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International Journal of Pharmacy and Integrated Life Sciences “Where improvisation meets innovation”

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REVIEW ARTICLE ISSN : 2320 - 0782 V1-(I2) PG(14-29)

Transferosome: an enhancement approach for transdermal drug

delivery system

NATHJI DHAVAL*1

, PATNI CHANDRA1, SHAH HIRAL

1,

DR. CHAUDHARY SUNITA1, SANGHAVI KINJAL

1,

DR. PATEL UPENDRA1

1 Arihant School of Pharmacy & BRI, Adalaj, Gandhinagar, Gujarat, India.

ABSTRACT

A novel vesicular drug carrier system called transfersomes, which is composed of

phospholipid, surfactant, and water for enhanced transdermal delivery. Transferosome is an

ultradeformable vesicle, elastic in nature which can squeeze itself through a pore which is

many times smaller than its size owing to its elasticity. 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. The transfersomal system was

much more efficient at delivering a low and high molecular weight drug to the skin in terms

of quantity and depth. Transfersomes can deform and pass through narrow constriction (from

5 to 10 times less than their own diameter) without measurable loss. The uniqueness of this

type of drug carrier system lies in the fact that it can accommodate hydrophilic, lipophilic as

well as amphiphilic drugs. Controlled release formulations can also be prepared with the help

of transferosomes. This review discusses the salient features, composition and mechanism of

action, mechanism of penetration of transfersomes, materials and method used for

preparation of transferosomes, application, scope and future of transferosomes.

KEYWORDS: Transfersomes, Transdermal, Vesicle, Ultradeformable, Osmotic gradient

Article received on : 16/12/2012 Article accepted on : 23/12/2012

Corresponding Author : Nathji Dhaval Chhotunath

Address : Arihant School of Pharmacy and Bio-Research Institute, Adalaj,

Gandhinagar, Gujarat, India.

Email ID : [email protected]

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INTRODUCTION

Delivery via the transdermal route is an

interesting option in this respect because a

transdermal route is convenient and safe.

This offers several potential advantages

over conventional routes[1]

like avoidance

of first pass metabolism, predictable and

extended duration of activity, minimizing

undesirable side effects, utility of short

half-life drugs, improving physiological

and pharmacological response, avoiding

the fluctuation in drug levels, inter-and

intra-patient variations, and most

importantly, it provides patients

convenience. To date many chemical and

physical approaches have been applied to

increase the efficacy of the material

transfer across the intact skin, by use of the

penetration enhancers, enhancers,

iontophoresis, sonophoresis and the use of

colloidal carriers such as lipid vesicles

(liposomes and proliposomes) and

nonionic surfactant vesicles (niosomes and

proniosomes).

Transfersomes were developed in

order to take the advantage of

phospholipids vesicles as transdermal drug

carrier. These self-optimized aggregates,

with the ultra flexible membrane are able

to deliver the drug reproducibly either into

or through the skin, depending on the

choice of administration or application,

with high efficiency. These vesicular

transfersomes are several orders of

magnitudes more elastic than the standard

liposomes and thus well suited for the skin

penetration. Transfersomes overcome the

skin penetration difficulty by squeezing

themselves along the intracellular sealing

lipid of the stratum corneum. There is

provision or this, because of the high

vesicle deformability, which permits the

entry due to the mechanical stress of

surrounding, in a self-adapting manner.

Flexibility of transfersomes membrane is

achieved by mixing suitable surface-active

components in the proper ratios[2]

.The

resulting flexibility of transfersome

membrane minimizes the risk of complete

vesicle rupture in the skin and allows

transfersomes to follow the natural water

gradient across the epidermis, when

applied under non occlusive condition.

Transfersomes can penetrate the intact

stratum corneum spontaneously along two

routes in the intracellular lipid that differ

in their bait layers properties[3]

. The

following figure shows possible micro

routes for drug penetration across human

skin intracellular and transcellular[4]

.The

high and self-optimizing deformability of

typical composite transfersomes

membrane, which are adaptable to ambient

tress allow the ultra deformable

transfersomes to change its membrane

composition locally and reversibly, when

Dhaval et. Al. , Volume 1 – Issue 2

Vol: 1(2) January 2013 16

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it is pressed against or attracted into

narrow pore. The transfersomes

components that sustain strong membrane

deformation preferentially accumulate,

while the less adaptable molecules are

diluted at sites of great stress. This

dramatically lowers the energetic cost of

membrane deformation and permits the

resulting, highly flexible particles, first to

enter and then to pass through the pores

rapidly and efficiently. This behavior is

not limited to one type of pore and has

been observed in natural barriers such as in

intact skin[5, 6]

.

Fig 1: Undeformable Vesicle (Transferosome)

Salient features of transferosomes[7,8]

Transfersomes possess an

infrastructure consisting of

hydrophobic and hydrophilic

moieties together and as a result

can accommodate drug molecules

with a wide range of solubility as

shown in fig 1.

Transfersomes can deform and

pass through narrow constriction

(from 5 to 10 times less than their

own diameter) without measurable

loss. This high deformability gives

better penetration of intact vesicles.

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.

They are biocompatible and

biodegradable as they are made

from natural phospholipids similar

to liposomes.



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They have high entrapment

efficiency, in case of lipophilic

drug near to 90%

They protect the encapsulated drug

from metabolic degradation.

They act as depot, releasing their

contents slowly and gradually.

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 of

pharmaceutically unacceptable

additives.

Limitations of transfersomes[9]

They are chemically unstable due

to their predisposition to oxidative

degradation.

Purity of natural phospholipids is

difficult to achieve so, world is

against adoption of transfersomes

as drug delivery vehicles.

These formulations are expensive.

Composition and mechanism of action

The carrier aggregate is composed of at

least one amphiphatic (such as

phosphatidylcholine), which inaqueous

solvents self-assembles into lipid bilayer

that closes into a simple lipid vesicle. By

addition of atleast one bilayer softening

component (such as a biocompatible

surfactant or an amphiphile drug) lipid

bilayer flexibility and permeability are

greatly increased. The resulting, flexibility

and permeability optimized, Transfer some

vesicle can therefore adapt its shape to

ambient easily and rapidly, by adjust in

glocal concentration of each bilayer

component to the local stress experienced

by the bilayer as shown in fig 2. In its

basic organization broadly similar to a

liposome), the Transfersome thus differs

from such more conventional vesicle

primarily by its "softer", more deformable,

and better adjustable artificial membrane.

Another beneficial consequence of strong

bilayer deformability is the increased

Transfersome affinity to bind and retain

water. An ultradeformable and highly

hydrophilic vesicle always seeks to avoid

dehydration; this may involve a transport

process related to but not identical with

forward osmosis. For example, a

Transfersome vesicle applied on an open

biological surface, such as non-occluded

skin, tends to penetrate its barrier and

migrate into the water-rich deeper strata to

secure its adequate hydration. Barrier

penetration involves reversible bilayer

deformation, but must not compromise

unacceptably either the vesicle integrity or

the barrier properties for the underlying

hydration affinity and gradient to remain

in place.



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Since it is too large to diffuse

through the skin, the Transfersome needs

to find and enforce its own route through

the organ. The Transfersome vesicles

usage in drug delivery consequently relies

on the carrier’stability to widen and

overcome the hydrophilic pores in the skin

or some other (e.g. plant cuticle) barrier.

The subsequent, gradual agent release

from the drug carrier allows the drug

molecules to diffuse and finally bind to

their target. Drug transport to an intra-

cellular action site may also involve the

carrier’s lipid bilayer fusion with the cell

membrane, unless the vesicle is taken-up

actively by the cell in the process called

endocytosis[10]

.

Fig 2: Diagrammatic Representation of the Stratum Corneum and the Intercellular and

Transcellular Routes of Penetration[11]

Mechanism of penetration of

transfersomes

The mechanism for penetration is the

generation of “osmotic gradient” due to

evaporation of water while applying the

lipid suspension (Transfersomes) on the

skin surface. The transport of these elastic

vesicles is thus independent of

concentration. The trans-epidermal

hydration provides the driving force for

the transport of the vesicles[12]

. As the

vesicles are elastic, they can squeeze



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through the pores in stratum corneum

(though these pores are less than one-tenth

of the diameter of vesicles)[13]

as shown in

Fig.3.

Fig 3: Illustration of pore penetration at molecular level

MATERIALS AND METHODS

Materials used for preparation of

transferosomes[14]

Materials commonly used for the

preparation of transfersomes are

summarized in table

Method of preparation[15]

All the methods of preparation of

transferosomes are comprised of two steps.

First, a thin film is prepared, hydrated then

brought to the desired size by sonication

and secondly, sonicated vesicles are

homogenized by extrusion through a

polycarbonate membrane.

The mixture of vesicles forming

ingredients, that is phospholipids and

surfactant were dissolved in volatile

organic solvent (chloroform-methanol),

organic solvent evaporated above the lipid

transition temperature (room temp, for

pure PC vesicles, or 50°C for dipalmitoyl

phosphatidylcholine) using a rotary

evaporator. Final traces of solvent were

removed under vacuum for overnight. The

deposited lipid films were hydrated with

buffer (pH 6.5) by rotation at 60 rpm min1

for 1 hr at the corresponding temperature.

The resulting vesicles were swollen for 2

hrs at room temperature.

To prepare small vesicles, resulting

LMVs were sonicated at room temperature

or 50°C for 30 min. using a bath sonicator

or probe sonicated at 4°C for 30 min

(titanium microtip). The sonicated vesicles

were homogenized by manual extrusion 10

times through a sandwich of 200 and 100

am polycarbonate membrane.



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Fig. 4: Flow Diagram for preparation of Transferosome

Phospholipids Surfactants

Incorporate Lipophilic Drug Dissolve in organic Solvent

Prepare thin film

(Using Rotary evaporator)

Keep under vaccum (12 hr)

Hydrate using buffer

(PH 6.5) at 60 rpm

Incorporate Hydrophilic Drug

Sonicate 30 minutes

Homogenize (extrusion 10 times

through sandwich of 200 and 100

nm polycarbonate membranes)

Transferosomes



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Sr.No Class Example Uses

1 Phosphohpids Soya phosphatidylcholine,

Egg phosphatidylcholine,

Dipalmitoyl phosphatidylcholine,

Distearoyl phosphatidylcholine

Vesicles forming

component

2 Surfactant Sod. Cholate

Sod. deoxycholate

Tween-80

Span-80

For providing flexibility

3 Alcohol

Ethanol

Methanol

As a solvent

4 Dye Rhodainine-123

Rhodamine-DHPE

Fluorescein-DHPE &Nile-red

For CSLM study

5 Buffering agent Saline phosphate buffer

(pH 6.4)

As a hydrating medium

Table 1 : “Materials used for preparation of transferosomes”

Characterization of transfersomes

The characterization of transfersomes is

given below.

Entrapment efficiency

The entrapment efficiency is expressed as

the percentage entrapment of the drug

added. Entrapment efficiency was

determined by first separation of the un

entrapped drug by the use of mini-column

centrifugation method. After

centrifugation, the vesicles were disrupted

using 0.1%TritonX-100 or 50% n-

propanol[16,17]

.

The entrapment efficiency is expressed as:

Amount entrapped / Total amount added x

100

Vesicle diameter



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Vesicle diameter can be determined using

photon correlation spectroscopy or

dynamic light scattering (DLS) method.

Samples were prepared in distilled water,

filtered through a 0.2 mm membrane filter

and diluted with filtered saline and than

size measurement done by using photon

correlation spectroscopy or dynamic light

scattering (DLS) measurements[18]

.

Confocal scanning laser microscopy

(CSLM) study[19]

Conventional light microscopy and

electron microscopy both face problem of

fixation, sectioning and staining of the skin

samples. Often the structures to be

examined are actually incompatible with

the corresponding processing techniques,

these give rise to misinterpretation, but can

be minimized by Confocal Scanning Laser

Microscopy (CSLM). In this technique

lipophilic fluorescence markers are

incorporated into the transfersomes and the

light emitted by these markers used for

following purpose.

For investigating the mechanism of

penetration of transfersomes across

the skin.

For determining histological

organization of the skin, shapes

and architecture of the skin

penetration pathways.

For comparison and differentiation

of the mechanism of penetration of

transfersomes with liposomes,

niosomes and micelles.

Different fluorescence markers used in

CSLM study are:

Fluorescein-DHPE(l,2-

dihcxadccanoyl-sn-glycero-3-

phosphoeihanolamine-N-(5-

fluresdentluocarbamoyl).

trielhylammonium salt)

Rhodamine-DHPE(l,2-

dihexadecanoyl-sn-glycero-3-

phosphoethanolaminc-N-Lissamine

rhodamine Bsulfonyl),

triethanolamine salt)

NBD-PE(1.2-dihexadecanoy-sn-

glycero-3-phosphoethanolamine-

N-(7-nitro-Benz-2-oxa-1,3 diazol-

4-yl) triethanolamine salt)

Nile red.

Degree of deformability or permeability

measurement

In the case of transferosomes the

permeability study is one of the important

and unique parameter for characterization.

The deformability study is done against

the pure water as standard. Transfersomal

preparation is passed through a large

number of pores known size (through a

sandwich or different micro porous filters,



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with pore diameter between 50 nm and

400 nm. depending on the starting

transferosomes suspension). Particle size

and size distributions are noted after each

pass by dynamic light scattering (DLS)

measurements[20]

.

In vitro drug release

In vitro drug release study is performed for

determining the permeation rate. Time

needed to attain steady state permeation

and the permeation flux at steady state and

the information from in-vitro studies are

used to optimize the formulation before

more expensive in vivo studies are

performed. For determining drug release,

transferosomes suspension is incubated at

32°C and samples are taken at different

times and the free drug is separated by

mini column centrifugation. The amount

of drug released is then calculated

indirectly from the amount of drug

entrapped at zero times as the initial

amount (100% entrapped and 0% released)

[21].

Application of transfersomes

Delivery of Insulin

Very large molecules incapable of

diffusing into skin as such can be

transported across the skin with the help of

Transfersomes. For example, insulin,

interferon can be delivered through

mammalian skin. Delivery of insulin by

Transfersomes is the successful means of

non invasive therapeutic use of such large

molecular weight drugs on the skin.

Insulin is generally administered by

subcutaneous route that is inconvenient.

Encapsulation of insulin into

Transfersomes (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[22]

.

Carrier For Interferons & Interlukin

Transfersomes have also been used as a

carrier for interferons like leukocytic

derived interferon-α (INF-α)) is a naturally

occurring protein having antiviral,

antiproliferive and some

immunomodulatory effects. Transfersomes

as drug delivery systems have the potential

for providing controlled release of the

administred drug and increasing the

stability of labile drugs. Hafer et al[23]

studied the formulation of interleukin-2

and interferone-α containing transferosmes

for potential transdermal application. They

reported delivery of IL-2 and INF- α

trapped by Transfersomes in sufficient

concentration for immunotherapy.

Carrier For Other Proteins & Peptides



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Transfersomes have been widely used as a

carrier for the transport of other proteins

and peptides. Proteins and peptides are

large biogenic molecules which are very

difficult to transport into the body, when

given orally they are completely degraded

in the GI tract and transdermal delivery

suffers because of their large size. These

are the reasons why these peptides and

proteins still have to be introduced into the

body through injections. Various

approaches have been developed to

improve these situations. The bioavaibility

obtained from Transfersomes is somewhat

similar to that resulting from subcutaneous

injection of the same protein suspension.

Human serum albumin or gap junction

protein was found to be effective in

producing the immune response when

delivered by transdermal route

encapsulated in Transfersomes[24,25]

.

Transport of certain drug molecules that

have physicochemical which otherwise

prevent them from diffusing across stratum

corneum can be transported.

Peripheral Drug Targeting

The ability of Transfersomes to target

peripheral subcutaneous tissues is due to

minimum carrier associated drug clearance

through blood vessels in the subcutaneous

tissue. These blood vessels are non-

fenestrated and also possess tight junctions

between endothelial cells thus not allowing

vesicles to enter directly into the blood

stream. This automatically increases drug

concentration locally along with the

probability of drug to enter peripheral

tissues.

Transdermal Immunization

Since ultradeformable vesicles have the

capability of delivering the large

molecules, they can be used to deliver

vaccines topically. Transfersomes

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[26]

has given good

results. A 12 times higher AUC was

obtained for zidovudine as compared to

normal control administration. Selectivity

in deposition in RES (which is the usual

site for residence of HIV) was also

increased[27]

.

Delivery of NSAIDS

NSAIDS are associated with number of GI

side effects. These can be overcome by

transdermal delivery using ultradeformable

vesicles. Studies have been carried out on

Diclofenac[28]

and Ketotifen. Ketoprofen in

a Transfersome formulation gained

marketing approval by the Swiss

regulatory agency (SwissMedic) in 2007;



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the product is expected to be marketed

under the trademark Diractin. Further

therapeutic products based on the

Transfersome technology, according to

IDEA AG, are in clinical development[29]

.

Delivery of steroidal hormones and

peptides

Transfersomes have also used for the

delivery of corticosteroids. Transfersomes

improves the site specificity and overall

drug safety of corticosteroid delivery into

skin by optimizing the epicutaneously

administered drug dose. Transfersomes

beased cortiosteroids are biologically

active at dose several times lower than the

currently used formulation for the

treatment of skin diseases[30]

. Flexible

vesicles of ethinylestradiol showed

significant anti-ovulatory effects as

compared to plain drug given orally and

traditional liposomes given topically.

Extensive work has been done on other

drugs like hormones and peptides viz

Estradiol, low molecular-weight Heparin,

Retinol, Melatonin, etc.

Delivery of Anesthetics

Transfersome based formulations of local

anesthetics- lidocaine and tetracaine

showed permeation equivalent to

subcutaneous injections. 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.

Delivery of Anticancer Drugs

Anti cancer drugs like methotrexate were

tried for transdermal delivery using

transfersome technology. The results were

favorable. This provided a new approach

for treatment especially of skin cancer.

Delivery of Herbal Drugs

Transfersomes can penetrate stratum

corneum and supply the nutrients locally

to maintain its functions resulting

maintenance of skin[31]

in this connection

the Transfersomes of Capsaicin has been

prepared by Xiao-Ying et al.[32]

which

shows the better topical absorption in

comparison to pure capsaicin.

Scope of transfersomes

Transfersome technology is best suited for

non-invasive delivery of therapeutic

molecules across open biological barriers.

The Transfersome vesicles can transport

across the skin, for example, molecules

that are too big to diffuse through the

barrier. Examples include systemic

delivery of therapeutically meaningful

amounts of macromolecules, such as

insulin orinterferon, across intact

mammalian skin. Other applications



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include the transport of small molecule

drugs which have certain physicochemical

properties which would otherwise prevent

them from diffusing across the barrier.

Another attraction of the Transfersome

technology is the carrier’s ability to target

peripheral, subcutaneous tissue. This

ability relies on minimisation of the

carrier-associated drug clearance through

coetaneous blood vessels plexus: the non-

fenestrated blood capillary walls in the

skin together with the tight junctions

between endothelial cells preclude vesicles

getting directly into blood, thus

maximizing local drug retention and

propensity to reach the peripheral tissue

targets[33]

.

Future of transferosomes[34]

Different types of pharmaceutical carriers

are present. They are - particulate,

polymeric, macromolecular, and cellular

carrier. Particulate type carrier also known

as a colloidal carrier system, includes lipid

particles (low and high density lipoprotein-

LDL and HDL, respectively),

microspheres, nanoparticles, polymeric

micelles and vesicular like liposomes,

niosomes pharmacosomes, virosomes, etc.

But Liposomal as well as niosomal

systems, are not suitable for transdermal

delivery, because of their poor skin

permeability, breaking of vesicles, leakage

of drug, aggregation, and fusion of

vesicles. To overcome these problems, a

new type of carrier system called

"transfersome", has recently been

introduced, which is capable of

transdermal delivery of low as well as high

molecular weight drugs.

Transfersomes are specially

optimized particles or vesicles, which can

respond to an external stress by rapid and

energetically inexpensive, shape

transformations. Such highly deformable

particles can thus be used to bring drugs

across the biological permeability barriers,

such as skin. When tested in artificial

systems transfersomes can pass through

even tiny pores (100 nm) nearly as

efficiently as water which is 1500 times

smaller.

Drug laden transferosomes can

carry unprecedented amounts of drug per

unit time across the skin (up to 100mgcm2

h-1

). The systemic drug availability thus

mediated is frequently higher than, or at

least approaches 80-90%. The

biodistribution of radioactively labelled

phospholipids applied in the form of

transfersomes after24 hr is essentially the

same after an epicutaneous application or

subcutaneous injection of the preparations.

When used under different application

conditions transfersomes can also be

positioned nearly exclusively and

essentially quantitatively into the viable



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skin region. Such a high efficacy of skin

passage by transfersomes is quite

reproducible even when carrier is loaded

with the peptide molecules with a

molecular weight of several KDa.

Increasing the carrier deformability

however does speed up the skin

penetration by transferosomes.

Transferosomes thus offer a

singularly good opportunity for the non-

invasive delivery of small, medium and

large sized drugs. The results of the first

human trials with the epicutaneously

applied transfersomal insulin support this

conclusion. The Transfersulin induced

systemic hypoglycemia in these

experiments is found to reach

approximately 30% of that induced by

subcutaneous insulin injections the

cumulative efficiency over a period of 12

hr being comparable (>75-100%) in both

cases. The former has a much slower

action however several unrelated

transfersulin formulations were proven to

be active hypoglycemically when applied

on the intact skin.

Multiliter quantities of sterile, well

defined transferosomes containing agent

can be and have been prepared relatively

easily. It therefore should be not before

long that the corresponding drug

formulation will find their way into clinics

to be tested for the widespread usages.

This it can be a logical conclusion that

transferosomes hold a promising future in

effective transdermal delivery.

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