Transfersomes- A Novel Carrier for
Transdermal Drug Delivery
Punasiya R*, Joshi A, Gupta S and Punasiya
J
GRY Institute of
Pharmacy Borawan Khargone
(M.P.) 451228
ABSTRACT
There
is considerable interest in the skin as a site of drug application both for
local and systemic effect. However, the skin, in particular the stratum corneum, poses a formidable
barrier to drug penetration thereby limiting topical and transdermal
bioavailability. Skin penetration enhancement techniques have been developed to
improve bioavailability and increase the range of drugs for which topical and
transdermal delivery is a viable option. This review describes enhancement
techniques based on drug/vehicle optimization such as drug selection, prodrugs and ion-pairs, supersaturated drug solutions,
eutectic systems, complexation, liposome, vesicles
and particles. Enhancement via modification of the stratum corneum
by hydration, chemical enhancers acting on the structure of the stratum corneum lipids and keratin, partitioning and solubility
effects are also discussed. The mechanism of action of penetration enhancer’s,
retarders and their potential for clinical application is described.1
KEYWORDS:
Transdermal
delivery, skin penetration, enhancer, retarder.
INTRODUCTION:
It
is refer to its proprietary drug delivery technology. The name Transfersome means “carrying body”, and is derived from the
Latin word ‘transferre’, and the Greek word “soma”,
for a ‘body’. A Transfersome carrier is an artificial
vesicle designed to be like a cell vesicle or a cell engaged in exocytosis, and thus suitable for controlled and,
potentially targeted, drug delivery.1
Trasfersomes are specially
optimized, ultra deformable (ultra flexible), lipid supermolecular
aggregates. Which are able to penetrate the mammalian skin intact?
These noble carries
are applied in the form of semi-dilute suspension, without occlusion. Due to
their deformability, Transfersome are good candidates
for the non-invasive delivery of small, medium, and large sized drugs.
Milliliter quantities of sterile lion skin intact.
Transfersomes have been proposed
for a variety of applications in humans. They are used a carrier for protein
and peptides like insulin, bovine serum albumin, vaccines, etc. The delivery of these large biogenic molecules
into the body is difficult.2
Delivering medicine to
general circulation through the skin is seen as desirable alternative to
talking it by mouth. Patients often forget to take their medicine, and even the
most faithfully complaint get tired of swallowing pill’s, especially if they
must take several each day. Additionally by passing the gastrointestinal (GI)
tract would obviate the GI irritation that frequently occurs and avoid partial
first pass inactivation by the liver. Further, steady absorption of drugs over
hours or day is usually preferable to blood level spikes and through produced
by oral dosage forms. Delivery by the transdermal route is interesting option
in this respect because transdermal drug delivery is low penetration rate
through the outermost layer of the skin, the stratum corenum.
Various
chemical and physical approach like penetration enhancer, iontophorosis,
electrophoresis sonosphorosis and use several carries
such as liposomes, niosomes,
and proniosomes were used to increase the lipid
fluidity in the outer skin and thus improves skin permeability to various agent.
Liposomal
as well as niosomal system are not suitable for trandermal delivery, because of their poor skin
permeability, breaking of vesicles, leakage of drug, aggregation and fusion of
vesicles. To overcome the problems, a new type of carrier system called “Transfersome”, has recently been introduced, which is
capable of transdemal delivery of low as well as high
molecular weight drugs. Trasfersomes are specially
optimized, ultra deformable (ultraflexible), lipid suypermolecular aggregates. Which are able to penetrate the
memmelion skin intact? Each Transforsome
consist of the least one inner aqueous compartment, which is surrounded by a
lipid bilayer with specially tailored properties, due
to incorporation of “edge activators” into the vesicular membrane. Surfactants
such as sodium deoxycholate, span 80, and Tween 80,
have been used as activators. It was suggested that transfersome
could respond to external stress by rapid shape transformation requiring low
energy. These noble carries are applied in the form of semi-dilute suspension,
without occlusion. Due to their deformability, Transfersome
are good candidates for the non-invasive delivery of small, medium, and large sized
drugs. Multiliter quantities of sterile, well-defined
Transfersome containing drug can be, and have been
prepared relatively easily.
Transfersomes improve the site
specificity, overall drug safety, and lower the doses several times than the
currently available formulations for the treatment of skin diseases. Because of
their good penetration power and flexibility, Transfersome
formulations are used for effective delivery of non-steroidal anti-inflammatory
agents like ibuprofen and diclofenac. Transfersome not only increase the penetration of diclofenac through intact skin, but also carry these agents
directly into the depth of the soft tissues under the application site Most of
the epidermally-applied Transfersome
penetrated the skin, leaving less than 5% of the drug-derived radioactivity on
the body surface. Elastic vesicles with rigid vesicles, in terms of their
interaction, was compared with human skin, and reported that unlike rigid
vesicles, in terms of their interaction, was compared
with human skin, and reported that unlike rigid vesicles, there is no ultra
structural changes takes place in the human skin on application of elastic
vesicles.
Transfersomes have been proposed
for a variety of applications in humans. They are used a carrier for protein
and peptides like insulin, bovine serum albumin, vaccines, etc. The delivery of
these large biogenic molecules into the body is difficult. When given orally,
they are completely degraded in the GI tract, and when used in a degradation
preventing formulation, their uptake in the gut becomes problematic and
extremely insufficient. These are the reasons an injection needle, in spite of
the inconvenience of this methods.
To overcome the above
problems, numerous attempts have therefore been made for delivery of peptides
and proteins across the skin. All recent approaches, either chemical
(penetration enhancers, lipid vesicles), or physicals (iontophorosis,
sonophorosis), have some limitaons3
Drug
Delivery Routes Across Human Skin: Sink is a major target
as well as a principle barrier for topical/ transdermal drug delivery. Despite
the many advantages of this system, the major obstacle is the low diffusion
rate of drugs across the stratum corneum. Under normal
circumstances, the predominant route is through the intercellular spaces.1-5
The
predominant route is via intercellular spaces. The diffusional
pathlength is therefore much longer than the simple
thickness of the stratum corneum (~20 mm) and has
been estimated as long as 500 mm. Importantly, the intercellular spaces contain
structured lipids and a diffusing molecule has to cross a variety of lipophilic and hydrophilic domains before it reaches the
junction between the stratum corneum and the viable
epidermis.1-5 The transepidermal route across the
continuous stratum corneum comprises transport via
intracellular and intercellular spaces. The polar molecules mainly diffuse
through the polar pathway consisting of “bound water” within the hydrated
stratum corneum, whereas the non polar molecules
dissolve and diffuse through the non aqueous lipid matrix of the stratum corneum. The transappendageal
route transports substances via the sweat glands and the hair follicles with
their associated sebaceous glands, but it is considered to be of minor
importance because of relatively smaller area.
Penetration
Enhancement through Optimization of Drug and Vehicle Properties:
Transdermal
delivery of drugs through the skin to the systemic circulation provides a
convenient route of administration for a variety of clinical indications. For
transdermal delivery of drugs, stratum corneum is the
main barrier layer for permeation of drug. So to circumvent the stratum corneum and to increase the flux through skin membrane,
different approaches of penetration enhancement are used. Many reviews had
described regarding the chemical penetration enhancement but vehicle based
enhancement approach is not exploited for reviews.
Figure 1. A schematic drawing of a skin cross-section. The skin is
composed of a dermis and an epidermis. In the basal layer of the epidermis
cells proliferate. Upon leaving the basal layer cells start to differentiate
and migrate in the direction of the skin surface. At the interface between
stratum granulosum–stratum corneum
final differentiation occurs, during which the viable cells are transformed
into dead keratin filled cells (corneocytes).The corneocytes are embedded in lipid lamellar regions.
Substances permeate mainly along the tortuous pathway in the intercellular
lamellar regions. The thickness of the stratum corneum
is approximately 15 mm. C = corneocyte filled with
keratin. Bar = 100 nm
Drug-vehicle
based enhancement methods such as drug selection, vesicles and particles,
liposome’s, prodrugs and ion-pairs, chemical
potential of drug, eutectic systems, complexation are
used in transdermal research as better alternative method to enhance permeation
of drugs through skin. The review presents mainly the routes of penetration
through skin and the approaches of drug vehicle interaction based enhancement
to optimize the transdermal delivery system.
Approaches
of penetration enhancement:
Some
ways for circumventing the stratum corneum barrier
are
A.
Drug vehicle based:
1.
Drug selection
2.
Vesicles and particles
3.
Prodrugs and ion pairs
4.
Chemical potential of drug
5.
Eutectic systems
6.
Complexes
B.
Chemical penetration enhancers:
1.
Sulphoxides
2.
Alcohols
3.
Polyols
4.
Alkanes
5.
Fatty acids
6.
Esters
7.
Amines and amides
8.
Terpenes
9.
Surface active agents
C.
Physical method:
1.
Iontophoresis
2.
Ultrasound (phonophoresis and sonophoresis)
3.
Magnetophoresis
4.
Electroporation
5.
Laser radiation and photomechanical waves
6.
Radio frequency
7.
Thermophoresis
8.
Microneedle based devices
9.
Skin puncture and perforation
10.
Needleless injection
11.
Suction ablation
12.
Application of pressure
13.
Skin stretching
14.
Skin abration6
The
current review deals with the drug vehicle based approaches of penetration
enhancement.
A.
Drug vehicle based:
1.
Drug selection:
Drug
should be selected in such a way that it fits in the criteria of transdermal
delivery as given in table
1. Parameters for Drug Selection:7-12
Parameters
Ideal limits:
Aqueous
solubility >1mg/ml
Lipophilicity 10<Ko/w<1000
Molecular
weight <500 Daltons
Melting
point <200oC
pH of aqueous
5-9
Dose
deliverable <10mg/day
2.
Vesicles and particles:
2.1. Liposomes:
These
are colloidal particles formed as concentric bimolecular layers that are
capable of encapsulating drugs. Their delivery mechanism is reported to be
associated with accumulation of the liposome and associated drug in the stratum
corneum and upper skin layers, with minimal drug
penetrating to the deeper tissues and systemic circulation. It is interesting
that the most effective liposome are reported to be those composed of lipids
similar to stratum corneum lipids, which are most
likely to enter stratum corneum lipid lamellae and
fuse with endogenous lipids.13 Studies have focused on delivery of
agents via liposomes like anti-psoriatic agent via
ethanolic liposomes14 caffeine for hyperproliferative
diseases15, catechins16, enoxacin17.
2.2. Transfersomes:
These
are vesicles composed of phospholipids as their main ingredient with 10-25%
surfactant and 3-10% ethanol. Liposomes are too large
to pass through pores of less than 50nm in size; transfersomes
up to 500nm can squeeze to penetrate the stratum corneum
barrier spontaneously. The driving force for penetration into the skin is the
“Transdermal gradient” caused by the difference in water content between the
restively dehydrated skin surface (approximately 20% water) and the aqueous
viable epidermis (close to 100%). Evidence of presence of vesicles between the corneocytes in the outer layers of the stratum corneum has been demonstrated by electron and fluorescence
microscopy18. For vesicles19 to remain swollen, they must
follow local hydration gradient and penetrate into hydrated and deeper skin
layers of viable epidermis and dermis. Traditionally liposomes
are expected to confine to surface or upper layers of stratum corneum, where they dehydrate and fuse with skin lipids.
Secondly transferosomes work best under in vivo
conditions. Vesicles must adapt their size and/or shape, dependent on bilayer stability and elasto-mechanics,
to overcome an otherwise confining pore. Ultradeformable
lipid vesicles (transferosomes) can penetrate the
skin and does not causes any changes in semi-permeable barriers that remain unfragmented after delivery. Evidence from double label confocal laser scanning microscopy (CLSM) experiments and
direct size measurements confirms it. Data indicate that as much as 50% of a
topical dose of a protein or peptide penetrates skin in vivo in 30
minutes. Five potential mechanisms of action of this liposome were assessed
1.
A free drug process-drug releases from vesicles and independently penetrates
skin.
2.
Enhancement due to release of lipids from vesicles and interaction with skin
lipids.
3.
Improved drug uptake by skin.
4.
That different entrapment efficiencies of the liposomes
controlled drug input.
5.
Penetration of stratum corneum by intact liposomes.
Studies
have been focused on delivery of agents like vaccines20, retinyl palmitate21,
estradiol22, copper, zinc, superoxide dimutase23, insulin24.
In some cases the transferosomes drug delivery with
some physical enhancement method iontophoresis for
estradiol25 and microneedles for docetaxel26
2.3 Prodrugs and Ion-Pairs:
The
prodrug approach has been investigated to enhance
dermal and transdermal delivery of drugs with unfavourable
partition coefficients. The prodrug design strategy
generally involves addition of a pro-moiety to increase partition coefficient
and solubility to increase the transport of the drug in the stratum corneum. Upon reaching the viable epidermis, esterase’s
release the active drug by hydrolysis thereby optimizing concentration in the
epidermis.
Charged
drug molecules do not readily partition into or permeate through human skin.
Formation of lipophilic ion pairs has been
investigated to increase stratum corneum penetration
of charged species. This strategy involves adding an oppositely charged species
to the charged drug, forming an ion-pair in which the charges are neutralized
so that the complex can partition into and permeate through the stratum corneum. The ion-pair then dissociates in the aqueous
viable epidermis releasing the parent charged drug that can diffuse within the
epidermal and dermal tissues.
2.4
Chemical potential of drug:
The
maximum skin penetration rate is obtained when a drug is at its highest
thermodynamic activity as is the case in a supersaturated solution. The
diffusion of paraben from saturated solutions in
eleven different solvents through a silicone membrane was determined. Due to
the different solubility of the parabens in the
various solvents, the concentration varied over two orders of magnitude.
However, paraben flux was the same from all solvents,
as the thermodynamic activity remained constant because saturated conditions
were maintained throughout the experiment. Supersaturated solutions can occur
due to evaporation of solvent or by mixing of co solvents. Clinically, the most
common mechanism is evaporation of solvent from the warm skin surface, which
probably occurs, in many topically applied formulations. In addition, if water
is imbibed from the skin into the vehicle and acts as an antisolvent,
the thermodynamic activity of the permeant would
increase. Increases in flux of drug upto five to ten
folds have been reported from supersaturated solutions of a number of drugs.
The potential benefit of supersaturated solutions was first recognized at least
three decades ago. Since then little work has been carried out in this area,
probably partly due to the thermodynamic instability of these solutions.
However, with an understanding of antinucleant
polymers, supersaturated solutions can be exploited to enhance percutaneous penetration. Supersaturated solutions were
produced by using a co-solvent system and this involves preparing a saturated
solubility curve for the drug in a binary co-solvent system. Supersaturated
systems have been successful at enhancing skin permeation. The technique
involves increasing the thermodynamic activity beyond saturated solubility
concentrations and as flux is proportional to thermodynamic activity, an
increase in the latter can lead to an increase in flux27. The major
advantage of this technique is its noninterference with the barrier properties
of the stratum corneum. However, supersaturated
systems are thermodynamically unstable. Some polymers like polyvinylpyrrolidone
(PVP), polyethyleneglycol (PEG), Eudragits,
polymethacrylates, polypropyleneglycol
(PPG), Dextrin derivatives, Cellulose esters like cellulose acetate butyrates(CAB) and cellulose acetate propionates(CAP) act
as anti-nucleating agents and can control the crystallization process and hence
enhance permeation of a number of drugs. The inhibition of crystallization by
these polymers has been rarely discussed in the past but more recently a
mechanism was proposed based on the adsorption of polymers onto the crystal
surface through hydrogen bonding. Hydroxypropyl-_-cyclodextrin
(HP-_- CD) acts as an antinucleating agent by
stabilizing the supersaturated system of Ibuprofen by forming inclusion
complexes and this was demonstrated by infrared spectroscopy and differential
scanning calorimetric studies.28 Magreb et al. reported that the
flux of oestradiol from an 18-times saturation system
was increased 18-fold across human membrane but only 13-fold in silastic membrane. They suggested that the complex mixture
of fatty acids, cholesterol, ceramides, etc. in the
stratum corneum might provide an antinucleating
effect thereby stabilizing the supersaturated system supersaturated solutions
(i.e. non equilibrated systems) may arise; either by design or via a cosolvent evaporating on the skin.28 The theoretical maximum flux may then increase many fold.
So, these polymers may be incorporated to inhibit crystallization in unstable
supersaturated preparations. The metastability period
is usually short, but may be prolonged in transdermal patches because of their
mode of preparation, drug dissolution in hot solvents, and evaporation to super
saturation and crystal inhibition by the polymers of the high viscosity matrix
or adhesive29
2.5
Eutectic systems:
The
melting points of a drug influences solubility and hence skin penetration.
According to regular solution theory “lower the melting point, greater the
solubility of a material in a given solvent, including skin lipids.” The
melting point of a drug delivery system can be lowered by formation of a
eutectic mixture: a mixture of two components which, at a certain ratio,
inhibit the crystalline process of each other, such that the melting point of
the two components in the mixture is less than that of each component alone.
EMLA cream, a formulation consisting of a eutectic mixture of lignocaine and prilocaine applied
under an occlusive film, provides effective local anaesthesia
for pain-free venepuncture and other procedures. The
1:1 eutectic mixture (melting point 18°C) is oil, which is formulated as an
oil-in-water emulsion thereby maximizing the thermodynamic activity of the
local anaesthetics. A number of eutectic systems
containing a penetration enhancer as the second components have been reported,
for example: Ibuprofen with terpenes, and methyl nicotinate, propranolol with
fatty acids, and lignocaine with menthol30.
In all cases, the melting point of the drug was depressed to around or below
skin temperature there by enhancing drug solubility.
Penetration
Enhancement by Stratum Corneum Modification:
1. Hydration
2. Lipid Disruption/Fluidization by Chemical
Penetration Enhancers
4. Increased Partitioning and Solubility in Stratum Corneum
5. Combined Mechanisms
6. Skin Irritancy and Toxicity Due to Chemical
Penetration Enhancers
7. Other Physical and Electrical Methods
8. Skin Penetration Retarders
CONCLUSIONS:
Transferosomes bearing
unique advantages over liposomes and niosomes vesicles have come up as potential alternative to
conventional vesicles. Like other vesicular drug delivery systems, Transferosomes, on
storage, undergo fusion and aggregation, as well chemical hydrolysis. Similar
to other vesicular system pharmacsomes still play an
important role in the selective targeting, and the controlled delivery of the
controlled delivery of various drugs. Current research trends are generally
based on using different approaches like pegylation, biotinyzation etc. for cellular targeting.29
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Received on 23.12.2009
Accepted on 21.03.2010
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Journal of Pharmaceutical Dosage Forms and Technology. 2(2): March –April.
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