Ethano-lipoidal Approach To Transdermal Drug Delivery System: An Ethosaomal Review

Abstract

Skin is the major target as well as a principal barrier for topical/ transdermal
drug delivery system. There is so many advantages of this system along with
some major obstacle like low diffusion rate of drugs across the stratum
corneum. A number of devices have been invented to increase the permeation
rate of drugs temporarily; among them one simple and convenient approach is
application of drugs in formulation with elastic vesicles or skin enhancers. The
vesicular system is known as one of the most controversial methods for
transdermal delivery of active substances in that ethosome is formulated as
ethanolic phospholipids vesicles which are used mainly for transdermal
delivery of drugs. Because of its high ethanolic content, Ethosomes have
higher penetration rate through skin. This article reviews various aspects of
ethosomes including their mechanism of penetration, preparation,
advantages, characterization, composition, preparation and patents granted
for ethosomes.

Full text

41
Skin is the major target as well as a principal barrier for topical/ transdermal
drug delivery system. There is so many advantages of this system along with
some major obstacle like low diffusion rate of drugs across the stratum
corneum. A number of devices have been invented to increase the permeation
rate of drugs temporarily; among them one simple and convenient approach is
application of drugs in formulation with elastic vesicles or skin enhancers. The
vesicular system is known as one of the most controversial methods for
transdermal delivery of active substances in that ethosome is formulated as
ethanolic phospholipids vesicles which are used mainly for transdermal
delivery of drugs. Because of its high ethanolic content, Ethosomes have
higher penetration rate through skin. This article reviews various aspects of
ethosomes including their mechanism of penetration, preparation,
advantages, characterization, composition, preparation and patents granted
for ethosomes.
Keywords: Ethosomes, Transdermal Drug Delivery, ethanolic liposome,
vesicular carrier, skin penetration
Ethano-lipoidal Approach To Transdermal Drug
Delivery System: An Ethosaomal Review
Ved Parkash*, Vandana Chaudhary**, Saurabh Maan* and Pawan Kaushik***
*B. S. Anangpuria
Institute of Pharmacy,
Ballabgarh, Faridabad,
** SGT College of Pharmacy
SGT University, Gurgaon
***Institute of Pharmaceutical
Sciences, Kurukshetra
University, Kurukshetra
*Corresponding author:
Ved Parkash
vedprakash.com@gmail.com
ISSN 2278-0580
INTRODUCTION
In conventional dosage forms; oral route possesses notable
advantages like easy administration, non-invasive, least likely
to harm the patient, availability of large variety of dosage form,
inspite of all these advantages this route can be cost prohibitive
and inconvenient due to first pass effect, poor bioavailability,
rapid blood level spikes and patient incompliance etc. To
overcome these difficulties a novel Transdermal drug delivery
involves the application of a drug to the skin to achieve
systemically active levels of the drug to treat disease remote
from the application site, avoidance of gastrointestinal (GI)
incompatibility, variable GI absorption, and first pass
metabolism along with reduced frequency of administration,
improved bioavailability, improved patient compliance, and
rapid termination of drug input. Additionally transdermal
delivery can maintain a suitable plasma concentration through
a noninvasive zero-order delivery (similar to intravenous
administration), which would enhance the efficacy of
contraceptive agent with high patient compliance and
pharmaco-economic incentives. [1,13].
There are number of drugs in 24 different therapeutic
categories for Transdermal delivery in prototype patches, for
the treatment of actinic keratosis, Alzheimer's disease, pain,
angina pectoris, convulsions, allergies, thrombosis, anxiety,
asthma, benign prostatic hypertrophy, cervical neoplasia,
glaucom a , hu m a n im m u n o de f i c i en c y vi r u s (H I V ) ,
hypertension, Meniere's syndrome, migraine, Paget's disease,
osteoporosis, Parkinson's disease, rheumatoid arthritis, and
smoking cessation, as well as contraceptive[1].
In transdermal drug delivery Systems (TTS), the skin patches
are designed to deliver the therapeutic agent at a controlled rate
from the device to and through the skin into the systemic
circulation and to maintain efficacious plasma levels of the
drug for periods of 1-7 days depending on the particular drug.
This route provides a precised amount of drug to be delivered
for systemic action. In general, under the most ideal
circumstances, only approximately 1 mg of a drug can be
2
delivered across a 1 cm area of skin in 24 hours. Drugs having
melting point above 150 °C and a molecular weight greater
than 500 Daltons may reduce this number 10-fold, 100-fold, or
even more.
For desired pharmacological action a number of factors
influences the rate of delivery of drug across the skin including
Penetration, thermodynamic activity of drug, interaction of
drug, variation in skin with age, race, anatomical region etc,
Whether it is for systemic effects or topical applications,
therapeutic agents must first pass through the stratum corneum
and epidermis, then enter the dermis layer and exert their
Global Journal of Pharmaceutical Education and Research | January-December 2015 | Vol.4 | Issue 1-2
ABSTRACT

42 Global Journal of Pharmaceutical Education and Research | January-December 2015 | Vol.4 | Issue 1-2
blood stream through the stratum corneum. Zhu et al [8]
reported that there were no significant changes in average
particle size, distribution, and structure of ethosomes over two
years storage that supports stable physical and chemical
properties of ethosomes. This has been also proved by another
study in which the size of liposomes significantly increased
with time, while the average size of ethosomes basically
remained constant over four weeks [9]. The physicochemical
characteristics of a vesicles strongly affects the effectiveness
of ethosomes, in particular its thermodynamic state. Liquid-
state vesicles have been found to be more effective in
enhancing drug transport as compared to gel-state vesicles
[10,11]. In this contrast in the early 1990s a novel series of
liquid-state vesicles with elastic lipid membranes were
developed [12].
The various types of vesicular formulations so far have been
developed are summarized in table 1.
further effects. As skin acts as a good barrier needs a broad
range of different enhancing strategies, which involve
chemical enhancers, vesicular carriers, iontophoresis,
electroporation, acoustical method, microneedle, jet injection
etc [2-5].
In the present review, vesicular system of transdermal drug
delivery in which Touitou E in 1996 [6] introduced ethosome
for the first time for the enhanced delivery of drug into or
through skin by the vesicular carrier, which is a novel liposome
composed of phospholipid, short chain alcohol (mostly
ethanol) at r elativel y high conce ntration , and water.
Ethosomes could efficiently penetrate skin (because of
penetration enhancer) and enhance compound delivery (as
they have vesicular structure) to deeper skin strata or system
[7].
The physical and chemical properties of ethosomes make more
efficacious than other forms of liposomes for drug delivery to
Table 1. Vesicles developed for Transdermal drug delivery system.
Identification Definition
Archaeosomes Archaeosomes are the archaebacteria lipids containing vesicles which are chemically distinct
from eukaryotic and prokaryotic species and are less sensitive to oxidative stress, high
temperature, and alkaline pH [14,15].
Cochleates Cochleates are the special form of liposomes which are suspended in an aqueous two-phase
polymer solution, and allow the logic partitioning of polar molecule-based structures by phase
separation. Cochleate are the precipitate of a particle size less than 1μm obtained by the liposome
2+
containing two-phase polymer solution treated with positively charged molecules such as Ca or
2+
Zn ions [16].
Dendrosomes Dendrosomes have shown excellence results when used as a vehicle for gene delivery compared
with other existing synthetic vehicles with advantages such as nontoxic, neutral, biodegradable,
covalent or self-assembled, hyperbranched, dendritic, spheroidal nanoparticles which are easy to
prepare, inexpensive, highly stable as well as easy to handle and apply [17].
Dried reconstituted vesicles (DRV) These are the small, "empty" unilamellar vesicles, containing different lipids or mixtures of them.
The small unilamellar vesicles are prepared by mixing with solubilized drug followed by
dehydration and then water is added for rehydration that leads to the formation of large quantities
of rather inhomogeneous, multilamellar vesicles which need further processing [18].
Ethosomes Ethosomal systems delivers a drug more efficiently to the skin, in terms of quantity and depth,
than either conventional liposomes or hydroalcoholic solutions and the studies of drug
permeation through the skin was demonstrated in diffusion cell experiments. These multilamellar
vesicles are composed of soy phosphatidylcholine and about 30% of ethanol [19].
Immunoliposomes Immunoliposomes are the modified liposomes established for in vitro and in vivo application
with antibodies, Fab's or peptide structures on the bilayer surface [20,21].
Immunosomes Immunosomes are the preformed liposomes prepared by the anchorage of glycoprotein
molecules, look like homogenous spherical vesicles (50-60 nm) evenly covered with spikes under
the electron microscope. They have structural and immunogen characteristics closer to those of
purified and inactivated viruses than any other form of glycoprotein lipids association [22].
Immune stimulating complex (ISCOM) ISCOMs are the spherical, micellar assemblies of about 40 nm composed of saponin mixture Quil
A, cholesterol, phospholipids and amphiphilic antigens like membrane proteins. ISCOMs already
contain a built-in adjuvant, Quillajasaponin, which is a structural part of the vehicle [23].
Lipoplexes Cationic lipid-DNA complexes are known as lipoplexes, are efficient carriers for cell transfection
with certain drawbacks due to their toxicity. In lipoplexes either cationic lipids or nucleic acids
may cause toxicity. [24,25].
LUVETs LUVETs are large unilamellar vesicles prepared by extrusion technique [26].
Niosomes Niosomes are small unilamellar vesicles made from nonionic surfactants also known as
Novasomes. Their chemically they are as stable as archaeosomes [27].
pH-sensitive liposomes The pH-sensitive liposomes have been described in four basic classes. The first class most
intensively studied, combines unsaturated polymorphic lipids like phosphatidylethanolamines,

43
Global Journal of Pharmaceutical Education and Research | January-December 2015 | Vol.4 | Issue 1-2
with mild acidic amphiphilic in nature and act as stabilizers at neutral pH. The second class
includes liposomes composed of permeability enhancer lipid derivatives to encapsulate solutes. A
third class of pH-sensitive liposomes is composed of pH-sensitive peptides or reconstituted
fusion proteins to destabilize membranes at low pH. The final and most advanced class of pH-
sensitive liposomes utilizes pH-titratable polymers to destabilize membranes following change
of the polymer conformation at low pH [28].
Proliposomes These are dry, free-flowing particles that immediately form a liposomal dispersion on contact
with water [29,30].
Proteosomes Proteosomes are the bacterial origin vesicles which were solubilised, followed by ammonium
sulphate precipitation and dialysis against detergent buffer. Proteosomes are highly immunogenic
as proteins and peptides are non-covalently complexed to the membrane [31].
Reverse-phase evaporation vesicles Reverse-phase evaporation vesicles are large unilamellar liposomes formed by evaporation of oil
in water emulsions [32].
Stealth liposomes Stealth liposomes are the liposomes coated with polyethylene glycol (PEG), a synthetic
hydrophilic polymer, would enhance their stability and lengthen their half-lives in circulation,
rendering the use of glycolipids obsolete. PEG coating inhibits protein adsorption and
opsonization of liposomes, and retards liposomal recognition by the reticuloendothelial system
(RES). These PEG-coated liposomes are also called as sterically stabilized or stealth liposomes.
[33-39].
Temperature-sensitive liposomes Temperature-sensitive liposomes are promising tool to achieve site-specific delivery of drugs.
Temperature-sensitive liposomes have been prepared using lipids which undergo a gel-to-liquid
crystalline phase transition a few degrees above physiological temperature. However,
temperature sensitizations of liposomes have been achieved by using thermo sensitive polymers
[40,41].
Transfersomes Transfersomes are ultradeformable vesicles consist of phosphatidylcholine and cholate and
enhances the skin-penetrating properties [42].
Virosomes Small unilamellar vesicles containing influenza hemagglutinin, by which they became fusogenic
with endocytic membranes. Coincorporation of other membrane antigens induces enhanced
immune responses [43].
of ethosomes by using minoxidil as a model drug and observed
that the ethosomal system dramatically enhanced the skin
permeation of minoxidil in vitro compared with either
ethanolic or hydroethanolic solution or phospholipid ethanolic
micellar solution of minoxidil. From this study it was
concluded that the ethosomes can efficiently entrap molecules
of various lyophilicities.
For the enhanced transdermal delivery Bendas et al [59]
prepared ethosomes by the solvent evaporation method [60]
u s in g s a lb u ta mo l su l fa te as a m o de l d ru g an d
phosphatidylcholine from soybean lecithin, cholesterol, and
dicetylphosphate by dissolving in a small volume of diethyl
ether: chloroform (1:1) mixture.
For the delivery of a drug having short biological half-life (4-6
hour) i.e. Lamivudine an antiviral drug for treatment of
acquired immunodeficiency syndrome (AIDS) and hepatitis
[61] prepared ethosomes and deliver it as transdermally by
us in g fl u or es c en c e m ar k er R ho da m in e 12 3 a n d
soyaphosphatidyl choline (99%) without further purification
as per well-known cast film method [62].
By using ethanol injection-sonication technique Ligustrazine-
ethosomes were prepared, with entrapment efficiency as an
indicator. The ethosome were prepared by 1% (w/v)
phospholipid, 0.4% (w/v) cholesterol, and 45% (v/v) ethanol
[63].
The vehicle used for the formulation of ethosomal transdermal
drug delivery system, have been widely studied. It was
suggested that highly elastic vesicles could facilitate an easy
drug transport across the skin as compared to rigid membrane
vesicles [44]. However, Phosphatidyl choline (PC) [45-48],
Span 80, hydrogenated PC, phosphatidic acid (PA) [49],
phosphatidylserine (PS), phosphatidylethanolamine (PE),
phosphatidylglycerol (PPG), phosphatidylinositol (PI),
hydrogenated PC, alcohol (ethanol or isopropyl alcohol),
water and propylene glycol (or other glycols) [50] elastic
vesicles were recently reported to be more effective in
enhancing the skin permeation of dexamethasone, diclofenac,
zidovudine, and norgestrel as compared to PC-cholesterol
rigid vesicles [51-55]. Apart from this, it has also been found
that ethosomes are well distributed when cholesterol is
included in the formulation, and that they are prone to
aggregation in the absence of cholesterol. This is because of
the cholesterol that stabilizes into a bilayer when ethosomes
are maintained in a gel state, and mobility of the vesicles is
ensured by the high concentration of ethanol in ethosomes, and
that a moderate amount of cholesterol could ensure stability
[56-58]. Different types of additives employed in formulation
of Ethosomes have been summarized in Table 2.
Literature Review of Ethosomes
Touitou et al [19] demonstrated the procedure of development

44 Global Journal of Pharmaceutical Education and Research | January-December 2015 | Vol.4 | Issue 1-2
Class Examples of lipid excipients Uses and importances
Phospholipid Soya phosphatidyl choline, Egg phosphatidyl choline, Help in the formation of vesicles
Dipalmitylphosphatidyl choline, Distearylphosphatidyl choline
Polyglycol Propylene glycol, Transcutol RTM Acts as a skin penetration enhancer
Alcohol Ethanol, Isopropyl alcohol Provides softness to the vesicle membrane and
enhances skin penetration
Cholesterol Cholesterol Stabilizes the vesicle membrane
Dye Rhodamine-123, Rhodamine red, FluoresceneIsothiocynate Dyes are used for the characterization of vesicles
(FITC), 6- Carboxy fluorescence
Vehicle Carbopol D934 Used in the ethosomal gel type formations
Table 2: Additives employed in formulation of Ethosomes
Maheshwari et al [45] prepared and compare the transdermal
potential of novel vesicular nanocarriers: ethosomes and
ultrad eformable liposomes, con taining an anti-fun gal
bioactive clotrimazole (CLT) and their results suggested that
among all types of formulations they prepared ethosomes are
the most proficient carrier system for dermal and transdermal
delivery of clotrimazole. Ethosomes were prepared by
mechanical-dispersion method, as reported and described
earlier [9,46,64].
The effect of cholesterol and ethanol on dermal delivery from
α-dipalmitoylphosphatidylcholine (α-DPPC) liposomes was
observed by Pinto et al [9] using minoxidil (Mx) as a model
drug.
By using soya phosphatidylcholine (PC) (99%), phospho-
tungstic acid, Rhodamine Red-X 1, 2 dihexadecanoyl- sn-
glycero-3-phosphoethanolamine trimethylammonium salt
(RR), ethanol and methotrexate (MTX) as model drug Dubey
[46] prepared ethanolic liposomes for Dermal and transdermal
delivery of an anti-psoriatic agent (MTX).
Dubey et al [64] prepared and evaluated novel ethanolic
liposomes of Melatonin Cast film method using Soya PC
(2.0% w/w) as lipid excipients and concluded that the
ethosomes provides an enhanced transdermal flux, lower lag
time, higher entrapment efficiency and low skin irritancy
potential, thus, this approach offers a suitable approach for
transdermal delivery of melatonin.
Paolino et al [47] prepared and evaluated various ethosomal
suspensions made up of water, phospholipids and ethanol at
various concentrations for their potential application in dermal
administration of ammonium glycyrrhizinate. 1-3% (w/v)
®
Phospholipon 90 , 30-45% (v/v) ethanol, active molecules as
described and water to 100% (w/v) were used to prepare
ethosomes colloidal suspensions as reported by Touitou [19].
Fang et al [65] used 5-aminolevulinic acid-photodynamic
therapy (ALA-PDT) to treat Psoriasis and prepared ethosomes
using phosphatidylethanolamine and ethanol according to the
thin-film hydration method [66] that was his previous study in
which 5-aminolevulinic acid-encapsulated liposomes were
compared to ethosomes for the skin delivery for photodynamic
therapy.
Verma et al [49] used ethanol with a commercially available
lipid mixture, NAT 8539, to improve the topical delivery of
cyclosporin A (CyA) and the size of vesicles were found to be
56.6 to 100.6 nm in diameter depending on the amount of
ethanol added in the formulation.
Liu et al [67] investigate the pharmacokinetics of the
ligustrazine ethosome patch and antimyocardial ischemia and
anti-ischemic reperfusion injury effect by applying ethosomal
patch in rats and found that prepared ligustrazine ethosome
patches could improve drug absorption and bioavailability.
Because ligustrazine degraded by first pass effect upon oral
administration while several ligustrazine preparations via
transdermal administration have been reported to improve its
bioavailability and safety [68-70].
Liu et al [71] prepared ethosomes by ethanol injection-
sonication and formulation as a patch of ligustrazine and
evaluated in vitro and in vivo.
In another research Dubey et al [50] prepared ethanolic
liposomes to deliver an anti-HIV agent (Indinavir), using
phospatidylcholine as lipid polymer and ethanol as penetrating
agent.
Godin et al [72] successfully permeate Bacitracin an
antimicrobial agent through cellular membrane using
ethosomes as a vehicle and support the previously suggested
mode of action of these soft vesicles. For this study Fluorescent
phospholi pid (rhodamine red dihexadecan oylglyce ro-
phosphoethanolamine, RR) and Phospholipon-90 were used.
Elsayed et al [73] prepared deformable liposomes (prepared by
conventional mechanical dispersion method) and ethosomes
(according to Dayan [74]) to investigate the possible
mechanisms by which deformable liposomes and ethosomes
could improve skin delivery of the model hydrophilic drug,
ketotifen fumarate (KT), under non-occlusive conditions.
According to the results observed deformable liposomes were
found to be the best way to deliver Ketotifen across the skin.
Verma et al [75] prepared ethanolic liposomes i.e. ethosomes
using Econazole nitrate as a model drug to treat skin infections
caused by various species of pathogenic dermatophytes by
cold method [55].

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Global Journal of Pharmaceutical Education and Research | January-December 2015 | Vol.4 | Issue 1-2
Zhang et al [76] prepared ethosomes according to [19] by
using Lipoid S 100-phosphatidylcholine (PC) from soybean
lecithin and 5-fluorouracil as a model drug and observed the
penetration of ethosomes in hypertrophic scar (HS) and skin
was analyzed by ethosomes labeled with rhodamine 6GO (a
fluorescent agent) and confocal laser scanning microscopy
(CLSM).
Chourasia et al [77] prepared nanosized ethosomes vesicles by
the method reported elsewhere with some modifications [64]
using Soya phosphatidyl choline as a major excipient and
Ketoprofen as a model drug and the results of the in-vitro
release study through the skin revealed higher transdermal flux
with ethosomal formulation compared to hydroalcoholic drug
solution.
Lodzki et al [78] used Cannabidiol (CBD) as a model drug
candidate for treatment of rheumatic diseases and prepared
ethosomes the method reported elsewhere with some
modifications [19] and the kinetic profile of CBD's plasma
concentration shows that steady-state (SS) levels were reached
at about 24 h and lasted at least until the end of the experiment
(72 hrs). The in vivo studies were conducted using male CD1
nude mice 8-9 weeks old.
Fang et al [79] prepared ethanolic liposomes with the aim to
develop and evaluate liposomal formulations encapsulating
tea catechins, which possess antioxidant and chemopreventive
activities using anionic surfactants such as deoxycholic acid
(DA) and dicetyl phosphate (DP) in the liposomes in the
prese nce o f 15% eth anol incr eas ed the ( +)- catechi n
permeation by five to seven-fold as compared to the control.
The in vitro release and skin permeation were determined
using a Franz diffusion cell along with a cellulose membrane or
female nude mouse skin.
Buspirone was used as model drug to treat Menopausal
syndromes in women by formulating ethosomes as a drug
carrier and it was observed that the ethosomal buspirone
transdermal system could be considered as a promising
delivery system for the treatment of menopausal syndromes.
The study also shows an enhanced skin permeation in-vitro,
good bio availab ility and e ffi cient pha rmacody namic
responses in animals [80].
Mechanism of Drug Penetration [47, 81]
The enhanced release of active drug ingredient from the
ethosomes can be described by an interaction between
ethosomes and skin lipids. The mechanism for this interaction
is not yet cleared but two types of effects have been assumed
while drug release from ethosomes. First part of the
mechanism is assumed due to the 'Ethanol Effect' whereby
intercalation of the ethanol into intercellular lipids increasing
lipid fluidity and decreases the density of the lipid multilayer.
After this is effect a second type of mechanism comes under
influence i.e. 'Ethosome Effect' that includes inter lipid
penetration and permeation by the opening of new pathways
due to the malleability and fusion of ethosomes with skin
lipids, resulting in the release of the drug in deep layers of the
skin. The drug absorption probably occurs in two phases as
discussed hereunder:
Ethanol effect: Topical ethanol solutions are also used as
penetration enhancers [47,82-84] and can also be used in
transdermal preparations in combination with Labrasol as a co-
surfactant [102]. Ethanol penetrates easily into intercellular
lipids and increases its fluidity and decrease the density of lipid
multilayer of cell membrane.
Ethosomes effect: The ethanol used in the preparation of
ethosomes increases cell membrane lipid fluidity results in
increased skin permeability. So the ethosomes permeates very
easily inside the deep skin layers i.e. Stratum corneum, where
it got fused with skin lipids and releases the drugs into deep
layer of skin [49].
Methods For Characterization of Ethosomes
Visualization
This is very important to visualize the ethosomes and this can
be done by using transmission electron microscopy (TEM) and
by scann i n g e l ectron micros c o p y ( SEM) [85]. T h e
visualization studies by electron microscopy reveals that the
ethosomal formulation exhibits vesicular structure ranging
from 300-400 nm in diameter.
Figure 1: Visualization of ethosomal vesicles. (a) TEM
(magnification 3,15,000) and (b) SEM (magnification
100 000) of ethosomal vesicles [19].
(a)
(b)

46 Global Journal of Pharmaceutical Education and Research | January-December 2015 | Vol.4 | Issue 1-2
Mean size is measured by dynamic light scattering (DLS) and
structure changes are observed by TEM [96]. The stability
studies can be carri ed out by storing the eth osomal
formulations at two different temperatures i.e. 4°C and
25±2°C. The drug content in ethosomal formulation can be
estimated by using high performance liquid chromatographic
[74] for every 15 days to identify any change in the entrapment
efficiency of ethosomal formulation.
Penetration and Permeation Studies
After the release of drug from ethosomal formulation it reaches
to the skin, and the depth of penetration from ethosomes can be
visualized by confocal laser scanning microscopy (CLSM)
[97].
Transition Temperature
The transition temperature (the transition temperature is the
temperature at which an amorphous solid becomes soft upon
heating or br ittle upon cooling. The glass transi tion
temperature is lower than the melting point of its crystalline
form) of the vesicular lipid systems can be determined by using
differential scanning calorimetry [98].
Statistical analysis
The statistical analysis of the experimental results can be
performe d by ANOVA. Differ ences we re considere d
statistically significant at p<0.05. All the data values should be
represented as mean ± standard deviation of 3 measurements.
Moreover, the in-vitro dissolution data can also be compared
using a model independent analysis involving determination
of similarity factor f2, which is a measure of similarity in two
drug release profiles. The following equation is used to
calculate the similarity factor [99]
Vesicle size and Zeta potential
The particle size and the charge on the vesicles i.e. zeta
potential can be determined by dynamic light scattering (DLS)
method, using a computerized inspection system and photon
correlation spectroscopy (PCS) (One drop of ethosomal
formulation is diluted to 10ml with hydroethanolic mixture
used in the formulation and the measurements have to be taken.
The size distribution of the liposomal formulation is
determined after diluting the formulation with distilled water.)
[59, 46, 86-88]. The size of ethosomes ranges from tens of
nanometers to microns and it is influenced by the composition
or ingredients used in the formulation. Whereas, the Zeta
potential is an important and useful parameter for prediction of
the particle surface charge, that defines and control the stability
of vesicles.
Entrapment Efficiency
Entrapment Efficiency is a measure of difference between the
un-entrapped and total amounts of drug and the un-entrapped
drug is determined by various techniques such as exhaustive
dialysis [89], gel filtration [12, 90-91] and centrifugation [92].
While the extent of drug entrapped by ethosomes (i.e.
en t ra p men t ef f ici e nc y ) c an b e m ea s ur ed b y t he
ultracentrifugation technique [93].The entrapment efficiency
of ethosomes is dependent on the chemical nature of the lipid
used in the formulation. Dayan and Touitou worked out on the
comparison of the entrapment efficiencies of ethosomes and
liposomes and found that ethosomes have much more
entrapment efficiency than that of liposomes [94].
Entrapment effic ien cy of ethosomal vesicles can b e
determined by centrifugation method [19, 59, 64, 74, 88]. The
vesicles are first separated in a high speed cooling centrifuge at
20,000 rpm for 90 minutes under maintained temperature
conditions of 4°C. The sediment and supernatant liquids are
then separated and amount of drug in the sediment is
determined by lysing the vesicles using methanol. From this,
the entrapment efficiency was determined by the following
equation,
Entrapment efficiency = D / D × 100
E T
Where,
D — Amount of drug in the ethosomal sediment
E
D — Theoretical amount of drug used to prepare the
T
formulation
(Equal to amount of drug in supernatant liquid and in the
sediment)
Surface Tension Activity Measurement
In aqueous solution the surface tension activity of drug can be
measured by the ring method according to Du Nouy ring
tensiometer [95].
Vesicle Stability
The stability studies of vesicles can be determined by assessing
the size and structure of the vesicles over a period of time.
CONCLUSION
Ethosomes is a carrier system offers new therapeutic
dimension and opportunities in while approaching transdermal
route to deliver a drug with more patient compliances.
Ethosomes has initiated a new area in vesicular research for
transdermal drug delivery that provides a better skin
permeation compared to the liposomal drug delivery systems.
The drugs having low drug diffusion rate across the stratum
corneum have been considered to be the major limiting factor
in case of transdermal drug delivery system which can be
bypassed by formulating as ethosomes. Recent advancements
and further research in this area will allow a more effective
approach in dermal/transdermal delivery of drugs.

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Global Journal of Pharmaceutical Education and Research | January-December 2015 | Vol.4 | Issue 1-2
Table 3. US Patents Granted For Ethosomes
Patent
publication
number
Inventors Title Date of
patent
Granted
Patent description in brief References
US
55,40,934
Elka Touitou Composition
for applying
active
substances to
or through
the skin
Jul. 30, 1996 The present invention relates to the cosmetic and or medical
composition for topical application to the skin, in which essential
ingredients used in this are phospholipid, a lower aliphatic alcohol
of two to four carbon atom instead of this propylene glycol may also
be optional, water and a compatible active ingred ient. The alcohol
used from 20 to 50% alone and upto 70% along with glycol.
6
US
57,16,638
Elka Touitou
Composition
for applying
active
substances to
or through
the skin
Feb. 10,
1998
The present invention relates to the cosmetic and or medical
composition for topical application to the skin, in which essential
ingredients used in this are phospholipid, a lower aliphatic alcohol
of two to four carbon atom instead of this propylene glycol may also
be optional, water and a compatible active ingredient. 0.5 to 10%
phospholipids, 5 to 35% C3
or C4- alcohol, 15 to 30% ethanol, that
contain at least 20% but not more than 40% by weight of ethanol
and upto 20% propylene glycol.
50
US
2009/00472
34 A1
Elka Touitou
Biana Godin
ShaherDuchi
Composition
for nasal
delivery
Feb. 19,
2009
The invention relates to the administration of least one active
pharmaceutical agent by intranasal route. The formulation includes
phospholipids (0.2-10%), one or more C2- C4alcohol (12-30%) and
water
100
CN1012739
71
LipingLiu;Yi
minLi;Liujian
gHu;Minggao
Shen;YangJin
Ethosomes
preparation
of
antimycotics
pharmaceutic
al and
method for
preparing the
same
Oct 01,
2008
Description is not available
101
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