Transdermal drug delivery system- structure of skin

UNIT 3
TRANSDERMAL DRUG
DELIVERY SYSTEM
AKANKSHA PATEL
ASSISTANT PROFESSOR
FACULTY OF TAGORE INSTITUTE OF
PHARMACYAND RESEARCH, BILASPUR
(C.G)

INTRODUCTION
• TDDS are defined as- “it is self contained,
discrete dosage form which, when applied
to the intact skin, deliver the drug through
the skin, at a controlled rate to the
systemic circulation”.
• The first transdermal system, Transderm
Scop (Baxter), was approved by FDA in
1979 for the prevention of nausea and
vomiting associated with travel.

CONTI….
• 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.
• TDDS was introduced more
than 200 years ago, it is
only recently that the
method appears to have
reached a practical stage.

ADVANTAGES
• Avoidance of first-pass effect,
• Long duration of action,
• Comparable characteristics with IV infusion,
• Ease of termination of drug action, if necessary,
• No interference with gastric and intestinal fluids,
• Suitable for administered of drug having- Very
short half-life, e.g. nitroglycerine.
• Narrow therapeutic window.
• Poor oral availability
• provides a large (1-2m2) surface area for drug
diffusion
• Patches can be self-administered

DISADVANTAGES
1. Poor diffusion of large molecules,
2. Skin irritation,
3. Requires high drug load,
4. Unsuitable –If drug dose is large,
5. Absorption efficiency is vary with
different sites of skin,
6. Some patients may develop severe skin
allergic reactions to transdermal
patches.

SKIN
• Skin is the part of Integrated system i.e. it helps to maintain
body temp and protect it from surrounding environment.
• It covers an area of about 2m2 and 4.5-5 kg i.e. about 16% of
total body weight in adults.
• Thickness is in range of 0.5mm (on eyelids ) to 4.0mm ( on
heels ).

TAXONOMICAL CLASSIFICATION OF
SKIN
Three scales-
1. Micro scale- can only be seen under the microscope and
cannot be differentiated or identified with human eye.
2. Meso scale- comprises of skin features, hair, freckles, moles,
pores, skin surface and wrinkles as they can be seen with the
normal eye.
3. Macro scale- comprises of body regions and body parts.

HISTOLOGICAL CLASSIFICATION OF
SKIN
Skin has mainly 3 layers…
1)Epidermis
• Stratum basal (basal cell layer)-
• Stratum spinosum (prickle cell layer)
• Stratum granulosum (granular cell
layer)
• Stratum lucidum (clear layer)
• Stratum corneum (horny layer)
2)Dermis
• Papillary layer
• Reticular layer
3)Subcutaneous layer

EPIDERMIS
• The main cell of the epidermis is the keratinocytes which make up
95% of the total cells present in the epidermis.
1. Stratum basal (basal cell layer)- It is the deepest sublayer of the
epidermis and is composed of a single layer cubical or columnar
keratinocytes of basal cells.
• It forms boundary to the dermis & It holds approximately 8% of the
water.
• With aging, stratum basal becomes thinner and loses the ability to
retain water.
2. Stratum spinosum (prickle cell layer)- It refers to 10 to 20 layers
that lie on top of the basal cell layer.
• The thickness of this sublayer is from 50 to 150 μm.

CONTI….
3. Stratum granulosum (granular cell layer)- It is composed of 2 to 4
granular cell layers with 3 μm thick and cell become flatter shaped.
• Cells become increasingly filled with keratin fibers and contain less
moisture as compared to basal and prickle cell layers.
4. Stratum lucidum (clear layer)- It can only found in soles and palms. Its
cells become flatter and more densely packed during turn-over.
5. Stratum corneum (horny layer)- The outermost layer of the skin &10-
15 μm thick.
• It is made up of dead flattened corneocytes which is surrounded by an
extracellular matrix of lipid.
• It is an interface between the body and the outer environment.

DERMIS
• It is mainly made of fibrous tissues and1-2 mm thick. The
dermis has a rich supply of blood vessels from where the drug
gets absorbed.
• The skin surface of human is contain an average of 10-70 hair
follicles and 200-250 sweat glands on every centimeter square
of the skin area.
• The dermis has the following sublayers:
• Papillary layer
• Reticular layer

CONTI…
A. 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
B. 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 skin.

HYPODERMIS/ SUBCUTANEOUS LAYER
• is the third layer beneath the dermis & made up of loose
connective tissue, including Adipose tissue.
• It 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 region.

ROUTES OF SKIN PENETRATION
• The main route of transport for water-soluble molecules is transcellular. It
involves the passage through the cytoplasm of corneocytes and lipid
arrangement of the stratum corneum.
• The pathway of transport for lipid soluble molecules is intercellular; it
implicates the passage apparently through the endogenous lipid within the
stratum corneum.
• The transcellular and intercellular route is collectively known as trans-
epidermal route.

BASIC COMPONENTS OF TDDS
1. Polymer matrix / Drug reservoir
2. Drug
3. Permeation enhancers
4. Pressure sensitive adhesive (PSA)
5. Backing laminate
6. Liner

1. POLYMER MATRIX
Polymers are the backbone of transdermal drug delivery system. System for
transdermal delivery are fabricated as multi layered polymeric laminates in which a
drug reservoir or a drug polymer
matrix is sandwiched between two polymeric layers, an outer impervious backing layer
that
prevents the loss of drug through the backing surface and an inner polymeric layer that
functions
as an adhesive, or rate controlled membrane.
Ideal properties of a polymer to be used in a transdermal system -
Molecular weight, chemical functionality of the polymer should be such that the
specific drug diffuses properly and gets released through it.
Stable, non-reactive with the drug.
Non-toxic or non- antagonistic to the host.
Easily of manufactured and fabricated into the desired product.
Inexpensive.
Large amounts of the active agent are incorporated into it.

2. DRUG SUBSTANCES
For successfully developing a transdermal drug delivery system, the drug should be
chosen with
great care. The following are some of the desirable properties of a drug for
transdermal delivery.
Physicochemical properties:
1. The drug should have a molecular weight less than 1000 Daltons.
2. The drug should have affinity for both lipophilic and hydrophilic phasea. Extreme
partitioning characteristics are not conductive to successful drug delivery via the skin.
3. The drug should have low melting point.
4. Along with these properties the drug should be potent, having short half life and be
nonirritating.

IDEAL PARAMETERS OF DRUG FOR TDDS
Parameter Properties
• Dose Less than 20 mg/day
• Half life < 10 hrs
• Molecular weight <400 Dalton
• Melting point <200°C
• Partition coefficient 1 to 4
• Aqueous Solubility >1mg/mL
• pH of the aqueous saturated solution 5-9
• Skin Permeability Coefficient >0.5×10-3cm/h
• Skin Reaction Non irritating and non-
sensitizing
• Oral Bioavailability Low

3. PENETRATION ENHANCER
• These are compounds which promote the skin permeability by altering the skin as barrier
to the flux of a desired penetrate.
• Ideal properties of penetration enhancers:
• It should be pharmacologically inert.
• It is should be nontoxic, nonirritating, and nonallergenic to the skin.
• Rapid working
• Predictable and reproducible duration of action
• No pharmacological activity within the body
• Work unidirectionally
• Compatible with both excipients and drugs
• Cosmetically acceptable.

4. PERMEATION ENHANCERS:
These are compounds which promote skin permeability by altering the skin as a Barrier to the
flux of desired penetrants.
Enhancement of flux across membranes reduces to considerations them as follows -
1.Molecular size and shape.
2.Reducing the energy required to make a molecular hole in the membrane. 3.
Thermodynamics (lattice energies, distribution coefficients).
5. PRESSURE SENSITIVE ADHESIVE:
A Pressure Sensitive Adhesive (PSA) is a material that helps in maintaining an intimate contact
between transdermal system and the skin surface. It should adhere with not more than
applied finger pressure, be aggressively and permanentaly tachy, exert a strong holding force.
Additionally, it should be removable from the smooth surface without leaving a residue 7 e.g.:
polyacrylamates, polyacrylates, polyisobutylene, silicone based adhesive. The selection of an
adhesive is based on numerous factors, including the patch design and drug formulation. PSA
should be physicochemical and biologically compatible and should not alter drug release. The
PSA can be positioned on the face of the device or in the back of the device and extending
peripherally.

6. BACKING LAMINATES:
While designing a backing layer the consideration of chemical resistance and
excipients may compatible because the prolonged contact between the backing layer
and the excipients, drug or penetration enhancer through the layer. They should a
low moisture vapour transmission rate.
They must have optimal elasticity, flexibility and tensile strength. eg: aluminium
vapour coated layer, a plastic film and heat real layer.
7. RELEASE LINEAR:
During storage release linear prevents the loss of drug that has migrated into the
adhesive layer and contamination. However, as the linear is inintimate contact with
the delivery system, it should comply with specific requirements regarding chemical
inertness and permeation
to the drug, penetration enhancer and water.

FACTORS AFFECTING PERMEATION
The principle transport mechanism across mammalian skin is by passive diffusion through
primarily the trans-epidermal route at steady state or through trans-appendageal route at
initially, non-steady state.
The factors that affect the permeability of the skin are classified into following three
categories:
A. Physicochemical properties of the permeate molecule
i. Partition co-efficient:
Drug possessing both water and lipid solubility are favorably absorbed through the skin.
Transdermal permeability co-efficient shows a linear dependence on partition coefficient.
Varying the vehicle may also alter a lipid/water partition co-efficient of a drug molecule.
The
partition co-efficient of a drug molecule may be altered by chemical modification without
affecting the pharmacological activity of the drug.
ii. Molecular size:
There is an inverse relationship existed between transdermal flux and molecular weight of
the
molecule. The drug molecule selected as candidates for transdermal delivery tend to lie
within
narrow range of molecular weight (100-500 Dalton).

CONTI….
iii. Solubility / Melting point:
Lipophilicity is a desired property of transdermal candidates as lipophilic molecules tend
to
permeate through the skin faster than more hydrophilic molecules. Drugs with high
melting
points have relatively low aqueous solubility at normal temperature and pressure.
iv. PH condition:
The pH mainly affects the rates of absorption of acidic and basic drugs whereas
unchanged form
of drug has better penetrating capacity. Transport of ionizable species from aqueous
solutions
shows strong pH dependence. According to pH partition hypothesis, only the unionized
form of
the drugs can permeate through the lipid barrier in significant amounts.

CONTI…
B. Physicochemical properties of the drug delivery system
i. The affinity of the vehicle for the drug molecules:
It can influence the release of the drug molecule from the carrier. Solubility in the carrier
determines the release rate of the drug. The mechanism of drug release depends on
whether the drug is dissolved or suspended in the delivery/carrier system and on the
interfacial partition coefficient of the drug from the delivery system to skin tissue.
ii. Composition of drug delivery system:
Composition of drug delivery system may affect not only the rate of drug release but also
the permeability of the SC by means of hydration.
iii. Enhancement of transdermal permeation:
Due to the dead nature of the SC the release of the drug from the dosage form is less.
Penetration enhancers thus can cause the physicochemical or physiological changes in SC
and increase the penetration of the drug through the skin. Various chemical substances
are found to possess such drug penetration enhancing property.

CONTI…..
C. Physiological and pathological condition of the skin:
a. Skin age:
Fetal and infant skin appears to be more permeable than mature adult skin and therefore
percutaneous absorption of topical steroids occurs more rapidly in children than in
adults
whereas, water permeation has shown to be same in adults and in children.
b. Lipid film:
The thin lipid film on skin surface is formed by the excretion of sebaceous glands and
cell lipids
like sebum and epidermal cell which contain emulsifying agent may provide a protective
film to
prevent the removal of natural moisturizing factor from the skin and help in maintaining
the
barrier function of the SC.
c. Skin hydration:
Hydration of SC can enhance transdermal permeability. The rate of penetration study of
salicylic
acid through skin with dry and hydrated corneum showed that when the tissues were
hydrated,
the rate of penetration of the most water-soluble esters increased more than that of the

CONTI….
d. Skin temperature:
Raising skin temperature results in an increase in the rate of skin permeation. Rise in
skin temperature may also increase vasodilation of blood vessels, which are in contact
with skin leading to an increase in percutaneous absorption.
e. Cutaneous drug metabolism:
After crossing the SC barrier, some of the drug reaches the general circulation in active
form and some of this in inactive form or metabolic form, because of the presence of
metabolic enzymes present in the skin layers. It was reported that more than 95% of
testosterone absorbed was metabolized as it present through the skin.
f. Species differences:
Mammalian skin from different species display wide differences in anatomy in such
characteristics as the thickness of SC, number of sweat glands and hair follicles per
unit surface area.
g. Pathological injury to the skin:
Injuries to the skin can cause the disturbance in the continuity of SC and leads to
increase in skin permeability

FORMULATION APPROACHES
• This Method is
classified into the
following categories:
• Chemical enhancement
• Drug vehicle based
• Natural
• Physical enhancement
• Bioconvertable prodrug

CHEMICAL PERMEATION ENHANCERS
• 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 coenhancer or
solvent into the stratum corneum.
• Examples: Sulfoxide- dimethyl sulfoxide, Surface active
agents- SLS, Amines & amides- urea Fatty acids etc

DRUG VEHICLE BASED
• Mechanism of action : Interaction of enhancers with stratum
corneum and development of SAR for enhances with optimal
characteristics and minimal toxicity.
• Examples Ion pairs and complex, Coacervates, chemical
potential adjustment.

NATURAL
Mechanism of action : It may increase one or more of following effects:
1. Partition coefficient
2. Diffusion coefficient
3. Lipid Extraction
4. Drug Solubility
5. Macroscopic Barrier Perturbation
6. Molecular Orientation of Terpenes Molecule with Lipid Bilayer
Examples: 1. Terpenes- Menthol, Linalool, Limonene, Carvacrol
2. Essential oil- Basil oil, Neem oil, Eucalyptus oil

PHYSICAL
1. Iontophoresis • Iontophoresis is defined as “the application of a small electric current
(0.5 mA/cm2 or less) with a low voltage, to drive ionic and polar molecules across the
skin and into the tissues”.
• It involves passing of current (few milliamperes) to skin limited to a certain area using the
electrode remains in contact with the formulation which is to be administered.
• Used to deliver molecules such as neutral and charged molecules, low and high molecular
weight drugs namely phenobarbital, ranitidine and zidovudine .
• Pilocarpine delivery can be taken as example to induce sweat in the diagnosis of cystic
fibrosis and Iontophoretic delivery of lidocaine is considered to be a nice approach for
rapid onset of anesthesia .
2. Microneedle Array - MN arrays are composed of multiple micron- sized projections which
are typically assembled on one side of a supporting base or patch.
• Length- 25μm to 2000μm, Therefore they can create little holes in the stratum corneum
without pain and become the effective way to enhance the delivery of therapeutic
molecules and macromolecules

CONTI…
3. Sonophoresis Synonyms - It involves the use of ultrasonic energy to
enhance skin penetration of active substances.
• Frequency range -20 KHz to 100 KHz
• e.g. Drugs given are tetracycline, biomycin and penicillin for skin diseases
4. Magnetophoresis- Acts as an external driving force to enhance drug
delivery across the skin.
• Mechanism of action : Drug delivery across the membrane by the application
of magnetic field
• e.g. Magnatoliposomes consisting of magnetic particles wrapped in
phospholipid bilayer which are applied for drug delivery, Magnetic
resonance imaging markers for cancer diagnosis .

CONTI…
5. Electroporation- It involves the application of short, high
voltage pulses to skin.
• Skin electroporation, also called electro-permeabilization,
creates transient aqueous pores in the lipid by application of
high voltage of electrical pulses of approximately 100–1000
V/Cm for short time (milliseconds).
6. Thermophoresis- Thermal energy when applied to skin, cause
increased skin permeability.
• Heating during topical application of a drug dilates penetration
pathway in the skin and increase kinetic energy and movement of
particles in the treated area which facilitates drug absorption .

CONTI…..
7. Ultrasound
In this technique, there is a mixing of drug substance with a coupling agent (usually
with gel,
cream or ointment) that causes ultrasonic energy transfer from the system to the skin.
This
involves rupturing the lipids present in stratum cornea, which allows the medicament
to permeate
via biological barrier.
8. Photomechanical Waves
Photomechanical waves significantly led to the stratum cornea highly permeable to
drug
substance through a possible permeabilisation mechanism due to development of
transient
channels.
9. Electroporation
It this method, short and high-voltage electrical pulses are applied to the skin thus the
diffusion
of drug is improved with the increasing permeability. The electrical pulses are
considered to form

CONTI….
10. Radiofrequency- It involves
exposure of the skin to a high
frequency alternating current of
100 KHz that result in the
formation of heat-induced micro
channels in the cell membrane.
• Rate of drug delivery is
controlled by number and
depth of microchannels.
• e.g. Skin delivery of
testosterone and growth

CONTI….
11. Electro-Osmosis- To the porous membrane which is having some charge, a voltage
difference is applied to it, thus a bulk fluid or volume flow takes place with no
concentration gradients. This process is known as
electro-osmosis.
12. Powder Ject Device- The solid drug particles are propelled across the skin with the
aid of high-speed gas flow. This consists of a gas canister that allows helium gas at
high pressure to enter a chamber at the end of which drug cassette containing
powdered drug between two polycarbonate membranes. After release, the
instantaneous rupturation of both membranes usually seen that results in the gas to
expand quickly which forms a strong motion like a wave that travels down the nozzle.
This takes place at the speed of 600-900 m/s.
13. Other Enhancement Techniques- Transfersomes This device penetrates the skin
barrier along the skin moisture gradient. Transfersome carriers can create a drug depot
in the systemic circulation that is having a high concentration of drug. Transfersomes
contain a component that destabilizes the lipid bilayers and thus leading to the
deformable vesicles.

CONTI….
14. Medicated Tattoos
Medical Tattoos is a modification of temporary tattoo which contains an active drug
substance
for transdermal delivery. This technique is useful in the administration of drug in those
children
who are not able to take traditional dosage forms.
15. Skin Abrasion
This involves direct removal or disruption of the upper layers of the skin to provide
better
permeation of topically applied drug substance. In general, one approach is adopted to
create
micro channels in the skin by eroding the impermeable outer layers with sharp
microscopic metal
granules are generally known as Microscissuining.

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