Transdermal drug delivery systems (TDDS) provide drugs through the skin for systemic effects. TDDS patches contain drug reservoirs that diffuse drug into the bloodstream over time. Key advantages are avoiding gastrointestinal degradation and first-pass metabolism. TDDS can provide steady drug levels for chronic conditions. However, only potent drugs are suitable and skin irritation may occur. TDDS composition includes a polymer matrix, drug, permeation enhancers, adhesive, and backing layer. Recent techniques like microneedles and macroflux create pathways to enhance skin permeability for transdermal delivery.

1. Transdermal Drug Delivery System
Prepared By:
Apoorv Mishra
M.Pharm(Pharmaceutics)
1st year
Under the guidance of
Dr. Anupriya Kapoor
Assistant Professor
School of Pharmaceutical Sciences,
CSJMU, Kanpur

2. Transdermal Drug Delivery system
Definition-
Transdermal drug delivery system are topically administered medicaments in the form of patches that deliver drugs
for systemic effects at a predetermined and controlled rate.
• In this method drug is generally applied as a patch on the skin for a long period of time and drug enters into the
bloodstream by diffusion process.
• Historically, the medicated plaster can be viewed as the first development of transdermal drug delivery .
• There is a high concentration of drug in the patch and low concentration in the blood due to which the drug will
keep diffusing into the blood for a long period of time , maintaining a constant concentration in blood .

3. Advantages of Transdermal Drug Delivery System(TDDS)
❖ As a substitute for the oral route .
❖ Transdermal delivery avoids the stomach environment where the drug can be degraded and rendered ineffective
or where it can cause unpleasant gastrointestinal symptoms for the patient (Gordon, 2005).
❖ Transdermal delivery avoids the first pass effect where active drug molecules can be converted to inactive
molecules or even to molecules responsible for side effects (Rios, 2007).
❖ Transdermal drug delivery provides steady plasma levels. When a patch is applied that lasts for 24 hours, or even
7 days

4. ❖ Therapeutic failure or adverse effects frequently associated with intermittent dosing for the chronic diseases can
be avoided (Magnusson et al., 1997).
❖ Self administration and removal when required.
❖ Pain, inconvenience of injections can be overcomed by this non- invasive and safe parenteral route of drug
delivery

5. Disadvantages of transdermal drug delivery system
❖ The drugs that require high blood levels can not be administered.
❖ It may cause irritation or sensitization of skin.
❖ The adhesives may not adhere well to all types of skin and may be uncomfortable to wear.
❖ High cost of the product is also a major drawback.
❖ Some patients develop contact dermatitis at the site of application.
❖ Only potent drugs are suitable candidates for transdermal patch.
❖ Some drugs e.g. Scopolamine transdermal patch placed behind the ear, it creates uncomfortable.

6. Composition of TDDS
Composition
Polymer
matrix Drug
Permeation
enhancers
Pressure
sensitive
adhesive
Backing
membrane
Release
liner
Other
excipients

7. 1. Polymer matrix-
➢ Polymer are the backbone of TDDS, which control the release of the 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 biocompatibility and chemical compatibility with the drug and other
components of the system.
➢ They should be easily fabricated to the desired product. Polymer and their degradation products must be non-
toxic and non-antigenic to the host

8. Polymer
Natural polymer
e.g. cellulose derivatives
(ethyl cellulose, methyl
cellulose), zein, gelatin,
waxes, etc.
Synthetic elastomers
e.g. hydrin rubber,
silicon rubber, nitrile,
neoprene,etc.
Synthetic polymers
e.g. polyvinylalcohol,
polyethylene,
polyamide, polyurea,
etc.
The polymers utilized for TDDS can be classified as-

9. 2. Drug-
➢ The transdermal route is an extremely attractive option for the drugs with appropriate pharmacology and physical
chemistry .
➢ The foremost requirement of TDDS is that the drug possesses the right mix of physiochemical and biological
properties for transdermal drug delivery.
➢ Ideal properties of a drug for TDDS are as follows.
S.no. Properties Comments
1 Shelf life Up to 2 years
2 Particle size <40 cm2
3 Dosing frequency Once in a day or once in a week
4 Half life 10 hr or less
5 Partition coefficient Between 1 and 3
6 Skin irritation It should be nonirritant
7 Oral bioavailability Low
8 Molecular weight <500 Dalton

10. 3. Permeation enhancer-
➢ These are the Substances that are capable of promoting penetration of drugs into skin.
➢ It causes reversible interaction with the membrane of skin.
➢ Ideal properties of Penetration enhancer.
I. They should have no pharmacological activity within the body i.e. should not bind to receptor site.
II. It should be non toxic, non irritating and non allergenic.
III. Onset of action should be rapid and duration of activity should be predictable and suitable for the drug used.
IV. When removed from the skin the barrier properties should return both rapidly and fully.
V. It should spread well on the skin, with a suitable skin feel.
VI. The accelerant should be chemically and physically compatible with all drugs.

11. Classification of penetration enhancer-
Penetration enhancer
Chemical enhancer
DMSO , dimethyl
formamide , ozones , fatty
acids ,amines etc.
Natural enhancer
Terpens-menthol , linaloal ,
neem oil , eucalyptus etc.
Physical enhancer
Iontophoresis , sonophorosis
, needleless injection etc.

12. Advantage of permeation enhancer-
o It is useful for unabsorbable drugs to facilitate their absorption through skin.
o It can improve transdermal absorption of topical preparation.
o It is a penetration rate determining factor in TDDS.
o It also act as rate limiting factor.
Disadvantage of permeation enhancer-
o The effective concentration varies from drug to drug.
o The uses of different penetration enhancer with various concentration are restricted completely.
o Physiochemical properties of enhancers are also affecting the side effects in the body.

13. 4. Pressure sensitive adhesive [PSA’s]-
➢ A pressure sensitive adhesive is a material that helps in maintaining an intimate contact between transdermal
system and the skin surface.
➢ It should be removable from the smooth surface without leaving a residue.
➢ Polyacrylates , Polyisobutylene , and Silicon based adhesive are widely used in TDDS.
➢ The selection of an adhesive is based on numerous factors, including the patch design and drug formulation.
➢ PSAshould be physicochemically and biologically compatible and should not alter drug release.

14. 5. Backing membrane-
➢ While designing a backing layer , the consideration of chemical resistance of the material is most important.
➢ Excipient compatibility should also be considered because 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 ,
drug etc.
➢ The most comfortable backing will be the one that exhibits lowest module or high flexibility , good oxygen
transmission and a high moisture vapor transmission rate.
➢ Example- vinyl , polyethylene , polyester films these are some backing materials.

16. 6. 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 regarded as a part of the primary packaging material rather than a part of dosage form for delivering the
drug.
➢ 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.

17. 7. Other excipients-
➢ Various solvents such as chloroform , methanol , acetone , isopropanol , and dichloromethane are used to
prepare drug reservoir.
➢ In addition plasticizers such as dibutylpthalate , triethylcitrate , polyethylene glycol , propyleneglycol are added
to provide plasticity to the transdermal patch.

18. TYPES OF TRANSDERMAL PATCHES:
1. Single layer drug in adhesive:
In this type the adhesive layer contains the drug. The adhesive layer not only serves to adhere the various layers
together and this type of layer is responsible for the releasing the drug to the skin. The adhesive layer is surrounded by
a temporary liner and a backing.

19. 2. Multi -layer drug in adhesive:
This type is also similar to the single layer but it contains a immediate drug release layer which is different from other
layer which will be a controlled release along with the adhesive layer. The adhesive layer is responsible for the
releasing of the drug. This patch also has a temporary liner-layer and a permanent backing

20. 3: Vapour patch:
In this type of patch the role of adhesive layer not only serves to adhere the various layers together but also serves
market, commonly used for releasing of essential oils in decongestion. Various other types of vapor patches are also
available in the market which are used to improve the quality of sleep and reduces the cigarette smoking conditions.
4: Reservoir system:
In this system the drug reservoir is embedded between the two layers; an impervious backing layer and a rate
controlling membrane. The drug releases only through the rate controlling membrane, which can be micro porous or
non porous. In the drug reservoir compartment, the drug can be in the form of a solution, suspension, gel or
dispersed in a solid polymer matrix. Hypoallergenic adhesive polymer can be applied as outer surface polymeric
membrane which is compatible with drug.

21. 5: Matrix system:
➢ Drug-in-adhesive system:
In this type the drug reservoir is formed by dispersing the drug in an adhesive polymer and then spreading the
medicated adhesive polymer by solvent casting or melting on an impervious backing layer. On top of the reservoir,
unmediated adhesive polymer layers are applied for protection purpose.

22. ➢ Matrix-dispersion system:
In this type the drug is dispersed homogenously in a hydrophilic or lipophilic polymer matrix. This drug containing
polymer disk is fixed on to an occlusive base plate in a compartment fabricated from a drug impermeable backing
layer. Instead of applying the adhesive on the face of the drug reservoir, it is spread along with the circumference to
form a strip of adhesive rim.

23. 6: Microreservoir Controlled TDDS:
➢ This drug delivery system is a combination of reservoir and matrix-dispersion systems.
➢ The drug reservoir is formed by first suspending the drug in an aqueous solution of water-soluble polymer and
then dispersing the solution homogeneously in a lipophilic polymer to form thousands of unreachable,
microscopic spheres of drug reservoirs. The thermodynamically unstable dispersion is stabilized quickly by
immediately cross linking the polymer in situ. A Transdermal system therapeutic system thus formed as a
medicated disc Positioned at the center and surrounded by an adhesive rim.
➢ Nitro-dur System (Nitroglycerin) for once a day treatment of angina pectoris.

24. FACTORS INFLUENCING TDDS:
The effective transdermal drug delivery can be formulated by considering three factors as Drug, Skin, and the
vehicles. So the factors affecting can be divided in to classes as biological factors and physicochemical factors.
1: Biological factors:
▪ Skin condition:
Acids and alkalis, many solvents like chloroform methanol damage the skin cells and promote penetration. Diseased
state of patient alters the skin conditions. The intact skin is better barrier but the above mentioned conditions affect
penetration.
▪ Skin age:
The young skin is more permeable than older. Children are more sensitive for skin absorption of toxins. Thus, skin
age is one of the factors affecting penetration of drug in TDDS.

25. ▪ Blood supply:
Changes in peripheral circulation can affect transdermal absorption.
▪ Regional skin site:
Thickness of skin, nature of stratum corneum, and density of appendages vary site to site. These factors affect significantly
penetration.
▪ Skin metabolism:
Skin metabolizes steroids, hormones, chemical carcinogens and some drugs. So skin metabolism determines efficacy of drug
permeated through the skin.
▪ Species differences:
The skin thickness, density of appendages, and keratinization of skin vary species to species, so affects the penetration

26. 2. Physicochemical factors:
▪ 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 humectants is done in transdermal delivery.
▪ Temperature and pH:
The permeation of drug increase ten fold 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. Thus, temperature and pH are important factors affecting drug
penetration.
▪ 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.

27. ▪ Drug concentration:
The flux is proportional to the concentration gradient across the barrier and concentration gradient will be higher if
the concentration of drug will be more across the barrier.
▪ Partition coefficient:
The optimal K, partition coefficient is required for good action. Drugs with high K are not ready to leave the lipid
portion of skin. Also, 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. Because of
partition coefficient domination, the effect of molecular size is not known.

28. •Weight uniformity:
➢The prepared patches are to be dried at 60°C for 4hrs before testing. A specified area of patch is to be cut in
different parts of patch and weight in digital balance. The average weight and standard deviation values are to be
calculated from the individual weight.
•Percentage Moisture uptake:
➢The weighed films are to be kept in a desiccator at room temperature for 24hrs containing saturated solution of
potassium chloride in order to maintain 84% RH. After 24 hrs the films are to be reweighed and determine the
percentage moisture up take from the below mentioned formula.
•Drug content:
➢A specified area of patch is to be dissolved in a suitable solvent in specific volume . Then the solution is to be
filtered through a filter medium and analyse the drug content with the suitable method ( UV or HPLC ).

29. Therapeutic application of TDDS
➢ Hisetal , used in the treatment of multiple sclerosis may be formulated in TDDS using oleic acid as penetration
enhancer to achieve sufficient drug delivery.
➢ Diclofenac sodium, celecoxib used as non-steroidal anti inflammatory drugs [NSAIDs], formulated in TDDS may
overcome the gastric lesions associated with oral dosing.
➢ Drugs used for long term dosing in the chronic disease like captopril, verapamil, propranolol, which have a short
biological half life , considered first pass metabolism may be formulated as TDDS to achieve prolonged steady
state plasma concentration.
➢ Hydrophilic polymers like Polyvinylpyrrolidone[PVP] may provide faster drug release whereas hydrophobic
polymers like ethyl cellulose can provide prolonged drug delivery.
➢ Gel formulation with lipid disperse system of betahis-tine has potential for the development of an efficient

30. controlled release transdermal system
➢ Enhancer and co-solvent may synergistically enhance the delivery of peptides like thyrotropin releasing hormone
across the human skin.
➢ Prazosin hydrochloride in membrane controlled TDDS may deliver the drug enough to maintain the minimum
effective concentration and can avoid hypotension associated with high initial oral dosing.
➢ TDDS of indomethacin in PVP polymer [ acting as antinucleating agent] may provide better anti-inflammatory
activity and lower ulcer indices compared to oral administration.
➢ Diclofenac sodium, existing in anionic form at skin pH may be formulated as ion-pairs with oppositely charged
enhancers to enhance the transdermal delivery compared to non-ionic paired forms.
➢ Iontophoresis may increase the permeation rate of hydrophilic atenolol to a greater extent than permeation
enhancer and overcome incomplete absorption in the GI tract.

31. Recent techniques for enhancing transdermal drug delivery-
1. Structure based enhancement techniques-
✓ Micro fabricated microneedles-
▪ Microneedles are recently used techniques for transdermal drug delivery designed to form a physical pathway
through the upper epidermis to enhance skin permeability.
▪ Micro-fabricated microneedles are devices which are hybrids of the hypodermic needle and transdermal patch in
this technology needles of micron dimensions are inserted in to skin surface.
▪ There are number of delivery approaches that have been employed to use the microneedles for TDDS these
include
i. Poke with patch approach ii. Coat and poke approach
iii. Biodegradable microneedles iv. Hollow microneedles

32. ✓ Macroflux-
▪ This system incorporates a titanium micro projection array that creates superficial pathway through the skin barrier
layer.
▪ The main component of the micro projection patch is a titanium disk affixed to a polymeric adhesive back. The
titanium disk is 8cm2 and consists of an array of microscopic , titanium, tooth like micro projection that are coated
with medicinal substances.
▪ There are as many as 300 micro projections per cm with the length of individual micro projection less than 200im.
▪ Three types of macroflux have been designed they include:
o Dry-coated macro flux system
o E-trans macro flux system
o D-trans macro flux system

33. ✓ Metered-dose transdermal spray[MDTS]-
▪ It is liquid preparation in the form of solution that are used topically which is made up of a vehicle that is volatile
come non volatile in nature, which consists the completely dissolved medicaments in solution.
▪ The use of MDTS reaches the sustained level and better permeation of the drug via skin. The MDTS has the
following advantages:
i. It improves delivery potential without skin irritation due to its non occlusive nature.
ii. Increased acceptability dose flexibility.
iii. Simple manufacture.

34. 2. Electrically-based enhancement techniques:
✓ Iontophoresis-
▪ In iontophoresis delivery devices, drug is placed on the skin under the active electrodes, and a current [<0.5mA]
passed between the two electrodes effectively repelling drug away from the active electrode into the skin.
✓Ultrasound:
▪ The application of ultrasound of a suitable frequency significantly enhances the transdermal transport of drugs by
means of skin system not larger than wrist watch a phenomenon referred to phonophoresis or sonophoresis.
▪ It is a combination of ultrasound therapy with topical drug therapy to achieve therapeutic drug concentration at
selected sites in the skin.
▪ In this technique ,the drug is mixed with a coupling agent usually a gel but sometimes a cream or ointment is used
which transfers ultrasonic energy from the device to the skin through this coupling agent. This involves rupturing

35. the lipids present in stratum cornea, which allows the medicament to permeate via biological factor
▪ It employs ultrasound waves ranging from 20 KHz to 10 MHz with intensities of up to 3W cm -2 have been
applied to mitigate the stratum corneum barrier property.
✓ Photomechanical waves:
▪ The mechanism of photomechanical waves was found to act by producing changes in the lacunar system which
results in the formation of transient channels through the stratum corneum by permeabilization mechanism.
✓ Electroporation :
▪ In this method , aqueous pores are generated in the lipid bilayers by the application of short electrical pulses of
approx 100-1000 volt/cm. It may combine with iontophoresis to enhance the permeation of peptide.
✓ Electro-osmosis:
If a charged porous membrane is subjected to a voltage difference, a bulk fluid or volumes flow, called electro

36. 3: Velocity based enhancement techniques-
▪ Needle free injection:
✓ Intraject
✓ Implaject
✓ Jet syringe
✓ I ject
▪ Powderject devices:
The powderject system fires solid particles [20-100mm] through stratum corneum into lower skin layers , using a
supersonic shock wave of helium gas.

37. 4. Other enhancement techniques:
✓ Liposomes-
▪ Liposomes are colloidal particles formed as concentric biomolecular layers that are capable of encapsulating
drugs.
▪ They are lipid vesicles that fully enclose an aqueous volume.
▪ Liposomes act by penetrating the epidermis , carrying the drug into skin.
✓ Transferosomes:
▪ Transferosomes are modified liposomes , i.e. they are liposomes with edge activators.
▪ Transferosomes by passes the cutaneous capillary bed because they are too large to enter the blood vessels locally
and reach subcutaneous tissue.
▪ Transferosomes carriers can create a drug depot in the systemic circulation that is having a high concentration of
drug.

38. ✓ Medicated tattoos:
Med-Tats 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 the children.
✓ Laser radiation:
This method involves direct and controlled exposure of a laser beam to the skin which results in the ablation of the
stratum corneum without significantly damaging the underlying epidermis.

39. Recent advancement in Transdermal drug delivery system-
I. Vitorino et al. carried out a research on delivering co-encapsulation of drugs as transdermal patch. In this work, a
comprehensive study for the en-capsulation of drugs with a differential lipophillicity, olanzapine and simvastatin,
and their transdermal delivery in a formulation containing nanostructured lipid carriers (NLC) is presented. The
developed formulations can be considered non-irritant.
II. Donnelly et al. carried out a research on developing Hydrogel-Forming Microneedle Arrays. They used
crosslinked polymers to produce unique microneedle arrays. Crooslinked polymers rapidly take up skin
interstitial fluid upon skin insertion to form continuous, unbloackable hydrogel conduits from attached patch
type drug reservoirs to the dermal microcirculation. They found such microneedles, which can be fabricated in a
wide range of patch size and microneedle geometries, and can be easily removed from the skin.
III. Zhang et al. reported that Genetronics Inc ( San Diego, California) have developed a prototype electroporation
transdermal device. This device has been tested with various compounds with a view to achieving gene delivery
, improving drug delivery.

40. Evaluation parameters-
The evaluation methods for transdermal dosage form can be classified in to following types.
1. Physicochemical evaluation
2. In vitro evaluation
3. In vivo evaluation
1. Physicochemical evaluation:
• Interaction studies:
➢ Excipients are integral coomponents of all pharmaceutical dosage forms.
➢ The drugs and excipients must be compatible with one another to produce a product i.e. stable, thus it is
mandatory to detect any possible physical or chemical interaction as it can affect the bioavailability and stability
of the drug.

41. •Adhesive studies:
➢ Tack properties-
oIt is the ability of the polymer to adhere to substrate with the little contact pressure. Tack is dependent on molecular
weight and composition of polymer as well as on the use of tackifying resins in polymer.
➢Thumb tack test-
oIt is a qualitative test applied for tack property determination of adhesive .The thumb is simply pressed on the
adhesive and the relative tack property is detected.
➢Rolling Ball Tack Test:
This test measures the softness of a polymer that relates to talk. In this test, stainless steel ball of 7/16 inches in
diameter is released on an inclined track so that it rolls down and comes into contact with horizontal, upward facing
adhesive. The distance the ball travels along the adhesive provides the measurement of tack, which is expressed in
inch .

42. ➢Peel adhesive test-
oIn this test, a length of tape is adhered to a surface and then the tape is removed by lifting away from the surface in a
specified manner.
oMolecular weight of adhesive polymer, the type and amount of additives are the variables that determined the peel
adhesion properties.

43. 2. In Vitro Evaluation:
✓ In vitro drug release studies:
The paddle over disc method (USP apparatus V) can be employed for assessment of the release of the drug from the
prepared patches.
✓ In vitro skin permeation studies:
•An in vitro permeation study can be carried out by using diffusion cell.
•Various types of skin permeation studies are:
•Horizontal-type skin permeation system
•Franz diffusion cell
•Flow-through diffusion cell

44. 3. In vivo Evaluation
In vivo evaluations are the true depiction of the drug performance. The variables which cannot be taken into account
during in vitro studies can be fully explored during in vivo studies. In vivo evaluation of TDDS can be carried out
using:
✓ Animal models :
oThe most common animal species used for evaluating transdermal drug delivery system are mouse, hairless rat,
hairless dog, hairless rhesus monkey, rabbit, guinea pig etc.
oVarious experiments conducted lead us to a conclusion that hairless animals are preferred over hairy animals in both
in vitro and in vivo experiments.
oRhesus monkey is one of the most reliable models for in vivo evaluation of transdermal drug delivery in man.

45. ✓ Human volunteers:
The final stage of the development of a transdermal device involves colletion of pharmacokinetic and pharmaco-
dynamic data following application of the patch to human volunteers.
Stability studies:
Stability studies are to be conducted according to the ICH guidelines by storing the TDDS samples at 40±0.5°c and
75±5% RH for 6 months. The samples were withdrawn at 0, 30, 60, 90 and 180 days and analyze suitably for the drug
content.

46. REFERENCE
✓ Aarti N, Louk ARMP, Russsel OP, Richard HG. Mechanism of oleic acid induced skin permeation enhancement in
vivo in humans. Journal of Controlled Release, 1995; 37(3): 299-306.
✓ Aggarwal, G. Development, fabrication and evaluation of transdermal drug delivery system- A Review [Internet].
2009 Available from: http://www.pharmainfo.net/reviews/development-fabrication-and-evaluation-transdermal-
drug-delivery-system-review, excssed on 19 September, 2013.
✓ Arunachalam A, Karthikeyan M, Kumar DV, Prathap M, Sethuraman S, Kumar SA et al. Transdermal Drug
Delivery System: A review. Current Pharma Research 2010; 1(1):70-81.
✓ Dipen MP, Kavitha K. Formulation and Evaluation Aspects of Transdermal Drug Delivery System. International
Journal of Pharmaceutical Sciences Review and Research, 2011; 6(2):83-88.