[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Next Article in Journal
Two-Birds-with-One-Stone Synthesis of Hydrophilic and Hydrophobic Fluorescent Carbon Nanodots from Dunaliella salina Biomass as 4-Nitrophenol Nanoprobes Based on Inner Filter Effect and First Derivative Redshift of Emission Band
Previous Article in Journal
Active Micro/Nanoparticles in Colloidal Microswarms
You seem to have javascript disabled. Please note that many of the page functionalities won't work as expected without javascript enabled.
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Nanomaterials
Volume 13
Issue 10
10.3390/nano13101688
nanomaterials-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Exploring the Versatility of Microemulsions in Cutaneous Drug Delivery: Opportunities and Challenges

by
Zouhair Ait-Touchente
1,*,
Nadia Zine
1,
Nicole Jaffrezic-Renault
1,
Abdelhamid Errachid
1,
Noureddine Lebaz
2,
Hatem Fessi
2 and
Abdelhamid Elaissari
1
1
Univ Lyon, Université Claude Bernard Lyon-1, CNRS, ISA-UMR 5280, 69100 Villeurbanne, France
2
Univ Lyon, Université Claude Bernard Lyon-1, CNRS, LAGEPP UMR 5007, 69100 Villeurbanne, France
*
Author to whom correspondence should be addressed.
Nanomaterials 2023, 13(10), 1688; https://doi.org/10.3390/nano13101688
Submission received: 3 May 2023 / Revised: 19 May 2023 / Accepted: 19 May 2023 / Published: 21 May 2023
Browse Figures
Figure 1
<p>Different configurations of MEs: water-in-oil, bicontinuous, and oil-in-water.</p> "> Figure 2
<p>An overview of surfactants: Their structures and classifications. Reproduced with permission [<a href="#B67-nanomaterials-13-01688" class="html-bibr">67</a>]. Copyright 2023, Elsevier.</p> "> Figure 3
<p>Commonly used co-surfactants with examples employed for formulating microemulsions.</p> "> Figure 4
<p>Illustration of the phase diagram indicating the microemulsion formation regions.</p> "> Figure 5
<p>Versatile applications of microemulsions in drug and gene delivery. Reproduced with permission from [<a href="#B11-nanomaterials-13-01688" class="html-bibr">11</a>]. Copyright 2023, Elsevier.</p> "> Figure 6
<p>Representation of different routes of penetration of microemulsions through the skin: (1) by the appendageal route, (2) by the intracellular route, or (3) by the intercellular route. The appendageal route involves particles entering sweat glands, hair follicles, or skin furrows for either penetration into the dermis or retention for increased release of the drug. The intracellular route comprises a direct path via cell membranes containing multiple epidermal layers. The intercellular route comprises a more tortuous path between epidermal cells. The path taken by particles depends on dimensions, charge, shape, and material. Reproduced with permission from [<a href="#B135-nanomaterials-13-01688" class="html-bibr">135</a>]. Copyright 2023, Multidisciplinary Digital Publishing Institute.</p> ">
Review Reports Versions Notes

Abstract

:
Microemulsions are novel drug delivery systems that have garnered significant attention in the pharmaceutical research field. These systems possess several desirable characteristics, such as transparency and thermodynamic stability, which make them suitable for delivering both hydrophilic and hydrophobic drugs. In this comprehensive review, we aim to explore different aspects related to the formulation, characterization, and applications of microemulsions, with a particular emphasis on their potential for cutaneous drug delivery. Microemulsions have shown great promise in overcoming bioavailability concerns and enabling sustained drug delivery. Thus, it is crucial to have a thorough understanding of their formulation and characterization in order to optimize their effectiveness and safety. This review will delve into the different types of microemulsions, their composition, and the factors that affect their stability. Furthermore, the potential of microemulsions as drug delivery systems for skin applications will be discussed. Overall, this review will provide valuable insights into the advantages of microemulsions as drug delivery systems and their potential for improving cutaneous drug delivery.

1. Introduction

Current skin drug delivery methods play a pivotal role in achieving effective therapeutic outcomes and addressing various dermatological conditions [1,2,3]. Topical administration is a widely utilized approach for delivering drugs to the skin, offering several advantages such as localized treatment, reduced systemic side effects, and enhanced patient compliance [4,5,6]. Traditional methods, such as creams, ointments, and gels, have been employed for decades to deliver drugs to the skin [7]. However, these conventional formulations often face limitations in terms of drug penetration and controlled release [8]. In recent years, advanced skin drug delivery techniques have emerged [9]. One such promising technology is microemulsions (MEs), which have gained significant attention in the pharmaceutical research field due to their unique properties and potential applications in delivering both hydrophilic and hydrophobic drugs [10,11,12,13]. Skin drug delivery is particularly important due to the accessibility and large surface area of the skin, enabling the effective treatment of dermatological conditions, wound healing, and localized therapy [14,15]. Moreover, by delivering drugs directly to the site of action, skin drug delivery can bypass first-pass metabolism and systemic degradation, resulting in enhanced bioavailability and therapeutic efficacy [16]. Exploring innovative approaches for skin drug delivery is crucial in expanding treatment options, improving patient outcomes, and advancing the field of dermatology [2].
Microemulsions are optically transparent [17], thermodynamically stable [10,18], and possess a low interfacial tension, making them an attractive option for drug delivery [19]. They are typically composed of an oil phase, a surfactant, a co-surfactant, and an aqueous phase [17,20]. The small droplet size, typically ranging from 10 to 100 nm, of microemulsions enables efficient drug solubilization and enhanced bioavailability [21,22]. However, the stratum corneum, the outermost layer of the skin, poses a significant barrier for drug penetration [23]. Microemulsions have emerged as a promising approach for enhancing drug delivery through the skin [11,17,21]. Their unique properties play a crucial role in overcoming the skin barrier and facilitating efficient drug absorption [21,24]. The use of microemulsions in cutaneous drug delivery offers several benefits, such as enhanced skin permeation, improved drug stability, and controlled release kinetics [10,24]. By exploiting the optimized formulation and characteristics of microemulsions, researchers can achieve the effective delivery of both hydrophilic and hydrophobic drugs to the target site on the skin [25].
In this comprehensive review, we aim to provide a detailed overview of microemulsions as an advanced drug delivery system, with a particular emphasis on their potential for cutaneous drug delivery. We will discuss the formulation and characterization of microemulsions, including the different types of microemulsions, their composition, stability, and characterization techniques. Moreover, we will highlight the advantages and limitations of microemulsions as a drug delivery system, as well as their potential use in topical formulations. Overall, this review aims to provide valuable insights into the role of microemulsions in overcoming drug delivery challenges and improving cutaneous drug delivery.

2. Background and Definition of Microemulsions

Microemulsions are a type of nanocarrier that consist of an oil phase, a surfactant, a co-surfactant, and an aqueous phase [26]. These components are carefully selected and mixed to form a thermodynamically stable system that is optically transparent and has a low interfacial tension [17,19,27]. In addition, microemulsions have several advantages over conventional drug delivery systems [28]. They can improve drug stability, enhance drug permeability, and provide sustained drug release [10,29]. Moreover, microemulsions are versatile and can be used to deliver drugs through various routes, including oral, parenteral, and topical [11].
Microemulsions have been in use for a long time, even before they were officially described. For example, Australian women used a transparent emulsion containing eucalyptus oil, water, soap flakes, and gasoline to wash wool. A patent was filed in the mid-1930s for the creation of a single-phase system by mixing water and oil with the assistance of a surfactant [17]. However, it was not until 1943 that the first academic research on the topic was conducted [30]. In 1959, Schulman et al. coined the term ‘microemulsion’ to describe the spontaneous emulsification process facilitated by a powerful surface-active agent. [31]. These systems typically contain a hydrophobic or a hydrophilic compound, a surfactant, and a cosurfactant [31]. However, the term “microemulsion” has been incorrectly used to describe other systems, such as micelles, reverse micelles, mesophase or liquid crystalline systems, and even coarse emulsions that have undergone micronization, causing confusion [32]. To address this, Danielsson and Lindmann proposed a definition in 1981 that states, “A microemulsion is a thermodynamically stable isotropic liquid system comprising an aqueous phase, an oil phase, and an amphiphilic substance” [33]. Microemulsions differ from emulsions in that they are transparent, thermodynamically stable, and contain droplets with sizes smaller than 200 nm, while emulsions are opaque, thermodynamically unstable, and have droplet sizes larger than 200 nm [34,35,36]. Additionally, microemulsions form spontaneously, while energy input is required for emulsions [37]. It is important to note that miniemulsions are a type of emulsion, and should not be confused with microemulsions [38,39].
Microemulsions can be classified based on their structure, which can be water-in-oil (W/O), bicontinuous, or oil-in-water (O/W) (Figure 1) [40]. In a W/O microemulsion, water droplets are dispersed within an oil phase, whereas in an O/W microemulsion, oil droplets are dispersed within a continuous aqueous phase [36]. Bicontinuous microemulsions have a complex, interconnected structure in which both the oil and water phases are continuous and dispersed throughout the system [40]. W/O microemulsions are typically used for delivering hydrophilic drugs [41], while O/W microemulsions are preferred for hydrophobic drugs [42]. Bicontinuous microemulsions have been shown to be effective for delivering both hydrophilic and hydrophobic drugs [43].

3. Formulation of Microemulsions

Formulation is a crucial aspect of developing microemulsions for drug delivery applications [44,45]. A well-designed formulation can ensure that the microemulsion system possesses the desired physicochemical properties such as stability, size, and drug loading capacity [46,47]. Typically, microemulsions are composed of four basic components: the oil phase, surfactant, co-surfactant, and aqueous phase [17,48]. The choice of these components depends on the physicochemical properties of the drug and the desired route of administration [49,50].
The oil phase, which can be hydrophobic or hydrophilic, is a key component in determining the stability of the microemulsion [35]. The selection of an appropriate oil phase is based on factors such as solubility of the drug and its compatibility with the surfactant [51]. The surfactant is another critical component, which lowers the interfacial tension between the oil and water phases and stabilizes the microemulsion system [51,52]. The selection of a surfactant depends on its ability to form a monolayer at the oil–water interface and its compatibility with the co-surfactant [53].
The co-surfactant is typically a short-chain alcohol or a glycol, which enhances the solubilization capacity of the surfactant and helps to stabilize the microemulsion [20,54]. The aqueous phase can be composed of water or an aqueous buffer, depending on the desired pH of the system [47,55]. Additionally, the presence of co-solvents, such as ethanol, can improve the solubility of the drug in the microemulsion [56,57].
Various methods can be used for formulating microemulsions, including phase inversion temperature (PIT) [58], spontaneous emulsification [38], and ultrasound-assisted emulsification [59]. In the PIT method, the microemulsion is formed by heating the mixture of oil, surfactant, co-surfactant, and water above the phase inversion temperature, followed by cooling to room temperature [60]. The spontaneous emulsification method involves the gradual addition of the aqueous phase to the mixture of oil, surfactant, and co-surfactant with constant stirring [61]. Ultrasound-assisted emulsification involves the application of high-frequency ultrasound waves to the mixture of oil, surfactant, co-surfactant, and aqueous phase to generate microemulsions [62].
The formulation of microemulsions should consider the desired route of administration, the physicochemical properties of the drug, and the stability of the microemulsion system [63]. The use of suitable oils, surfactants, and co-surfactants can enhance the stability and drug loading capacity of the microemulsion [64]. The selection of an appropriate method for formulation is also crucial in determining the quality of the microemulsion system [65].

3.1. Surfactants

When formulating microemulsions for drug delivery, the choice of surfactant is crucial for achieving successful outcomes [49,66]. Several factors should be considered when selecting a surfactant, including microemulsifying properties, compatibility with the route of administration, and the solubility of active ingredients. There are different classes of surfactants (Figure 2) [67]. Ionic and nonionic surfactants are the two main types [68], with ionic surfactants being further divided into anionic, cationic, and amphoteric surfactants based on the dissociation of their hydrophilic group in water [69,70]. Cationic surfactants such as hexadecyltrimethylammonium bromide [71] and dodecyl trimethyl ammonium bromide [72], anionic surfactants such as dioctyl sodium sulfosuccinate [73] and sodium dodecyl sulfate [74], and amphoteric surfactants such as lecithins and phospholipids [75] have been commonly used in studies. Nonionic surfactants, which include a wide range of options such as polysorbate 80 [76], PEG-8 [77], Pluronic F-68 [78] and vitamin E TPGS [79], do not dissociate into ions in aqueous solutions, and are classified based on their specific hydrophilic group [80]. Alkyl polyglycosides such as Oramix CG-110 have gained attention for their excellent biodegradability and renewable sources, making them an attractive option for microemulsion formulation for various applications, including skin delivery [81]. The selection of surfactant should be based on the specific requirements of the intended application [67].

3.2. Co-Surfactants

In order to induce a much lower interfacial tension decrease, the addition of a co-surfactant is often necessary in microemulsion formulations [82]. Short-chain alcohols such as ethanol and isopropanol, alkanediols such as propylene glycol, sucrose ethanol blends, medium chain monoglycerides and diglycerides, alkyl monoglycosides, and geraniol are commonly used co-surfactants [83]. Additionally, glycol ethers such as Transcutol® have been shown to have amphiphilic properties and absorption-enhancing capabilities, making them widely used co-surfactants for oral and dermal applications due to their high solubilizing potency [84,85]. Figure 3 provides examples of the most commonly used co-surfactants in microemulsion formulations. The addition of co-surfactants can lead to the thinning of the interfacial film, which prevents the formation of liquid crystalline structures. These co-surfactants are also distributed between the aqueous and oil phases, helping to moderate the hydrophilicity and lipophilicity of the two phases [5,6,13,14,15]. Recent studies have also explored the use of natural co-surfactants such as lecithin and phospholipids for microemulsion formulation, which have been shown to have good biocompatibility and potential for drug delivery applications.

3.3. Oil Phase

The oil phase in microemulsions can consist of various types of compounds, including fatty acids such as oleic acid, alcohols such as octanol and decanol, and esters of fatty acids or alcohols such as isopropyl myristate, isopropyl palmitate, ethyl oleate, isostearyl isostearate, and cetearyl octanoate [66]. Medium-chain triglycerides of caprylic or capric acid and triesters of glycerol and acetic acid such as triacetin are also common in oil phase formulations [25,66]. In addition, some terpenes such as limonene, cineole, camphor, and menthol have also been used in recent studies [86]. The selection of the oil phase depends on various factors such as solubility of the drug, targeted application, and stability of the microemulsion [21].

3.4. Aqueous Phase

The choice of aqueous phase in microemulsion formulation is crucial for achieving the desired properties and functionality [86]. In addition to water, viscosifiers such as Carbopol® and xanthan gel can be used to control the viscosity and stability of the microemulsion [87]. For microemulsions intended for parenteral or ocular routes, NaCl is added to ensure the osmolarity with plasma and tear fluid [52,88]. Buffer solutions are also added when lecithin is used as a surfactant to maintain pH values between 7 and 8, which is important to protect phospholipids and triglycerides from degradation [89,90]. Absorption enhancers can be added to improve drug delivery [91], but their compatibility with the other components of the microemulsion should be carefully evaluated to avoid chemical incompatibilities that may compromise the stability of the system [92]. Overall, the choice of aqueous phase and any additives used should be carefully considered to achieve optimal stability and functionality of the microemulsion [66].

3.5. Active Pharmaceutical Ingredients (API)

The selection of the appropriate active pharmaceutical ingredient (API) is crucial in the formulation of microemulsions for drug delivery applications [17]. The physicochemical properties of the API such as logP, pKa, structure, molecular weight, and presence of ionizable groups can significantly influence the phase behavior and microemulsion structure [93]. For example, ionic surfactants such as dioctyl sodium sulphosuccinate could be affected by the presence of diclofenac sodium hydrochloride, leading to changes in the properties of the resulting microemulsions [93]. On the other hand, certain active ingredients with surface activity can expand the area in which microemulsions are formed [94], while others, such as tricyclic amines, can act as co-surfactants and reduce the amount of surfactant required [49,95].
It is important to note that some lipophilic compounds may also act as oils and compete or be added to the oil phase during microemulsion formation, which may require an adjustment in the amount of surfactant or co-surfactant used [49,95]. Therefore, the selection and study of the API should be considered an essential step in achieving a stable and effective drug delivery system using microemulsions [17,93].
It is also important to consider the issue of using high concentrations of surfactants in microemulsion formulation, as this can lead to potential toxicity concerns [96]. Recent studies have investigated the use of natural surfactants and co-surfactants, as well as the incorporation of stimuli-responsive polymers and nanoparticles, to reduce the surfactant concentration and enhance the stability and performance of microemulsions as drug delivery systems [97,98]. These approaches offer promising directions for future research in microemulsion drug delivery systems [99].

4. Characterization of Microemulsions

The importance of microemulsions in the pharmaceutical industry has made their characterization a widely studied aspect in the literature [83]. There are several methods available for the characterization of microemulsions, which can provide information about their droplet size, zeta potential, viscosity, and thermodynamic stability [100,101].
One commonly used method for microemulsion characterization is dynamic light scattering (DLS), which measures the size distribution of the droplets in the microemulsion [102]. DLS is a non-invasive, fast, and reliable method that provides information on the particle size distribution, polydispersity index, and zeta potential of the droplets [103]. Other methods such as transmission electron microscopy (TEM) [104] and cryogenic transmission electron microscopy (Cryo-TEM) can also be used to visualize the microemulsion droplets and their structure [105].
The thermodynamic stability of microemulsions can be assessed using different techniques, such as conductivity measurements, phase behavior studies, and centrifugation tests [54,106,107]. Conductivity measurements can provide information about the amount and type of surfactants present in the microemulsion [54]. Phase behavior studies involve the construction of ternary phase diagrams to identify the regions of microemulsion formation and to determine the optimal composition for the microemulsion [106]. Centrifugation tests can provide information about the stability of the microemulsion by measuring the sedimentation rate of the droplets [107].
Several factors can affect the characterization of microemulsions, including the composition of the microemulsion, the method of preparation, and the storage conditions [93,108]. The method of preparation, such as the order of addition and mixing speed, can also impact the droplet size and stability of the microemulsion [109]. Storage conditions, such as temperature and time, can affect the physical and chemical properties of the microemulsion and alter its stability [37].
The toxicity or biocompatibility of a drug delivery system is a crucial consideration in its development [110]. To assess the suitability of microemulsions as drug carriers, various characterization methods are employed to evaluate their potential toxicity and biocompatibility [26]. Cytotoxicity assays play a significant role in assessing the effects of microemulsions on cell viability and proliferation [111,112]. Techniques such as the MTT assay [113], Alamar Blue assay [114], and LDH release assay [115] are commonly used to determine cell viability and measure the cytotoxic effects of microemulsions. Hemocompatibility assays are employed to evaluate the compatibility of microemulsions with blood components, including assessments of hemolysis, coagulation, platelet activation, and complement activation [116]. Furthermore, skin irritation and sensitization tests, such as the Draize test and patch testing, are conducted to determine the potential of microemulsions to cause skin irritation or allergic reactions [117,118]. Additionally, in vitro and in vivo biocompatibility studies provide insights into the response of living tissues or organisms to microemulsions, including histological analysis, the assessment of inflammatory responses, immunotoxicity evaluations, and systemic toxicity studies in animal models [26,116]. Genotoxicity and mutagenicity assessments are performed to investigate whether microemulsions induce DNA damage or mutations [119,120]. Techniques such as the Ames test [121], micronucleus assay [122], and comet assay [123] are employed for this purpose. Furthermore, the biodegradation and biocompatibility of microemulsions are examined through enzymatic degradation assays and studies on their fate and clearance in biological systems [124,125]. These characterization methods enable researchers to evaluate the toxicity and biocompatibility profiles of microemulsions, providing valuable insights into their safety and potential as effective drug delivery systems.
In conclusion, the characterization of microemulsions is crucial to ensure their efficacy and safety as a drug delivery system. Various methods are available to characterize the microemulsion droplets, and the stability of the microemulsion can be assessed using different techniques. Several factors can affect the characterization of microemulsions, and a thorough understanding of these factors is necessary for the optimal formulation and characterization of microemulsions. It is worth mentioning that there exist a range of techniques that can be utilized for the evaluation of microemulsions’ toxicity and biocompatibility.

5. Ternary Phase Diagrams of Microemulsions

A phase diagram is a graphical representation that displays the thermodynamic equilibrium between phases of a system at different compositions, temperatures, and pressures [126]. In the case of microemulsions, a phase diagram is used to determine the region of thermodynamic stability for different microemulsion formulations [126].
The phase diagram for microemulsions typically displays the composition of the oil, surfactant, co-surfactant, and water, as well as the regions of the different types of microemulsions formed [127]. These regions include the oil-in-water (O/W) region, the water-in-oil (W/O) region, and the bicontinuous region, which represents a mixture of both O/W and W/O microemulsions (Figure 4).
The phase behavior of microemulsions is influenced by several factors, including the chemical nature and concentration of the components, temperature, pressure, and the presence of electrolytes [45]. The phase diagram can be used to optimize the formulation of microemulsions, as it enables the selection of the most stable composition and the identification of the boundaries of the different microemulsion types [128].
Various techniques can be used to construct a phase diagram, including the titration method, conductivity measurement, visual observation, and turbidity measurement [129]. These techniques are used to determine the point at which the microemulsion forms and the region of stability [129].
In conclusion, the phase diagram is a crucial tool for the formulation of microemulsions, as it enables the identification of the composition and stability of the microemulsion system. It is important to consider the factors that influence the phase behavior of microemulsions when constructing a phase diagram, and to use appropriate techniques to accurately determine the phase boundaries.

6. Life Science Applications of Microemulsions

Microemulsions have been extensively studied in the pharmaceutical research field due to their unique properties and potential applications in drug delivery [19,75]. As mentioned before, their optically transparent and thermodynamically stable nature, coupled with their ability to deliver both hydrophilic and hydrophobic drugs, make them an attractive option for drug delivery.
Microemulsions have shown great promise in overcoming bioavailability concerns and enabling sustained drug delivery (Figure 5). In drug delivery, microemulsions have been used for various applications, including oral, topical, and parenteral administration [11]. Oral microemulsions have been used to enhance the bioavailability of poorly soluble drugs [57]. Topical microemulsions have shown potential for enhancing the delivery of drugs across the skin [21]. Parenteral microemulsions have been used for the delivery of lipophilic drugs and targeting the lymphatic system [130].
Of particular interest in this review is the potential of microemulsions for cutaneous drug delivery [21,41]. Microemulsions have been shown to improve the skin permeation and retention of drugs following the mechanism shown (and explained in the figure caption) in Figure 6 [24]. Additionally, they have been used for the topical delivery of various drugs, including anti-inflammatory active molecules [131], anti-cancer drugs [132], and anti-fungal agents [133]. The ability of microemulsions to deliver drugs through the skin has been attributed to their small droplet size (generally below 100 nm) and the ability to penetrate through the lipid bilayers of the skin [134].
Table 1 presents the compositions and applications of recently developed microemulsions, with a specific focus on their applications in skin delivery. It is evident from the table that the majority of the active pharmaceutical ingredients (APIs) were hydrophobic in nature, and the microemulsions were designed for various applications. The transdermal delivery of drugs via microemulsions offers a convenient method for achieving systemic pharmacological action. In the reviewed microemulsions, water was the most commonly used continuous phase, while isopropylmyristate and isopropylpalmitate were frequently employed as oil phases. In addition to their use as drug delivery systems, microemulsions have also found applications in various other fields [136]. For instance, they have been used as templates for the synthesis of polymer-based nanoparticles and nanocapsules. They have also been used as lubricants, cutting fluids, and in the food industry, including as a nanoreservoir of flavors.
However, it is important to note that the application of microemulsions in drug delivery is still in its early stages, and several challenges remain to be addressed [75]. For instance, the optimization of microemulsion formulations for specific drugs and routes of administration requires a thorough understanding of the factors that affect their stability, such as surfactant and co-surfactant concentrations, and the pH and ionic strength of the system [75]. Furthermore, the toxicity and safety of microemulsions must be thoroughly investigated before their clinical use can be considered [50].
In conclusion, microemulsions are promising drug delivery systems that have shown potential for various applications in pharmaceuticals, including cutaneous drug delivery. Their unique properties and advantages have made them an attractive option for drug delivery, and their potential applications in other fields further highlight their versatility. However, further research is needed to optimize their formulation and characterization, as well as to investigate their safety and toxicity before their clinical use can be fully realized.

7. Advantages of Microemulsions as a Drug Delivery System

As previously mentioned, microemulsions have been extensively studied as a drug delivery system due to their unique properties and potential applications in delivering both hydrophilic and hydrophobic drugs. One of the main advantages of microemulsions is their ability to improve drug solubilization and bioavailability, which are major challenges for drug delivery [163]. Their small droplet size enables efficient drug solubilization and enhanced bioavailability, making them an attractive option for drug delivery [163]. Additionally, they have a low interfacial tension and a large interfacial area, which promote drug release and absorption [164]. Compared to other drug delivery systems, microemulsions have several advantages, including their high drug solubilization capacity, low toxicity, and cost-effectiveness [165].
Microemulsions have a high solubilizing power for a variety of molecules, including hydrophilic, lipophilic, and amphiphilic compounds [51,166]. The solubilizing power of microemulsions has been demonstrated for a variety of hydrophobic drugs, such as ibuprofen, cyclosporine A, and curcumin [167]. In addition to their solubilizing power, microemulsions have also been shown to improve the skin permeation of drugs [24]. The small droplet size of a microemulsion allows for enhanced penetration of drugs through the skin barrier [168]. Additionally, the use of surfactants in microemulsions can disrupt the stratum corneum, further enhancing skin permeation [169].
The potential of microemulsions for cutaneous drug delivery is noteworthy, as they have shown efficient skin penetration and drug delivery [21,41]. Microemulsions can penetrate the skin more efficiently than other delivery systems, such as creams and ointments, due to their small droplet size [170]. This makes them a potential candidate for delivering drugs to treat skin diseases and disorders [140]. Overall, the ability of microemulsions to solubilize various molecules and facilitate skin permeation makes them promising delivery systems for a wide range of drugs, including those with poor solubility or low skin permeability.

8. Challenges and Future Directions

Despite the numerous advantages of microemulsions as drug delivery systems, there are still several challenges and limitations that need to be addressed [52,165]. One major challenge is the complexity of microemulsion formulation, which requires a thorough understanding of the physicochemical properties of the components and their interactions [171]. Furthermore, the optimization of microemulsion formulations can be time-consuming and costly [172].
Another limitation is the potential toxicity of the surfactants and co-surfactants used in microemulsion formulations [50,96]. Although the toxicity of these components can be minimized by selecting biocompatible surfactants and co-surfactants, there is still a risk of adverse effects, particularly with chronic use [97,98].
In addition, the stability of microemulsions can be affected by environmental factors such as temperature, pH, and ionic strength, which can lead to phase separation or droplet aggregation [35]. Therefore, there is a need for the development of more stable microemulsion formulations that can withstand these challenges.
To overcome these challenges, several potential solutions have been proposed. One strategy is to use natural surfactants and co-surfactants, such as phospholipids and bile salts, which are biocompatible and have lower toxicity compared to synthetic surfactants [97,98]. Another approach is to use nanoparticles, such as liposomes or solid lipid nanoparticles, as carriers for the microemulsion, which can improve stability and enhance drug targeting [173].
Future directions for research in microemulsion drug delivery systems include the development of new methods for characterizing and optimizing microemulsion formulations, as well as the exploration of new applications in different therapeutic areas. Additionally, there is a need for further investigation of the pharmacokinetics and toxicity of microemulsion formulations, particularly with chronic use.
In conclusion, microemulsions represent promising drug delivery systems with numerous advantages, including high solubilization capacity, improved bioavailability, and versatility in delivering both hydrophilic and hydrophobic drugs. However, there are still challenges and limitations that need to be addressed, such as formulation complexity, potential toxicity, and stability issues. With the development of new strategies and the advancement of research in this field, microemulsions have the potential to become widely used drug delivery systems for various therapeutic applications.
To illustrate the advantages and limitations of microemulsions for drug delivery, Table 2 is provided in this review. This table highlights the potential benefits of microemulsions, such as improved drug permeability, sustained drug release, and versatile drug delivery routes. It also summarizes the limitations of microemulsions, including potential toxicity, formulation complexity, and scaling-up challenges. The table serves as a useful reference for researchers and practitioners working in the field of drug delivery. By carefully considering the benefits and limitations of microemulsions, researchers can develop more efficient and effective drug delivery systems that can improve patient outcomes.

9. Conclusions

In this comprehensive review, we have discussed the potential of microemulsions as innovative cutaneous delivery systems. We began by providing a brief overview of drug delivery systems in pharmaceuticals and explaining the characteristics of microemulsions, including their composition and properties. We then discussed the formulation of microemulsions and the various techniques used for their preparation.
We also highlighted the importance of characterizing microemulsions and discussed the different methods for their characterization, as well as the factors affecting their characterization. Furthermore, we provided an overview of the potential applications of microemulsions in drug delivery, with a particular emphasis on their use in cutaneous drug delivery.
The advantages of microemulsions as drug delivery systems were also discussed, including their high stability, efficient drug solubilization, and potential for targeted drug delivery. We also compared microemulsions with other drug delivery systems, such as liposomes and nanoparticles.
Despite their many benefits, microemulsions face some challenges and limitations in drug delivery. We reviewed these challenges, including the complexity of formulation and potential toxicity concerns. We also discussed potential solutions to overcome these challenges, including the use of safer surfactants and co-surfactants.
In conclusion, microemulsions represent a promising and innovative drug delivery system for cutaneous applications. Their unique properties, such as high stability and efficient drug solubilization, make them an attractive option for targeted drug delivery. However, further research is needed to address the challenges and limitations of microemulsions and to explore their full potential in drug delivery. With ongoing advancements in microemulsion technology, it is clear that these systems have a bright future in the field of pharmaceutical research and development.

Author Contributions

Z.A.-T. and A.E. (Abdelhamid Elaissari) contributed to conceptualization and to writing—review and editing; Z.A.-T. contributed with formal analysis and writing—original draft; N.Z., N.J.-R., A.E. (Abdelhamid Errachid) and H.F. contributed to investigation; Z.A.-T. and A.E. (Abdelhamid Elaissari) contributed with methodology; A.E. (Abdelhamid Elaissari) contributed with validation and N.L. assisted in editing and finalizing the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sala, M.; Diab, R.; Elaissari, A.; Fessi, H. Lipid Nanocarriers as Skin Drug Delivery Systems: Properties, Mechanisms of Skin Interactions and Medical Applications. Int. J. Pharm. 2018, 535, 1–17. [Google Scholar] [CrossRef] [PubMed]
  2. Gupta, M.; Agrawal, U.; Vyas, S.P. Nanocarrier-Based Topical Drug Delivery for the Treatment of Skin Diseases. Expert Opin. Drug Deliv. 2012, 9, 783–804. [Google Scholar] [CrossRef] [PubMed]
  3. Sun, M.-C.; Xu, X.-L.; Lou, X.-F.; Du, Y.-Z. Recent Progress and Future Directions: The Nano-Drug Delivery System for the Treatment of Vitiligo. Int. J. Nanomed. 2020, 15, 3267–3279. [Google Scholar] [CrossRef] [PubMed]
  4. Cui, M.; Wiraja, C.; Chew, S.W.T.; Xu, C. Nanodelivery Systems for Topical Management of Skin Disorders. Mol. Pharm. 2021, 18, 491–505. [Google Scholar] [CrossRef] [PubMed]
  5. Tanner, T.; Marks, R. Delivering Drugs by the Transdermal Route: Review and Comment. Ski. Res. Technol. 2008, 14, 249–260. [Google Scholar] [CrossRef]
  6. Güng, S.; Erdal, M.S.; Aksu, B. New Formulation Strategies in Topical Antifungal Therapy. J. Cosmet. Dermatol. Sci. Appl. 2013, 3, 56–65. [Google Scholar] [CrossRef]
  7. Patil, P.B.; Datir, S.K.; Saudagar, R.B. A Review on Topical Gels as Drug Delivery System. J. Drug Deliv. Ther. 2019, 9, 989–994. [Google Scholar] [CrossRef]
  8. Kathe, K.; Kathpalia, H. Film Forming Systems for Topical and Transdermal Drug Delivery. Asian J. Pharm. Sci. 2017, 12, 487–497. [Google Scholar] [CrossRef]
  9. Yan, L.; Alba, M.; Tabassum, N.; Voelcker, N.H. Micro- and Nanosystems for Advanced Transdermal Delivery. Adv. Ther. 2019, 2, 1900141. [Google Scholar] [CrossRef]
  10. Üstündağ Okur, N.; Çağlar, E.Ş.; Siafaka, P.I. Novel Ocular Drug Delivery Systems: An Update on Microemulsions. J. Ocul. Pharmacol. Ther. 2020, 36, 342–354. [Google Scholar] [CrossRef]
  11. Rajpoot, K.; Tekade, R.K. Chapter 10—Microemulsion as Drug and Gene Delivery Vehicle: An inside Story. In Drug Delivery Systems; Tekade, R.K., Ed.; Advances in Pharmaceutical Product Development and Research; Academic Press: Cambridge, MA, USA, 2019; pp. 455–520. ISBN 978-0-12-814487-9. [Google Scholar]
  12. Lu, B.; Bo, Y.; Yi, M.; Wang, Z.; Zhang, J.; Zhu, Z.; Zhao, Y.; Zhang, J. Enhancing the Solubility and Transdermal Delivery of Drugs Using Ionic Liquid-In-Oil Microemulsions. Adv. Funct. Mater. 2021, 31, 2102794. [Google Scholar] [CrossRef]
  13. Alkrad, J.A.; Assaf, S.M.; Hussein-Al-Ali, S.H.; Alrousan, R. Microemulsions as Nanocarriers for Oral and Transdermal Administration of Enoxaparin. J. Drug Deliv. Sci. Technol. 2022, 70, 103248. [Google Scholar] [CrossRef]
  14. Dianzani, C.; Zara, G.P.; Maina, G.; Pettazzoni, P.; Pizzimenti, S.; Rossi, F.; Gigliotti, C.L.; Ciamporcero, E.S.; Daga, M.; Barrera, G. Drug Delivery Nanoparticles in Skin Cancers. BioMed Res. Int. 2014, 2014, e895986. [Google Scholar] [CrossRef]
  15. Kamble, P.; Sadarani, B.; Majumdar, A.; Bhullar, S. Nanofiber Based Drug Delivery Systems for Skin: A Promising Therapeutic Approach. J. Drug Deliv. Sci. Technol. 2017, 41, 124–133. [Google Scholar] [CrossRef]
  16. Shingade, G.M. Review on: Recent trend on transdermal drug delivery system. J. Drug Deliv. Ther. 2012, 2. [Google Scholar] [CrossRef]
  17. Paliwal, H.; Solanki, R.S.; Chauhan, C.S.; Dwivedi, J. Pharmaceutical Considerations of Microemulsion as a Drug Delivery System. J. Drug Deliv. Ther. 2019, 9, 661–665. [Google Scholar] [CrossRef]
  18. Al-Adham, I.S.I.; Jaber, N.; Al-Remawi, M.; Al-Akayleh, F.; Al-Kaissi, E.; Ali Agha, A.S.A.; Fitzsimmons, L.B.; Collier, P.J. A Review of the Antimicrobial Activity of Thermodynamically Stable Microemulsions. Lett. Appl. Microbiol. 2022, 75, 537–547. [Google Scholar] [CrossRef]
  19. Suhail, N.; Alzahrani, A.K.; Basha, W.J.; Kizilbash, N.; Zaidi, A.; Ambreen, J.; Khachfe, H.M. Microemulsions: Unique Properties, Pharmacological Applications, and Targeted Drug Delivery. Front. Nanotechnol. 2021, 3, 754889. [Google Scholar] [CrossRef]
  20. Ande, S.N.; Sonone, K.B.; Bakal, R.L.; Ajmire, P.V.; Sawarkar, H.S. Role of Surfactant and Co-Surfactant in Microemulsion: A Review. Res. J. Pharm. Technol. 2022, 15, 4829–4834. [Google Scholar] [CrossRef]
  21. Souto, E.B.; Cano, A.; Martins-Gomes, C.; Coutinho, T.E.; Zielińska, A.; Silva, A.M. Microemulsions and Nanoemulsions in Skin Drug Delivery. Bioengineering 2022, 9, 158. [Google Scholar] [CrossRef]
  22. Anuar, N.; Sabri, A.H.; Bustami Effendi, T.J.; Abdul Hamid, K. Development and Characterisation of Ibuprofen-Loaded Nanoemulsion with Enhanced Oral Bioavailability. Heliyon 2020, 6, e04570. [Google Scholar] [CrossRef]
  23. Moghadam, S.H.; Saliaj, E.; Wettig, S.D.; Dong, C.; Ivanova, M.V.; Huzil, J.T.; Foldvari, M. Effect of Chemical Permeation Enhancers on Stratum Corneum Barrier Lipid Organizational Structure and Interferon Alpha Permeability. Mol. Pharm. 2013, 10, 2248–2260. [Google Scholar] [CrossRef] [PubMed]
  24. Kogan, A.; Garti, N. Microemulsions as Transdermal Drug Delivery Vehicles. Adv. Colloid Interface Sci. 2006, 123–126, 369–385. [Google Scholar] [CrossRef] [PubMed]
  25. Talegaonkar, S.; Azeem, A.; Ahmad, F.J.; Khar, R.K.; Pathan, S.A.; Khan, Z.I. Microemulsions: A Novel Approach to Enhanced Drug Delivery. Recent Pat. Drug Deliv. Formul. 2008, 2, 238–257. [Google Scholar] [CrossRef]
  26. Gharbavi, M.; Manjili, H.K.; Amani, J.; Sharafi, A.; Danafar, H. In Vivo and in Vitro Biocompatibility Study of Novel Microemulsion Hybridized with Bovine Serum Albumin as Nanocarrier for Drug Delivery. Heliyon 2019, 5, e01858. [Google Scholar] [CrossRef]
  27. Sahoo, C.K.; Rao, S.R.M.; Sudhakar, M. Hema Challenges of Micro-Emulsion as a Novel Carrier for Drug Delivery. Res. J. Pharm. Dos. Form. Technol. 2019, 11, 227. [Google Scholar] [CrossRef]
  28. Patil, P.; Nene, S.; Shah, S.; Singh, S.B.; Srivastava, S. Exploration of Novel Drug Delivery Systems in Topical Management of Osteoarthritis. Drug Deliv. Transl. Res. 2023, 13, 531–546. [Google Scholar] [CrossRef]
  29. Ibrahim, M.M.; Maria, D.N.; Wang, X.; Simpson, R.N.; Hollingsworth, T.J.; Jablonski, M.M. Enhanced Corneal Penetration of a Poorly Permeable Drug Using Bioadhesive Multiple Microemulsion Technology. Pharmaceutics 2020, 12, 704. [Google Scholar] [CrossRef]
  30. Galindo-Rosales, F.J.; Campo-Deaño, L.; Afonso, A.M.; Alves, M.A.; Pinho, F.T. Proceedings of the Iberian Meeting on Rheology (IBEREO 2019); Springer Nature: Cham, Switzerland, 2019; ISBN 978-3-030-27701-7. [Google Scholar]
  31. Rakshit, A.K.; Naskar, B.; Moulik, S.P. Commemorating 75 Years of Microemulsion. Curr. Sci. 2019, 116, 898–912. [Google Scholar] [CrossRef]
  32. Salager, J.-L.; Marquez, R.; Rondón, M.; Bullón, J.; Graciaa, A. Review on Some Confusion Produced by the Bicontinuous Microemulsion Terminology and Its Domains Microcurvature: A Simple Spatiotemporal Model at Optimum Formulation of Surfactant-Oil-Water Systems. ACS Omega 2023, 8, 9040–9057. [Google Scholar] [CrossRef]
  33. Danielsson, I.; Lindman, B. The Definition of Microemulsion. Colloids Surf. 1981, 3, 391–392. [Google Scholar] [CrossRef]
  34. Burguera, J.L.; Burguera, M. Analytical Applications of Emulsions and Microemulsions. Talanta 2012, 96, 11–20. [Google Scholar] [CrossRef] [PubMed]
  35. Rao, J.; McClements, D.J. Food-Grade Microemulsions, Nanoemulsions and Emulsions: Fabrication from Sucrose Monopalmitate & Lemon Oil. Food Hydrocoll. 2011, 25, 1413–1423. [Google Scholar] [CrossRef]
  36. McClements, D.J. Nanoemulsions versus Microemulsions: Terminology, Differences, and Similarities. Soft Matter 2012, 8, 1719–1729. [Google Scholar] [CrossRef]
  37. Rao, J.; McClements, D.J. Formation of Flavor Oil Microemulsions, Nanoemulsions and Emulsions: Influence of Composition and Preparation Method. J. Agric. Food Chem. 2011, 59, 5026–5035. [Google Scholar] [CrossRef] [PubMed]
  38. Kale, S.N.; Deore, S.L. Emulsion Micro Emulsion and Nano Emulsion: A Review. Syst. Rev. Pharm. 2017, 8, 39. [Google Scholar] [CrossRef]
  39. Schork, F.J.; Luo, Y.; Smulders, W.; Russum, J.P.; Butté, A.; Fontenot, K. Miniemulsion Polymerization. In Polymer Particles; Okubo, M., Ed.; Advances in Polymer Science; Springer: Berlin/Heidelberg, Germany, 2005; pp. 129–255. ISBN 978-3-540-31565-0. [Google Scholar]
  40. Han, X.; Lu, M.; Fan, Y.; Li, Y.; Holmberg, K. Recent Developments on Surfactants for Enhanced Oil Recovery. Tenside Surfactants Deterg. 2021, 58, 164–176. [Google Scholar] [CrossRef]
  41. Naoui, W.; Bolzinger, M.-A.; Fenet, B.; Pelletier, J.; Valour, J.-P.; Kalfat, R.; Chevalier, Y. Microemulsion Microstructure Influences the Skin Delivery of an Hydrophilic Drug. Pharm. Res. 2011, 28, 1683–1695. [Google Scholar] [CrossRef]
  42. Junyaprasert, V.B.; Boonme, P.; Songkro, S.; Krauel, K.; Rades, T. Transdermal Delivery of Hydrophobic and Hydrophilic Local Anesthetics from o/w and w/o Brij 97-Based Microemulsions. J. Pharm. Pharm. Sci. 2007, 10, 288–298. [Google Scholar]
  43. Peng, K.; Sottmann, T.; Stubenrauch, C. Gelled Non-Toxic Bicontinuous Microemulsions as Promising Transdermal Drug Carriers. Mol. Phys. 2021, 119, e1886363. [Google Scholar] [CrossRef]
  44. Soliman, S.M.; Malak, N.A.; El-Gazayerly, O.N.; Rehim, A.A. Formulation of Microemulsion Gel Systems for Transdermal Delivery of Celecoxib: In Vitro Permeation, Anti-Inflammatory Activity and Skin Irritation Tests. Drug Discov. Ther. 2010, 4, 459–471. [Google Scholar]
  45. Bourrel, M.; Schechter, R.S. Microemulsions and Related Systems: Formulation, Solvency, and Physical Properties; Editions TECHNIP: Paris, France, 2010; ISBN 978-2-7108-0956-2. [Google Scholar]
  46. Yuan, Y.; Li, S.; Mo, F.; Zhong, D. Investigation of Microemulsion System for Transdermal Delivery of Meloxicam. Int. J. Pharm. 2006, 321, 117–123. [Google Scholar] [CrossRef]
  47. Jeirani, Z.; Mohamed Jan, B.; Si Ali, B.; Noor, I.M.; Chun Hwa, S.; Saphanuchart, W. The Optimal Mixture Design of Experiments: Alternative Method in Optimizing the Aqueous Phase Composition of a Microemulsion. Chemom. Intell. Lab. Syst. 2012, 112, 1–7. [Google Scholar] [CrossRef]
  48. Liu, C.-H.; Chang, F.-Y. Development and Characterization of Eucalyptol Microemulsions for Topic Delivery of Curcumin. Chem. Pharm. Bull. 2011, 59, 172–178. [Google Scholar] [CrossRef]
  49. Kreilgaard, M. Influence of Microemulsions on Cutaneous Drug Delivery. Adv. Drug Deliv. Rev. 2002, 54, S77–S98. [Google Scholar] [CrossRef]
  50. Karasulu, H.Y. Microemulsions as Novel Drug Carriers: The Formation, Stability, Applications and Toxicity. Expert Opin. Drug Deliv. 2008, 5, 119–135. [Google Scholar] [CrossRef] [PubMed]
  51. Sapra, B.; Thatai, P.; Bhandari, S.; Sood, J.; Jindal, M.; Tiwary, A. A Critical Appraisal of Microemulsions for Drug Delivery: Part I. Ther. Deliv. 2013, 4, 1547–1564. [Google Scholar] [CrossRef]
  52. Vandamme, T.F. Microemulsions as Ocular Drug Delivery Systems: Recent Developments and Future Challenges. Prog. Retin. Eye Res. 2002, 21, 15–34. [Google Scholar] [CrossRef] [PubMed]
  53. Sripriya, R.; Muthu Raja, K.; Santhosh, G.; Chandrasekaran, M.; Noel, M. The Effect of Structure of Oil Phase, Surfactant and Co-Surfactant on the Physicochemical and Electrochemical Properties of Bicontinuous Microemulsion. J. Colloid Interface Sci. 2007, 314, 712–717. [Google Scholar] [CrossRef]
  54. Karamustafa, F.; Çelebi, N. Development of an Oral Microemulsion Formulation of Alendronate: Effects of Oil and Co-Surfactant Type on Phase Behaviour. J. Microencapsul. 2008, 25, 315–323. [Google Scholar] [CrossRef]
  55. Cao, X.; Gu, Y.; Tian, H.; Fang, Y.; Johnson, D.; Ren, Z.; Chen, C.; Huang, Y. Microemulsion Synthesis of Ms/Tz-BiVO4 Composites: The Effect of PH on Crystal Structure and Photocatalytic Performance. Ceram. Int. 2020, 46, 20788–20797. [Google Scholar] [CrossRef]
  56. Sun, M.; Si, L.; Zhai, X.; Fan, Z.; Ma, Y.; Zhang, R.; Yang, X. The Influence of Co-Solvents on the Stability and Bioavailability of Rapamycin Formulated in Self-Microemulsifying Drug Delivery Systems. Drug Dev. Ind. Pharm. 2011, 37, 986–994. [Google Scholar] [CrossRef]
  57. He, C.-X.; He, Z.-G.; Gao, J.-Q. Microemulsions as Drug Delivery Systems to Improve the Solubility and the Bioavailability of Poorly Water-Soluble Drugs. Expert Opin. Drug Deliv. 2010, 7, 445–460. [Google Scholar] [CrossRef] [PubMed]
  58. Calligaris, S.; Valoppi, F.; Barba, L.; Pizzale, L.; Anese, M.; Conte, L.; Nicoli, M.C. Development of Transparent Curcumin Loaded Microemulsions by Phase Inversion Temperature (PIT) Method: Effect of Lipid Type and Physical State on Curcumin Stability. Food Biophys. 2017, 12, 45–51. [Google Scholar] [CrossRef]
  59. Kara, D.; Fisher, A.; Hill, S. Extraction of Trace Elements by Ultrasound-Assisted Emulsification from Edible Oils Producing Detergentless Microemulsions. Food Chem. 2015, 188, 143–148. [Google Scholar] [CrossRef] [PubMed]
  60. Jintapattanakit, A. Preparation of Nanoemulsions by Phase Inversion Temperature (PIT). Pharm. Sci. Asia 2018, 42, 1–12. [Google Scholar] [CrossRef]
  61. Li, Z.; Xu, D.; Yuan, Y.; Wu, H.; Hou, J.; Kang, W.; Bai, B. Advances of Spontaneous Emulsification and Its Important Applications in Enhanced Oil Recovery Process. Adv. Colloid Interface Sci. 2020, 277, 102119. [Google Scholar] [CrossRef] [PubMed]
  62. Valasques, G.S.; dos Santos, A.M.P.; Teixeira, L.S.G.; da Mata Cerqueira, U.M.F.; de Souza, V.S.; Bezerra, M.A. Applications of Emulsified Systems in Elemental Analysis by Spectroanalytical Techniques. Appl. Spectrosc. Rev. 2017, 52, 729–753. [Google Scholar] [CrossRef]
  63. Patel, R.B.; Patel, M.R.; Bhatt, K.K.; Patel, B.G. Formulation Consideration and Characterization of Microemulsion Drug Delivery System for Transnasal Administration of Carbamazepine. Bull. Fac. Pharm. Cairo Univ. 2013, 51, 243–253. [Google Scholar] [CrossRef]
  64. Hu, L.; Jia, Y.; Niu, F.; Jia, Z.; Yang, X.; Jiao, K. Preparation and Enhancement of Oral Bioavailability of Curcumin Using Microemulsions Vehicle. J. Agric. Food Chem. 2012, 60, 7137–7141. [Google Scholar] [CrossRef]
  65. Mao, S.; Wang, Y.; Ji, H.; Bi, D. Preparation of solid lipid nanoparticles by microemulsion technique. Yao Xue Xue Bao 2003, 38, 624–626. [Google Scholar] [PubMed]
  66. Santos, P.; Watkinson, A.C.; Hadgraft, J.; Lane, M.E. Application of Microemulsions in Dermal and Transdermal Drug Delivery. Ski. Pharmacol. Physiol. 2008, 21, 246–259. [Google Scholar] [CrossRef] [PubMed]
  67. Sakamoto, K.; Lochhead, R.Y.; Maibach, H.I.; Yamashita, Y. Cosmetic Science and Technology: Theoretical Principles and Applications; Elsevier: Amsterdam, The Netherlands, 2017; ISBN 978-0-12-802054-8. [Google Scholar]
  68. Alves, J.L.; Rosa, P. de T.V. e; Morales, A.R. Evaluation of Organic Modification of Montmorillonite with Ionic and Nonionic Surfactants. Appl. Clay Sci. 2017, 150, 23–33. [Google Scholar] [CrossRef]
  69. Goto, Y.; Nema, Y.; Matsuoka, K. Foam Separation of Dyes Using Anionic, Cationic, and Amphoteric Surfactants. J. Oleo Sci. 2020, 69, 549–555. [Google Scholar] [CrossRef] [PubMed]
  70. Chen, Y.M.; Matsumoto, S.; Gong, J.P.; Osada, Y. Effect of Hydrophobic Side Chain on Poly(Carboxyl Acid) Dissociation and Surfactant Binding. Macromolecules 2003, 36, 8830–8835. [Google Scholar] [CrossRef]
  71. Chai, J.; Wu, Y.; Li, X.; Yang, B.; Chen, L.; Shang, S.; Lu, J. Phase Behavior of the Microemulsion Systems Containing Alkyl Polyglucoside and Hexadecyl-Trimethyl-Ammonium Bromide. J. Chem. Eng. Data 2011, 56, 48–52. [Google Scholar] [CrossRef]
  72. Zhang, R.; Xia, Y.; Guo, F.; Sun, W.; Cheng, H.; Xing, Y.; Gui, X. Effect of Microemulsion on Low-Rank Coal Flotation by Mixing DTAB and Diesel Oil. Fuel 2020, 260, 116321. [Google Scholar] [CrossRef]
  73. Rahdar, A.; Almasi-Kashi, M. Dynamic and Spectroscopic Studies of Nano-Micelles Comprising Dye in Water/ Dioctyl Sodium Sulfosuccinate /Decane Droplet Microemulsion at Constant Water Content. J. Mol. Struct. 2017, 1128, 257–262. [Google Scholar] [CrossRef]
  74. Hassan, R.R.A. Sodium Dodecyl Sulfate Micro-Emulsion as a Smart Cleaning Agent for Archeological Manuscripts: Surface Investigations. Eur. Phys. J. Plus 2021, 136, 37. [Google Scholar] [CrossRef]
  75. Callender, S.P.; Mathews, J.A.; Kobernyk, K.; Wettig, S.D. Microemulsion Utility in Pharmaceuticals: Implications for Multi-Drug Delivery. Int. J. Pharm. 2017, 526, 425–442. [Google Scholar] [CrossRef]
  76. Kaur, G.; Mehta, S.K. Developments of Polysorbate (Tween) Based Microemulsions: Preclinical Drug Delivery, Toxicity and Antimicrobial Applications. Int. J. Pharm. 2017, 529, 134–160. [Google Scholar] [CrossRef]
  77. Djekic, L.; Primorac, M. The Influence of Cosurfactants and Oils on the Formation of Pharmaceutical Microemulsions Based on PEG-8 Caprylic/Capric Glycerides. Int. J. Pharm. 2008, 352, 231–239. [Google Scholar] [CrossRef]
  78. Ashok, P.; Meyyanathan, S.N.; Jawahar, N.; Vadivelan, R. Irbesartan Formulation and Evaluation of Loaded Solid Lipid Nanoparticles by Microemulsion Techinque. Asian J. Pharm. Technol. 2020, 10, 228–230. [Google Scholar] [CrossRef]
  79. Subongkot, T. Development and Mechanistic Study of a Microemulsion Containing Vitamin E TPGS for the Enhancement of Oral Absorption of Celecoxib. Int. J. Nanomed. 2019, 14, 3087–3102. [Google Scholar] [CrossRef] [PubMed]
  80. Grant, L.M.; Ederth, T.; Tiberg, F. Influence of Surface Hydrophobicity on the Layer Properties of Adsorbed Nonionic Surfactants. Langmuir 2000, 16, 2285–2291. [Google Scholar] [CrossRef]
  81. Fernández-Peña, L.; Gutiérrez-Muro, S.; Guzmán, E.; Lucia, A.; Ortega, F.; Rubio, R.G. Oil-In-Water Microemulsions for Thymol Solubilization. Colloids Interfaces 2019, 3, 64. [Google Scholar] [CrossRef]
  82. Ghosh, P.K.; Murthy, R.S.R. Microemulsions: A Potential Drug Delivery System. Curr. Drug Deliv. 2006, 3, 167–180. [Google Scholar] [CrossRef]
  83. Fanun, M. Microemulsions: Properties and Applications; CRC Press: Boca Raton, FL, USA, 2008; ISBN 978-1-4200-8960-8. [Google Scholar]
  84. Moiseev, R.V.; Morrison, P.W.J.; Steele, F.; Khutoryanskiy, V.V. Penetration Enhancers in Ocular Drug Delivery. Pharmaceutics 2019, 11, 321. [Google Scholar] [CrossRef]
  85. Yeom, D.W.; Chae, B.R.; Son, H.Y.; Kim, J.H.; Chae, J.S.; Song, S.H.; Oh, D.; Choi, Y.W. Enhanced Oral Bioavailability of Valsartan Using a Polymer-Based Supersaturable Self-Microemulsifying Drug Delivery System. Int. J. Nanomed. 2017, 12, 3533–3545. [Google Scholar] [CrossRef]
  86. Liu, C.-H.; Chang, F.-Y.; Hung, D.-K. Terpene Microemulsions for Transdermal Curcumin Delivery: Effects of Terpenes and Cosurfactants. Colloids Surf. B Biointerfaces 2011, 82, 63–70. [Google Scholar] [CrossRef]
  87. Špaglová, M.; Papadakos, M.; Čuchorová, M.; Matušová, D. Release of Tretinoin Solubilized in Microemulsion from Carbopol and Xanthan Gel: In Vitro versus Ex Vivo Permeation Study. Polymers 2023, 15, 329. [Google Scholar] [CrossRef] [PubMed]
  88. Karasulu, H.Y.; Oruç, N.; Üstündağ-Okur, N.; İlem Özdemir, D.; Ay Şenyiğit, Z.; Barbet Yılmaz, F.; Aşıkoğlu, M.; Özkılıç, H.; Akçiçek, E.; Güneri, T.; et al. Aprotinin Revisited: Formulation, Characterization, Biodistribution and Therapeutic Potential of New Aprotinin Microemulsion in Acute Pancreatitis. J. Drug Target. 2015, 23, 525–537. [Google Scholar] [CrossRef] [PubMed]
  89. Peira, E.; Carlotti, M.E.; Trotta, C.; Cavalli, R.; Trotta, M. Positively Charged Microemulsions for Topical Application. Int. J. Pharm. 2008, 346, 119–123. [Google Scholar] [CrossRef]
  90. Changez, M.; Chander, J.; Dinda, A.K. Transdermal Permeation of Tetracaine Hydrochloride by Lecithin Microemulsion: In Vivo. Colloids Surf. B Biointerfaces 2006, 48, 58–66. [Google Scholar] [CrossRef] [PubMed]
  91. Cano-Cebrian, M.J.; Zornoza, T.; Granero, L.; Polache, A. Intestinal Absorption Enhancement Via the Paracellular Route by Fatty Acids, Chitosans and Others: A Target for Drug Delivery. Curr. Drug Deliv. 2005, 2, 9–22. [Google Scholar] [CrossRef]
  92. Patil, N.H.; Devarajan, P.V. Enhanced Insulin Absorption from Sublingual Microemulsions: Effect of Permeation Enhancers. Drug Deliv. Transl. Res. 2014, 4, 429–438. [Google Scholar] [CrossRef] [PubMed]
  93. Date, A.A.; Patravale, V.B. Microemulsions: Applications in Transdermal and Dermal Delivery. Crit. Rev. Ther. Drug Carr. Syst. 2007, 24, 547–596. [Google Scholar] [CrossRef]
  94. Roy, B.K.; Moulik, S.P. Functions of Hydrotropes (Sodium Salicylate, Proline, Pyrogallol, Resorcinol and Urea) in Solution with Special Reference to Amphiphile Behaviors. Colloids Surf. A Physicochem. Eng. Asp. 2002, 203, 155–166. [Google Scholar] [CrossRef]
  95. Malcolmson, C.; Satra, C.; Kantaria, S.; Sidhu, A.; Jayne Lawrence, M. Effect of Oil on the Level of Solubilization of Testosterone Propionate into Nonionic Oil-in-Water Microemulsions. J. Pharm. Sci. 1998, 87, 109–116. [Google Scholar] [CrossRef]
  96. Gautam, N.; Kesavan, K. Development of Microemulsions for Ocular Delivery. Ther. Deliv. 2017, 8, 313–330. [Google Scholar] [CrossRef]
  97. Szűts, A.; Szabó-Révész, P. Sucrose Esters as Natural Surfactants in Drug Delivery Systems—A Mini-Review. Int. J. Pharm. 2012, 433, 1–9. [Google Scholar] [CrossRef]
  98. Amiri-Rigi, A.; Abbasi, S. Microemulsion-Based Lycopene Extraction: Effect of Surfactants, Co-Surfactants and Pretreatments. Food Chem. 2016, 197, 1002–1007. [Google Scholar] [CrossRef]
  99. Chen, J.; Ma, X.; Yao, G.; Zhang, W.; Zhao, Y. Microemulsion-Based Anthocyanin Systems: Effect of Surfactants, Cosurfactants, and Its Stability. Int. J. Food Prop. 2018, 21, 1152–1165. [Google Scholar] [CrossRef]
  100. Boonme, P. Applications of Microemulsions in Cosmetics. J. Cosmet. Dermatol. 2007, 6, 223–228. [Google Scholar] [CrossRef] [PubMed]
  101. Acharya, D.P.; Hartley, P.G. Progress in Microemulsion Characterization. Curr. Opin. Colloid Interface Sci. 2012, 17, 274–280. [Google Scholar] [CrossRef]
  102. Blochowicz, T.; Gögelein, C.; Spehr, T.; Müller, M.; Stühn, B. Polymer-Induced Transient Networks in Water-in-Oil Microemulsions Studied by Small-Angle x-Ray and Dynamic Light Scattering. Phys. Rev. E 2007, 76, 041505. [Google Scholar] [CrossRef]
  103. Ansari, A.A.; Singh, I.B.; Tobschall, H.J. Role of Monsoon Rain on Concentrations and Dispersion Patterns of Metal Pollutants in Sediments and Soils of the Ganga Plain, India. Environ. Geol. 2000, 39, 221–237. [Google Scholar] [CrossRef]
  104. Marchand, K.E.; Tarret, M.; Lechaire, J.P.; Normand, L.; Kasztelan, S.; Cseri, T. Investigation of AOT-Based Microemulsions for the Controlled Synthesis of MoSx Nanoparticles: An Electron Microscopy Study. Colloids Surf. A Physicochem. Eng. Asp. 2003, 214, 239–248. [Google Scholar] [CrossRef]
  105. Lee, H.S.; Morrison, E.D.; Zhang, Q.; Mccormick, A.V. Cryogenic transmission electron microscopy study: Preparation of vesicular dispersions by quenching microemulsions. J. Microsc. 2016, 263, 293–299. [Google Scholar] [CrossRef] [PubMed]
  106. Safavi, A.; Maleki, N.; Farjami, F. Phase Behavior and Characterization of Ionic Liquids Based Microemulsions. Colloids Surf. A Physicochem. Eng. Asp. 2010, 355, 61–66. [Google Scholar] [CrossRef]
  107. Batra, G.; Gortzi, O.; Lalas, S.I.; Galidi, A.; Alibade, A.; Nanos, G.D. Enhanced Antioxidant Activity of Capsicum annuum L. and Moringa oleifera L. Extracts after Encapsulation in Microemulsions. ChemEngineering 2017, 1, 15. [Google Scholar] [CrossRef]
  108. Shaaban, H.A.; Edris, A.E. Factors Affecting the Phase Behavior and Antimicrobial Activity of Carvacrol Microemulsions. J. Oleo Sci. 2015, 64, 393–404. [Google Scholar] [CrossRef]
  109. Lu, G.W.; Gao, P. CHAPTER 3—Emulsions and Microemulsions for Topical and Transdermal Drug Delivery. In Handbook of Non-Invasive Drug Delivery Systems; Kulkarni, V.S., Ed.; Personal Care & Cosmetic Technology; William Andrew Publishing: Boston, MA, USA, 2010; pp. 59–94. ISBN 978-0-8155-2025-2. [Google Scholar]
  110. Kohane, D.S.; Langer, R. Biocompatibility and Drug Delivery Systems. Chem. Sci. 2010, 1, 441–446. [Google Scholar] [CrossRef]
  111. Vicentini, F.T.M.C.; Fonseca, Y.M.; Pitol, D.L.; Iyomasa, M.M.; Bentley, M.V.L.B.; Fonseca, M.J.V. Evaluation of Protective Effect of a Water-In-Oil Microemulsion Incorporating Quercetin Against UVB-Induced Damage in Hairless Mice Skin. J. Pharm. Pharm. Sci. 2010, 13, 274–285. [Google Scholar] [CrossRef]
  112. Hosmer, J.; Reed, R.; Bentley, M.V.L.B.; Nornoo, A.; Lopes, L.B. Microemulsions Containing Medium-Chain Glycerides as Transdermal Delivery Systems for Hydrophilic and Hydrophobic Drugs. AAPS PharmSciTech 2009, 10, 589–596. [Google Scholar] [CrossRef] [PubMed]
  113. Cespi, M.; Quassinti, L.; Perinelli, D.R.; Bramucci, M.; Iannarelli, R.; Papa, F.; Ricciutelli, M.; Bonacucina, G.; Palmieri, G.F.; Maggi, F. Microemulsions Enhance the Shelf-Life and Processability of Smyrnium olusatrum L. Essential Oil. Flavour Fragr. J. 2017, 32, 159–164. [Google Scholar] [CrossRef]
  114. Khunt, D.; Shrivas, M.; Polaka, S.; Gondaliya, P.; Misra, M. Role of Omega-3 Fatty Acids and Butter Oil in Targeting Delivery of Donepezil Hydrochloride Microemulsion to Brain via the Intranasal Route: A Comparative Study. AAPS PharmSciTech 2020, 21, 45. [Google Scholar] [CrossRef]
  115. Sargazi, S.; Hajinezhad, M.R.; Barani, M.; Rahdar, A.; Shahraki, S.; Karimi, P.; Cucchiarini, M.; Khatami, M.; Pandey, S. Synthesis, Characterization, Toxicity and Morphology Assessments of Newly Prepared Microemulsion Systems for Delivery of Valproic Acid. J. Mol. Liq. 2021, 338, 116625. [Google Scholar] [CrossRef]
  116. Rhyaf, A.; Naji, H.; Al-Karagoly, H.; Albukhaty, S.; Sulaiman, G.M.; Alshammari, A.A.A.; Mohammed, H.A.; Jabir, M.; Khan, R.A. In Vitro and In Vivo Functional Viability, and Biocompatibility Evaluation of Bovine Serum Albumin-Ingrained Microemulsion: A Model Based on Sesame Oil as the Payload for Developing an Efficient Drug Delivery Platform. Pharmaceuticals 2023, 16, 582. [Google Scholar] [CrossRef] [PubMed]
  117. Patel, P.; Pol, A.; Kalaria, D.; Date, A.A.; Kalia, Y.; Patravale, V. Microemulsion-Based Gel for the Transdermal Delivery of Rasagiline Mesylate: In Vitro and in Vivo Assessment for Parkinson’s Therapy. Eur. J. Pharm. Biopharm. 2021, 165, 66–74. [Google Scholar] [CrossRef]
  118. Nigam, P.K. Adverse Reactions to Cosmetics and Methods of Testing. Indian J. Dermatol. Venereol. Leprol. 2009, 75, 10. [Google Scholar] [CrossRef]
  119. Quiñones, O.G.; Mata dos Santos, H.A.; Kibwila, D.M.; Leitão, Á.; dos Santos Pyrrho, A.; de Pádula, M.; Rosas, E.C.; Lara, M.G.; Pierre, M.B.R. In Vitro and in Vivo Influence of Penetration Enhancers in the Topical Application of Celecoxib. Drug Dev. Ind. Pharm. 2014, 40, 1180–1189. [Google Scholar] [CrossRef]
  120. Sullivan, D.W.; Gad, S.C.; Julien, M. A Review of the Nonclinical Safety of Transcutol®, a Highly Purified Form of Diethylene Glycol Monoethyl Ether (DEGEE) Used as a Pharmaceutical Excipient. Food Chem. Toxicol. 2014, 72, 40–50. [Google Scholar] [CrossRef]
  121. Marena, G.D.; Girotto, L.; Saldanha, L.L.; Ramos, M.A.d.S.; Grandis, R.A.D.; da Silva, P.B.; Dokkedal, A.L.; Chorilli, M.; Bauab, T.M.; Pavan, F.R.; et al. Hydroalcoholic Extract of Myrcia Bella Loaded into a Microemulsion System: A Study of Antifungal and Mutagenic Potential. Planta Med. 2022, 88, 405–415. [Google Scholar] [CrossRef]
  122. Qin, X.; Yin, J.; Zhang, W.; Li, J.; Wen, J.; Chen, S. Acute and Subchronic Toxicities in Dogs and Genotoxicity of Honokiol Microemulsion. Regul. Toxicol. Pharmacol. 2018, 95, 362–370. [Google Scholar] [CrossRef] [PubMed]
  123. Natesan, S.; Sugumaran, A.; Ponnusamy, C.; Jeevanesan, V.; Girija, G.; Palanichamy, R. Development and Evaluation of Magnetic Microemulsion: Tool for Targeted Delivery of Camptothecin to BALB/c Mice-Bearing Breast Cancer. J. Drug Target. 2014, 22, 913–926. [Google Scholar] [CrossRef]
  124. Liu, W.; Zhai, Y.; Heng, X.; Che, F.Y.; Chen, W.; Sun, D.; Zhai, G. Oral Bioavailability of Curcumin: Problems and Advancements. J. Drug Target. 2016, 24, 694–702. [Google Scholar] [CrossRef]
  125. Ben Yehuda Greenwald, M.; Frušić-Zlotkin, M.; Soroka, Y.; Ben Sasson, S.; Bitton, R.; Bianco-Peled, H.; Kohen, R. Curcumin Protects Skin against UVB-Induced Cytotoxicity via the Keap1-Nrf2 Pathway: The Use of a Microemulsion Delivery System. Oxidative Med. Cell. Longev. 2017, 2017, e5205471. [Google Scholar] [CrossRef] [PubMed]
  126. Marques, E.F.; Silva, B.F.B. Surfactants, Phase Behavior. In Encyclopedia of Colloid and Interface Science; Tadros, T., Ed.; Springer: Berlin/Heidelberg, Germany, 2013; pp. 1290–1333. ISBN 978-3-642-20665-8. [Google Scholar]
  127. Flores, S.E.; Rial-Hermida, M.I.; Ramirez, J.C.; Pazos, A.; Concheiro, A.; Alvarez-Lorenzo, C.; Peralta, R.D. Microemulsions for Colorectal Cancer Treatments. General Considerations and Formulation of Methotrexate. Mini-Rev. Med. Chem. 2016, 16, 498–508. [Google Scholar] [CrossRef] [PubMed]
  128. Kumar, R.; Sinha, V.R. Preparation and Optimization of Voriconazole Microemulsion for Ocular Delivery. Colloids Surf. B Biointerfaces 2014, 117, 82–88. [Google Scholar] [CrossRef]
  129. Nai, X.; Bao, H.; Liu, M.; Zhang, Q.; Liu, J. Measuring Boundaries in Phase Diagrams of Ternary Systems Using Titration Calorimetry. J. Mol. Liq. 2021, 321, 114451. [Google Scholar] [CrossRef]
  130. Cannon, J.B.; Shi, Y.; Gupta, P. Emulsions, Microemulsions, and Lipid-Based Drug Delivery Systems for Drug Solubilization and Delivery—Part I: Parenteral Applications. In Water-Insoluble Drug Formulation; CRC Press: Boca Raton, FL, USA, 2017; ISBN 978-1-315-12049-2. [Google Scholar]
  131. Alves, L.P.; da Silva Oliveira, K.; da Paixão Santos, J.A.; da Silva Leite, J.M.; Rocha, B.P.; de Lucena Nogueira, P.; de Araújo Rêgo, R.I.; Oshiro-Junior, J.A.; Damasceno, B.P.G.d.L. A Review on Developments and Prospects of Anti-Inflammatory in Microemulsions. J. Drug Deliv. Sci. Technol. 2020, 60, 102008. [Google Scholar] [CrossRef]
  132. Dehghani, F.; Farhadian, N.; Golmohammadzadeh, S.; Biriaee, A.; Ebrahimi, M.; Karimi, M. Preparation, Characterization and in-Vivo Evaluation of Microemulsions Containing Tamoxifen Citrate Anti-Cancer Drug. Eur. J. Pharm. Sci. 2017, 96, 479–489. [Google Scholar] [CrossRef]
  133. Date, A.A.; Nagarsenker, M.S. Parenteral Microemulsions: An Overview. Int. J. Pharm. 2008, 355, 19–30. [Google Scholar] [CrossRef]
  134. Szumała, P.; Macierzanka, A. Topical Delivery of Pharmaceutical and Cosmetic Macromolecules Using Microemulsion Systems. Int. J. Pharm. 2022, 615, 121488. [Google Scholar] [CrossRef]
  135. Palmer, B.C.; DeLouise, L.A. Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting. Molecules 2016, 21, 1719. [Google Scholar] [CrossRef] [PubMed]
  136. Flanagan, J.; Singh, H. Microemulsions: A Potential Delivery System for Bioactives in Food. Crit. Rev. Food Sci. Nutr. 2006, 46, 221–237. [Google Scholar] [CrossRef] [PubMed]
  137. Aloisio, C.; Longhi, M.R.; De Oliveira, A.G. Development and Characterization of a Biocompatible Soybean Oil-Based Microemulsion for the Delivery of Poorly Water-Soluble Drugs. J. Pharm. Sci. 2015, 104, 3535–3543. [Google Scholar] [CrossRef]
  138. Sintov, A.C. Transdermal Delivery of Curcumin via Microemulsion. Int. J. Pharm. 2015, 481, 97–103. [Google Scholar] [CrossRef]
  139. Wan, T.; Xu, T.; Pan, J.; Qin, M.; Pan, W.; Zhang, G.; Wu, Z.; Wu, C.; Xu, Y. Microemulsion Based Gel for Topical Dermal Delivery of Pseudolaric Acid B: In Vitro and in Vivo Evaluation. Int. J. Pharm. 2015, 493, 111–120. [Google Scholar] [CrossRef] [PubMed]
  140. Cavalcanti, A.L.M.; Reis, M.Y.F.A.; Silva, G.C.L.; Ramalho, Í.M.M.; Guimarães, G.P.; Silva, J.A.; Saraiva, K.L.A.; Damasceno, B.P.G.L. Microemulsion for Topical Application of Pentoxifylline: In Vitro Release and in Vivo Evaluation. Int. J. Pharm. 2016, 506, 351–360. [Google Scholar] [CrossRef] [PubMed]
  141. Patel, H.K.; Barot, B.S.; Parejiya, P.B.; Shelat, P.K.; Shukla, A. Topical Delivery of Clobetasol Propionate Loaded Microemulsion Based Gel for Effective Treatment of Vitiligo: Ex Vivo Permeation and Skin Irritation Studies. Colloids Surf. B Biointerfaces 2013, 102, 86–94. [Google Scholar] [CrossRef]
  142. Hathout, R.M.; Nasr, M. Transdermal Delivery of Betahistine Hydrochloride Using Microemulsions: Physical Characterization, Biophysical Assessment, Confocal Imaging and Permeation Studies. Colloids Surf. B Biointerfaces 2013, 110, 254–260. [Google Scholar] [CrossRef]
  143. Zhao, L.; Wang, Y.; Zhai, Y.; Wang, Z.; Liu, J.; Zhai, G. Ropivacaine Loaded Microemulsion and Microemulsion-Based Gel for Transdermal Delivery: Preparation, Optimization, and Evaluation. Int. J. Pharm. 2014, 477, 47–56. [Google Scholar] [CrossRef]
  144. Zhu, W.; Yu, A.; Wang, W.; Dong, R.; Wu, J.; Zhai, G. Formulation Design of Microemulsion for Dermal Delivery of Penciclovir. Int. J. Pharm. 2008, 360, 184–190. [Google Scholar] [CrossRef] [PubMed]
  145. Carvalho, A.L.M.; da Silva, J.A.; Lira, A.A.M.; Conceição, T.M.F.; de Souza Nunes, R.; de Albuquerque Junior, R.L.C.; Sarmento, V.H.V.; Leal, L.B.; de Santana, D.P. Evaluation of Microemulsion and Lamellar Liquid Crystalline Systems for Transdermal Zidovudine Delivery. J. Pharm. Sci. 2016, 105, 2188–2193. [Google Scholar] [CrossRef]
  146. Zhang, J.; Wang, Z.; Liao, M.; Li, S.; Feng, Q.; Cao, X. Curcumin-Laden Amphiphilic Chitosan Microemulsion with Enhanced Transdermal Delivery, Skin Compatibility and Anti-Arthritic Activity. J. Drug Deliv. Sci. Technol. 2022, 78, 103997. [Google Scholar] [CrossRef]
  147. Al Saqr, A.; Annaji, M.; Poudel, I.; Aldawsari, M.F.; Alrbyawi, H.; Mita, N.; Dhanasekaran, M.; Boddu, S.H.S.; Neupane, R.; Tiwari, A.K.; et al. Topical Delivery of Diacetyl Boldine in a Microemulsion Formulation for Chemoprotection against Melanoma. Pharmaceutics 2023, 15, 901. [Google Scholar] [CrossRef] [PubMed]
  148. Wang, Y.; Wang, X.; Wang, X.; Song, Y.; Wang, X.; Hao, J. Design and Development of Lidocaine Microemulsions for Transdermal Delivery. AAPS PharmSciTech 2019, 20, 63. [Google Scholar] [CrossRef] [PubMed]
  149. Virani, A.; Puri, V.; Mohd, H.; Michniak-Kohn, B. Effect of Penetration Enhancers on Transdermal Delivery of Oxcarbazepine, an Antiepileptic Drug Using Microemulsions. Pharmaceutics 2023, 15, 183. [Google Scholar] [CrossRef]
  150. Çağlar, E.Ş.; Okur, M.E.; Aksu, B.; Üstündağ Okur, N. Transdermal Delivery of Acemetacin Loaded Microemulsions: Preparation, Characterization, in Vitro—Ex Vivo Evaluation and in Vivo Analgesic and Anti-Inflammatory Efficacy. J. Dispers. Sci. Technol. 2023, 1–11. [Google Scholar] [CrossRef]
  151. Panoutsopoulou, E.; Zbytovská, J.; Vávrová, K.; Paraskevopoulos, G. Phospholipid-Based Microemulsions for Cutaneous Imiquimod Delivery. Pharmaceuticals 2022, 15, 515. [Google Scholar] [CrossRef] [PubMed]
  152. Üstündağ Okur, N.; Onay, E.; Kadioğlu Yaman, B.; Sίpahί, H. New Topical Microemulsions of Etofenamate as Sufficient Management of Osteoarthritis. Braz. J. Pharm. Sci. 2022, 58, e20123. [Google Scholar] [CrossRef]
  153. Mehanna, M.M.; Abla, K.K.; Domiati, S.; Elmaradny, H. Superiority of Microemulsion-Based Hydrogel for Non-Steroidal Anti-Inflammatory Drug Transdermal Delivery: A Comparative Safety and Anti-Nociceptive Efficacy Study. Int. J. Pharm. 2022, 622, 121830. [Google Scholar] [CrossRef]
  154. Subongkot, T.; Charernsriwilaiwat, N.; Chanasongkram, R.; Rittem, K.; Ngawhirunpat, T.; Opanasopit, P. Development and Skin Penetration Pathway Evaluation Using Confocal Laser Scanning Microscopy of Microemulsions for Dermal Delivery Enhancement of Finasteride. Pharmaceutics 2022, 14, 2784. [Google Scholar] [CrossRef]
  155. Duangjit, S.; Rattanachithawat, N.; Opanasopit, P.; Ngawhirunpat, T. Development and Optimization of Finasteride-Cinnamon Oil-Loaded Ethanol-Free Microemulsions for Transdermal Delivery. J. Drug Deliv. Sci. Technol. 2022, 69, 103107. [Google Scholar] [CrossRef]
  156. Sae Yoon, A.; Sakdiset, P. Development of Microemulsions Containing Glochidion Wallichianum Leaf Extract and Potential for Transdermal and Topical Skin Delivery of Gallic Acid. Sci. Pharm. 2020, 88, 53. [Google Scholar] [CrossRef]
  157. Wang, C.; Zhu, J.; Zhang, D.; Yang, Y.; Zheng, L.; Qu, Y.; Yang, X.; Cui, X. Ionic Liquid—Microemulsions Assisting in the Transdermal Delivery of Dencichine: Preparation, in-Vitro and in-Vivo Evaluations, and Investigation of the Permeation Mechanism. Int. J. Pharm. 2018, 535, 120–131. [Google Scholar] [CrossRef]
  158. Zainuddin, N.; Ahmad, I.; Zulfakar, M.H.; Kargarzadeh, H.; Ramli, S. Cetyltrimethylammonium Bromide-Nanocrystalline Cellulose (CTAB-NCC) Based Microemulsions for Enhancement of Topical Delivery of Curcumin. Carbohydr. Polym. 2021, 254, 117401. [Google Scholar] [CrossRef]
  159. Mojeiko, G.; de Brito, M.; Salata, G.C.; Lopes, L.B. Combination of Microneedles and Microemulsions to Increase Celecoxib Topical Delivery for Potential Application in Chemoprevention of Breast Cancer. Int. J. Pharm. 2019, 560, 365–376. [Google Scholar] [CrossRef] [PubMed]
  160. Souza de Araujo, G.R.; Mendonça da Cruz Macieira, G.; Xavier de Oliveira, D.; Santos Matos, S.; Nery dos Santos, Q.; Otubo, L.; Antunes de Souza Araújo, A.; Cavalcante Duarte, M.; Moreira Lira, A.A.; de Souza Nunes, R.; et al. Microemulsions Formed by PPG-5-CETETH-20 at Low Concentrations for Transdermal Delivery of Nifedipine: Structural and in Vitro Study. Colloids Surf. B Biointerfaces 2022, 214, 112474. [Google Scholar] [CrossRef] [PubMed]
  161. Subongkot, T.; Sirirak, T. Development and Skin Penetration Pathway Evaluation of Microemulsions for Enhancing the Dermal Delivery of Celecoxib. Colloids Surf. B Biointerfaces 2020, 193, 111103. [Google Scholar] [CrossRef] [PubMed]
  162. Ryu, K.-A.; Park, P.J.; Kim, S.-B.; Bin, B.-H.; Jang, D.-J.; Kim, S.T. Topical Delivery of Coenzyme Q10-Loaded Microemulsion for Skin Regeneration. Pharmaceutics 2020, 12, 332. [Google Scholar] [CrossRef]
  163. Pires, P.C.; Paiva-Santos, A.C.; Veiga, F. Nano and Microemulsions for the Treatment of Depressive and Anxiety Disorders: An Efficient Approach to Improve Solubility, Brain Bioavailability and Therapeutic Efficacy. Pharmaceutics 2022, 14, 2825. [Google Scholar] [CrossRef]
  164. Paul, B.K.; Moulik, S.P. Uses and Applications of Microemulsions. Curr. Sci. 2001, 80, 990–1001. [Google Scholar]
  165. Viswanathan, P.; Muralidaran, Y.; Ragavan, G. Chapter 7—Challenges in Oral Drug Delivery: A Nano-Based Strategy to Overcome. In Nanostructures for Oral Medicine; Andronescu, E., Grumezescu, A.M., Eds.; Micro and Nano Technologies; Elsevier: Amsterdam, The Netherlands, 2017; pp. 173–201. ISBN 978-0-323-47720-8. [Google Scholar]
  166. Silva, A.E.; Barratt, G.; Chéron, M.; Egito, E.S.T. Development of Oil-in-Water Microemulsions for the Oral Delivery of Amphotericin B. Int. J. Pharm. 2013, 454, 641–648. [Google Scholar] [CrossRef]
  167. Shukla, T.; Upmanyu, N.; Agrawal, M.; Saraf, S.; Saraf, S.; Alexander, A. Biomedical Applications of Microemulsion through Dermal and Transdermal Route. Biomed. Pharmacother. 2018, 108, 1477–1494. [Google Scholar] [CrossRef]
  168. Lopes, L.B. Overcoming the Cutaneous Barrier with Microemulsions. Pharmaceutics 2014, 6, 52–77. [Google Scholar] [CrossRef] [PubMed]
  169. Ling, Y.; Yu, M.; Guo, F.; Li, N.; Tan, F. Synergistic Effect of Mixed Cosurfactants on Transdermal Delivery of Indomethacin from O/W Microemulsion. Chem. Res. Chin. Univ. 2013, 29, 338–343. [Google Scholar] [CrossRef]
  170. Patel, K.; Patel, R.; Patel, M. Formulation and Characterization of Microemulsion Based Gel of Antifungal Drug. PharmaTutor J. 2018, 2, 79–89. [Google Scholar]
  171. Illner, M.; Kozachynskyi, V.; Esche, E.; Repke, J.-U. Fast-Track Realization of Reactive Microemulsion Systems—Systematic System Analysis and Tailored Application of PSE Methods. Chem. Eng. Sci. 2022, 252, 117290. [Google Scholar] [CrossRef]
  172. Silva, C.A.; Aurora-Prado, M.S.; Altria, K.D.; Tavares, M.F.M. Separation of Steroids and the Determination of Estradiol Content in Transdermic Patches by Microemulsion Electrokinetic Chromatography. Chromatographia 2011, 73, 373–378. [Google Scholar] [CrossRef]
  173. Duan, Y.; Dhar, A.; Patel, C.; Khimani, M.; Neogi, S.; Sharma, P.; Kumar, N.S.; Vekariya, R.L. A Brief Review on Solid Lipid Nanoparticles: Part and Parcel of Contemporary Drug Delivery Systems. RSC Adv. 2020, 10, 26777–26791. [Google Scholar] [CrossRef] [PubMed]
  174. Sabale, V.; Vora, S. Formulation and Evaluation of Microemulsion-Based Hydrogel for Topical Delivery. Int. J. Pharm. Investig. 2012, 2, 140–149. [Google Scholar] [CrossRef] [PubMed]
  175. Narang, A.S.; Delmarre, D.; Gao, D. Stable Drug Encapsulation in Micelles and Microemulsions. Int. J. Pharm. 2007, 345, 9–25. [Google Scholar] [CrossRef]
  176. Ruan, J.; Liu, J.; Zhu, D.; Gong, T.; Yang, F.; Hao, X.; Zhang, Z. Preparation and Evaluation of Self-Nanoemulsified Drug Delivery Systems (SNEDDSs) of Matrine Based on Drug–Phospholipid Complex Technique. Int. J. Pharm. 2010, 386, 282–290. [Google Scholar] [CrossRef] [PubMed]
Nanomaterials 13 01688 g001 550
Figure 1. Different configurations of MEs: water-in-oil, bicontinuous, and oil-in-water.
Figure 1. Different configurations of MEs: water-in-oil, bicontinuous, and oil-in-water.
Nanomaterials 13 01688 g001
Nanomaterials 13 01688 g002 550
Figure 2. An overview of surfactants: Their structures and classifications. Reproduced with permission [67]. Copyright 2023, Elsevier.
Figure 2. An overview of surfactants: Their structures and classifications. Reproduced with permission [67]. Copyright 2023, Elsevier.
Nanomaterials 13 01688 g002
Nanomaterials 13 01688 g003 550
Figure 3. Commonly used co-surfactants with examples employed for formulating microemulsions.
Figure 3. Commonly used co-surfactants with examples employed for formulating microemulsions.
Nanomaterials 13 01688 g003
Nanomaterials 13 01688 g004 550
Figure 4. Illustration of the phase diagram indicating the microemulsion formation regions.
Figure 4. Illustration of the phase diagram indicating the microemulsion formation regions.
Nanomaterials 13 01688 g004
Nanomaterials 13 01688 g005 550
Figure 5. Versatile applications of microemulsions in drug and gene delivery. Reproduced with permission from [11]. Copyright 2023, Elsevier.
Figure 5. Versatile applications of microemulsions in drug and gene delivery. Reproduced with permission from [11]. Copyright 2023, Elsevier.
Nanomaterials 13 01688 g005
Nanomaterials 13 01688 g006 550
Figure 6. Representation of different routes of penetration of microemulsions through the skin: (1) by the appendageal route, (2) by the intracellular route, or (3) by the intercellular route. The appendageal route involves particles entering sweat glands, hair follicles, or skin furrows for either penetration into the dermis or retention for increased release of the drug. The intracellular route comprises a direct path via cell membranes containing multiple epidermal layers. The intercellular route comprises a more tortuous path between epidermal cells. The path taken by particles depends on dimensions, charge, shape, and material. Reproduced with permission from [135]. Copyright 2023, Multidisciplinary Digital Publishing Institute.
Figure 6. Representation of different routes of penetration of microemulsions through the skin: (1) by the appendageal route, (2) by the intracellular route, or (3) by the intercellular route. The appendageal route involves particles entering sweat glands, hair follicles, or skin furrows for either penetration into the dermis or retention for increased release of the drug. The intracellular route comprises a direct path via cell membranes containing multiple epidermal layers. The intercellular route comprises a more tortuous path between epidermal cells. The path taken by particles depends on dimensions, charge, shape, and material. Reproduced with permission from [135]. Copyright 2023, Multidisciplinary Digital Publishing Institute.
Nanomaterials 13 01688 g006
Table
Table 1. Some examples of microemulsions for skin delivery.
Table 1. Some examples of microemulsions for skin delivery.
APIME TypeAqueous PhaseSurfactant/Co-Surfactant
(S and Co-S)		Oil PhaseApplicationRef.
Sulfamerazine
Indomethacin		O/WWater
Or
PBS		S: Phosphatidylcholine; sodium oleate; Eumulgin® HRE40;
Co-S: N/A		Soybean oilAntimicrobial[137]
CurcuminW/OWaterS: Labrasol®, glyceryl oleate
Co-S: propylene carbonate		Isopropyl palmitateAnti-inflammatory[138]
Pseudolaric acid BO/WWaterS: Cremphor EL®
Co-S: Transcutol P®		Isopropyl MyristateFungicidal[139]
PentoxifyllineW/OWaterS: Tween 80; Brij 52
Co-S: N/A		Caprylic/Capric TriglyceridesInflammatory dermatological diseases[140]
ClobetasolO/WWaterS: Cremophor EL
Co-S: isopropyl alcohol		Isopropyl myristateVitiligo[141]
Betahistine hydrochlorideW/OWaterS: Capryol 90®
Co-S: Transcutol®		Ethyl oleateRegulation of feeding behavior and weight control[142]
RopivacaineO/WWaterS: Labrasol®
Co-S: Ethanol		Capryol® 90Anesthesia[143]
PenciclovirO/WWaterS: Cremorphor EL
Co-S: Ethanol		Oleic acidAntiviral[144]
ZidovudineO/WWaterS: Labrosol
Co-S: Oleic Plurol		Isopropyl myristateAntiretroviral therapy[145]
CurcuminO/WWaterS: Chitosan
Co-S: Ethanol		Oleic acidRheumatoid arthritis anti-inflammatory[146]
Diacetyl boldine (DAB)W/OWaterS: Solutol® HS 15; ethanol and Lecithin
Co-S: Propylene glycol (co-surfactant)		Medium-chain triglycerideMelanoma skin cancer treatment[147]
LidocaineO/WWaterS: Polyoxyl 15 hydroxystearate
Co-S: Ethanol		Ethyl oleateAnesthetic therapy[148]
OxcarbazepineW/OWater/buffer solutionS: Tween 80; Labrasol
Co-S: PEG 400; Transcutol® P		Oleic acid and cineoleAntiepileptic drug for epilepsy[149]
AcemetacinO/WWaterS: Transcutol HP; Labrafil M1944 CS
Co-S: Ethanol		Isopropyl myristateanalgesic and anti-inflammatory[150]
ImiquimodO/WWaterS: Phospholipids (PL)
Co-S: Ethanol		Oleic acidpsoriasis anti-inflammatory[151]
EtofenamateO/WWaterS: Cremophor EL or Span 80 with Tween 20
Co-S: Transcutol HP; Ethanol		Oleic acidOsteoarthritis treatment[152]
DiclofenacW/OWaterS: Labrasol®
Co-S: Labrafil®		LimoneneNon-steroidal anti-inflammatory drugs[153]
FinasterideW/OWaterS: Poloxamer 124
Co-S: Transcutol P		Oleic acidAndrogenetic alopecia treatment[154]
Finasteride-cinnamonW/OReverse osmosis waterS: Tween® 20
Co-S: Propylene glycol		Cinnamon oilAndrogenetic alopecia treatment[155]
Gallic acidW/OWaterS: Labrasol®/HCO-40® or Tween 80/Span 80
Co-S: Transcutol® or Ethanol		Isopropyl myristateAntioxidant activity[156]
DencichineO/WWater/[HOEIM]ClS: Tween 80/[BMIM]C12SO3
Co-S: Propylene glycol		Isopropyl myristateHemostatic activity[157]
CurcuminO/WWaterS: Cremophor® RH 40
Co-S: Transcutol P		Oleic acid/limoneneAnticancer/antioxidant…[158]
CelecoxibW/OWaterS: Phosphatidylcholine; decylglucoside
Co-S: Ethanol; propylene glycol		MonocaprylinBreast cancer treatment[159]
NifedipineO/WPBSS: PPG-5-Ceteth-20
Co-S: N/A		Oleic acidAnti-hypertensive Activity[160]
CelecoxibW/OWaterS: PEG-6 Caprylic/Capric Glycerides
Co-S: PEG-35 castor oil or PEG-7 glyceryl cocoate		Isopropyl myristateAnti-inflammatory drugs[161]
Coenzyme Q10O/WWaterS: Cremophor EL®
Co-S: Transcutol® HP		Isopropyl myristateAntioxidant activity[162]
API: active pharmaceutical ingredient; ME: microemulsion.
Table
Table 2. Advantages and limitations of microemulsions for drug delivery.
Table 2. Advantages and limitations of microemulsions for drug delivery.
Advantages of MicroemulsionsLimitations of Microemulsions
-
Enhanced drug solubilization [24];
-
Improved drug stability [93];
-
Increased drug permeability [24];
-
Sustained drug release [174];
-
Versatile drug delivery [21];
-
Biocompatibility [26]
-
Long shelf life [82]
-
Ease of formulation [93];
-
Targeted drug delivery [19];
-
Reduced toxicity [131];
-
Versatility (oral, parenteral, and topical) [11];
-
Stable thermodynamically after preparation [25,75]
-
Toxicity of high surfactant and co-surfactant concentrations [57];
-
Limited drug loading capacity [175];
-
Risk of leakage, which can lead to drug loss and reduced efficacy [176];
-
Regulatory issues (safety and efficacy testing before approval for human use) [24]
-
Sensitivity to environmental factors during the preparation steps (Temperature, pH, and salt concentration) [133]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Ait-Touchente, Z.; Zine, N.; Jaffrezic-Renault, N.; Errachid, A.; Lebaz, N.; Fessi, H.; Elaissari, A. Exploring the Versatility of Microemulsions in Cutaneous Drug Delivery: Opportunities and Challenges. Nanomaterials 2023, 13, 1688. https://doi.org/10.3390/nano13101688

AMA Style

Ait-Touchente Z, Zine N, Jaffrezic-Renault N, Errachid A, Lebaz N, Fessi H, Elaissari A. Exploring the Versatility of Microemulsions in Cutaneous Drug Delivery: Opportunities and Challenges. Nanomaterials. 2023; 13(10):1688. https://doi.org/10.3390/nano13101688

Chicago/Turabian Style

Ait-Touchente, Zouhair, Nadia Zine, Nicole Jaffrezic-Renault, Abdelhamid Errachid, Noureddine Lebaz, Hatem Fessi, and Abdelhamid Elaissari. 2023. "Exploring the Versatility of Microemulsions in Cutaneous Drug Delivery: Opportunities and Challenges" Nanomaterials 13, no. 10: 1688. https://doi.org/10.3390/nano13101688

APA Style

Ait-Touchente, Z., Zine, N., Jaffrezic-Renault, N., Errachid, A., Lebaz, N., Fessi, H., & Elaissari, A. (2023). Exploring the Versatility of Microemulsions in Cutaneous Drug Delivery: Opportunities and Challenges. Nanomaterials, 13(10), 1688. https://doi.org/10.3390/nano13101688

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop