This document discusses various transdermal drug delivery systems. It describes 6 electrically assisted methods - ultrasound (phonophoresis), iontophoresis, electroporation, magnetophoresis, photomechanical waves, and controlled heat aided drug delivery. It provides details on the mechanisms of these methods and compares iontophoresis and electroporation. It also discusses basic components of transdermal drug delivery systems, types of systems, evaluation methods, and some marketed products.

1. TRANSDERMAL
DRUG
DELIVERY
SYSTEMS Dr Jayapal Reddy Gangadi

3. 1.Ultrasound ( Phonophoresis /
Sonophoresis )
2.Iontophoresis
3.Electroporation
4.Magnetophoresis
5.Photomechanical waves
6.Controlled Heat Aided Drug Delivery

4. Electrically Assisted methods
1.Ultrasound (Phonophoresis / Sonophoresis)
 Used originally in physiotherapy and sports medicine, applies a
preparation topically and massages the site with an
ultrasound source.
 The ultrasonic energy (at low frequency) disturbs the lipid
packing in stratum corneum by cavitation.
 Sonicators operating at frequencies in the range of 20kHz to
3MHz are available commercially and can be used for
Sonophoresis.
• Therapeutic ultrasound (1–3MHz) - for massage,
• Low-frequency ultrasound (23-40kHz) - in dentistry,
• High-frequency ultrasound (3–10MHz)-diagnostic
purposes.

5. Mechanism of action of phonophoresis:
41

6. MECHANISM
Thermal effect
Cavitational
effects
Acoustic
(auditory)
streaming
Radiation
pressure
force
42
Mechanisms in phonophoresis:

7. Ultrasound to Enhance Skin Permeability

8. Phonophoresis (sonophoresis)
44

9. 2.Iontophoresis
Iontophoresis is an effective and painless
method of delivering medication to a
localized tissue area by applying
electrical current to a solution of the
medication.

10. 2.Iontophoresis
 The electrical driving of charged molecules into tissue,
passes a small direct current (approximately 0.5 mA/cm2)
through a drug containing electrode in contact with the
skin.

11. Three main mechanisms enhance molecular transport:
Charged species are driven primarily by electrical repulsion
from the driving electrode.
Flow of electric current may increase the permeability of skin
and
Electroosmosis may affect uncharged molecules and large polar
peptides.
Limitations: Hair follicle damage is possible.

13. Iontophoretic Patches
49

14. Reverse iontophoresis:
Iontophoresis can be used in reverse to
remove molecules from the circulation.
One example, the GlucoWatch, a needleless
means of monitoring blood glucose levels in
diabetic patients, uses an electrical signal that
is proportional to the amount of glucose in the
extracellular fluid.
50

15. Merits of Iontophoresis :
1. Efficient degree of enhancement achieved.
2. Iontophoresis enlarges the range of drug
candidates for transdermal administration
(polar and/or charged drugs whose passive
skin permeation is severely restricted)
3. Fast skin recovery
4. Minor irritation
5. Less sensitive to the condition of the skin at
the application site.
51

16. 3.Electroporation
 Skin electroporation (electropermeabilization) 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).
 These pores provide pathways for drug penetration that travel
straight through the horny layer.

17. i) Before field application
ii) When the electric field is
applied, the ions move
according to their charge.
iii) Pathways are formed
across the cell
membrane allowing DNA
to enter.
iv) When the electric field is
deactivated, the
membrane heals.
53

20. FACTOR IONTOPHORESIS ELECTROPORATION
Electric input
• Constant current; low voltage
• Current intensity (<0.5mA/cm2)
• High voltage pulse up to 100 V
Electrode
• It must avoid electrolysis of
water (Ag-AgCl electrode)
• It also withstand high instantaneous
current (platinum electrode)
Drug property
• Charge of drug - high
• Size of drug- small
• Structure of drug- compact
• Lipophilicity- water soluble
• M.Wt.- max.12000
• Charge of drug - no significant
effect
• M.Wt. – no upper limit
Formulation factor
• Concentration of drug
• pH of solution
• Ionic strength
• Concentration of the drug
Electroosmosis
• Significant electroosmotic flow • Insignificant
Reversibility • At low current density • At low pulse voltage
Comparison of Iontophoresis and Electroporation
56

21. 4.Magnetophoresis
 Magnetophoresis is a novel approach in enhancing drug
delivery across biological barriers.
 Benzoic acid, a diamagnetic substance, was selected as a drug
candidate.
 The influence of magnetic field strength on diffusion flux was
determined and was found to increase with increasing applied
strength.

22. 5.Photomechanical waves
 A drug solution, placed on the skin and covered by a black
polystyrene target, is irradiated with a laser pulse.
 The resultant photomechanical wave stresses the horny layer
and render the stratum corneum more permeable to
macromolecules due to the formation of transient channels and
enhances drug delivery.

23. 6.Controlled Heat Aided Drug Delivery (CHADD) System
 Heat increases skin temperature that leads to increase in
microcirculation and blood vessel permeability, thus facilitating
drug transfer to the systemic circulation.
 Drug solubility, both in the patch formulation and within the
skin increase with a rise in temperature.
 A technology known as Controlled Heat-aided Drug Delivery
system was developed and
 The CHADD system contains a small heating unit that can be
placed on top of a traditional patch. An oxidation reaction
within the unit provides heat at a limited intensity and duration.

25. Basic components of TDDS
 Drug
 Polymer matrix
 Penetration enhancers
 Other Excipients
• Rate controlling membrane
• Adhesive
• Release liner
• Backing membrane

26. Types of Transdermal delivery devices

27. Technology Of Transdermal
Delivery Systems (2 Types)
1. Monolithic systems - incorporate a drug matrix layer
between backing and frontal layers.
The drug matrix layer is composed of a polymeric material in
which the drug is dispersed.
The polymer matrix controls the rate at which drug is released for
percutaneous absorption.
Examples: Nitro-Dur and Nitrodisc
2. Membrane controlled transdermal system –
are design to contain a drug reservoir, usually in liquid
or gel form, a rate controlling membrane, and backing,
adhesive, and protecting layers
Examples: Transderm-Nitro and Transderm-Scop

28. Transdermal matrix system
Rate controlling factors
Drug concentration in polymer matrix
Chemical nature of polymer matrix
Geometry of device
Polymers: PVC, PVP, Ethylene vinylacetate, microporous polypropylene.
Initially the drug is released rapidly, then rate declines as matrix is depleted.
Advantages: Sleeker and thinner, daily or multiple-day Applications.
Appropriate for drugs that penetrate readily and/or have low
dosage requirements.

29. Transdermal reservoir system
Rate controlling factors
Membrane thickness
Membrane permeability
Polymers: Cellulosic esters, polyamides or PVC.
Advantages: Used when matrix systems cannot penetrate skin and drugs
require significant penetration enhancement and/or high dosage levels.

30. Release liners
 Protects the skin-contacting adhesive during storage.
 Substrate carries a very thin release coating.
 Provides low energy surface for ease of removal.
e.g.: polyester or polystyrene based films.
Backing material
 Contains formulation throughout shelf life and during wear
period.
 They have laminate structure.
 They must be compatible with the formulation
(nonadsorptive).
 They are occlusive and completely water impermeable in
nature.
e.g.: Poly urethane films, Ethyl vinyl acetate, Poly olefins.
Adhesive layer
Acrylic copolymers, polyisobutylene and polysiloxane.

31. These studies are predictive of transdermal
dosage forms and can be classified into
following types:
Physicochemical evaluation
• In vitro evaluation
• In vivo evaluation
67

32. Physicochemical Evaluation:
 Thickness:
 Uniformity of weight
 Drug content determination:
 Moisture content:
 Flatness:
 Folding Endurance:
 Tensile Strength:
 Water vapour transmission studies(WVT):
 Microscopic studies:
68

33. Thickness of the patch
The thickness of the drug prepared patch is measured
by using a digital micrometer at different point of patch
and determines the average thickness and standard
deviation for the same to ensure the thickness of the
prepared patch.
69

34. Content uniformity test
10 patches are selected and content is determined for individual
patches.
If 9 out of 10 patches have content between 85% to 115% of the
specified value and
one has content not less than 75% to 125% of the specified value ,
then transdermal patches pass the test of content uniformity.
But if 3 patches have content in the range of 75% to 125%, then
additional 20 patches are tested for drug content.
If these 20 patches have range from 85% to 115%, then the
transdermal patches pass the test
70

35. Drug content determination
An accurately weighed portion of film (above 100 mg)
is dissolved in 100 mL of suitable solvent in which drug
is soluble and then the solution is shaken continuously
for 24 h in shaker incubator.
Then the wholesolution is sonicated.
After sonication and subsequent filtration, drug in
solution is estimated spectrophotometrically by
appropriate dilution.
71

36. Moisture content:
The prepared films are weighed individually and kept in a
desiccators containing calcium chloride at room
temperature for 24 h.
The films are weighed again after a specified interval
until they show a constant weight.
The percent moisture content is calculated using
following formula.
Initial weight – Final weight
% Moisture content = ------------------------------------ X100
Final weight
72

37. Moisture Uptake:
Weighed films are kept in a desiccator at room
temperature for 24 h.
These are then taken out and exposed to 84% relative
humidity using saturated solution of Potassium
chloride in a desiccator until a constant weight is
achieved.
% moisture uptake is calculated as given below.
Final weight – Initial weight
% moisture uptake = ---------------------------------- X 100
Initial weight
73

38. Flatness:
A Transdermal patch should possess a smooth surface and should
not constrict with time.
This can be demonstrated with flatness study.
For flatness determination, one strip is cut from the centre and
two from each side of patches.
The length of each strip is measured and variation in length is
measured by determining percent constriction.
Zero percent constriction is equivalent to 100 percent flatness.
74

39. Folding Endurance
Evaluation of folding endurance involves determining the
folding capacity of the films subjected to frequent extreme
conditions of folding .
Folding endurance is determined by repeatedly folding the film
at the same place until it break.
The number of times the films could be folded at the same place
without breaking is folding endurance value.
Tensile Strength
To determine tensile strength, polymeric films are sandwiched
separately by corked linear iron plates.
One end of the films is kept fixed with the help of an iron screen
and other end is connected to a freely movable thread over a
pulley.
The weights are added gradually to the pan attached with the
hanging end of the thread.
75

40. Tensile strength =F/a .b (1 + L/l) (2)
F is the force required to break;
a is width of film;
b is thickness of film;
L is length of film;
l is elongation of film at break point.
76

41. Peel Adhesion properties
Tack properties
Thumb tack test
Rolling ball test
Quick stick (Peel tack) test
Probe tack test
Shear strength properties or creep resistance
Adhesive studies:
77

42. In this test, the force required to remove an adhesive coating form
a test substrate is referred to as peel adhesion.
Molecular weight of adhesive polymer, the type and amount of
additives are the variables that determined the peel adhesion
properties.
A single tape is applied to a stainless steel plate or a backing
membrane of choice and then tape is pulled from the substrate at a
180°C angle, and the force required for tape removed is measured
Peel Adhesion Test:
Figure: 1 Peel Adhesion test 78

43. Tack properties:
•It is the ability of the polymer to adhere to substrate with
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
The force required to remove thumb from adhesive is a
measure of tack.
Rolling ball tack test
This test measures the softness of a polymer
79

44. 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 (Figure-2). The distance
the ball travels along the adhesive provides the
measurement of tack, which is expressed in inch
Figure: 2 Rolling ball tack test 80

45. Quick stick (peel-tack) test
In this test, the tape is pulled away from the substrate at 90ºC at a
speed of 12 inches/min.
The peel force required breaking the bond between adhesive and
substrate is measured (Figure-3)
And recorded as tack value, which is expressed in ounces or
grams per inch width.
Figure: 3 Quick stick (peel-tack) test 81

46. Shear strength properties
or
creep resistance
Shear strength is the measurement of the cohesive strength of an
adhesive polymer i.e., device should not slip on application
determined by measuring the time it takes to pull an adhesive
coated tape off a stainless plate.
Figure: Shear strength properties or creep resistance
82

47. Probe Tack test
In this test, the tip of a clean probe with a defined surface
roughness is brought into contact with adhesive, and when a bond
is formed between probe and adhesive.
The subsequent removal of the probe mechanically breaks it
(Figure-4).
The force required to pull the probe away from the adhesive at
fixed rate is recorded as tack and it is expressed in grams.
Figure: 4 Probe Tack test
83

48.  In vitro studies
SELECTION
OF SKIN
SEPARATION
 Human
 Animal
 Artificial
Heat
Chemical
Physical
 One chambered
(Vertical type)
 Two chambered
84

49. In vivo Studies
Animal models
Human volunteers
85

50. Transdermal patches available in the market

51. Other imp.Transdermal
Therapeutic Systems
1. Testosteron transdermal system - Testoderm, is
available for hormone replacement in men who have an
absence or deficiency of testosterone.
Dose: 10 mg for delivery of 4 mg/day; 15 mg for
delivery of 6 mg/day. The patches are applied to
scrotal skin where optimal absorption occurs. The
patches is worn 22 to 24 hours daily for 6 to 8 weeks.
2. Trans-Ver-Sal - contains 15% salicylic acid in a vehicle
consisting of karaya, a substance known for its non -
irritating and self-adhesive properties. It is use for the
treatment of viral wart infections

52. Marketed Products of Modified Transdermal Drug Delivery Technologies

53. 1. Clonidine - Catapress -TTS
Four-layered patch:
(1) backing layer of pigmented polyester film
(2) drug reservoir of clonidine, mineral oil,
polyisobutylene, and colloidal silicon dioxide,
(3) a microporous polypropylene membrane controlling
the rate of drug delivery, and
(4) an adhesive formulation of agents
Uses: antihypertensive clonidine at a constant rate
for 7 days, once a week dosing in the upper arm
or torso.
Products on the market, or in development
include:

54. • Clonidine
• Works as an agonist of adrenaline at the
presynaptic a2 adrenergic
• Product name = Catapres-TTS®
• used to treat hypertension

55. Examples Of TDD Systems
2. Estradiol - Estraderm
Four layered patch:
1. Transparent polyester film,
2. Drug reservoir of estradiol and alcohol gelled with hydroxypropyl
cellulose,
3. an ethylene vinyl acetate copolymer membrane, and
4. an adhesive formulation of light mineral and polyisobutylene.
Uses: Design to release 17 B-estradiol continuously.
Applied twice weekly over a cycle of 3 weeks.
The patch is generally applied to the abdomen, altering
sites with each application.

56. This patch contains estradiol that is a form of estrogen in female sex
hormone the regulates many processes in the body.

57. Examples Of TDD Systems
3. Nicotine - Nicotrol
Multi-layered rectangular patch:
(1)outer backing of laminated polyester
film, (2) rate-controlling adhesive,
nonwoven material, and nicotine, (3)
disposable liner removed prior to use -
Aid in smoking cessation programs

58. This helps avoid the discomfort of nicotine withdrawal
symptoms when you quit smoking by giving you a
controlled, sustained dose of nicotine

59. It is used as a temporary aid for smoking-cessation programs. It helps to control the
symptoms of nicotine withdrawal (irritability, headache, fatigue, insomnia) and thus
helps you to concentrate on overcoming the psychological and behavioral aspects of
your smoking habit.

60. 4. Nitroglycerin - Deponit
Nitroglycerin in a matrix of
lactose, plasticizer,
polyisobutylene, and
aluminized plastic
Use: to provide controlled
release of nitroglycerin
continuously for a 24 hour
period. Patches are applied
to inner part of upper arm,
shoulders, or chest.
5. Nitroglycerin - Nitro - Dur
Nitroglycerin in a gel like
matrix composed of
glycerin, water, lactose,
polyvinyl alcohol, povidone
and sodium citrate sealed
in a polyester foil
polyethylene laminate.
Use: same as # 4

61. This contains nitroglycerin which is a type of vasodilator.
This is used to prevent chest pain caused by angina. It will
not help to stop an episode of chest pain.

62. • Nitroglycerin
• Works by producing nitric oxide (NO), which then acts as
a vasodilator
• Product Names = Nitro-Dur®, Transderm-Nitro®
• Used for: Angina
• Type of Patch = Nitro-Dur is Drug-in-adhesive
Nitrodisc is reservoir
• Frequency of administration = Daily

63. Examples Of TDD Systems
6. Scopolamine - Transderm - Scop
Four layered patch: (1) backing layer of
aluminized polyester film, (2) drug reservoir of
scopolamine, mineral oil, and polyisobutylene,
(3) a microporous polypropylene membrane for
rate delivery of scopolamine, and (4) adhesive of
polyisobutylene, mineral oil, and scopolamine
Use: for continuous release of scopolamine
over a 3-day period as required for the
prevention of nausea and vomiting associated
with motion sickness. The patch is placed
behind the ear. When repeated administration
is desired, the first patch is removed and the
second patch placed behind the other ear

65. VIVELLE-DOT
This contains estradiol in a multipolymeric adhesive that helps in
the development and maintenance of the female reproductive
system and secondary sexual characteristics.

66. This is a skin patch designed to treat symptoms of early Parkinson's
disease.

67. This is a band-aid-like patch inserted on your gum to numb
it before an injection

68. This is used to treat Attention Deficit Hyperactivity Disorder (ADHD) in
children six to 12 years of age.

69. It is a contraceptive used by women
to prevent pregnancy

70. This patch is designed to release Estradiol continuously upon
application to intact skin for the treatment of moderate to severe
vasomotor and vulvovaginal symptoms associated with menopause,
and for prevention of postmenopausal osteoporosis

71. This contains a low dose of nicotine that is intended to help quit
smoking by reducing the unpleasant nicotine withdrawal effects

72. • Ethinylestradiol (EO) and norelgestromin (N)
• Product name = Ortho-Evra®
• Used for Contraception
• Type of patch = Drug-in-Adhesive
• Frequency of application = weekly

73. • Fentanyl
• Product Name = Duragesic®
• Used for: Analgesia
• Type of Patch = Drug-in-Adhesive
• Frequency of Application = Weekly

74. • Lidocaine
• Product Name = Lidoderm®
• Used for: analgesia of postherpetic neuralgia
(PHN), a painful condition caused by the
varicella zoster virus (herpes zoster = shingles)

75. Lidoderm Patch
• Type of Patch = Reservoir
• Frequency of Application = Daily

76. • Nicotine
• Product name = Habitrol®, Nicoderm –
CQ®, Nicotrol®, Prostep®
• Used for: Smoking cessation
• Frequency of administration = Daily

77. • Estradiol
• Product Name = Alora®, Climara®, Esclim®,
Estraderm®, FemPatch®, Vivelle®, Vivelle-DOT®
• Used for: Hormone replacement
• Type of Patch: Drug-in-adhesive
• Frequency of application = weekly

78. • Estradiol + Norethindrone
• Product name = CombiPatch®
• Used for: Hormone Replacement

79. • Oxybutynin
• Works as competitive antagonist of the
muscarinic acetycholine receptor
• Product name = Oxytrol®
• Used for: Overactive bladder (antispasmodic)
• Type of Patch: Drug-in-adhesive
• Frequency of application = twice a week

80. • Scopolamine
• Works as competitive antagonist of acetylcholine
at the muscarinic receptor
• Product Name = Transderm Scop®
• Used for: Motion Sickness

81. • Testosterone
• Product Names = Androderm®, Testoderm TTS®,
Testoderm®
• Used for: Hypogonadism

82. • Lidocaine + Epinephrine
• Product name = Lidosite
• Used for: Dermal anesthesia
• Type of Patch = Reservoir,
iontophoretic.
Epinephrine acts as vasoconstrictor, thus prolonging the duration of
action of lidocaine (by delaying resorption) at the site

83. Iontophoretic Patches
• Iontophoretic patches use a tiny electrical
current to promote flow of the drug
(usually charged) through the skin.

84. Iontophoretic Patches

85. Iontophoretic Patches

88. Microneedles Patches
• Microneedles patches are currently being
explored as mechanisms to deliver
vaccines and larger macromolecules.

89. Transdermal Vaccine Technology

90. References
 Controlled drug delivery –concepts and advances – by S.P.Vyas
R.K.Khar.
 Encyclopedia of pharmaceutical technology -third edition edited
by James Swarbrick volume-4 Microsphere Technology and
Applications by Diane J. Burgess and Anthony J. Hickey.
 Controlled and Novel drug delivery edited by N.K.Jain reprint
2007
 Encyclopedia of controlled drug delivery volume 2
encyclopedia of controlled drug delivery
 Asian Journal of Pharmaceutical and Clinical Research
transdermal drug delivery system: a review p. k.gaur,s. mishra,
s. purohit, k. dave..

91.  European Journal of Pharmaceutical Sciences Review -Novel
mechanisms and devices to enable successful transdermal drug
delivery by B.W. Barry.
 Transdermal drug delivery- penetration enhancement
techniques- Heather A.E. Benson.
 Microneedles : The option for painless delivery by Geeta M
Patel.