1. Seminar on…..
TRANSDERMAL DRUG
DELIVERY SYSTEMS
Presented by…..
P.CHAKRADHAR
M. Pharm 1st
Year
Dept. of Pharmaceutics
K.L.E. University, 1

2. Contents
 Introduction.
 Advantages & Disadvantages
 Structure of the skin.
 Permeation through skin.
 Factors affecting permeation.
 Basic components of TDDS
 Formulation approaches used in the
development of TDDS
 Evaluation of TDDS
 Advances in TDDS
 References.
2

3. Introduction
 Definition – Transdermal
therapeutic systems are
defined as self contained ,self
discrete dosage forms ,which
when applied to the intact skin
deliver the drug at a controlled
rate to the systemic circulation.
 A simple patch that you stick
onto your skin like an adhesive
bandage, which utilize passive
diffusion of drugs across the
skin as the delivery
mechanism.
3

4. Advantages
1. It delivers a steady infusion of the drug over an extended
period of time .Adverse effects and therapeutic failures can
be avoided .
3. It increases the therapeutic value of many drugs by avoiding
specific problems associated with the drug .
5. The simplified medication regimen leads to an improved
patient compliance and reduce inter patient and intra patient
variability.
7. Self medication is possible with this type of system.
9. The drug input can be terminated at any point of time by
removing the patch.
4

5.  Transdermal Drug Delivery Offers the Best of IV
and Oral Administration
IV Oral TDD
 Reduced first-pass effects Yes No Yes
 Constant drug levels Yes No* Yes
 Self-administration No Yes Yes
 Unrestricted patient activity No Yes Yes
5

6. 1. The drug must have desired physicochemical properties for
penetration through the stratum corneum.
3. Skin irritation or contact dermatitis due to excipient and enhancers of
the drug used to increase the percutaneous absorption, is the other
limitation.
5. The barrier function of the skin changes from one site to the another
on the same person , from person to person and with age .
7. 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.
9. The patches fall off during bathing and sleeping. … has resorted to
using medical tape to help secure patches.
11. Patches fall off completely during bathing or swimming; patches
sometimes fall off during walking.
13. Slight movement and sweating will cause patches not to stick.
6

7. History
 The first Transdermal patch was approved in 1981 to
prevent the nausea and vomiting associated with motion
sickness.
 The FDA has approved, till 2003, more than 35
Transdermal patch products, spanning 13 molecules
( In USA).
 The US Transdermal market approached $1.2 billion in
2001
 It was based on 11 drug molecules: fentanyl,
nitroglycerin, estradiol, ethinylestradiol,
norethindroneacetate, testosterone, clonidine, nicotine,
lidocaine, prilocaine, and scopolamine.
 Two new, recently approved Transdermal patch products
(a contraceptive patch containing ethinylestradiol and
nor elgestromin ,and a patch to treat overactive bladder,
containing oxybutynin.
7

8. More than 35 TDD products have now been
approved for sale in the US 。
And approximately 16 active ingredients are
approved for use in TDD products globally

9. Where as 13 compounds
currently exist in approved
Transdermal products in the
US
Six new (i.e., new to the
Transdermal market) low
molecular weight molecules
are currently in either
preclinical or clinical
development.
Another noteworthy element
of Table 1is that several of the
compounds (macromolecules
and vaccines) in development
are outside of the normal
niche for TDD

10. Structure of the skin
 Anatomically the skin has many histological layers, but
it is divided into three layers –
2. Epidermis .
4. Dermis .
6. Subcutaneous tissue.
10

11. 11
Structure of Skin

14. Epidermis
 The epidermis is divided into following parts
The stratum corneum and stratum germinativum.
 The stratum corneum forms the outer most layer of the
epidermis and consists many layers of compacted ,
flattened, dehydrated keratinized cells in the stratified
layer .
 Water content of stratum corneum is around 20%.
 The moisture required for stratum corneum is around
10% (w/w) to maintain flexibility and softness.
14

15.  The stratum corneum is responsible for the barrier
function of the skin and behaves as a primary
barrier to the percutaneous absorption.
 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.
15

16. 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.
 Below the dermis there is a fat containing subcutaneous
tissue .
 Upper portion of the dermis is formed into ridges
containing lymphatics and nerve endings.
16

17. Subcutaneous
 This is a sheet of the fat containing areolar
tissue known as the superficial fascia.
attaching the dermis to the underlying
structures .
17

18.  BIOCHEMISTRY OF THE SKIN
Epidermis –
4. The main source of energy for the lower portions of the
epidermis is the glucose and the end product is the lactic
acid.
6. Fatty acids are required for the cellular functions of the
skin and cells derives their energy from the degradation
of the phospholipids .
8. The energy derived is used for the synthesis of proteins
and construction of the stratum corneum.
10. Proteolytic enzymes are present in the stratum corneum
and epidermis consists of specialized organelles like
lysosymes .
18

19.  Dermis-
2. Protein synthesis is the key factor in the dermal
metabolism.
3. Fibroblast extracellularly deposit large quantities of
collagen and elastin.
4. Protein synthesis occurs in the hair follicles .
5. The sebaceous gland produce large quantities of lipids
and the energy is derived from the intracellular aerobic
carbohydrate metabolism is used for cellular synthetic
process.
19

20.  Skin surface –
2. The skin surface has a population of micro
organisms and can contribute to enzymology.
4. The diversity and abundance varies from
individual to individual.
6. The microorganism alter the skin surface lipid
composition via hydrolysis of secreted sebum
20

21. Permeation through skin
 The permeation through the skin occurs by the following
routes-
 Transepidermal absorption.
 Transfollicular (shunt pathway absorption).
 Clearance by local circulation .
21

22. Pathways of permeation
through skin
22

23. Transepidermal Absorption
 Stratum corneum is the main resistance for absorption
through this route .
 Permeation involves partitioning of the drug into the
stratum corneum.
 Permeation through the skin depends upon the o/w
distribution tendencies of the drug.
 Lipophilic drug concentrate in and diffuse with relative
ease .
 Permeation through the dermis is through the
interlocking channels of the ground substance .
23

24. Transfollicular Absorption
 The skin appendages (sebaceous and eccrine glands )
are considered as shunts for by passing the stratum
corneum.
 Follicular route is important for permeation because the
opening of the follicular pore is relatively large and
sebum aids in the diffusion of the penetrant.
 Partitioning into the sebum followed by the diffusion to
the depths of the epidermis is the mechanism
24

25. Clearance by local circulation
 The earliest point of entry of drugs into the systemic
circulation is within the papillary plexus in the upper
epidermis
 The process is thus regarded as the end point.
25

26. Factors affecting permeation
through skin
 Age has an effect on the permeation of drugs
through the skin.
 Blood flow (dermal clearance of the molecule
transversing the tissue ) tends to decrease with
age and could reduce transdermal flux.
26

27.  The other factors that affect the
permeation of the drug through the skin
are –
 The stratum corneum thickness .
 Presence of hair follicles .
 Injury or trauma to the skin .
 Hydration of the skin.
 Effect of humidity and temperature .
 Chemical exposure.
 Chronic use of certain drugs .
27

28. Basic Components of TDDS
 The components of the transdermal drug delivery system
include –
 Polymer matrix or matrices
 The drug
 The permeation enhancers
 Other excipients
28

29. Basic components of Transdermal
drug delivery
29

30. Polymer matrix
 It releases the drug from the device and should
satisfy the following criteria-
ii. Molecular weight , chemical functionality of the
polymer should be such that specific drug
diffuses properly and gets released through it .
iii. It should be stable , non reactive with the drug,
easily manufactured and fabricated into the
desired product
iv. The polymer and its degradation products must
be non toxic or non antagonistic to the host .
30

31.  The mechanical properties of the polymer should
not deteriorate excessively when the large
amount of the active agents are incorporated into
it.
 The polymers used in the transdermal drug
delivery systems are –
 Natural polymers – cellulose derivatives ,zein ,
gelatin , shellac ,waxes , proteins , gums and
their derivatives , natural rubber starch etc .
31

32.  Synthetic elastomers- poly butadiene , hydrin
rubber , poly siloxane silicone rubber , nitrile ,
acrylonitrile ,butyl rubber, butadiene Neoprene etc
.
 Synthetic polymers-polyvinyl chloride,
polyethylene, poly propylene, polyacrylate
,polyamide ,polyurea, polyvinyl pyrrolidone, poly
methyl methaacrylate
32

33. Drug
 For successful development of a transdermal drug
delivery, the following are the desirable properties of a
drug for transdermal drug delivery.
 Physicochemical properties .
 Biological properties .
33

34.  Physicochemical properties.-
 It is generally accepted that the best drug
candidates for passive adhesive Transdermal
patches must be ：
 Non-ionic.
 Low molecular weight (less than 500 Daltons),
 Adequate solubility in oil and water .
 Low melting point (less than 200℃ )
 Potent (dose is less than 50 mg per day, and ideally
less than 10 mg per day) .
34

35.  Biological properties –
3. The drug should be potent with a daily dose of
order of a few mg/ day.
4. The half life of the drug should be short.
5. The drug must not induce a cutaneous irritant or
allergic response.
6. Drugs degraded in the GIT or inactivated by the
hepatic first pass are suitable candidates for
transdermal drug delivery.
35

36. Permeation enhancers
 These are compounds which promote skin
permeability by altering the skin as a barrier to the
flux of the desired penetrant .
 The flux of the drug (J) is given by-
dc
J D
dx
D= diffusion coefficient
C = conc. of the diffusing species .
X= spatial coordinate
36

37.  Classification of Permeation enhancers:-
a. Solvents
b. Surfactants
i) Anionic surfactants: Dioctyl sulphosuccinate, Sodium
lauryl sulphate.
ii) Non-ionic surfactants: Pluronic F127, Pluronic F68
iii) Bile salts : Sodium taurocholate,Sodium
deoxycholate.
c. Binary systems : Propylene glycol, oleic acid
d. Miscellaneous chemicals : Urea, Calcium thioglycholate.
37

38. Other excipients
 Adhesives –The fastening of the transdermal device
is usually done by the adhesive .The adhesive should
satisfy the following criteria .
 Do not irritate or sensitize the skin.
 Adhere to the skin during the dosing interval.
 It should be easily removed .
 It should not leave any unwashable residue.
38

39.  The face adhesive system should satisfy the
following criteria .
 It should be physically and chemically compatible
with the drug, excipients and the enhancers.
 Permeation of the drug should not be affected .
 The delivery of the permeation enhancers should
not be affected. Polymers used in the adhesives are
polyisobutylenes , acrylic and silicones .
39

40. 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 (nonadsorptive)
• Printable
 Eg: metallic plastic laminate , plastic backing with adsorbent
pad adhesive foam pad .
40

41. Schematic Skin absorption of
drug
41

42.  Transdermal Drug Delivery mechanism
 Passive
 Matrix (Oxytrol,)
 Reservoir ( Duragesic)
 Active
 Iontophoresis
 Electroporation
 Sonophoresis
 Heat or thermal energy
 Micro needles

43. Formulation Approaches used in the
development of TDDS
1. Membrane permeation – controlled systems.
3. Adhesive dispersion – type systems.
5. Matrix diffusion – controlled systems.
7. Microreservoir type or Microsealed dissolution – controlled
systems.
9. Poroplastic – type systems.
11. Transdermal delivery of Macromolecules.
43

44. 1. Membrane permeation – controlled
systems
 The drug reservoir is totally encapsulated in a shallow
compartment moulded from a drug – impermeable metallic
plastic laminate & a rate controlling polymeric membrane
which may be microporous or non-porous.
 The rate of drug release from this type of TDDS can be
tailored by varying the composition of polymer, permeability
coefficient, thickness of the rate limiting membrane &
adhesive.
 Example:- i) Nitroglycerine-releasing Transdermal system
(Transderm-nitro) for once a day medication in angina
pectoris.
ii) Scopolamine-releasing Transdermal system (Transderm-
scop) for 72 hrs. prophylaxis of motion sickness.
44

45. Fig. Membrane moderated Transdermal drug delivery system
45

46. Continued…
 The intrinsic rate of drug release from this type is…
dQ CR
dt 1 1
Pm Pa ……………………(1)
Where, CR = Drug conc. In the reservoir
compartment.
Pa & Pm = permeability coefficients of Adhesive & the rate
controlling membrane respectively.
46

47. Continued…
 For microporous membrane, Pm is the sum of permeability
coefficients for simultaneous penetration across the pores &
polymeric material, hence…
Km/r Dm Ka/m Da
Pm & Pa
hm …….(2) ha …….(3)
47

48. Continued…
 In case of micro porous membrane, the porosity of the
membrane should be taken in to the calculation of Dm & hm
values,
Substituting eq. (2) & (3) in eq. (1)…
dQ Km/r Ka/m Dm Da
CR
dt Km/r Dm ha Ka/m Da ha
…………...(4)
48

49. 2. Adhesive dispersion – type systems
 The drug reservoir is formulated by directly dispersing the
drug in an adhesive polymer & then spreading the medicated
adhesive by hot melt, on to a flat sheet of drug impermeable
metallic plastic backing to form a thin drug reservoir layer.
 Example: Isosorbide dinitrate-releasing Transdermal
therapeutic system (Frandol tape) for once a day medication
of angina pectoris.
49

50. Fig. Adhesive dispersion type Transdermal drug delivery system
50

51. Continued…
 The rate of drug release in this system is defined by…
dQ Ka/r Da
CR
dt ha
Where, Ka/r = Partition coefficient for the interfacial partitioning
of the drug from the reservoir layer to adhesive layer.
51

52. 3. Matrix diffusion – controlled systems
i) It is prepared by homogeneously dispersing the drug particles
with a liquid polymer or a highly viscous base polymer
followed by cross linking of the polymer chains or
homogeneously blending the drug solids with a rubbery
polymer at an elevated temp.
ii) It can also be prepared by dissolving the drug & polymer in a
common solvent followed by solvent evaporation in a mould
at an elevated temp. or in a vaccum. It is then pasted on to an
occlusive base plate in a compartment fabricated from a
drug impermeable plastic backing, the adhesive polymer is
then spread along the circumference to form a strip of
adhesive rim around the medicated disc.
52

53. Fig. Matrix diffusion controlled Transdermal drug delivery system
53

54. Continued…
 Example: Nitroglycerine-releasing Transdermal system
(Nitro- Dur & Nitro- Dur II ) at a daily dose of
0.5 g/cm2 for therapy of angina pectoris.
 The rate of drug release from this type is given by…
dQ ACp Dp 1/2
dt 2t
Where, A = Initial drug loading dose dispersed in the polymer
matrix.
Cp & Dp = Solubility & diffusivity of the drug in the polymer
respectively.
54

55. 4. Microreservoir type or Microsealed
dissolution – controlled systems
 This is the combination of reservoir & matrix diffusion type
drug delivery systems.
 Drug reservoir is formed by first suspending the drug solids in
an aqueous solution of a water soluble liquid polymer & then
dispersing the drug suspension homogeneously in a lipophilic
polymer such as silicone elastomers by high dispersion
technique.
 Example: Nitroglycerine-releasing Transdermal system
(Nitro disc) for once a day therapy of angina
pectoris.
55

56. rim
Fig. Micro reservoir dissolution-controlled transdermal drug delivery system
56

57. 5. Poroplastic– type systems
 It is made utilizing the concept of the water coagulation
of cellulose triacetate solution in organic acids at low
temp.
 The coagulation is performed under controlled condition.
 The water may be exchanged subsequently for another
vehicle by a diffusional exchange process, & hence it is
also known as “solid composed mostly of liquid.”
57

58. 6. Transdermal delivery of
Macromolecules
 Macromolecules such as Hormones, interferon's, bioactive
peptides can be deliver by Transdermal delivery system.
 The devices used for this purpose are divided in to two
categories….
a. Devices based on ethylene vinyl acetate copolymers
(EVAc).
b. Devices based on silicone elastomers.
 This both the systems utilize one common concept i.e.
matrix must have channels to facilitate the release of
macromolecules.
 These devices are used as implants.
58

59. Transdermal
patch designs
Matrix Reservoir
Multilaminate Drug in adhesive
Backing Drug Membrane Adhesive Liner / skin

61. Evaluation of TDDS
1. Evaluation of Adhesive :
A. Peel adhesion properties:-
i) It is the force required to remove an
adhesive coating from a test
substrate.
ii) It is affected by molecular wt. of the
adhesive polymer, the type &
amount of additives & polymer
composition.
iii) It is tested by measuring the force
required to pull a single coated tape,
applied to a substrate, at an angle of
1800, no residue on the substrate
indicates ‘Adhesive failure’
signifying a deficit of cohesive Fig. Peel adhesion test for
strength in the coating. adhesive evaluation
61

62. B. Tack properties:-
i) It is the ability of polymer to
adhere to a substrate with little
contact pressure.
ii) It is dependent on the
molecular wt. & composition of
the polymer as well as the use
of tackifying resins in the
polymer.
iii) It includes….
a. Rolling ball tack test :
It involves the measurement of
the distance that a stainless
steel ball travels along an
upward-facing adhesive, less
tacky the adhesive, the further
Fig. Rolling ball tack test for
the ball will travel. adhesive evaluation
62

63. b. Quick- stick (peel tack)
test :
The peel force required to
break the bond between an
adhesive & substrate at 900 at
a speed of 12 inch/min. The
force recorded as the tack
value & is expressed in ounces
(or grams) per inch width with
higher values indicating
increasing tack.
Fig. Quick stick test for
adhesive evaluation
63

64. c. Probe tack test :
The force required to pull a probe away from an adhesive
at a fixed rate is recorded as tack. (expressed in grams)
Probe
Force gauge
Fig. Probe tack test for adhesive
evaluation
64

65. C. Shear strength properties
i) It is affected by molecular wt. as well
as the type & amount of tackifier
added.
ii) Shear strength is determined by
measuring the time it takes to pull an
adhesive coated tape of stainless steel
plate when a specified wt. is hung from
the tape which pulls the tape in a
direction parallel to the plate. Fig. Shear strength test
for adhesive evaluation
65

66. 2. In-vitro drug release evaluation :
i) In these studies, excised skin is mounted on skin permeation
cells.
ii) Skin of hairless mouse is used rather than human cadaver
skin.
iii) In-vitro system should be designed in such a way that the
intrinsic rate of release or permeation which is theoretically
independent of the in-vitro design can be accurately
determined.
iv) Several designs of the in-vitro membrane permeation
apparatus are in existence.
E.g. Valia-Chien (V-C) cell, Ghannam-Chien (G-C) membrane
permeation cell, Jhawer-Lord (J-L) rotating disc cell, Franz
diffusion cell & Keshary-Chien (K-C) cell.
66

67.  Keshary-Chien (K-C) cell : It has an effective receptor
volume 12 ml & a skin surface area of 3.14 cm2. The receptor
solution is stirred by a star-head magnet rotating at a constant
speed of 600 rpm driven by 3 W Synchronous motor.
Fig. K-C cell for permeation study
67

68. 3. In-vivo evaluation :
A. Animal models:-
 The species used for this are mouse, rat, guinea pig, rabbit,
hairless mouse, hairless cat, hairless dog, cat, dog, pig, goat,
squirrel, monkey, rhesus monkey, chimpanzee.
 The rhesus monkey is the most reliable model for in-vivo
evaluation of TDDS.
 Standard radio tracer methodology is used .
 The application site is generally the forearm or abdomen
which are less hairy sites on the animals body.
 The compound is applied after light clipper shaving of the
site.
68

69. B. Human volunteers:-
 Procedures for in-vivo evaluation in humans were first
described by Feldmann & Mailbach in 1974.
 They involve the determination of cutaneous absorption by an
indirect method of measuring radioactivity in excreta following
topical application of the labelled drug.
 This method is used since plasma level following Transdermal
administration of a drug are too low to use chemical assay
procedure.
 The % of dose absorbed transdermally is calculated by…
Total radioactivity excreted after topical administration
% of dose absorbed = x 100
Total radioactivity excreted after I. V. administration
69

70.  Various modifications have been made for above method…
“Reservoir” technique:- It involves a simple, short exposure of
the skin to the compound (radio labelled) under study followed
by removal of the striatum corneum by tape striping &
analysis of the content of the compound in the striatum
corneum. From this it is possible to predict amount of drug
that will penetrate over a long period of time.
 Limitations:
i) Invasive nature of the technique due to the tape striping
required.
ii) The single measurement obtained which does not allow
detailed kinetic analysis & the administration of large dose of
radioactive material is required.
70

71. OTHER EVALUATION PARAMETERS
2) Thickness .
3) Moisture content.
4) Folding endurance.
5) Tensile strength .
Break force ∆L
T.S = 1+
L
a.b.
71

72. Advances in TDDS
 Active Transdermal Systems:-
 Micro structured Transdermal System (MTS) is a state-of-
the-art micro needle system for transcutaneous drug delivery
that has potential for providing a drug delivery solution for a
wide variety of molecules, including vaccines, proteins and
peptides. MTS provides targeted delivery to the
dermal/epidermal layers of the skin.
 Further, MTS has the potential to enhance the efficacy of
vaccines while improving the overall delivery efficiency for
vaccines, proteins, or peptides.
 Finally, MTS is an easy-to-use system with the potential to
improve health care providers vaccine regimen.
72

73. 73

74. Find an appropriate place to put the patch.
 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 .
• 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.
• Attach the adhesive side of the patch to your skin in the
chosen area.

75. • 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.

77. References
 Y. W. Chien, Novel drug delivery systems, 2nd edition, Revised
& expanded, Marcel Dekker, Inc., New York, 1992.
 N. K. Jain, Controlled & Novel drug delivery, CBS Publishers
& Distributors, New Delhi, First edition, 1997.
 Controlled drug delivery devices by Pravin Tyle, Marcel
Dekker, Inc., New York, 1992, pg. no. 406 – 408.
 Mechanisms of Transdermal drug delivery system by Y. W.
Chien, Marcel Dekker, Inc., New York.
 www.google.com
77

78. THANK YOU
FOR..
78