A REVIEW ON ETHOSOMES: A PROMISING NOVEL VESICULAR …

Harshitha et al. World Journal of Pharmacy and Pharmaceutical Sciences

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A REVIEW ON ETHOSOMES: A PROMISING NOVEL VESICULAR

CARRIER FOR TRANSDERMAL DRUG DELIVERY

Harshitha K.*1, Dr. A. R. Shabaraya

1 and Vinayak K.

Department of Industrial Pharmacy, Srinivas College of Pharmacy, Valachil, Mangaluru,

574143, Karnataka, India.

ABSTRACT

Transdermal drug delivery refers to self-contained, discrete dose forms

that, when applied to intact skin, transfer the drug to the systemic

circulation at a controlled rate. Ethosomes are noninvasive delivery

vehicles made composed of phospholipids, ethanol, and water that allow

medications to reach deep into the epidermal layers or the systemic

circulation. This review article summarizes structure, advantages,

disadvantages, composition, additives used and mechanism of drug

penetration, method of preparation, characterization and applications

of ethosomes.

INTRODUCTION

For topical/transdermal (TT) medication delivery, the skin serves as a significant target as

well as a primary barrier.[1]

Around the body, the skin forms a protective covering.[2]

The

stratum corneum, which is the epidermis' thin outer layer, is responsible for the skin's major

barrier characteristics.[3]

Except for lipophilic and low molecular weight medications, the skin

provides a good barrier to molecular transport, as the stratum corneum is the most formidable

barrier to the passage of most pharmaceuticals. The drug must be able to permeate the skin

barrier and reach the target site for transdermal and topical drug delivery systems to be

successful.[4,5]

Crossing the stratum corneum is the goal of a transdermal drug delivery device.

The penetration rate of drug has been measured using a variety of approaches. Because to its

non-invasive administration approach, TDDS is gaining popularity. Despite the difficulties,

TDD has several distinct advantages, including the elimination of gastric acid contact,

increased patient compliance, longer duration of activity, fewer side effects, improved

physiological and pharmacological response, and avoidance of drug fluctuation and first pass

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 10, Issue 8, 634-645 Review Article ISSN 2278 – 4357

*Corresponding Author

Harshitha K.

Department of Industrial

Pharmacy, Srinivas College

of Pharmacy, Valachil,

Mangaluru, 574143,

Karnataka, India.

Article Received on

21 May 2021,

Revised on 18 June 2021,

Accepted on 08 July 2021

DOI: 10.20959/wjpps20218-19512



635

metabolism.[6]

To enhance drug absorption through the skin Iontophoresis, sonophoresis,

radio frequency, electroporation, and other physical and chemical approaches have all been

examined. Liposomes, niosomes, transferosomes, and ethosomes are examples of vesicular

systems that have been shown to promote medicine permeability through the percutaneous

barrier.[4,5,7,8,9]

Ethosomes are the most innovative vesicular system, containing a high quantity

of ethanol that allows medications to penetrate deeper into the skin.[4]

Ethosomes are a slightly

modified version of the well-known drug carrier liposome.[10]

Ethosomes are surrounded by

three key components: lipid, which serves as the delivery system's spine, water, and ethanol,

which has a wide range of chemical applications.[11]

Touitou and her colleagues initially

discovered ethosomes in 1997. This transporter has intriguing properties that are related to its

ability to permeate completely through human skin due to its high deformability.[12]

The

physicochemical properties of ethosomes allow these vesicular phospholipids to function as

the ethosomal system's vesicle-forming component. Phospholipids with different chemical

structures, such as phosphatidyl choline and phosphatidyl ethanolamine, are employed in

quantities ranging from 0.5 to 10%.[12]

Fig. 1: Structure of Ethosomes.

Structure of Skin

The outermost layer of epidermis is known as the stratum corneum. It consists of 10 to 25

layers of dead, elongated, completely keratinized corneocytes encased in a lipid bilayer

matrix. It has been established that the the major barrier to skin penetration is stratum

corneum. When a topical formulation's active component is applied to the skin, it must pass

through the stratum corneum and into live tissue to be effective. These mechanisms are

limited by the slow diffusion through the dead horny layer of skin. The stratum corneum acts

as a hydrophobic barrier. The stratum corneum determines the rates of penetration of low and

high molecular weight organic non-electrolytes into the skin.[5,13]



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Fig.2: Structure of skin.

Types of Ethosomes[14,15,16]

1.) Classical Ethosomes

2.) Binary Ethosomes

3.) Transethosomes

1.) Classical Ethosomes

Phospholipids, water, and a high ethanol concentration make up traditional ethosomes.

Because of their small size, negative zeta potential, and increased entrapment efficiency,

traditional ethosomes outperform standard liposomes.

2.) Binary Ethosomes

Binary ethosomes are created by adding another type of alcohol to classical ethosomes, such

as propylene glycol or isopropyl alcohol.

3.) Transethosomes

Transethosomes are a novel type of ethosomal system that combines the benefits of both

traditional ethosomes and transfersomes into a single formula. They have fundamental

components like classical ethosomes and a penetration enhancer or edge activator in their

structure.



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Fig.3: Types of Ethosomes.

Advantages of Ethosomes[17,18,19]

Poor oral absorption and bioavailability, GI degradation

Drug penetration and systemic impact have improved.

It's made up of non-toxic raw materials.

Patient compliance is very high. Since the ethosomal drug is given in a semisolid form (gel

or cream), it is well tolerated by patients.

The Ethosomal method is non-invasive, passive, and ready to use.

Increased drug entrapment performance, decreased side effects, and consistent systemic

levels are all benefits of ethosomes

Major drug accumulation in the skin.

Ethosomes increase drug permeation across the skin, allowing for transdermal and dermal

delivery.

Disadvantage of Ethosomes[17,18,19]

Drugs that require high blood levels can't be given – only potent molecules with a daily

dose of 10mg or less are allowed.

To enter the dermal microcirculation and gain access to the systemic circulation, the drug

must be soluble in both lipophilic and aqueous environments.

The drug should have a small molecular size and be able to be absorbed through the skin.



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It's possible that it's not cost-effective because of the low yield.

Excipients and enhancers in drug delivery systems cause skin irritation or dermatitis.

The key advantage of ethosomes over liposomes is that they allow for more drug

permeation.

Material loss during the transition from organic to water media.

Ethosomes Composition

Ethosomes are vesicular carriers made up of hydroalcohalic or hydrolglycolic phospholipids

with high water and alcohol concentrations. The ethosome is distinct because of its high

ethanol concentration.[20]

It is mostly made up of phospholipids, which are amphipathic (they

have affinity for both aqueous and non-aqueous moieties) and have a hydrophobic/nonpolar

tail and a hydrophilic/polar head. The hydrophilic tail is made up of two fatty acid chains,

each with 10-24 carbon atoms and 0-6 double bonds Phosphoric acid linked to water soluble

compounds is the most common hydrophilic head end of molecules. When an amphiphilic

lipid encounters a membrane, the hydrophilic and hydrophobic domains/segments within the

molecular geometry align and self-organize in order to form supramolecules (Lasic, 1995).

Phosphatidylcholine, Hydrogenated PC, Phosphatidic acid, Phosphatidylserine(PS),

Phosphatidylethanolamine(PE), Phosphatidylglycerol (PPG), and Phosphatidylinositol are

some of the phospholipids found in it. The final product's alcohol content could range from

20% to 50%. The non-aqueous phase (alcohol and glycol mixture) can have a concentration

of 22 to 70 percent.[15,16,20,21,22]

Additives used in ethosomal preparation[17,18,20,23]

Class Example Uses

Phospholipid Soya phosphatidyl choline,

Egg phosphatidyl choline

Component that causes vesicles to

form.

Alcohol Ethanol, Isopropyl alcohol As a penetration enhancer, giving

softness for the vesicle membrane.

Polyglycol Propylene glycol,

Transcutol RTM As an enhancer of skin penetration.

Cholesterol Cholesterol For providing the stability to vesicle

membrane.

Dye Rhodamine-123,

Rhodamine red

For the purpose of characterisation

study.

Vehicle Carbapol934 In the capacity of a gel forming.

Mechanism of Drug Penetration[9,18,19,24,26]

The main advantage of ethosomes over liposomes is that they allow for more drug



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penetration. The mechanism of the medication absorption from ethosomes is not much

established. The drug absorption probably occurs in following two phases:

1. Ethanol effect

2. Ethosomes effect

1. Ethanol effect: Ethanol helps products penetrate deeper into the skin. Its penetration-

enhancing effect has a well-understood mechanism. Ethanol penetrates intercellular lipids,

increasing the fluidity of cell membrane lipids and lowering the density of the cell

membrane's lipid multilayer.

2. Ethosome effect: Increased skin permeability is induced by increased cell membrane

lipid fluidity caused by the ethanol of ethosomes. As a result, ethosomes easily penetrate deep

skin layers, where they fuse with skin lipids and release medicines into the deeper layers of

skin.

Fig. 4: Mechanism of drug penetration.

Methods of Preparation of Ethosomes[2,6,7,16]

Ethosomes can be prepared by three very simple and convenient methods that is;

1. Hot method

2. Cold method

3. Classic Mechanical Dispersion Method



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1. Hot Method[5,7,18]

Phospholipid was dispersed in water using this method by heating it in a water bath at 400°C

until a colloidal solution was formed. Ethanol and propylene glycol were combined

appropriately and heated to 400°C in a separate vessel. Combine the organic and aqueous

phases. Based on the solubility of the drug, it was dissolved in either ethanol or water. Using

probe sonication or extrusion, the vesicle size of an ethosomal formulation can be reduced to

the desired level.

2. Cold Method[5,7,19]

For ethosomal preparation, this is the most popular and widely utilised approach. The drug

and phospholipid were dissolved in ethanol, which was then mixed with propylene glycol and

heated to 300°C for 1 hour. To make the final dispersion, double distilled water was added

and stirred continuously for 5 minutes. Using sonication or extrusion, the vesicle size of an

ethosomal formulation can be reduced to the desired extent. Finally, properly store the

formulation refrigerated.

3. Classic Mechanical Dispersion Method[9]

In a round bottom flask, soya phosphotidylcholine is dissolved in a 3:1 mixture of chloroform

and ethanol. The organic solvents are evaporated using a rotating vacuum evaporator at

temperatures above the lipid transition temperature, resulting in the formation of a thin lipid

coating on the flask's wall. Finally, by vacuuming the contents overnight, traces of the solvent

mixture are removed from the deposited lipid coating. Hydration is accomplished by rotating

the flask at a proper temperature while using varied concentrations of hydroethanolic mixture

containing drug.

Characterization of Ethosomes[25]

The characterisation of ethosomes can be done in a variety of ways. The following are

the details:

Physical Characterization: Motic Image Plus software can be used to physically describe

ethosomes. It is a cost-effective method of determining whether or not the ethosomes

have been created. A main particle size evaluation for the formulation can also be

performed. Malvern Zetasizer should be used for further examination and proper sizing.[25]

Visualization: Transmission electron microscopy (TEM) and scanning electron

microscopy (SEM) can be used to visualise ethosomes (SEM). The ethosome preparations



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vesicular shape is evaluated using Transmission Electron Microscope (TEM). The

samples are dried on a carbon-coated grid and stained negatively with a phosphotungstic

acid aqueous solution. Following drying, the specimen is examined under a microscope at

10–100 k fold enlargements using a 100 Kv accelerating voltage. To examine the size and

morphology of the vesicles Scanning Electron Microscopy is used (SEM). On a clear glass

stub, one drop of ethosomal suspension is attached. It is then air-dried and gold-coated

with sodium aurothiomalate before being examined using a scanning electron microscope

at a magnification of 10,000.[26]

Vesicle size and Zeta potential: For detect the particle size and zeta potential of ethosomes

Dynamic light scattering system and photon correlation spectroscopy are used.[27]

Entrapment Efficiency: The centrifugation method can be used to measure the entrapment

effectiveness of ethosomal vesicles. The vesicles were separated for 90 minutes at 20,000

rpm in a high-speed cooling centrifuge with a temperature of 4°C. By lysing the vesicles

with methanol and separating the sediment and supernatant liquids, the amount of drug in

the sediment may be measured.

Transition Temperature: Differential scanning calorimetry (DSC)can be used to estimate

the transition temperature of vesicular lipid systems.[8]

Surface Tension Activity Measurement: The ring method in a Du Nouy ring tensiometer

can be used to determine the surface tension activity of a medication in aqueous

solution.[29]

Vesicle Stability: The size and shape of vesicles can be assessed over time to determine

their stability. DLS measures mean size, while TEM examines structural changes.[22]

Drug Content: A UV spectrophotometer can be used to determine the drug content in

ethosomes. A modified high-performance liquid chromatographic method can also be

used to quantify this.[4]

Penetration and Permeation Studies: Confocal laser scanning microscopy(CLSM) can be

used to see the depth of penetration from ethosomes.[13,30]

APPLICATION OF ETHOSOMES

Ethosomes can be employed for a variety of drug delivery applications. Ethosomes are most

commonly utilised to replace liposomes. The transdermal mode of drug delivery is more

preferred. Ethosomes can be utilised to transfer hydrophilic and impermeable drugs to the

skin via transdermal administration.[25,31] Ethosomal carrier has been employed with a variety

of drugs.[32]



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Transcellular delivery

In comparison to commercially available anti-HIV medication, ethosomes appear to be a

viable alternative. As a result, drug action is prolonged, drug toxicity is reduced, and

transdermal flux is improved.[16,28]

Ethosomes are used in pilosebeceous targeting

Pilosebaceous units have been used in the treatment of follicle-related illnesses like acne and

alopecia(Targeted drug therapy). Minoxidil, a lipid soluble drug used to treat baldness,

accumulates two to seven times more in the skin of naked mice, allowing it to be used for

pilosebaceous targeting for improved clinical efficacy.[13,16]

Transdermal delivery of hormones

Oral hormone administration is linked to difficulties such as high first-pass metabolism,

limited oral bioavailability, and a variety of additional dose-dependent adverse effects. With

every pill, the risk of treatment failure is anticipated to increase.[9]

Ethosomal system for Menopausal syndromes

Ethosomal compositions have been evaluated for their efficacy in the treatment of androgen

deficiency in men and menopausal syndroms in women. Testosome ethosomal patch system of

treatment is used in males with androgen deficiency.[16,29]

Delivery of anti arthritis drug

Topical anti-arthritis drug administration is a better choice for selective drug delivery to the

intended spot for a prolong period of time.[16]

Delivery of problematic drug molecules

Large biogenic molecules like peptides or proteins, as well as insulin, are difficult to transfer

orally because they are totally degraded in the GIT tract, hence transdermal delivery is a

better option. However, traditional transdermal formulations of biogenic molecules like

peptides or protein, as well as insulin, have low penetration. The incorporation of these

compounds into ethosomes greatly improves permeability and therapeutic efficacy.[5]

CONCLUSION

The ethosomal carrier presents new challenges and potential for the creation of fresh, better

therapeutics. For systemic effect, the transdermal method is a viable option to drug delivery.



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Permeation of the epidermal barrier is a major challenge in formulating transdermal drug

delivery systems. Better skin permeability can be achievable with ethosomes because alcohol

is a major component. Ethosomes have opened a new era of vesicular research for

transdermal drug administration that is superior to liposomes in terms of skin permeability.

Ethosomes are also known for their ease of production, efficacy, and safety. They can

transport medications with a variety of qualities, and the formulation can be modified for

both topical and systemic drug delivery. Hydrophilic drugs, cationic drugs, proteins, and

peptides have all been investigated in ethosomes. As a result, ethosomal formulations have a

bright future in the delivery of bioactive agents transdermally.

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A REVIEW ON ETHOSOMES: A PROMISING NOVEL VESICULAR …