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  • Transfersomes and Ethosomes for Enhanced Transdermal Drug Delivery: Mechanistic Insights and Comparative Evaluation

  • Photo Vaishnavi Gaddam*

  • Department of Pharmaceutics, D. K. Patil Institute of Pharmacy, Loha Nanded India 431708

Abstract

Transdermal drug delivery systems (TDDS) provide a non-invasive alternative to conventional dosing but are often restricted by the skin’s primary barrier, the stratum corneum. This review evaluates second- and third-generation ultradeformable vesicles—transfersomes and ethosomes—designed to overcome these limitations. Transfersomes utilize edge activators to achieve extreme elasticity, allowing them to squeeze through narrow pores via a transdermal osmotic gradient. Conversely, ethosomes leverage high ethanol concentrations to fluidize skin lipids, facilitating deep penetration through a "push-pull" mechanism. The review compares their composition, mechanisms, and applications in delivering diverse therapeutic agents, including proteins and lipophilic drugs. While challenges such as physical instability and regulatory hurdles remain, emerging hybrid systems like transethosomes and integration with microneedles represent the future of efficient, localized, and systemic transdermal therapy.

Keywords

Transdermal Drug Delivery,Transfersomes,Ethosome,Vesicle,Stratum Corneum

Introduction

Overview of Transdermal Drug Delivery Systems (TDDS)

Transdermal drug delivery systems (TDDS) are designed to transport therapeutic agents across the skin and into the systemic circulation (1). These systems offer a non-invasive alternative to oral and parenteral routes, providing sustained and controlled drug release (4). By maintaining constant drug levels in the plasma, TDDS can eliminate the "peaks and valleys" associated with conventional dosing, thereby improving therapeutic outcomes (3).

Limitations of Conventional Transdermal Formulations

The primary challenge for any TDDS is the stratum corneum (SC), the skin's outermost layer, which acts as a formidable physiological barrier (1). Conventional formulations are often restricted by:

  • Physicochemical Constraints: Passive diffusion is generally limited to molecules with a molecular weight of less than 500 Daltons and moderate lipophilicity (Log P 1–3) (1, 2).
  • Low Permeability: Many active pharmaceutical ingredients (APIs) cannot permeate the skin at therapeutic rates, leading to poor bioavailability (1, 4).
  • Skin Irritation: Some chemical enhancers used in traditional patches can cause localized irritation or damage to the skin's lipid barrier (1, 3).

Need for Vesicular Carrier–Based Enhancement Strategies To broaden the range of drugs that can be delivered transdermally—including hydrophilic compounds and large macromolecules—researchers have turned to vesicular carriers (3). These nanostructured systems can encapsulate drugs, protect them from degradation, and facilitate their transport through the skin's "brick and mortar" structure (5). Emergence of Ultra deformable Vesicles: Transfersomes and Ethosomes. Standard liposomes often fail to penetrate deep skin layers, instead remaining trapped in the upper stratum corneum (3). This led to the development of ultra-deformable vesicles (UDVs):

  • Transfersomes: Second-generation elastic vesicles composed of phospholipids and edge activators (surfactants like Tween 80). These surfactants destabilize the lipid bilayer, allowing the vesicle to become highly flexible (2, 3).
  • Ethosomes: Third-generation vesicles characterized by a high concentration of ethanol (20–50%). Ethanol fluidizes both the vesicle membrane and the skin's intercellular lipids, significantly increasing penetration depth (2, 4).

Scope and Objectives of the Review

The objective of this review is to provide a comprehensive analysis of transfersomes and ethosomes as advanced transdermal platforms. It explores:

  • The mechanistic insights into how these vesicles navigate the skin barrier.
  • The comparative evaluation of their efficiency in delivering diverse drug types (hydrophilic vs. lipophilic).
  • Recent innovations, such as transethosomes, which combine the advantages of both systems for superior skin flux (2, 5).

2. Skin Barrier and Challenges in Transdermal Drug Delivery

Anatomy and Physiology of Skin

The skin is the largest organ of the human body, serving as a protective shield against environmental insults. It is composed of three primary integrated layers:

  1. Epidermis: The outermost non-vascular layer, containing melanocytes and keratinocytes.
  2. Dermis: A thick layer of connective tissue containing blood vessels, hair follicles, sweat glands, and nerve endings.
  3. Hypodermis (Subcutaneous layer): The deepest layer consisting of adipose (fat) tissue that provides insulation and mechanical protection (6).

Fig 1: Anatomy of Skin Layers

Role of Stratum Corneum as a Barrier

The stratum corneum (SC), the superficial layer of the epidermis, is the rate-limiting barrier for drug absorption. It is often described using the "brick and mortar" model:

  • The Bricks: Corneocytes (dead, flattened keratinocytes filled with keratin filaments).
  • The Mortar: Intercellular lipid lamellae composed of ceramides, cholesterol, and free fatty acids (5).

This structure creates a highly organized, tortuous path that prevents the entry of foreign substances and the loss of water (transepidermal water loss). Most drugs fail to pass through this barrier because of its dense protein-lipid matrix (7).

Pathways of Transdermal Permeation

Once a drug is applied to the skin, it can take three main routes to reach the systemic circulation:

  1. Intercellular Route: The drug diffuses through the lipid-rich channels between the corneocytes. This is the most common path for small, lipophilic molecules.
  2. Transcellular Route: The drug passes directly through both the corneocytes and the lipid bilayers. This is a difficult path as it requires the drug to partition repeatedly between hydrophilic (keratin) and lipophilic (lipid) environments (6, 8).
  3. Appendageal Route (Shunt Pathway): The drug bypasses the SC via hair follicles, sebaceous glands, or sweat ducts. While fast, this route accounts for less than 0.1% of the total skin surface area, limiting its overall contribution (5).

Factors Affecting Drug Permeation Through Skin

The efficiency of drug transport is influenced by the physicochemical properties of the drug and the physiological state of the skin.

Table 1: Factors affecting Permeation

Factor Category

Parameter

Impact on Permeation

Physicochemical

Molecular Weight

Ideal drugs should be < 500 Da; larger molecules cannot penetrate (6).
 

Partition Coefficient

A moderate Log P (1–3) is required to cross both lipid and aqueous layers (7).
 

Drug Concentration

Permeation is generally proportional to the concentration gradient (Fick’s Law) (8).

Physiological

Skin Hydration

Increased hydration swells the SC and opens up the dense structure, enhancing flux (5).
 

Skin Temperature

Higher temperatures increase the diffusion coefficient and lipid fluidity (6).
 

Regional Anatomy

Permeability varies by site (e.g., behind the ear vs. the palm of the hand) (8).

3. Vesicular Drug Delivery Systems: An Overview

Vesicular drug delivery systems (VDDS) are highly ordered assemblies of one or more concentric bilayers formed by the self-assembly of amphiphilic building blocks in an aqueous environment (9). These systems have revolutionized pharmacology by providing a means to encapsulate both hydrophilic and lipophilic drugs, thereby protecting them from degradation and controlling their release (11).

Conventional Vesicles: Liposomes and Niosomes

Liposomes

Liposomes are the first generation of vesicular carriers, primarily composed of phospholipids (such as phosphatidylcholine) and cholesterol (9, 13). They are biocompatible and biodegradable, mimicking the structure of biological membranes.

  • Structure: A spherical shell with an aqueous core surrounded by a lipid bilayer.
  • Key Advantage: Ability to carry both water-soluble drugs (in the core) and oil-soluble drugs (within the bilayer) (10, 11).

Niosomes

Niosomes were developed as an alternative to liposomes to improve stability and reduce costs. They are formed by the self-assembly of non-ionic surfactants (e.g., Span, Tween) and cholesterol (12, 14).

  • Structure: Structurally similar to liposomes but composed of synthetic surfactants rather than natural phospholipids.
  • Key Advantage: Higher chemical stability, lower production cost, and easier large-scale manufacturing (12).

Limitations of Conventional Vesicular Systems

Despite their versatility, conventional liposomes and niosomes face significant hurdles, particularly in transdermal delivery:

  1. Poor Skin Penetration: Conventional vesicles are relatively rigid. They are often too large to pass through the narrow pores (< 50 nm) of the stratum corneum and tend to accumulate on the skin surface (9, 11).
  2. Physical Instability: They are prone to aggregation, fusion, and drug leakage during storage (12).
  3. Chemical Sensitivity: Phospholipids in liposomes are susceptible to oxidative degradation and hydrolysis (13, 14).

Table no 2: Comparative between Liposomes and Niosomes

Feature

Liposomes

Niosomes

Main Component

Phospholipids

Non-ionic Surfactants

Stability

Lower (prone to oxidation)

Higher (chemically stable)

Cost

High

Low

Skin Penetration

Limited to upper layers

Limited to upper layers

Flexibility

Rigid

Rigid

Evolution Toward Elastic and Soft Vesicles

To overcome the "rigidity" barrier of first-generation vesicles, researchers introduced Second and Third Generation Vesicles. This evolution was driven by the need for ultradeformability—the ability of a vesicle to squeeze through pores much smaller than its own diameter (11, 15).

  1. Elastic Liposomes (Transfersomes): Introduced by Cevc and Blume in 1992, these contain "edge activators" (surfactants) that destabilize the bilayer, making it highly flexible (15).
  2. Soft Vesicles (Ethosomes): These incorporate high concentrations of ethanol, which fluidizes both the vesicle membrane and the skin lipids, allowing for deep penetration (11).

4. Transfersomes

4.1 Concept and Definition

Historical Background

The concept of the transfersome was first introduced in 1991 by Gregor Cevc and colleagues (16, 17). The term is derived from the Latin word transferre (to carry across) and the Greek word soma (body) (16, 17). These vesicles were developed to overcome the limitations of conventional liposomes, which are too rigid to penetrate the skin's dense stratum corneum (17, 21).

Principle of Ultra deformability

Transfersomes are defined as ultradeformable or elastic vesicles that possess a unique ability to squeeze through pores significantly smaller than their own diameter (16, 18). While a typical skin pore is approximately 50 nm, a transfersome (often 100–200 nm) can undergo extreme shape deformation to bypass this barrier without rupturing (17, 20). This "self-optimizing" flexibility allows them to reach deeper skin layers and even the systemic circulation with efficiencies comparable to subcutaneous injections (17, 18).

4.2 Composition of Transfersomes

Fig 2: Transfersomes

Transfersomes are complex aggregates consisting of two primary functional components:

  • Phospholipids: These serve as the vesicle-forming components (16, 20). Common examples include Soya phosphatidylcholine and Dipalmitoyl phosphatidylcholine (19, 21). They self-assemble into a lipid bilayer that protects the encapsulated drug (21).
  • Edge Activators (Surfactants): These are the "secret ingredient" that differentiates transfersomes from liposomes (17, 19). They are typically single-chain surfactants like Tween 80, Span 80, or sodium cholate (17, 20).

Table no 3: Role of Each Component

Component

Primary Role

Phospholipids

Provides the basic structural integrity and biocompatibility of the vesicle (19).

Edge Activators

Destabilizes the lipid bilayer to increase its elastic modulus and flexibility. They accumulate at the site of high stress when a vesicle enters a narrow pore (17, 18).

Hydrating Medium

Usually a buffer (e.g., phosphate buffer pH 6.5–7.4) that facilitates vesicle formation and drug loading (19, 21).

4.3 Mechanism of Skin Penetration

Deformation-Driven Transport

Unlike conventional carriers that rely on passive diffusion, transfersomes use deformation-driven transport (16, 17). When applied to the skin, they do not simply stay on the surface; instead, they change their membrane flexibility to squeeze through the narrow intracellular lipid lamellae of the stratum corneum (16, 20).

Hydration Gradient Theory

This is the primary driving force for transfersome movement (16, 18). Under non-occlusive conditions, water evaporates from the skin's surface, creating a "dry" environment. Since transfersomes are highly hydrophilic and "xerophobic" (moisture-seeking), they are pulled from the dry surface toward the water-rich deeper strata of the skin (16, 18). This osmotic gradient acts as a powerful pump that draws the intact vesicles across the barrier (16, 17).

Interaction with Skin Lipids

Transfersomes also act as penetration enhancers (18, 20). The surfactants within the vesicle can temporarily disrupt the highly organized intercellular lipid matrix of the stratum corneum, effectively widening the "hydrophilic gaps" and facilitating deeper drug delivery (16, 21).

4.4 Preparation Methods

The preparation of transfersomes requires precise control over the lipid-to-surfactant ratio to ensure maximum elasticity. The following methods are commonly employed:

  • Thin Film Hydration: This is the most widely used laboratory technique (22, 23). Phospholipids and edge activators are dissolved in a volatile organic solvent (e.g., chloroform-methanol). The solvent is evaporated using a rotary evaporator above the lipid transition temperature, leaving a thin lipid film on the flask wall (23, 26). This film is then hydrated with an aqueous buffer (e.g., pH 7.4) under rotation, followed by sonication or extrusion to achieve the desired vesicle size (22, 26).
  • Reverse Phase Evaporation: Lipids and edge activators are dissolved in an organic phase to which the aqueous phase is added, creating a water-in-oil emulsion (23). The organic solvent is then slowly removed under reduced pressure, causing the mixture to transform into a viscous gel and eventually into a stable vesicular suspension (23, 31). This method is particularly efficient for encapsulating large hydrophilic molecules (23).
  • Ethanol Injection Method: An ethanolic solution of phospholipids and edge activators is rapidly injected into an aqueous buffer solution through a fine needle (24, 31). This process causes the lipids to self-assemble into vesicles almost instantaneously (31).

4.5 Evaluation Parameters

To ensure quality and performance, transfersomes are characterized using several physicochemical and functional parameters:

  • Vesicle Size and Polydispersity (PDI): Size is typically measured using Dynamic Light Scattering (DLS). Transfersomes usually range from 100–200 nm (23, 27). The PDI indicates the uniformity of the distribution; a value below 0.3 suggests a narrow, stable size distribution (23, 28).
  • Entrapment Efficiency (%EE): This measures the percentage of drug successfully loaded into the vesicles. It is determined by separating free drug from the vesicles using ultracentrifugation or minicolumn centrifugation (22, 23).
  • Deformability Index: This is a unique parameter for transfersomes. It is calculated by measuring the flux of vesicles through a microporous membrane (with pores smaller than the vesicles) under constant pressure (22, 30).
  • In Vitro and Ex Vivo Skin Permeation Studies: These are conducted using Franz diffusion cells with synthetic membranes or animal/human skin. These studies determine the cumulative amount of drug permeated, the steady-state flux (J), and the permeability coefficient (K_) (22, 30).
  • Stability Studies: Conducted according to ICH guidelines, these studies monitor changes in vesicle size, drug leakage, and chemical degradation (oxidation) over time (23, 30).

4.6 Applications of Transfersomes

Transfersomes have expanded the therapeutic potential of transdermal delivery across various drug classes:

  • Delivery of Peptides and Proteins: They are highly effective for large molecules like insulin, interferons, and growth hormones, which otherwise cannot cross the skin (22, 29). For example, insulin-loaded transfersomes can achieve glucose-lowering effects comparable to subcutaneous injections (29).
  • Anti-inflammatory Drugs: Transfersomes enhance the penetration of NSAIDs like diclofenac, ibuprofen, and ketoprofen (29, 30). Studies show they provide higher drug concentrations in joint tissues, offering superior relief for conditions like osteoarthritis (22).
  • Anticancer Agents: Used for localized treatment of skin cancers, transfersomes improve the delivery of 5-fluorouracil, methotrexate, and paclitaxel, reducing systemic toxicity while increasing tumoral inhibition (29, 32).
  • Herbal and Phytoconstituents: They are increasingly used to deliver antioxidants and herbal extracts (e.g., resveratrol, curcumin) that have poor solubility or stability, protecting them from oxidation and enhancing their skin deposition (27, 29).

5. Ethosomes

5.1 Concept and Definition

Ethanol-Based Vesicular Systems

Ethosomes are novel lipid-based vesicular carriers specifically designed for enhanced transdermal delivery. Introduced by Touitou et al. in 1996, these systems are characterized by their high concentration of ethanol (typically 20% to 45%) (33, 34). Unlike conventional vesicles, ethosomes are "soft" and highly malleable, allowing them to penetrate deep into the skin layers and even reach the systemic circulation (35).

Comparison with Conventional Liposomes

The primary difference between ethosomes and conventional liposomes lies in their deformability and penetration depth.

  • Liposomes: Generally rigid; they tend to remain on the surface of the skin or in the upper layers of the stratum corneum (33, 36).
  • Ethosomes: The presence of ethanol creates a "soft" vesicle with a lower transition temperature, enabling them to squeeze through skin pores that are otherwise impermeable to liposomes (34, 37).

5.2 Composition of Ethosomes

Fig 3: Ethosome

The formulation of ethosomes is relatively simple but requires precise ratios to ensure stability and efficacy.

  • Phospholipids: Similar to liposomes, ethosomes use phospholipids (e.g., Soya phosphatidylcholine, Egg lecithin) as the primary bilayer-forming agent (33, 35). These provide biocompatibility and the basic structure of the vesicle.
  • High Ethanol Concentration: This is the defining feature of ethosomes (20%-45%). Ethanol acts as a powerful solvent and a chemical penetration enhancer (34, 38).
  • Water/Buffer: Serves as the aqueous phase to complete the vesicular structure (35).

Role of Ethanol in Vesicle Formation

Ethanol plays a dual role in ethosomes. Firstly, it imparts a negative charge to the vesicle surface, which prevents aggregation due to electrostatic repulsion, leading to a smaller and more stable vesicle size (33, 37). Secondly, it provides the vesicle membrane with fluidity and softness, allowing it to change shape easily during skin penetration (34, 36).

5.3 Mechanism of Skin Penetration

The superior penetration of ethosomes is attributed to a dual-action mechanism involving both the ethanol and the vesicles themselves.

Ethanol-Induced Lipid Fluidization

Ethanol acts as a "push" effect on the skin. It interacts with the polar head groups of the stratum corneum (SC) lipids, significantly increasing their fluidity and decreasing the density of the lipid multilayer (34, 38). This "softens" the skin's barrier, making it more permeable (33, 39).

Vesicle Fusion and Permeation Enhancement

Following the fluidization of the SC lipids, the "soft" ethosome vesicles themselves can penetrate through the disorganized lipid lamellae (35, 37). This is often referred to as the "pull" effect. Once inside the deeper layers, the vesicles may fuse with the skin cell membranes, releasing the encapsulated drug directly into the deeper tissues (34, 36).

Synergistic Effect of Ethanol and Phospholipids

The high-speed penetration is not due to ethanol or phospholipids alone, but their synergy. Ethanol fluidizes both the skin lipids and the vesicle membrane, while the phospholipids provide the vehicle for drug transport and integration into the skin's natural lipid structure (33, 39). This results in a significantly higher transdermal flux compared to hydroalcoholic solutions or standard liposomes (34, 40).

5.4 Preparation Methods

The preparation of ethosomes is generally simpler and less energy-intensive than that of conventional liposomes, as the high ethanol content facilitates the spontaneous formation of vesicles.

  • Cold Method: This is the most common technique for preparing ethosomes (41, 42). Phospholipids and the drug are dissolved in ethanol at room temperature. This mixture is stirred vigorously while the aqueous phase (water or buffer) is added in a fine stream. The system is then stirred for an additional 30–60 minutes and may be sonicated to achieve the desired vesicle size (41, 44).
  • Hot Method: Phospholipids are dispersed in water at until a colloidal solution is formed. In a separate vessel, ethanol and glycol (if used) are heated to 40 degree Celsius and mixed. The organic phase is then added to the aqueous phase. This method is preferred when using lipids with higher transition temperatures (42, 43).
  • Classical Ethanol Injection: Similar to the cold method, a lipid-ethanol solution is rapidly injected into an aqueous phase through a needle. The sudden change in solvent environment causes the lipids to precipitate and self-assemble into vesicles (41, 45).

5.5 Evaluation Parameters

  • Vesicle Size and Morphology: The size of ethosomes typically ranges from 30 nm to 200 nm (41). Morphology is confirmed using Transmission Electron Microscopy (TEM) or Scanning Electron Microscopy (SEM), which reveals their spherical, vesicular structure (42, 46).
  • Zeta Potential: This measures the surface charge of the vesicles. Ethosomes usually possess a negative charge due to the ethanol, which provides stability by preventing vesicle aggregation through electrostatic repulsion (41, 43).
  • Drug Loading Efficiency: This indicates the percentage of the drug successfully encapsulated. High ethanol concentrations often lead to higher entrapment efficiency for lipophilic drugs compared to conventional liposomes (42, 47).
  • Skin Permeation and Deposition Studies: Performed using Franz diffusion cells. Ethosomes are evaluated not just for how much drug reaches the receptor compartment (permeation), but also for how much remains within the skin layers (deposition/retention), which is critical for local treatments (44, 46).
  • Stability Assessment: Ethosomes are stored at various temperatures to monitor changes in size, zeta potential, and drug leakage over time (43, 45).

5.6 Applications of Ethosomes

Ethosomes have shown remarkable versatility in delivering both local and systemic therapeutics:

  • Antifungal and Antibacterial Drugs: Ethosomes significantly improve the penetration of drugs like clotrimazole, ketoconazole, and erythromycin into the deep skin layers to treat resistant infections like candidiasis or deep-seated pyoderma (41, 48).
  • Hormonal Delivery: They are used for the transdermal delivery of hormones such as testosterone and estradiol. The ethosomal carriers bypass first-pass metabolism and provide more consistent plasma levels than oral doses (42, 49).
  • Anti-acne and Cosmetic Applications: Ethosomes are ideal for delivering salicylic acid, tretinoin, and minoxidil. Their ability to penetrate the pilosebaceous unit makes them highly effective for treating acne and hair loss (41, 44).
  • Phytopharmaceutical Delivery: Like transfersomes, ethosomes are used to enhance the bioavailability of poorly soluble plant-derived compounds such as quercetin, apigenin, and curcumin, protecting them from degradation while ensuring deep skin penetration (46, 50).

6. Mechanistic Comparison of Transfersomes and Ethosomes

While both systems are designed to overcome the stratum corneum barrier, they utilize distinct biophysical strategies to achieve deep skin penetration.

  • Mode of Skin Permeation: Transfersomes primarily rely on the "Transdermal Osmotic Gradient" or "Xerophobia." Because they are highly hydrophilic, they "push" themselves through skin pores to avoid dehydration on the skin surface (51, 52). Ethosomes, conversely, utilize the "Ethanol Effect," where ethanol creates a "soft" vesicle and simultaneously disrupts the skin's lipid organization to "pull" the drug through (53, 54).
  • Role of Formulation Components: In transfersomes, the Edge Activator (surfactant) is the functional lead, providing the bilayer with the ability to undergo extreme curvature (52). In ethosomes, Ethanol is the functional lead, acting as both a vesicle fluidizer and a potent chemical penetration enhancer (54, 55).
  • Vesicle Deformability vs. Lipid Fluidization: Transfersomes are defined by their elasticity; they remain intact while squeezing through narrow intercellular spaces (51). Ethosomes focus on fluidization; they make the skin barrier more permeable and the vesicle membrane more flexible, often fusing with the skin lipids to release their cargo (53, 56).
  • Drug Suitability: Transfersomes are exceptionally well-suited for large macromolecules (peptides, proteins, and vaccines) because they can carry them intact through the hydration gradient (52, 57). Ethosomes are often superior for lipophilic drugs and small molecules, as the high ethanol content increases the solubility and entrapment of "greasy" compounds (54, 58).

7. Comparative Evaluation of Transfersomes and Ethosomes

The following table summarizes the key differences between these two advanced vesicular systems:

Table no 4: Transfersome vs. Ethosomes

Parameter

Transfersomes

Ethosomes

Primary Composition

Phospholipids + Edge Activators (Surfactants) (51, 52)

Phospholipids + High Ethanol (20-45%) (53, 54)

Key Mechanism

Osmotic gradient (Xerophobia) and deformability (52, 55)

Lipid fluidization and "Push-Pull" effect (54, 56)

Vesicle Structure

Highly elastic/ultradeformable bilayer (51)

Soft, malleable, and low-transition temp bilayer (53)

Penetration Depth

Can reach systemic circulation effectively (57)

High deposition in deep skin layers and systemic (58)

Drug Loading

Better for hydrophilic and large proteins (52)

Excellent for lipophilic and poorly soluble drugs (54)

Stability

Moderate; susceptible to oxidative degradation (55)

High; ethanol prevents aggregation (Zeta potential) (53)

Skin Irritation

Low; but surfactants may cause sensitivity (56)

Generally safe; high ethanol may cause dryness (54)

Scale-up Feasibility

Complex; requires precise EA/Lipid ratios (52)

Relatively simple; "Cold method" is easy to scale (53)

8. Recent Advances and Research Trends

The field of vesicular drug delivery is rapidly evolving, moving beyond simple transfersomes and ethosomes toward integrated and multi-functional platforms.

  • Hybrid Systems (Transethosomes): To harness the benefits of both platforms, researchers developed transethosomes. These hybrid vesicles contain both a high concentration of ethanol (typical of ethosomes) and an edge activator or surfactant (typical of transfersomes) (59, 61). This combination results in a vesicle that is both extremely soft and highly elastic, providing superior skin flux compared to either system alone (60).
  • Surface-Modified Vesicles: Modern research focuses on functionalizing the vesicle surface with ligands like folic acid, transferrin, or peptides to achieve targeted delivery, particularly in skin cancer therapy (62). Additionally, coating vesicles with polymers like polyethylene glycol (PEG)—known as "stealth" vesicles—can increase stability and circulation time (59, 63).
  • Nano-gel and Patch-Based Systems: To improve the residence time and ease of application, vesicles are often incorporated into hydrogel matrices or transdermal patches. These "vesicle-in-gel" systems (nanogels) provide a controlled release environment and prevent the rapid evaporation of ethanol, thereby maintaining a consistent hydration gradient for deeper penetration (60, 64).
  • Clinical and Preclinical Studies: Recent clinical trials have explored the use of these vesicles for vaccine delivery (e.g., Hepatitis B), hormone replacement therapy, and pain management (61). Preclinical data suggests that ultradeformable vesicles can deliver large proteins that were previously only administrable via injection (62).

9. Regulatory and Safety Considerations

Despite the promising therapeutic potential, the transition from lab to market involves rigorous safety and regulatory hurdles.

  • Skin Toxicity and Irritation Studies: While phospholipids are generally safe, high concentrations of ethanol in ethosomes can cause localized skin dryness or erythema (65). Similarly, certain edge activators (surfactants) in transfersomes can disrupt the skin's barrier too aggressively, leading to irritation. Comprehensive in vivo and in vitro (e.g., MTT assays) toxicity studies are mandatory to ensure biocompatibility (66).
  • GRAS Status of Components: Most components used—such as soya phosphatidylcholine, span 80, and Tween 80—are listed as Generally Recognized as Safe (GRAS) by the FDA (61, 65). However, when used in novel nanostructured forms, their metabolic fate and long-term accumulation in the skin must be evaluated (67).
  • Regulatory Challenges: One of the biggest hurdles is the lack of specific regulatory guidelines for "nanovesicular" products (66). Establishing Good Manufacturing Practices (GMP) for large-scale production, ensuring batch-to-batch uniformity in vesicle size, and maintaining long-term stability (avoiding drug leakage) are significant challenges in obtaining FDA or EMA approval (61, 67).

LIMITATIONS AND CHALLENGES

While transfersomes and ethosomes offer significant advantages, several technical and commercial hurdles remain:

  • Stability Issues: Both systems are prone to physical instability. Over time, vesicles may undergo aggregation, fusion, or sedimentation. Phospholipids are also susceptible to chemical degradation, such as oxidation and hydrolysis, which can lead to drug leakage (68, 70).
  • High Ethanol Content Concerns: In ethosomes, the ethanol concentration (up to 45%) can cause skin dryness, irritation, or peeling with chronic use. Furthermore, ethanol is volatile; if the formulation is not stored in airtight containers, the concentration may change, altering the vesicle's penetration properties (69, 71).
  • Cost and Scale-up Difficulties: The use of high-purity phospholipids and specialized surfactants increases the cost of raw materials. Transitioning from small laboratory batches to industrial-scale production requires expensive equipment like high-pressure homogenizers to maintain uniform vesicle size (72).
  • Reproducibility: Achieving consistent vesicle size, polydispersity, and entrapment efficiency across different batches is challenging. Minor variations in stirring speed, temperature, or the rate of aqueous phase addition can significantly affect the final product's quality (68, 73).

FUTURE PERSPECTIVES

The next decade of transdermal research is expected to focus on "smart" and combined delivery platforms:

  • Personalized Transdermal Therapy: Advances in 3D printing and digital health may allow for the creation of personalized patches where vesicle concentration and drug dose are tailored to an individual’s skin type and condition (71, 74).
  • Integration with Microneedles and Iontophoresis: Combining vesicular carriers with physical enhancement techniques—such as microneedles—creates a "dual-action" system. Microneedles create micro-channels in the skin, allowing elastic vesicles to bypass the stratum corneum entirely and reach the dermis with almost 100% efficiency (69, 75).
  • Commercialization Potential: As more patents expire and manufacturing technologies like microfluidics improve, the cost of production will decrease, leading to a surge in FDA-approved vesicular transdermal products for chronic diseases (72, 76).
  • Scope for Herbal and Biologics Delivery: There is massive potential for delivering unstable biologics (mRNA, CRISPR components) and poorly soluble herbal extracts (curcuminoids, flavonoids) using these soft carriers to protect them from environmental degradation (70, 74).

CONCLUSION

  • Summary of Key Mechanistic Insights: Transfersomes and ethosomes have redefined transdermal delivery by moving beyond passive diffusion. Transfersomes utilize a hydration gradient and extreme elasticity to "squeeze" through skin pores, while ethosomes use the "push-pull" effect of ethanol to fluidize skin lipids and facilitate deep penetration (68, 69).
  • Comparative Advantages and Limitations: Transfersomes are the gold standard for delivering large molecules and vaccines due to their ultra-deformability. Ethosomes, however, excel in delivering lipophilic drugs and offer a simpler preparation process, though they carry a higher risk of skin irritation (71, 72).

Final Remarks: Both systems represent a significant leap in pharmaceutical technology. While challenges in stability and scale-up persist, their ability to transform non-invasive drug delivery makes them indispensable tools for the future of clinical and industrial pharmacy (73, 76).

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  12. Karami, N., Karami, M., & Moghimipour, E. (2024). Vesicular drug delivery systems: Promising approaches in ocular drug delivery. Pharmaceutics, 16(4), 512. https://doi.org/10.3390/pharmaceutics16040512
  13. Ge, X., Wei, M., He, S., & Yuan, W. E. (2019). Advances of non-ionic surfactant vesicles (niosomes) and their application in drug delivery. Pharmaceutics, 11(2), 55. https://doi.org/10.3390/pharmaceutics11020055
  14. Umbarkar, S. (2021). Niosome as a novel pharmaceutical drug delivery: A brief review highlighting formulation, types, composition and application. Indian Journal of Pharmaceutical Education and Research, 55(1), S12-S22.
  15. Chauhan, S., & Das, A. (2024). Niosomes: A promising approach for targeted drug delivery. GSC Biological and Pharmaceutical Sciences, 26(3), 142-154.
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  17. Chauhan, N. (2017). An updated review on transfersomes: A novel vesicular system for transdermal drug delivery. Universal Journal of Pharmaceutical Research, 2(4), 49–52. https://doi.org/10.22270/ujpr.v2i4.rw2
  18. Opatha, S. A. T., Titapiwatanakun, V., & Chutoprapat, R. (2020). Transfersomes: A promising nanoencapsulation technique for transdermal drug delivery. Pharmaceutics, 12(9), 855. https://doi.org/10.3390/pharmaceutics12090855
  19. Chen, R. P., Chavda, V. P., Patel, A. B., & Chen, Z. S. (2022). Phytochemical delivery through transferosome (phytosome): An advanced transdermal drug delivery for complementary medicines. Frontiers in Pharmacology, 13, 850862. https://doi.org/10.3389/fphar.2022.850862
  20. Muthangi, S., Pallerla, P., & Nimmagadda, S. (2023). Transdermal delivery of drugs using transferosomes: A comprehensive review. Journal of Advanced Scientific Research, 14(06), 30-35. https://doi.org/10.55218/jasr.202314604
  21. Sudhakar, K., Fuloria, S., Subramaniyan, V., et al. (2021). Ultraflexible liposome nanocargo as a dermal and transdermal drug delivery system. Nanomaterials, 11(10), 2557. https://doi.org/10.3390/nano11102557
  22. Chen, R. P. (2022). Phytochemical delivery through transferosome (phytosome): An advanced transdermal drug delivery for complementary medicines. Frontiers in Pharmacology, 13, 850862. https://doi.org/10.3389/fphar.2022.850862
  23. Opatha, S. A. T., Titapiwatanakun, V., & Chutoprapat, R. (2020). Transfersomes: A promising nanoencapsulation technique for transdermal drug delivery. Pharmaceutics, 12(9), 855. https://doi.org/10.3390/pharmaceutics12090855
  24. Shaikh, J. S., & Akbari, B. (2025). Transfersomes in advanced drug delivery: A comprehensive review of design, mechanism, and clinical applications. Asian Journal of Pharmacy and Technology, 15(4), 395-401.
  25. Gupta, A. (2012). Transfersomes: A novel vesicular carrier for enhanced transdermal delivery of sertraline: Development, characterization, and performance evaluation. Scientia Pharmaceutica, 80(4), 1061–1080. https://doi.org/10.3797/scipharm.1208-02
  26. Chauhan, N. (2017). An updated review on transfersomes: A novel vesicular system for transdermal drug delivery. Universal Journal of Pharmaceutical Research, 2(4), 49–52. https://doi.org/10.22270/ujpr.v2i4.rw2
  27. Muthangi, S., Pallerla, P., & Nimmagadda, S. (2023). Transdermal delivery of drugs using transferosomes: A comprehensive review. Journal of Advanced Scientific Research, 14(06), 30-35.
  28. Sudhakar, K., et al. (2025). Development and evaluation of trans-resveratrol-loaded transfersomes. Nanotechnology, Science and Applications, 18, 45-58.
  29. Amasya, G., et al. (2025). Formulation and characterization of transfersomes for ocular delivery of tonabersat. Drug Development and Industrial Pharmacy, 51(1), 1-12. https://doi.org/10.1080/10837450.2025.2501991
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  33. Rai, S., Pandey, V., & Rai, G. (2017). Transfersomes as versatile and flexible nano-vesicular carriers in skin cancer therapy: The state of the art. Nano Reviews & Experiments, 8(1), 1325708. https://doi.org/10.1080/20022727.2017.1325708
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  40. Akiladevi, D., & Basak, S. (2025). Ethosomes – A noninvasive approach for transdermal drug delivery system. International Journal of Current Pharmaceutical Research, 17(1), 1-8.
  41. Zhang, J. P., Wei, Y. H., Zhou, Y., Li, Y. Q., & Wu, X. A. (2012). Ethosomes, binary ethosomes and transfersomes of terbinafine hydrochloride: A comparative study. Archives of Pharmacal Research, 35(1), 109-117. https://doi.org/10.1007/s12272-012-0112-0
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  58. Rai, S., Pandey, V., & Rai, G. (2017). Transfersomes as versatile and flexible nano-vesicular carriers in skin cancer therapy: The state of the art. Nano Reviews & Experiments, 8(1), 1325708.
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  62. Witika, B. A., et al. (2026). The future of vesicular drug delivery: Transferosomes in therapeutic advancement—applications, innovations and challenges. Journal of Drug Delivery Science and Technology, 91, 12777116.
  63. Garg V., Singh, H., & Beg, S. (2025). Evolution of ethosomal systems for the delivery of diverse therapeutic agents. Drug Delivery and Translational Research, 15(2), 442-460. https://doi.org/10.1007/s13346-024-01612-4
  64. Chauhan, N. (2017). An updated review on transfersomes: A novel vesicular system for transdermal drug delivery. Universal Journal of Pharmaceutical Research, 2(4), 49–52.
  65. Sharma, G., et al. (2026). Phytopharmaceutical delivery through ethosomes: A focus on antioxidant compounds. Phytomedicine Plus, 6(1), 100412.
  66. Opatha, S. A. T., Titapiwatanakun, V., & Chutoprapat, R. (2020). Transfersomes: A promising nanoencapsulation technique for transdermal drug delivery. Pharmaceutics, 12(9), 855. https://doi.org/10.3390/pharmaceutics12090855
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  69. Abdulbaqi, I. M., Darwis, Y., Khan, N. A. K., Assi, R. A., & Khan, A. A. (2016). Ethosomal nanocarriers: The impact of constituents and formulation techniques on ethosomal properties, in vivo studies, and clinical efficacy. International Journal of Nanomedicine, 11, 2279-2304. https://doi.org/10.2147/IJN.S105016
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  73. Shingade, G. M. (2023). A review on: Transdermal drug delivery system. International Journal of Research Publication and Reviews, 4(5), 4503-4512.
  74. Garg, V., Singh, H., & Beg, S. (2025). Evolution of ethosomal systems for the delivery of diverse therapeutic agents. Drug Delivery and Translational Research, 15(2), 442-460. https://doi.org/10.1007/s13346-024-01612-4
  75. Iizhar, S. A., Syed, M. A., Khan, S., & Baboota, S. (2026). Ethosomes: A review on the novel vesicular system for transdermal drug delivery. Nanomedicine Journal, 13(1), 12-28.
  76. Akiladevi, D., & Basak, S. (2025). Ethosomes - A noninvasive approach for transdermal drug delivery system. International Journal of Current Pharmaceutical Research, 17(1), 1-8.

Reference

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  2. Opatha, S. A. T., Titapiwatanakun, V., & Chutoprapat, R. (2020). Transfersomes: A promising nanoencapsulation technique for transdermal drug delivery. Pharmaceutics, 12(9), 855. https://doi.org/10.3390/pharmaceutics12090855
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  4. Zhan, B., Wang, J., Li, H., Xiao, K., Fang, X., Shi, Y., & Jia, Y. (2024). Ethosomes: A promising drug delivery platform for transdermal application. Chemistry, 6(5), 993–1019. https://doi.org/10.3390/chemistry6050058
  5. Witika, B. A., Mweetwa, L. L., Tshiamo, K. O., Edler, K., Matafwali, S. K., Ntemi, P. V., Chikukwa, M. T. R., & Makoni, P. A. (2021). Vesicular drug delivery for the treatment of topical disorders: current and future perspectives. Journal of Pharmacy and Pharmacology, 73(11), 1427–1441. https://doi.org/10.1093/jpp/rgab082
  6. Benson, H. A. E., Grice, J. E., Mohammed, Y., Namjoshi, S., & Roberts, M. S. (2019). Topical and transdermal drug delivery: From simple absorption to novel frontier technologies. Pharmaceutics, 11(6), 249. https://doi.org/10.3390/pharmaceutics11060249
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  8. Tanner, T., & Marks, R. (2008). Delivering drugs by the transdermal route: review and update. Skin Research and Technology, 14(3), 249–260. https://doi.org/10.1111/j.1600-0846.2008.00316.x
  9. Alkilani, A. Z., McCrudden, M. T., & Donnelly, R. F. (2015). Transdermal drug delivery: Innovative pharmaceutical developments based on disruption of the barrier properties of the stratum corneum. Pharmaceutics, 7(4), 438–470. https://doi.org/10.3390/pharmaceutics7040438
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  12. Karami, N., Karami, M., & Moghimipour, E. (2024). Vesicular drug delivery systems: Promising approaches in ocular drug delivery. Pharmaceutics, 16(4), 512. https://doi.org/10.3390/pharmaceutics16040512
  13. Ge, X., Wei, M., He, S., & Yuan, W. E. (2019). Advances of non-ionic surfactant vesicles (niosomes) and their application in drug delivery. Pharmaceutics, 11(2), 55. https://doi.org/10.3390/pharmaceutics11020055
  14. Umbarkar, S. (2021). Niosome as a novel pharmaceutical drug delivery: A brief review highlighting formulation, types, composition and application. Indian Journal of Pharmaceutical Education and Research, 55(1), S12-S22.
  15. Chauhan, S., & Das, A. (2024). Niosomes: A promising approach for targeted drug delivery. GSC Biological and Pharmaceutical Sciences, 26(3), 142-154.
  16. Salmani, A. A., & Shrivastava, S. (2017). Elastic liposomes as novel carriers: Recent advances in drug delivery. International Journal of Nanomedicine, 12, 5087–5108. https://doi.org/10.2147/ijn.s141868
  17. Chauhan, N. (2017). An updated review on transfersomes: A novel vesicular system for transdermal drug delivery. Universal Journal of Pharmaceutical Research, 2(4), 49–52. https://doi.org/10.22270/ujpr.v2i4.rw2
  18. Opatha, S. A. T., Titapiwatanakun, V., & Chutoprapat, R. (2020). Transfersomes: A promising nanoencapsulation technique for transdermal drug delivery. Pharmaceutics, 12(9), 855. https://doi.org/10.3390/pharmaceutics12090855
  19. Chen, R. P., Chavda, V. P., Patel, A. B., & Chen, Z. S. (2022). Phytochemical delivery through transferosome (phytosome): An advanced transdermal drug delivery for complementary medicines. Frontiers in Pharmacology, 13, 850862. https://doi.org/10.3389/fphar.2022.850862
  20. Muthangi, S., Pallerla, P., & Nimmagadda, S. (2023). Transdermal delivery of drugs using transferosomes: A comprehensive review. Journal of Advanced Scientific Research, 14(06), 30-35. https://doi.org/10.55218/jasr.202314604
  21. Sudhakar, K., Fuloria, S., Subramaniyan, V., et al. (2021). Ultraflexible liposome nanocargo as a dermal and transdermal drug delivery system. Nanomaterials, 11(10), 2557. https://doi.org/10.3390/nano11102557
  22. Chen, R. P. (2022). Phytochemical delivery through transferosome (phytosome): An advanced transdermal drug delivery for complementary medicines. Frontiers in Pharmacology, 13, 850862. https://doi.org/10.3389/fphar.2022.850862
  23. Opatha, S. A. T., Titapiwatanakun, V., & Chutoprapat, R. (2020). Transfersomes: A promising nanoencapsulation technique for transdermal drug delivery. Pharmaceutics, 12(9), 855. https://doi.org/10.3390/pharmaceutics12090855
  24. Shaikh, J. S., & Akbari, B. (2025). Transfersomes in advanced drug delivery: A comprehensive review of design, mechanism, and clinical applications. Asian Journal of Pharmacy and Technology, 15(4), 395-401.
  25. Gupta, A. (2012). Transfersomes: A novel vesicular carrier for enhanced transdermal delivery of sertraline: Development, characterization, and performance evaluation. Scientia Pharmaceutica, 80(4), 1061–1080. https://doi.org/10.3797/scipharm.1208-02
  26. Chauhan, N. (2017). An updated review on transfersomes: A novel vesicular system for transdermal drug delivery. Universal Journal of Pharmaceutical Research, 2(4), 49–52. https://doi.org/10.22270/ujpr.v2i4.rw2
  27. Muthangi, S., Pallerla, P., & Nimmagadda, S. (2023). Transdermal delivery of drugs using transferosomes: A comprehensive review. Journal of Advanced Scientific Research, 14(06), 30-35.
  28. Sudhakar, K., et al. (2025). Development and evaluation of trans-resveratrol-loaded transfersomes. Nanotechnology, Science and Applications, 18, 45-58.
  29. Amasya, G., et al. (2025). Formulation and characterization of transfersomes for ocular delivery of tonabersat. Drug Development and Industrial Pharmacy, 51(1), 1-12. https://doi.org/10.1080/10837450.2025.2501991
  30. Witika, B. A., et al. (2026). The future of vesicular drug delivery: Transferosomes in therapeutic advancement—applications, innovations and challenges. Journal of Drug Delivery Science and Technology, 91, 12777116.
  31. Pawar, Y. A., et al. (2014). Formulation and evaluation of transferosomal gel of isotretinoin for severe acne. Research Journal of Topical and Cosmetic Sciences, 5(2), 65-72.
  32. Salmani, A. A., & Shrivastava, S. (2017). Elastic liposomes as novel carriers: Recent advances in drug delivery. International Journal of Nanomedicine, 12, 5087–5108. https://doi.org/10.2147/ijn.s141868
  33. Rai, S., Pandey, V., & Rai, G. (2017). Transfersomes as versatile and flexible nano-vesicular carriers in skin cancer therapy: The state of the art. Nano Reviews & Experiments, 8(1), 1325708. https://doi.org/10.1080/20022727.2017.1325708
  34. Touitou, E., Dayan, N., Bergelson, L., Godin, B., & Eliaz, M. (2000). Ethosomes – novel vesicular carriers for enhanced delivery: Characterization and skin penetration properties. Journal of Controlled Release, 65(3), 403-418. https://doi.org/10.1016/S0168-3659(99)00222-9
  35. Abdulbaqi, I. M., Darwis, Y., Khan, N. A. K., Assi, R. A., & Khan, A. A. (2016). Ethosomal nanocarriers: The impact of constituents and formulation techniques on ethosomal properties, in vivo studies, and clinical efficacy. International Journal of Nanomedicine, 11, 2279-2304. https://doi.org/10.2147/IJN.S105016
  36. Zhan, B., Wang, J., Li, H., Xiao, K., Fang, X., Shi, Y., & Jia, Y. (2024). Ethosomes: A promising drug delivery platform for transdermal application. Chemistry, 6(5), 993–1019. https://doi.org/10.3390/chemistry6050058
  37. Verma, P., & Pathak, K. (2010). Therapeutic and cosmeceutical potential of ethosomes: An overview. Journal of Advanced Pharmaceutical Technology & Research, 1(3), 274–282.
  38. Iizhar, S. A., Syed, M. A., Khan, S., & Baboota, S. (2026). Ethosomes: A review on the novel vesicular system for transdermal drug delivery. Nanomedicine Journal, 13(1), 12-28.
  39. Garg, V., Singh, H., & Beg, S. (2025). Evolution of ethosomal systems for the delivery of diverse therapeutic agents. Drug Delivery and Translational Research, 15(2), 442-460. https://doi.org/10.1007/s13346-024-01612-4
  40. Akiladevi, D., & Basak, S. (2025). Ethosomes – A noninvasive approach for transdermal drug delivery system. International Journal of Current Pharmaceutical Research, 17(1), 1-8.
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Vaishnavi Gaddam
Corresponding author

Department of Pharmaceutics, D. K. Patil Institute of Pharmacy, Loha Nanded India 431708

Vaishnavi Gaddam*, Transfersomes and Ethosomes for Enhanced Transdermal Drug Delivery: Mechanistic Insights and Comparative Evaluation, Int. J. Sci. R. Tech., 2026, 3 (2), 65-80. https://doi.org/10.5281/zenodo.18519387

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