Skin and Drug Permeation

The skin is the largest organ in the human body and is indispensable in its function as a physical barrier to foreign
substances. It is comprised of two layers, the epidermis and dermis. The epidermis is the outermost layer containing
keratinocytes and melanocytes. Keratinocytes provide a mechanical barrier to protect underlying tissues while
melanocytes are responsible for skin pigmentation. This is also the same layer that contains the oil and sweat glands.
Meanwhile, the dermis is the innermost layer of the skin and consists of collagen, which is produced by fibroblast
cells. This later is flexible and its main role is to regulate temperature and supply the epidermis with nutrientsaturated blood. The dermis is also the location of hair follicle base, nerve endings, and pressure receptors. Lastly,
this bottom layer defends the body against infections that pass through the epidermis, the first defense against
disease.
At the outermost level, molecules to be delivered can
penetrate through three different pathways to viable
tissue. They can pass through hair follicles with
associated sebaceous glands, or through sweat ducts, or
across the continuous stratum corneum between these

appendages. See image below:

For transdermal drug delivery, as well as non-invasive
chemical sensing, the rapid and controlled transport of
molecules across human skin is of immediate interest. In
light of this, the primary barrier to the transport of
molecules across the skin surface is the stratum corneum
(SC), which is typically thought of as a brick wall model
where dead, hydrated corneocytes are analogous to the
bricks, and the surrounding multi-lamellar lipid bilayer
membranes form the mortar. Whereas small lipid-soluble molecules find their way through the SC, subsequently
diffusing through the lipid bilayer membranes, hydrophilic, or water-soluble, molecules, such as polar or charged
molecules, have more difficulty permeating far by this route.
On a more specific level, peptide drugs cross the epithelium by two distinct
pathways: the transcellular or intracellular route. The intracellular route
involves solute diffusion into the extracellular space between adjacent cells.
This route is restricted by the molecules size and charge with the presence of
tight junctions. The transcellular route involves the movement of the solute
through the cells interior and across the basolateral membrane by either
active or passive processes. The former requires a carrier or receptor
molecule and is highly substrate specific while the latter is mediated by a
concentration gradient. In the absence of active transport components, most
peptides cross the nasal epithelium by the paracellular route, driven by
passive diffusion. Due to hydrophilicity of peptides the transcellular route is
mainly relevant for carrier or receptor mediated transport processes or for
transcytosis.

A Definition of Dermal Absorption

In fact, many substances do pass into the body from the outer surface of the skin and into the circulation. To
understand how this works, imagine a tightly woven fabric. While from a distance it may appear impervious, at close
range it is actually highly porous. It is this porous nature of the skin, with its millions of tiny openings, that allows not
only sweat and other toxins to escape, but also enables the absorption of some substances.
The process is known as dermal absorption. Once a substance passes through the outer layers of skin, it passes into
the lymph and local vascular (blood vessel) system and soon after into the bloodstream.1

Routes of Absorption of Topical Magnesium

While the exact mechanisms of skin transfer are yet to be completely understood, three routes of penetration have
been hypothesized:

Intercellular Skin Absorption, which occurs between the cells of the stratum corneum, the outermost
layer of the skin
Transcellular Skin Absorption, where substances actually pass through the skin cells themselves
Skin Absorption Through the Follicles and Glands, also known as appendageal absorption, which may
also exhibit reservoir effects in which substances may be stored within the glands for absorption over time

Skin Permeability: The Good and The Bad

Some of the most convincing stories of substances passing into the body via the skin come from governmental
agencies actively studying and monitoring dermal absorption through their chemical safety divisions.
A 2005 report published by the World Health Organization takes a very clear position on skin permeability:

While the skin does act as a barrier, it is not a complete barrier. Many chemicals do penetrate
the skin, either intentionally or unintentionally, and cutaneous metabolism does occur. Because
of its large surface area, the skin may be a major route of entry into the body in some exposure
situations.

This major route of entry has become a concern in many circumstances where toxic substances are released into
air, water, and even city water supplies.

The California Environmental Protection Agency issued a report entitled Chlorinated Chemicals in Your

Home, warning of the risks of cancer due to chlorinated chemicals. The agency issued the statement: Taking a
long, hot shower in a typical small shower stall can substantially increase your exposure to chloroform. If you use
indoor spas, hot tubs, or swimming pools, you are also likely to be exposed to high levels of chloroform.2
Health Canada has estimated that skin exposure to certain toxic hydrocarbons in the Great Lakes may be

as dangerous as oral exposure, issuing alerts to bathers, especially those affected by sunburn, which may
enhance absorption.3
Worker safety is an issue. Workers in various industries have suffered poisoning, in some cases fatal, from

substances penetrating exclusively through the skin and into the bloodstream, such as through dermal exposure to
leaded gasoline and insecticides.4
The European Commission and the World Health Organization have both issued Guidance Documents,
such as the Guidance Document on Dermal Absorption and International Programme on Chemical
Safety Environmental Health Criteria serve to instruct agencies on how to protect workers from exposure to toxic
compounds.
While government agencies such as those above work to stop the transfer of chemicals through the skin, transdermal
drug delivery methods seek to take advantage of it. Transdermal patches are produced as delivery systems for
nicotine, hormones, pain killers, and others.
These methods are coveted for their clear advantages over oral medications, as outlined by Stanley Scheindlin,
pharmaceutical chemist, in the journal Molecular Interventions:

Patients often forget to take their medicine, and even the most faithfully compliant get tired of
swallowing pills, especially if they must take several each day. Additionally, bypassing the
gastrointestinal (GI) tract would obviate the GI irritation that frequently occurs and avoid partial
first-pass inactivation by the liver.

While transdermal drugs are well known in the medical community, the difference with magnesium oil topical
treatments is, of course, the fact that magnesium is an essential mineral to the human body, in a natural form. Thus,
use of topical magnesium oil products brings all the advantages of transdermal applications, but none of the
disadvantages of introducing foreign substances into the body.
Transdermal magnesium is a needed substance. While the chemicals in transdermal pharmaceuticals are actively
filtered, inactivated, and excreted by the bodys detoxification systems, magnesium is welcomed and actively taken in
by the cells.

Strategies for Skin Penetration Enhancement

Rolf Daniels
1 Introduction
Dermatological and cosmetic preparations frequently contain active principles which can only act when
they penetrate at least the outermost layer of the skin. However, the efficacy of topically applied actives is
often suboptimal because the transport into the skin is slow due to the resistance of the outermost layer
of the skin, the stratum corneum. Most small water-soluble non-electrolytes therefore diffuse into the
systemic circulation a thousand times more rapidly when the horny layer is absent. Thus, a variety of
means have been studied in attempts to overcome this barrier. Such strategies include physical,
biochemical, and chemical methods (figure 1)

2 Structure of the skin barrier

The skin is the largest human organ and consists of three functional layers: epidermis, dermis, and
subcutis. It has a wide variety of functions. One major task of the skin is to protect the organism from
water loss and mechanical, chemical, microbial, and physical influences. The protective properties are
provided by the outermost layer of the skin, the epidermis. Although its thickness measures on average
only 0.1 mm (from 0.02 mm on the face up to 5 mm on the soles of the feet) it is specially structured to
fulfil this challenging task. Out of the five layers of the epidermis, it is mainly the uppermost layer (horny
layer; stratum corneum) which forms the permeability barrier.

The stratum corneum consists of horny skin cells

(corneocytes) which are connected via desmosomes
(protein-rich appendages of the cell membrane). The
corneocytes are embedded in a lipid matrix. Thus the
structure of the stratum corneum can be roughly
described by a brick and mortar model [1]. The
corneocytes of hydrated keratin comprise the bricks
and the epidermal lipids fill the space between the
dead cells like mortar
Figure 2: Schematic structure of the stratum corneum
The epidermal lipids comprise 10 to 30 % of the total
according to the brick & mortar model. The horny cells are
embedded in a lamellar structured lipid matrix
volume of the stratum corneum. The major
components are: ceramides, fatty acids, cholesterol,
and cholesterol esters [2].
The lipids are organized as multiple lipid bilayers which form regions of semi-crystalline gel and liquid
crystals domains [3].

3 Routes of Penetration
Figure 3 illustrates the possible pathways for a penetrant to cross
the skin barrier. Accordingly, a molecule may use two diffusion
routes to penetrate normal intact human skin: the appendageal
route and the trans-epidermal route.
The appendageal route comprises transport via the sweat glands
and the hair follicles with their associated sebaceous glands. These
routes circumvent penetration through the stratum corneum and are
therefore known as shunt routes.
Although these routes offer high permeability, they are considered
to be of minor importance because of their relatively small area,
approximately 0.1% of the total skin area. The appendageal route
seems to be most important for ions and large polar molecules
which hardly permeate through the stratum corneum [4].
Trans-epidermal transport means that molecules cross the intact
horny layer. Two potential micro-routes of entry exist, the
transcellular (or intracellular) and the intercellular pathways (Figure
4).
The principal pathway taken by a penetrant is decided mainly by
the partition coefficient (log K). Hydrophilic drugs partition
preferentially into the intracellular domains, whereas lipophilic
permeants (octanol/water log K > 2) traverse the stratum corneum
via the intercellular route. Most molecules pass the stratum
corneum by both routes. However, the tortuous intercellular
pathway is widely considered to provide the principal route and
major barrier to the permeation of most drugs [5].
Considering that the skin is such a heterogeneous membrane, it is
surprising that simple diffusion laws can be used to describe the
transport through the skin.

Figure 3: Possible pathways for a penetrant

to cross the skin barrier. (1) across the intact
horny layer, (2) through the hair follicles with the
associated sebaceaous glands, or (3) via the
sweat glands

Figure 4: Schematic diagram of the two

microroutes of penetration.

J=

KD
h

(Co Ci)

For steady-state conditions this can be described with Ficks first

law of diffusion:
Where J is the flux per unit area, K is the stratum corneum-formulation partition coefficient of the active,
and D is its diffusion coefficient in the stratum corneum of the thickness h; c0 is the concentration of
active substance applied to the skin surface, and ci is its concentration inside the skin.
4 Penetration Enhancement
The perfect barrier properties of the epidermis restricts the transport through the skin to molecules with
certain properties such as low molecular weight (< 500 Dalton), moderate lipophilicity (octanolwater
partition coefficient between 10 and 1000), and modest melting point (< 200 C) correlating with good
solubility. Even when an active substance exhibits such properties, it is usually necessary to find
additional means to increase its transport across the skin.
4.1 Supersaturation
Supersaturation is a means to increase skin penetration without alteration of stratum corneum structure
[6]. The mechanism of enhancement is based simply on the increased thermodynamic activity of the
drug. This increases the concentration gradient (c0 ci) in the Ficks law and thus forces the active
principle out of the formulation and into and across the stratum corneum. Several methods can be used
to produce supersaturated systems:

Heating and subsequent cooling

Removal of a solvent


Reaction of two or more solutes to produce a compound which is less soluble

Addition of a substance to a solution that reduces the solubility of the solute

However, supersaturated systems are thermodynamically unstable and inherently tend to
recrystallise. Therefore special efforts are necessary to transiently stabilize the supersaturated
system for an appropriate period of time, e.g. addition of polymers as anti-nucleant in order to delay
re-crystallisation.
4.2 Water as penetration enhancer
Hydration of the stratum corneum is one of the primary measures to increase the penetration of most
active compounds. Water opens up the compact structure of the horny layer. The water content of the
horny layer can be increased either by delivering water from the vehicle to the skin or by preventing
water loss from the skin when partially occlusive formulations are applied to the skin.
Table 1 summarises general effects of carrier systems on the stratum corneum water content and on the
penetration of active ingredients.
Table 1: Effects of carrier systems on the stratum corneum water content and on the penetration of
active ingredients
Vehicle

Example/Constituents

OcclusiveDressings Plastic film, imperforated

waterproof patch

Effect on
skin hydratation

Effect on skin
permeability

Prevent water loss;

full hydration

Marked increase

Paraffins, oils, fats, waxes,

fatty acids, fatty
alcohols, esters, silicones

Prevent water loss;

may produce full
hydration

Marked increase

Absorption bases

Unhydrous lipids plus wlo

emulsifiers

Prevent water loss;

marked hydration

Marked increase

Absorption bases

Unhydrous lipids plus o/w

emulsifiers

Prevent water loss;

marked hydration

Marked increase

Lipohihc vehicles

W/O systems

O/W systems

Humectants

Powder

W/O creams
W/O emulsions

Retard water loss:

raised hydration

Increase

W/O creams
W/O emulsions

Can donate water;

slight hydration
increase

Slight increase

Water-soluble vehicles:
gylcerol, glycols

Can withdraw water;

decreased hydration

Clays, shake lotions

Aid water evaporation:

Negligible effect on
decreased excess
stratum corneum
hydration

Possible decrease or
act
as chemical enhancer

4.3 Chemical Enhancers

Several excipients are able to promote the transport of an active substance across the skin barrier by a
variety of mechanisms. The most important are [7]:
Extraction of lipids from the stratum corneum
Displacement of bound water
Alteration of the vehicle/skin partitioning
Loosening of horny cells

coefficient
Disruption of the lipid bilayer structure

Delamination of stratum corneum

Chemical enhancers can be categorized into different

groups (Figure 5). Solvents like alcohols, alkylmethyl
sulfoxides, and polyols mainly increase solubility and
improve partitioning coefficient. Moreover, some
solvents, e.g. Dimethylsulphat (DMSO), ethanol, may
extract lipids, making the stratum corneum more
permeable. Oleic acid, Azone (epsilonLaurocapram), and isopropyl myristate are typical
examples of chemical enhancers which intercalate
into the structured lipids of the horny layer where
they disrupt the packing.
This effect makes the regular structure more fluid
and thus increases the diffusion coefficient of the
permeant. Ionic surfactants, decylmethyl sulfoxide,
DMSO, urea interact with the keratin structure in the
corneocytes. This opens up the tight protein structure Figure 5: Chemical structure of typical chemical penetration
enhancers
and leads to an increased diffusion coefficient D
mainly for those substances which use the
transcellular route.
An unfortunate feature of many potent chemical enhancers is that they irritate due to their ability to
interact effectively with the corneocytes and the intercellular lipid structure.
4.4 Physical Enhancement Techniques
Hydration of the horny layer and addition of chemical enhancers that temporarily alter the barrier
properties can enhance the flux of active substances. However, all these principles have clear limitations
concerning the delivery of sufficiently high amounts of ionic molecules, large molecular weight actives
and substances with low potency. These limitations of chemical enhancement can be overcome to some
extent by physical enhancement technologies [8].
4.4.1 Phonophoresis
Phonophoresis (or sonophoresis) uses ultrasound energy in order to enhance the skin penetration of
active substances [8]. When skin is exposed to ultrasound, the waves propagate to a certain level and
cause several effects that assist skin penetration. Figure 6 depicts the processes that can contribute to
phonophoresis. One of these effects is the formation and subsequent collapse of gas bubbles in a liquid
called cavitation. The force of cavitation causes the formation of holes in the corneocytes, enlarging of
intercellular spaces, and perturbation of stratum corneum lipids.
Another effect is heating which is mainly due to the
energy loss of the propagating ultrasound wave due
to scattering and absorption effects. The resulting
temperature elevation of the skin is typically in the
range of several degrees centigrade.
This temperature rise will increase the fluidity of the
stratum corneum lipids as well directly increase the
diffusivity of molecules through the skin barrier.
These main effects can be assisted by acoustic
micro-streaming caused by the acoustic shear stress
which is due to unequal distribution of pressure
forces. In addition, ultrasound can push particles
through by pressure increase in the skin, although
only slightly.

Figure 6: Basic principle of phonophoresis. Ultrasound pulses

are passed through the probe into the skin fluidizing the lipid bilayer
by the formation of bubbles caused by cavitation.

4.4.2 Iontophoresis
The basic principle of iontophoresis is that a small
electric current is applied to the skin. This provides
the driving force to primarily enable penetration of
charged molecules into the skin. A drug reservoir is
placed on the skin under the active electrode with the
same charge as the penetrant. An indifferent counter
electrode is positioned elsewhere on the body.
The active electrode effectively repels the active
substance and forces it into the skin (Figure 7). This
simple electrorepulsion is known as the main
mechanism responsible for penetration enhancement
by iontophoresis. The number of charged molecules
which are moved across the barrier correlates
directly to the applied current and thus can be
controlled by the current density.

Figure 7: Basic principle of iontophoresis. A current passed

between the active electrode and the indifferent electrode repelling
drug away from the active electrode and into the skin.

Other factors include the possibility to increase the permeability of the skin barrier in the presence of a
flow of electric current and electroosmosis.

Contrary to electrorepulsion, electroosmosis can be

used to transport uncharged and larger
molecules.Electroosmosis results when an electric
field is applied to a charged membrane such as the
skin and causes a solvent flow across this
membrane. This stream of solvent carries along with
it dissolved molecules. It enhances the penetration of
neutral and especially polar substances.
4.4.3 Electroporation
Electroporation is also based on the application of a
voltage to the skin [9]. In contrast to iontophoresis
where a low voltage is applied, electroporation
requires a large voltage treatment for a short period
of 10 s to 100 ms.
Electroporation produces transient hydrophilic pores
(aqueous pathways) across the skin barrier (Figure
8). These pores allow the passage of
macromolecules via a combination of diffusion,
electrophoresis and electroosmosis.

Figure 8: Basic principle of electroporation. Short pulses of high

voltage current are applied to the skin producing hydrophilic pores
in the intercellular bilayers via momentary realignment of lipids.

4.4.4 Microneedles
In the last years, several attempts have been made
to enhance the transport of substances across the
skin barrier using minimally invasive techniques [10].
The proper function of an appropriate system
requires that the thickness of the stratum corneum
( 10 to 20 m) has to be breached. More recent
developments focus on the concept of microneedles.
Microneedles are needles that are 10 to 200 m in
height and 10 to 50 m in width (Figure 9). They are
solid or hollow and are connected to a reservoir
which contains the active principle.
Microneedle arrays are applied to the skin surface so
that they pierce the upper epidermis far enough to
Figure 9: Basic design of microneedle deliver devices. Needles
increase skin permeability and allow drug delivery,
of approximately with or without centre hollow channels are placed
but too short to cause any pain to the receptors in the onto the skin surface so that they penetrate the stratum corneum
and epidermis without reaching the nerve endings present in the
dermis. Therefore there is no limitation concerning
upper dermis.
polarity and molecular weight of the delivered
molecules. The fabrication of such tiny structures
became possible with the advent of micromachining
technology which is an essential technology for the
microelectronic industry.
It is not difficult to imagine that microneedle systems can be easily combined with microelectronic
elements which can fully control the delivery rate. Furthermore, this type of system could be linked to a
micro sensor system which measures the actual concentration of an active molecule which then triggers
the release. It can be envisioned that such a pharmacy on a chip may be the future of drug delivery.
4.5 Formulation approaches
Penetration enhancement with special formulation
approaches is mainly based on the usage of colloidal
carriers. Submicron sized particles are intended to
transport entrapped active molecules into the skin.
Such carriers include liposomes, nanoemulsions, and
solid-lipid nanoparticles (Figure 10) [11]. Most reports
cite a localizing effect whereby the carriers
accumulate in stratum corneum or other upper skin
layers. Generally, these colloidal carriers are not
expected to penetrate into viable skin. However, the
effectiveness of these carriers is still under debate.

Figure 10: Structure of nanodispersed vehicle systems

More recently a new type of liposomes called transferosomes has been introduced [12, 13].
Transferosomes consist of phospholipids, cholesterol and additional surfactant molecules such as
sodium cholate. The inventors claim that transferesomes are ultradeformable and squeeze through pores
less than one-tenth of their diameter. Thus 200 to 300 nm sized transfereosmes are claimed to penetrate
intact skin. Penetration of these colloidal particles works best under in vivo conditions and requires a
hydration gradient from the skin surface towards the viable tissues.
Another formulation approach aiming to enhance skin penetration is the preparation of microemulsions.
Such systems consist of water, oil, and amphiphilic compounds (surfactant and co-surfactant) which yield
a transparent, single optically isotropic, and thermodynamically stable liquid. Microemulsions can be
either oil continuous, water continuous, or bi-continuous. The main difference between macroemulsions
and microemulsions lies in the size of the particles of the dispersed phase: these are at least an order of
magnitude smaller in the case of microemulsions ( 10 200 nm) than those of conventional emulsions (1
20 m). Typical properties of microemulsions include optical transparency, thermodynamic stability, and

solubility of both hydrophobic and hydrophilic components. Penetration enhancement from

microemulsions is mainly due to an increase in drug concentration which provides a large concentration
gradient from the vehicle to the skin. Furthermore it has been suggested that the surfactants and the oil
from the microemulsion interact with the rigid lipid bilayer structure and acts as a chemical enhancer [14].
5 Measurement of skin penetration
The penetration behavior of an active ingredient can
be evaluated in vitro, ex vivo, and in vivo.
Most of the data on percutaneous penetration have
been gained with in vitro or ex vivo studies by
experiments using a Franz-Diffusion chamber (Figure
11). The donor (formulation) is separated from the
acceptor (aqueous buffer solution) by an appropriate
barrier. For in vitro studies this barrier can consist of
an artificial skin construct (ASC). ASC is cultivated
from different cell types and comprises a dermis and
a epidermis equivalent [15]. The advantage of ASC is
that the properties are more consistent than in
natural skin. However, the barrier properties of
Figure 11: The Franz Diffusion Chamber
artificial skin are more closely to that of baby skin.
This means it is less restrictive than the skin of
adults.
Ex vivo studies use animal or human cadaver skin as the barrier. Due to market differences in the barrier
properties animal skin is not always an accurate predictor for the situation in human. The cadaver skin
can be used in a whole but more frequently excised skin is taken for the experiments. In this case the
stratum corneum is separated from the rest of the skin by a special preparation technique.
Also very useful for ex vivo studies is the bovine
udder skin (BUS) model which was developed 10
years ago [16]. The udder is from slaughter house
material and can be maintained in culture at high
vitality for 8 10 hours. A warmed, oxygen enriched
Tyrode solution is pumped through the venous
system of the udder.
Test substances are applied topically and the
perfusate can be analyzed for the penetrant (Figure
12). In addition, the BUS model allows to assess the
distribution of a substance in the udder skin from
either tape stripping or punched biopsies. Moreover,
the BUS model can be used to measure irritation
caused by a certain formulation.

Figure 12: Scheme of the experimental set up of the isolated

perfused bovine udder skin model

For human in vivo penetration studies the active

content in different layers of the stratum corneum can
be determined after tape stripping or with the aid of
some advanced spectroscopic methods, e.g. ATR
(attenuated total reflection) spectroscopy.
A more advanced in vivo technique is
microdialysis(Figure 13). For cutaneous microdialysis
a small probe equipped with a semipermeable hollow
fiber is inserted superficially in the dermis.
The principle of microdialysis is that a physiological
solution pumped through the probe is in equilibrium

Figure 13: Schematic drawing of the principle of microdialysis

with the diffusible molecules in the surrounding

tissue. Therefore the concentration of a solute in the
dialysate is proportional to the concentration in the
tissue and allows direct monitoring of the in vivo
penetration behavior of a active ingredient. With such
studies the influence of formulation variables as well
as skin condition can be evaluated.
6 Conclusions
The skin has an extremely good barrier function and to improve the penetration of active ingredients it is
frequently necessary to employ enhancement strategies. The understanding of the barrier architecture
and the mechanisms of penetration has improved and many of the different determinants are
understood. This knowledge enables to develop both passive (chemical) and active (physical)
approaches to facilitate the entry of active molecules into the skin. However, skin penetration
enhancement could destroy the skin barrier formed by the lipid and protein and thus induce side effects.
Such unwanted effects are in most cases directly correlated to an increase in transepidermal water loss
(TEWL). Briefly, high TEWL means high skin penetration, and high skin penetration means greater skin
barrier impairment. Future strategies should therefore aim to optimize the balance between the TEWL
increase and effectiveness of the penetration enhancement.

This review article is mainly focused on the recent and efficient

methods of drug delivery in Transdermal drug delivery system; namely
Sonophoresis

and

Nanotechnology

as

Nanoparticles).

Application of these methods in transdermal drug delivery has

improved patient compliance and opened new techniques in T.D.D.S

REFERENCE ID: PHARMATUTOR-ART-1752

INTRODUCTION:
Human skin serves a protective function by imposing physicochemical
limitations to the type of permeant that can traverse the barrier. For a
drug to be delivered passively via the skin it needs to have a suitable
lipophilicity and a molecular weight <500 Da.

Unfortunately, a

significant obstacle to dermal and transdermal drug delivery alike is

the resilient barrier that the epidermal layers of the skin, primarily the
stratum corneum, presents for the diffusion of exogenous chemical
agents.

STRUCTURE OF THE HUMAN SKIN

The number of commercial available products based on transdermal or
dermal delivery has been limited by these requirements. In recent
years various passive and active strategies have emerged to optimize
Delivery. The passive approach entails the optimization of formulation
or drug carrying vehicle to increase skin permeability. However passive
methods do not greatly improve the permeation of drugs with
molecular weights >500 Da. In contrast active methods, normally
involving physical or mechanical methods of enhancing delivery have
been shown to be generally superior.

A transdermal delivery system mainly is composed of drug reservoir,

drug release (release rate controlling) membrane, a polymer system,
an adhesive. The membrane system is usually perforated for better
drug transport through the skin surface.

COMPONENTS OF A TRANSDERMAL PATCH

Example: Scopolamine transdermal patch, nicotine patch

SCOPALAMINE TRANSDERMAL PATCH

MECHANISM

OF

DRUG

DELIVERY

THROUGH

SKIN

The drug release process mainly consists of four stages: the drug
releases from the formulation, diffuses across the stratum corneum
(SC) via tortuous intercellular lipid path-way, transfers from SC into
epidermis, and then enters the systemic circulation via capillary
network.

Various Approaches involved in Transdermal drug delivery to

enhance permeation of drugs:
PHYSICAL

APPROACHES

Iontophoresis

Phonophoresis ( also known as sonophoresis-uses ultrasound

apparatus generating frequencies in the range 0.7-1.1 MHz)

CHEMICAL
Permeation

APPROACHES
enhancers:

a)

Solvents

b)

Surfactants

These

include

the

following:

Anionic

surfactants

Cationic

surfactants

* Bile salts
c)

Binary systems

d)

Miscellaneous chemicals

Newer and Recent techniques used in Transdermal drug

delivery
Sonophoresis:
Application of ultrasound to the skin increases its permeability
(sonophoresis) and enables the delivery of various substances into and
through the skin. Ultrasound has been used extensively for medical
diagnostics and to a certain extent in medical therapy.The generation
of ultrasound and mechanism of sonophoresis with particular emphasis
on the role of cavitation (both inside and outside the skin), thermal
effects, convective transport, and mechanical effects also included.
Sonophoresis is a localized, non?invasive, convenient and rapid
method

of

delivering

low

molecular

weight

drugs

as

well

as

macromolecules into the skin.

The ultrasound waves generate tiny bubbles of water on skin surface;
this causes the skin surface to lightly get worn out. This allows the
drug to pass through the skin surface efficiently. Sonophoresis occurs
because ultrasound waves stimulate micro-vibrations within the skin
epidermis and increase the overall kinetic energy of molecules making
up topical agents.Sonophoresis, or ultrasound, creates holes in the
skin, and allows fluids to travel into or out of the body. When sound is
emitted at a particular frequency, the sound waves disrupt the lipid
bilayers. This method can be used for delivery of steroids, systemic
drugs such as Insulin and antigens for vaccination. Ultrasound
transdermal drug delivery system in noninvasive way is used for
Diabetics to control blood sugar level through short term and long
term delivery of Insulin.

Noninvasive drug delivery (as capsule

formulation) is used for acne, psoriasis. These systems enhance

activity of transdermal patches.The higher the frequency, the more
dispersed the transmission.

Advantages of using sonophoresis as a physical penetration

enhancer
Enhanced drug penetration (selected drugs) over passive transport.

Allows

strict

control

of

transdermal

penetration

rates.

Low risk of introducing infection as the skin remains intact

Reduction

of

dosing

frequency

and

patient

compliance.

Improved control of the concentrations of drugs with small

therapeutic

Reduction

indices.
of

fluctuations

in

plasma

levels

of

drugs.

Avoids hepatic first pass elimination and gastrointestinal irritation.

Substitutes oral administration when the route is unsuitable as in
case

of

vomiting,

diarrhea.

Permit both local and systemic effects and less risk of systemic
absorption

than

injection.

Easy termination of drug delivery in case of toxicity, through

termination of ultrasound.
Disadvantages of using sonophoresis as a physical penetration
enhancer
Stratum corneum must be intact for effective drug penetration.
Can be time consuming to administer.