Department of Pharmaceutics, Yashwantrao Bhonsale College of Pharmacy, Sawantwadi, Maharashtra, India.
The most successful novel drug delivery research area was the transdermal route, which was in competition with oral treatment. In recent years, there has been an increased interest in the utilization of lipid vesicles in skin therapy delivery systems. The transdermal drug delivery system's primary goal is to penetrate the stratum corneum. The vesicular system is among the most contentious approaches to transdermal medication delivery. Ethosomes are non-invasive delivery vehicles that allow medications to enter the systemic circulation or the deep layers of the skin. Ethosomes are a unique and inventive vesicular system. Ethosomes are composed of phospholipid, alcohol, polyglycol and water. Ethanol enhances skin permeability, facilitating deeper drug delivery into the underlying skin layers. Ethosomes are easy to make and safe to utilize, and their existence makes these systems more effective at delivering chemicals to the skin. The primary goal of this review article is to offer comprehensive insights into ethosomes including their mechanism of penetration, vesicular systems, types of ethosomes, preparation, composition, characterization, advantages, ethosomal dosage forms, application and marketed formulation of ethosomes.
As one of the largest and most accessible organs in the human body, the skin can provide a number of benefits over conventional drug delivery methods, such as reduced variations in plasma drug levels, prevention of gastrointestinal issues and first-pass drug metabolism, and increased patient compliance. One of the biggest drawbacks of transdermal drug delivery is that only a limited number of pharmaceuticals may be administered this way due to the skin's low permeability. It goes without saying that the drug must be able to pass through the skin barrier and reach the intended location in order for transdermal and topical drug delivery systems to work.[1]. Over the last few decades, scientists have created a variety of methods to penetrate the skin's protective layer and allow medications to enter the body via the skin's undamaged layer. To improve the effectiveness of transdermal transport, numerous techniques have been studied, including chemical skin permeation enhancers, iontophoresis, sonophoresis, electroporation, microneedles, and many more. Due to their limited effectiveness, potential for skin irritation, difficulty in use, and/or expense, none of these techniques have been widely used up to this point [2,3,4]. Lipid-based suspensions including liposomes, niosomes, and microemulsions have also been suggested as low-risk drug carriers; however, because they only penetrate the epidermis' outermost layers, they are not very useful for transdermal drug administration [5]. A number of researchers have created new elastic lipid vesicular systems that can easily and thoroughly enter the skin. To create these elastic vesicles, phospholipids, ethanol, bile salts, and many surfactants have been utilized. Because vesicular membranes are so flexible, these elastic vesicles can pass through stratum corneum pores, which are far smaller than their own vesicular diameters [6]. The first generation elastic lipid vesicular carrier, known as Transfersomes, was initially shown by Cevc et al. in 1992. It is primarily composed of phospholipids and an edge activator, which is a non-ionic surfactant. When used in non-occlusive settings, they were said to be able to transfer the medication into and across the skin while penetrating intact skin [7,8].
Structure Of Skin:
The epidermis' uppermost layer is called the stratum corneum. In a matrix of lipid bilayers, it is composed of 10 to 25 layers of dead, elongated, completely keratinized corneocytes. It has been demonstrated that the primary barrier to penetration through the skin is the stratum corneum. The active medication must enter the living tissue through the stratum corneum when a topical preparation is applied to the skin. The slow diffusion through the dead horny layer of skin is the limiting factor for these processes. The stratum corneum functions as a membrane that is hydrophobic. The stratum corneum primarily determines the rates at which low and high molecular weight organic nonelectrolytes penetrate the skin [9,10].
Figure No. 1: Structure of Skin
Vesicular Systems:
Liposomes
They are tiny water-containing vesicles that resemble the phospholipid bilayer structure of skin. In certain situations, the phospholipid chain from soy or egg yolk and cholesterol
[11]. Mezei was the first to use liposomes as delivery vehicles. It addressed the need for innovative techniques because it only assisted the drug in reaching the reservoir in the epidermis' outermost layer; no percutaneous absorption was accomplished. According to some research, using liposomes resulted in increased miconazole nitrate deposition in the upper skin stratum with minimal penetrability. [12].
Niosomes
They are more stable and less expensive than classical liposomes because they are composed similarly, with the exception of the nonionic surfactants. Drug physico-chemical characteristics, vesicle type, and lipid composition all influence the processes [13]. The thin film hydration approach produced fluconazole niosomes with span 60, span 40, and Brij 72, which demonstrated longer-lasting drug release and increased cutaneous retention.[14].
Transferosomes
Their increased flexibility and deformability have earned them the names liposomes or ultra-deformable vesicles. The flexibility and effectiveness of phospholipids and other surfactants make them an effective delivery system for both topical and transdermal administration of medications, genetic materials, and vaccinations. When clotrimazole-loaded ethosomes were studied, it was discovered that the drug flux was higher in the system than in regular transferosomes. This eventually demonstrated the ethosomes' superior vesicular delivery efficiency.
Aquasomes
The ceramic carbon nanocrystalline particulate core of this three-layered self-assembled nanoparticle system is coated with glassy cellobiose, which aids in molecular shielding and targeted specificity.
Cubosomes
These methods have been experimentally employed to distribute herbal medicine for the KIOM-MA 128 medication, which is used to treat atopic dermatitis. Compared to suspension form, cubosomes improved the permeability feature of M-A 128.
Ethosome
Touitou et al. (2000) have developed a unique lipid carrier called ethosome, which exhibits improved skin delivery. The components of the ethosomal system include water, ethanol, and phospholipid. Ethosomes range in size from a few nanometers to micrometers, contingent on the preparation process and the use of methods such as sonication. Many investigations looked into how ethanol affected the ethosomal vesicles' physicochemical properties. Ethosomes have been described as being smaller than liposomes when both are prepared without any size reduction procedures. The addition of a high ethanol concentration may be the cause of this decrease in vesicle size. The liposome gains a surface negative net charge from ethanol, which reduces the size of the vesicles. In the range of 20–45% ethanol concentration, it was observed that the size of ethosomal vesicles increased as the ethanol concentration decreased. The impact of phospholipid concentration on ethosomal vesicle size was also examined. [15].
Lipophilic medicines are among the many compounds for which ethosomes have demonstrated high encapsulation effectiveness. This may be explained by the ethosomal vesicles' multilamellarity and the ethanol present in ethosomes, which improves the solubility of many medications. It was demonstrated through encapsulation tests that ethosomes may trap both hydrophilic and hydrophobic medications.
Figure No.2: Structure of ethosome
Types Of Ethosomes
1.) Classical Ethosomes
Classical ethosomes consist of phospholipids, water and high ethanol concentration. Classical ethosomes are better than conventional liposomes because of small size, negative zeta potential and higher entrapment efficiency [16-18].
2.) Binary Ethosomes
Binary ethosomes are formed by introducing another form of alcohol such as propylene glycol and isopropyl alcohol etc to the classical ethosomes [19,20].
3.) Transethosomes
Transethosomes are a new form of ethosomal system and have been designed to combine the advantages of classical ethosomes and transfersomes in a single formula. In their structure, they contain basic components such as that of classical ethosomes and a penetration enhancer or an edge activator [21-24].
Figure No.3: Types of Ethosomes
Ethosome Composition:
Ethosomes are vesicular carriers composed of hydroalcoholic or hydro/alcoholic/glycolic phospholipids that contain a significant amount of alcohols or alcohols in combination. [25-30]. The various type of additives used in the Ethosomes Preparation are represented in table1.
Table 1: Different additives employed in formulation of Ethosomes
|
Additives |
Uses |
Examples |
|
Phospholipid |
Vesicles forming Component |
Soyaphosphatidyl choline, Egg Phosphatidylcholine, Dipalmityl phosphatidyl Choline, Distearyl phosphatidyl choline. |
|
Polyglycol |
Skin penetration enhancer |
Propylene glycol, Transcutol |
|
Cholesterol |
Stabilizer |
Cholesterol |
|
Alcohol |
For providing the softness for vesicle membrane as a penetration enhancer |
Ethanol Isopropyl alcohol |
|
Vehicle |
As a gel former |
Carbopol 934 |
|
Dye |
For characterization study |
6-Carboxy Fluorescence, Rhodamine-123, Rhodamine red, Fluorescence |
Advantages Of Ethosomes Drug Delivery: [ 31-35]
Disadvantages Of Ethosomes Drug Delivery:
Mechanism Of Drug Penetration:
Ethanol effect: Ethanol works to improve the penetration of the skin. Its boosting action through absorption has a well-established mechanism. By penetrating intercellular lipids, ethanol increases the fluidity of cell membrane lipids while decreasing their density.
Ethosome effect: An increase in skin permeability is the result of ethosome ethanol's greater lipid fluidity in cell membranes. Ethosomes thus penetrate the deep skin layer relatively rapidly, where they interact with skin lipids to release medications into the deep skin layers [36,37].
Figure No.4: Drug Penetration through Ethosomes
Figure No.5: Mechanism of action of ethosomes
Method Of Preparation of Ethosomes:
1. Cold method: For ethosome preparation, the cold approach is one of the most popular techniques. First, phospholipid is vigorously stirred in ethanol at room temperature to dissolve it. Next, polyols such as propylene glycol are added gradually while being stirred frequently, and the mixture is heated to 30ºC in a water bath. The water is then heated to 30 degrees Celsius in a different vessel, and the two combinations are combined. The mixture is then stirred for five minutes in a covered vessel. The ethosomal formulation can have its size reduced to the necessary degree by employing the sonication technique. [38,39].
Figure No.6: Formulation method of ethosomes by cold method
2. Hot method: In the hot process, phospholipid is added to water and heated on a water bath to 40ºC until an aqueous phase, or colloidal solution, is formed. In a separate vessel, ethanol and propylene glycol are properly combined and heated to 40ºC (Organic phase). Under continuous stirring, the organic phase is introduced to the aqueous phase. A desired degree of ethosomal formulation size reduction can be achieved by employing the sonication technique. [40,41].
Figure No.7: Formulation method of ethosomes by hot method
3. Classic mechanical dispersion method: Using a round-bottom flask, this approach dissolves phospholipid in an organic solvent or a combination of organic solvents. To produce a thin layer of lipids on the RBF surface, the organic solvent is removed using a rotating vacuum evaporator. By keeping the contents under vacuum for the entire night, traces of the solvent are extracted from the lipid film that has formed. The drug's hydro-ethanolic solution is used to hydrate the lipid layer by spinning the flask at the proper temperature. Cool the resultant ethosomal suspension at room temperature.[42].
4. The ethanol injection–sonication method: This procedure involves injecting the organic phase, which contains the phospholipid dissolved in ethanol, into the aqueous phase using a 200-flow syringe system at a rate of 38?l per minute. An ultrasonic probe is then used to homogenize the mixture for five minutes.
Characterization Of Ethosomes:
Therapeutic Application Of Ethosomes:
Several studies have demonstrated the effectiveness of ethosomal technology, which involves transdermal administration, in delivering medications with low oral bioavailability. The numerous uses of ethosomal technology in diverse scientific domains include the following:
These days, a lot of people throughout the world suffer from hair problems like acne, excessive hair loss, and seborrhea. Therefore, selective distribution of the particular medicine to hair follicles is crucial for the efficient treatment of pilosebaceous illnesses. A lipophilic medication called minoxidil is applied topically to the scalp to cure hair loss. To study minoxidil targeting to pilosebaceous units via ethosomes, minoxidil ethosomes were made and assessed in vivo in hairless rats. The findings demonstrated that minoxidil was found in the pilosebaceous units, suggesting that ethosomal carriers were used to transport minoxidil more effectively. [49]
Researchers used rabbit pinna skin to compare the effects of transdermal patches and ethosomal preparations of testosterone. They found that the ethosomes of testosterone had a roughly 30-fold higher penetration rate through the skin barrier than the transdermal patch. Since ethosomes minimize the possibility of first-pass metabolism and some dose-related adverse effects, they are a superior delivery method for several hormones. Compared to alternative methods, ethosomal preparation produced satisfactory patient compliance. [50].
Ethosomes can also be used to administer a number of anti-arthritic medications because they offer site specificity, which improves treatment with fewer adverse effects and eliminates first-pass metabolism at lower dosages. The ethosomal vesicles of the anti-arthritic medication cannabidol (CBD) were created by Lodzki et al. Better penetration and longer residence duration in the skin for roughly 72 hours were the outcomes of their examination of the formulation's penetration into the skin. [51].
Large macromolecules like proteins, peptides, and insulin are difficult to administer orally since the GIT tract completely breaks them down. Transdermal delivery is therefore a superior substitute. However, typical transdermal formulations of biomolecules, such as insulin and peptides or proteins, have minimal penetration. By incorporating these compounds into ethosomes, the therapeutic efficacy and penetration are increased. [52].
To improve the therapeutic efficacy of these agents, topical administration is a superior choice. Along with a number of adverse effects, traditional oral therapy causes a lot of allergic responses. Traditional external medications don't penetrate deeply into the skin or subcutaneous tissues very well. By releasing adequate medicines into the deeper layers of the skin, ethosomes can resolve this problem. Ethosomes may readily pass through the epidermis, transport significant amounts of medication into the skin's deeper layers, and eradicate infections at their source. Godin and Touitou developed ethosomal formulations containing erythromycin and bacitracin for both intracellular and cutaneous administration. The study's findings demonstrated that antibacterial ethosomal formulation could be quite successful in resolving issues related to conventional therapy. [53].
Ethosomes are an appealing therapeutic approach for anti-HIV treatment, as evidenced by the MT-2 cell line's superior cellular absorption of zidovudine and lamivudine, two anti-HIV medications, from ethosomes compared to commercial formulations. [54]
It is possible to apply gene therapy using ethosomes. Ethosomal formulation has been demonstrated to improve gene delivery and expression in skin cells as well as intracellular DNA processing. Recent research has indicated that immunization by transfersomal formulation may be possible. These types of dosage forms can be used to provide immunization agents because to ethosomes' increased ability for skin penetration. [55]
Ethosomes were generated using a variety of antifungal medications, including fluconazole, betamethasone, clobetasol, and others. These antifungal medications' ethosomal vesicles have been developed and tested for skin penetration rate in comparison to other commercially available formulations, which ultimately demonstrated improved clinical efficacy and patient compliance. [56]
Dayan and Touitou created an ethosomal formulation of the psychoactive medication trihexyphenidyl hydrochloride (THP) and contrasted its distribution with that of a traditional liposomal formulation. THP is used to treat Parkinson's disease because it is an antagonist of M1 muscarinic receptors. The findings demonstrated the ethosomal-THP formulation's improved skin penetration capacity and its application for improved Parkinson disease treatment. [57]
Additionally, antiviral medications can be administered by means of a sophisticated transdermal delivery system. Since the ethosomal administration system avoids the first pass metabolism impact and minimizes dose-related side effects, it exhibits superior patient
compliance when compared to alternative delivery methods. Numerous antiviral ethosomal vesicles, such as zidovudine, acyclovir, and stavudine, have been developed; their penetration effectiveness was evaluated in comparison to both their other topical formulation and the commercially available oral formulation. So, the study found that the antiviral drug's ethosomal formulation was more effective and produced better clinical results.
Marketed Formulation Of Ethosomal Drug Delivery System:
Ethosomes were created and patented by Professor Elka Touitou and her students from the Hebrew University School of Pharmacy's Pharmaceutics Department. Using an ethosomal delivery technology, Hebrew University's Novel Therapeutic Technologies Inc. (NTT) has successfully introduced several medicines to the market.
Table 2: Marketed products based on Ethosomal drug delivery system
|
Product Name |
Drug Name |
Company Name |
Use |
|
Noicellux |
Methylxanthine Caffeine |
Novel Therapeutic Technologies, Israel |
Topically Applied Anti Cellulite Cream |
|
Cellotight |
Powerful Combination of Ingredients to Increase Metabolism and Break Down Fat |
Hampden Health, USA |
Applied Anti Cellulite Cream |
|
Lipoduction |
Pure Grape Seed Extracts |
Osmotics, Israel |
Anti Cellulite Cream, Antioxidant |
|
Skin Genuity |
Caffeine/ Retinol Or The Antioxidant Dimethylaminoethanol |
Physonics Nottingham, Uk |
Anticellulite Gel |
|
Nanominox |
Minoxidil At 4% Concentration. |
Sinere, Germany |
Hair Growth Promoter |
|
Decorin Cream |
Decorin Proteoglycan |
Genome Cosmetics, Pennsylvania, Usa |
Anti-Aging Cream |
|
Supravir Cream |
Acyclovir |
Trima, Israel |
Against Retroviral Disease Like Herpes Virus. |
Significance Of Ethosomes:
Significance of ethosomes can be describes on the basis of different studies related to specific applications of ethosomes as a carrier system in transdermal delivery of different drugs which are as follows;
Ethosomal Dosage Forms:
Due to the high alcohol content of the ethosomal system, its incorporation into a suitable dermal/transdermal administration vehicle prolongs skin contact time, decreases ethanol evaporation, improves drug effectiveness, extends the system's stability and shelf life, and increases patient compliance. It has been claimed that the ethosomal system can be loaded into a variety of topical dose forms, such as creams, gels, and transdermal patches.
Ethosomal Gels:
Gel, which is often based on carbopol, is a frequently used dosage form for loading the ethosomal system. [60, 64-66], or hydroxypropyl methylcellulose [67-69], like gel-forming substances. Ethosomal gels are distinguished by their pH, viscosity, spreadability, and extrudability. It has been established that these polymers are compatible with ethosomal systems, providing them with the required adhesion and viscosity properties. Many researches have examined the skin penetration and deposition of various medications from ethosomal gels and discovered that they are better than those of traditional or commercially available gels or creams. [65]
Ethosomal patches and creams:
In contrast to creams, patches and creams are less frequently used as ethosomal system vehicles. This is often because gel bases are easier to prepare and work well with the high alcoholic content of ethosomes. Additionally, patch development can be challenging because specific molds are needed. [70,71] However, patches provide occlusive conditions for the administration of the loaded medicines, which may enhance skin penetration and deposition. But according to Godin and Touitou, there was no discernible change in the ethosomal system's ability to deliver the loaded agents in occlusive and nonocclusive conditions. [72]
Limitations Of Ethosomal Drug Delivery:
Future Perspectives:
CONCLUSION
Ethosomes are a non-invasive way to deliver unique medications with a range of physicochemical characteristics to the skin. It is best suited for systemic and local applications. Ethosomes have a number of benefits in the pharmaceutical industry, including controlled/sustained drug release, high biocompatibility, and decreased toxicity. However, ethosomes are appealing drug delivery vehicles due to their ease of manufacture and composition. For topical or transdermal applications, the inclusion of ethanol in vesicles offers a number of advantages over other lipidic vesicles. It is also simple to add ethosomes into other dosage forms, such as gels, patches, and lotions. It follows that ethosomal formulations will find a role in the therapeutic field in the years to come because of improved permeability for better therapeutic efficacy. Thus, ethosomal formulations possess promising future in effective dermal/transdermal delivery of bioactive agents.
REFERENCES
Shilpa Tigote*, Rashmi Mahabal, Namita Bhosale, Vijay Jagtap, Comprehensive Review on Ethosomes: A Novel Vesicular Approach for Topical Drug Delivery, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 12, 2882-2897. https://doi.org/10.5281/zenodo.14543929
10.5281/zenodo.14543929
