NDDS UNIT 3 chapter TDDS

1. TRANSDERMAL DRUG DELIVERY
SYSTEM
(UNIT -3)
By : Dr. Kajale Neha Sachin
Associate professor
Department of Pharmaceutics
College of pharmacy , Akluj
.
1

2. INTRODUCTION
 TDDS are topically administered medicaments in
the form of patches that deliver drugs for systemic
effects at predetermine and controlled rate.
 TDDS are adhesive drug-containing devices of
defined surface area that deliver a predetermined
amount of drug to the surface of intact skin at a
programmed rate to reach the systemic circulation.
2

3. ADVANTAGES
 Avoidance of first-pass effect.
 Long duration of action.
 Comparable characteristics with IV infusion.
 No interference with gastric and intestinal fluids.
 Suitable for administered of drug having- Very
short half-life, e.g. nitroglycerine, Narrow
therapeutic window, poor oral bioavailability.
 Poor oral availability minimizing undesirable side
effects.
 Provide utilization of drug with short biological half
lives, narrow therapeutic window.
 Avoiding the fluctuation in drug levels.
 Inter and intra patient variation.
3

4.  Termination of therapy is easy at any point of time.
 Self-administration is possible
 Transdermal patches are cost effective
 The activity of drugs having a short half life is
extended through the reservoir of drug in the
therapeutic delivery system and its controlled
release.
 It is of great advantages in patients who are
nauseated or unconscious.
 Transdermal patches are better way to deliver
substances that are broken down by the stomach
and, not well absorbed from the gut, or extensively
degraded by the liver.
4

5. DISADVANTAGE
 Poor diffusion of large molecules.
 Not suitable for high drug dose
 Many drugs especially drugs with hydrophilic
structures permeate the skin too slowly may not
achieve therapeutic level.
 Absorption efficiency is vary with different sites of skin.
 Transdermal drug delivery system cannot deliver ionic
drugs.
 It cannot achieve high drug levels in blood.
 It cannot deliver drugs in a pulsatile fashion.
 Sufficient aqueous and lipid solubility, a log P (octanol/
water) between 1 and 3 is required for permeate to
transverse stratum corneum and underlying aqueous
layer. 5

6.  Only potent drugs are suitable candidates for
transdermal patch because of the natural limits of
drug entry imposed by the skin’s impermeability.
 Long time adherence is difficult.
 Unsuitable – for
1. Drug has large molecular size.
2. Drug causes Skin irritation and sensitization
3. Drug cause allergic reaction
4. Drug metabolized in skin
5. Drug undergoes protein binding in skin
6. Drug dose is large,
6

7. STRUCTURE OF SKIN
7

8. ANATOMY AND PHYSIOLOGY OF SKIN/STRUCTURE
OF SKIN
 The skin is the largest organ of the human body
which covers a surface area of approximately 2
sq.m. and receives about one third of the blood
circulation through the body. It serves as a
permeability barrier against the transdermal
absorption of various chemical and biological
agents.
 Serves as a barrier against physical, chemical and
microbiological attacks.
 Acts as a thermostat in maintaining body
temperature.
 Plays role in the regulation of blood pressure.
 Protects against the penetration of UV rays.
8

9. SKIN HAS MAINLY 3 LAYERS
 Epidermis
 Stratum Corneum (horny layer)
 Stratum Lucidum
 Stratum Granulosm
 Stratum Spinosum
 Stratum Basal
 Dermis
 Subcutaneous layer
9

10. 1.EPIDERMIS
 The multilayered envelop of the epidermis varies in
thickness, depending on cell size and number of
cell layers ranging from 0.8 mm on palms and soles
down to 0.06 mm on eyelids.
 It consists of two parts
 Stratum corneum
 Viable epidermis
10

11.  Stratum corneum:
 This is the outermost layer of skin also called as horny
layer. It is the rate limiting barrier that restricts the inward
and outward movement of chemical substances.
 The barrier nature of the horny layer depends critically on
its constituents: 75-80% proteins, 5-15% lipids, and 5-10%
ondansetron material on a dry weight basis.
 Stratum corneum is approximately 10 mm thick when dry
but swells to several times when fully hydrated. It is flexible
but relatively impermeable. The architecture of horny layer
(as shown in figure ) may be modeled as a wall-like
structure with protein bricks and lipid mortar.
 It consists of horny skin cells (corneocytes) which are
connected via desmosomes (protein-rich appendages of
the cell membrane). The corneocytes are embedded in a
lipid matrix which plays a significant role in determining the
permeability of substance across the skin.
11

12.  Viable epidermis:
 This is situated beneath the stratum corneum and
varies in thickness from 0.06 mm on the eyelids to
0.8mm on the palms. Going inwards, it consists of
various layers as stratum lucidum, stratum
granulosum, stratum spinosum, and the stratum
basale.
 In the basale layer, mitosis of the cells constantly
renews the epidermis and this proliferation
compensates the loss of dead horny cells from the
skin surface. As the cells produced by the basale
layer move outward, they itself alter morphologically
and histochemically, undergoing keratinization to
form the outermost layer of stratum corneum
12

13. 2.DERMIS:
 Dermis is the layer of skin just beneath the
epidermis which is 3 to 5 mm thick layer and is
composed of a matrix of connective tissues, which
contains blood vessels, lymph vessels, and nerves.
 The cutaneous blood supply has essential function
in regulation of body temperature.
 It also provides nutrients and oxygen to the skin,
while removing toxins and waste products.
 Capillaries reach to within 0.2 mm of skin surface
and provide sink conditions for most molecules
penetrating the skin barrier. The blood supply thus
keeps the dermal concentration of permeate very
low, and the resulting concentration difference
across the epidermis provides the essential driving
force for transdermal permeation.
13

14. 14

15. 3.HYPODERMIS:
 The hypodermis or subcutaneous fat tissue
supports the dermis and epidermis. It serves as a
fat storage area.
 This layer helps to regulate temperature, provides
nutritional support and mechanical protection.
 It carries principal blood vessels and nerves to skin
and may contain sensory pressure organs. For
transdermal drug delivery, drug has to penetrate
through all three layers and reach in systemic
circulation
15

16. ROUTES OF DRUG PENETRATION THROUGH
SKIN/
 For any molecules applied to the skin, two main
routes of skin permeation can be defined:
 1. Transfollicular/appendageal route/shunt
pathway/minor route
 2. Trans epidermal route/epidermal route
16

17.  This route comprises transport via the sweat glands
and the hair follicles with their associated
sebaceous glands.(shown as no 1, 2, 3 in fig)
 These route bypass penetration through the
stratum corneum and are therefore known as Shunt
routes.
 Although these routes offer high permeability, they
are considered to be of minor importance because
of their relatively small area, approximately 0.1%
area of the total skin.
 This route seems to be most important for ions and
large polar molecules which hardly permeate
through the stratum corneum. 17
TRANSFOLLICULAR/APPENDAGEAL
ROUTE/SHUNT PATHWAY/MINOR ROUTE

18. 18

19. TRANS EPIDERMAL ROUTE/EPIDERMAL ROUTE
 In transepidermal transport, molecules cross the
intact horny layer. Two potential micro-routes of
entry exist,
 1. Transcellular ( intracellular)
 2. Intercellular pathway (paracelluar)
19

20. TRANSCELLULAR ROUTE/INTRACELLULAR ROUTE
 Drugs entering the skin via the transcellular route
pass through the corneocytes. Corneocytes
containing highly hydrated keratin provide an
aqueous environment from which hydrophilic drugs
can pass.
 The transcellular pathway requires not only
partitioning into and diffusion through the keratin
bricks but also into and across the intercellular
lipids.
 These include passive transport of small moecules,
active transport of ionic and polar compounds and
endocytosis and transcytosis of macromolecules.
20

21. INTERCELLULAR ROUTE/PARACELLULAR ROUTE
 Paracellular pathway means transport of molecules
around or between the cells.Tight junction or similar
situations exist between the cells
 The intercellular route involves drug diffusion
through the continuous lipid matrix.
 Thus the principal pathway taken by a penetrant is
decided mainly by the partition coefficient (log K).
Hydrophilic drugs partition preferentially into the
intracellular domains, whereas lipophillic permeants
(octanol/water log K > 2) traverse the stratum
corneum via the intercellular route. Most molecules
pass the stratum corneum by both routes.
21

22. FACTORS AFFECTING PERMEATION THROUGH SKIN
OR FACTORS INFLUENCING TDDS
A. Biological factors:
 Skin condition: Acids and alkalis, many solvents like
chloroform methanol damage the skin cells and promote
penetration. Diseased state of patient alters the skin
conditions. The intact skin is better barrier but the above
mentioned conditions affect penetration.
 Blood supply: Changes in peripheral circulation can affect
transdermal absorption. Potent vasoconstricting agents, such
as topical steroids, could decrease their own clearance rate or
that of another drug.
 Skin age: The young skin is more permeable than older.
Children are more sensitive for skin absorption of toxins.
Thus, skin age is one of the factors affecting penetration of
drug in TDDS.
22

23.  Regional skin site: Thickness of skin, nature of
stratum corneum, and density of appendages vary
site to site. These factors affect significantly
penetration.
 Skin metabolism: Skin metabolizes steroids,
hormones, chemical carcinogens and some drugs.
So skin metabolism determines efficacy of drug
permeated through the skin.
 Species differences: The skin thickness, density of
appendages, and keratinization of skin vary species
to species, so affects the penetration.
23

24.  Hydration of skin
Generally, when water saturates the skin, it swells tissues,
softens wrinkles on the skin and its permeability increases
for the drug molecules that penetrate through the skin.
Thus hydration is most important factor increasing the
permeation of skin. So use of humectants is done in
transdermal delivery
 Temperature and pH of the skin
The permeation of drug increase ten fold with temperature
variation. The diffusion coefficient decreases as
temperature falls. Weak acids and weak bases dissociate
depending on the pH and pKa or pKb values. The
proportion of unionized drug determines the drug
concentration in skin.
24
PHYSICOCHEMICAL FACTORS

25.  Diffusion coefficient: Penetration of drug depends on
diffusion coefficient of drug. At a constant temperature
the diffusion coefficient of drug depends on properties
of drug, diffusion medium and interaction between
them.
 Drug concentration: The flux is proportional to the
concentration gradient across the barrier and
concentration gradient will be higher if the
concentration of drug will be more across the barrier.
 Partition coefficient: The optimal K, partition coefficient
is required for good action. Drugs with high K are not
ready to leave the lipid portion of skin. Also, drugs with
low K will not be permeated.
 Molecular size and shape: Drug absorption is
inversely related to molecular weight; small molecules
penetrate faster than large ones. Because of partition
coefficient domination, the effect of molecular size is
not known.
25

26. ENVIRONMENTAL FACTORS
 Sunlight
Because of to sunlight, the walls of blood vessels become
thinner, leading to bruising, with only minor trauma in the sun-
exposed areas. Also, pigmentation, the most noticeable sun-
induced pigment change, is a freckle (spot) or solar lentigo.
 Cold season
The cold season often results in itchy and dry skin. The skin
responds by increasing oil production to compensate for the
weather’s drying effects. A good moisturizer will help ease
symptoms of dry skin. Also, drinking lots of water can keep your
skin hydrated and looking radiant.
 Air pollution
Dust can clog pores and increase bacteria on the face and the
surface of skin, both of which lead to acne or spots, which
affects drug delivery through the skin. Invisible chemical
pollutants in the air can interfere with the skin’s natural
protection system, breaking down the skin’s natural oils that
normally trap moisture in the skin. 26

27. BASIC COMPONENTS OF TDDS
 Polymer matrix / Drug reservoir
 Drug
 Permeation enhancers
 Pressure sensitive adhesive (PSA)
 Backing laminate
 Liner
27

28. 1.POLYMER
 Polymer Matrix: The Polymer controls the release
of the drug from the device. Possible useful
polymers for transdermal devices are:
a. Natural Polymers: e.g., cellulose derivatives, Zein,
Gelatin, Shellac, Waxes, Proteins, Gums and their
derivatives, Natural rubber, Starchetc.
b. Synthetic Elastomers: e.g., polybutadieine, Hydrin
rubber, Polysiloxane, Silicone rubber,Nitrile,
Acrylonitrile, Butyl rubber, Styrenebutadieine rubber,
Neoprene etc.
c. Synthetic Polymers: e.g., polyvinyl alcohol,Polyvinyl
chloride, Polyethylene, Polypropylene,Polyacrylate,
Polyamide, Polyurea, Polyvinyl pyrrolidone,
Polymethylmethacrylate, Epoxy
28

29. The following criteria should be chosen in selecting the
polymer to be used in the transdermal system:
 (i) Molecular weight, glass transition temperature and
chemical functionality of the polymer should be such
that the specific drug diffuses properly and gets
released through it.
 (ii) The polymer should be stable, nonreactive with the
drug, easily manufactured and fabricated into the
desired product, and should be inexpensive.
 (iii) The polymer and its degradation products must
be nontoxic
 iv) The mechanical properties of the polymer should
not deteriorate excessively when large amounts of
active ingredients are incorporated into it.
 V) The polymer should permit the incorporation of a
large amount of drug. 29

30. 2.DRUG
 For successfully developing a transdermal drug delivery
system, the drug should be chosen with great care. The
following are some of the desirable properties of a drug for
transdermal delivery.
PHYSICOCHEMICAL PROPERTIES:
 The drug should have a molecular weight less than
approximately 1000 Daltons.
 The drug should have affinity for both lipophilic and
hydrophilic phases. Log P (octanol–water) between 1.0
and 4.0
 The drug should have low melting point( less than 200 °F).
 Oil solubility >1 mg/ml
 Water solubility > 1 mg/ml
 pH Between 5.0 and -9.0
30

31. BIOLOGICAL PROPERTIES –
 The drug should be potent with a daily dose of order
of a few mg/ day.(ideally less than 25 mg/day)
 The half life of the drug should be short.
 The drug must not induce a cutaneous irritant or
allergic response.
 Drugs degraded in the GIT or inactivated by the
hepatic first pass are suitable candidates for
transdermal drug delivery.
 Non irritant and non allergic to human skin.
 Not get extensively metabolised in the skin
 Drug having short half life (10 or less h)
31

32. 3.PENETRATION ENHANCERS:
 These are the compounds, which promote skin
permiability.
 Substances used to increase permeation of skin
mucosa.
 Increases the absorption of penetrant through the
skin.
 Synonyms: absorption promoter and sorption
accelerants.
32

33. IDEAL PROPERTIES OF PENETRATION ENHANCERS
 1. These materials should be non toxic, non irritating,
pharmacologically inert, non allergic.
 2. There should not be any kind of interaction of
penetration enhancer with drug and excipient.
 3. It should have no pharmacological activity within
body.
 4. It should be well accepted cosmetically.
 5. It should be odorless, tasteless, colorless and
inexpensive and have good solvent properties.
 6. It should be compatible with the drug being given.
33

34. IDEAL PROPERTIES OF PENETRATION ENHANCER
 7. It should be chemically and physically stable.
 8. Duration of action should be both predictable and
reproducible and work rapidly and unidirectionally .
 9. It should be tested in research laboratories.
 10. It should posses good solvent properties
 11.It should not cause leakage of body fluids and
endogenous materials (unidirectional flow), and as
soon as such substances are removed, the skin
should immediately restore its natural barrier
properties
34

35. USES OF PENETRATION ENHANCER
 1. To increase the delivery of ionisable drugs. E.g.:
timolol maleate etc
 2. To deliver the impermeable drugs. E.g.: heparin
etc
 3. To maintain level of drug into blood stream
 4. To improve the efficacy of less potent drugs with
higher dose. E.g.: oxymorphane
 5. To deliver the drugs having high molecular
weight like peptide and hormones
 6. To decrease lag time of transdermal drug
delivery system 35

36. MERITS
 Merits of Penetration Enhancers-
 1) Most drugs penetrate at rates sufficiently high for
therapeutic efficiency by using penetration enhancers
 2) It is useful for unabsorbable drugs to facilitate their
absorption through skin
 3) It can improve transdermal absorption of topical
preparation
 4) No adverse effect on skin
 5) Do not affect zero order skin permeation profile of
skin
 6) The terpenes like limonene in propylene glycol
solution are effective penetration enhancer for
cytotoxic drugs VNS Group of Institutes
36

37. DEMERITS
 Demerits of Penetration Enhancer-
 1. The effective concentration varies from drug to
drug
 2. The uses of different penetration enhancer with
various concentrations are restricted completely
 3. Physicochemical properties of enhancers are
also affecting the side effects in the body
37

38. MOA
 Mechanism of action:
 1. By distruption of highly ordered structure of
stratum corneum lipid
 2. By interaction with intercellular protein
 3. By improved partition of the drug or solvent into
stratum corneum
38

39. METHODS OR TYPES OF PENETRATION
ENHANCER/APPROACHES FOR PERMEATION
ENHANCEMENT:
 The method employed for modifying the barrier
properties of the stratum corneum to improve drug
penetration and absorption through skin may be
classified into the following categories
 1. Chemical methods of enhancement
 2. Physical methods of enhancement
 3. Biochemical methods of enhancement
39

40. CHEMICAL PENETRATION ENHANCERS
 Alcohols: Alcohols can increase skin permeation by a various
mechanisms such as lipids and protein extraction, stratum
corneum swelling and thus improving partitioning of drug into
host skin or drug solubility in the formulation.
 e.g. Ethanol, PEG
 Amines and Amides: promotes drug penetration trans-
dermally by Promoting hydration of the SC (Stratum
Corneum)Formation of diffusive channels with water
attraction(hydrophilic) property for drug. E.g. urea
 Sulfoxides: Dimethylsulfoxide (DMSO) is also used as a
compound to increase permeation of drugs. It acts as an
aprotic solvent as it undergoes intracellular hydrogen bonding
rather than forming hydrogen bonds with water.it is also
termed as a “Universal Solvent
40

41.  Surface active agents:
 Cationic surfactants: Surface active agents are absorbed
at interfaces and therefore increase permeation. Cationic
surfactants cause a greater penetration than anionic ones.
Therefore they damage the skin more.
 Anionic surfactants: Anionic surfactants remove the water
soluble agents and thus change the barrier function of the
stratum corneum. Sodium lauryl sulphate is a prime
example for bringing about a change in the SC and thus
increasing penetration.
 Non-ionic surfactants: Nonionic surfactants are perforated
so that they can emulsify sebum. Thus the permeation is
increased due to change in the partitioning potential.
 Other e.g. Fatty acids and its ester, Terpenes, N-
methylpyrrilidone, azones 41

42.  Azones: Azone forms one of the major classes of
surface permeation enhancers. Azone promotes
intercellular transport. Azone is known to facilitate the
flow through the lipid bilayer.
 Fatty acids (FAs): Fatty acids and ester derivatives of
these are used as absorption enhancers. Unsaturated
FAs are better enhancers than saturated ones. e.g.
oleic acid
 Cyclodextrines: Cyclodextrins are reportedly
biocompatible. In order to increase solubility
especially in aqueous solutions they get complexed
with lipophilic drugs.
42

43. PHYSICAL PENTRATION ENHANCERS OR APPROACH
43

44. BIOCHEMICAL APPROACH
 I.Synthesis of bio-convertible pro-drugs:Prodrugs
help to obtain an optimal partition coefficient for
entering the skin barrier. After absorption and
diffusion to the viable tissues, enzymes convert the
prodrug into the active form. Many steroids have
been designed using this approach. N-acyl
derivatives were formed to increase permeability of
5-fluorouracil to 25 times.
 II. Co-administration of skin metabolism
inhibitors: Fluvastatin increases the octanol/water
partition coefficient of lidocaine hydrochloride by 50
times, the in vivo uptake doubled
44

45. 4.ADHESIVES
 Adhesives: The adhesion of all transdermal devices to the
skin has been done by using a pressure sensitive adhesive
Commonly used adhesives are polyisobutylenes adhesives,
silicone adhesives and polyacrylate based adhesives
 adhesive systems should possess the following properties:
 Should adhere to the skin strongly during dosing, should be
easily removed after treatment completion.
 Should not leave any unwashable residue on the skin.
 Should not irritate or sensitize the skin.
 The face adhesive system should also possess the
following properties:
 Physical and chemical compatibility with the drug, excipients
and enhancers of the device .
 Permeation of drug should not be affected.
 The delivery of simple or blended permeation enhancers
should not be affected. 45

46. 5.BACKING MEMBRANE
 Backing membranes are flexible and they provide a support
to drug reservoir
 This layer is protecting the patch from the external
environment.
 They must be impermeable to drug substance and
permeation enhancer.
 They must chemically compatible with drug and other
excipients of system
 They have optimal elasticity, flexibility and tensile strength
 They must be relatively inexpensive and must allow printing
 They protects the product during use on the skin
 e.g. metallic plastic laminate, plastic backing with absorbent
pad and occlusive base plate (aluminium foil), adhesive
foam pad (flexible polyurethane) with occlusive base plate
(aluminium foil disc) etc
46

47. 6. RELEASE LINER
 During storage, the patch is covered by a protective
liner that is removed before the application of the
patch to the skin.
 Because the liner is in intimate contact with the
TDDS, the liner should be chemically inert.
 Protects the patch during storage
 Prevent the drug loss that migrated into adhesive
layer during storage.
 It is composed of a base layer that may be non
occlusive (e.g, paper fabric) or occlusive (e.g,
polyethylene, polyvinyl chloride) and a release
coating layer made up of silicon or Teflon. Other
materials used for TDDS release liner are polyester
foil and metalized laminates.
47

48. OTHER EXCIPIENTS LIKE PLASTICIZERS AND
SOLVENTS
 Various solvents such as chloroform, methanol,
acetone,isopropanol and dicholoromethane are used to
prepare drug reservoir.
 In addition, plasticizers such as dibutylphthalate,
triethyl citrate, polyethylene glycol and propylene glycol
are added to provide plasticity to the transdermal
48

49.  CLASSIFICATION OF TDDS:
 A. Rate-Programmed Systems
 Drug in Reservoir
 Drug in Matrix
 Drug in Adhesive
 Drug in Microreservoir
 B. Physical Stimuli- Activated Systems
 Structure-Based Systems – microneedle
 Electrically-Based Systems - Iontophoresis
Electroporation ,Sonophoresis, photomechnical waves
 Velocity based system e. g Jet propulsion
49

50. TYPES OF RATE PROGRAMMED TDDS
50

51. 1.DRUG IN RESERVOIR/POLYMER MEMBRANE CONTROLLED
 Drug reservoir is embedded between an impervious
backing layer and a rate controlling membrane.
 Drug release only through the rate controlling polymeric
membrane, which may be microporous or non-porous
 In drug reservoir compartment, it can be in the form of
solution, suspension or gel or dispersed in a solid
polymer matrix.
 The rate of drug release from this type of TDDS can be
controlled 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.
51

52. 52

53. 2.DRUG IN MATRIX/POLYMER MATRIX DIFFUSION
CONTROLLED
 The drug is uniformly dispersed in a polymeric matrix,
through which it diffuses into skin.
 This drug containing polymer layer is then fixed onto an
occlusive base plate in a compartment fabricated from a
drug impermeable backing layer.
 Instead of applying adhesive on the face of the drug
reservoir, it is spread along the circumference to form a
strip of adhesive rim around the medicated disc.
 Example: Nitroglycerine-releasing Transdermal system
(Nitro- Dur & Nitro- Dur II ) at a daily dose of 0.5 g/cm2
for therapy of angina pectoris
53

54. 54

55. 3.DRUG IN ADHESIVE OR ADHESIVE
DISPERSION – TYPE SYSTEMS
 In this type, the drug reservoir is formed by dispersing
the drug in an adhesive polymer and then spreading
the medicated adhesive polymer by solvent casting or
melting (in the case of hot melt adhesives) on an
impervious backing layer. On the top face of the
reservoir, unmedicated adhesive polymer layers are
applied for protection purpose
 Example: 1. Isosorbide dinitrate-releasing
Transdermal therapeutic system (Frandol tape) for
once a day medication of angina pectoris
 2. Verapamil releaseing TDDS 55

56. 56

57. 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
57

58. 58

59. 1. IONTOPHORESIS-
 Iontophoresis- It involves transport of ionic or charged
molecules into a tissue by a passage of direct or
alternating electric current through electrolyte solution
containing the ionic molecules to be delivered. It
involves electromotive force for transfer of ions.
 Ions with positive charge are driven into the skin at the
anode and those with negative charge at the cathode.
 Drug is administered through an electrode having same
charge as that of drug and a return electrode opposite
to charge of drug.
 Operator then selects current intensity below the pain
threshold level of the patient and allows the current to
flow for an appropriate period of time. 59

60.  Current intensity should be increased slowly ,
maintained for the length of the treatment and then
slowly decreased at the end of the treatment.
 Current must be between the tolerance of the patient
with a current density less than 0.5 m.amp/cm2 of the
electrode surface.
 Placing a moist pad between electrode plate and the
skin is necessary for making perfect contact, preventing
any skin burns, overcoming skin resistance and
protecting the skin from absorbing any caoustic metallic
compound formed on the metal plate surface.
 The drug should be applied through the electrode with
correct polarity , since any reversal of polarity may
result in no penetration of the drug.
60

61.  The applications of iontophoresis
 Therapeutic applications. Lidocaine,protein,
harmone
 Diagnostic applications. diagnosing cystic fibrosis
and recently for monitoring blood glucose levels .The
major advantage of iontophoresis in diagnostic
applications is that there is no mechanical
penetration or disruption of the skin involved in this
approach
 Factors affect iontophoretic TDD, including pH of
the donor solution, electrode type, buffer
concentration, current strength and the type of
current employed The molecular size of the
solute/drug is an important factor in determining its
feasibility for successful iontophoretic delivery. The
flux of smaller and more hydrophilic ions is faster
than larger ions 61

62. COMMERCIAL AVAILABLE IONTOPHORIC
DELIVERY SYSTEM
62

63. 63

64. 64

65. 2.SONOPHORESIS
 Sonophoresis: Sonophoresis is the
phenomenon in which the permeability of skin
is increased under the influence of ultrasound.
 Mechanism of action:
 Cavitation effects.
 Convective transport.
 Thermal effects.
 Mechanically occurring effects.
.
65

66.  a) Cavitation effects: When a liquid medium is exposed with
US then vapor cavities are formed. This process is called
cavitation.
 b) Convective transport: When porous medium exposed to
ultrasound, interference occurs between the incident and
reflected US waves. Cavitation bubbles also undergo
oscillations due to which different velocities are produced in
the fluid.
 c) Thermal effects: When US is absorbed the temperature of
the absorbing medium rises. This rise in temperature is
directly proportional to the intensity of US and the time for
which it been exposed. As a result the medium becomes more
absorbing as its absorption coefficient increases.
 Mechanical effects: Ultrasound causes many variations in the
skin such as sinusoidal pressure variation and thus sinusoidal
density variations. As a result, disruptions occur in the lipid
bilayers and thereby increasing the permeation through it. 66

67. 67

68. 3.ELECTROPORATION
 In electroporation, cells are temporarily exposed to
high intensities of electric pulses that lead to the
formation of aqueous pores in the lipid bilayers of the
stratum corneum, thus allowing the diffusion of drugs
across skin
 Usage of high voltage pulses (50–500 V) for short
times of only one second have been shown to increase
transport across the skin for different molecular weight
drugs ranging from small e.g., fentanyl, timolol to high
molecular weight drugs such as LHRH, calcitonin,
heparin
 the main drawbacks are the lack of quantitative
delivery, cell death with high fields and potential
damage to labile drugs, e.g., those of protein origin 68

69. 69

70. 4.MICRONEEDLES
 Transdermal patches with microscopic projections
called microneedles were used to facilitate
transdermal drug transport.
 Needles ranging from approximately 10-100 μm in
length are arranged in arrays. When pressed into the
skin, the arrays make
 microscopic punctures that are large enough to
deliver macromolecules, but small enough that the
patient does not feel the penetration or pain. The
drug is surface coated on the microneedles to aid in
rapid absorption. They are used in development of
cutaneous vaccines for tetanus and influenza. 70

71. 71

72. 5.VELOCITY BASED DEVICES-JET INJECTOR
 Velocity based devices, either powder or liquid jet injections,
employ a high-velocity jet with velocities ranging from 100 to
200 m/s to puncture the skin and deliver drugs using a power
source (compressed gas or a spring) [91].
 Types
 1. liquid jet injectors
 single-dose jet injectors (disposable cartridge jet injectors)
 multi-use-nozzle jet injectors (MUNJIs)
 2.Powder jet injectors
 Use -for parenteral delivery of vaccines, as well as small
molecules, such as anesthetics and antibiotics
 A jet injector is a needle free device capable of delivering
electronically controlled doses of medication which result in
improved consistency of delivery and reduced pain for the
patient
72

73. LIQUID-JET INJECTORS
 Liquid-jet injectors propel liquid from a nozzle with
an orifice diameter ranging from 50 to 360 μm,
which is much smaller than the outer diameter of a
standard hypodermic needle (810 μm for a 21G
needle) .
 The jet can deliver drug into different layers of skin
e.g., intradermal (i.d.), subcutaneous (s.c.) or
intramuscular (i.m.), by changing the jet velocity
and orifice diameter.
 The major advantage of using needle free devices
relates to concerns regarding safe needle disposal
and avoidance of accidental needle stick injuries 73

74. POWDER JET INJECTORS
 Powder jet injectors have an advantage over liquid
jet injectors of delivering solid drugs or vaccines to
the skin, so the stability of the formulation will be
increased and the necessity for cold storage will be
avoided, which simplifies transportation and reduces
associated costs.
 Powder jet injectors may be formulated from nano-or
micro-particles containing the active or lyophilised
drugs and antigens.
74

75. 75

76. EVALUATION METHODS
The evaluation methods for transdermal dosage form
can be classified into following types:
 Physicochemical evaluation
 In vitro evaluation
 In vivo evaluation
76

77. PHYSICOCHEMICAL EVALUATION
 1. Interaction studies -Thermal analysis, FTIR, UV
and chromatographic techniques by comparing
their physicochemical properties like assay, melting
point, wave numbers, absorption maxima
 2.Thickness of the patch- Digital micrometer
used.
 3.Weight uniformity -The prepared patches are to
be dried at 60°c for 4hrs before testing. A specified
area of patch is to be cut in different parts of the
patch and weigh in digital balance. The average
weight and standard deviation values are to be
calculated from the individual weights
77

78.  4.Folding endurance- a film for specific area is to be
cut evenly and repeatedly folded at same place till it
broke.
 5.Percentage moisture content –Desiccator
containing fused calcium chloride at room temperature.
Percentage moisture content = [Initial weight- Final
weight / Final weight] ×100
 6.Percentage moisture uptake-Desiccator containing
saturated solution of potassium chloride in order to
maintain 84% RH. Percentage moisture uptake = [Final
weight- Initial weight/ initial weight] ×100.
 7.Polariscopic examination- A specific surface area
of the piece is to be kept on the object slide of
Polariscope and observe for the drugs crystals to
distinguish whether the drug is present as crystalline
form or amorphous form in the patch
78

79.  8. Water vapour permeability (WVP) evaluation- a
natural air circulation oven replaces the air forced oven
used for this study.
WVP=W/A Where, WVP is expressed in gm/m2 per
24 hrs,
W is the amount of vapour permeated through the patch
expressed in gm/24 hrs,
A is the surface area of the exposure samples expressed
in m2
9. Drug content- UV or HPLC technique used to
analyse the drug content.
 10.Content uniformity test- 10 patches are selected and
content is determined for individual patches.
79

80.  11.Flatness test
 Three longitudinal strips are to be cut from each film at different
portion like one from the center, other one from the left side, and
another one from the right side. The length of each strip was
measured and the variation in length because of non-uniformity in
flatness was measured by determining percent constriction, with
0%constriction equivalent to 100% flatness .
 % constriction = I1 – I2/I1 X 100
where, I1 = Initial length of each strip.
I2 = final length of each strip.
 12.Percentage elongation break test
 The percentage elongation break is to be determined by noting
the length just before the break point, the percentage elongation
can be determined from the below formula
 Elongation percentages == L1 – L2 X 100 .
L2
Where, L1= is the final length of each strip.
L2= is the initial length of each strip.
80

81.  11.Adhesive studied /Evaluation of Adhesive
 Peel Adhesion test: In this test, the force required to remove an
adhesive coating form a test substrate is referred to as peel
adhesion. 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 .
 12.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
 Rolling ball tack test
 Quick-Stick test
 Probe tack test
 12 a.Thumb tack test: It is a qualitative test applied for tack
property determination of adhesive. The thumb is simply pressed
on the adhesive and the relative tack property is detected 81

82. 12b.Rolling ball tack test
 This test measures the softness of a polymer that
relates to talk. In this test, stainless steel ball of
7/16 inches in diameter is released on an inclined
track so that it rolls down and comes into contact
with horizontal, upward facing adhesive. The
distance the ball travels along the adhesive
provides the measurement of tack which is
expressed in inch .
82

83. 12c.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 and recorded as tack value,
which is expressed in ounces or grams per inch width
83

84.  12d.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
 The force required to pull the probe away from the
adhesive at fixed rate is recorded as tack and it is
expressed in grams .
84

85.  13.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.Minghetti et al., (2003) performed the test with an
apparatus (Figure-9) which was fabricated according
toPSTC-7 (pressure sensitive tape council)
specification.
85

86.  14.Stability studies
 Stability studies are to be conducted according to
the ICH guidelines by storing the TDDS samples at
40±0.5°c and 75±5% RH for 6 months. The
samples were withdrawn at 0, 30, 60, 90 and 180
days and analyze suitably for the drug content
86

87. IN VITRO EVALUATION OF TDDS
 In vitro Evaluation of TDDS
 In vitro drug release studies
 The paddle over disc method (USP apparatus V) can be
employed for assessment of the release of the drug from
the prepared patches. Dry films of known thickness is to be
cut into definite shape, weighed, and fixed over a glass
plate with an adhesive. The glass plate was then placed in
a 500-mL of the dissolution medium or phosphate buffer
(pH 7.4), and the apparatus was equilibrated to 32±
0.5°C.The paddle was then set at a distance of 2.5 cm from
the glass plate and operated at a speed of 50 rpm.
Samples(5ml aliquots) can be withdrawn at appropriate
time intervals up to 24 h and analyzed by UV
spectrophotometer or HPLC. The experiment is to be
performed in triplicate and the mean value can be
calculated .
87

88. 88

89.  In vitro skin permeation studies
 An in vitro permeation study can be carried out by usingFull
thickness abdominal skin of male Wistar rats weighing 200 to 250
gm. Hair from the abdominal region is to be removed carefully by
using an electric clipper; the dermal side of the skin was thoroughly
cleaned with distilled water to remove any adhering tissues or blood
vessels, equilibrated for an hour in dissolution medium or
phosphate buffer pH 7.4 before starting the experiment and was
placed on a magnetic stirrer with a small magnetic needle for
uniform distribution of the diffusant. The temperature of the cell was
maintained at 32 ± 0.5°C using a thermostatically controlled heater.
The isolated rat skin piece is to be mounted between the
compartments of the diffusion cell, with the epidermis facing
upward into the donor compartment. Sample volume of definite
volume is to be removed from the receptor compartment at regular
intervals, and an equal volume of fresh medium is to be replaced.
Samples are to be filtered through filtering medium and can be
analyzed spectrophotometrically or HPLC. Flux can be determined
directly as the slope of the curve between the steady-state values
of the amount of drug permeated (mg cm2) vs. time in hours and
permeability coefficients were deduced by dividing the flux by the
initial drug load (mg cm2) .
89

90. 90

91. IN VIVO EVALUATION
 In vivo evaluations are the true depiction of the In vivo
evaluations are the true depiction of the drug performance.
The variables which cannot be taken
 into account during in vitro studies can be fully explored
during in vivo studies. In vivo evaluation of TDDS can
becarried out using:
 Animal models
 Human volunteers
 Animal models: Considerable time and resources are
required to carry out human studies, so animal studies are
preferred at small scale. The most common animal species
used for evaluating transdermal drug delivery system are
mouse, hairless rat, hairless dog, hairlessrhesus monkey,
rabbit, guinea pig etc. Various experiments conducted lead
us to a conclusion that hairless animals are preferred over
hairy animals in both in vitro and in vivo experiments.
Rhesus monkey is one of the most reliable models for in
vivo evaluation oftransdermal drug delivery in man . 91

92.  Human models:
 The final stage of the development of a transdermal
device involves collection of pharmacokinetic and
pharmacodynamic data following application of
thepatch to human volunteers. Clinical trials have been
conducted to assess the efficacy, risk involved, side
effects, patient compliance etc. Phase I clinical trials
are conducted to determine mainly safety in volunteers
and 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 and phase IV trials at post marketing
surveillance are done for marketed patches to detect
adverse drug reactions. Though human studies require
considerable resources but they are the best to assess
the performance of the drug . 92

93.  Skin Irritation study
 Skin irritation and sensitization testing can be
performed on healthy rabbits (average weight 1.2 to
1.5 kg). The dorsal surface (50 cm2) of the rabbit is to
be cleaned and remove the hair from the clean dorsal
surface by shaving and clean the surface by using
rectified spirit and the representative formulations can
be applied over the skin. The patch is to be removed
after 24 hr and the skin is to be observed and classified
into 5 grades on the basis of the severity of skin injury .
93

94. APPLICATION
For treatment of Angina Pectoris,
 Smoking cessation(Nicotine Patch),
 Contraceptive
 Antiemetic
 Anti-inflammatory
 Cosmetics
94

95. REFERENCES
 1. Jain, N.K. (1997) Novel drug deliverysystem 2 nd ed.Nirali
prakashan pune chapter Transdermal Drug Delivery System 6.1-
6.36.
 2. Brahmankar D M, Jaiswal S B. Biopharmaceutics and
Pharmacokinetics, 3 rd ed. A Tretise, Vallabh Prakashan,
Delhi:1995; pp.499-505
 3.Miss. Kore Priyanka et al. Use of Novel Penetration Enhancers
and Techniques in TDDS. Indo American Journal of
Pharmaceutical Research.2015:5(09).
 4. Rastogi V, Yadav P. Transdermal drug delivery system: An
overview. Asian J Pharm 2012;6:161-70.
 5.Roy N, Agrawal M, Chaudhary S, Tirkey V, Dhwaj A and Mishra
N: Review article on permeation enhancers: a major breakthrough
in drug delivery technology. Int J Pharm Sci Res 2017; 8(3): 1001-
11.doi: 10.13040/IJPSR.0975-8232.8(3).1001-11.
 6.Ahlam Z A, Maelíosa T.C., McCrudden, and Ryan F. Donnelly:
Transdermal Drug Delivery: Innovative Pharmaceutical
Developments Based on Disruption of the Barrier Properties of the
stratum corneum. Pharmaceutics 2015, 7(4), 438-470;
https://doi.org/10.3390/pharmaceutics7040438 95