Research J. Pharm. and Tech.

8 (2): February 2015

ISSN 0974-3618 www.rjptonline.org

REVIEW ARTICLE

The Structure of Skin and Transdermal Drug Delivery System- A Review

Sajid Ali, Maryam Shabbir, Nabeel Shahid
Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
*Corresponding Author E-mail: sajidalichishti@hotmail.com

ABSTRACT:
Transdermal drug delivery system (TDDS) provides various merits over conventional drug delivery systems such as
oral delivery and injections including avoidance of hepatic first pass metabolism, reduction of pain, and possible
sustained release of drug. Still, transdermal passage of molecule is tedious due to less permeability of stratum corneum
(SC), the outermost layer of the skin. In its intact state the skin is a formidable barrier, resistant to chemicals and
tissue-harmful ultraviolet rays and virtually impenetrable to the life threatening microorganisms. The stratum corneum
(SC) develops a thin, tough, relatively impermeable membrane which usually provides the rate limiting step in
transdermal drug delivery system. To overcome this barrier function chemical permeation enhancers (CPEs) are used
that facilitate the absorption of permeate through the skin by temporarily decreasing the impermeability of the skin.
The present review article highlights the different layer of skin and the passage of drug through a transdermal patch
into the stratum corneum for local or systematic effect.

KEYWORDS: Skin, transdermal drug delivery system, permeation enhancers, transcellular route, intercellular
route.

INTRODUCTION:
Transdermal drug delivery systems (TDDS) are defined as
self-contained, discrete dosage forms which, when applied
to the intact skin, deliver the drug(s), through the skin, at a
controlled rate to the systemic circulation1. A transdermal
patch or skin patch is a medicated adhesive patch that is
placed on the skin to deliver a specific dose of medication
through the skin and into the bloodstream2.
The first transdermal system, Transderm Scop (Baxter), was
approved by Food and Drug Administration in 1979 for the
prevention of nausea and vomiting associated with travel,
particularly at sea. In a broad sense, the term transdermal
drug delivery system (TDDS) includes all topically
administered drug formulations intended to deliver the
active ingredient into the general circulation. Transdermal
drug delivery systems (TDDS) have been designed to
provide controlled continuous delivery of drugs via the skin
to the systemic circulation. Adhesive patches and
transdermal drug delivery system (TDDS) of defined shape
and size are marketed for systemic action and are intended
for treatment or prevention of a systemic disease. Drug
released from transdermal drug delivery system (TDDS) is
absorbed through the stratum corneum (SC), epidermis and
dermis into the blood circulation and transported to target
tissue to achieve therapeutic effect. Ideally, entire of the
drug should penetrate through the skin to the underlying
blood supply without any drug accumulation in the layers of
the skin for successful Transdermal deliver3,4.

Transdermal drug delivery systems (TDDS) are considered

new drug delivery systems and often involve a
demonstration of clinical safety and effectiveness of the
drug. Transdermal drug delivery system (TDDS) are
Received on 05.10.2014 Modified on 27.10.2014 considered control release dosage forms and should
Accepted on 12.11.2014 © RJPT All right reserved scientifically support in vivo and in vitro claims for
Research J. Pharm. and Tech. 8(2): Feb. 2015; Page 103-109
controlled release features and should assure in vivo and in

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vitro reproducibility. As transdermal drug delivery system Epidermis

(TDDS) are regarded as new dosage form for the potent Non-viable epidermis and viable epidermis together makes
drugs thus it has to be approved based on clinical safety and up the epidermis13. Stratum corneum is known as the non-
efficacy studies5. Although TDDS was introduced more viable epidermis whereas the layer below the stratum
than 200 years ago4, it is only recently that the method corneum is called viable epidermis. The viable epidermis is
appears to have reached a practical stage6. Closely related made of various sublayers of epidermis which collectively
term is percutaneous delivery, which is transportation of is 50-100 µm thick and cells in this layer are held together
drugs into the tissues, with an attempt to avoid systemic by tonofibrils14. Blood capillaries and nerve fibers reach
effects. The concept of percutaneous absorption of drugs the epidermis by passing through the dermis and
was given by Stoughton in 19897. subcutaneous fat layer3. The main cell of the epidermis is
the keratinocytes which make up 95% of the total cells
The Skin present in the epidermis. These cells ascend from the
The skin often has been referred to as the largest of the epidermal basement membrane towards the skin surface,
body organs: an average adult’s skin has a surface area of fashioning several definite layers during its transit. The
about 2m2.The ease with which some drugs can pass separate layers of the epidermis are formed by the differing
through the skin barrier into the circulating blood means stages of keratin maturation11. The epidermis has the
that the transdermal route of medication is a possible following sublayers:
substitute to the oral route. However, the number of drugs
available as marketed transdermal drug products is limited Stratum basale (basal cell layer)
to those that display the correct physicochemical and It is the deepest sublayer of the epidermis and is composed
pharmacokinetic properties which facilitate their effective of a single layer of basal cells. Keratinocytes are produced
delivery across the skin8. in this sublayer. Stratum basale forms the boundary to the
dermis. It holds approximately 8% of the water in the
When a transdermal patch is applied to the human skin, it epidermis. With aging, stratum basale becomes thinner and
may retain the drug or active substance on the surface of the loses the ability to retain water. Melanocytes also lie in this
skin, without any absorption, e.g. in case of cosmetics and layer.
antiseptics or it may allow the drug permeation through the
skin into the deeper regions i.e. dermis and the epidermis. Stratum spinosum (prickle cell layer)
These formulations are also called diadermal or endodermal It refers to the 10 to 20 layers that lie on top of the basal cell
formulations. The third enviable function is to have the layer. Basal cells, through the process of turn-over, make
drug absorbed systematically9. their shape somewhat flatter and form these layers. These
cells are hence called prickle cells and have little spines on
Skin is one of the most readily accessible organs of the the outside of their membrane. The thickness of this
human body10. There are two kinds of human skin; one that sublayer is from 50 to 150 µm.
is hair-less such as soles of foot and palms of hand, and the
other kind which bears hair and sebaceous glands such as Stratum granulosum (granular cell layer)
arms and face11. The structure of skin is given in Figure 1. It is composed of 2 to 4 granular cell layers. The thickness
of this layer is 3 µm. In this sublayer, cornification or
Taxonomical classification keratinization of keratinocytes begins. In this process,
The skin is divided taxonomically into three scales; namely organelles such as nuclei and mitochondria start to resolve.
micro scale, meso scale and macro scale. The components Cells become increasingly filled with keratin fibers and
of cell and layers of skin constitutes the micro scale as they contain less moisture as compared to basal and prickle cell
can only be seen under the microscope and cannot be layers. The shape of these cells becomes much flatter during
differentiated or identified with human eye. The meso scale this process.
comprises of skin features, hair, freckles, moles, scale
comprises of skin features, hair, freckles, moles pores, skin Stratum lucidum (clear layer)
surface and wrinkles as they can be seen with the naked eye It can only be found in soles and palms. Its cells become
and more clearly under the micro-scale if necessary. The flatter and more densely packed during turn-over12.
macro scale comprises of body regions and body parts. The
skin morphology and appearance appears different at Stratum corneum (horny layer)
different parts of the body12. The outermost layer of the skin, the stratum corneum, is
responsible for the barrier function of the skin15. It is also
Histological classification known as non-viable epidermis14. The stratum corneum is
The skin is divided histologically into the epidermis, the 10-15 µm in thickness and is made up of dead flattened
dermis, and the hypodermis; which collectively forms a corneocytes which is surrounded by an extracellular matrix
cover against external agent and loss of water from the of lipid13. Corneocytes are the final product of mortal
body. differentiation of epidermal keratinocytes, and are
constantly renewed16. It is an interface between the body
and the outer environment. It conceals different enzymes
which aid in its healthy maintenance. It also helps to
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regulate the exchange of moisture and oxygen with the
external environment17. The chief route of permeation is
around the corneocytes. Therefore, the larger the size of
corneocytes the longer will be the route for the permeation.
Corneocyte size relies upon the site on the body e.g. the size
of corneocyte is smaller in the skin of the face as compared
to the arm18. The cells are joined together by desmosomes
which maintains the cohesiveness of the layer19.
Reticular layer
It constitutes the lower part of the dermis and represents a
continuous transition to the subcutis or hypodermis.
Reticular layer has a denser and thicker network as
compared to the papillary layer and includes fewer nerve
fibers and capillaries. In this sublayer, collagen fibers are
aggregated into thick bundles which are mostly aligned
parallel to the surface of skin12.

The stratum corneum is composed of approximately 40% Hypodermis

protein, mostly keratin, and 40% water, with the balance of
lipid components. On the surface of the skin is a film of
emulsified material which is composed of a complex blend
of sweat, sebum, and desquamating cells of epidermis.
However, this layer offers little obstruction for the drug to
permeate3. The major lipid classes in human stratum
corneum involve ceramides, cholesterol and saturated long
chain fatty acids15, 19. Another essential component of
stratum corneum is water which acts as a plasticizer and
prevents cracking and provides flexibility20.
Subcutis, or hypodermis in histology, is the third layer
beneath the dermis. Subcutis is an elastic layer and includes
a large amount of fat cells that work as a shock absorber for
blood vessels and nerve endings. The thickness of this layer
is 4 to 9 mm on average. However, the actual thickness
differs from person to person and it also depends on the
body region12.

Dermis
Once drug molecule is through the stratum corneum, it may
pass through the deeper epidermal tissues and enter into the
dermis. It is mainly made of fibrous tissues and is 1-2 mm
thick. The dermis has a rich supply of blood vessels from
where the drug gets absorbed into the general circulation
(Samantha Andrews et al., 2012). Sebaceous glands, sweat
glands, and hair follicles rises to the surface of the skin
from dermis and subcutaneous layer where they originates3.
The skin surface of human is recognized to contain an
average of 10-70 hair follicles and 200-250 sweat glands on Figure 1.1: Structure of skin11
every centimeter square of the skin area10. The dermis has
the following sublayers: Routes of skin penetration
The main route of transport for water-soluble molecules is
Papillary layer transcellular21. It involves the passage through the
It is the upper sublayer of the dermis that clearly segregates cytoplasm of corneocytes and lipid arrangement of the
from the epidermis. Papillary layer is a loosely connected stratum corneum9. The pathway of transport for lipid-
tissue and includes a large amount of nerve fibers, soluble molecules is intercellular; it implicates the passage
capillaries, water and cells (e.g. fibroblasts). In this apparently through the endogenous lipid within the stratum
sublayer, collagen fibers form a finer network than those of corneum21. The transcellular and intercellular route is
the reticular layer. collectively known as transepidermal route14, 22.

Figure 2: Transepidermal route23

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However, it is an oversimplification of the situation as each Advantages of TDDSs27-30

route cannot be viewed in segregation. A molecule crossing 1. The novel matrix formulation provide for the
via the transcellular route must partition into and diffuse preservation of moderately uniform concentration of
through the keratinocytes, but in order to move to the next diffusible drug in the formulation, thereby avoiding the
keratinocytes, the molecule must partition into and diffuse formation of drug-depleted regions within the topical
through the estimated 4-20 lipid lamellae between each formulation and helping to ensure relatively constant
keratinocyte. This series of partitioning into and diffusing drug-release rate.
across multiple hydrophilic and hydrophobic regions is 2. Skin occlusion by the water-impermeable backing film
unfavorable for most drugs10, 20. aids systemic efficacy by increasing skin hydration and
temperature with a subsequent increase in the rate and
Solute molecules may penetrate the skin through the hair extent of skin permeation.
follicles, sweat duct or through the sebaceous glands. These 3. The inclusion of skin penetration enhancers in the
passages are collectively known as shunt or appendageal transdermal drug delivery system serve to decrease
route21. It is generally accepted that the skin appendages diffusional resistance and increase transport.
comprises of approximately 0.1% of fractional area for drug 4. The skin, particularly the stratum corneum, provides a
permeation. Thus the main focus is to develop permeation large (1-2m2) surface area for drug diffusion
strategies through the stratum corneum rather than through 5. Transdermal administration, as compared to other
the appendages3, 20. routes, is moderately noninvasive and helps in
avoidance of the inconvenient parenteral therapy.
The passage through damaged skin is increased over normal 6. Patients are willing to accept the use of a simple-
skin. For example, skin with a disrupted epidermal layer looking patch as it can be easily applied and removed.
will allow up to 80% of hydrocortisone to pass through the 7. Transdermal drug delivery system can avoid
surface into the dermis as compared to 1% through intact gastrointestinal drug absorption difficulties caused by
skin21. gastrointestinal pH, enzymatic activity, interactions
with food, drink and other orally administered drugs.
Two factors are involved in percutaneous absorption of 8. They can be alternated for oral administration of
drug; partitioning of active constituent between the vehicle medication when that route is not suitable, as with
and skin, and diffusion of active constituent in the stratum vomiting and diarrhea.
corneum. Percutaneous absorption is defined as penetration 9. They avoid the first-pass effect i.e. deactivation by
of substance into different layers of skin and permeation digestive and liver enzymes of the initial pass of drug
across the skin into systemic circulation. The percutaneous substance through the systemic and portal circulation
absorption is a step wise including: Penetration: the entry of following gastrointestinal absorption.
a substance into a particular layer; Permeation: the 10. They provide extended therapy with a single
penetration from one layer into another, which is different application thus improving compliance over most of
both functionally and structurally from the first layer; the other dosage forms requiring more frequent dose
Absorption: the uptake of a substance into systemic administration.
circulation24. 11. The activity of drugs having a short half-life is
extended through the reservoir of drug in the
In case of transdermal drug delivery system the transdermal therapeutic delivery system.
absorption occurs through a slow process of diffusion 12. Drug therapy may be terminated rapidly by removal of
which is driven by the gradient between the high the patch from the surface of the skin.
concentration of drug in the drug delivery system and the 13. Patches can be self-administered.
zero concentration prevailing in the skin. Thus the delivery 14. The transdermal patches avoid peak and trough drug
system must be kept in continuous contact with the skin for levels and provides longer, multiday dosing interval.
a considerable time25. 15. They have an ability to deliver drug at a more specific
site.
Methods of Modifying Barrier Properties of Stratum 16. The transdermal drug delivery system allows an
Corneum opportunity for the utilization of drug candidate with
The methods employed for modifying the barrier properties short half-life and low therapeutic index.
of the stratum corneum to enhance drug penetration and 17. The patches are easily identified in case of
absorption through the skin may be classified into the emergencies e.g. for unresponsive, comatose patients,
following categories because of their physical presence, features and
 Chemical enhancement identifying marks (Loan Honeywell Nguyen et al.,
 Physical enhancement 2005; Meghan Wilkosz et al., 2003).
 Biochemical enhancement
 Supersaturation enhancement Disadvantages10, 28, 31
 Bioconvertable prodrug26 1. The increased residence time of patch on the skin
surface leads to an increased incidence of skin
maceration and adverse cutaneous reactions.

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2. Relatively potent drugs are suitable candidates for
transdermal delivery because of the natural limits of
drug entry imposed by the skin’s permeability.
Effective skin permeation is limited to relatively small
(<1 kD), lipophilic drug molecule.
3. The increased residence time of patch may increase the
chances of localized bacterial population.
4. The transdermal drug delivery system is not suitable
for drug with high doses.
5. Adhesion of patch on skin may vary according to the
patch size, skin type and environmental conditions.
6. Patch location, age and person to person variability
may play an important role in release of drug from the
system.
7. Some patients may develop severe skin allergic
reactions to transdermal patches.
8. Many drugs with a hydrophilic structure permeate the
skin too slowly to be of therapeutic benefit.
9. Damage to a transdermal patch can result in poor
control over the release of drug.
10. Drugs that have high melting point are poor candidates
for transdermal drug delivery system due to their low
solubility both in water and fat.
Penetration enhancer
Penetration enhancers are also known as accelerants,
sorption promoter32 or permeation enhancer33. The barrier
function is essential for the protective role of stratum
corneum but at the same time it may hinder the transdermal
delivery of drug through it34. As the major route of drug is
through the intracellular channels, the lipid section is a
viable determinant in the first step of absorption3.
lipid interface. This process can also occur due to simple
hydration.
With increased concentrations of solvents e.g.
dimethylsulfoxide (DMSO), dimethylacetamide (DMA),
and diethyltoluamide (DEET), propylene glycol (PG), a
direct effect may be a temporal alteration in chemical
composition of the bulk. In such cases so much of the
solvent penetrates the aqueous domain of the tissue that it
turns a good solvent for substances like corticosteroids and
estradiol etc. Simply the resultant partition now privileges a
raised percentage of the drug in the tissue. The solvent then
is transferred into the dermis along with the drug due to
concentration gradient thus created. Chemical permeation
enhancers can also modify lipid bilayer by their insertion
into the hydrophobic tails, disturbing compacting and
permitting facilitated passage of lipid permeants. Further
the addition of co-enhancers and solvents can show
enhanced permeability of the drugs, probably by
synergism35, 36, 37.
Fluidization of lipid bilayer
Penetration enhancers such as dimethyl sulphoxide
(DMSO), alcohols and fatty acids have been demonstrated
to modify the barrier property by fluidizing or loosening
highly ordered bilayer structure of stratum corneum thus
increasing its permeability. They do this function by
forming microcavities or permeable pores within the lipid
bilayer which increases the free volume ratio hence
increasing the diffusion coefficient of the drug. These
enhancers may also modify protein material in bilayer
structure to enhance permeability34.

Mechanism of action Lipid disruption

Chemical permeation enhancers can work by one or more In some cases the penetration enhancers penetrates into and
of the following three principle mechanisms: mix homogeneously with the lipids. They disorganize the
 Relaxation of the extremely ordered lipid structure of intercellular lipids thereby forming aqueous channels within
the stratum corneum. the stratum corneum which increases the permeability13.
 Interacting with aqueous domain of bilayer of lipid.
 Enhanced partition of the drug, by addition of co- Interaction with keratin
enhancer or solvent into the stratum corneum. The penetration enhancers, such as DMSO, urea and
surfactants, can also interact with the keratin filaments
Chemical permeation enhancers exert their effect through present in corneocytes which leads to disruption within the
above modifications in the skin structure. Various Chemical cell thereby 39
increasing diffusion coefficient and
permeation enhancers interact with the polar head groups permeability .
through hydrogen bonding and ionic interactions. The
resultant disruption of the lipid hydration spheres and Increased partitioning and solubility in stratum
change in head group properties cause the relaxation at the corneum
head portion. This relaxation can decrease the resistances of Penetration enhancers like ethanol and polyethylene glucol
this lipid enriched domain for polar molecules. Another (PG) increases solubility within the stratum corneum
aspect can be an increase in the volume of the water layer because they shift the solubility parameter (δ) of the skin
resulting in more water flow to the tissue, a process known closer to their solubility parameter by disrupting the stratum
as solvent swelling, leading to increased cross sectional area corneum. This increases
20, 39
the miscibility and hence alters the
for diffusion of polar molecules. A portion of free water partition coefficient .
becomes available, besides the water in structure, at the

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Figure 3: Action of penetration enhancers within the intercellular lipid domain38

Ideal properties of penetration enhancer32, 37, 39, 40
The ideal properties of penetration enhancers are:
 It should be pharmacologically inert.
 It is should be nontoxic, nonirritating, and non-
allergenic to the skin.
 It should produce rapid onset of action; predictable and
suitable duration of action for the drug used
 Following removal of the enhancer, the stratum
corneum should immediately and fully recover its
normal barrier property.
 The barrier function of the skin should decrease in one
direction only i.e., they should permit therapeutic
agents into the body and efflux of endogenous
materials should not occur
 It should be chemically and physically compatible with
the delivery system.
 It should be non-damaging to viable cells.
 Inexpensive and cosmetically.
 Penetration enhancer used should be economical.

Figure 4: Possible mechanisms of action of skin penetration enhancers41

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