Kumar Ravi et al.

IRJP 2012, 3 (1)

INTERNATIONAL RESEARCH JOURNAL OF PHARMACY

www.irjponline.com

Review Article

ISSN 2230 8407

TRANSFEROSOMES: A NOVEL APPROACH FOR TRANSDERMAL DRUG DELIVERY

Kumar Ravi*1, Manvir Singh1, Rajni bala1, Nimrata seth1, A.C Rana2
1

Department of Pharmaceutics, Rayat Institute of Pharmacy, Railmajra, Punjab, India

Department of Pharmacology, Rayat Institute of Pharmacy, Railmajra, Punjab, India

Article Received on: Revised on: Approved for publication:

*Kumar Ravi, Department of Pharmaceutics, Rayat Institute of Pharmacy, Railmajra, District Nawashehar-144533, Punjab, India
Email: ravishing50pharmacy@gmail.com
ABSTRACT
Transdermal drug delivery system appears to be most promising delivery system due to their merits over conventional delivery systems. Recently,
various strategies have been used to augment the transdermal delivery of bioactives. Mainly, they include iontophoresis, electrophoresis,
sonophoresis, chemical permeation enhancers, microneedles, and vesicular system (liposomes, niosomes, elastic liposomes such as ethosomes and
transfersomes). Among these strategies transferosomes appear promising. Transfersomes possess an infrastructure consisting of hydrophobic and
hydrophilic moieties together and as a result can accommodate drug molecules with wide range of solubility. A novel vesicular drug carrier system
called transfersomes, which is composed of phospholipid, surfactant, and water for enhanced transdermal delivery. Transfersomes can deform and
pass through narrow constriction (from 5 to 10 times less than their own diameter) without measurable loss.. The system can be characterized by in
vitro for vesicle shape and size, entrapment efficiency, degree of deformability, number of vesicles per cubic mm. Flexibility of transferosomes
membrane is achieved by mixing suitable surface active agents in the proper ratios. Transferosomes have beneficial advantages over other vesicular
systems such as their high penetration power across skin, higher stability, systemic drug release possible and higher deformability than other vesicular
systems such as niosomes, liposomes etc. They can act as a carrier for low as well as high molecular weight drugs e.g. analgesic, anesthetic,
corticosteroids, sex hormone, anticancer, insulin, gap junction protein, and albumin.
KEYWORDS: Transferosomes, ultradeformale vesicle

INTRODUCTION
The systemic treatment of disease via transdermal route
has gained increasing interest. So, transdermal controlled
drug delivery system appears to be most promising
delivery system over conventional delivery systems in
order to either avoid hepatic first-pass effect improving
drugs bioavailability or to decrease the dosing frequency
required for oral treatment and most importantly, it
provides patient compliance.1,2 In the last years, the
vesicular systems have been promoted as a mean of
sustained or controlled release of drugs. These vesicles
serve as a depot for release of active compounds as well
as rate-limiting membrane barrier for the modulation of
systemic absorption in the case of transdermal
formulations. The vesicles are composed of phospholipids
or nonionic surfactants. The reason for using vesicles in
transdermal drug delivery is based on the fact that they act
as drug carriers to deliver entrapped drug molecules
across the skin, as well as penetration enhancers because
of their composition. Elastic or ultradeformable vesicles
were introduced first by Gregor Cevc as a new generation
of vesicles, known as Transfersomes. These are artificial
designed vesicle composed of one natural amphiphillic
(such as phosphatidylcholine) and later are then
supplemented by at least one bilayer softener (e.g. a
biocompatible surfactant) (shown in figure 1).
Interdependency of local composition and shape of the
Transferosomes bilayer makes the vesicle both selfregulating and self-optimising. This enables the
trransfersome to cross various transport barriers
efficiently, and then act as a drug carrier for non-invasive
targeted drug delivery and controlled release of
therapeutic agents. Transfersomes exibit their action by
penetrating the intact stratum corneum spontaneously

along two routes in the intracellular lipid that differ in

their bilayers properties. The following figure 2 shows
possible micro routes for drug penetration across human
skin intracellular and transcellular.3,4,5 Due to the presence
of amphiphilic surfactants and lipophilic phospholipids
membrane, allow the ultra deformable transfersomes to
modify its membrane composition locally and reversibly,
when it approached towards narrow pore.
Salient Features Of Transferosomes
i) They are biocompatible and biodegradable as they are
made from natural phospholipids similar to liposomes.
They have high entrapment efficiency, in case of
lipophilic drug near to 90%.
ii) They protect the encapsulated drug from metabolic
degradation. They act as depot, releasing their contents
slowly and gradually.6, 7, 8
iii) They can be used for both systemic as well as topical
delivery of drug. Easy to scale up, as procedure is simple,
do not involve lengthy procedure and unnecessary use or
pharmaceutically unacceptable additives.
iv) They can be used for low molecular as well as high
molecular weight drugs
v) There are highly flexible so have higher flux rate
across skin and higher rate of skin penetration as
comparison to other vesicular systems.9,10
Mechanism Of Penetration Of Transferosomes
Transfersomes when applied under suitable condition can
transfer 0.1 mg of lipid per hour and cm2 area across the
intact skin. This value is substantially higher than that
which is typically driven by the transdermal concentration
gradients. The reason for this high flux rate is naturally
occurring "transdermal osmotic gradients" i.e. another
much more prominent gradient is available across the
skin. This osmotic gradient is developed due to the skin

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penetration barrier, prevents water loss through the skin
and maintains a water activity difference in the viable part
of the epidermis (75%water content) and nearly
completely dry stratum corneum, near to the skin surface
(15%water content).11,12,13
The mechanism of penetration of transferosome
systematically can be described in three purposed
mechanisms
i) Interaction between hydrophilic lipid residues and
proximal water makes the polar lipids to attract water
molecules induce hydration, lipid vesicles moved to the
site of higher water conc. The difference in water content
across skin stratum and epidermis develops transadermal
osmotic gradient that leads to penetration of
transferosomes across skin.
ii) Transferosomes by enforcing its own route induce
hydration that widen the hydrophilic pores of skin,
through the widen pores there is gradual release of drug
occurs that binds to targeted organ.
iii) Transferosomes act as penetration enhancers that
disrupt the intercellular lipids from stratum which
ultimatally widens the pores of skin and facilitate the
molecular interaction and penetration of system across
skin.
Studies have revealed that the transdermal osmotic
gradient develops across skin in case of Transferosomes
is higher than that of other vesicular systems. So that they
have higher rate of penetration as comparison to other
vesicular systems. It is also possible that Transferosomes
follows the three above mentioned at the same time and
most prominent in most of the cases is the first one. The
figure 3 describes the three purposed mechanisms.14,15,16
MATERIALS AND METHODS
Materials commonly used for the preparation of
transfersomes are summarized in Table 1
All the methods of preparation of transfersomes are
comprised of two steps. First, a thin film is prepared
hydrated and then brought to the desired size by
sonication; and secondly, sonicated vesicles are
homogenized by extrusion through a polycarbonate
membrane. The basic method of preparation describes in
figure 4.17,18
Transferosomes v/s Other Carrier Systems

Transferosomes have higher deformability and

penetration power as comparison to other vesicular
systems such as liposomes, niosomes and mixed micelles.
The reason behind higher deformability and penetration
includes the presence of lipophilic phospholipid and
amphilic surfactant together, lipid bilayer packing pattern,
higher surface hydrophilicity, higher transdermal osmotic
gradient as comparison to other vesicular systems such as
liposomes, niosomes and mixed micelles. Even the
confocal scanning laser microscopy showed that
Transferosomes transverse the stratum corneum while the
other vesicular systems failed to do so. Chapman &
Walsh also showed that the liposomes and niosomes types
of aggregates are confined to the outer half of the horny
layer, where as the Transferosomes transverse the stratum
corneum. Pure lipid vesicles or micelles seem to have
access to the low-resistance pathway only and thus very
seldom reach the lower stratum corneum or even get into
the viable part of the skin in significant quantities. The
comparison in tabular form describes in table 2.19,20,21
Evaluation
Vesicles Shape and Type
Transmission electron microscope (TEM) techniques are
used to visualize transferosomes with an applied voltage
of 100 kV A sample drop of Transferosomes was treated
with carbon coated grid. A thin film was formed on a
carbon coated grid and allowed the film to be dried. After
drying, the film was now negatively strained with 1%
phototungustic acid, a film was now mixed with excess of
straining solution and drained off grid with filter paper.
View the dried grid on TEM. Transferosomes without
sonication can also viewed by phase contrast microscopy
and optical microscope
Vesicles per Cubic mm
This is the most important parameter to optimize the
composition and other process variables such as speed of
rota evaporator, duration of processing. Transfersomal
formulation (without sonication) was diluted 3-5 times
with 0.9% of NaCl solution, and the number of vesicles
per cubic mm was counted by optical microscopy by
using a haemocytometer. The counting of Transferosomes
was done on 80 small squares and calculated by using the
.
following formula.22,23

Total no. of Transferosomes = Total no. of Transferosomes counteddilution factor4000

per cubic mm
Total no. of squares counted
Propensity of penetration
The magnitude of the transport driving force plays an
important role
Flow = Area x (Barrier) Permeability x (Transbarrier) force
Therefore, the flow of transferosome lipid by chemical
driven force across the skin always decreases dramatically
when lipid solution is replaced by the some amount of
lipids in a suspension.
Entrapment Efficiency
The entrapment efficiency is expressed as the drug
percentage which was entrapped. Entrapment efficiency
was evaluated by first separation of the unentrapped drug
by use of mini-column centrifugation method. After

centrifugation, the vesicles were allowed to disrupt using

50% n-propanol. The entrapment efficiency is expressed
as:
Amount entrapped 100
Total amount added
Confocal Scanning Laser Microscopy (CSLM) study
In this technique lipophilic fluorescence are allowed to
treat with transfersomes and the light emitted by these
markers used for following purpose:
-To determine the individual mechanism of penetration of
transferosomes and comparable mechanism of penetration
with other vesicular systems.
-To investigate the histological organization of skin
penetration pathways.

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Kumar Ravi et al. IRJP 2012, 3 (1)

Different fluorescence markers used in CSLM study are
I. Fluorescein
II. Rhodamine
III. NBD-PE
IV. Nile red.
Confocal Scanning Laser Microscopy overcome the
demerits of other techniques e.g. Conventional light
microscopy, Electron microscopy such as Difficulty of
fixation, sectioning and staining of skin samples Often the
structures to be examined are actually incompatible with
the corresponding processing techniques; these give rise
to misinterpretation.
Degree
of
Deformability
or
Permeability
Measurement
It is one of the most important factor of characterization.
In this case the Transferosomes suspensions are allowed
to pass through microporous filters of size 50 and 100 nm.
After each batch passage the particle size and particle size
distribution noted down.
The degree of deformability was calculated by using the
following formula, as reported by Berge vanden et
al.24,25,26

Where D = deformability of vesicles membrane, J =

amount of suspension which was extruded during 5 min,
rv = size of vesicles (after passes), rp = pore size of the
barrier
Turbidity Measurement
Aqueous solution of drug used for turbidity measurement
using nephelometer.
Surface Charge and Charge Density
Surface charge and charge density of transferosomes can
be determined using zetasizer.
Penetration Ability
Penetration ability of transferosomes can be evaluated
using fluorescence microscopy.
In vitro Drug Release
In vitro release study of Transferosomes basically done by
franz diffusion cell. In this case Transferosomes
formulation placed on cellophane membrane b/w donor
compartment and receptor compartment constituting
buffer. The samples were taken at an particular interval of
time with replacing fresh buffer at each time to maintain
the sink conditions. Absorbance of each sample was noted
and in vitro drug release is calculated.27,28
Stability Studies
Transfersomes stability was determined at 4C and 37C
by TEM visualization and DLS size measurement at
different time intervals (30, 45, and 60 days), following
vesicles preparation.
APPLICATIONS
Controlled release and stability enhancement
Transferosomes as drug delivery systems have the
potential for providing controlled release of the
administered drug and increasing the stability of labile
drugs.
Utilization of high molecular weight drugs
Very large molecules incapable of diffusing into skin as
such can be transported across the skin with the help of

transferosomes. For example, insulin, interferon can be

delivered through mammalian skin. Insulin is generally
administered by subcutaneous route that is inconvenient.
Encapsulation
of
insulin
into
transferosomes
(transfersulin) overcomes the problems of inconvenience,
larger size (making it unsuitable for transdermal delivery
using conventional method) along with showing 50%
response as compared to subcutaneous injection.
Transferosomes have also been used as a carrier for
interferons like leukocytic derived interferon- (INF-).
Transport of proteins and peptides
Delivery of proteins and peptides by oral route is not
favourable due to their degradation in g.i.t and by
transdermal route due to large size of proteins and
peptides. Transferosomes help obtain somewhat similar
bioavailability to subcutaneous injection. Human serum
albumin or gap junction protein showed effective
immunological response when encapsulated in
transferosomes.
Transport of corticosteroids
Transferosomes improves the site specificity and overall
safety margin of the corticosteroids which is difficult to
maintain by other routes. Also the dose of corticosteroids
encapsulated in transferosomes is far less than as given by
oral route.29,30
Application of anaesthetics
Application of anesthetics in the suspension of highly
deformable vesicles, transferosomes, induces topical
anesthesia, under appropriate conditions, with less than 10
min. Maximum resulting pain insensitivity is nearly as
strong (80%) as that of a comparable subcutaneous bolus
injection, but the effect of transferosomal anesthetics last
longer. Transferosmes has also been used for the topical
analgesics, anaesthetics agents, NSAIDS and anti-cancer
agents.31
Peripheral drug targeting
Minimal carrier associated drug clearance of
Transferosomes helps in targeting to peripheral blood
vessels in the subcutaneous tissue. Endothelial cells tight
junction restrict the vesicles in peripheral tissues.
Transdermal immunization
Since ultradeformable vesicles have the capability of
delivering the large molecules, they can be used to deliver
vaccines topically. Transferosomes containing proteins
like integral membrane protein, human serum albumin,
gap junction protein are used for this purpose. Advantages
of this approach are injecting the protein can be avoided
and higher IgA levels are attained. Transcutaneous
hepatitis-B vaccine 32 has given good results. A 12 times
higher AUC was obtained for zidovudine in ultradeformable form as compared to normal control
administration. All the application in brief form describes
in table 3. 32
CONCLUSION
Transfersomes are specially optimized particles or
vesicles, which can respond to an external `stress by rapid
and energetically inexpensive, shape transformations.
Drug laden transfersomes can carry unprecedented
amount of drug per unit time across the skin (up to
100mgcm2h-1).Transferosomes are emerging vesicular
systems due to their abilities of site specificity, sustained
release, systemic release possible, higher penetration

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Kumar Ravi et al. IRJP 2012, 3 (1)

power across skin, higher deformability, higher stability,
encapsulation of higher molecular weight drugs as
comparison to other vesicular sytems.
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Ultradeformable Vesicular Carrier for Transdermal Drug Delivery, Vol.
5 No. 9 October 2005, article=395.
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percutaneous penetration, 1993; Vol. 3b, STS Publishing, Cardiff, 226234.
3. Cevc G, Blume G, Schatzlein A: Transfersomes-mediated
transepidermal delivery improves the regiospecificity and biological
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5. Bain KR, Hadgkraft AJ, James WJ, Water KA: Prediction of
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Publishing, Cardiff 1993; 3b: 226-234.
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pathway for systemic treatment with patches and lipid-based agent
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7. Cevc G, Schatzlein A, Blume G. Transdermal Drug Carriers: Basic
Properties, Optimization and Transfer Efficiency in the Case of
Epicutaneous Applied Peptides. J Control Rel. 1995; 36:3-16.
8. Cevc G: Isothermal lipid phase. Transitions Chemistry and Physics of
Lipids 1991; 57:293-299.
9. Schatzlein A, Cevc G. Skin penetration by phospholipids vesicles,
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Microscopy, in characterization, metabolism, and novel biological
applications. Champaign. AOCS Press 1995; 191-209.
10. Panchagnula R. Transdermal delivery of drugs Indian Journal
Pharmacology 1997; 29:140-156.
11. Bain KR, Hadgkraft AJ, James WJ, and Water KA. Prediction of
Percutaneous Penetration STS Publishing, Cardiff. 1993; 3b: 226-234.
12. Cevc G, Blume G, Sehatzlein A, Gebauer D, Paul A. The skin a
Pathway for Systemic Treatment with Patches and Lipid-Based Agent
Carriers Advance Drug Delivery Reviews 1996; 18: 349- 378
13. Chapman SJ, Walsh A. Arch. Dermatol, 1998; Res. 282: 304-320.
14. Gompper G, Kroll DM: Driven transport of fluid vesicles through
narrow pores Physical Reviews. 1995; E.52: 4198-4211.
15. Heather AE, Benson. Transdermal Drug Delivery: Penetration
Enhancement Techniques. Current Drug Delivery, 2005; 2: 23-33.
16. Sapee R, Jain NK. Proultraflexible lipid vesicles for effective
transdermal delivery of norgesterol, proceedings of 25th conference of
C.R.S., U.S.A., 1998; 32-35.
17. Maghraby EI, Williams M, Barry BW. Optimization of Deformable
vesicles for epidermal Delivery of Oestradiol. J.Pharm. Pharmacol 1998;
(50): 146.
18. Jain NK. Advances in Controlled and Novel Drug Delivery. CBS
Publishers and Distributers First edition2001. New Delhi, 426-451
19. Gompper G, Kroll DM. Phys. Rev, 1995; E.52: 4198-4211.
20. Wearner RR, Myers MC, Taylar DA. , J.Inves.Dermatol. 1988; 90:
218-224.
21.Rand RP, Parsegian VA. Biochem. Biophys Acta.1989; 988: 351377.
22. Cevc G, Blume G, Schatzlein A. Control. Rel, 1997; 45:211-226.
23. Cevc G, Grbauer D, Schatzlein A, Blume G: Biochem. Acta 1998;
1368:201-215.
24. Bai BV, Wertz PW, Junginger HE, Bouwstra JA. Elasticity of
Vesicles Assessed by Electron Spin Resonance. Electron Microscopy
and Extrusion Measurement. Int J Pharm. 2001;217:132
25. Fry DW, White JC, Goldman ID. J.Anal.Biochem, 1978, 90:809815.
26. Hafer C, Goble R, Deering P, Lehmer A, Breut J. Formulation of
interleukin-2 and Interferon-a containing ultradeformable carriers for
potential transdermal application.Anticancer Res., 1999; 19(2c): 15051512.
27. Heather A.E. Benson. Transdermal Drug Delivery: Penetration
Enhancement Techniques. Current Drug Delivery, 2005, 2, 23-33
28. Jain S., Sapee R., Jain N.K., Proultraflexible lipid vesicles for
effective transdermal delivery of norgesterol, proceedings of 25th
conference of C.R.S., U.S.A., 1998: 32-35.
29. Maghraby EI, Williams M, Barry BW. Optimization of Deformable
vesicles for epidermal Delivery Oestradiol. J.Pharm. Pharmacol 1998;
50: 146.
30. Schatzlein A, Cevc G. Skin penetration by phospholipids vesicles,
Transfersomes as

visualized by means of the Confocal Scanning Laser Microscopy, In;

characterization,
metabolisim, and novel biological applications. Champaign. AOCS
Press, 1995; 191-209.
31. Shaw JE, Chandrasekaran SK: In pharmacology of the skin,
Greaves. Springer- Verlag, Berlin 1999; 115-122.
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Figure 1: Ultradeformable Vesicle (Transferosomes)

Figure 2: Diagrammatic Representation of the Stratum Corneum

and the Intercellular and Transcellular Routes of Penetration

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Kumar Ravi et al. IRJP 2012, 3 (1)

Table: 1 Basic material required for transferosomes

CLASS
EXAMPLE
USES
Phospholipids
Soya phosphatidyl
Vesicles
choline
forming
Dipalmitoyl
component
phosphatidyl choline
Distearoyl phoshatidyl
choline
Surfactant
Sod. Cholate
For providing
Sod.deoxycholate
flexibility
tween-80
Span-80
Alcohol
Ethanol
As a solvent
Buffering
Saline phosphate buffer
As a
agent
(pH 6.4)
hydrating
medium
For CSLM
Dye
Rhodamine-123,
Rhodamine-DHPE,
Study
Nile Red

Table: 2 Comparison b/w Transferosomes and other vesicular systems

Advantage
Disadvantage
Method
Liposomes
Phospholipid vesicle,
Less skin penetration
biocompatible, biodegradable
less stable
Phospholipid vesicle, more stable
Less penetration,
Proliposome
than liposome
cause aggregation
Niosomes
Less skin penetration,
Non-ionic surfactants vesicle,
greater stability
easy handling
Proniosomes
Will convert into noisome in situ,
But will not reach
stable
into deeper skin layer
Transfersomes
More stable, high penetration due to
None, but for some
Protransferosomes
high deformability, Biocompatible
limitations
and biodegradable, suitable for both
low and high molecular weight and
also for lipophilic as well as
hydrophilic drugs and reach up to
deeper skin layers.

Drug
Insulin
Soluble proteins
Corticosteroids
Anaesthetics
Capsaicin
Colchicine
Vincristine
Norgesterol
Tamoxifen
Oestradiol

Table: 3 Brief applications of transferosomes

Application
Target disease
More response than s.c route
Diabetes mellitus
Transdermal Immunization
Immunization
Maximize action at lower dose
Skin diseases
Anaesthesia period prolong
For operation purposes
Increase skin penetration
For pain reduction
Increase skin penetration
For gout treatment
Increase entrapment efficiency
For cancer treatment
Increase transdermal flux
For cancer treatment
Increase transdermal flux
For cancer treatment
Increase transdermal flux
For cancer treatment

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