ETHOSOMES AS DRUG CARRIERS 1. Introduction Transdermal drug delivery offers many advantages as compared to traditional drug delivery systems, including oral and parenteral drug delivery system. Transdermal route is therefore, a better alternative to achieve constant plasma levels for prolonged periods of time, which additionally could be advantageous because of less frequent dosing regimens. Advantages claimed are increased patient acceptability (non invasiveness), avoidance of gastrointestinal disturbances and first pass metabolism of the drug 1 . The major advances in vesicle research was the finding a vesicle derivatives known as an “Ethosomes 2 ”. Ethosomes are non-invasive delivery carriers that enable drugs to reach the deep skin layers and/or the systemic circulation. Ethosomes are soft, malleable vesicles composed mainly of phospholipids (phosphatidylcholine, phosphatidylserine, and phosphatitidic acid), ethanol (relatively high concentration) and water 3 . These “soft vesicles” represents novel vesicular carrier for enhanced delivery through skin. The soft, malleable vesicles tailored for enhanced delivery of active agents. The size of ethosomes can be modulated to range anywhere from 30nm to a few microns. Although ethosomal systems are conceptually sophisticated, they are characterized by 1
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ETHOSOMES AS DRUG CARRIERS
1. Introduction
Transdermal drug delivery offers many advantages as compared to traditional drug
delivery systems, including oral and parenteral drug delivery system. Transdermal
route is therefore, a better alternative to achieve constant plasma levels for prolonged
periods of time, which additionally could be advantageous because of less frequent
dosing regimens. Advantages claimed are increased patient acceptability (non
invasiveness), avoidance of gastrointestinal disturbances and first pass metabolism of
the drug1. The major advances in vesicle research was the finding a vesicle derivatives
known as an “Ethosomes2”.
Ethosomes are non-invasive delivery carriers that enable drugs to reach the deep skin
layers and/or the systemic circulation. Ethosomes are soft, malleable vesicles
composed mainly of phospholipids (phosphatidylcholine, phosphatidylserine, and
phosphatitidic acid), ethanol (relatively high concentration) and water3. These “soft
vesicles” represents novel vesicular carrier for enhanced delivery through skin. The
soft, malleable vesicles tailored for enhanced delivery of active agents. The size of
ethosomes can be modulated to range anywhere from 30nm to a few microns.
Although ethosomal systems are conceptually sophisticated, they are characterized by
simplicity in their preparation, safety and efficacy that can highly expand their
application. Ethosomal systems were much more efficient at delivering a fluorescent
probe to the skin in terms of quantity and depth than either liposomes or
hydroalcoholic solution. Ethosomes provides a number of important benefits
including improving the drug's efficacy, enhancing patient compliance, comfort and
reducing the total cost of treatment. Ethosomes were found to be suitable for various
applications within the pharmaceuticals, biotechnology, veterinary, cosmetic and
nutraceutical markets. Enhanced delivery of bioactive molecules through the skin and
cellular membranes by means of an ethosomal carrier opens numerous challenges and
opportunities for the research and future development of novel improved therapies.
Ethosomes are lipid vesicles containing phospholipids, alcohol (ethanol and isopropyl
alcohol) in relatively high concentration and water4. Ethosomes are soft vesicles made
of phospholipids and ethanol (in higher quantity) and water. Ethosomes permeate
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through the skin layers more rapidly and possess significantly higher transdermal flux
in comparison to conventional liposomes5, 6. Visualization of ethosomes is shown in
Figure 1. Although, the exact mechanism for better permeation into deeper skin layers
from ethosomes is still not clear. The synergistic effects of combination of
phospholipids and high concentration of ethanol in vesicular formulations have been
suggested to be responsible for deeper distribution and penetration in the skin lipid bi-
layers.
1.1 Definition:
Ethosomes are vesicular carrier comprise of hydroalcoholic or hydro/ alcoholic
/glycolic phospholipids in which the concentration of alcohols or their combination is
relatively high.
1.2 Composition of ethosomes:
Typically, ethosomes may contain phospholipids with various chemical structures like
Alcohol Ethanol; Isopropyl alcohol For providing the softness for vesicle membrane; As a skin penetration enhancer
Cholesterol Cholesterol For providing the stability for vesicle membrane
Dyes Rhodamine 123; Rhodamine red
For characterization studies
Vehicles Carbopol D934 As a gel former
2. Advantages 9, 10:
Ethosomes have enhanced permeation of drug through skin for transdermal drug
delivery.
The delivery of large molecules (peptides, protein molecule) is possible. It contains
non-toxic raw material in formulation.
High patient compliance- The ethosomal drug is administrated in semisolid form (gel
or cream) hence producing high patient compliance.
Ethosomal system is passive, non-invasive and is available for immediate
commercialization.
Simple method for drug delivery in comparison to Iontophoresis and Phonophoresis
and other complicated methods.
Ethosomes are platform for the delivery of large and diverse group of drugs.
(peptides, protein molecules)
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Ethosome composition is safe and the components are approved for pharmaceutical
and cosmetic use.
Low risk profile- The technology has no large-scale drug development risk.
High market attractiveness for products with proprietary technology. Relatively
simple to manufacture with no complicated technical investments required for
production of Ethosomes.
Various application in Pharmaceutical, Veterinary, Cosmetic field.
3. Disadvantages:
Drugs that require high blood levels cannot be administered – limited only to potent
molecules, those requiring a daily dose of 10mg or less.
Ethosomal administration is not a means to achieve rapid bolus type drug input,
rather it is usually designed to offer slow, sustained drug delivery.
Adequate solubility of the drug in both lipophilic and aqueous environments, to reach
dermal microcirculation and gain access to the systemic circulation.
The molecular size of the drug should be reasonable that it should be absorbed
percutaneously.
Adhesive may not adhere well to all types of skin.
Uncomfortable.
May not be economical.
Skin irritation or dermatitis due to excipients and enhancers of drug delivery system.
4. Mechanism Of Drug Penetration 12:
The main advantage of ethosomes over liposomes is the increase permeation of the
drug. The mechanism of the drug absorption from ethosomes is not clear. The drug
absorption probably occurs in following two phases. 13, 14 (Figure 2):
1. Ethanol effect: Ethanol acts as a penetration enhancer through the skin. The
mechanism of its penetration enhancing effect is well known. Ethanol
penetrates into intercellular lipids and increases the fluidity of cell membrane
lipids and decrease the density of lipid multilayer of cell membrane.
2. Ethosomal effect: Increased cell membrane lipid fluidity caused by the
ethanol of ethosomes results increased skin permeability. So the ethosomes
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permeates very easily inside the deep skin layers, where it gets fused with skin
lipids and releases the drugs into deep layer of skin.
FIGURE 2: Mechanism of action of ethosomes
5. Method of preparation15 :
There are two methods which can be used for the formulation and preparation of
ethosomes. Both of the methods are very simple and convenient and do not involve
any sophisticated instrument or complicated process. The formulation of ethosomes
involves hot and cold method (table 2).
1. Hot method: In this method disperse phospholipids in water by heating in a water
bath at 40°C until a colloidal solution is obtained. In a separate vessel properly
mix ethanol and propylene glycol and heat up to 40°C. Add the organic phase into
the aqueous phase. Dissolve the drug in water or ethanol depending on its
solubility. The vesicle size of ethosomal formulation can be decreased to the
desire extent using probe sonication or extrusion method.
2. Cold method: This is the most common and widely used method for the
ethosomal preparation. Dissolve phospholipids, drug and other lipid materials in
ethanol in a covered vessel at room temperature with vigorous stirring. Add
propylene glycol or other polyglycol during stirring. Heat the mixture up to 30°C
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in a water bath. Heat the water up to 30°C in a separate vessel and add to the
mixture and then stir it for 5 min in a covered vessel. The vesicle size of
ethosomal formulation can be decreased to desire extend using sonication. or
extrusion method. Finally, the formulation should be properly stored under
refrigeration.
TABLE 3: Flow chart representation for method of preparation:
6. Various methods for characterization of ethosomes:
Visualization: Visualization of ethosomes can be done using transmission
electron microscopy (TEM) and by scanning electron microscopy (SEM) 16.
Vesicle size and zeta potential: Particle size and zeta potential can be
determined by dynamic light scattering (DLS) using a computerized inspection
system and photon correlation spectroscopy (PCS) 17.
Entrapment efficiency: The entrapment efficiency of drug by ethosomes can be
measured by the ultracentrifugation technique 18.
Transition temperature: The transition temperature of the vesicular lipid
systems can be determined by using differential scanning calorimetry 19.
Surface tension activity measurement: The surface tension activity of drug in
aqueous solution can be measured by the ring method in a Du Nouy ring
tensiometer 20.
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Vesicle stability: The stability of vesicles can be determined by assessing the
size and structure of the vesicles over time. Mean size is measured by DLS and
structure changes are observed by TEM 21.
Drug content: Drug can be quantified by a modified high performance liquid
chromatographic method 22.
Penetration and permeation studies: Depth of penetration from ethosomes can
be visualized by confocal laser scanning microscopy (CLSM) 23.
7. Applications:
a. Therapeutic application of ethosomes:
5% acyclovir ethosomal preparation compared to the 5% acyclovir cream
showed significant improvements in treatment of herpetic infections 24.
New approach to treat deep skin and soft tissue bacterial infections by dermal
application of erythromycin in an ethosomal carrier.
The effect of an ethosomal insulin formulation that was applied to the skin and
there is a significant decrease in blood glucose level.
b. Ethosomes as a drug carrier:
Ethosomes can be used for many purposes in drug delivery. Ethosomes are
mainly used as replacement of liposomes. Ethosomes can be used for transdermal
delivery of hydrophilic and impermeable drugs through the skin. Following drugs
have been used with ethosomal carrier.
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TABLE 4: Drug incorporated in ethosomal carrier
NAME OF DRUG
DRUG INCORPORATED IN ETHOSOMAL CARRIER
USES
Acyclovir25 Improved skin permeation. Improved in pharmacodynamics profile. Improved in biological activity two to three times.
Treatment of Herpes labialis
Anti-HIV agents26
(Zidovudine, Lamivudine)
Reduced drug toxicity. Prolonging drug action. Improved transdermal flux. Affected the normal histology of skin. Improved in biological activity two to three times.
Anti-HIV
Azelaic acid27 Ammonium glycyrrhizinate28
Prolong drug release. Improved in biological anti-inflammatory activity. Improved dermal deposition exhibiting sustained release.
Treatment of various inflammatory based skin diseases