Ethosomes: A Novel Tool for Vesicular Drug Delivery

 

Pallavi U. Jadhav*, Sandhya G. Gujare, Mulchand A. Shende

Department of Pharmaceutics, Government College of Pharmacy,

Karad, Shivaji University, Kolhapur, Saidapur, Karad, Maharashtra, India.

 

ABSTRACT:

Ethosomes are elastic, phospholipid-based nanovesicles with a high concentration of ethanol (20-45%). Ethosomes exhibit desirable features as vesicular systems. As a result of their bilayer composition (aqueous and lipid), they exhibit improved bioavailability for both hydrophilic and lipophilic drugs. Higher ethanol concentrations (30–45%) cause stearic stability, which allows the loaded medication to penetrate deeper into the stratum corneum, and deeper skin layers with a high transdermal flux. Due to the ease of preparation. non-irritancy, efficiency to encapsulate wide range of drug molecules with varying lipophilicity/hydrophilicity and higher stability than previously formulated other vesicular systems ethosomes are the optimal carriers for topical drug delivery. The use of ethosomal transporter opens up a variety of challenges and opportunities for researchers for future study and the creation of novel, superior treatments. The scope of this small review is to elaborate on the novel concept of ethosomes and to describe their methods of preparation, mechanism of penetration, composition, characterization, marketed products of ethosomes, patents and their applications.

 

 

 

INTRODUCTION:

Researchers have been working toward effective medicine delivery into and across the skin for many years¹, the body's expanding skin typically has a surface area of 2m² and gets around 33% of the blood flow². As is obvious, the skin is the largest and most accessible organ in the body, making it a viable channel for administering drugs for both topical and systemic effects^3,4. The stratum corneum (SC), the skin's outermost layer, is subordinated by the epidermis and dermis, making up the skin's multi-layered structure. Fibroblasts, sweat glands and hair follicles that originate in the dermis blood supply are interspersed within various layers of skin⁵. The use of the skin as a drug delivery method has many benefits, including the ability to target the active ingredient for a local effect, avoidance of first-pass metabolism, reduced dose fluctuations, controlled drug delivery, and improved patient compliance because it is a non-invasive delivery method^6,7. The SC, which is the skin's outermost layer, is the layer that most effectively prevents drugs from penetrating the epidermis, due to the fact that it is made up of insoluble bundled keratins that are stabilised by cross-linked proteins and covalently attached lipids, which restricts the drug's transdermal bioavailability⁸.

 

In order to transfer drug molecules with various physicochemical qualities to the deep layers of skin and systemic circulation, specific carriers are needed to overcome the natural skin barrier^3,4. Novel lipid vesicles have recently been created to get around the problem of transporting medications to and via the SC. When liposomes were first created, they were used to deliver medications topically. Since then, numerous innovative vesicular systems based on lipids have been created⁹. New lipid vesicles such as transferosome, ethosomes, binary ethosomes, etc. were created to address the limitation of conventional liposomes' drug permeability through various skin layers¹⁰.

 

Figure 1: Schematic representation of ethosomes

 

Ethosomes, a third-generation of elastic lipid carriers created by Touitou, are frequently utilised for transdermal drug delivery¹¹. Ethosomes are the novel non-invasive drug delivery systems that allow drug molecules to penetrate deeply into the bloodstream or the epidermal layers of the skin. These are flexible, squishy vesicles designed to carry active ingredients more effectively¹². In essence, ethanolic liposomes are ethosomes.  Ethosomes vary from liposomes in that they also contain phospholipids, water, and rather high quantities of ethanol¹³. Later generations of ethosomal systems have been developed by adding other substances to the fundamental ethosomal formula in an effort to improve skin permeation.¹⁴

 

Types of Ethosomal Systems:

Classical ethosomes^14,15:

Classical ethosomes are an alternative form of classical liposomes and consist of phospholipids, water, and significant amount of ethanol (up to 45% w/w). For transdermal drug delivery, classical ethosomes are a better alternative to classical liposomes attributed to their smaller size, negative potential, and higher entrapment efficiency.

 

Binary ethosomes^14,15,16:

Introduction to binary ethosomes was given by Zhou et al. in 2010. By combining a different type of alcohol with the conventional ethosomes, binary ethosomes were created. Propylene glycol (PG) and isopropyl alcohol (IPA) are the two alcohols that are most frequently utilised in binary ethosomes.

 

Transethosomes^14,15,17:

The new generation of ethosomal systems, known as transethosomes, was initially described by Song et al. in 2012. This ethosomal system includes a substance, such as a surfactant or a penetration enhancer, in addition to the fundamental elements of classical ethosomes.  These unique vesicles were created in an effort to create transethosomes by fusing the benefits of traditional ethosomes with deformable liposomes (transferosomes) into a single formulation. Numerous studies have found that transethosomes have better qualities than traditional ethosomes.

 

Advantages of Ethosomes^{5,18,19,20,21}:

1.   Enhances the permeation of drug to the skin and to the systemic circulation

2.   Increased cutaneous drug delivery compared to transferosomes, both in occlusive and non-occlusive conditions.

3.   Large-scale and varied medication delivery (peptides, protein molecules).

4.   Safe formulation and authorised ingredients for use in medicinal, veterinary, and cosmetic products.

5.   Improved patient compliance because ethosomal medication can be applied topically (as cream or gel)

6.   Rather easy to create, and doesn't require any expensive technical instruments.

7.   System is non-intrusive, passive, and ready for rapid commercialization.

 

Disadvantages of Ethosomes^18,19,20,21:

1.   Limited yield of products.

2.   If shell locking fails, the ethosomes may agglomerate and disintegrate when transferred into the water.

3.   Product loss when switching from organic to water media.

 

Limitations of Ethosomes^{5,18,19,20,21}:

1.     Ethosomal administration is not a technique for achieving rapid bolus-type drug input; instead, it is intended to offer slow, sustained drug delivery, hence making it ineffective foe immediate action.

2.     The drug needs to be sufficiently soluble in both lipophilic and aqueous conditions in order to enter the dermal microcirculation and reach the systemic circulation.

3.     The drug's molecular size needs to be appropriate for percutaneous absorption.

4.     May show poor adherence to all types of skin.

5.     Only potent drug molecules may be used; as a result, medications that demand high blood levels cannot be given via ethosomes.

 

Table 1: Types of phospholipids

 

Composition of Ethosomes^14,22:

Phospholipids:

Phospholipids from many sources have been used in the ethosomal system's composition. When creating an ethosomal system, choosing the right phospholipid type and concentration is crucial because it affects the vesicle's size, entrapment effectiveness, potential, stability, and penetration properties. The different types of phospholipids used in the preparation of ethosomal systems are summarized in the table 1.

 

Alcohols:

1.     Ethanol: Ethanol is an efficient penetration enhancer. By giving the vesicles distinguishable properties in terms of size, potential, stability, entrapment efficiency, and increased skin permeability, it plays a pivotal role in ethosomal systems. There have been reports of ethanol concentrations in ethosomal systems ranging from 10% to 50%.  Many researcher scholars have found that when the concentration of ethanol is increased in the formulation, the size of the ethosomes will decrease.

2.     Propylene glycol: A common penetration enhancer is PG.  When used to create binary ethosomes, it has been shown to have an effect on the ethosomal characteristics of size, entrapment efficiency, permeability, and stability at concentrations between 5% and 20%. Particle size is decreased significantly more in ethosomal systems with PG added than in ethosomal systems without PG. According to one hypothesis, PG improves viscosity and has antihydrolysis properties to enhance ethosome stability.

3.     Isopropyl alcohol: The effect of Isopropyl Alcohol on the effectiveness of entrapment and skin permeation of ethosomes loaded with diclofenac was studied and investigated by Dave et al. The results showed that IPA had a significant impact on entrapment effectiveness but little on drug release. To assess the impact of IPA or other alcohols on other ethosomal system features, additional research is necessary²².

 

Cholesterol:

The stability and efficiency of drug entrapment are increased by the addition of cholesterol to ethosomal systems since it is a rigid steroid molecule. Along with minimizing leaks, it also reduces vesicular fusion and permeability. In a small number of formulations, it has been used up to 70% of the formulation's total phospholipid concentration. It is commonly used at a concentration of 3% of the total formulation. Numerous investigations have shown that cholesterol increased the size of the vesicles in ethosomal systems.

 

Edge Activators or Penetration Enhancers:

Since edge activators and penetration enhancers have a significant impact on the characteristics of the ethosomal system, choosing the right edge activator or penetration enhancer is an important step in the formulation of transethosomes. The following are the few edge activators or penetration enhancers used in ethosomal preparations:

 

1.   N-Decylmethyl sulfoxide and dimethyl sulfoxide

2.   Tweens and Spans

3.   Oleic acid

4.   L-Menthol

5.   Sodium stearate

6.   Bile acids and salts

7.   Polyethylene glycol 4000

8.   Hexadecyltrimethylammonium bromide

9.   Cremophor

10. Skin-penetrating and cell-entering (SPACE) peptide

11. Sodium dodecyl sulfate

 

METHODS OF PREPARATION FOR ETHOSOMES:

1.   Cold method

2.   Hot method

3.   Thin-film hydration method

4.   Reverse-phase evaporation method

5.   Transmembrane pH-gradient method

 

Cold method^13,23:

The most straightforward and popular technique for creating ethosomal systems is this one. It consists of the preparation of the organic phase and aqueous phase in separate vessels. The organic phase is obtained by dissolving the phospholipids (in addition to surfactants or penetration enhancer) in ethanol or mixture of solvents (ethanol/PG) at room temperature and then by heating the mixture to 30°C in water bath. The aqueous phase is heated to 30˚C in a separate vessel and is added to the organic phase in a fine stream, dropwise or using a syringe pump at a constant rate. The drug to be loaded in the ethosomal system will be dissolved in either the aqueous or the organic phase, depending on its physicochemical properties.

 

Hot method^13,23:

This technique involves heating phospholipid in a water bath at 40°C until a colloidal suspension is formed. Propylene glycol and ethanol are combined and heated to 40°C in a different vessel. The organic phase is introduced dropwise to the aqueous phase under continuous mixing with a mechanical or magnetic stirrer once both mixtures have reached 40°C. Depending on whether the medication is hydrophilic or hydrophobic, it dissolves in either water or ethanol.

 

Thin-film hydration method^24,25:

This is an advancement over the standard liposome synthesis technique, but in this technique, a hydroethanolic solution hydrates the lipid film. The phospholipid is first dissolved in chloroform only or a chloroform–methanol mixture at a ratio which may vary in a clean, dry, round-bottom flask. A rotary vacuum evaporator operating at a temperature higher than the lipid-phase transition temperature removes organic solvents. The solvent residues are then removed from the deposited lipid film overnight under vacuum. Then, a water-ethanol solution or phosphate buffered saline-ethanol solution is used to hydrate the lipid film. During the hydration process, the lipid film is spun and heated for as long as necessary at the required temperature, depending on the phospholipid properties.

 

Reverse-phase evaporation method¹⁴:

This technique, which was created specifically to make enormous unilamellar vesicles, is the least popular. The phospholipid is dissolved in diethyl ether to prepare the organic phase, which is then combined with the aqueous phase in a 3:1 v/v ratio in an ultrasonic bath at 0°C for five minutes to create an oil-in-water emulsion.  Under reduced pressure, the organic solvent is withdrawn to create a gel that, when vigorously mechanically stirred, transforms into a colloidal dispersion.

 

Transmembrane pH-gradient method¹⁴:

In all the methods mentioned above, the drug is added in either the organic phase or the aqueous phase, and it is spontaneously or “passively” loaded into the ethosomal system. Based on the pH gradient difference between the basic exterior of the external phase and the acidic interior of the internal phase, the medication is loaded "actively" in the transmembrane pH-gradient approach. This procedure consists of three steps: ethosomal blank preparation, active drug loading, and incubation. Any of the aforementioned procedures are used to prepare the empty ethosomal suspension in the first stage, however an acidic buffer is used during the aqueous phase of the hydration process (usually citrate buffer, pH 3). The medication is actively loaded into the ethosomal suspension in the second stage, which is followed by continual stirring. In order to generate the pH gradient between the basic external phase of the ethosomal system and the acidic internal phase (pH 3), an alkali, typically a sodium hydroxide solution of 0.5 M, is introduced to the external phase to raise its pH to 7. In the third stage, the ethosomal system is incubated for a predetermined amount of time and at a predetermined temperature (30°C–60°C) to allow the unionised drug to actively traverse the bilayer of the ethosomal vesicles and become trapped.

 

ETHOSOMAL SIZE^26,27,28:

The size and lamellarity of ethosomal nanocarriers are crucial since they are specifically made for topical and transdermal medication delivery. To be acceptable for this mode of administration, these vesicles' size should be decreased to <300 nm or 400nm. In order to achieve the desired size or lamellarity, the obtained ethosomal systems are therefore subjected to various additional processing steps in all of the aforementioned methods—except for the reverse-phase evaporation approach. Extrusion and sonication (probe or bath sonication) operations are the two main methods utilised to minimise the size of ethosomal systems.

 

ETHOSOMAL DOSAGE FORMS^14,29,30:

Most published papers have examined ethosomal systems for various tests in their original suspension forms. The ethosomal suspension has a high alcohol content and thus incorporating the system into an appropriate vehicle for dermal/transdermal administration has certain advantages, i.e., it prevents evaporation of ethanol, lengthens the contact time with the skin, improves the therapeutic effect of the encapsulated drug, improving the stability and storage of the final dosage form and better patient compliance. New formulations have been created using ethosome systems in various vehicles, including ethosome gels, transdermal patches, and creams.

 

Ethosomal gels:

Ethosomal gels get evaluated for pH, viscosity, spreadability, and extrudability. For incorporating ethosomal systems, Carbopol and hydroxypropyl methylcellulose in all of their related grades are the two most often employed gel forming agents. These polymers provide the necessary viscosity and bioadhesive characteristics, and it has been demonstrated that they are compatible with ethosomal systems.

 

Ethosomal patches:

As ethosomal patch preparation requires forming of a mould, their preparation and evaluation is much more difficult than for ethosomal gels.

 

Ethosomal creams:

The formulation of ethosomal creams has only been reported in two research. Both of them involve the incorporation of Curcuma longa extract-loaded ethosomal systems in a cream base as a photoprotective and antiwrinkle agent. In both studies, C. longa extract-loaded ethosomal creams were applied to human volunteers and showed promising results as either a photoprotective²⁹ or an antiwrinkle agent³⁰.

 

MECHANISM OF DRUG PENETRATION^18,20:

The enhanced penetration of the medication is the primary benefit of ethosomes over liposomes. It's unclear what causes ethosomes to absorb drugs. The drug absorption most likely occurs in following two phases:

1.   Ethanol effect

2.   Ethosomes effect

 

1. Ethanol effect:

Ethanol works as a penetration enhancer through the skin. Its penetration-enhancing effect has a well-known mechanism. Intercellular lipids are permeable to ethanol, which makes them more fluid and reduces the density of the multilayer of lipids that makes up the cell membrane.

 

2. Ethosomes effect:

The ethanol of ethosomes increases the fluidity of cell membrane lipids, which in turn increases the skin permeability.  As a result, the ethosomes easily penetrate the deep skin layers, where they combine with skin lipids to release the medicines there.

 

CHARACTERIZATION OF ETHOSOMES^20,31:

Characterization of ethosomes includes various test to assess its morphology, vesicle size, stability, drug release, thermal behaviour etc.

 

Table 2: Characterization of ethosomes:

 

MARKETED ETHOSOME FORMULATIONS^{32, 33}:

Table 3: Marketed ethosome formulations:

 

PATENTS CLAIMED FOR ETHOSOME FORMULATIONS^34,35:

Table 4: Patents claimed for ethosome formulations:

 

APPLICATION OF ETHOSOMES:

Various research using ethosomes have shown improved skin permeability of drugs. The uses of ethosomes as vesicle carrier for different types of delivery are given below.

 

Table 5: Application of ethosomes:

 

FUTURE PROSPECTS:

The discovery of ethosomes has opened up a brand-new field of study for transdermal medication administration. Numerous researches have shown that ethosomes have a bright future in enhancing the efficacy of transdermal distribution of various medicines. Additionally, this research will improve physician control over drug release in vivo, enhancing the efficacy of the therapy. The non-invasive delivery of small, medium, and large therapeutic molecules is made possible via ethosomes. It is relatively simple to create large volumes of ethosomal formulation. Despite the fact that ethosomes provide many advantages, there are still variety of challenges that need to be resolved before they can be widely applied in clinical practise. This includes regulatory issues, stability problems and toxicity issues. But with additional research in this area, it's possible to overcome these obstacles and realise the full potential of ethosomes for medication delivery. Therefore, it shouldn't take long for the relevant drug formulation to enter clinics for testing prior to being used widely. It is logical to say that ethosomal formulations have a prosperous future in the efficient dermal/transdermal administration of bioactive substances.

 

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Received on 29.04.2023         Modified on 18.09.2023

Accepted on 25.11.2023   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2024; 14(1):45-52.