Transdermal Drug Delivery System

Transdermal Drug Delivery System

Intended
Learning Objectives

At the end of this
lecture student will be able to:

•   Explain factors
that affect transdermal permeation

•   Discuss components
of a transdermal delivery system

•   Identify the
components of a transdermal patch

•   Discuss the
importance of the various components

•   Suggest suitable
materials for the various components

•   Enlist the
approaches for fabrication of TDDS

•   Describe the
design of patch in each approach

•   Suggest a suitable
design for a drug with given physicochemical properties

•   Explain the need
for permeation enhancement methods for transdermal drug delivery

•   Discuss methods
employed to improve transdermal permeation of drugs

Transdermal
drug delivery system

History

• The first use of transdermal can be found in ancient
China, where medicated plasters were slathered on the skin and left to dry

• The method was devised to allow a medication to have
direct and constant contact with the skin.

• The first patch certified and accepted by the United States
Food and Drug Administration was for a motion sickness patch. It was approved
in 1979.

• Nicotine patches rose the profile of transdermal patches
in the 1990s when it was approved for patient use.

• Since then, patches have been designed for many
medications, including those used to treatment of Alzheimer’s           disease, Parkinsons, and those to
administer birth control.

Definition

• Self-contained discrete dosage forms which when applied to
the intact skin, deliver the drugs through the skin at a controlled rate to the
systemic circulation

Or

• Systems that utilize skin as a site for continuous drug
administration into the systemic circulation

Comparison
of drug travel- oral v/s transdermal

Transdermal
patch – more than a surgical tape

Drug in a transdermal patch

Permeates through the skin

Drug in blood stream

Advantages

• The system avoids the chemically hostile GI environment

• No GI distress or other physiological contraindications of
the oral route

• Can provide adequate absorption of certain drugs

• Increased patient compliance

• Avoids first-pass effect

• Allows effective use of drugs with short biological
half-life

• Allow administration of drugs with narrow therapeutic
windows

• Provides controlled plasma levels of very potent drugs

• Drug input can be promptly interrupted when toxicity
occurs

• Self-medication possible

Disadvantages
of TDDS

• Varying barrier function of the skin: site to site; person
to person; with age…

• Not suitable for drugs requiring high plasma levels

• Adhesive failure

• Skin irritation and sensitization

• May be uncomfortable

• May not be economical

Anatomy of
Human Skin

Skin

1.       Epidermis

Ø 
Stratum corneum

Ø 
Stratum granulosum

Ø 
Stratum spinosum

Ø 
Stratum lucidum

Ø 
Stratum germinativum

2.       Dermis

3.       Subcutaneous tissue

Epidermis

• Outer layer of the skin

• Stratified squamous epithelial cells

• Primary barrier to percutaneous absorption

• Removal of this layers results in increased permeability

• Water content of stratum corneum is around 20%

• The moisture required for stratum corneum is around 10%
(w/w) to maintain flexibility and softness

Dermis

• Network of collagen and elastic fibres

• Embedded in mucopolysaccharide matrix

• This network or the gel structure is responsible for the elastic
properties of the skin

• Upper portion of the dermis is formed into ridges
containing lymphatics and nerve endings

Hypodermis

• Innermost and thickest layer of the skin

• Sheet of the fat containing areolar tissue

• Known as the superficial fascia

• Acts as energy reserve

• Attaches the dermis to the underlying structures

Transdermal
permeation routes

1. Transepidermal

Ø 
Transcellular /Intracellular

Ø 
Paracellular /Intercellular

2. Transfollicular

Transdermal
drug permeation

Transepidermal
absorption

• Stratum corneum is the main resistance for absorption through
this route.

• Permeation involves partitioning of the drug into the
stratum corneum.

• Permeation through the skin depends upon the o/w distribution
tendencies of the drug.

• Lipophilic drug concentrate in and diffuse with relative
ease.

• Permeation through the dermis is through the interlocking channels
of the ground substance

Transcellular route

•   Direct route -Path
of shortest distance

• Drugs cross the skin by directly passing through both the
phospholipids membranes and the cytoplasm of the dead keratinocytes that
constitute the stratum corneum

• Drugs must cross the lipophilic membrane of each cell,
then the hydrophilic cellular contents containing keratin, and then the
phospholipid bilayer of the cell one more time

• Series  of  steps 
is  repeated  numerous 
times  to  traverse 
the  full thickness of the stratum
corneum

Paracellular /
intercellular route

• Pass through the small spaces between the cells of the
skin

• More tortuous

• Thickness of the stratum corneum is only about 20 µm, the
actual diffusional path of most molecules crossing the skin is on the order of
400 µm

• The 20-fold increase in the actual path of permeating molecules
greatly reduces the rate of drug penetration

Transfollicular
absorption

• The skin appendages (sebaceous and eccrine glands) are considered
as shunts for by passing the stratum corneum.

• Follicular route is important for permeation because the
opening of the follicular pore is relatively large and sebum aids in the
diffusion of the penetrant.

• Partitioning into the sebum followed by the diffusion to
the depths of the epidermis is the mechanism

Transdermal
drug permeation

Clearance by local circulation

The earliest point of entry of drugs into the systemic
circulation is within the papillary plexus in the upper epidermis

Factors
Affecting Transdermal Permeation

Biological factors

Age

Blood flow

Site of patch application / stratum corneum thickness

Skin metabolism

Presence of hair follicles

Injury or trauma to the skin

Hydration of the skin

Effect of humidity and temperature

Chronic use of certain drugs

Skin hydration

Physicochemical factors

Diffusion coefficient

Drug concentration

Partition coefficient

Molecular size and shape

Skin age

➢ the young skin is more
permeable than older

➢ Children are more sensitive
for skin absorption of toxins

➢ Advancing age causes epidermis
to atrophy

➢ Dermoepidermal junctions
flatten – dermis thins

➢ Irritant and allergic
interaction reactions are weaker in older individuals

Blood flow

➢ Changes in peripheral
circulation can affect transdermal absorption

➢ Blood flow limits the
absorption of the drug from the dermis

➢ Vasoconstrictor drug administered
through other routes can significantly affect blood flow to the dermis hence
dermal clearance of the drug into the general circulation

Site of application

➢ Thickness of skin, nature of
stratum corneum and density of appendages vary site to site

➢ Variations in stratum corneum
thickness, the number of sebaceous glands, and hydration status can all affect
absorption

➢ Regional permeability: nail
< < palm/sole < trunk/extremities < face/scalp < < scrotum

Skin metabolism

• Skin metabolizes steroids, hormones, chemical carcinogens
and some drugs

• Skin metabolism determines efficacy of drug permeated
through the skin

• If the penetrating drug is subject to biotransformation
during skin permeation local and systemic bioavailability can be affected
drastically

Hair follicles

• Hair follicles and sweat glands could provide shunt routes
for drugs and chemicals through the stratum corneum

• Hair follicles are considerable weak spots in our
protective sheath against certain hydrophilic drugs and may allow a fast
delivery of topically applied substances

• Surface area of the follicular epithelium can be seen as a
considerable enlargement of the skin surface

• Hair follicles can act as a relevant reservoir for
topically applied substances and that nanoparticles and liposomes at a size of
300–750 nm preferentially penetrate into the hair follicles

Injury or trauma to
the skin

• Changes in the integrity of skin affects transepidermal
water loss (TEWL)

• Increased percutaneous absorption is characteristic in
patients with inflamed eczematous skin

Hydration of the skin

• In contact with water the permeability of skin increases
significantly

• Permeability of the stratum corneum is substantially
higher in hydrated state

• Skin occlusion with wraps or impermeable plastic films
prevents the loss of surface water from the skin and this causes increased
level of hydration in the stratum corneum thereby decreasing the protein
network density and the diffusional path length

• Occlusion of the skin surface also increases skin
temperature by 2-3oC resulting in increased molecular motion and skin
penetration

Chronic use of
certain drugs

• Long term use of keratolytics like salicylic acid results
in increased drug penetration

Humidity and
temperature

• The permeation of drug increase ten folds with temperature
variation

• The diffusion coefficient decreases as temperature falls

• Heat increases skin permeability

• Increased body fluid circulation

• Increased blood vessel wall permeability, rate-limiting
membrane permeability, and drug solubility

Skin hydration

• In contact with water the permeability of skin increases
significantly.

• Hydration is most important factor increasing the
permeation of skin.

• So use of humectant is done in transdermal delivery.

Temperature and pH

• The permeation of drug increase ten folds with temperature
variation

• The diffusion coefficient decreases as temperature falls

• Weak acids and weak bases dissociate depending on the pH
and pKa or pKb values.

• The proportion of unionized drug determines the drug concentration
in skin

Diffusion coefficient

• Penetration of drug depends on diffusion coefficient of
drug.

• At a constant temperature, the diffusion coefficient of
drug depends on properties of drug, diffusion medium and interaction between
them.

Drug concentration

• The flux is proportional to the concentration gradient
across the barrier

• Concentration gradient will be higher if the concentration
of drug will be more across the barrier

Partition coefficient

• The optimal partition coefficient (K) is required for good
action

• Drugs with high K are not ready to leave the lipid portion
of skin

• Drugs with low K will not be permeated

Molecular size and
shape

• Drug absorption is inversely related to molecular weight

• Small molecules penetrate faster than large ones

Kinetics of
Transepidermal Permeation

• The release of a therapeutic agent from a TDDS applied to
the skin surface and its transport to the systemic circulation involves the following
steps:

– Dissolution within
and release from the formulation

– Partitioning
into the outermost layer of the skin, SC

– Diffusion through
the SC

– Partitioning
from the SC into the aqueous viable epidermis

– Diffusion
through the viable epidermis and into the upper dermis

– Uptake into the
local capillary network and eventually the systemic circulation

A Multilayer Skin
Model Showing Sequence of Transdermal Permeation of Drug for Systemic Delivery

•   Trandermal
permeation can be possible if the drug possesses certain physico-chemical
properties. The rate of permeation across the skin (dQ / dt) is given by:

dQ/dt=Ps(Cd-Cr)   ————–
Eq. 1

Where, Cd = concentration of skin penetrant in the donar
compartment (e.g., on the surface of stratum corneum)

Cr = concentration in the receptor compartment (e.g., body)
respectively

Ps = the overall permeability constant of the skin tissue to
the penetrant

Ps=KsDss/hs———–Eq. 2

• Ks is the
partition coefficient for the interfacial partitioning of the penetrant
molecule from a solution medium or a transdermal therapeutic system onto the
stratum corneum

• Dss is the
apparent diffusivity for the steady state diffusion of the penetrant molecule
through a thickness of skin tissues

• hs is the
overall thickness of skin tissues

Components
of a TDDS

The components of the transdermal drug delivery system
include –

•   The drug

•    Polymer matrix or
matrices

•   The permeation
enhancers

•   Drug reservoir components

•   Backing laminate

•   Rate controlling
membrane

•   Adhesive

•   Release liner

Desirable
properties of drugs in TDDS

Physicochemical
properties

• Solubility

• Melting point

• Molecular weight

• pH

• Hydrogen bonding

Biological properties

• Potent

• Half life

• Irritancy

• Stability

• Tolerance

• Binding

• Metabolism

Physicochemical
properties of the drug

• Should have some degree of solubility in both oil and
water (ideally greater than 1 mg/ml)

• Should have melting point less than 200°F

• Molecular weight of less than 1000 Daltons

• A saturated aqueous solution of the drug should have a pH
value between 5 and 9

• Drugs highly acidic or alkaline in solution are not
suitable for TDD; because they get ionized rapidly at physiological pH

• Hydrogen bonding groups should be less than 2

Biological properties
of the drug

• Drug should be very potent, i.e., it should be effective
in few mgs per day (ideally less than 25 mg/day)

• Should have short biological half life

• Should be nonirritant and non-allergic to human skin

• Should be stable when in contact with the skin

• Should not stimulate an immune reaction to the skin

• Tolerance to drug must not develop under near zero order
release profile of transdermal delivery

• Should not get irreversibly bound in the subcutaneous
tissue

• Should not get extensively metabolized in the skin

Polymer

• Integral and foremost important component of transdermal
drug delivery systems

• Mechanism of drug release depends upon the physicochemical
properties of the drug and polymer used in the manufacture of the device

• Molecular weight, glass transition temperature, chemical
functionality of polymer must allow diffusion and release of the specific drug

• The polymer should permit the incorporation of a large
amount of drug

• The polymer should not react, physically or chemically
with the drug

• The polymer should be easily manufactured and fabricated
into the desired product and inexpensive

• The polymer must be stable and must not decompose in the
presence of drug and other excipients used in the formulation, at high humidity
conditions, or at body temperature

• Polymers and its degradation products must be non-toxic

• No single material may have all these attributes; e.g.,
cosolvents such as ethanol, propylene glycol, PEG 400 could be added to
increase drug solubility

Polymers in TDDS

Techniques employed
to modify the polymer properties and thus drug release rates

• Cross linked
polymers: The higher the degree of cross linking, the denser the polymer
and slower the diffusion of drug molecules through the matrix.

• Polymer blends:
Polymers have been blended on varying ratios to combine the advantages of the
individual polymers.

• Plasticizers:
Plasticizers have been known to reduce the stiffness of the polymer backbone,
thereby increasing the    diffusion
characteristics of the drug.

Penetration enhancers

• Compounds, which promote skin permeability by altering
stratum corneum the as a barrier to the flux of a desired

• Resistance of skin to diffusion of drugs has to be reduced
in order to allow drug molecules to cross skin and to maintain therapeutic
levels in blood.

• They can modify the skin’s barrier to penetration either
by interacting with the formulation that applied or with the skin itself.

• Pharmacologically inert, nontoxic, non-allergenic, non-irritating
and ability to act specifically, reversibly and for   predictable duration

• Should not cause loss of body fluids, electrolytes or
other endogeneous materials

Ex: Terpenes,
Terpenoids, Pyrrolidones

Solvents like alcohol, Ethanol, Methanol

Surfactants like Sodium Lauryl sulfate, Pluronic F127,
Pluronic F68

Drug reservoir
components

• It must be compatible with the drug

• Must allow for drug transport at the desired rate

• Drug reservoir must possess the desired viscosity
attributes to ensure reliable manufacturing process

• Must possess the desired adhesive and cohesive properties
to hold the system together

Backing laminates

• Primary function is to provide support

• Should be able to prevent drug from leaving the dosage
form through top

• Must be impermeable to drugs and permeation enhancers

• Should allow moisture vapour transmission rate

• Must have optimal elasticity, flexibility, and tensile
strength

•   Must be chemically
compatible with the drug, enhancer, adhesive and other excipients

•   Must be relatively
inexpensive and must allow printing and adhesive lamination

•   Composed of

– Pigmented layers

– An aluminium vapor coated layer

– A plastic film (polyethylene, polyvinyl chloride,
polyester)

– A heat seal layer

Rate controlling
membrane

• Rate controlling membranes in transdermal devices govern
drug release from the dosage form

Adhesive layer

• For fastening of transdermal devices to the skin

• A pressure sensitive adhesive

• Positioned on the face or in the back of device

• Should not cause irritation, sensitization or imbalance in
the normal skin flora during its contact with the skin.

Classes of polymers evaluated for potential adhesive
applications in

TDDS include:

➢ Polyisobutylene type pressure
sensitive adhesives

➢ Acrylic type pressure
sensitive adhesives

➢ Silicone type pressure
sensitive adhesives

Release liners

• The release liner has to be removed before the application
of transdermal system

• Prevents the loss of the drug that has migrated into the
adhesive layer during storage

• Helps to prevent contamination

• Composed of

– A base layer, which may be nonocclusive or occlusive

– Release coating layer made of silicon or Teflon.

• Other materials include polyesters, foil, Mylar and
metallized laminate

Approaches
to Transdermal Therapeutic Systems

• Membrane permeation controlled systems

• Adhesive dispersion controlled systems

• Matrix dispersion type systems

• Microreservoir system

Membrane permeation
controlled systems

• The drug reservoir is totally encapsulated in a shallow
compartment moulded from

– A drug – impermeable metallic plastic laminate

– Rate controlling polymeric membrane which may be
microporous or non-porous.

– Drug can be in the form of solution, suspension, gel or
dispersion in polymer matrix in the reservoir compartment

• The rate of drug release from this type of TDDS can be
tailored by varying the composition of polymer, permeability coefficient,
thickness of the rate limiting membrane & adhesive.

• On the outer surface of polymeric membrane, a thin layer
of adhesive polymer is applied

Membrane permeation controlled systems…

Adhesive
Dispersion Type TDDS

• In this type, the drug reservoir is prepared by directly
dispersing the drug in an adhesive polymer

• Then this medicated adhesive polymer is spread over a flat
sheet of drug impermeable backing membrane

• The drug reservoir layer is then covered by a
non-medicated rate controlling polymer of constant thickness to produce an
adhesive diffusion controlling DDS

Example: Isosorbide dinitrate-releasing Transdermal
therapeutic system (Frandol tape) for once a day medication of angina pectoris.

Matrix dispersion
type TDDS

Preparation of a drug polymer blend

Then pasted on to an occlusive base plate in a compartment
fabricated from a drug impermeable plastic backing

Adhesive polymer is then spread along the circumference to
form a strip of adhesive rim around the medicated disc

Matrix dispersion type TDDS

Microreservoir
type TDDS

• A combination of reservoir and matrix diffusion type drug
delivery system.

• A drug reservoir is formed by first suspending the solid
drug in an aqueous solution of water soluble polymer. This drug suspension is
homogenously dispersed in a lipophilic polymer by high energy dispersion
technique.

• This forms the microscopic spores of drug reservoir which
are supported over an occlusive pad and are thermodynamically unstable

• Stabilization by cross linking the polymer chain in-situ
using cross linking agent

• It can be further coated with a layer of biocompatible
polymer to improve the drug release

Permeation
Enhancement Methods

Physical Enhancement Techniques

1. Stature Based

Microneedles

2. Electrically Based

Iontophoresis

Electroporation

Ultrasound

Photomechanical wave

3. Velocity Based

Jet Propulsion

Microneedles
– Microporation

Basic design of microneedle delivery system devices. Needles
with or without hollow centre channels are placed onto the skin surface so that
they penetrate the SC and epidermis without reaching the nerve endings present
in the upper epidermis.

• Involves the use of micro needles that are applied to the
skin

• They pierce only the SC and increase skin permeability

• Uses needles that are 10 to 200 μm in height and 10 to 50
μm in width

• Micro needles do not stimulate the nerves, so the patient
does not experience pain or discomfort

• They are usually drug coated projections of solid silicon
or hollow, drug filled metal needles

Improving
Transdermal Permeation

Iontophoresis

• Process of enhancing the permeation of topically applied therapeutic
agents through the skin by the application of electric current

• Drug is applied under an electrode of the same charge as
the drug

• An indifferent counter electrode is positioned elsewhere
on the body

• Active electrode effectively repels the active substance
and forces it into the skin

Sonophoresis

• Involves the use of ultrasonic energy to enhance skin penetration
of active substances

• Low frequency regimes (20 KHz < f <100 KHz)

• Mechanism of transdermal skin permeation involves the disruption
of the SC lipids by the formation of gaseous cavities, thus allowing the drug
to pass through the skin

• Several antibiotics have been delivered through this
technique

Electroporation

• Application of short (microsecond or millisecond), high
voltage (50-1000 volts) pulses to the skin

• Mechanism of penetration is the formation of transient
pores due to electric pulses

• Allow the passage of macromolecules from the outside of
the cell to the intracellular space via a combination of processes such as
diffusion and electrophoresis

• Macromolecules that have been delivered by electroporation
include: insulin,vaccines, oligonucleotides and microparticles

Magnetophoresis

• Application of a magnetic field which acts as an external
driving force to enhance the diffusion of a diamagnetic solute across the skin

• Exposure to magnetic field might induce structural
alterations in the skin

• Magnetophoresis can be combined with chemical permeation enhancers
for enhanced drug permeation

Jet propulsion

Needle free injectors

• Technique involves firing the liquid or solid particles at
supersonic speeds through the SC

• A pain-free method of administration of drugs to the skin

Mechanism involves

• Forcing compressed gas such as helium or nitrogen through
the nozzle with the resultant drug particles entrained within the jet flow,
reportedly traveling at sufficient velocity for skin penetration

Injection without needles – Dermal powder jet

Thermal ablation

• Thermal ablation selectively heats the skin surface to
generate micron-scale perforations in the stratum corneum.

• Transiently heating the skin’s surface to hundreds of
degrees for microseconds to milliseconds

• Localizes heat transfer to the skin surface without
allowing heat to propagate to the viable tissues below

• This spares these tissues from damage or pain

• Mechanistically, thermal ablation may involve rapidly
vaporizing water in the stratum corneum

• Resulting volumetric expansion ablates micron-scale
craters in the skin’s surface

• Skin heating has been achieved using ohmic microheaters
and radio-frequency ablation

Microdermabrasion

• A final way to remove the stratum corneum barrier employs abrasion
by microdermabrasion or simply using sandpaper.

• Microdermabrasion is a widely used method to alter and
remove skin tissue for cosmetic purposes

• Shown to increase skin permeability to drugs, including
lidocaine and 5-fluorouracil

• Vaccine delivery across the skin has also been facilitated
by skin abrasion using sandpaper

Commercially
Available Transdermal Patches

• Nicotine patch

Nicotine patch helps to give up smoking by relieving the
desire to smoke, and some of the unpleasant effects which smokers experience when
they stop smoking

• Transdermal scopolamine patches

• Hormone patch

• Clonidine patches for hypertension

• Testosterone patches

• Fentanyl patches

• Nitroglycerine patches

Summary

• Self-contained
discrete dosage forms which when applied to the intact skin, deliver the drugs
through the skin at a controlled rate to the systemic circulation

Transdermal patch –
more than a surgical tape

Drug in blood

Permeates Stream through the skin

Drug in a transdermal patch

Anatomy of Human Skin

1. Epidermis

·        
Stratum corneum

·        
Stratum granulosum

·        
Stratum spinosum

·        
Stratum lucidum

·        
Stratum germinativum

2. Dermis

3. Subcutaneous tissue

Transdermal
permeation routes

1. Transepidermal

·        
Transcellular /Intracellular

·        
Paracellular /Intercellular

2. Transfollicular

Factors Affecting
Transdermal Permeation

Biological factors

Age

Blood flow

Site of patch application / stratum corneum thickness

Skin metabolism

Presence of hair follicles

Injury or trauma to the skin

Hydration of the skin

Effect of humidity and temperature

Chronic use of certain drugs

Skin hydration

Physicochemical
factors

Diffusion coefficient

Drug concentration

Partition coefficient

Molecular size and shape

Kinetics of
Transepidermal Permeation…

•   Trandermal
permeation can be possible if the drug possesses certain physico-chemical
properties. The rate of permeation across the skin (dQ / dt) is given by:

dQ/dt=Ps(Cd-Cr)   ————–
Eq. 1

Ps=KsDss/hs———–Eq. 2

• Components –
drug, polymer, adhesive, release liner, backing mambrane

• Polymer – drug
matrix/ rate controlling membrane, backing membrane

• Permeation
enhancers in the formulation – to increase the drug flux across the skin

Approaches

• Membrane permeation controlled systems

• Adhesive dispersion controlled systems

• Matrix dispersion type systems

• Microreservoir system

Physical Enhancement
Techniques

1. Stature Based

Microneedles

2. Electrically Based

Iontophoresis

Electroporation

Ultrasound

Photomechanical wave

3. Velocity Based

Jet Propulsion

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