Recently, transdermal drug delivery systems have been created with the goal of achieving systemic treatment through topical application to the intact skin surface. A transdermal treatment system is a set of discrete, self-contained dosage forms that are applied to the skin and release the drug into the systemic circulation at a controlled rate. Enhanced efficacy, increased safety, and improved patient compliance are just a few benefits that transdermal administration can offer.¹ One of the largest and easiest organs in the human body to access is the skin. When using the skin to deliver drugs, it has several benefits over more conventional methods, such as reduced variations in plasma drug levels, prevention of gastrointestinal issues, drug’s first-pass metabolism and increased patient compliance. The limited permeability of skin restricts the number of medications that may be administered trans-dermally, which is one of the biggest drawbacks of this method of drug delivery. Except for lipophilic and low molecular weight medications, the stratum corneum is the strongest barrier preventing the passage of most pharmaceuticals, making the skin a great barrier to molecular transport.² In the current period of global research, the application of vesicular systems has drawn significant consideration. The exterior part of these aqueous vesicular carriers is made up of lipid bilayers. The lipid bilayer of the vesicular carrier traps the lipophilic medications, while the hydrophilic pharmaceuticals are contained in the interior aqueous environment. The medication contained within these carriers travels through the skin by disrupting the lipid arrangement of the stratum corneum, hence adjusting the delivery rate.³

Following are some major classifications of ethosomes.

1.Classical ethosomes

These modified classical liposomes exhibit significantly improved skin penetration. These consist of phospholipids, water and ethanol at a significantly higher concentration of up to 45% w/v. For transdermal drug delivery, the classical ethosomes are thought to be superior to liposomes due to their smaller vesicular size, negative zeta potential, and higher entrapment efficiency.

2.Binary ethosomes

These were made by mixing a different type of alcohol with the conventional ethosomes. The two most often used alcohols are propylene glycol and isopropyl alcohol.

3.Transethosomes

This is recognized as the newest and most sophisticated ethosomal system. It consists of the basic components of traditional ethosomes plus an additional component that functions as a surfactant or an edge activator to improve penetration.⁵

Ethosomes typically contain phospholipids with a range of different chemical structures, such as hydrogenated PC, phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylglycerol (PPG), phosphatidylinositol (PI), hydrogenated PC, ethanol, water, and propylene glycol (or other glycols).⁶

Mechanism Of Drug Penetration⁷

There are two steps to the drug absorption mechanism from ethosomes.

1. Ethanol effect
2. Ethosome effect

1.Ethanol effect

Through the skin, ethanol improves permeation. It is commonly understood how the penetration increasing effect works. Ethanol seeps into the internal lipid sand and increases the permeability of the lipid in the cell membrane while decreasing the density of the lipid multilayer.

2.Ethosome effect

Advantages¹¹

1. It is feasible to deliver big molecules, such as peptides and protein molecules.

2. The formulation uses non-toxic raw materials.

3. Improved medication permeability through skin for transdermal administration.

4. The ethosomal drug delivery technology has broad applications in the veterinary, cosmetic, and pharmaceutical industries.

5. Great patient compliance: Because the ethosomal medication is administered as a gel or cream, it is semisolid, which results in great patient compliance.

6. A straightforward approach to medication distribution that contrasts phonophoresis, iontophoresis, and other more intricate techniques

7. The Ethosomal system may be commercialized right away and is passive and non-invasive.

Disadvantages¹¹

1. They need elevated blood pressure. Only strong molecules—those needing a daily dosage of 10 mg or less—are included.

2. It is usually intended to provide steady, sustained drug delivery rather than a way to produce quick bolus-type drug input.

3. Sufficient solubility of the medication in aqueous and lipophilic conditions to enter the systemic circulation and reach the cutaneous microcirculation.

4. The drug's molecular size should be appropriate for transdermal absorption. 5. Not every type of skin can cling to adhesive properly.

5. It might not be cost-effective.

6. Low yield.

7. Dermatitis or skin irritation brought on by enhancers and excipients used in medication delivery systems.

Methods Of Ethosome Preparation^12,13

The following techniques are typically used to prepare ethosomes:

1.Hot method

2.Cold method

3.Classic mechanical dispersion method

1.Hot method:

 The phospholipids are first heated to 40°C and dissolved in water in this process. Ethanol and propylene glycol are heated to the same temperature as the aqueous phase at the same time. Depending on the properties it has, the medication dissolves in ethanol or water. To reduce particle size, the organic phase is introduced to the aqueous phase and sonicated.

2.Cold method

Soya phosphotidyl choline is dissolved in a round bottom flask with a 3:1 ratio of methanol to chloroform. Using a rotating vacuum evaporator, the organic solvents are eliminated above the lipid transition temperature, forming a thin lipid film on the flask wall. Lastly, by vacuuming the contents for an entire night, any remaining solvent combination is extracted from the deposited lipid film. Rotating the flask at an appropriate temperature allows for the addition of various concentrations of drug-containing hydroethanolic mixture for hydration.

Characterizations Of Ethosomes:^14,15,16

1.  Visualization

Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) can both be used to visualize ethosomes.¹⁴

2. Zeta potential and vesicle dimensions

Photon correlation spectroscopy (PCS) and dynamic light scattering (DLS) with an automated inspection system can be used to detect particle size and zeta potential.¹⁴

3.Skin permeation studies:

Confocal laser scanning microscopy (CLSM) can be employed to evaluate how well the ethosomal preparation penetrates the skin layers.¹⁴

4. Measurement of Surface Tension Activity

A Du Nouy ring tensiometer can be used to measure the surface tension activity of a medication in an aqueous solution using the ring method.¹⁴

5.Transition temperature:

 Differential scanning calorimetry (DSC) can be used to find the vesicular lipid systems' transition temperature. The Mettler DSC 60 computerized with Mettler Toledo star software system is utilized. By heating the aluminum crucibles at a rate of 10 degrees per minute, the transition temperature was determined between 20 and 300 degrees Celsius.¹⁵

6.Degree of turbidity and deformability:

The ethosomal preparation's turbidity can be measured with a nephelometer, and the degree of deformability can be determined using the extrusion method.¹⁵

7.Efficiency of Entrapment (EE)

How thoroughly a drug is trapped in ethosomes can be ascertained using the ultracentrifugation method. Because a lipid that forms a bilayer structure effectively maintains the drug in place, the chemical makeup of the lipid has a substantial impact on the EE of the drug in the ethosomes. However, the drug may fit because of the lipid structure's flaws. The vesicles are separated in a high-speed cooling centrifuge that rotates at 20,000 rpm for ninety minutes at a temperature of 4°C.After lysing the vesicles in methanol and removing the liquid supernatant from the sediment, use the following formula to calculate the drug concentration in the sediment.

 % Entrapment= Actual Content / Theoretical Content x 100¹⁶

8.Studies of Stability

The ability of ethosomal preparations to retain the drug (i.e., show drug-retentive behavior) can be evaluated when they are held for varying amounts of time at various temperatures, such as 25 °C (room temperature, RT), 37 °C, and 45 °C (1, 20, 40, 60, 80, and 120 days). After being nitrogen flushed, the ethosomal preparations were put into sealed vials with a capacity of 10 mL. The size and appearance of the vesicles were evaluated using DLS and TEM to ascertain the stability of the ethosomes.¹⁶

9.Drug Content

The amount of drug present is calculated using a UV spectrophotometer. The dosage of the medication can also be ascertained by employing an altered HPLC method.¹⁶

10. drug deposition and in vitro drug release

It is possible to utilize dialysis bag diffusion or Franz diffusion cells with synthetic or biological membranes for in vitro drug release investigations and drug deposition of ethosomal preparation.¹⁶

11.Phospholipid Interaction with Ethanol

Proton decoupled 31P-NMR and differential scanning calorimetry were employed to look at how phospholipids and ethanol interacted.¹⁶

Table 2: Compilation of reported works on Ethosome

Table 3: Applications of ethosomes as a drug carrier^28,29,30,31