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Mistry et al., IJPSR, 2015; Vol. 6(10): 4129-4136. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4129
IJPSR (2015), Vol. 6, Issue 10 (Review Article)
Received on 24 March, 2015; received in revised form, 10 May, 2015; accepted, 23 June, 2015; published 01 October, 2015
ETHOSOMES: UNIQUE ELASTIC VESICULAR CARRIER – AN OVERVIEW
A. Mistry*, P. Ravikumar and S. Pathare
Department of Pharmaceutics, SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W).
Mumbai-400056, M.S. India
ABSTRACT: Ethosomes are phospholipid-based elastic vesicles which have a
potential as novel topical and transdermal drug delivery systems. They are ethanolic
phospholipids vesicles which can act as carriers for various medicaments.
Ethosomes have gained importance in the area of research, because of their
intensified skin permeation, better delivery of drug and increased drug entrapment
efficiency. These systems are more efficient in delivering substances to the skin
because of the presence of ethanol, which provides a net negative charge on the
surface, which helps to avoid aggregation of vesicles due to electrostatic repulsion
than either conventional liposomes or hydroalcoholic solutions in terms of quantity
and depth. Ethosomes are simple to prepare and safe to use. This review attempts to
compile the various aspects like mechanism of action, methods of preparation (Hot
method, Cold Method, Dispersion method using rotary evaporator) ,advantages,
limitations, characterization, applications in different conditions like Anti-
inflammatory, Arthritis, Acne, Fungal infections, Bronchial asthma, chronic
bronchitis, emphysema, Diabetic condition, Scleroderma, systemic lupus
erythematosus and psoriasis, etc of reported ethosomal formulations for topical and
transdermal use. Also, the patented literature has been tabulated.
INTRODUCTION: The main disadvantage of
transdermal drug delivery is the poor penetration of
most compounds into the human skin. The main
barrier of the skin is the uppermost layer; the
stratum corneum (SC). Several approaches have
been reported to improve the penetration through
the skin. One of the approaches is the use of
vesicular systems like Ethosomes and Liposomes.
Ethosomes:
Ethosomes are phospholipid-based elastic vesicles
containing 20–45% ethanol and water 1. For the
preparation of elastic vesicles; ethanol is a proven
permeation enhancer that has been added in the
vesicular systems.
QUICK RESPONSE CODE
DOI:
10.13040/IJPSR.0975-8232.6(10).4129-36
Article can be accessed online on:
www.ijpsr.com
DOI link: http://dx.doi.org/10.13040/IJPSR.0975-8232.6(10).4129-36
High flexibility imparted by ethanol of vesicular
membranes permits the elastic vesicles to squeeze
themselves through the pores. The proposed
mechanism of penetration enhancement with the
ethosomal system suggests the intercalation of
ethanol into the polar head group environment
resulting in increased membrane permeability.
With respect to stability, Ethosomes have been
reported to be more stable than liposomes because
of the presence of ethanol, which provides a net
negative charge on the surface 2, which helps to
avoid aggregation of vesicles due to electrostatic
repulsion. Topically applied ethosomes can
increase the residence time of active ingredients in
the stratum corneum, epidermis and reduce the
systemic absorption of drugs. These properties
allow Ethosomes to permeate easily into the deeper
layers of the skin.
Advantages and Limitations of Ethosomes:
Advantages of ethosomes as a product include;
ease of manufacture, high patient compliance,
Keywords:
Ethosomes, Permeation,
Topical, Transdermal, Vesicles
Correspondence to Author:
A. Mistry
(M. Pharm, Pharmaceutics Research
Student), SVKM’s Dr. Bhanuben
Nanavati College of Pharmacy, Vile
Parle (W). Mumbai-400056, India.
E-mail: ankitam.1208@gmail.com
Mistry et al., IJPSR, 2015; Vol. 6(10): 4129-4136. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4130
enhancement of solubility and smaller size as
compared to conventional vesicles. Ethosomes
enhances the permeation of the drug through skin,
disperse better, exhibit improved therapeutic
efficacy and good storage stability, improved
bioavailability and provide protection from
toxicity. Ethosomes have applications in
Veterinary, Pharmaceutical, Cosmetic,
Biotechnology and Nutraceutical markets 3.
However, limitations include; Poor yield 2, 4,
unsuccessful vesicle formation can coalesce
ethosomes 2 and product loss during transfer form
organic to water media 2, 5.
Mechanism of Action of Ethosomes:
Methods of Preparation for Ethosomes: The following Table 1 describes different preparation methods
of ethosomes 2, 6, 7
TABLE 1: METHODS OF PREPARATION
Components
Order of
Addition
Working
temperature
Mixing time
and speed
Size Reduction
Technique
Aqueous
Organic
Cold Method
Water
Phospholipid,
other lipid
materials, drug,
ethanol
Aqueous to
organic
30C
5minutes at
700-1000
rpm
Using high
pressure
homogeniz-ation,
at 15,000 psi, in
3cycles
Hot method
Water, Ethanol,
Propylene
Glycol, drug
Phospholipid,
drug
Aqueous to
Organic
40C
5minutes at
700- 1000
rpm
Using sonication
or extrusion
technique.
Dispersion
method using
rotary
vaccum
evaporator
Hydro-ethanolic
Mixture, drug
Phospholipid,
cholesterol,
chloroform,
methanol
Aqueous to
Organic
Heating above
lipid transition
temperature for
film formation
Suitable
speed,
temperature
and time.
Not Reported
Characterization of Ethosomes: The following Table 2 summarizes the tests and their techniques which
enable characterization of Ethosomes 7, 8, 9
Mistry et al., IJPSR, 2015; Vol. 6(10): 4129-4136. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4131
TABLE 2: CHARACTERIZATION OF ETHOSOMES
Test
Technique/Instrument
Particle shape
Scanning Electron Microscopy, Transmission Electron
Microscopy
Particle size analysis
Optical Microscopy
Drug Content
High Performance Liquid Chromatography/UV.
Drug Entrapment Efficiency
Ultra centrifugation technique.
In Vitro drug release study
Franz Diffusion cell.
In Vitro skin permeation study
Franz Diffusion cell.
Transition Temperature
Differential scanning calorimetry
Patents:
In 1995 and 1996 Touitou E filed first patent on
ethosomes titled Composition for applying active
substances to or through the skin US 5716638 and
Compositions for applying active substances to or
through the skin US5540934 A, respectively. It
concluded the transdermal passage of an active
ingredient, or in the introduction of such agent into
the skin. 10, 11 The following Table 3 summarizes
patented literature on Ethosomes.
TABLE 3: PATENTS ON ETHOSOMES
Title
Patent Number
Inventors
Year
Reported Results
Chinese medicinal
ethosome gel patch for
treating herpes zoster
and preparation method
thereof 12
CN103536700 (A)
Bu Ping; Hu
Rong; Chen Lin;
Wei Rong; Wu
Huanhuan; Huang
Xiaoli
2014
Easy in medication and
convenient to use, has a good
therapeutic effect, quick
response, strong analgesic
action but no adverse
reaction.
Ethosome gel film-
coating agent with
multiple wound repair
effects and preparation
method of ethosome gel
film-coating agent 13
CN103893394 (A)
Chen Jie; Huang
Changping; Zheng
Maoxin; Nie
Kaipin
2014
The Ethosome entrapped
film-coating agent helps to
promote healing and nutrition
supplying of the wound
tissue. The ethosome gel
film-coating agent is suitable
for wound clinical care and
treatment.
Leflunomide ethosome
composition and its
preparation method14
CN103800277 (A)
Zhang Tao; Ding
Yanji; Deng Jie;
Luo Jing; Zhong
Xiaodong
2014
Improves the transdermal rate
of leflunomide, can
significantly reduce side
effects of oral administration
of leflunomide and improves
curative effects.
Daptomycin ethosome
preparation 15
CN103006562 (A)
Li Chong; Liu
Xia; Yin Qikun;
Wang Xiaoying;
Chen Zhangbao
2013
The daptomycin ethosome
preparation is a stable
translucent dispersion system
with light blue opalescence,
small and uniform in particle
size, high in entrapment
efficiency and excellent in
transdermal performance,
drug release and has certain
slow-release effect, and the
preparation method is simple
and convenient, low in cost
and good in stability.
Bullatacin ethosome gel
and preparation method
thereof 16
CN102552147 (A)
Jianping Tan;
Lixin Jiang;
Tanran Chang;
Zhiwen Zhou
2012
The bullatacin ethosome gel
provided by the invention can
reduce irritation to the skin
and has good percutaneous
penetration effects.
Ethosome preparation of
male hormone
CN102406605 (A)
Shu Meng; Jianxin
Li; Yanmin Guan;
2012
To improve transdermal
transport of male hormone
Mistry et al., IJPSR, 2015; Vol. 6(10): 4129-4136. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4132
medicaments and its
preparation method17
Dan Yang
medicaments and enhancing
their curative effects.
Lidocaine ethosome and
preparation method there
of 18
CN102813624 (A)
Zhao Xianying; Su
Yongping; Gao
Jining; Liu Yimin;
Zhao Huawen;
Xiao Xiang; Zhou
Xiaoxia; Zhang
Dinglin; Wu
Liping
2012
The lidocaine ethosome of
the present invention
provides advantages of rapid
onset, prolonged drug action
time, further has advantages
of small particle size, high
penetration efficiency, high
encapsulation efficiency and
good stability.
Paclitaxel ethosome gel
and preparation method
there of 19
CN102579323 (A)
Jianping Tan;
Lixin Jiang;
Tanran Chang;
Zhiwen Zhou
2012
The action of stimulation to
the skin can be reduced, and
the percutaneous permeation
effect is good.
Progesterone ethosome,
and preparation method
and application there of
20
CN102397255 (A)
Shu Zhang; Hong
Deng; Huaqing
Lin; Xiaoling
Zhang
2012
The progesterone ethosome is
mainly applied to hormone
replacement therapy,
secondary amenorrhea,
functional aplastic bleeding,
premenstrual syndrome and
the like clinically.
Acyclovir ethosome and
preparation method there
of 21
CN102133183 (A)
Xuewen Wu; Yan
Xiong
2011
Acyclovir ethosome has high
stability and narrow particle
size distribution.
Podophyllotoxin
ethosomes and
preparation methods
there of 22
CN102144972 (A)
Nianping Feng;
Yanyan Yu; Jihui
Zhao; Haiting
Weng; Xiaoqin
Shi
2011
The aims of increasing
curative effect and reducing
relapse and toxic and side
effects are fulfilled. The
invention also discloses two
preparation methods for the
podophyllotoxin ethosomes.
Applications of Ethosomal Formulations:
Reported literature indicates enhanced topical
delivery of Azelaic acid, 5 aminolevulinic acid,
Tretinoin, Isotretinoin, Naproxen, Ketotifen,
Tetradrine, Apigenin, Bacitracin, Cyclosporin A,
Mycophenolic Acid, Paclitaxel, Ammonium
Glycyrrhizinate, Ketoconazole, Fluconazole and
also enhanced transdermal delivery of Repaglinide,
Tramadol, Aceclofenac, CiclopiroxOlamine,
Alfuzosin Hydrochloride, Salbutamol, Valsartan,
Curcumin, Diclofenac, Clotrimazole, Ketoprofen.
Several phytochemicals and herbal extracts have
also been successfully delivered via ethosomes
which exhibit some distinct advantages over
conventional drug delivery systems. 3 Following is
a compilation of available literature on ethosomal
formulations for specific conditions.
1. Acne Treatment:
Sheba Rani Nakka David et al., compared
ethosomal based Isotretinoin gel with
marketed formulations of isotretinoin.
Organoleptic properties, drug entrapment,
drug content uniformity, in vitro drug release
and skin permeation studies were compared.
Ethosomal vesicles containing 2%w/w
lecithin and 30%w/w ethanol were found to
have shown the best entrapment percentage
(99.21%). However, the in vitro skin
permeation was increased with the addition
of enhancers. It was concluded that the
ethosomal vesicles and enhancers increased
the skin permeation and depot formation of
drug in the skin. 23
2. Anti-Inflammatory:
In vitro and Ex vivo skin deposition and
transdermal flux of Apigenin loaded in
deformable liposomes, ethosomes and
liposomes were compared by Li-Na Shen et
al. The efficiency of apigenin encapsulation
increased with an increase in the amount of
phospholipids in ethosomal formulations.
Skin deposition and transdermal flux of
apigenin improved with an increase in the
levels of phospholipids (Lipoid S 75) and
Mistry et al., IJPSR, 2015; Vol. 6(10): 4129-4136. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4133
short-chain alcohols like ethanol and
propylene glycol, but decreased with an
increase in the ratio of propylene glycol to
ethanol. Optimized ethosomes showed
superior skin targeting both in vitro and in
vivo. They also reported the reduction of
cyclooxygenase-2 levels in mouse skin
inflammation induced by ultraviolet B (UVB)
light and represent a promising therapeutic
approach for the treatment of UVB-induced
skin inflammation. 24
3. Arthritis:
Chao Fan, et al., worked to explore the
feasibility of ethosomes prepared by pH
gradient loading method for improving the
antiarthritic efficacy of Tetrandrine by topical
application. Ex vivo permeation and
deposition behavior demonstrated that the
drugs flux across rat skin and deposition of
the drug in rat skin for ethosomes was 2.1
higher and for liposomes 1.7-fold higher.
Confocal laser scanning microscopy
confirmed that ethosomes could enhance the
topical delivery of the drug in terms of depth
and quantity compared with liposomes. 25
4. Bronchial asthma, chronic bronchitis, and
emphysema:
Ehab R. Bendas, et al., compared the
transdermal delivery of salbutamol sulfate
(SS), from ethosomes and classic liposomes
containing various cholesterol and
dicetylphosphate concentrations. The vesicle
size was significantly decreased by
decreasing cholesterol concentration and
increasing concentrations of dicetylphosphate
and ethanol. The entrapment efficiency
percentage was significantly increased by
increasing concentrations of ethanol,
cholesterol and dicetylphosphate.
In vitro permeation studies of the prepared
gels containing the selected vesicles showed
that ethosomal systems were much more
efficient at delivering SS into mice skin (in
terms of quantity and depth)than were
liposomes or aqueous or hydroalcoholic
solutions. 26
5. Diabetic condition:
A.R. Rathore et al., evaluated the transdermal
sustained release delivery systems potential
of ‘ethosomes’. Effect of different
concentration of lipid studied, concluded that
the size of the vesicles increased with
increasing lipid concentration. Varying
concentration of ethanol studied found that
the size of the vesicles decreased with
increasing ethanol concentration. The
optimized formulation of ethosomes showed
highest release (73.23 ± 2.32). Repaglinide
encapsulated ethosomes in gel was found to
have shown maximum in-vitro drug release
(89.67 ± 2.35) as compared to other carbopol
concentrations and free drug gel. It was
concluded that ethosomes were a promising
candidate for transdermal delivery of
repaglinide. It possessed better skin
permeation potential, leading to improvement
in bioavailability of drug, reduction of dose
and dosing frequency. 27
6. Fungal Infections:
Rahul G.S. Maheshwari et al, compared the
transdermal potential of novel vesicular
nanocarriers: ethosomes and ultradeformable
liposomes, containing Clotrimazole. The
ethosomal formulation and ultradeformable
liposomal formulation showed entrapment in
the range of 68 to 69% and 55-56%
respectively and optimal nanometric size
range 132 ± 9nm and 121± 9.7 nm
respectively. The ethosomal formulation
provided enhanced transdermal flux, smallest
polydispersity index and decreased the lag
time of 0.9 h in comparison to
ultradeformable liposomal formulation. Skin
interaction and FT-IR studies revealed
greater penetration enhancing effect of
ethosomal formulation.
The ethosomal formulation also had the
highest zone of inhibition, in contrast to
liposomal formulation and marketed cream
against candidal species. It was concluded
that ethosomes are the most proficient carrier
system for dermal and transdermal delivery
of Clotrimazole. 28
Mistry et al., IJPSR, 2015; Vol. 6(10): 4129-4136. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4134
7. Scleroderma, systemic lupus
erythematosus and psoriasis:
T. Limsuwana et al., have developed
ethosomes containing Mycophenolic Acid
(MPA) for topical delivery. Ethosomal
formulation composed of 4% w/v soya
phosphotidylcholine with cholesterol,
Tween80 and deoxycholic acid as additives
in a molar ratio of 6:2:1:1 respectively. The
dispersion medium was 30% v/v ethanol in
phosphate buffer pH 7.4. The vesicle size,
Zeta potential, entrapment efficiency of
ethosomes are 371 ± 8nm (PI = 0.27 ± 0.02
nm), -46 ± 5 mV, 56 ± 1% respectively. 29
The following Table 4 summarizes formulation
details of reported literature of Ethosomes for
topical use.
TABLE 4: ETHOSOMES FOR TOPICAL USE
Active Pharmaceutical
Ingredient
Medical
Condition
Dosage form
In-vitro/Ex
vivo release
medium and
time
Reported Results
Alfuzosin
Hydrochloride 30
Inflammation
Suspension
Phosphate
Buffer Saline
pH 7.4 for
24hrs
Ethosomes are better carriers for
Alfuzosin hydrochloride transdermal
delivery.
5-aminolevulinic acid
(ALA) 31
Inflammation
Suspension
pH 5 citrate–
phosphate buffer
for 12 hours.
ALA containing ethosomes improved
penetration of ALA and the formation of
protoporphyrin IX and reduced tumor
necrosis factor -a compared to ALA
aqueous solution
Ammonium
Glycyrrhizinate 32
Inflammation
Suspension
pH 7.4 isotonic
phosphate-
buffered
solution for
24hours
Prolongation of its therapeutic activity,
promising carrier for topical
administration due to the enhanced
delivery of drugs
Azelaic acid 33
Acne
Ethosomal Gel
Isotonic
Palitzsch
Buffer/Ethanol
70:30 (v/v) for
6hours
Release rate was more rapid from
ethosomal system than from liposomal
system
Ciclopirox Olamine 34
Fungal infections
Suspension
Not Reported
Enhanced accumulation of
ciclopiroxolamine via ethosomal carrier
within the skin might help to optimize
targeting to the epidermal and dermal
sites.
Curcumin 35
Inflammation
Solution
0.25%
sodium dodecyl
sulfate and 10%
ethanol solution
for 24hours
Curcumin-Propylene glycol liposome had
the best encapsulation efficiency and the
highest and longest inhibition on paw
edema, followed by Ethosomes and
Traditional liposomes
Diclofenac 36
Inflammation,
Benign prostatic
hyperplasia.
Suspension
Saline (NaCl
0.9%, w/v) for
24hours
Diclofenac loaded Penetration enhancer-
containing vesicles, are capable of
localizing the drug at the site of
inflammation as compared to
conventional.
Fluconazole 37
Fungal infections
Ethosomal
cream
Phosphate
Buffer Saline,
pH 7.4 and 10%
methanol for
72hours
Better antifungal activity compared to
marketed formulation.
Ketoconazole 38
Fungal infections
Suspension
Phosphate
buffer, pH 7.4
with 1% sodium
lauryl for
72hours
Enhanced properties with increasing
concentrations of ethanol and by
subjecting vesicles for sonication.
Mistry et al., IJPSR, 2015; Vol. 6(10): 4129-4136. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4135
Ketoprofen 39
Inflammation
Suspension
Phosphate
Buffer Saline,
pH 7.4 for
24hours
Enhanced transdermal delivery.
Ketotifen 40
As mast cell
stabilizer
Suspension
pH 7.4 isotonic
phosphate buffer
with 0.11%
(w/v)
formaldehyde
for 24hours
Ethosomes containing Ketotifen both
inside and outside the vesicles exhibit
superior skin deposition.
Paclitaxel 41
Actinic keratoses
_
Water/ethanol
solution for
24hours.
Paclitaxel-loaded ethosomes represent a
promising topical drug delivery system
for the clinical treatment of Actinic
keratoses and Squamous cell carcinoma.
Tramadol
Hydrochloride 6
Ethosomal gel
Phosphate-
buffered
saline,pH 7.4 for
12hours
Optimum drug release and efficiency and
non irritant on skin.
Tretinoin 42
Acne
Suspension
Mixture of 0.01
M saline
phosphate
buffer,pH7.4
and 0.1% PEG-
40 for 6hours
Tretinoin–ultradeformable vesicles
formulation proved to be suitable for
dermal delivery.
Valsartan 43
Hypertension
Suspension
Ethanol:
Phosphate-
buffered saline,
pH 7.4 for
24hours
Nanoethosomal formulation potentially
useful carrier for transdermal delivery.
Enhancement of skin permeation and
bioavailability of valsartan.
CONCLUSION: A review of the published data
suggests that topically used ethosomes prove to be
superior when compared with conventional
formulations and offer improved safety and
efficacy. Drugs entrapped in ethosomes remain in
intact vesicles and exhibit penetration enhancing
effect. Drug vesicular based delivery systems are
hence promising in the treatment of a variety of
skin disorders.
ACKNOWLEDGEMENT: I would like to
express my sincere gratitude to P. Ravikumar for
her constant help and support in writing this
review. Also would like to thank S. Pathare for her
assistance.
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How to cite this article:
Mistry A Ravikumar P and Pathare S: Ethosomes: Unique Elastic Vesicular Carrier – An Overview. Int J Pharm Sci Res 2015; 6(10):
4129-36.doi: 10.13040/IJPSR.0975-8232.6(10).4129-36.
