To p i c a l &

TRANSDERMAL DRUG
D E L I V E RY S Y S T E M S

Ahla sheraz
• Transdermal system
• Percutaneous Absorption
• Ointments
• Creams
• Pastes
• Poultice
• Plasters
• Lotions
• Liniments
• Collodions
• Topical gels
• Topical Tinctures
• Topical solutions
• Topical Powders
 TRANSDERMAL DRUG DELIVERY
SYSTEMS
• A transdermal product is designed to deliver drugs through
the skin (percutaneous absorption) to the general
circulation for systemic effects, with the skin not being the
target organ.
• TDD system allow delivery of a drug into the systemic
circulation at a controlled rate.
• In 1965, Stoughton first conceived of the percutaneous
absorption of drug substances. The first transdermal
system, Transderm Scop ( Baxter), was approved by FDA
in 1979 for prevention of nausea and vomiting associated
with travel, particularly at sea.
• Transdermal drug delivery offers an attractive alternative
to the oral administration and injection.
• The skin poses an extremely good barrier to drug
penetration
• Drug delivery through the skin (for systemic effect ) is
commonly known as TDD and differs from traditional
topical drug delivery.
• Also known popularly as ‘patches’.Transdermal patches:
are dosage forms designed to deliver a therapeutically
effective amount of drug from the outside of the skin
through its layers.
• Innovative research exploiting penetration- enhancing
strategies such as iontophoresis, electroporation,
microneedles and sonophoresis, holds promise for the
successful use of these drugs
Types of TDDS
Examples
• Nitro glycerin releasing TDDS for once a day
medication in angina pectoris
• Scopolamine releasing TDDS for 72hrs
propylaxis of motion sickness
• Estradiol releasing TDDS for treatment
menopausal syndrome
• Clonidine releasing TDDS for 7 day therapy of
hypertension.
• Prostaglandin derivatives of TDDS
ADVANTAGES
• They can avoid gastrointestinal drug absorption
difficulties caused by gastrointestinal pH, enzymatic
activity, and drug interactions with food, drink, and other
orally administered drugs.
• They can substitute for oral administration of medication
when that route is unsuitable, as with vomiting and
diarrhea.
• They avoid the first-pass effect, i.e., the initial pass of a
drug substance through the systemic and portal
circulation following gastrointestinal absorption, possibly
avoiding the deactivation by digestive and liver
enzymes.
• They are noninvasive, avoiding the inconvenience of
parenteral therapy.
• They provide extended therapy with a single
application, improving compliance over other dosage
forms requiring more frequent dose administration.
• The activity of drugs having a short half-life is
extended through the reservoir of drug in the
therapeutic delivery system and its controlled release.
• Drug therapy may be terminated rapidly by removal
of the application from the surface of the skin.
• They are easily and rapidly identified in emergencies
(e.g., unresponsive, unconscious, or comatose
patient) because of their physical presence, features,
and identifying markings.
DISADVANTAGES
• Only relatively potent drugs are potential candidates
for transdermal delivery because of the natural limits
of drug entry imposed by the skin’s impermeability.
• Some patients develop contact dermatitis at the site of
application from one or more of the system
components, necessitating discontinuation.
• Ointments, creams, and gels are semisolid dosage
forms intended for topical application. They may be
applied to the skin, placed on the surface of the eye,
or used nasally, vaginally, or rectally.

• Most of these preparations are used for the effects

of the therapeutic agents they contain. The
unmedicated ones are used for their physical effects
as protectants or lubricants.
 Percutaneous absorption
• Percutaneous absorption is defined as “penetration of
substances into various layers of skin and permeation
across the skin in to systemic circulation”.

• The percutaneous absorption is a step wise process and

can be divided in to three steps.
• Penetration: is the entry of substance in to a particular
layer.
• Permeation: is the penetration from one layer into
another and is different both functionally and structurally
from the first layer.
• Absorption: is the uptake of a substance into systemic
circulation.
 FACTORS AFFECTING PERCUTANEOUS
ABSORPTION
• Drug concentration is an important factor. Generally, the
amount of drug percutaneously absorbed per unit of surface
area per time interval increases with an increase in the
concentration of the drug in the TDDS.
• The larger the area of application (the larger the TDDS), the
more drug is absorbed.
• Generally, the longer the medicated application is permitted
to remain in contact with the skin, the greater is the total
drug absorption.
• Drugs with molecular weights of 100 to 800 and adequate
lipid and aqueous solubility can permeate skin. The ideal
molecular weight of a drug for transdermal drug delivery is
believed to be 400 or less.
• Hydration of the skin generally favors percutaneous absorption.
The TDDS acts as an occlusive moisture barrier through which
sweat cannot pass, increasing skin hydration.
• Percutaneous absorption appears to be greater when the TDDS is
applied to a site with a thin horny layer than with a thick one.
• The drug should have a greater physicochemical attraction to the
skin than to the vehicle so that the drug will leave the vehicle in
favor of the skin.
• Some solubility of the drug in both lipid and water is thought to
be essential for effective percutaneous absorption. In essence,
the aqueous solubility of a drug determines the concentration
presented to the absorption site, and the partition coefficient
influences the rate of transport across the absorption site.
• Generally, drugs penetrate the skin better in their unionized
form. Nonpolar drugs tend to cross the cell barrier through the
lipid-rich regions (transcellular route), whereas the polar drugs
favor transport between cells (intercellular route). For
example, erythromycin base demonstrates better
percutaneous absorption than erythromycin ethyl succinate.

 These general statement apply to the skin in normal state.

Skin that is abraded or cut permits drugs to gain direct access
to the subcutaneous tissue and the capillary network defeating
the function of TDDS.
 Ideal properties of drugs used for TDDS
Dose Should be low (>20g/day)

Half life 10 or less

Molecular weight <400

Partition coefficient log P (octanol-water)

between 1-4

Skin permeability coefficient >0.5ˣ10-ᶟ cm/hr

Skin reaction Non irritating and non sensitizing

Oral bioavailability Low

Therapeutic index Low

Enhancer's
Various technologies have been developed to bypass or
modulate the barrier function of the skin and to allow easier
passage of drug into dermal microcirculation.
Can be categorized into
chemical and physical

Chemical included
 Penetration enhanser
 Prodrug approaches
Physical approaches
 Ionotophoresis
 Electroporation
 Microporation
 Heat
 Needless injections
 Medicated tattoos
 Sono phoresis
 Pressure valve
 Radiofrequency
 Magnetophoresis
 CHEMICAL ENHANCERS
By definition, a chemical skin penetration enhancer
increases skin permeability by reversibly damaging or
altering the physicochemical nature of the stratum
corneum to reduce its diffusional resistance .
Among the alterations are increased hydration of the
stratum corneum, a change in the structure of the
lipids and lipoproteins in the intercellular channels
through solvent action or denaturation, or both.
• Some drugs have an inherent capacity to permeate the skin
without chemical enhancers. However, when this is not the
case, chemical permeation enhancers may render an
otherwise impenetrable substance useful in transdermal drug
delivery.
• More than 275 chemical compounds have been cited in the
literature as skin penetration enhancers; they include acetone,
azone, dimethyl acetamide, dimethyl formamide, dimethyl
sulfoxide, ethanol, oleic acid, polyethylene glycol, propylene
glycol, sodium lauryl sulfate, Spans, Tweens, lecithin, terpenes,
glycerin and many others.
• The selection of a permeation enhancer should be based not
only on its efficacy in enhancing skin permeation but also on
its dermal toxicity (low) and its physicochemical and biologic
compatibility with the system’s other components .
Different classes of penetration enhancer includes:

 Alcohols and polyols (ethanol, propylene glycol).

 Surfactants (tween, span, SLS).

 Fatty acids (oleic acid).

 Amines and amides (azone, N- methyl pyrrolidone).

 Terpenes (limonene).

 Sulfoxides (dimethyl sulfoxide).

 Esters (isopropyl myristate).

5. Delamination of stratum corneum.
6. Enhancing solubility.
7. Increasing partitioning in to the stratum corneum.
8. Interaction with intercellular protein and keratin
denaturation.
2. Prodrug
• Prodrugs are therapeutically inactive derivatives of active drugs.

• A prodrug undergoes metabolism to produce the

therapeutically active drug.

• A prodrug is more lipophilic than the parent drug and has

different physicochemical properties.
• Different prodrugs were developed for estradiol and
transdermal bioactive hormone delivery devices were
developed based on the results. The release rate of
estradiol from transdermal bioactive hormone delivery is
dependent on the chain length of the ester group at the
17th position.

• Alkyl ester prodrugs of ketorolac having optimum

lipophilicity could improve the transdermal delivery of
ketorolac. Also the prodrug approach is a very feasible way
to increase the skin permeation of protein/ peptide drugs.
IONTOPHORESIS

• Iontophoresis is delivery of a charged chemical

compound across the skin membrane using an
electrical field.
• A number of drugs have been the subject of
iontophoretic studies; they include lidocaine;
dexamethasone; amino acids, peptides, and insulin;
verapamil; and propranolol.
• Iontophoresis is the process of enhancing the
permeation of topically applied therapeutic agents.
• The drug is applied under an electrode of the same
charge as the drug and an indifferent counter electrode
is positioned elsewhere on the body.
• The active electrode effectively repels the active substance
and forces it on the skin and rough the skin by the
application of electric current.
• Therapy can help managing pain, swelling and edema,
calcium deposit in the body, scar tissue, muscle spasm,
inflammation
 Mechanism
• First mechanism proposes that the drug is forced across the skin
by simple electronic repulsion of similar charges. Anionic drugs can
cross the skin by using negatively charged working electrodes.
Similarly cationic drugs can cross the skin when a positively
charged electrode is used.
• The second the electric current enhances the permeation by
inhibiting the skin’s ability to perform its protective barrier
function.
2. Electroporation
• Electroporation is another electrical enhancement method
which involves the application of short (microsecond or
millisecond), high voltage (50-1000volts) pulses to the
skin.
• Larger molecules have also been delivered by
electroporation, including insulin, vaccines,
oligonucleotides and microparticles.
• A few model compounds such as calcein and LHRH
drugs have also been studied for increased transdermal
absorption by electroporation.
• The mechanism of penetration is the formation of
transient pores due to electric pulses that subsequently
allow the passage of macromolecules from the outside of
the cell to the intracellular space via a combination of
processes.
 3.Sonophoresis
• Sonophoresis is a technique which involves the use of
ultrasonic energy to enhance skin penetration of active
substances.
• Transdermal enhancement is particularly significant at low
frequency regimes (20 KHz < f < 100 KHz) than when high
frequency ultrasound.
• Ultrasound parameters such as treatment duration, intensity,
pulse length and frequency are all known to affect percutaneous
absorption with frequency being the most important.
• Sonophoresis of hypotensive agents and papain has been used in
the treatment of eye disease.
• Several antibiotics including tetracycline, biomycin and penicillin
have been sonophoretically administered for the therapy of skin
disease.
 4.Microporation
• Microporation involves the use of
microneedles that are applied to
the skin so that they pierce only the
stratum corneum and increase
skin permeability.
• Microneedles are needles that are
10 to 200 µm in height and 10 to
50 µm in width.
• They are usually drug coated
projections of solid silicon or hollow
drug filled metal needles.
 5. Heat
• Heat enhances the skin permeation of drugs by increasing
body fluid circulation, blood vessel wall permeability, rate
limiting membrane permeability and drug solubility, thus
facilitating drug transfer to the systemic circulation.
• The effect of temperature on in vitro transdermal fentanyl flux was
estimated at temperature of 32 and 37 ºC. drug flux approximately
doubled over this 5 range.
• Heat may also cause changes in physicochemical properties of
patches, sweating and increased hydration of skin thus
increasing the permeation of drugs.
• When heat is applied the kinetic energy of drug molecules,
proteins, lipids and carbohydrates is known to increase in the cell
membrane.
• Also drug solubility both in the patch and within the skin may
increase with a rise in temperature.
6. Needle injection
• Needle injection involves a pain free method of
administration of drugs to the skin.
• This technique involves firing the liquid or solid particles at
supersonic speeds through the stratum corneum.
• Problem with this technique include the high developmental cost
for both the device and dosage form and the inability to program
or control drug delivery to compensate for intersubject
differences in skin permeability.
• The mechanism involves forcing compressed gas such as helium
or nitrogen through the nozzle with the resultant drug particles
entrained within the jet flow, reportedly travelling at sufficient
velocity for skin penetration
7.Medicated tattoos
• Medicated tattoos are a modification of temporary tattoos
which contain an active drug medicament for transdermal
delivery.
• They are very attractive and fun to wear and are applied by
wetting with water and pressing against the skin.
• The tattoos contains a drug layer, a color design layer and
an adhesive layer that binds to the skin.
• There is no predetermined duration of therapy. The
manufacturer provides a color chart that can be
compared to the colors of the patient’s tattoos to
determine when tattoos should be removed.
• It gives a visual indication as the drug is absorbed in to the
skin. Upon absorption the tattoos gradually fades away and is
painless to remove with a simple astringent wash containing
isopropyl alcohol. The drugs used in medicated tattoos
prototype include acetaminophen, vitamin C etc.
 8.Pressure waves
• Pressure waves generated by intense laser radiation can
permeabilize the stratum corneum as well as the cell
membrane.
•Pressure wave is only applied for a very short time
(100ns- 1µs). It is thought that the pressure waves form a
continuous or hydrophilic pathway across the skin due to
expansion of lacunae domains in the stratum corneum
and allow the transport of macromolecules in to the
epidermis and dermis.
• In addition the drug delivered in to the epidermis can enter
the vasculature and produce a systemic effect.
• Insulin delivered by pressure waves resulted in reducing
blood glucose level over many hours.
• The application of pressure waves does not cause any pain or
discomfort and the barrier function of the stratum corneum
 9.Magnetophoresis
• The term “Magnetophoresis” was used to indicate
application of a magnetic field and acts as an external
driving force to enhance drug delivery across the skin.
• It induces alteration in the skin’s structure that could
contribute to an increase in permeability.
• Magnetoliposomes consist of magnetic nanoparticles wrapped by
a phospholipid bilayer which can be successfully applied for drug
delivery systems, magnetic resonance imaging for cancer
diagnosis and thermal cancer therapy.
 10.Radiofrequency
• Radiofrequency involves exposure of the skin to a high frequency
alternating current of 100 KHz that results in the formation of heat
induced microchannels in the cell membrane.
• The drug delivery rate is controlled by the number and depth of
microchannels formed which depends on the properties of the
microelectrodes in contact with the skin during treatment.
• Skin delivery of testosterone and human growth hormone are
in progress by use of this method.
DESIGN FEATURES
• TDDSs may be constructed of a number of layers,
including:
(a) An occlusive backing membrane to protect the system
from environmental entry and from loss of drug from the
system or moisture from the skin.
(b) A drug reservoir or matrix system to store and release
the drug at the skin site;
(c) A release liner, which is removed before application
and enables drug release; and
(d) An adhesive layer to maintain contact with the skin
after application.
• Two types of adhesive layers, the peripheral adhesive
and the face adhesive, can be used.
• The peripheral adhesive contains adhesive around the
outer edge of the TDDS, usually in a wide strip
surrounding the active drug portion.
• The face adhesive, which covers the entire face of the
TDDS, is very common.
• In some TDDSs, the adhesive layer contains the drug.
Polybutyl acrylate is commonly used as the adhesive in
TDDSs.
• The drug release membranes are commonly made of
polyethylene, with microporous structures of varying
pore sizes to fit the desired specifications of the
particular transdermal system.
• The backing layer must be occlusive to retain skin
moisture and hydrate the site of application, enabling
increased drug penetration.
• Preferred backing materials are approximately 2 to 3
mm thick and have a low moisture vapor transmission
rate, less than about 20 g/m2 in 24 hours.
• Transparent or pigmented films of polypropylene,
polyethylene, and polyolefin are in use in TDDSs as
backing liners.
 Polymer matrix
• Polymers are the backbone of TDDS, which control the
release of drug from the device.
• Polymer matrix can be prepared by dispersion of drug in
liquid or solid state synthetic polymer base.
• Polymers used in TDDS should have bio and chemical
compatibility with the drug and other components of the
system such as permeation enhancers and PSAs.
• Additionally they should provide consistent and effective
delivery of a drug throughout the product's intended shelf
life and should be safe status.
• Natural polymers:
e.g.cellulose derivatives, zein, gelatin, shellac, waxes, gums,
natural rubber and chitosan.

• Synthetic Elastomers:
e.g. polybutadiene, hydrin rubber, polyisobutylene, silicon
rubber, nitrile, acrylonitrile, neoprene and butyl rubber etc.

• Synthetic polymers:
e.g. polyvinyl alcohol, polyvinyl chloride, polyethylene,
polypropylene, polyacrylate, polyamide, polyurea,
polyvinylpyrrolidone and polymethylmethacrylate etc.
Drug
• The transdermal route is an extremely attractive option for
the drugs with appropriate pharmacology and physical
chemistry.
• Transdermal patches offer much to drugs which undergo
extensive first pass metabolism, drugs with narrow
therapeutic window or drugs with short half life which
causes non- compliance due to frequent dosing.
• The foremost requirement of TDDS is that the drug
possesses the right mix of physicochemical and biological
properties for transdermal drug delivery.
• It is generally accepted that the best drug candidates for
passive adhesive transdermal patches must be:
 Nonionic
 Of low molecular weight (less than 500 Daltons).
 Have adequate solubility in oil and water
(log P in the range of 1-3).

 A low melting point (less than 200 ºC).

 Potent (dose in mg per day).

 Permeation
Enhancers
• These are the chemical compounds that increase
permeability of stratum corneum so as to attain higher
therapeutic levels of the drug candidate.
• Penetration enhancers interact with structural components
of stratum corneum i.e. proteins or lipids
• They alter the protein and lipid packaging of stratum
corneum thus chemically modifying the barrier functions
leading to increased permeability.
• Over the last 20 years a tremendous amount of work has
been directed towards the search for specific
chemicals which can act as a penetration enhancers
 Pressure Sensitive Adhesives
• A 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 permanently tachy,
exert a strong holding force.
• Additionally it should be removeable from the smooth
surface without leaving a residue.
• Polyacrylates, polyisobutylene and silicon based adhesives
are widely used in TDDSs.
• The selection of an adhesive is based on numerous factors,
including the patch design and drug formulation.
• For matrix systems with a peripheral adhesive, an
incidental contact between the adhesive and the drug
and penetration enhancer should not cause instability of
the drug, penetration enhancer or the adhesive.
• In case of reservoir system that include a face adhesive
the diffusing drug must not affect the adhesive.
• In case of drug-in-adhesive matrix systems, the selection
will be based on the rate at which the drug and the
penetration enhancer will diffuse through the adhesive.
• Ideally, PSA should be physicochemically and biologically
compatible and should not alter drug release
Backing Laminate
• While designing a backing layer, the consideration of
chemical resistance of the material is most important.
• Excipients compatibility should also be considered
because of the prolonged contact between the backing
layer and the excipients may cause the additives to leach
out of the backing layer or may lead to diffusion of
excipients, drugs or penetration enhancer through the
layer.
• However an overemphasis on the chemical resistance
may lead to stiffness and high occlusivity to moisture
vapor and air, causing patches to lift and possibly irritate
the skin during long wear.
• The most comfortable backing will be the one that
exhibits lowest modulus or high flexibility, good oxygen
transmission and a high
•moisture vapor transmission rate.

•Examples:

 Vinyl.

 Polyethylene.

 Polyester films.
 Release Liner
• During storage the patch is covered by a protective liner that
is removed and discharged immediately before the
application of the patch to skin.
• It is therefore regarded as a part of the primary packaging
material rather than a part of dosage form for delivering the
drug
• However the liner is in intimate contact with the delivery
system it should comply with specific requirements regarding
chemical inertness and permeation to the drug, penetration
enhancer and water.
• Typically release liner is composed of a base layer which may be
non- occlusive (e.g. paper fabric) or occlusive (e.g. polyethylene,
polyvinylchloride) and a release coating layer made up of silicon or
Teflon.
• Other materials used for TDDS release liner include
polyester foil and metallized laminates.
• Other Excipients
• Various solvents such as chloroform, methanol, acetone,
isopropanol and dichloromethane are used to prepare drug
reservoir.
• In addition plasticizer such as dibutylpthalate, triethylcitrate,
polyethylene glycol and propylene glycol are added to
provide plasticity to the transdermal patch.
 Methods For Preparation Of TDDS
• Asymmetric TPX membrane method.

• Circular Teflon mould method.

• Mercury substrate method.

• By using IPM membrane method.

• By using EVAC membrane method.

• Aluminium backed adhesive film method.

 Asymmetric TPX membrane method
• A prototype patch can be fabricated for this a heat sealable
polyester film (type 1009,3m) with a concave of 1cm
diameter will be used as the backing membrane
Circular Teflon mould method.
• The solvent is allowed to evaporate for 24 hrs. the dried
films are to be stored for another 24 hrs at 25 0.5C in a
dessicators containing silica gel before evaluation to
eliminate aging effects.the type films are to be evaluated
within one week their
Mercury substrate method.
By using IPM membrane method.
By using EVAC membrane method.
Aluminium backed adhesive film
method
 Evaluation
1. Interaction studies.

2. Thickness of the patch.

3. Weight uniformity.

4. Folding endurance.

5. Percentage moisture content.

6. Percentage moisture uptake.

7. Drug content.

8. Water vapor permeability (WVP) evaluation.

9. Uniformity of dosage unit.

10. Shear adhesion test.

11. Peel adhesion test.

12. Flatness test.

13. Percentage elongation break test.

14. Rolling ball tack test

15. Quick stick (peel-tack) test.

16. Skin irritation study.

17. Invitro drug release studies.

18. Invitro skin permeation studies.

19. Stability studies

 PACKAGING
• TDDSs are packaged in individual sealed
packets to preserve and protect them until use.
• For nonoral rate controlled drug delivery
systems, the drug release pattern ranges in
duration from 24 hours for most transdermal
patches to 3 months for the estradiol vaginal
ring insert (Estring, Pharmacia).
ANSEL'S PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS 9th Edition

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