ISSN 0974-3618
(Print) www.rjptonline.org
0974-360X (Online)
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.
Received on 05.10.2014 Modified on 27.10.2014
Accepted on 12.11.2014 © RJPT All right reserved
Research J. Pharm. and Tech.
8(2): Feb. 2015; Page 103-109
DOI: 10.5958/0974-360X.2015.00019.0
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 considered control release dosage forms and should scientifically
support in vivo and in vitro claims for controlled release features and should
assure in vivo and in vitro reproducibility. As transdermal drug delivery
system (TDDS) are regarded as new dosage form for the potent drugs thus it has
to be approved based on clinical safety and efficacy studies5.
Although TDDS was introduced more than 200 years ago4, it is only
recently that the method appears to have reached a practical stage6.
Closely related term is percutaneous delivery, which is transportation of drugs
into the tissues, with an attempt to avoid systemic effects. The concept of
percutaneous absorption of drugs was given by Stoughton in 19897.
The Skin
The skin often has been referred
to as the largest of the body organs: an average adult’s skin has a surface
area of about 2m2.The ease with which some drugs can pass through
the skin barrier into the circulating blood means that the transdermal route of
medication is a possible substitute to the oral route. However, the number of
drugs available as marketed transdermal drug products is limited to those that
display the correct physicochemical and pharmacokinetic properties which
facilitate their effective delivery across the skin8.
When
a transdermal patch is applied to the human skin, it may retain the drug or
active substance on the surface of the skin, without any absorption, e.g. in
case of cosmetics and antiseptics or it may allow the drug permeation through
the skin into the deeper regions i.e. dermis and the epidermis. These
formulations are also called diadermal or endodermal formulations. The third
enviable function is to have the drug absorbed systematically9.
Skin is one of the most readily accessible
organs of the human body10. There are two kinds of human skin; one
that is hair-less such as soles of foot and palms of hand, and the other kind
which bears hair and sebaceous glands such as arms and face11. The
structure of skin is given in Figure 1.
Taxonomical classification
The skin is divided
taxonomically into three scales; namely micro scale, meso scale and macro
scale. The components of cell and layers of skin constitutes the micro scale as
they can only be seen under the microscope and cannot be differentiated or
identified with human eye. The meso
scale comprises of skin features, hair, freckles, moles, scale comprises of
skin features, hair, freckles, moles pores, skin surface and wrinkles as they
can be seen with the naked eye and more clearly under the micro-scale if
necessary. The macro scale comprises of body regions and body parts. The skin
morphology and appearance appears different at different parts of the body12.
The skin is divided histologically into the
epidermis, the dermis, and the hypodermis; which collectively forms a cover
against external agent and loss of water from the body.
Epidermis
Non-viable
epidermis and viable epidermis together makes up the epidermis13.
Stratum corneum is known as the non-viable epidermis whereas the layer below
the stratum corneum is called viable epidermis. The viable epidermis is made of
various sublayers of epidermis which collectively is 50-100 µm thick and cells
in this layer are held together by tonofibrils14. Blood capillaries and nerve fibers reach the
epidermis by passing through the dermis and subcutaneous fat layer3.
The main cell of the epidermis is the keratinocytes which make up 95% of the
total cells present in the epidermis. These cells ascend from the epidermal
basement membrane towards the skin surface, fashioning several definite layers
during its transit. The separate layers of the epidermis are formed by the
differing stages of keratin maturation11. The epidermis has the
following sublayers:
Stratum
basale (basal cell layer)
It is
the deepest sublayer of the epidermis and is composed of a single layer of
basal cells. Keratinocytes are produced in this sublayer. Stratum basale forms
the boundary to the dermis. It holds approximately 8% of the water in the
epidermis. With aging, stratum basale becomes thinner and loses the ability to
retain water. Melanocytes also lie in this layer.
Stratum
spinosum (prickle cell layer)
It
refers to the 10 to 20 layers that lie on top of the basal cell layer. Basal
cells, through the process of turn-over, make their shape somewhat flatter and
form these layers. These cells are hence called prickle cells and have little
spines on the outside of their membrane. The thickness of this sublayer is from
50 to 150 µm.
Stratum
granulosum (granular cell layer)
It is
composed of 2 to 4 granular cell layers. The thickness of this layer is 3 µm.
In this sublayer, cornification or keratinization of keratinocytes begins. In
this process, organelles such as nuclei and mitochondria start to resolve.
Cells become increasingly filled with keratin fibers and contain less moisture
as compared to basal and prickle cell layers. The shape of these cells becomes
much flatter during this process.
Stratum
lucidum (clear layer)
It
can only be found in soles and palms. Its cells become flatter and more densely
packed during turn-over12.
Stratum corneum (horny layer)
The outermost layer of the skin, the
stratum corneum, is responsible for the barrier function of the skin15.
It is also known as non-viable epidermis14. The stratum corneum is
10-15 µm in thickness and is made up of dead flattened corneocytes which is
surrounded by an extracellular matrix of lipid13. Corneocytes are
the final product of mortal 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 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.
The
stratum corneum is composed of approximately 40% 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.
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 every centimeter square of the skin area10. The dermis has
the following sublayers:
Papillary
layer
It is
the upper sublayer of the dermis that clearly segregates from the epidermis.
Papillary layer is a loosely connected tissue and includes a large amount of
nerve fibers, capillaries, water and cells (e.g. fibroblasts). In this
sublayer, collagen fibers form a finer network than those of the reticular
layer.
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.
Hypodermis
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.
Figure 1.1: Structure of skin11
The
main route of transport for water-soluble molecules is transcellular21.
It involves the passage through the cytoplasm of corneocytes and lipid
arrangement of the stratum corneum9. The pathway of transport for
lipid-soluble molecules is intercellular; it implicates the passage apparently
through the endogenous lipid within the stratum corneum21. The
transcellular and intercellular route is collectively known as transepidermal
route14, 22.
Figure
2: Transepidermal route23
However,
it is an oversimplification of the situation as each route cannot be viewed in
segregation. A molecule crossing via the transcellular route must partition
into and diffuse through the keratinocytes, but in order to move to the next
keratinocytes, the molecule must partition into and diffuse through the
estimated 4-20 lipid lamellae between each keratinocyte. This series of
partitioning into and diffusing across multiple hydrophilic and hydrophobic
regions is unfavorable for most drugs10, 20.
Solute
molecules may penetrate the skin through the hair follicles, sweat duct or
through the sebaceous glands. These passages are collectively known as shunt or
appendageal route21. It is generally accepted that the skin
appendages comprises of approximately 0.1% of fractional area for drug
permeation. Thus the main focus is to develop permeation strategies through the
stratum corneum rather than through the appendages3, 20.
The
passage through damaged skin is increased over normal skin. For example, skin
with a disrupted epidermal layer will allow up to 80% of hydrocortisone to pass
through the surface into the dermis as compared to 1% through intact skin21.
Two factors are involved in percutaneous
absorption of drug; partitioning of active constituent between the vehicle and
skin, and diffusion of active constituent in the stratum corneum. Percutaneous
absorption is defined as penetration of substance into different layers of skin
and permeation across the skin into systemic circulation. The percutaneous
absorption is a step wise including: Penetration: the entry of a substance into
a particular layer; Permeation: the penetration from one layer into another,
which is different both functionally and structurally from the first layer;
Absorption: the uptake of a substance into systemic circulation24.
In case of transdermal drug
delivery system the transdermal absorption occurs through a slow process of
diffusion which is driven by the gradient between the high concentration of
drug in the drug delivery system and the zero concentration prevailing in the
skin. Thus the delivery system must be kept in continuous contact with the skin
for a considerable time25.
The methods employed for
modifying the barrier properties of the stratum corneum to enhance drug
penetration and absorption through the skin may be classified into the
following categories
·
Chemical enhancement
·
Physical enhancement
·
Biochemical enhancement
·
Supersaturation enhancement
·
Bioconvertable prodrug26
Advantages of TDDSs27-30
1. The novel matrix formulation
provide for the preservation of moderately uniform concentration of diffusible
drug in the formulation, thereby avoiding the formation of drug-depleted
regions within the topical formulation and helping to ensure relatively
constant drug-release rate.
2. Skin occlusion by the water-impermeable
backing film aids systemic efficacy by increasing skin hydration and
temperature with a subsequent increase in the rate and extent of skin
permeation.
3. The inclusion of skin
penetration enhancers in the transdermal drug delivery system serve to decrease
diffusional resistance and increase transport.
4. The skin, particularly the
stratum corneum, provides a large (1-2m2) surface area for drug
diffusion
5. Transdermal administration, as
compared to other routes, is moderately noninvasive and helps in avoidance of
the inconvenient parenteral therapy.
6. Patients are willing to accept
the use of a simple-looking patch as it can be easily applied and removed.
7. Transdermal drug delivery system
can avoid gastrointestinal drug absorption difficulties caused by gastrointestinal
pH, enzymatic activity, interactions with food, drink and other orally
administered drugs.
8. They can be alternated for oral
administration of medication when that route is not suitable, as with vomiting
and diarrhea.
9. They avoid the first-pass effect
i.e. deactivation by digestive and liver enzymes of the initial pass of drug
substance through the systemic and portal circulation following
gastrointestinal absorption.
10. They provide extended therapy
with a single application thus improving compliance over most of the other
dosage forms requiring more frequent dose administration.
11. The activity of drugs having a
short half-life is extended through the reservoir of drug in the therapeutic
delivery system.
12. Drug therapy may be terminated
rapidly by removal of the patch from the surface of the skin.
13. Patches can be
self-administered.
14. The transdermal patches avoid
peak and trough drug levels and provides longer, multiday dosing interval.
15. They have an ability to deliver
drug at a more specific site.
16. The transdermal drug delivery
system allows an opportunity for the utilization of drug candidate with short
half-life and low therapeutic index.
17. The patches are easily
identified in case of emergencies e.g. for unresponsive, comatose patients,
because of their physical presence, features and identifying marks (Loan
Honeywell Nguyen et al., 2005; Meghan Wilkosz et al., 2003).
Disadvantages10, 28, 31
1. The increased residence time of
patch on the skin surface leads to an increased incidence of skin maceration
and adverse cutaneous reactions.
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.
Mechanism of action
Chemical permeation enhancers
can work by one or more of the following three principle mechanisms:
·
Relaxation of the extremely ordered lipid structure of the stratum
corneum.
·
Interacting with aqueous domain of bilayer of lipid.
·
Enhanced partition of the drug, by addition of co-enhancer or
solvent into the stratum corneum.
Chemical permeation enhancers
exert their effect through above modifications in the skin structure. Various
Chemical permeation enhancers interact with the polar head groups through
hydrogen bonding and ionic interactions. The resultant disruption of the lipid
hydration spheres and change in head group properties cause the relaxation at
the head portion. This relaxation can decrease the resistances of this lipid
enriched domain for polar molecules. Another aspect can be an increase in the
volume of the water layer resulting in more water flow to the tissue, a process
known as solvent swelling, leading to increased cross sectional area for
diffusion of polar molecules. A portion of free water becomes available,
besides the water in structure, at the 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.
Lipid disruption
In some cases the penetration enhancers
penetrates into and mix homogeneously with the lipids. They disorganize the
intercellular lipids thereby forming aqueous channels within the stratum
corneum which increases the permeability13.
Interaction with keratin
The penetration enhancers, such as DMSO,
urea and surfactants, can also interact with the keratin filaments present in
corneocytes which leads to disruption within the cell thereby increasing
diffusion coefficient and permeability39.
Increased partitioning and solubility in
stratum corneum
Penetration enhancers like ethanol and
polyethylene glucol (PG) increases solubility within the stratum corneum
because they shift the solubility parameter (δ) of the skin closer to
their solubility parameter by disrupting the stratum corneum. This increases
the miscibility and hence alters the partition coefficient20, 39.
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