The document discusses transdermal drug delivery systems (TDDS), outlining their definition, benefits, and disadvantages, along with their clinical significance. It details the structure of skin and mechanisms of drug absorption, factors affecting permeation, and basic components necessary for TDDS development. Additionally, it covers various formulation approaches and examples of TDDS for therapeutic applications.

1. TRANSDERMAL DRUG DELIVERY SYSTEM
Ravish Yadav

2. CONTENTS
Introduction
Objectives of TDDS
Advantages & disadvantages
Mechanism of percutenious absorption
Permeation through skin
Kinetics of transdermal drug delivery system
Factors affecting permeation
Basic components of TDDS
Formulation approaches used in development of TDDS and
their evaluation
Permeation enhancer.
References
2

3. When one hears the words transdermal drug
delivery, what comes to mind? More than likely
one thinks about a simple patch that one stick onto
skin like an adhesive bandage such as nicotine
patch.
TRANSDERMAL DRUG
DELIVERY SYSTEM (TDDS)
3

4. 4
•The NDDS may involve a new dosage form e.g., from
thrice a day dosage to once a day dosage form or
developing a patch form in place of injections.
•Throughout the past 2 decades, the transdermal patch
has become a proven technology that offers a variety of
significant clinical benefits over other dosage forms.
•Because transdermal drug delivery offers controlled
release of the drug into the patient, it enables a steady
blood-level profile, resulting in reduced systemic side
effects and, sometimes, improved efficacy over other
dosage forms
Brief History of TDDS

5. •Transdermal drug delivery system was first introduced
more than 20 years ago.
•The technology generated tremendous excitement and
interest amongst major pharmaceutical companies in
the 1980s and 90s.
•First transdermal patch was approved in 1981 to
prevent the nausea and vomiting associated with
motion sickness, the FDA has approved, throughout the
past 22 years, more than 35 transdermal patch products,
spanning 13 molecules.
5
Brief History of TDDS

6. INTRODUCTION
• Definition:
Transdermal drug delivery is defined as a self
contained discrete dosage form, which when applied to
the intact skin, will deliver the drug at a controlled rate to
the systemic circulation.
6

7. POTENTIAL BENEFITS OF
TRANSDERMAL DRUG DELIVERY
(ADVANTAGES)
• Easy to use.
• Avoid GIT absorption problems for drugs.
• Avoids FP hepatic metabolism of drugs.
• More improved and convenient patient compliance.
• Rapid termination in case of toxicity is possible.
• Self medication is possible.
• Reduces frequency of dosing.
• Maintains therapeutic level for 1 to 7 days.
• Controlled delivery resulting in more reliable and
predictable blood levels.
7

8. DISADVANTAGES
• Daily dose of more than 10mg is not possible.
• Local irritation is a major problem.
• Drug requiring high blood levels are unsuitable.
• Drug with long half life can not be formulated in TDDS.
• Uncomfortable to wear.
• May not be economical.
• Barrier function changes from person to person and within the
same person.
• Heat, cold, sweating (perspiring) and showering prevent the
patch from sticking to the surface of the skin for more than one
day. A new patch has to be applied daily.
8

9. STRUCTURE OF SKIN
• Epidermis:
Stratum corneum (Horny cell layer)
 Stratum lucidum (Clear layer)
 Stratum granulosum ( Granular Layer)
 Stratum spinosum (Prickly layer)
 Stratum germinativum
• Dermis:
• Hypodermis or Subcutaneous layer:
9

10. STRUCTURE OF SKIN
Epidermis:
 The outer layer of skin is made up of Stratified
Squamous epithelial cells.
Epidermis is thickest in palms and soles.
The stratum corneum forms the outer most layer (10-
15µm thick ) which consists of many layers of compacted
, flattened, dehydrated keratinized cells.
Keratin contains cells called as Corneosites.
 Stratum corneum layer forms permeability barrier for
external environment.
10

11. Water content of stratum corneum is around 20%.
The moisture required for stratum corneum is around
10% (w/w) to maintain flexibility and softness.
It consists of Cermides and neutral lipids such as Sterols,
free fatty acids and triglycerides.
 The stratum corneum is responsible for the barrier
function of the skin and behaves as a primary barrier to
the percutaneous absorption.
11
STRUCTURE OF SKIN

12. It is made up of three layers in thicker parts stratum
granulosum, stratum lucidum,stratum spinosum.
 Removal of these layers results in increased
permeability and water loss.
12
STRUCTURE OF SKIN

13. DERMIS:
 The dermis is made up of regular network of robust
collagen fibers of fairly uniform thickness with regularly
placed cross striations .
This network or the gel structure is responsible for the
elastic properties of the skin.
It is supplied by blood to convey nutrients, remove waste &
regulate body temp.
Drug is well absorbed by this route.
Upper portion of the dermis is formed into ridges
containing lymphatics and nerve endings.
13
STRUCTURE OF SKIN

14. SUBCUTANEOUS TISSUE:
This is a sheet of the fat containing areolar tissue
known as the superficial fascia attaching the dermis to the
underlying structures .
SKIN APPENDAGES:
Sweat glands produces sweat of pH 4-6.8 & absorbs
drugs, secretes proteins, lipids and antibodies. Its function
is to control heat.
HAIR FOLLICLES
They have sebaceous glands which produces sebum
and includes glycerides, cholesterol and squalene.
14
STRUCTURE OF SKIN

15. Mechanism of absorption through skin
Mechanism involved is passive diffusion
This can be expressed by FICK’s LAW of DIFFUSION
dq = D K A ( c1 – c2 )
dt h
dq /dt = rate of diffusion
D = diffusion co-efficient
K = partition co- efficient
A = surface area of membrane
H = thickness of membrane
15

16. Routes of drug absorption through skin
 Trans follicular route
 Trans epidermal route
16

17. Routes of drug absorption through skin
Trans follicular route:
• Fractional area available through this route is 0.1 %
• Human skin contains 40-70 hair follicles, 200 to 250
sweat glands on every sq.cm. of skin area.
• Mainly water soluble substance are diffused faster
through appendages than that of other layers.
• Sweat glands and hair follicles act as a shunt i.e. easy
pathway for diffusion through rate limiting ST corneum.
17

18. Routes of drug absorption through skin
Trans Epidermal route
Epidermal barrier function mainly resides in horny layer
The viable layer may metabolize, inactivate or activate a
prodrug.
Dermal capillary contains many capillaries so residence
time of drug is only one minute.
Within stratum corneum molecule may penetrate either
transcellularly or intercellular.
Intracellular region is filled with lipid rich amorphous
material.
18

19. Routes of drug absorption through skin
19

20. FACTORS AFFECTING
TRANSDERMAL PERMEABILITY
Physico chemical properties of parent molecule
Solubility and partition co- efficient
pH condition
Penetrant concentration
Physico chemical properties of drug delivery system
Release characteristic
Composition of drug delivery system
Permeation enhancer used
20

21. Physiological and pathological condition of skin
Lipid film
Skin hydration
Skin temperature
Effect of vehicle
Pathological injury to skin
Biological factors
Skin age
Thickness of S. Corneum
Skin condition
21

22. Solubility and partition co- efficient:
 Solubility of a drug influences its ability to penetrate
the skin.
 pKa is index of solubility of drug in vehicle and ST
corneum has influence on transfer of drug from vehicle
to skin.
Drug solubility determines concentration presented to
absorption site which will effect rate and extent of
absorption.
 Skin permeation can be enhanced by increasing
lipophilic character of drug, so that drug penetrates
through STC but not through epidermis due to decreased
water solubility.
 Drug which is lipid & water soluble is favored.
22

23. pH & penetration concentration:
 Moderate pH is favorable because if solutions with
high or low pH will result in destruction to the skin.
 Higher the concentration of the drug in vehicle faster
the absorption.
 At higher concentrations than solubility the excess
solid drug will function as a reservoir and helps to
maintain a constant drug constitution for prolonged
period of time.
23

24. FACTORS AFFECTING
TRANSDERMAL PERMEABILITY
24
Physico-chemical properties of drug delivery system
Release characteristic
 Solubility of drug in vehicle determines the release rate.
Composition of drug delivery system
 It not only effects the rate of drug release but also the
permeability of STC by means of hydration mixing with skin
lipids. Example methyl salicylate is more lipophilic than its
parent acid (Salicylic acid). When applied to skin from fatty
vehicle methylsalicylate yielded higher absorption.

25. FACTORS AFFECTING
TRANSDERMAL PERMEABILITY
25
Physiological and pathological condition of skin
Lipid film:
It acts as protective layer to prevent removal of
moisture from skin. Defeating of this film will decrease TD
absorption.
Skin hydration:
It can be achieved by covering skin with plastic
sheeting, which leads to accumulation of sweat, condensed
water vapors, increase hydration and increase porosity.

26. FACTORS AFFECTING
TRANSDERMAL PERMEABILITY
26
Effect of vehicle:
A vehicle can influence absorption by its effect on
physical state of drug and skin. Example greases, paraffin
bases are more occlusive while water in oil bases are less.
Humectants in bases will dehydrate the skin and decrease
percutaneous absorption.

27. FACTORS AFFECTING
TRANSDERMAL PERMEABILITY
27
Biological factors:
Skin age:
Skin of foetus, young ones and elders is more
permeable than adult tissue.
Skin metabolism:
Viable epidermis is metabolically active than
dermis. If topically applied drug is subjected to
biotransformation during permeation local and systemic
bioavailability is affected.

28. BASIC COMPONENTS OF TRANSDERMAL
DRUG DELIVERY SYSTEM
COMPONENT OF TRANSDERMAL DEVICE INCLUDE:
1) POLYMER MATRIX
2) THE DRUG
3) PERMEATION ENHANCER
4) OTHER EXCEPIENTS
28

29. 29
29
Basic components of Transdermal
drug delivery

30. POLYMER MATRIX
Following criteria to be considered in selection a
polymer:
Molecular weight, physical of polymer must allow
diffusion of drug at desired rate.
 Polymer must be non-reactive, inert, non-toxic, easy
to manufacture, inexpensive.
 It should not decompose on storage of the device &
not deteriorate when large amount of active ingredient is
in corporated into it.
30

31. LIST OF POLYMERS USED
NATURAL POLYMERS:
Cellulose derivatives, Zein, Gelatin, Shellac, Waxes,
Gums & Natural rubber
SYNTHETIC ELASTOMER POLYBUTADIENE:
Polysiloxane, Silicon rubber, Nitrile, Acrylonitryle, Butyl
rubber, Styrene butadiene rubber.
SYNTHETIC POLYMER
Poly vinyl alcohol, Poly vinyl chloride, Polyethylene,
Poly propylene, Poly urea, PVP, Polymethacrylate
31

32. DRUG
For successful developing transdermal delivery,
drug should be chosen with great care
physicochemical properties
1. Mol. wt. less than 1000 Daltons
2. Affinity for both lipophilic & hydrophilic phase
3. Drug should have low melting point
32

33. BIOLOGICAL PROPERTIES
It should be potent with daily dose of few mg/ day.
Half life of drug should be short.
Non irritant to skin.
Drug prone to ‘first pass effect’ and which degrade in
GIT are ideal candidate.
33

34. Ideal properties of drug candidate
PARAMETER PROPERTIES
Dose Sh’d be low( < 20mg/day)
Half life 10 or less
Molecular weight < 400
Skin permeability co- efficient > 0.5 X 10 -3 cm/ hr
Skin reaction Non irritating & non sensitizing
Oral Bioavailability low
Therapeutic index low
34

35. 35
35
Backing membrane
They are flexible and provide a good bond to the drug
reservoir, prevent the drug from leaving the dosage form
through top.
It is an impermeable membrane that protects the product
during the use on the skin.
 Contains formulation throughout shelf-life and during
wear period
 Must be compatible with formulation (non adsorptive)
 Printable
E.g.: Metallic plastic laminate , plastic backing with
adsorbent pad adhesive foam pad.

36. PERMEATION ENHANCERS
These are the agents which promote the skin
permeability by altering the skin as a barrier to the flux
of desired penetrant.
Flux J across the skin can be given by
J= D. dc/dx
D= diffusion coefficient
C= concentration
x=Spatial coordinate
D is function of size, shape, flexibility of diffusing drug
molecule
36

37. Activity of penetration enhancers
Interaction with the polar head groups of lipid via
hydrogen and ionic bonding
Change in hydration sphere of lipids and affect the
packing at the head region
Increase volume of the aqueous layer swelling and
hydration
Protein modification- open up the dense keratin structure
and make it more permeable
37

38. IDEAL CHARACTERISTIC OF PENETRATION
ENHANCERS
1) IT SHOULD BE INERT
2) NON-TOXIC, NON- IRRITATING
3) ACTION SHOULD BE IMMEDIATE& PREDICTABLE
4) SHOULD NOT CAUSE REMOVAL OF BODY FLUID
5) SHOLD BE COMPATIBLE WITH DRUG& EXIPIENTS
6) COSMETICALLY ACCEPTABLE
7) ODORLESS, TASTELESS, COLORLESS & CHEAP
38

39. SOLVENTS
The compounds increase penetration possibly by
swelling the polar pathway and fluidizing the lipid
e.g.. Methanol, ethanol, DMSO, DMA, DMF,
pyrolidiones, propylene glycol, glycerol etc..
SURFACTANTS
They enhance polar pathway transport of hydrophillic
drugs
39

40. ANIONIC SURFACTANTS -
Dioctyl sulpho succinate, SLS, decodemethyl
sulphoxide
CATIONIC SURFACTANTS -
Pluronic F127, pluronic F58
40

41. BINARY SYSTEMS
•These systems open up the multilaminate path way as
well as the continuous path way
e.g. Propylene glycol-oleic acid.
1,4, butane diol- linoleic acid.
MISCELLANIOUS CHEMICALS
e.g. Urea, N,N- dimethyl m- toluamide
41

42. 42
42
Schematic Skin absorption of drug

43. Topical application-absorption & action
of drugs
SYSTEMIC
DRUG IN TARGET TISSUE
DRUG IN BLOOD CIRCULATION
DISTRIBUTION
ELIMINATION
PHARMACOLOGICAL
RESPONSE
TOPICAL
ABSORPTION
DRUG IN DELIVERY
SYSTEM
DRUG IN SKIN SECRETION
FLUIDS, SWEAT, SEBUM,
pH 4.5--5.5
TRANSDERMAL
LOCALIZED
RELEASE
43

44. FORMULATION APPROACHES FOR
DEVELOPMENT OF TRANSDERMAL
DRUG DELIVERY SYSTEM
44

45. TYPES OF FORMULATION
PLATFORM FOR THE DRUG:
•Liquids
•Semisolids : ointments and gels
•Non flowing material
That is …
Polymeric film or rubbery gels and
 Solid-state platform
45

46. TYPES OF PLATFORM
MONOLITH : slabs, reservoir, vehicle, film, polymer matrix
FILMS :
Natural or synthetic
Porous and non porous
ADHESIVES: viscoelastic materials which remains permanently
tacky
E.g. Natural or synthetic rubber, polyacrylates and silicon
elastomer
46

47. 1. POLYMER MEMBRANE PERMEATION
CONTROLLED SYSTEM
47

48. 1. POLYMER MEMBRANE PERMEATION
CONTROLLED SYSTEM
RCM made up of EVA copolymer
A thin layer of drug compatible, hypoallergenic
adhesive polymer e.g. Silicon or polyacrylet
adhesive may be applied to the external surface.
Rate of drug release affect by varying the polymer
composition, permeability coefficient and thickness
of rate limiting membrane and adhesive.
48

49. 1. POLYMER MEMBRANE PERMEATION
CONTROLLED SYSTEM
Accidental breakage of the rate controlling
membrane can result in dose dumping or a rapid
release of the entire drug content.
E.g.
Nitroglycerine releasing trans dermal system for
once a day medication for angina
49

50. 1. POLYMER MEMBRANE PERMEATION
CONTROLLED SYSTEM
Scopolamine-releasing transdermal system for 72 hr.
prophylaxis of motion sickness.
Clonidine releasing transdermal system for 7 day
therapy of hypertension.
Estradiol-releasing transdermal system for treatment
of menopausal syndrome for 3-4 days.
50

51. 1. POLYMER MEMBRANE PERMEATION
CONTROLLED SYSTEM
The intrinsic rate of the drug release from this type
of drug delivery system is defined by
dq CR
dt 1/pm + 1/pa
51
=

52. 1. POLYMER MEMBRANE PERMEATION
CONTROLLED SYSTEM
Pm and pa respectively defined as….
pm km/r . Da
hm
ka/m . Da
ha
52
=
=pa

53. 1. POLYMER MEMBRANE PERMEATION
CONTROLLED SYSTEM
Where,
 Km/r and ka/m are the partition coefficient for the
interfacial partitioning of the drug from reservoir to
the membrane and from the membrane to adhesive
layer respectively.
 Dm and Da are diffusion coefficient and
 hm and ha are the thickness
53

54. 1.POLYMER MEMBRANE PERMEATION
CONTROLLED SYSTEM
Substituting the pm and pa equation in equation 1
dq km/r . Ka/m . Dm . Da
dt km/r. Dm. ha + ka/m . Da . hm
Which define the intrinsic rate of drug release from a
membrane moderated drug delivery system.
54
= cr

55. 2. ADHESIVE DISPERSION-TYPE
SYSTEM
55

56. 2. ADHESIVE DISPERSION-TYPE
SYSTEM
e.g. of adhesive polymer is poly(isobutylene) or
poly(Acrylet) adhesive
E.g. of this type of system is isosorbide dinitrate
releasing transdermal therapeutic system for once a
day medication of angina pectoris.
It is used for the administration of verapamil.
56

57. 2. ADHESIVE DISPERSION-TYPE
SYSTEM
The rate of drug release in this system is defined by:
dq ka/r . Da
dt ha
where,
Ka/r is partition coefficient for the interfacial partitioning
of the drug from the reservoir layer to adhesive layer.
57
=
cr

58. 3. GRADIENT CONTROLLED TDDS
Drug – impermeable metallic
plastic laminate
58
Drug reservoir
gradient layers
R1>R2>R3
R1R1
R2
R3
}

59. 3. GRADIENT CONTROLLED TDDS
The rate of drug release from this drug reservoir
gradient controlled system is given by:
dq ka/r . Ds
dt ha (t)
Thickness of the adhesive layer for drug molecules
to diffuse through increases with time h(t)
E.g. Nitroglycerine TDD patch
59
A (ha)=

60. 4. POLYMER MATRIX DIFFUSION
CONTROLLED TDDS SYSTEM
60
60

61. 4. POLYMER MATRIX DIFFUSION
CONTROLLED TDDS SYSTEM
E.g. of this type of system is nitro-dur I and nitro-
dur II. for continuous transdermal fusion of
nitroglycerine at a daily dose of 0.5 mg/cm2 for
therapy of angina pectoris.
Nitro dur II is modified version of I in which the drug
is dispersed in acrylic based polymer adhesive with a
resinous cross linking agent which result in much
thinner and more elegant patch.
61

62. 4. POLYMER MATRIX DIFFUSION
CONTROLLED TDDS SYSTEM
The rate of drug release from this type of system is
defined as:
A is the initial drug loading dose dispersed in the polymer matrix and
Cp and Dp are the solubility and diffusivity of the drug polymer
respectively.
Since only the drug species dissolved in the polymer can release .
62
1/2
=
dq ACp Dp
dt 2t

63. 5. MICRORESERVIOR TYPE OR MICROSEALED
DISSOLUTION CONTROLLED SYSTEM
63
rim

64. 5. MICRORESERVIOR TYPE OR MICROSEALED
DISSOLUTION CONTROLLED SYSTEM
Silicon elastomer the lipophillic polymer is used for
dispersion technique to form unleachable
microscopic sphere of drug reservoir.
The quick stabilization occur by cross linking of the
polymer chain which produced medicated polymer
disc with a constant surface area and fixed thickness
according to requirement of drug release.
64

65. 5. MICRORESERVIOR TYPE OR MICROSEALED
DISSOLUTION CONTROLLED SYSTEM
Extra coating is available as a biocompatible
polymer to modify the mechanism and rate of drug
release.
A trans dermal therapeutic system is produced by
positioning the medicated disc at the centrally and
surrounded bit with an adhesive rim.
65

66. 5. MICRORESERVIOR TYPE OR MICROSEALED
DISSOLUTION CONTROLLED SYSTEM
It is successfully utilized in the preparation of nitro-
disc, a nitroglycerine releasing trans dermal
therapeutic system used in angina pectoris.
This system followed zero order release of drug
without the danger of dose dumping.
66

67. 5. MICRORESERVIOR TYPE OR MICROSEALED
DISSOLUTION CONTROLLED SYSTEM
The rate of release of drugs of the micro reservoir system is defined
by,
dq Dp .Dd .m .kp
dt Dphd+Ddhpmkp
67
DISl (1-n)
+n.Sp
hI
1
kI
1
km
=

68. 5. MICRORESERVIOR TYPE OR MICROSEALED
DISSOLUTION CONTROLLED SYSTEM
Where, m=a/b is the ratio of the bulk of the elution
medium over drug solubility of the same medium
and b is the ratio of drug concentration at the outer
edge of the polymer coating for the drug solubility
in the same polymer composition.
 n is the ratio of the drug concentration at the inner
layer of the interfacial barrier over drug solubility in
the polymer matrix.
68

69. 5. MICRORESERVIOR TYPE OR MICROSEALED
DISSOLUTION CONTROLLED SYSTEM
Dl, Dp and Dd and hl, hp and hd; are diffusivities and
thickness of liquid layer surrounding the drug particle,
polymer coating membrane surrounding the polymer matrix
and the hydrodynamic diffusion layer surrounding the
polymer coating .
Kl, km and kp are the partition coefficient for the interfacial
partitioning of the drug from the liquid compartment to the
polymer matrix, from the polymer matrix to the polymer
coating membrane and from the polymer coating membrane
to the elution solution respectively.
69

70. 5. MICRORESERVIOR TYPE OR MICROSEALED
DISSOLUTION CONTROLLED SYSTEM
Sl and SP are the solubility of the drug in the liquid
compartment and in the polymer matrix respectively.
The release of drug from this system can follow either
a partition control or matrix diffusion control process
depending upon the relative magnitudes of Sl and SP
70

71. 6. POROPLASTIC TYPE SYSTEM
Poroplastic film consists of ultra micro porous
membranes which are not sensitizing to skin and are
fairly stable at higher than normal temperature and at
biological pH.
It is made utilizing the concept of water coagulation
of cellulose triacetate solution in organic acid at low
temperature.
The coagulation is performed under controlled
condition.
71

72. 7. TRANSDERMAL DELIVERY OF THE
MACROMOLECULE
Macromolecules such as Hormones, interferons,
bioactive peptides can be delivered by Trans dermal
delivery system.
The devices used for this purpose are divided in to two
categories….
1. Devices based on ethylene vinyl acetate
copolymers (EVAc).
2. Devices based on silicone elastomer.
72

73. 7. TRANSDERMAL DELIVERY OF THE
MACROMOLECULE
This both the system utilize one common concept i.e.
Matrix must have channel to facilitate the release of macro molecule
This device is used as implants
73

74. 8. OTHER TDDS
 Built-in battery layer
 Comparable in size to a normal transdermal patch
 The Lectro Patch, General Medical Co.
 Treatment time : 20 min
 Recommended maximum current : 4mA
 Lidocaine (local anesthesia), dexamethasone (arthritis), hydrocortisone (arthritis),
acetic acid (calcified tendinitis) etc.
74
 IONTOPHORESIS

75. 75
IONTOPHORESIS

76. 8. OTHER TDDS
Sonophoresis:
The application of high frequency ultrasound to enhance
drug penetration.
Examples:. Lidocaine, hydrocortisone, salicylic acid.
Electroporation:
Transient high-voltage electrical pulses, to cause rapid
permeabilization of the stratum corneum through which
large and small peptides, oligonucleotides and other drugs
can pass in significant amounts.
76

77. 8. OTHER TDDS
Reverse iontophoresis:
Current passage causes ions and other molecules to
move in both directions under both electrodes.
Hence it is possible to sample an analyte in the body,
and to provide a drug in response to the analyte
level, e.g., sugar, glucose.
77

78. Trandermal Matrix patch designs
78
Matrix
Reservoir
Drug in adhesive
Multilaminate
Backing Drug Membrane Adhesive Liner / skin

79. Transdermal Production Process
79

80. Transdermal Controlled-Release Products
and Devices
80
Drug Trade Name Type of Devices Indication
Scopolamine Transderm-Scop Reservoir Motion sickness
Nitroglycerine Transderm-Nitro Reservoir Angina
Nitro-Dur Monolithic
Nitrodisc Monolithic
Estradiol Estraderm Reservoir and
ethanol enhancer
Hormone
treatment

81. Transdermal Products under Development
81
Drug Trade name Producer-Marketer
Minocycline Sunstar American Cyanamide, Takeda
Estradiol+Noret
histerone
Estracombi
TIS
Ciba-Geigy, Alza
DHEA Pharmedic
Fentanyl
Triamcinolone
acetonide
Whitby Pharm.

82. Recently approved transdermal contraceptive
Recently approved by FDA (Ortho-McNeil)
Once a week for three weeks, fourth week patch free
99 percent effective when used as directed
Combination estrogen and progestin
One-and-three-quarter inch square applied to the
lower abdomen, buttocks or upper body.
Skin irritation or detachment reported in 2-5% of
patients
82

83. EVALUATION
83

84. 1.EVALUATION OF ADHESIVE
A. Peel adhesion properties
 Peel adhesion is the force required to remove an
adhesive coating from a test substrate.
 This properties are affected by the molecular wt. of
the adhesive polymer, the type and amount of
additives, and polymer composition.
84

85. 1.EVALUATION OF ADHESIVE
It is tested by measuring the force required to pull a
single coated tape, applied to a substrate, at a 180o
angle.
85

86. B. Tack properties:
Tack is ability of the polymer to adhere to substrate
with little contact pressure.
It is dependent on the molecular weight and
composition of polymer as well as the use of
tackifying resin in the polymer.
Tests for tack include....
86
1.EVALUATION OF ADHESIVE

87. a. Rolling ball test:
This test involves measurement of the distance that
a stainless steel ball travels along an upward facing
adhesive. The less tacky the adhesive, the farther the
ball will travel.
87

88. b. Quick-stick (or peel-tack) test:
The peel force require to break the bond between an
adhesive and substrate is measured by pulling the
tape away from the substrate at 90o at a speed at 12
inch/min.
The force is recorded as the tack value and is
expressed in ounce or grams per inch width with
higher values indicating increasing tack.
88

89. 89
1.EVALUATION OF ADHESIVE

90. c. Probe tack test:
Here, the force required to pull a probe away from
an adhesive at a fixed rate is recorded as tack (in
grams)
90
Adhesive
film
Annular
weight
Dial
Probe

91. C. Shear strength properties:
Shear strength is the measurement of the cohesive
strength of an adhesive polymer.
It is affected by molecular weight as well as the type
and amount of tackifier added.
Shear strength or creep resistance is determined by
measuring the time it takes to pull an adhesive coated
tape off a stainless steel plate when a specified weight
is hung from the tape which pulls the tape in a
direction parallel to the plate
91

92. Stainless steel plate
Adhesive
coated tape
Weight
92
1.EVALUATION OF ADHESIVE

93. 2. IN-VITRO DRUG RELEASE
EVALUATION
In these studies, excised skin is mounted on skin
permeation cells.
Skin of hairless mouse is used rather than human
cadaver skin.
In-vitro system should be designed in such way that
the intrinsic rate of release or permeation which is
theoretically independent of the in-vitro design can
be accurately determined.
93

94. 2. IN-VITRO DRUG RELEASE
EVALUATION
Several designs of the in-vitro membrane permeation
cell, the Jhawer-Lord (J-L), Valia-Chien (V-C) Cell,
Ghannam-Chein (G-C) membrane permeation
enhancer, Franz Diffusion Cell and the Keshry-
Chien(K-C) Cell.
K-C Cell has an effective receptor volume 12ml, skin
surface area of 3.14cm2. the receptor solution is stirred
by star-head magnet rotating at a constant speed of
600rpm driven by 3W synchronous motor.
94

95. Franz Diffusion Cell
95

96. ADVANTAGES
It can help in investigating the mechanism of skin
permeation of the drug before it can be developed in
TDDS.
Time needed to attain steady state permeation and the
permeation flux at steady state can be obtained.
It is use to optimize the formulation before more
expensive in vivo studies are performed.
Studies on skin metabolism can also be performed.
96

97. ADVANTAGES
It includes also ease of methodology, analytical
assay since there are no complication arising from
the disposition of the drug in the body and better
control over experimental condition than is possible
in vivo.
97

98. 3. EFFECT OF SKIN UPTAKE AND
METABOLISM
In this study, a piece (3cm by 3cm) of full thickness skin
(human cadaver skin) or stripped skin freshly excised from
a hair less mouse, 5-7 week old, was mounted between the
two compartments of each V-C permeation cell.
It was mounted in such a way that either the stratum
corneum or the dermis faced the drug solution and the
other side of the skin was protected with impermeable
aluminum foil.
98

99. 3. EFFECT OF SKIN UPTAKE AND
METABOLISM
The compartment with the skin surface uncovered was
filled with a saturated solution of drug in normal saline
and the compartment with the skin surface covered with
aluminum foil remained empty.
Both the compartment were maintained isothermally at
37oC. Samples were withdrawn from solution
compartment at predetermined times and assayed for drug
and any possible metabolite.
99

100. 4.IN-VIVO EVALUATION
a. Animal models:
The rhesus monkey is the most reliable model for in
vivo evaluation of transdermal drug in man.
Standard radiotracer methodology is used.
The application site is generally the forearm or
abdomen which are the least hairy sites on the animal’s
body.
100

101. 4. IN-VIVO EVALUATION
Limitation of using this animal include cost and handling
capabilities required.
Ethical consideration also limit the use of rhesus
monkey.
Other animals are weanling pig and human skin grafted
nude mouse.
Difficulties in using these animals are their non
availability and the facilities and skill required for their
handling.
101

102. 4. IN-VIVO EVALUATION
b. Human models:
Procedure for in vivo evaluation in humans were first
described by feldmann and maibach in 1974.
They involve the determination of cutaneous
absorption by an indirect method of measuring radio
activity in excreta following topical application of the
labelled drug.
This method is used since plasma level following trans
dermal administration of a drug are too low to use
chemical assay procedure.
102

103. 4. IN-VIVO EVALUATION
The % of dose absorbed transdermally is calculated by
Total radioactivity excreted after topical adm.
Total radioactivity excreted after i.v. adm.
Various modification have been made for this method, it
is given below.
103
% Drug absorbed =

104. RESERVOIR TECHNIQUE
It is simple technique, short exposure of the skin to the
compound (radio-labelled) under study followed by removal
of the stratum corneum.
From this analysis, it is possible to predict the amount of
drug that will penetrate over a longer period of time.
LIMITATION:
oInvasive nature of the technique due to the tape stripping
required.
oThe single measurement obtained which does not allow
detailed kinetic analysis & adm. of large dose of radio active
material is required.
104

105. 5. CUTANEOUS TOXICOLOGICAL
EVALUATION
 CONTACT DERMATITIS:
It can be either
I. Contact irritant dermatitis or
II. Contact allergic dermatitis
I. Contact irritant dermatitis:
 It results from direct toxic injury to cell membrane,
cytoplasm or nuclei.
105

106. 5. CUTANEOUS TOXICOLOGICAL
EVALUATION
 Two types of protocols are used
o Ten days primary irritation test &
o Twenty one days irritation test
II. Contact allergic dermatitis:
 It involves a host immunological reaction to an
antigen.
 It can be screened by the guinea pig maximization
test.
106

107. ADVANCED RESEARCHES
MICROARRAY NEEDLE
Advanced micro-needle Patch transdermal system
allowing continuous delivery through the skin of
proteins and water-soluble drugs.
107

108. ADVANCED RESEARCHES
•The device create painlessly micropores in the S.C.
known as microstructered arrays or microneedles.
•These devices have about 400 microneedles.
•The solid silicone needles (coated with drug) or hollow
metal needles (filled with drug solution) penetrate the
horny layer without breaking it or stimulating nerves in
deeper tissues.
•Flux increase up to 1,00,000 fold are reported.
108

109. MICRONEEDLE ARRAY
109

110. Multidose Transdermal Drug Delivery
System
It is comprises a laminate composite with a plurality of
compartments.
Each compartment is a reservoir for a unit dose of a drug
active to be transdermally administered.
Individual seals are provided for resealably enclosing the
drug active in each of the reservoirs.
The individual enclosing seals are removable to release
the unit dose into contact with the skin of the patient and
are actuable to control the transdermal absorption of the
drug actives.
110

111. MICRO TRANS
111
Applications :
 Delivery of large proteins, fragile antibodies, and
hormones.
 Delivery of small molecules, particularly those
with difficulty diffusing through skin layers.
 Delivery of vaccines, both conventional and DNA-
based.
 Fluid sensing of glucose, hormones, blood gases,
and therapeutic drug levels.

112. • This system makes oversaturation of adhesive
polymer with drug forcing partial crystallization.
• Presence of both molecular and solid state, allow
higher conc. & consistent supply of drug.
• As skin absorbs dissolved drug, crystals re-
dissolve to maintain drug at solubility limit (max.
thermodynamic activity) at the site of contact.
• This results in smaller thinner patches with better
patient acceptability. Clinical trials with this
technology with β2 adrenergic agonist tulobutarol
confirmed superiority of TDDS formulation over
oral formulation
112
Crystal reservoir technology

113. Key Features
Simple for patient to use, and fully disposable.
Unique manufacturing techniques result in very low
cost.
Accurate, reliable delivery of drug to epidermis or
dermis, circumventing the stratum corneum.
Passive or active drug delivery profiles.
Can be used with Valeritas' e-Patch and h-Patch™
device to deliver a wide range of drug volumes under
various extended or time-release profiles
113

114. Choose a dry, unbroken, non-hairy part of your skin. The
buttocks, lower abdomen, lower back, and upper arm (outer
part) are good choices. If the area you choose has body hair,
clip (do not shave) the hair close to the skin with scissors.
Make sure that the area is clean. If there is any oil or
powder (from bath products, for example), the patch may
not stick properly.
Attach the adhesive side of the patch to your skin in the
chosen area.
114
Find an appropriate place to put the
patch

115. A stiff protective liner covers the sticky side of the patch
- the side that will be put on your skin. Hold the liner at
the edge and pull the patch from the liner. Try not to
touch the adhesive side of the patch. Throw away the
liner.
Press the patch firmly on your skin with the palm of
your hand for about 30 seconds. Make sure the patch
sticks well to your skin, especially around the edges. If
the patch does not stick well, or loosens after you put it
on, tape the edges down with first aid tape.
Wash your hands after applying the patch.
115
Find an appropriate place to put the
patch

116. 116
Find an appropriate place to put the
patch

117. Product Development Challenges
Flux sufficient but manageable size
Adequate skin adhesion
Adequate shelf life stability
Non-irritating
Aesthetically pleasing
Easy to handle and use
Comfortable
Unobtrusive
Product cost
117

118. REFERENCES
Transdermal controlled systems medication by Y.W. Chein.
 Controlled drug delivery – Fundamental and Application, 2nd edition, by
Joseph R. Vincent, H.C. Lee page no.: 524 – 589.
Controlled drug delivery – Concepts and Advances, by S.P. Vyas and Roop
K. Khar page no.: 411 – 447.
118

119. REFERENCES
Novel drug delivery systems, 2nd edition, by Y.W.
Chein page no.: 338 – 380.
The Eastern Pharmacist - “Transdermal drug
delivery system”, vol.34,1991
http://www.google.com
119