B. Pharm, Laddhad College of Pharmacy Yealgao, Buldhana, Maharashtra, India
Transdermal drug delivery systems (TDDS) provide an effective route for administering therapeutic agents through the skin into systemic circulation, offering advantages such as improved patient compliance, avoidance of first pass metabolism, and sustained drug release. However, the major challenge limiting their efficiency is the skin’s outermost layer, the stratum corneum, which acts as a strong barrier to drug permeation. Conventional formulations often fail to achieve sufficient bioavailability for many drugs, particularly hydrophilic and large molecular weight compounds. In recent years, vesicular drug delivery systems have gained prominence as advanced carriers for enhancing skin permeation. Among these, ethosomes have emerged as a promising nanocarrier system due to their soft, flexible vesicular structure composed of phospholipids, ethanol, and water. Ethosomes are distinguished by their high ethanol content, which imparts malleability to vesicles and disrupts lipid packing in the stratum corneum, leading to increased drug permeation and deposition within deeper skin layers.The unique composition and mechanism of ethosomes allow for the efficient delivery of both hydrophilic and lipophilic drugs, improving therapeutic efficacy while minimizing side effects. This review critically discusses the design aspects, formulation parameters, and mechanisms underlying ethosomal skin permeation. It also explores the broad therapeutic applications of ethosomes, emphasizing their superiority over conventional transdermal systems. Overall, ethosomes represent a breakthrough in nanocarrier-mediated transdermal delivery, paving the way for more effective, patient-friendly therapeutic approaches.
Transdermal drug delivery systems (TDDS) have evolved as a novel and non-invasive route for systemic drug administration, offering several benefits over traditional oral or parenteral drug delivery. These systems enable the controlled release of drugs through the skin, ensuring steady plasma concentrations and improved patient adherence to treatment regimens (1). TDDS bypass the hepatic first pass effect and minimize gastrointestinal degradation, making them ideal for drugs with poor oral bioavailability or short half-lives (2). Despite these advantages, conventional transdermal carriers such as ointments, gels, and patches face major limitations due to the highly selective permeability of the stratum corneum. This outermost skin layer, rich in keratinized cells and lipids, restricts the penetration of most therapeutic agents, especially those with high molecular weight or hydrophilic characteristics (3). To address these limitations, researchers have explored various enhancement techniques, including chemical penetration enhancers, iontophoresis, and the use of vesicular systems. Vesicular drug delivery systems such as liposomes, niosomes, and transfersomes have emerged as promising platforms for improving drug solubility, stability, and penetration through the skin (4). These carriers can encapsulate both hydrophilic and lipophilic drugs and modulate release kinetics. Among them, ethosomes have attracted considerable interest for their exceptional skin permeability and stability. Ethosomes are soft, malleable lipid vesicles composed primarily of phospholipids, ethanol, and water (5). The incorporation of ethanol confers elasticity and fluidity to the vesicles while simultaneously enhancing skin permeability by disrupting the lipid organization within the stratum corneum (6). This unique combination allows ethosomes to traverse the skin barrier efficiently and deposit drugs into deeper layers, achieving both localized and systemic effects. The significance of ethosomes lies in their ability to overcome the shortcomings of conventional transdermal carriers and deliver a broad spectrum of drugs, including peptides, hormones, antivirals, and anti-inflammatory agents (7). Their non-invasive nature, high entrapment efficiency, and controlled drug release profile have positioned them as a superior alternative for transdermal drug delivery. The objective of this review is to provide a comprehensive discussion on ethosomes as advanced transdermal carriers. It explores their structural design, formulation parameters, mechanisms of skin permeation, and therapeutic applications. Additionally, it critically evaluates their clinical relevance and future potential in enhancing the efficacy and safety of transdermal drug delivery systems.
Figure 1. Ethosomes as advanced transdermal drug delivery systems.
The figure illustrates the limitations of conventional transdermal formulations due to the stratum corneum barrier and highlights how ethosomes ethanol-rich, phospholipid vesicles enhance skin permeation. The presence of ethanol improves vesicular flexibility and disrupts skin lipid organization, enabling deeper drug penetration, controlled release, and improved systemic and localized therapeutic outcomes.
2. Ethosomes: Classification
Ethosomes are flexible lipid vesicular systems characterized by a high concentration of ethanol, which enhances drug penetration through the skin. The concept of ethosomes was introduced in the mid-1990s by Touitou and colleagues as an innovative approach to improve transdermal drug delivery by integrating ethanol into phospholipid vesicles (8). The inclusion of ethanol not only imparts flexibility to the vesicles but also increases the permeability of the stratum corneum by disrupting its lipid bilayer, thereby allowing deeper drug diffusion (9). Since their inception, ethosomes have gained significant attention for their potential to deliver a wide range of therapeutic agents across the skin in a non-invasive manner (10). The classification of ethosomes has evolved based on compositional modifications aimed at improving drug loading and penetration. Classical ethosomes consist primarily of phospholipids, ethanol, and water. Binary ethosomes incorporate an additional solvent such as propylene glycol or isopropyl alcohol to further enhance solubility and permeability (11). Transethosomes represent an advanced version that combines ethosomal components with edge activators or surfactants to increase vesicular elasticity and skin penetration (12). These transethosomes integrate the properties of ethosomes and transfersomes, resulting in superior deformability and deeper penetration into skin layers (13). When compared to other vesicular systems such as liposomes, niosomes, and transfersomes, ethosomes exhibit higher ethanol content, which improves their stability and enhances the penetration of both hydrophilic and lipophilic drugs through the skin barrier (14).
3. Composition and Design of Ethosomes
The fundamental composition of ethosomes includes phospholipids, ethanol, water, and sometimes co-solvents and stabilizers. Phospholipids, such as phosphatidylcholine, act as the primary structural components forming the bilayer vesicular structure that encapsulates the drug (15). Ethanol plays a dual role: it acts as a penetration enhancer by fluidizing the lipid bilayers of both the vesicle and the stratum corneum, and it contributes to the vesicle’s softness and deformability (16). The concentration of ethanol typically ranges from 20% to 45%, as this proportion provides optimal flexibility without compromising vesicle integrity (17). Water serves as the dispersion medium, while co-solvents like propylene glycol may be incorporated to improve solubility and stability. Additional agents, such as cholesterol, can be used as stabilizers to enhance vesicle rigidity and prevent leakage (18). In terms of design considerations, the physicochemical properties of ethosomes such as vesicle size, surface charge, and entrapment efficiency play a crucial role in determining their stability and therapeutic performance. The vesicle size generally ranges between 100 and 400 nm, influencing both the rate and depth of skin penetration (19). A negatively charged surface due to ethanol ensures repulsion among vesicles, minimizing aggregation and improving stability (20). Entrapment efficiency depends on the drug’s lipophilicity and the ethanol concentration, with higher ethanol levels usually leading to greater entrapment of lipophilic drugs (21). Stability studies have demonstrated that ethosomes maintain their structural integrity over extended periods when stored at low temperatures, making them suitable for long-term formulations (22). Overall, the integration of ethanol into lipid vesicles represents a significant advancement over traditional liposomes and niosomes, allowing ethosomes to deliver a wide range of therapeutic agents effectively across the skin barrier. Their tunable composition and versatile design parameters make them promising candidates for future transdermal and dermal applications.
Figure 2. Schematic representation of the composition and key physicochemical properties of ethosomes.
The figure illustrates the structural organization of ethosomal vesicles composed of phospholipids, ethanol (20–45%), water, and optional co-solvents and stabilizers, along with their influence on vesicle size, surface charge, drug entrapment efficiency, skin penetration, and formulation stability for transdermal drug delivery.
4. Mechanism of Skin Permeation
The mechanism by which ethosomes enhance transdermal drug delivery is primarily attributed to their interaction with the complex structure of the skin barrier, particularly the stratum corneum. The stratum corneum, the outermost layer of the epidermis, consists of corneocytes embedded within a dense lipid matrix composed mainly of ceramides, cholesterol, and free fatty acids. This lipid organization serves as the principal barrier to the penetration of most drugs, allowing only small and lipophilic molecules to pass through passively (23). The dense lipid packing and low hydration level of this layer make it highly resistant to drug permeation, thereby necessitating specialized carrier systems such as ethosomes that can transiently disrupt or bypass this barrier (24). Ethanol, a key component of ethosomal systems, plays a dual role in enhancing skin permeation. Firstly, ethanol acts as a penetration enhancer by fluidizing the intercellular lipids of the stratum corneum, thereby reducing their density and increasing the permeability of the skin (25). It disrupts the hydrogen bonding among lipid molecules, which leads to an increased lipid disorder and a decrease in transition temperature, allowing easier diffusion of drug molecules into deeper layers (26). Secondly, ethanol confers flexibility to the ethosomal vesicles themselves, reducing their size and increasing their deformability, which facilitates their passage through narrow intercellular spaces within the skin (27). This synergistic effect of ethanol on both the skin lipids and the ethosomal vesicles forms the basis of their superior transdermal delivery potential. Another critical factor in ethosomal permeation is vesicle deformability and fusion with skin lipids. The ethosomal vesicles possess high elasticity due to the combined effect of phospholipids and ethanol, allowing them to deform and squeeze through the tight junctions between corneocytes without rupturing (28). Upon reaching the deeper skin layers, these vesicles can fuse with the lipid bilayers of the skin, releasing their encapsulated drugs directly into the intracellular matrix (29). This fusion mechanism enhances the drug concentration gradient across the skin, which further drives the diffusion process. Ethosomes utilize multiple pathways for skin penetration. They can follow intercellular routes, where they traverse between corneocytes through lipid domains, or transcellular routes, where they penetrate directly through the corneocyte membranes (30). Studies using confocal laser scanning microscopy and fluorescence imaging have demonstrated that ethosomes are capable of penetrating both through and between skin cells, indicating the coexistence of these pathways (9). Moreover, ethosomal vesicles have shown the ability to deposit drugs in both the epidermal and dermal layers, ensuring sustained release and prolonged therapeutic action. Overall, the unique composition of ethosomes, characterized by their ethanol-induced deformability and lipid affinity, enables them to overcome the formidable barrier properties of the stratum corneum. Their combined mechanism of lipid fluidization, vesicular flexibility, and multiple permeation pathways makes ethosomes one of the most efficient vesicular carriers for transdermal drug delivery (31).
Figure 3. Mechanism of ethosomes in transdermal drug delivery.
Schematic representation illustrating how ethosomal vesicles enhance drug permeation across the skin. Ethanol present in ethosomes fluidizes and disrupts the stratum corneum lipid matrix, increasing skin permeability while simultaneously imparting flexibility and deformability to the vesicles. The highly elastic ethosomes penetrate the skin via both intercellular and transcellular pathways, followed by fusion with skin lipids in deeper layers, leading to efficient drug release and deposition in the epidermis and dermis, thereby enabling sustained and enhanced transdermal drug delivery.
5. Methods of Ethosome Preparation
The preparation of ethosomes involves the entrapment of both hydrophilic and lipophilic drugs within phospholipid vesicles containing a high concentration of ethanol and water. Among the different techniques, the cold method and hot method are most commonly used. The cold method is widely preferred due to its simplicity and ability to preserve the stability of thermolabile drugs. In this technique, phospholipids, ethanol, and drug are dissolved together under continuous stirring at room temperature, followed by the slow addition of distilled water under constant mixing until vesicles form (32). This method produces nanosized vesicles with uniform distribution and high entrapment efficiency. In contrast, the hot method involves dissolving phospholipids in water heated to around 40°C while ethanol containing the drug is separately heated to the same temperature before mixing the two phases under constant stirring (33). This method facilitates faster vesicle formation but may not be suitable for thermolabile compounds. The thin film hydration technique represents another approach where phospholipids and drug are dissolved in organic solvents and evaporated under reduced pressure to form a thin lipid film on the flask wall. The film is then hydrated with an ethanol-water mixture at a specific temperature to form ethosomal vesicles (34). This method allows for the control of vesicle size and uniformity by adjusting hydration parameters. Advanced techniques, including high-pressure homogenization, ultrasonication, and microfluidic-assisted preparation, have recently been explored to improve vesicle uniformity and scalability. These methods yield ethosomes with smaller particle sizes, enhanced drug entrapment, and improved stability suitable for industrial applications (35). Each preparation method offers unique advantages and limitations. The cold method is energy-efficient and preserves sensitive drugs but requires longer processing times. The hot method allows rapid vesicle formation but may compromise drug stability. The thin-film hydration method provides better size control but involves complex equipment, while advanced methods offer scalability at a higher cost (36).
6. Formulation Parameters Affecting Ethosomal Performance
The efficiency and stability of ethosomal formulations are strongly influenced by several formulation parameters, primarily the concentrations of phospholipids and ethanol, the physicochemical nature of the drug, and environmental conditions such as pH, temperature, and hydration medium. An increase in phospholipid concentration generally enhances vesicle stability and entrapment efficiency by providing a stronger bilayer structure; however, excessive phospholipid content can lead to vesicle aggregation and decreased skin permeability. Conversely, a lower lipid content results in smaller vesicles but with reduced entrapment capacity. The ethanol concentration plays a pivotal role in ethosome performance. Ethanol imparts fluidity to vesicle membranes, reduces vesicle size, and enhances penetration through the stratum corneum by disrupting intercellular lipids (37). However, excessively high ethanol levels can lead to vesicle leakage or instability due to the dissolution of phospholipid bilayers. An optimized ethanol concentration between 20–45% is typically ideal for achieving maximum skin permeation and stability (38). The physicochemical properties of the drug, including lipophilicity, molecular weight, and ionization state, significantly influence its entrapment efficiency and release profile. Lipophilic drugs exhibit higher incorporation into phospholipid bilayers, while hydrophilic drugs are usually confined within the aqueous core of vesicles (39). Environmental parameters such as pH, temperature, and hydration medium also affect ethosomal characteristics. The pH of the hydration medium should be compatible with both the drug and phospholipid stability, as extreme pH conditions can cause vesicle rupture. Temperature during hydration influences vesicle formation dynamics, with higher temperatures promoting faster formation but risking component degradation. Similarly, the nature of the hydration medium affects drug solubility and the vesicle’s physical properties (40).
7. Characterization of Ethosomal Formulations
Characterization of ethosomal formulations is a crucial step in determining their physicochemical properties, stability, and drug delivery performance. Vesicle size and size distribution play a significant role in defining the penetration efficiency of ethosomes through the stratum corneum. Smaller vesicles exhibit higher deformability and improved skin permeation, while size distribution ensures uniformity in drug delivery. Ethosomes typically range from 100 to 400 nanometers in size depending on the formulation parameters such as lipid concentration and ethanol content (41). Zeta potential analysis provides insight into the surface charge and stability of ethosomal vesicles. A high zeta potential value, either positive or negative, indicates electrostatic repulsion between vesicles, preventing aggregation and enhancing storage stability. The ethanol content and phospholipid composition greatly influence zeta potential, with values typically ranging from -30 to -50 mV (42). Morphological characterization using techniques such as scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM) reveals the spherical, smooth, and flexible nature of ethosomal vesicles. SEM and TEM images confirm the uniformity and lamellarity of ethosomes, while AFM provides topographical details at nanoscale resolution (43). Drug entrapment efficiency (EE) reflects the capability of ethosomes to retain active pharmaceutical ingredients within the lipid bilayer or aqueous core. The efficiency largely depends on drug lipophilicity, ethanol concentration, and preparation method, often ranging between 70% and 95% (44). In-vitro drug release studies demonstrate the sustained and controlled release behavior of ethosomal formulations. The ethanol content in ethosomes facilitates enhanced solubility of the drug and contributes to a biphasic release pattern with an initial burst followed by a steady release phase (45). Ex-vivo skin permeation and deposition studies are essential to assess the extent and rate of drug transport across biological membranes. Using excised animal or human skin, ethosomal formulations show significantly higher drug deposition within skin layers compared to conventional liposomes due to the ethanol-induced fluidization of lipids (46). Stability studies evaluate the long-term integrity of ethosomal vesicles under varying storage conditions. Parameters such as vesicle size, zeta potential, and entrapment efficiency are monitored over time. Ethosomes stored at refrigerated conditions (4°C) generally maintain stability for up to three months without significant aggregation or drug leakage (47).
8. Therapeutic Applications of Ethosomes
Ethosomes have been extensively studied as promising carriers for transdermal and dermal drug delivery across multiple therapeutic categories. Their ability to enhance skin permeability and provide sustained release makes them superior to traditional systems.
8.1 Delivery of Anti-inflammatory and Analgesic Drugs
Ethosomal formulations have shown remarkable potential in delivering anti-inflammatory and analgesic agents such as diclofenac, ketoprofen, and ibuprofen. These drugs, when incorporated into ethosomes, exhibit enhanced skin penetration, improved local accumulation, and prolonged therapeutic effect compared to conventional gels and creams (48,49). The ethanol and phospholipid composition facilitates deep dermal delivery, providing effective management of arthritis and localized inflammation.
8.2 Antifungal and Antibacterial Agents
Ethosomes have proven effective in delivering antifungal drugs like fluconazole, ketoconazole, and terbinafine, as well as antibacterial agents such as erythromycin and ciprofloxacin (50). Their enhanced permeation allows drug retention in skin layers where fungal infections persist, resulting in improved therapeutic efficacy and reduced recurrence rates (51).
8.3 Cardiovascular and CNS Drugs
Transdermal ethosomal systems have also been explored for the delivery of cardiovascular drugs such as propranolol and nitrates, and central nervous system (CNS) agents including rivastigmine and lamotrigine (52). The ethosomal approach ensures steady-state plasma concentrations and mitigates side effects associated with oral administration, improving patient adherence and therapeutic outcomes (53).
8.4 Hormonal and Cosmetic Applications
Ethosomes have gained popularity in the transdermal delivery of hormones like estradiol and testosterone for hormone replacement therapy. Their efficient permeation profile allows for non-invasive delivery with consistent hormone levels (54). In cosmetics, ethosomes are used to deliver active ingredients such as coenzyme Q10, vitamin E, and antioxidants, improving skin hydration, elasticity, and appearance (55).
8.5 Herbal and Phytoconstituent Delivery
Herbal drugs and phytoconstituents such as curcumin, quercetin, and capsaicin have been successfully incorporated into ethosomal formulations for enhanced skin penetration and therapeutic activity (56). These systems overcome solubility issues associated with natural compounds and enable targeted delivery to affected tissues, increasing bioavailability and stability (57).
9. Therapeutic Efficacy and Clinical Evidence
Ethosomes have demonstrated superior therapeutic efficacy compared to conventional transdermal and topical formulations due to their enhanced skin permeation and targeted drug delivery properties. The ethanol component of ethosomal vesicles fluidizes the stratum corneum lipids and improves drug solubility, resulting in increased transdermal flux and enhanced drug bioavailability (58). Studies have shown that ethosomal formulations achieve higher skin deposition and systemic absorption than liposomal or hydroalcoholic systems, thereby enhancing bioavailability and therapeutic outcomes (59). Ethosomal gels of anti-inflammatory and analgesic drugs, such as diclofenac and ketoprofen, exhibited faster onset and prolonged therapeutic effects compared to conventional creams or patches (60). Moreover, ethosomes have been successfully utilized in delivering antifungal, antiviral, and hormonal agents, offering better efficacy with reduced dosing frequency (61). Preclinical studies confirmed the ability of ethosomes to localize drugs in deeper skin layers, minimizing systemic exposure and side effects (62). Clinical evaluations further validated ethosomal formulations for treating skin disorders like psoriasis, herpes simplex, and acne, highlighting their safety, tolerability, and improved patient compliance (63).
10. Advantages and Limitations of Ethosomal Drug Delivery
Ethosomal systems present several advantages over conventional transdermal carriers. Their unique composition enhances drug permeation across the skin barrier, enabling both localized and systemic delivery (64). The high ethanol content improves vesicle deformability, facilitating drug transport through narrow intercellular spaces, while also providing antimicrobial properties that enhance formulation stability (65). Improved patient compliance results from their non-invasive nature, ease of application, and sustained drug release, which reduce dosing frequency (66). Furthermore, ethosomal formulations minimize systemic side effects by maintaining drug localization within the target tissue (67). However, certain limitations remain. Ethanol, while beneficial for enhancing permeability, can induce skin irritation and erythema, particularly with chronic use (68). Stability issues such as vesicle aggregation and ethanol evaporation may affect long-term storage, while scalability and reproducibility challenges hinder industrial production (69).
11. Recent Advances and Patented Technologies
Recent research has focused on optimizing ethosomal formulations through compositional and structural modifications. Novel ethosomal variants, including transethosomes, binary ethosomes, and niosomal-ethosomal hybrids, have demonstrated enhanced entrapment efficiency, stability, and controlled drug release (70). These systems often integrate other nanocarriers like nanoparticles or microneedles to further improve delivery precision and therapeutic outcomes. Several patents have been filed for ethosomal-based drug formulations targeting pain relief, hormone therapy, and antimicrobial applications, indicating growing commercial interest. Ethosomal technology has also been incorporated into cosmetic and dermatological products, including anti-aging and skin-lightening formulations, showing successful market translation. Integration with nanotechnology and smart drug delivery systems such as stimuli-responsive ethosomes and 3D-printed transdermal patches represents the latest frontier in ethosomal research, aimed at achieving personalized therapy (71).
12. Regulatory Considerations and Safety Aspects
The regulatory landscape for ethosomal drug delivery systems remains under development, as these vesicles occupy a niche between conventional formulations and nanocarriers. Toxicological evaluations have demonstrated that ethosomal formulations are generally safe, exhibiting minimal irritation or sensitization under controlled concentrations (72). However, ethanol-induced dehydration of the skin and potential disruption of barrier function require careful optimization during formulation (73). Regulatory challenges primarily involve establishing standardized methods for characterization, stability testing, and bioequivalence assessments for nanocarrier-based TDDS (20). Agencies such as the FDA and EMA emphasize the need for robust clinical data and consistent manufacturing practices to ensure safety, efficacy, and reproducibility of ethosomal systems (74).
13. Future Perspectives and Research GAPS
Future research on ethosomes must address long-term safety and efficacy through extended clinical trials across diverse patient populations. There remains a need for scalable production methods that maintain vesicle integrity and reproducibility while ensuring cost-effectiveness for commercial applications. Industrial translation of ethosomal formulations also requires improved regulatory frameworks and quality assurance standards. Integration with advanced nanotechnologies and data-driven design approaches may lead to personalized transdermal therapies tailored to individual patient profiles. The future of ethosomal drug delivery lies in the convergence of nanotechnology, biotechnology, and material sciences to achieve precise, controlled, and patient-specific drug delivery with minimal side effects and maximum therapeutic efficacy (75).
CONCLUSION
Ethosomes have emerged as a highly promising and versatile vesicular nanocarrier for transdermal drug delivery, effectively addressing the major limitations associated with conventional topical and transdermal formulations. Their unique composition, characterized by a high ethanol content combined with phospholipids and water, enables simultaneous fluidization of the stratum corneum lipids and enhanced vesicular deformability. This dual mechanism allows ethosomes to penetrate the skin barrier efficiently through both intercellular and transcellular pathways, resulting in improved drug deposition in deeper skin layers and enhanced systemic absorption. Throughout this review, the design aspects, preparation methods, formulation parameters, and characterization techniques of ethosomes have been critically discussed, highlighting their influence on stability, entrapment efficiency, and therapeutic performance. Ethosomes have demonstrated superior efficacy across a wide range of therapeutic applications, including anti-inflammatory, antifungal, cardiovascular, CNS, hormonal, cosmetic, and herbal drug delivery. Preclinical and clinical evidence further supports their ability to enhance bioavailability, prolong drug release, and improve patient compliance while minimizing systemic side effects. Despite these advantages, challenges related to ethanol-induced skin irritation, long-term stability, large-scale manufacturing, and regulatory standardization remain. Addressing these limitations through formulation optimization, advanced manufacturing technologies, and robust clinical validation will be essential. Overall, ethosomes represent a significant advancement in transdermal drug delivery and hold strong potential for future clinical and commercial translation.
REFERENCE
Aishwarya Morkhade*, Sakshi Sisodiya, Vishvesh Bajad, M. A. Mapari, Ethosomes As Advanced Transdermal Drug Carriers: A Critical Review of Design, Skin Permeation Mechanisms, Formulation Parameters, and Therapeutic Efficacy, Int. J. Sci. R. Tech., 2026, 3 (1), 215-226. https://doi.org/10.5281/zenodo.18296248
10.5281/zenodo.18296248
