserving their inherent functional properties [20]. This method operates solely through the mechanical compression of plant materials to release the volatiles from the oil glands as an aqueous emulsion, which is then separated via centrifugation to obtain the EO [20,22]. Cold pressing is also recognized for its safety and environmental benefits, as it does not necessitate the use of chemical inputs such as organic solvents for the extraction process. Additionally, the thermal degradation of heat-labile bioactive components can be prevented using this method, as it ensures that the operating temperature remains below 40 °C [23].

3.1.4. Other Extraction Methods

Conventional methods of EO extraction, particularly steam distillation and hydrodistillation, are associated with various limitations, including the degradation of unsaturated or ester compounds, lengthy extraction times, high energy consumption, low extraction yields, and poor selectivity [4,20]. To tackle these challenges, numerous novel methods for EO extraction, such as supercritical fluid extraction, solvent-free microwave extraction, and pressurized liquid extraction, have been explored. These approaches prioritize minimizing energy and time consumption while maximizing EO recovery [24].

3.2. Strengths and Drawbacks of EOs

The biological activity of EOs is chiefly attributed to their major chemical compounds. Typically, one to two major chemical compounds (Table 1) constitute 20–70% of the EOs [25]. However, the impact of minor components should not be disregarded, as they have the potential to interact with major components, leading to indifferent, additive, antagonistic, or synergistic effects [26,27]. Various EOs have been documented to have promising applications across several domains, including cosmeceuticals, food preservatives, and pharmaceuticals, owing to their antimicrobial, antiviral, anti-inflammatory, antidiabetic, antitumor, antioxidant, and aromatic properties [28].
Chemical instability stands as a major drawback observed with numerous EOs, potentially leading to the loss of bioactivity or triggering allergic reactions upon the oxidation of certain EO components [9,18,25]. Therefore, EOs should be stored in a cool and dark environment and in tightly sealed amber bottles to ensure their preservation. Moreover, EOs derived from the citrus family may contain psoralen and bergapten as their native constituents. These phototoxic compounds have been reported to induce skin photosensitization upon exposure to sunlight or ultraviolet A (UVA) radiation [29]. For this reason, it is advisable to dilute the EO with a carrier oil accordingly or conduct patch tests prior to application to ensure both safety and effectiveness [30].

4. Fabrication of EO Nanoemulgel

The preparation of plant EO nanoemulgel can be generally divided into two stages (Figure 3). In the first stage, a nanoemulsion is prepared, and in the second stage, a gelling agent is incorporated into the prepared nanoemulsion [31].

4.1. First Stage: Nanoemulsion Preparation

Nanoemulsion is a non-equilibrium system of structured liquid created with the aid of an internal or external energy source [32]. It can be prepared using either low-energy or high-energy methods, as discussed below.

4.1.1. Low-Energy Methods

Low-energy methods utilize the internal chemical energy of the systems and require only gentle stirring, such as using a magnetic stirrer or vortex mixer, to generate nanoemulsions [33]. The most popular low-energy methods are self-emulsification and phase inversion.
Self-emulsification, also known as spontaneous or direct-emulsification, relies on the chemical energy stored in molecules to facilitate the transition between a W/O emulsion and an O/W emulsion without the input of external energy, pressure, or a phase transition [34]. When the continuous and dispersed phases are combined under stirring, the solvent in the dispersed phase dissolves into the continuous phase (Figure 4). This process drags and disperses the micelles from the initial mixture, forming nanoemulsion droplets. These droplets are typically produced only when the turbulence at the interface of both phases is triggered and a co-surfactant is used [35]. One limitation of self-emulsification is the requirement to use large amounts of surfactant and co-surfactant.
Meanwhile, phase inversion relies on the chemical energy generated during the emulsification process due to the change in the spontaneous curvature of surfactant molecules, which can shift from positive to negative (resulting in a W/O nanoemulsion) or from negative to positive (resulting in an O/W nanoemulsion) [36]. The change in surfactant curvature can be achieved either with a rapid variation in temperature without altering the composition (known as the phase inversion temperature, PIT) or by varying the composition while maintaining a constant temperature (known as the phase inversion composition, PIC).
In the PIT approach, the thermosensitive surfactants are hydrophilic with a positive spontaneous curvature at low temperatures. As the temperature increases, the surfactants become more hydrophobic with a negative spontaneous curvature [35]. A W/O nanoemulsion is favored at elevated temperatures, whereas an O/W nanoemulsion is favored at lower temperatures. While this approach offers advantages such as cost-effectiveness and precise temperature regulation, its applicability is limited to non-ionic surfactants, especially when used in larger quantities [35].
In the PIC approach, surfactants are mixed separately with EO and ultrapure water, followed by the gradual introduction of the aqueous phase into a predetermined volume of the oil phase at a constant temperature [32]. This process continues until a specific mixture composition is achieved, resulting in a clear or transparent and easily flowable emulsion mixture, which indicates the successful formation of a nanoemulsion. In certain scenarios, hydrophobic drugs such as NSAIDs or antibiotics may be incorporated into the oil phase for concurrent delivery with the EO [37]. The PIC method offers substantial benefits, including economic efficiency and the simplicity of the apparatus involved [32]. However, the dropwise addition of one phase into another makes the PIC method time-consuming.

4.1.2. High-Energy Methods

Solely relying on low-energy methods may not be sufficient to generate emulsion droplets in the nanometric range; therefore, high-energy methods are employed to further reduce the droplet size through the application of intense mechanical energy [35]. Another rationale for adopting high-energy methods is their versatility in producing nanoemulsions, as they are generally not limited by the type of oil and surfactant, unlike low-energy methods. The common high-energy methods are sonication, high-speed homogenization (HSH), microfluidization, and high-pressure valve homogenization (HPH).
Sonication, also known as ultrasonic homogenization, employs either a probe sonicator or a sonicator water bath to generate ultrasonic waves with high frequencies typically falling within the range of 20–35 kHz [38]. Ultrasound induces disruptions at the oil-water interface through rapid oscillations known as cavitation, where bubbles form and collapse swiftly. The intense waves resulting from bubble collapse propagate throughout the solution, causing the rupture of the interface between oil and water to produce nano-scale droplets [32]. Ultrasonic emulsification offers substantial benefits, including heightened stability and enhanced emulsification efficiency [39]. However, challenges such as the non-uniform distribution of the ultrasonic field and potential contamination with fine metal particles may arise when employing a probe sonicator [39].
The HSH utilizes a rotor and stator to generate intense shear, stress, and grinding forces [40]. These forces are induced via the high-frequency vibrations resulting from the rotational motion of the rotary scissor or blade [35]. While this method is recognized for its ease of operation and scalability, nanoemulsion droplets produced through HSH often tend to be larger in size, increasing the susceptibility to droplet coalescence [40]. Additionally, a higher surfactant-to-oil phase ratio is often necessary to stabilize the nanoemulsion system effectively in HSH.
In microfluidization, coarse emulsions undergo compression as they pass through narrow channels within the microfluidizer chambers, subjecting them to homogenization pressures ranging between 50 and 200 MPa [41]. The microfluidization channels are engineered to prompt collisions among emulsion currents, inducing cavitation and turbulence stress to disrupt the coarse emulsion and result in their rupture. Like HSH, microfluidization is easy to execute and can be easily scaled up, but it is known for its ability to produce uniform and finely dispersed nanoemulsion droplets [35]. However, it is crucial to mention that prolonged microfluidization can elevate the temperature of the nanoemulsion, accompanied by a higher chance of droplet coalescence [13].
On the other hand, in HPH, the coarse emulsion is subjected to compression through a narrow valve, usually below 500 µm, with pressure ranging from 500 to 5000 psi into a homogenization chamber to produce nanoemulsions [35]. The breakdown of large droplets into smaller ones is driven by shear forces, turbulence, and cavitation stress [42]. The properties of the resultant nanoemulsion droplets may be influenced by variables including the diameter of the valve, the viscosity of the raw materials, and the number of homogenizations passes. Low surfactant consumption, a short production time, and a reduced rate of droplet coalescence would be the advantages of this method [35]. Additionally, HPH shares the limitation of microfluidization, whereby the temperature of the nanoemulsion may be elevated with an increase in the number of homogenization cycles.

4.2. Second Stage: Gelation of Nanoemulsion

In the second stage, the gelling agent is dissolved in ultrapure water and then homogenized with the nanoemulsion liquid at a specific ratio to produce nanoemulgel [31]. Xanthan gum and guar gum can be readily dissolved in cold water with gentle stirring [43]. Carbomers are pH-dependent and must be neutralized to pH 6.5-7.5 using a strong base such as sodium hydroxide, potassium hydroxide, or triethanolamine before blending with the nanoemulsion to ensure proper gelation and achieve optimal viscosity [44]. When poloxamers are used as a gelling agent, thermally induced gelation is required [45].

5. Factors Affecting the Preparation of EO Nanoemulgel

The nanoemulgel is structured according to the mixture of the nanoemulsion and the gelling agent, with the nanoemulsion comprising oil, an aqueous phase, and surfactant components [15]. This section will delve into the rationale behind the selection of surfactants and gelling agents. Surfactant and co-surfactant screening relies predominantly on factors such as safety profiles, hydrophilic–lipophilic balance (HLB), and the required HLB (rHLB) value corresponding to the employed oil phase [46]. On the other hand, the selection of gelling agents may depend on their source, categorized as natural, semi-synthetic, or synthetic. Additionally, the strengths and weaknesses of various gelling agent sources are also discussed.

5.1. Surfactants and Co-Surfactants

Surfactants are amphiphilic molecules that can interact with both water and oil. The surfactant molecules stabilize the nanoemulsion system by reducing the interfacial tension between these immiscible liquids through electrostatic repulsion among the head groups of similar charge, steric hindrance, or electro-steric stabilization [47]. Surfactants are generally divided into four categories: non-ionic, anionic, cationic, and zwitterionic. Different types of surfactants impact the droplet size, polydispersity index, and zeta potential of the nanoemulsion, contributing to its overall physical stability [48]. Non-ionic surfactants are particularly favored in cosmeceutical applications due to their low cytotoxicity and minimal skin irritation compared to other surfactants [49]. Additionally, the performance of non-ionic surfactants is known to be more stable, with a higher tolerance against a wide range of pH and the presence of electrolytes [50].
The HLB value, on a scale typically extending from 0 to 20, measures the affinity of a surfactant for solubilization in either oil or water [36]. A hydrophilic surfactant, characterized by a higher HLB value (8–18), allows it to be distributed more evenly within the continuous phase of water, and it tends to form an O/W emulsion [51]. Polysorbates, commercially known as the Tween family (HLB = 9.6–16.7), are among the non-ionic surfactants with relatively high HLB values, and they have been widely utilized in the practical production of lipid-based nanocarriers, such as nanoemulsions, especially those incorporating EO as their oil phase [52,53]. According to the literature, factors such as affordability, biocompatibility, commercial accessibility, ease of handling, and environmentally friendly characteristics collectively position Tween 80 as an ideal surfactant candidate in EO nanoemulsion studies [54].
Moreover, the HLB value of a surfactant should be close to the required hydrophilic–lipophilic balance (rHLB) of the employed oil phase to obtain a stable emulsion system [44]. Sometimes, a co-surfactant is utilized in conjunction with the primary surfactant to optimize the emulsion system according to Griffin’s formula [55], as shown below:
HLBsmix = HLBA × XA + HLBB × (1 − XA)
where A denotes the primary surfactant, B represents the co-surfactant, and XA indicates the mass fraction of the primary surfactant.
Although it has been suggested that a stable nanoemulsion system can be achieved with a higher concentration of surfactant relative to the oil, it is worth noting that surfactants like Tween 20 have been reported to potentially cause eye and skin irritation when used in excessive amounts [36,56]. Hence, it is crucial to examine and determine the threshold of surfactant concentration via in vitro or in vivo studies to mitigate the risk of adverse effects.

5.2. Choice of Gelling Agent

Gelling agents serve to thicken nanoemulsion liquids, enhancing the semi-solid consistency of the resulting nanoemulgel [15]. This modification contributes to improved bio-adhesivity, facilitating its application for topical use. These materials also help stabilize the formulation by establishing a three-dimensional cross-polymerization network, which limits the mobility and collision of the nanoemulsion droplets, thereby preventing instability phenomena such as coalescence and phase separation [13]. Moreover, gelling agents influence the swelling index, rheological characteristics, and pharmacokinetic profile of the nanoemulgel, which are crucial for achieving the optimal transdermal delivery of the encapsulated contents [57].
The selection of a gelling agent may depend on its source, which can vary between natural, semi-synthetic, or synthetic origins; a wide range of biopolymers have been explored as natural gelling agents, including those derived from bacteria (gellan gum and xanthan gum), plants (gum acacia, guar gum, locust bean gum, and fenugreek seed mucilage), and animals (chitosan). Biocompatibility, non-toxicity, inexpensiveness, and commercial availability represent significant advantages of opting for a natural gelling agent; however, biodegradability can also pose limitations if these agents are susceptible to microbial degradation [58]. Poor mechanical strength is another limitation of natural gelling agents, often resulting in challenges during manipulation processes. Semi-synthetic gelling agents, such as sodium alginate and carboxymethylcellulose, exhibit strengths comparable to natural gelling agents. They also offer comparatively greater stability than their natural counterparts in response to physicochemical changes, including variations in pH and temperature [57].
On the other hand, several FDA-approved synthetic gelling agents have been extensively employed in studies involving nanoemulgels. For instance, carbomers, which are polymerization products of acrylic acids and are often marketed under the trademark Carbopol, are available in different grades (e.g., Carbopol 934 and Carbopol 940). They are favored for their ability to achieve high clarity and transparency upon gelation [59]. Nanoemulgels formulated with synthetic gelling agents also exhibit highly reproducible properties, enhanced flexibility for tailoring chemical and mechanical characteristics, and more precisely controlled structural parameters [60]. However, synthetic gelling agents may not achieve an excellent degree of biocompatibility as natural gelling agents. In addition to carbomers, poloxamers are widely used as gelling agents, featuring diverse grades characterized by the length of the polymer blockchain.

6. Characterization of EO Nanoemulgels

The cosmeceutical potential of EO nanoemulgels is usually evaluated using the techniques summarized in Table 2.

7. Potential Cosmeceutical Application of EO Nanoemulgels

In the last decade, a variety of plant oils, especially EOs, have been formulated into nanoemulgels (Table 3). The versatile cosmeceutical potential of these nanoemulgels, attributed to their anti-inflammatory, antimicrobial, antioxidant, and permeation-enhancing properties, are discussed in this section.

7.1. Anti-Inflammatory Properties

EOs derived from N. sativa, clove, and eucalyptus are recognized for their inherent anti-inflammatory properties. Badri et al. [88] developed the N. sativa EO nanoemulgel loaded with indomethacin, a gold standard of NSAIDs for the topical treatment of inflammation. Their study revealed that the N. sativa EO nanoemulgel enhanced the anti-inflammatory activity of indomethacin while simultaneously mitigating its adverse effects. Using the croton oil-induced mouse skin inflammation model, Aman et al. [70] fabricated and studied the anti-inflammatory activities of clove EO nanoemulgel. Their findings suggested that the anti-inflammatory efficacy of clove EO nanoemulgel exceeded that of its pure EO form, implying promising applications for clove EO nanoemulgel in treating skin inflammatory disorders. This could potentially reduce the reliance on NSAIDs and their associated adverse effects. Similarly, Md et al. [37] also developed a clove EO nanoemulgel for the topical administration of diclofenac sodium. It was reported that clove EO exhibited superior efficacy in alleviating inflammation symptoms compared to the commercially available conventional diclofenac gel [37]. In addition, Shehata et al. [79] fabricated eucalyptus EO-based nanoemulgel loaded with meloxicam (an NSAID). As a significant discovery, the application of eucalyptus EO as a nanoemulgel was found to synergistically enhance the anti-inflammatory effects of meloxicam in the carrageenan-induced rat paw edema model. While NSAIDs are not typically associated with the realm of cosmeceuticals, addressing inflammatory disorders like rheumatological diseases could potentially alleviate associated skin manifestations, thereby aiding in restoring the patient’s normal appearance [103].

7.2. Antimicrobial Properties

Antimicrobial properties, encompassing both antibacterial and antifungal activities, could be further enhanced when these EOs are integrated into a nanoemulgel formulation [95]. Eid et al. [31] formulated a nanoemulgel containing rosemary EO and evaluated its antimicrobial effects against selected bacteria and fungi. Both ampicillin (an antibiotic) and rosemary EO served as the controls, and their obtained results are summarized in Table 4. The results indicated that the nanoemulgel exhibited greater antimicrobial activity than its pure oil form, possibly due to the small particles of the nanoemulgel leading to greater penetration than the oil, which enhances the interaction of the nanoemulgel with microorganisms [31].
Razdan et al. [72] fabricated a levofloxacin-loaded clove EO nanoemulgel and evaluated its in vivo anti-biofilm activity. It was reported that the created nanoemulgel effectively eradicated P. aeruginosa biofilm-infected burn wounds in a mice model, owning to the synergistic effects between clove EO and levofloxacin. However, the use of antibiotics is not favored in modern antibacterial treatment to mitigate the continued emergence of antimicrobial resistance (AMR) strains. Eid et al. [64] developed a lemongrass EO-based nanoemulgel and loaded it with benzoyl peroxide (BPO), a non-antibiotic bactericidal agent specifically targeted against Cutibacterium acnes, the bacterium implicated in acne development. Surprisingly, the developed nanoemulgel exhibited superior antimicrobial effectiveness against C. acnes, MRSA, and Proteus mirabilis when compared to the marketed BPO gel in the agar well diffusion assay. Using the same method, Noor et al. [100] combined Timur and rosemary EOs in fabricating a nanoemulgel and assessed its antifungal activity. The formulated nanoemulgel showed remarkable antifungal effects against C. albicans (zone of inhibition = 15 mm) when compared to the pure oils (10 mm) and marketed ketoconazole cream (13 mm). The improved antimicrobial effects of EOs in nanoemulgel might be attributed to the reduced droplet size, which facilitates the membrane penetration, at the same time providing a larger surface area for greater interaction with specific targets in the microbial cell.

7.3. Antioxidant Properties

Aromatic plants are good sources of natural antioxidants [104]. Antioxidants are compounds that, at low doses compared to the oxidized substrates, significantly delay or inhibit the oxidation of the latter [105]. The antioxidant capacity of EOs is gaining interest among dermatologists because of their ability to prevent the oxidation of active ingredients in cosmeceutical products and to slow down the skin aging process by enhancing skin glow and minimizing sunspots, age spots, wrinkles, and fine lines [106].
The antioxidant properties of EOs are associated with the presence of the major active compound within. For instance, the main active compound detected in both clove and cinnamon EOs was eugenol (517.8 mg/mL and 547.0 mg/mL, respectively), whereas the main active compound in lavender, thyme, and peppermint EOs was linalool (307.5 mg/mL), thymol (304.0 mg/mL), and menthol (383.0 mg/mL), respectively [107]. When these oils were subjected to DPPH radical scavenging assay analysis, a dose-dependent increase in scavenging DPPH free radical activity was noticed. The half-maximal effective concentration (EC50), which refers to the concentration of the antioxidant in EO required to decrease 50% of the initial DPPH [108], is an important index to evaluate the antioxidant potential of EOs. The DPPH free radical scavenging activity of cinnamon (EC50 = 0.03 mg/mL) and clove (EC50 = 0.05 mg/mL) EOs showed no significant difference compared to the positive control Trolox (EC50 = 0.04 mg/mL), and it was greater than that of thyme (EC50 = 0.14 mg/mL), lavender (EC50 = 12.1 mg/mL), and peppermint (EC50 = 33.9 mg/mL) EOs [107].
Most studies have utilized the antioxidant activity of EOs, as measured via a DPPH radical scavenging assay, to postulate the antioxidant activity of formulated EO nanoemulgels [31,109,110,111]. The study by Rasti et al. [84] demonstrated that the antioxidant activities of Mentha spicata L. EO and its nanogel increased with increasing concentrations. Their study also showed that the formulation of M. spicata L. EO into a nanogel form drastically improved its antioxidant activities by about twofold.

7.4. Penetration Enhancer

Nearly 40% of emerging drug candidates are water-insoluble, posing multiple challenges during the formulation stage [112]. The clinical application of mangiferin, a class IV drug under Biopharmaceutics Classification System (BCS) classification, is usually limited due to its low hydrosolubility and poor transmembrane permeability [113]. Eid et al. [16] investigated the solubility of fusidic acid and sodium fusidate in various oils, including olive, corn, pine, and paraffin oils. Among these, pine oil was ultimately chosen as the oil phase for creating the nanoemulgels due to its excellent drug-solubilizing properties, which are likely influenced by its high content of linoleic acid and oleic acid. In the same vein, Morteza-Semnani et al. [74] opted for cumin EO as the solvent for diclofenac sodium in the development of a nanoemulgel. This decision stemmed from the oil’s terpene content, which is affirmed in its generally-recognized-as-safe (GRAS) status by the Food and Drug Administration (FDA) and is known to serve as an effective penetration enhancer in topical formulations [74]. In these scenarios, the synergistic effects of EOs on the functional properties of drugs are not taken into account. Instead, the EO acts primarily as a solvent medium for the drugs, while the formulated nanoemulgels serve as a penetration enhancer.

8. Future Prospects of EO Nanoemulgels

Most of the literature focuses on the development and characterization of EO nanoemulgels. Further research could compare the cosmeceutical effects of these developed EO nanoemulgels with those of commercial products currently on the market. Additionally, consumer surveys could be conducted to assess awareness, perception, and attitudes toward EO nanoemulgels. Moreover, the safety profiles of EO nanoemulgels have been primarily based on cell line cytotoxicity studies [31,109]. Further research on the acute and chronic toxicity of the surfactants used in the formulation, as well as topical application, of EO nanoemulgels should focus on animal trials, as these data can provide better insights into safety concerns regarding their use.

9. Conclusions

In summary, the equivalent or potentially heightened anti-inflammatory properties exhibited in plant EOs suggest their feasibility as alternative therapies to NSAIDs in treating skin inflammatory disorders. Combining the anti-inflammatory, antimicrobial, antioxidant, as well as drug-solubilizing properties of EOs, the developed nanoemulgel formulations hold promise for versatile applications in the cosmeceutical industry. The nanoemulgel incorporating plant EOs may also serve as a penetration enhancer for various cosmeceutical agents, depending on their intended application. The utilization of nanoemulgel technology not only enhances the bioadhesivity and skin permeation of EOs for topical delivery but also shields the EO components from oxidation through encapsulation. Nevertheless, the cosmeceutical potential of plant EO nanoemulgels is still under investigation, and currently, EO-based nanoemulgel products have not been commercialized. The formulation of the nanoemulgel, with regard to EO content and surfactant concentration, should be meticulously controlled during the fabrication process to prevent potential adverse effects. Further studies involving clinical trials are essential to substantiate the safety and efficacy of plant EO nanoemulgels before they can be clinically translated into routine applications.

Author Contributions

Conceptualization: X.F.Y., S.H.S., V.L. and C.X.T.; validation: S.H.S., V.L. and C.X.T.; formal analysis: X.F.Y.; investigation: S.H.S., V.L. and C.X.T.; data curation: X.F.Y.; writing—original draft preparation: X.F.Y.; writing—review and editing: S.H.S., V.L. and C.X.T.; supervision: S.H.S., V.L. and C.X.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by Ministry of Higher Education, Malaysia (MoHE), through Fundamental Research Grant Scheme (FRGS/1/2024/STG01/UTAR/02/1) and Universiti Tunku Abdul Rahman (UTAR), through UTAR Research Fund (IPSR/RMC/UTARRF/2023-C2/T03).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Fabrication of nanoemulgel for topical delivery of EO.
Figure 1. Fabrication of nanoemulgel for topical delivery of EO.
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Figure 2. Rationales of developing EO nanoemulgel.
Figure 2. Rationales of developing EO nanoemulgel.
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Figure 3. Nanoemulgel preparation.
Figure 3. Nanoemulgel preparation.
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Figure 4. Continuous and dispersed phases in (A) W/O emulsion and (B) O/W emulsion.
Figure 4. Continuous and dispersed phases in (A) W/O emulsion and (B) O/W emulsion.
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Table 1. Main chemical compounds of selected EOs.
Table 1. Main chemical compounds of selected EOs.
EOMain Compounds
Bergamot Limonene, linalool
Clove Eugenol
ChamomileBisabolol, matricin
CedarwoodCedrol, widdrol
Eucalyptus1,8-Cineole, limonene
Frankincenseα-Pinene, limonene
GingerGingerol, zingiberene
LavenderLinalool, linalyl acetate
LemongrassGeranial, neral
PatchouliPatchoulol
PeppermintMenthol, menthone
Rosemary1,8-Cineole, α-pinene
Sandalwood Santalol
Tea treeTerpinen-4-ol, γ-terpinene
VetiverVetivone, khusimol
Ylang ylangLinalool, geranyl acetate
Source: Durczyńska and Żukowska [25].
Table 2. Common techniques used in nanoemulgel characterization.
Table 2. Common techniques used in nanoemulgel characterization.
ParameterRationale
Rheological behaviorTo understand the flow characteristics of nanoemulgels, a viscometer can be used. The higher the viscosity of nanoemulgels, the more difficult the diffusion through the skin [61]. This results in low bioavailability. Moreover, nanoemulgels exhibit pseudoplastic properties [61], indicating that the viscosity of nanoemulgels decreases as the shear rate increases.
Droplet size The droplet size influences the rate of release and absorption [61]. Smaller droplets result in greater bioavailability due to the smaller particle size and larger interfacial region. The conversion of a plant EO or plant oil nanoemulsion into nanoemulgel form did not cause a substantial variation in their droplet size [31,61].
Dispersion stabilityThe stability of nanoemulgels is influenced by the magnitude of zeta potential. Large positive and negative values of the zeta potential lead to a repulsion force between particles [61], resulting in dispersion-stable nanoemulgels.
Release testTo understand the release of the drug or active ingredient from the nanoemulgel, the dialysis bag technique can be used. The results of this test assist in selecting the optimal concentration of the gelling agent used in the nanoemulgel [16].
Spreadability Spreadability measures how readily a nanoemulgel can spread over the site of application on the skin. Nanoemulgels with good spreadability are preferred. The spreadability of a nanoemulgel decreases with an increase in the gelling agent concentration used [62]. Additionally, the spreadability of nanoemulgels is inversely related to their viscosity [15,63].
HomogeneityThe polydispersity index (PDI), also known as droplet size distribution, is commonly used to measure homogeneity. When the PDI is near zero, particles form a more uniform emulsion, resulting in higher physical stability [64].
Organoleptic testThe color and odor of nanoemulgels can be visually inspected [65].
Phase separationPhase separation measures the kinetic stability of nanoemulgels using a centrifugation approach [63]. No phase separation after centrifugation indicates that the nanoemulgels are kinetically stable and can be stored for at least one year [66].
pHThe topical nanoemulgel should be skin pH-friendly to prevent any irritation or allergic reactions [62]. However, pH levels typically shift from neutral to acidic during wound healing, while chronic wounds often remain in a persistently elevated alkaline environment [67]. Hence, for the management of chronic wounds, nanoemulgels with a slightly acidic pH (4.9 to 5.3) were recommended [62].
Table 3. Cosmeceutical properties of plant EO nanoemulgels.
Table 3. Cosmeceutical properties of plant EO nanoemulgels.
Oil Phase Functional Properties of EOSurfactant Gelling Agent Potential ApplicationReference
Basil EOAntimicrobial; anti-biofilmSpan 60Gellan gumMicrobial skin infections treatment[68]
Caraway EOAntibacterialTween 80; polyglycerol myristate; polyglycerol monolaurateCarbopol 940Bacterial skin infection treatment[69]
Clove EOAnti-inflammatoryTween 80; LabrasolChitosan + guar gum + gum acaciaSkin inflammatory disorders treatment[70]
Clove EO + diclofenac sodiumAnti-inflammatoryTween 20; PEG 400Carbopol 980Skin inflammatory disorders treatment[37]
Clove EOAntibacterialMethanolSquid chitosan + ρ-coumaric acidBacterial skin infection treatment[71]
Clove EO + levofloxacinAntibacterial; antibiofilmTween 80; PEG 300Carbopol 934PBiofilm-infected burn wound treatment[72]
Copaiba EOAntibacterialTween 80; Span 80Poly (ε-caprolactone)Bacterial skin infection treatment[73]
Cumin seeds EO + diclofenac sodiumPermeation-enhancingTween 80; Span 80Carbopol 940Penetration enhancer/topical carrier[74]
Cumin EOAntioxidant; antibacterialTween 80; Tween 20CarboxymethylcelluloseSkin disorder treatment[75]
Eucalyptus EO + Saussurea lappa root extractUnspecifiedTween 80; Span 80Carbopol 940Skin inflammatory disorders and wound healing treatment[76]
Eucalyptus EO + luliconazoleAntifungalTween 20; PEG 200Carbopol 934Skin fungal infections treatment[77]
Eucalyptus EOAntibacterialTween 20Carboxymethyl chitosan (CMC) and carbomer 940Burn wound treatment[78]
Eucalyptus EO + meloxicamAnti-inflammatoryTween 80; PEG 400Hydroxypropylmethyl cellulose (HPMC)Skin inflammatory disorders treatment[79]
Eucalyptus EO + mupirocinAntibacterialTween 80; Span 80Carbopol 940Skin lesions and inflammatory disorders treatment[80]
Lavender EO + ofloxacinAntibacterial; antioxidantTween 80Gellan gumWound healing treatment[81]
Lemon EOUnspecifiedTween 80; Span 20Pectin gelGeneral cosmeceutical applications[82]
Lemongrass EO + benzoyl peroxideAntibacterialTween 80; Span 80Carbopol 940Acne treatment[64]
Lippia sidoides EOAntimicrobial; anti-inflammatoryKolliphor P 188PolycaprolactoneGeneral cosmeceutical applications[83]
Mint EOAntioxidant; antibacterialTween 20CarboxymethylcelluloseSkin disorder treatment[84]
Myrrh EO + brucineUnspecifiedTween 80; PEG 400Carboxymethylcellulose sodium (NaCMC)Skin inflammatory disorders treatment[85]
Myrrh EO + curcuminAnti-inflammatoryTween 80; propylene glycol (PG)Carboxymethylcellulose sodium (NaCMC)Skin inflammatory disorders treatment[86]
Myrrh EO + fusidic acidAntibacterialTween 80; Transcutol PCarboxymethylcellulose sodium (NaCMC)Bacterial skin infection treatment[87]
Nigella sativa L. seeds EO + indomethacinAnti-inflammatoryTween 80Poly (ε-caprolactone)Skin inflammatory disorders treatment[88]
Piper betle EO + soybean oilAntioxidantTween 80Carbopol 940Penetration enhancer/topical carrier[89]
Ridolfia segetum EOAnti-inflammatory; antioxidantTween 80Hydroxypropylmethyl cellulose (HPMC)Penetration enhancer/topical carrier[90]
Rose EOAntioxidantα-cyclodextrinHPMCSunscreen product[91]
Rosemary EO + cetyl palmitateAntioxidantTween 20Carbopol Ultrez 21Skin disorder treatment[92]
Rosemary EOAntioxidant; antibacterialTween 80; Span 80Carbopol 940Bacterial skin infection treatment[31]
Sweet fennel EO + clove EO + 8-methoxsalenUnspecifiedPluronic F68; Cremophor RH40ChitosanPsoriasis and vitiligo treatment[93]
Sweet fennel EOAntimicrobial; antioxidant; anti-inflammatoryCremophor RH40Chitosan + polyvinyl alcohol (PVA)Wound healing treatment[94]
Tea tree EO Antibacterial; antifungalTween 20; Cremophor ELCarbopol 940Skin bacterial and fungal infections treatment[95]
Tea tree EO Anti-inflammatory; antiedematogenicTween 80; Span 80Carbopol UltrezSunscreen and cutaneous wound treatment[96]
Tea tree EO + adapaleneAntibacterialTween 80; Span 80Carbopol 934Acne vulgaris treatment[97]
Tea tree EO + caprylic acid + isopropyl myristate + thymolAntimicrobial; anti-inflammatoryTween 20; PEG 400Carbopol 940Acne vulgaris treatment[98]
Tea tree EO + neomycinAntibacterialTween 80; Transcutol PCarboxymethylcellulose sodium (NaCMC)Bacterial skin infection treatment[99]
Timur EO + rosemary EOAntifungalTween 80; Transcutol PCarbopol 940Skin fungal infection treatment[100]
Zataria multiflora EOAntimicrobial; anti-inflammatoryTween 80Cellulose acetate + gelatinWound healing treatment[101]
Zataria multiflora EOAntimicrobial; anti-inflammatoryTween 20; Tween 80; Span 80Hydroxypropylmethyl cellulose (HPMC)Wound healing treatment[102]
Table 4. Antimicrobial activity of rosemary EO, its nanoemulgel, and ampicillin.
Table 4. Antimicrobial activity of rosemary EO, its nanoemulgel, and ampicillin.
MicroorganismsZone of Inhibition (mm)
EOEO NanoemulgelAmpicillin
Staphylococcus aureus11138
Klebsiella pneumoniae1517Resistance
Escherichia coli101315
MRSA10636
Proteus vulgarisResistanceResistanceResistance
Pseudomonas aeruginosa712Resistance
Candida albicans1216-
Source: Eid et al. [31]. MRSA: methicillin-resistant Staphylococcus aureus; resistance: no inhibition zone.
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Yap, X.F.; Saw, S.H.; Lim, V.; Tan, C.X. Plant Essential Oil Nanoemulgel as a Cosmeceutical Ingredient: A Review. Cosmetics 2024, 11, 116. https://doi.org/10.3390/cosmetics11040116

AMA Style

Yap XF, Saw SH, Lim V, Tan CX. Plant Essential Oil Nanoemulgel as a Cosmeceutical Ingredient: A Review. Cosmetics. 2024; 11(4):116. https://doi.org/10.3390/cosmetics11040116

Chicago/Turabian Style

Yap, Xing Fui, Seow Hoon Saw, Vuanghao Lim, and Chin Xuan Tan. 2024. "Plant Essential Oil Nanoemulgel as a Cosmeceutical Ingredient: A Review" Cosmetics 11, no. 4: 116. https://doi.org/10.3390/cosmetics11040116

APA Style

Yap, X. F., Saw, S. H., Lim, V., & Tan, C. X. (2024). Plant Essential Oil Nanoemulgel as a Cosmeceutical Ingredient: A Review. Cosmetics, 11(4), 116. https://doi.org/10.3390/cosmetics11040116

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