1. Transdermal drug delivery system

2. 2
Transdermal Therapeutic
Systems
Diffusion of the medication (drug) through skin into
the systemic circulation for distribution and
therapeutic effect
Most TDD systems use passive delivery

3. 3
13.1 13.1 AAddvvaannttaaggeess ooff TTTTSS’’ss
1. Eliminates oral absorption variables.
2. Eliminates first-pass metabolism
3. Provides controlled constant drug.
4. Can accommodate potent drugs
5. Permits self-administration
6. Non-invasive (no needles or injections)
7. Improves patient compliance
8. Easy treatment termination

4. 4
Limitations of TDD Systems
• Poor diffusion of large molecules
• Skin irritation

5. 5
TDD System Design Factors
• Therapeutic indication
• Desired drug delivery profile
- Dose level, duration, etc.
• Skin adhesion profile
• Application site
• Ease of application
• Patch size, shape, appearance, comfort
• Wear period
• Packaging
• Patch disposal
• Patch cost

6. 6
Process of transdermal permeation.

7. 7
BASIC COMPONENTS OF TDDS
1.Polymer matrix
2.The drug
3.Permeation enhancers
4.Other excipients
1.Polymer matrix
Ideal polymer
٠MWT,and chemical functionality of the polymer should not affect the
diffusivity of drug and its release
٠stable
٠non reactive
٠easily manufactured
٠easily fabricated into desired product
٠inexpensive
٠degaradation product must be non toxic or non antagonistic to the host
٠ should retain its mechanical properties when the large amount of drug is
loaded in to it

8. 8
Polymers used in TDDS
• Natural polymers
– Cellulose derivatives
– Zein
– Gelatin
– Shellac
– Waxes
– Proteins
– Gums
– Natural rubbers
– starch
• Synthetic elastomers
--polybutadiene
--hydrin rubber
--polysiloxone
--silicone rubber
--nitrile
--acrylonitrile
--butyl rubber
--styrene butadiene rubber
--neoprine etc.
• Synthetic polymers
PVA,PVC,PE,PP,Poly amide,Poly acrylate,Polyurea,PVP,PMMA,Epoxy etc.

9. 9
2. Suitable drug candidate
• Physico chemical properties of drug
– Should have MW less than 1000 daltons(800-1000)
– Should have affinity for both lipophilic and hydrophilic phases
– Should have low melting pont
• Biological properties of drug
– Should be potent(less than 20mg)
– Half life should be short
– Must not induce a cutaneous irritant or allergic response
– Drugs which degrade in the GI tract or inactivated by hepatic
first pass effect are suitable candidate
– Tolerance to the drug must not develop
– Drugs which has to be administered for a longer period of time
can be formulated
– Drugs which cause adverse effects to non target tissues can
also be formulated

10. 10
3.PERMEATION ENHANCERS
(to enhance stratum corneum permeability)
• Solvents
Increases penetration by swelling the polar pathway transport or fluidising lipids
Eg.water,ethanol,methanol,DMS,homologs of methyl sulphoxide,dimethyl
acetamide,and DMF,2-pyrrolidone,N-methyl,2-
pyrrolidone,laurocapram,PG,glycerol,silicone fluids,isopropyl palmitate.
• Surfactants
Enhances the polar pathway transport of hydrophilic drugs
• Anionic surfactants
Dioctyl sulpho succinate,SLS,deco decylmethyl sulphoxide etc.
• Non ionic surfactants
Pluronic F127,Pluronic F68,etc.
• Bile salts
Sodium taurocholate,sodium deoxy cholate,sodium tauroglycocholate.
• Binary systems
Propylene glucol-oleic acid and 1,4-butane diol-linoleic acid
• Miscellaneous
Urea-hydrating and keratolytic agent,N,N-dimethyl-m-toluamide,calcium
thioglycolate,anti cholinergic agents
• Potential permetion enhancers
Euclyptol,di-o-methyl-ß-cyclodextrin and soyabean casein

11. 11
Permeability Coefficient Is the Critical
Predictor of Transdermal Delivery
Transport = Flux = (mg/cm2/sec) = P x A x (Cd – Cr)
Permeability Coefficient = P = D x K (cm/sec)
h
Where A = Surface area of patch
D = Diffusivity of drug in membrane (skin)
K = Partition coefficient (patch/skin)
C = Concentration in donor or receptor
(patch or skin)
h = Thickness of membrane (skin)

12. 12
4.OTHER EXCIPIENTS
• Adhesives
Ideal properties
• Should not irritate or sensitize the skin or affect normal functions of the skin
• Should adhere to the skin aggressively
• Should be easily removed
• Should not leave an un washable residue on the skin
• Should have an intimate contact with the skin
• Should be compatible with the drug,excipients and permeation enhancers
• Permeation of drug should not be affected
• Backing membrane
Ideal properties
• Flexible and provide good bond to the drug reservoir
• Prevent drug from leaving the dosage form
• Should be impermeable
• E.g.metallic plastic laminate,plastic backing with absorbent pad and
occlusive base plate,adhesive foam pad with occlusive base plate.

13. • Liner: Protects the drug during storage
and is removed prior to use
• Drug
• Adhesive: Serves to bind the components
of the patch to the skin
• Membrane: Controls the release of the
drug from the reservoir in certain types of
patches
• Backing: Protects the patch from the outer
environment.
13

14. 14
Formulation of TDDS
1.Membrane-moderated or permeation controlled TDDS
• Drug reservoir(homogenous dispersion of drug with polymeric matrix or
suspension of drug in un leachable viscous liquid medium such as silicone
fluid) is encapsulated within drug impermeable metallic plastic laminate and
a rate controlling polymeric membrane(ethylene vinyl acetate co polymer)
• The cross sectional view of this system is shown in the following Fig.1

15. 15
Reservoir Patches
• The reservoir system has a drug layer that
is separate from the adhesive.

16. 16
Schematic Drawing of the Reservoir type of patch.
Film Backing
Drug Layer
Rate-controlling Membrane
Contact Adhesive
Protective Peel Strip (removed prior to use)
skin

17. 17
• Drug molecule are permitted to release through this rate controlling
membrane
• A thin layer of silicone or poly acrylate adhesive may be applied to the
external surface of the rate controlling membrane to achieve intimate
contact of the TDDS and the skin surface
• Release rate of this TDDS depends upon the polymer
composition,permeability co efficient and thickness of the rate cotrolling
membrane and adhesive
• The intrinsic rate of drug release from this TDDS is calculated by the
following formula.1
CR
dQ/dt= --------------------
1/Pm+1/Pa

18. 18
Where
CR-con.of drug in the reservoir compartment
Pm-permeability co efficient of rate controlling polymeric
membrane
Pa- permeability co efficient of adhesive
For microporous membrane
Km/r. Dm
Pm = --------------------
hm
Ka/m. Da
Pa = --------------------
ha
Substituting these values in formula.1, it becomes
Km/r .Ka/m .Dm.Da
dQ/dt= ---------------------------------------------CR
Km/r. Dm.ha + Ka/m. Da. hm

19. 19
Where
• Km/r --partition co-efficient of drug between membrane and reservoir
• Ka/m --partition co-efficient of drug between adhesive and membrane
• Dm --diffusion co-efficient of drug in the membrane
• Da -- diffusion co-efficient of drug in the adhesive
Example of this system are
1.Nitro glycerin releasing TDDS (Transderm-Nitro/ciba,USA)for once a day
medication in angina pectoris
2.Scopolamine releasing TDDS (Transderm-Scop/ciba,USA)for 72
hrs.prophylaxis of motion sickness
3. Estradiol releasing TDDS (Estraderm/ciba)for treatment of menopausal
syndrome
4. Clonidine releasing TDDS (Catapres/Boehringer Ingelheim)for 7 day therapy
of hyper tension
5. Prostaglandin-derivatives TDDS

20. 20
2.Adhesive diffusion/dispersion-controlled
TDDS
Drug reservoir
• homogenous dispersion of drug with adhesive polymer(poly(isobutylene) or
poly acrylate)
• Then spreading of this medicated adhesive polymer on flat sheet of drug
impermeable metallic plastic backing to form thin drug reservoir layer
• On top of the drug reservoir layer,thin layers of rate controlling adhesive
polymer of specific permeability and constant thickness are applied to
produce an adhesive diffusion/dispersion-controlled TDDS
• The cross sectional view of this system is shown in the following Fig.2

21. 21
Drug in Adhesive
Patches
• A system in which the drug is incorporated
directly into the adhesive, rather than into
a separate layer. Usually used for smaller
molecular weight compounds.
• These can be either a single layer or multi-layer.
• Sometimes referred to as the “matrix type
patch”

22. 22
Schematic Drawing of the Matrix (Drug-in-Adhesive) type
of patch.
Film Backing
Drug/Adhesive Layer
Protective Liner (removed prior to use)
skin

23. 23
• The rate of drug release in this system is defined by
Ka/r.Da
dQ/dt= -----------------CR
ha
Where
Ka/r-partition co-efficient of drug bw adhesive layer and reservoir layer
Da-diffusion co-efficient of drug in the adhesive layer
ha-thickness of adhesive layer
Examples for this system
1.Iso sorbide dinitrate-releasing TDDS
2.Verapamil releasing TDDS

24. 24
• 3.Matrix diffusion-controlled TDDS
Drug reservoir
• homogenous dispersion of drug with hydrophilic or lipophilic polymer matrix by any
one of the following methods
• Homogenous dispersion of finely ground drug particles with liquid polymer or highly
viscous base polymer followed by cross linking of polymer chains
• Homogenous mixing of drug solid with rubbery polymer at an elevated temperature
• Dissolving the drug and polymer in a common solvent follwed by solvent evaporation
in a mould at an elevated temperature or under vaccum.
• Medicated polymer is moulded in to desired surface area and controlled thickness
• This medicated polymer disc is pasted on to an occlusive base plate with
impermeable plastic backing
• Then the adhesive polymer is spread along the circumference to form a strip of
adhesive rim around the medicated disc

25. 25
• the rate of drug release from this sytem is defined as
A Cp Dp
Dq/dt = [ ---------------------] 1/2
2t
where
A initial drug loading dose
Cp and Dp are solubility and diffusivity of drug in poymer matrix
the rate of drug release from this system at steady state is defined as
Q/t1/2= [(2A-Cp) Cp Dp] 1/2

26. 26
Example of this system are
1.Nitro glycerin releasing TDDS (Nitro-Dur and Nitro-Dur II /Key pharmaceuticals,USA)
2. Estradiol di acetate releasing TDDS
3. Verapamil releasing TDDS
The cross sectional view of this system is shown in the following Fig.3

27. 27
4.Micro reservoir type/micro sealed dissolution-controlled
TDDS
Combination of the reservoir and matrix diffusion
Drug reservoir
•suspension of drug with aqueous solution of water soluble liquid polymer
•Homogenous dispersion of drug suspension in a lipophilic polymer(silicone elastomer)
•As a result discrete un leachable microscopic spheres of drug reservoir is formed which is stabilized
by cross linking
•Medicated polymer is moulded in to desired surface area and controlled thickness and it is coated
with a layer of bio compatible polymer to modify mechanism and rate of drug release
•This medicated polymer disc is pasted on to an occlusive base plate with impermeable plastic backing
•Then the adhesive polymer is spread along the circumference to form a strip of adhesive rim around
the medicated disc
Example of this system are
1.Nitro glycerin releasing TDDS (Nitrodisc /searle,USA)
The cross sectional view of this system is shown in the following Fig.4

28. 28

29. Products on the market, or in development include:
• Clonidine
• Works as an agonist of adrenaline at the
presynaptic a2 adrenergic
• Product name = Catapres-TTS®
• used to treat hypertension
29

30. 30
• Ethinylestradiol (EO) and norelgestromin (N)
• Product name = Ortho-Evra®
• Used for Contraception
• Type of patch = Drug-in-Adhesive
• Frequency of application = weekly

31. 31
• Fentanyl
• Product Name = Duragesic®
• Used for: Analgesia
• Type of Patch = Drug-in-Adhesive
• Frequency of Application = Weekly

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• Lidocaine
• Product Name = Lidoderm®
• Used for: analgesia of postheretic neuralgia
(PHN), a painful condition caused by the
varicella zoster virus (herpes zoster = shingles)
• Type of Patch = Reservoir
• Frequency of Application = Daily

33. 33
• Nicotine
• Product name = Habitrol®, Nicoderm –
CQ®, Nicotrol®, Prostep®
• Used for: Smoking cessation
• Frequency of administration = Daily

34. • 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
34
Nitrodisc is reservoir
• Frequency of administration = Daily

35. 35
• 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

36. 36
• Estradiol + Norethindrone
• Product name = CombiPatch®
• Used for: Hormone Replacement

37. 37
• 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

38. • Scopolamine
• Works as competitive antagonist of acetylcholine
at the muscarinic receptor
• Product Name = Transderm Scop®
• Used for: Motion Sickness
38

39. 39
• Testosterone
• Product Names = Androderm®, Testoderm
TTS®, Testoderm®
• Used for: Hypogonadism

40. • 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
40

41. Manufacturer Trade name Drug Strength available
41
Ciba
Estraderm Estradiol 25 μg, 50 μg, 100 μg
Transderm-Scop Scopolamine 1.5 mg
Transderm-Nitro Nitroglycerin 0.1 mg, 0.2 mg
Janssen Duragesic Fentanyl 25 μg, 50 μg, 100 μg
Basel Habritol Nicotine 21 μg
Parke-Davis Nicotrol Nicotine 21 μg
Lederle Prostep Nicotine 21 μg

42. 42
TTS Available in market
Large scale mfg of TTS

43. 43
Evaluation Parameters
Physical parameters
Evaluation of adhesive
In-vitro testing
In-vivo assessment
Cutaneous metabolism
Stability studies
Evaluation of skin reactions.
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44. 44
Thickness
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45. 45
Weight variation
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46. 46
Folding endurance
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47. 47
Moisture content
% Moisture content = Initial weight – Final weight X 100
Final weight
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48. 48
Moisture uptake
% moisture uptake = Final weight – Initial weight X 100
Initial weight
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49. 49
Flatness
% constriction = I1 – I2 X 100
I1
I2 = Final length of each strip
I1 = Initial length of each strip
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50. 50
Drug content
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51. 51
Water Vapor Transmission studies
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52. 52
Evaluation of adhesive
1} Peel adhesion
properties
It is the force required to remove adhesive from test substrate.
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53. 53
2} Tack properties
It is the ability of the polymer to adhere to substrate with little contact
pressure.
2.1} Thumb tack test
2.2} Rolling ball tack test
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54. 54
2.3}Quick-stick (or peel-tack)
test
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55. 55
2.4} Probe tack
test
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56. Shear strength is the measurement of the cohesive strength of adhesive polymer.
56
3} Shear strength properties
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57. 57
Tensile strength
Tensile strength= F/a.b (1+L/l)
F - the force required to break
a - width of film
b - thickness of film
L - length of film
l - elongation of film at break point
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58. 58
In-vitro testing
The Paddle over Disc
The Cylinder modified USP Basket
The reciprocating disc
Diffusion Cells e.g. Franz Diffusion Cell and its modification
Keshary- Chien Cell
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59. 59
In-vitro testing
Importance
(1)Defining skin permeation kinetic studies using a
diffusion cell system and cadaver skin during the drug
development process.
(2) in vitro drug release kinetics, to be used for batch-to-
batch release and as a compendial test.
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60. Preparation of skin for permeation studies
• Intact Full thickness skin
• Separation of epidermis from full
thickness skin:
60

61. 61
K-C cell for permeation studies
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62. 62

63. Effect of skin uptake metabolism
63

64. 64
In-vivo assessment
1} Animal model
Mouse, hairless rat, hairless dog, hairless rhesus monkey,
rabbit, guinea pig
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65. 65
In-vivo assessment
2} Human model
. Phase I clinical trials are conducted to determine mainly safety in
volunteers.
Phase II clinical trials determine short term safety and mainly effectiveness
in patients.
 Phase III trials indicate the safety and effectiveness in large number of
patient population.
Phase IV trials at post marketing surveillance are done for marketed
patches to detect adverse drug reactions.
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66. Skin irritation studies
• Group I was served as normal, without
any treatment.
• Group II, control, was applied with
marketed adhesive tape.
• Group III Transdermal systems (blank)
• Group IV Transdermal systems (drug
loaded)
• Group V standard irritant .
66
Contact dermatitis

67. 67
Evaluation of skin reactions.
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68. 68
Stability studies
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69. Study Storage conditions Time period
Temperature Relative
humidity
Long Term 25°C± 2°C
OR
30°C± 2°C
60%± 5%
OR
65%± 5%
12 months
Intermediate 30°C± 2°C 65%± 5% 6 months
Accelerated 40°C± 2°C 75%± 5% 6 months
69

70. 70
APPLICATIONS
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71. 71
The Past
• 3000 BC--Pharmaceuticals and plasters first
recorded in Babylonia.
• 1500 BC--Plasters recorded in the Ebers
Papyrus (Egypt).
• Plasters made by physicians or pharmacists at
the time of dispensing
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72. 72
The Past
P Plasters, Poouullttiicceess aanndd CCeerraatteess
• Used for topical and deep tissues
• Counterirritants, protective dressings, belladonna,
salicylic acid, flaxseed, mustard,
• Adhered to skin with stiff ointments, waxes,
melted waxes and rubber resins, kaolin
• Applied hot, could absorb water
• Backings made of cloth or animal skin
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73. 73
The Past: Adhesives
Example of plaster formula (1909)
Rubber 20 grams
Petrolatum 20 grams
Lead Plaster 960 grams
To make, 1000 grams
Add any one of the following Belladonna Leaves,
Oleoresin of Capsicum, Mercury, Opium, Soap
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74. The Past
The last 150 years:
• Electrically assisted applications first occurred
in late 1800s and in early 1900s.
• Rubber became available in the 1800s
• Nitroglycerin was applied topically as an
ointment for delivery to the bloodstream in
the 1950 to present.
• Belladonna, capsicum, mustard and salicylic
acid plasters
74
09/30/14 74

75. 75
The Present Day
• 1970-- Alza Research (US) began first
development of the modern transdermal
• 1980-- Scopolamine first transdermal reached
US
• 2002– Many Rx and non-RX products in US
market.
• Transdermals deliver drugs from a few hours
up to 7 days.
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