Ethosomes: A Novel Drug Delivery System And Their Therapeutic Applications -A Review


Moghal. Roohi Shabreen, Dr. S. Sangeetha*

Department of Pharmaceutics, SRM Institute of science and technology, Kattankulathur-603203

*Corresponding Author E-mail:



“Ethosomes” are soft vesicles made up of Phospholipids, Ethanol and water. They are “novel carrier system” used for delivery of drugs having low penetration through biological membrane i.e., Skin “Transdermal delivery of drugs” plays a major role in the Ethosomes. In this review we are going to discuss about various applications of ethosomes i.e. Delivery of antibiotic, Delivery of NSAIDS, Anti-cancer, Anti-fungal, Skin cancer, Anti-Acne etc. Ethosomes are loaded with drugs like Indomethacin (NSAIDS), Clotrimazole (Anti-fungal), Raloxifene HCl (Anti-cancer), Fluconazole (Antibiotic) etc. This review explains about the preparation methods used in the preparation of ethosomes such as cold method, Hot method, Injection method, Mechanical dispersion method and Classic methods. Evaluation tests performed in the ethosomes are Drug entrapment efficiency, permeation characteristics, Assay of HPLC, FT-IR studies, stability studies, size analysis, zeta potential etc. Various Penetrtion enhancers like Labrasol, Transcutol, and Terpenes were used in the formulation of ethososmes. Improve the penetration of both lipophilic and hydrophilic drugs through stratum corneum [SC] into deeper layers of the skin very effectively when compared with liposomes. Ethosomes can act as a carrier for large and diverse group of drugs with different physicochemical properties and found a number of applications in pharmaceutical, biotechnological and cosmetic fields. Enhanced delivery of bioactive molecules through the skin and cellular membranes by means of an ethosomal transporter opens numerous confronts and prospects for the research and future development of novel improved therapies. The formulation of ethosomes possesses promising future in effective dermal or transdermal delivery of bioactive agents.


KEYWORDS: Ethosomes, Transdermal delivery, penetration enhancers, stratum corneum, novel carrier system.





Ethosomes are “novel carrier system” which are soft vesicles made up of “Ethanol”, “Phospholipids” and “Water”. They are used for delivery of drugs having low penetration through biological membrane i.e., Skin. These are the little alterations of drug carrier Liposomes.1-4 Ethosomes can implicate the drug molecules with several physiochemical properties like “lipophilic”, “hydrophilic”, or “amphiphilic” and the size range may vary from nanometres to microns (μ).5,6 Ethosomes can be Unilamellar or Multilamellar which are showed by visualization by Electron microscopy.7-9


Preparations of ethosomes provide sustained delivery of drugs and they act as reservoir system for continuous delivery of drugs.10 Ethosomes are unique because of high concentration of ethanol present in it and this ethanol caused disruption of skin lipid bilayer organization. When ethosomes are incorporated into a vesicle membrane it increases the ability to penetrate the stratum corneum corneum.11,12 For transdermal and dermal delivery, ethosomes are “Efficient systems”. Due to the presence of high concentration of ethanol ethosomes increase the topical drug delivery.13,14 Ethanol is said to be an efficient permeation enhancer.15 Adverse to deformable liposomes, ethosomes are capable to increase delivery of drugs through skin by both occlusive and non-occlusive conditions.16 Ethosomes which are as a lipid vesicle has more effectiveness in “percutaneous drug delivery” and has preferable pharmaceutical properties, high entrapment efficiency, improved compatibility with the stratum corneum [SC], as well as stability at room temperature. Hence improve the penetration of both lipophilic and hydrophilic drugs through stratum corneum [SC] into deeper layers of the skin very effectively when compared with liposomes.13,17Ethosomes produce greater capacity of deformability, liquidity and more encapsulation efficiency. They can develop the drug to penetrate through the skin and enhance drug accumulation in it.18 They are flexible liposomes and are elastic in nature. Due to its elastic deformation it enhances the therapeutic delivery through pores and provides deep penetration into the skin.19 Increase in membrane permeability and fluidity is due to the interaction of ethanol with lipid molecules in polar head group region. Dug releases at several points along the penetration pathway which is the result of fusion of ethosomes with skin lipids.13 Enhanced drug delivery through ethosomes was recognized by enhancing fluorescent activity and depth in another studies.20 There is an “Ethanol effect” as well as “Ethosomal effect”. In an Ethanol effect, interaction of lipid molecule with ethanol takes place in the polar head group region and shows reduction in transition temperature of lipids in stratum corneum and enhances the fluidity there by with reducing the density of lipid multilayer. Whereas in Ethosomal effect, permeation and penetration is due to fusion and malleability of ethosomes with skin lipids. Release of drug into deeper layer of skin are the results of this step. Due to this transdermal absorption, drug releases at several points and fusion of ethosomes with skin lipids are the conclusion of this effect. 21




1.       Ethosomes are non-invasive, passive and contains non-toxic raw materials in the preparation.22

2.       Its composition is safe and are used in the cosmetic and pharmaceutical use.5

3.       Deliver several molecules with different physiochemical properties, peptides, other macromolecules, hydrophilic and lipophilic molecules.5

4.       They are administered in semi solid dosage form and has good patient compliance.23

5.       Large and diverse groups of drugs has platform provided by ethosomes.23



1.       Ethosomes may clump together and gets precipitated with poor shells and are not economical.

2.       Adhesives will not stick to all kinds of skin.

3.       Because of enhancers and excipients of drug delivery system there is dermatitis and skin irritation

4.       Product loss occurs when ethosomes are transferred from organic to aqueous layer.

5.       Administration of ethosomes did not achieve rapid bolus type drug input

6.       They were designed for slow and sustained drug delivery.24-29



The mechanism involves two steps they are as follows.

Ethanol effect- It is a first part of mechanism, where the ethanol and lipids molecules interact togethers in the polar head group region. The results of these are increase in fluidity, decrease in the density of the lipid multilayer, transition temperature of the lipids in stratum corneum are reduced.


Ethosome effect- It includes permeation of lipids as well as penetration of them by the opening of new pathways. This is because of the fusion and malleability of ethosomes with skin lipids, release of drug into deep layers of the skin are the results. Vesicles are soft flexible provided by the ethanol, grant them to penetrate into the deeper layers more easily. Fusion of ethosomes with skin lipids and release of drug at different points and its transdermal absorption are the results.30-35





The formulation of ethosomes are convenient and don’t require any sophisticated equipment’s and scale up, at industrial level is easy and are prepared by following methods. They are as follows:



Ethosomes are formulated by cold method which is the most common method used for formulating them. During formulation of ethosomes the drug, phospholipid and other lipid materials are dissolved in ethanol which is kept in a closed vessel at room temperature. By using mixer continuous stirring is done by adding polyol or propylene glycol to the above mixture. It is then heated at 300℃ in a water bath. To this mixture the water which was previously heated is added and stirred for 5 mins. By using “sonication” or extrusion method” the vesicle size of the ethosomal formulation was reduced and can be stored in a refrigeration at 40℃.36



Ethosomes are formulated in hot method, in this method the phospholipids are dispersed in water by heating at 400℃ in a water bath. The above solution was heated until the colloidal solution is obtained. Propylene glycol and ethanol are mixed and heated to 400℃ in a separate vessel. The organic phase is added the aqueous phase when both the mixture reaches to 400℃. Depending on their hydrophilic or hydrophobic properties the drug can be dissolved in ethanol or water.37




In the injection method the ethosomes are formulated using various concentration of ethanol, isopropyl alcohol, propylene glycol and lecithin. The drug and phospholipids are dissolved in propylene glycol and ethanol then heated to 30℃ on the thermoregulated magnetic stirrer. In a closed vessel, double distilled water with constant stirring at 700 rpm is added slowly with the speed of 200µl/min and the temperature was maintained at 30º C. The ethosomes are stored at 4℃ after mixing it continuously for 5 minutes. By using probe sonicator, ethosomes are formulated and sonicated at 4º C. this was done in 3 cycles of 5 mins and then rest between the cycles was for 5 mins.38



In this method soya phospotidylcholine which are used in formulating ethosomes are dissolved in chloroform and methanol in a “round bottom flask”. Rotary vacuum evaporator removes the organic solvent to form a thin lipid film on the wall of the round bottom flask. Solvent mixture’s fine traces are removed from the lipid film (deposited already) by leaving some residues under vacuum for a night. By using various concentrations of hydroethanolic mixture which has drug in it, hydration is done by rotating the round bottom flask at proper temperature.39



1.Drug Entrapment Efficiency:

Ethosomes possess lower Tm when compared to liposomes are disclosed by Differential scanning calorimetry thermograms and Anisotropy measurement of AVPC. By using High degree of lamellarity and by the presence of ethanol in the vesicles, the ethosomes can entrap lipophilic and hydrophilic drugs efficiently. Ethosome preparations has more entrapment capability when compared to liposomes.


2.Permeation Characteristics:

Ethosomal preparations increase the permeation of both “Hydrophobic” and “Hydrophilic” molecules when compared to conventional liposomes and were explained by Invitro and Invivo studies. According to various workers it has been disclosed that ethosomal preparations has good skin permeation than conventional liposome preparations whereas Ethanol plays a key role in enhancing property.


3.Vesicle Skin Interaction Study:

Ethosomal preparations has better skin permeation the evaluation is done by various visualization techniques i.e. eosinhematoxylin staining, transmission electron microscopy, confocal scanning laser microscopy (CSLM) and confocal scanning laser microscopy (CSLM). The above visualization techniques gave good idea when used in combination about the penetration pathways, structure modification of vesicles. There are no ultrastructural changes seen in cell layers below the stratum corneum. The results states that “liquid state” vesicles not only act in stratum corneum layers but also provides liquid perturbations in the stratum corneum’s deep layers. Whereas “gel state” vesicles interact only with the outermost layers in the stratum corneum. Drug permeation enhancement between conventional liposomal and ethosomal preparations are explained.22,41-43


4. Stability studies:

Ethosomal preparations which are stored at two different temperatures i.e. 4℃ and 25±2℃ were carried out by stability studies. To identify any change in the entrapment efficiency of ethosomal preparation the drug was predicted for every 15 days. 44-46


5.Size analysis:

Size determination and size distribution of ethosomes were determined by various methods which comprise of size exclusion chromatography [SEC], microscopy techniques and dynamic or static light scattering. Atomic force microscopy {AFM}a newly developed microscopic technique which is powerful, rapid, and non-invasive was used to study the size, stability and morphology of the ethosomes and they can be evaluated without manipulations. They provide information about the size, morphology and aggregation process during their storage.47 Ethosomes population under physiological conditions are separated and quantified by SEC along with HPLC thus leads to separation of large particles before small particles. HPLC-SEC for analysis provides enhanced resolution of liposomal population thereby increase reproducibility and decrease the sample size.48 Collision between the solvent molecules as well as suspended particles occurs.49


6. Zeta potential:

A laser is used to give a light source of illuminating particles within the samples for measuring thezeta potentialwhich is a physical property displayed by overall charge of any particle in suspension. Particles suspension are said to be stable when it has zeta potential of about > +30 mV or < −30 mV. 50


7. Vesicle shape:

Transmission electron microscopy {TEM} and Scanning electron microscopy{SEM} are used for the visualization of ethosomes. Ethosomal preparations gives vesicular structure of about 300-400 nm in diameter was declared by visualization done by electron microscopy. Vesicles are incomplete round shape and are malleable.51



1.Pilosebaceous targeting:

Sebaceous glands and hair follicles are highly identified as important elements in percutaneous drug delivery. Pilosebaceous units are used as depots for follicle related disorders like alopecia or acne treatment and as localised therapy. Later it has been concentrated on exploiting the follicles as transport shunts with the purpose of pilosebaceous targeting for systemic drug delivery. 52


PP. Udapurkar, studied on Ethosomes-novel vesicle carrier for enhancing transdermal drug delivery. They aimed that skin plays a important role like a major target as well as principal barrier for delivery of topical drugs. One of the major drawback was low diffusion rate of drugs across the stratum corneum. For drugs to reach deep layers of skin and to systemic circulation “Ethosomes” are used which are non-invasive delivery. Active agents are delivered by Ethosomes. Lipophilic molecules and cationic drugs are delivered through skin because of Ethosomes which are soft and has a unique structure. Several challenges and research opportunities as well as development of novel improved therapies are done by delivery of bioactive molecules through skin.53


2. Antibiotics Delivery:

Ethosomes have better efficacy for enhancing topical delivery of antibiotics. Various side effects and allergic reactions are caused by such Prevailing oral therapy. Low permeability to skin layers and various tissues is acquired by such prevailing external preparation. 54

Gashin Zandi, studied on “A comparative study on the potentials of nanoliposomes and nanoethosomes for Fluconazole delivery and stated that fungal incidence has spread worldwide. Poor response to prevailing antibiotic therapy due to variety of persistent infections is caused mainly by Biofilms (assembly of microorganism). Fluconazole, an imidazole derivative is effective against fungal infections. Flucanazole was encapsulated by nano liposome [Thin film hydration method] and nano ethosome [Ethanol injection method] preparations and are compared their particle size, morphology, zeta potential, and encapsulation efficiency. By the study of invitro drug release nano liposome and nano ethosome preparations release 40-80% of drug after 48 hrs. compared to nano ethosome, nano liposomes are more relevant.55


3. Delivery of Anti hyperlipidemic agent:

Bile excretes 95% of simvastatin which was metabolized by liver. After oral administration Active structures which are below 5% were found in blood circulation. Keyo An, had formulated simvastatin as Ethosome and In vitro evaluation was carried out. Lipid levels and coronary artery diseases are enhanced and thereby reduces Low Density Lipoprotein Cholesterol [LDL]56.


4. Delivery of NSAIDs agent:

Evaluation of Transdermal potential of novel vesicular carrier, ethosome containing “Aceclofenac”. Aceclofenac is a Non-steroidal anti-inflammatory drug {NSAIDS} has less transdermal permeation. Aceclofenac (ethosomes) were prepared.57 Bhale Shwetaet al in 2013 raised a topical application to enhance skin permeation by using a potential ethosome for delivering of Etodolace which is water insoluble NSAID through skin.58 Vivek Dave1, studied on Ethosome for Enhanced Transdermal Drug Delivery of Aceclofenac. The aim of their study was to evaluate ethosomes containing Aceclofenac [NSAIDS]. For characterisation of vesicular size, stability, vesicular shape, surface morphology, invitro release study entrapment efficiency and scanning electron microscopy Aceclofenac (Ethosomes) were prepared. Transdermal flux for ethanolic solution is greater than isopropyl alcohol and was showed by ethosomal preparation. Ethosome preparation has effective transdermal delivery in future and it was said to be more efficient and safe.


Pajaree Sakdiset, studied on Formulation development of ethosomes containing indomethacin for transdermal delivery. In their study Indomethacin (ethosome) was formulated with different concentrations of Ethanol and Soya phosphatidyl choline [SPC] and also with additives and dispersion media. Size, physical appearance and entrapment efficiency are the properties of Ethosomes and were identified. There is a preferable decrease in vesicular size, observed at 20 % & 30% ethanol. Through the skin of a pig ethosomes show high permeation of indomethacin for 24hours when compared to ethanol solution and commercial solution of indomethacin. When the formulation was stored for three months, the entrapment efficiency, drug content and physical appearance was stable.59


5. Delivery of Antifungal agent:

“Ethosomes” and “Ultra deformable liposomes” for transdermal delivery of “Clotrimazole” was established by Rahul G.S. Maheshwari et al, 2012.60 “Ketoconazole” [Ethosome] was prepared by Sarat Chandarn C et al 2012 Ketoconazole. 61


Sara M. Abdel Samie, has studied on Terbinafine hydrochloride nanovesicular gel: In vitro characterization, ex vivo permeation and clinical investigation. The aim of their work was to formulate Nano vesicular Chitosan gel for delivering Terbinafine Hydrochloride [TBN HCl]. Various Penetrtion enhancers like Labrasol, Transcutol, and Terpenes were formulated by ethososmes. Physical characteristics as well as skin interactions are evaluated by the prepared vesicles which are fused into chitosan gel. By using rat induced superficial Candida infection model An in vivo animal study was performed. For comparing the response of the selected nano vesicular gel adjacent to the market product a randomised double blind clinical study was performed. Limonene nano vesicular gel displays cure rate of 86% within 7 days when compared to market product [Lamisil® cream] which is of about 20% during the clinical studies.62


6. Anticancer:

Syed Mahmood, studied on Transdermal delivery of raloxifene HCl via ethosomal system: During their study they explained about the breast cancer drug which is Raloxifene HCl resides to the class of “selective estrogen receptor modulators” [SERMs]. The aim of their study was to compare the ethosomal preparation (Raloxifene HCl) for transdermal route with oral route and the disadvantage was that it has poor bioavailability up to 2%. By using Rotatory method five ethosomal preparations with various concentrations were formulated and the formulations were evaluated by Atomic force microscopy{AFM}, High resolution transmission electron microscopy{HRTEM}, X RAY Diffraction {XRD}, PNMR study and Force emission electron microscopy{FESEM} and the results of it was found that the ethosome formulation was well explained by its size, bilayer formation, and shape. When compared to conventional liposomes optimised ethosomes has transdermal flux of about 22.14 ± 0.83 µg/ml/cm2 which was 21 times high. Coumarin- 6 dye containing ethosomes has increased permeation to deep layers of skin when compared to conventional liposomes. The gel has elastic behaviour and it was pseudoplastic. There is a high bioavailability in rats during Invivo studies for ethosomal preparation when it was compared with oral preparation. 63



Tunyaluk Limsuwan,, studied on Ethosomes of Phenylethyl Resorcinol as Vesicular Delivery System for Skin Lightening Applications. The aim of their study was to formulate ethosomes containing Phenylethyl Resorcinol. By using lanolin, cholesterol, ethanol, water and L-α-phosphatidylcholine from soybean. Permeation coefficient of Phenylethyl Resorcinol is more when invitro studies were done on skin of the pig. Ethosomes displays more tyrosinase inhibition activity and reduce melanin content when they are compared with other formulations and they don’t give acute dermal irritation in albino rats. Thus their study explained that Phenylethyl Resocinol has better availability for topical application of skin lightening products.64


Jiesi Xie, studied on Hyaluronic acid-containing ethosomes as a potential carrier for transdermal drug delivery. Their work was to prepare ethosomes containing Hyaluronic acid as the transdermal drug delivery system a Rhodamine B [ RB] was used which was to be encapsulated. The evaluation tests i.e. Entrapment efficiency, stability, surface morphology were done. According to the results it has been found that Hyaluronic acid [ethosomes] and RB are spherical in shape and has better stability and dispersion. Rat dorsal skin is used for invitro studies with Franz diffusion cell for skin permeation experiment and it has been proved that it has good penetration into the dermis by fluorescence microscopy. The results of their study was ethosomes has good biocompatibility, can be self-administered and are highly efficient.65


Guiling Li et. al., studied on Tacrolimus-loaded ethosomes: Physicochemical characterization and in vivo evaluation. During their study they formulated and evaluated Tacrolimus (a novel ethosomal carrier) it is used as an immunosuoppresant for treating “Atopic dermatitis” [AD] and has identifies the inhibition action, it has poor penetration capability when compared to Glucocorticoid. The results of their study was ethosomes has high encapsulation efficiency, lower vesicle size. Tacrolimus (ethosomes) has higher penetration. When applied topically Tacrolimus shows ear swelling in BALB/c mice model when repeated dose of 2,4-dinitofluoro benzene when compared with commercial ointment and traditional liposomes. And finally, it has been proved that Tacrolimus is used for treating AIDs.66


Thasleem Moolakkadath, studied on Fisetin loaded binary ethosomes for management of skin cancer by dermal application on UV exposed mice. Fisetin (ethosomes) were prepared and optimized by using “Box Behnken design” to treat skin cancer and used as dermal application. Evaluation tests like entrapment efficiency, vesicle size, and flux of Fisetin and other evaluation tests are done by transmission electron microscopy, confocal laser microscopy, dermatokinetic study, and vesicle skin interaction. The confocal image of rat skin explains “Rhodamine B” has deeper penetration and thus the rat skin shows increase in Cskin max and AUC0-8 when compared with conventional gel. The mice which was pre-treated with fisetin gel shows decrease in the levels of TNF-α and IL-1α during invivo studies and they are compared with the mice expoised to UV only. It has been explained that it has improved dermal delivery. The final conclusion of their study was it has potential dermal system for the treatment of skin cancer.67


Inayat B. Pathan, studied on Curcumin loaded ethosomes for transdermal application: Formulation, optimization, in-vitro and in-vivo study. During their study they have explained that Curcumin has an anti-inflammatory, antioxidant, antimicrobial, anticancer, anti-tumoral activity and has a very good safety profile with various pleiotropic actions and the major obstacle was it has poor oral bioavailability which reduce its usage as an oral dosage form. Their investigation was proved that curcumin was used as transdermal application. By using Box Behnken method with three independent variables and three response variables using thin film dispersion method and the evaluation tests includes vesicle size, zeta potential, entrapment efficiency, vesicular stability study, vesicle size, invitro permeation study, invivo studies. Hence curcumin was used for transdermal delivery in the treatment of pain.68


Joo-EunKim, studied on Transformer-ethosomes with palmitoyl pentapeptide for improved transdermal delivery. The purpose of their study was to formulate Palmitoyl Pentapeptide (PPP) [lipid carriers]. Transformer ethosomes were prepared by using “Extrusion method” and comprises of fatty acids and phosphatidylcholine. Incorporation of myristic acid [MA] and capric acid [CA] into the lipid bilayers alter the transition temperature and improved flexibility was displayed by Differential scanning calorimetry. Transformer-ethosomes were determined by “confocal laser scanning microscopy” to find out the accumulation of fluorescence in the skin penetration and skin. Transformer-ethosomes were most widely used for transdermal delivery of various drugs as well as palmitoyl pentapeptide.69




Table 1: current research areas of ethosomes









Selective delivery of drug to desired side for prolong period of time





Increase skin permeation,

Improved in biological activity two to three times







Significant decrease in blood glucose level, Provide control release






Improved dermal deposition, Increased bioavailability





Anti-HIV agents


Improved transdermal flux,Prolonging drug action, Reduced drug toxicity



Azelaic acid

Dicarboxylic acids

Prolong drug release



Trihexyphenidyl hydrochloride



Improved patient compliance, Provide controlled release, Improved transdermal flux





effective in reducing low-density lipoprotein cholesterol





Improved therapeutic efficacy, better dispersity, and good storage stability



Raloxifene HCl


used in the treatment of breast cancer





antimicrobial, anti-tumoral, antioxidant properties





Treatment of atopic dermatitis,

Improved pharmacological effect



Phenylethyl Resorcinol


Used in skin lightening products






effective dermal delivery system, slight skin irritation.





Enhanced drug delivery through skin with ethosomes

81, 82




Enhance skin accumulation, prolong release and improve the specificity

81, 82




Sustained release of drug trans dermally






 From this review we can conclude that ethosomes has various applications which includes Anti-cancer, Antibiotics, Anti-acne, Anti-inflammatory etc. Ethosomes are formulated into various types like ethosomal gels, loaded with drug or bioactive agents etc, ethosome containing creams. Ethosomes plays a significant role in transdermal permeation enhancement techniques by providing safety, long term stability, efficacy and better patient compliance. Hence, they are said to offer better skin permeation than liposomes. Finally, it has been concluded that in future research with ethosomes can become a promising drug carrier not only for topical treatment of local and systemic disorders but also for the cosmetic and cosmeceutical fields for developing novel improved therapies.



This work was supported by the respected Dean of SRM college of pharmacy, SRM Institute of Science and Technology, Kattankulathur.



This article does not contain any conflict of interest.



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Received on 19.09.2019            Modified on 20.10.2019

Accepted on 02.11.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(4): 1970-1978.

DOI: 10.5958/0974-360X.2020.00355.8