B.PHARM VII SEMESTER.

1. TRANSDERMAL DRUG DELIVERY
SYSTEM
1
Mr. M.Balasundaresan M.Pharm.,
Associate Professor,
Dept. of Pharmaceutics,
Arunai College of Pharmacy,
Tiruvannamalai.

2. INTRODUCTION
❑DEFINITION
➢Transdermal drug delivery system(TDDS) is also known as
“patches,”
➢It defined as a self contained discrete dosage form, which
when applied to the intact skin, will deliver a therapeutically
effective amount of drug across a patient’s skin at a
predetermined and controlled rate to systemic circulation.
➢The first transdermal system, Transderm Scop(Baxter), was
approval by the Food and Drug Administration in 1979 for
prevention of nausea and vomiting associated with
travel(sea).
2

3. ❑ ADVANTAGES OF TDDS
➢Avoidance of first pass metabolism.
➢Avoidance of gastro intestinal incompatibility.
➢Predictable and extended duration of activity.
➢Minimizing undesirable side effects.
➢Enhance therapeutic efficacy.
➢Drug administration stops with patch removal.
➢Alternate route for patients who are unable to take oral
medications.
➢Suitable for administered of drug having
❖ Very short half life Eg : nitroglycerine.
❖ Narrow therapeutic window.
❖ Poor oral availability.
➢Improved patient compliance and comfort via non-invasive,
painless and simple application. 3

4. ❑ DISADVANTAGES OF TDDS
➢Not suitable for high drug doses.
➢Drug with longer half life cannot be formulated.
➢Drug molecule must be potent because patch size limits
amount.
➢Drugs with very low or high partition coefficient fail to reach
blood circulation.
➢Uncomfortable to wear /apply.
➢Skin irritation and hypersensitivity (Erythema, itching, and
local edema )reactions may occur.
➢The barrier functions of the skin change from one site to
another on the same person ,from person to person and with
age.
4

5. Structure of skin
➢Skin is the part of integrated system i.e. it helps to maintain
body temperature protect it from surrounding environment.
➢Skin is the largest organ of the body. It is not uniformly
thick. At some places it is thick and at some places it is thin.
➢The average thickness of the skin is about 1 to 2 mm.
➢In the sole of the foot, palm of the hand - thick, about 5 mm.
➢In other areas of the body, the skin is thin. It is thinnest over
eyelids - about 0.5 mm only.
5

6. 6

7. ❑LAYERS OF EPIDERMIS
Skin is made up of three layers:
I. Outer epidermis
II. Inner dermis
III. Subcutaneous Tissue
I. EPIDERMIS
➢Epidermis is the outer layer of skin.
➢It is formed by stratified epithelium, it does not have blood vessels.
Nutrition is provided to the epidermis by the capillaries of dermis.
➢Microscopic section of epidermis consists of following layers
1. Stratum corneum
2. Stratum lucidum
3. Stratum granulosum
4. Stratum spinosum
5. Stratum germinativum
7

8. 8

9. 1. STRATUM CORNEUM
➢Stratum corneum is also known as horny layer. The stratum
corneum is responsible for primary barrier to percutaneous
absorption.
➢It is the outermost layer and consists of dead cells, which are
called corneocytes.
➢These horny cells have lost their nuclei and are
physiologically rather inactive due to pressure and become
dead cells.
➢They are formed and continuously replenished by the slow
upward migration of cells produced by the basal cell layer of
stratum germinativum (regenerative layer of the epidermis).
➢Stratum corneum is replenished about every 2 weeks in
mature adult. Normally corneum cells have water content
20%.
➢Stratum germinativum -70% of water content.
9

10. ➢The stratum corneum requires a minimum moisture content of
10% to maintain flexibility and softness.
➢It becomes rough and brittle resulting in dry skin, when its
moisture content decreases at a rate faster than resupplied
from the underlying tissues.
2. STRATUM LUCIDUM
➢Stratum lucidum is made up of flattened epithelial
cells(keratin).
➢As these cells exhibit shiny character, the layer looks like a
homogeneous translucent zone. So, this layer is called stratum
lucidum (lucid = clear).
10

11. ➢ It mostly present in sole of feet, palm of hands .
3. STRATUM GRANULOSUM
➢Stratum granulosum is a thin layer with two to five rows of flattened
cells.
➢Cytoplasm contains granules of a protein called keratohyalin is the
precursor of keratin. With organelles slowly being destroyed due to
absence of blood supply.
11

12. 4. STRATUM SPINOSUM
➢Stratum spinosum is also known as prickle cell layer
because, the cells of this layer possess some spinelike
protoplasmic projections.
➢ By these projections, the cells are connected to one another.
Its called desmosomal junction.
➢It contains dendritic cells –basically part of immune system
responsible for taking up pathogen and destroying pathogen.
12

13. 5. STRATUM GERMINATIVUM(BASALE)
➢Stratum germinativum is a thick layer made up of polygonal
cells, superficially and columnar or cuboidal epithelial cells
in the deeper parts.
➢Here, new cells are constantly formed by mitotic division.
The newly formed cells move continuously towards the
stratum corneum.
➢Another type of cells called melanocytes, tactile (merkel)cell.
1.Melanocytes
produce
Pigment called melanin,
response
Color of the skin depends
upon melanin.
13

14. 2. Tactile (merkel)cell
Few in numbers
response
Nerve endings(sense of touch)
14

15. II.DERMIS
➢Dermis is the inner layer of the skin. It is a connective tissue
layer, made up of dense and stout collagen fibers, fibroblasts
macrophage.
➢Collagen fibers exhibit elastic property and are capable of
storing or holding water.
➢Layers of Dermis:
Dermis is made up of two layers:
1. Superficial papillary layer
➢ Lies directly beneath epidermis
➢ It provide sense of touch- pain, heat, cold, pressure.
2. Deeper reticular layer(80% of dermis)
➢It contains fibroblasts, elastin fiber, collagen fiber.
15

16. LAYER OF DERMIS
16

17. III.SUBCUTANEOUS
➢It is also referred as Hypodermis (Fat tissue).
➢It is a loose connective tissue, which connects the skin with
internal structures of the body. It act as fat storage, participates
in thermal regulation (when we cold it helps us to heat up)
➢Lot of smooth muscles called arrector pili are also found in
skin around the hair follicles.
➢The arrector pili muscle is responsible for the movement of
hair when cold, or scared. The contraction of the muscle pulls
on the hair follicle causing the hair to stand up and tightens the
skin around the hair forming goose bumps.
17

18. ❑ GLANDS OF SKIN:
Two types of glands
1.Sebaceous glands 2.Sweat glands
Found all over the body
(expect palm, sole of feet) Eccrine Apocrine
produce
Natural oil of skin
called sebum.
function
Antibacterial, antifungal action
Lubricate our hair,
Defense against pathogen
18

19. FEATURES ECCRINE GLANDS APOCRINE GLANDS
1.Distribution Throughout the
body
Only in limited
areas like
(axilla, pubis,
Umbilicus)
2.Period of
functioning
Function throughout
life
Start functioning
only at puberty
3.Secretion Clear and watery Thick and milky
4.Regulation of
body temperature
Regulate body
temperature
Do not play any role
in temperature
regulation
5.Conditions when
secretion increases
During increased
temperature and
emotional condition
Only during
emotional
conditions
6.Control of
secretory activity
Under nervous
control
Under hormonal
control 19

20. Functions of skin
Function Description
Protection
Barrier against injury, microbes,
chemicals, UV
Sensation
Awareness of touch, temperature,
pain
Thermoregulation
Maintains body temperature via
sweat and blood flow
Fluid & Waste Control
Minimizes water loss & removes
waste via sweat
Absorption/Secretion Drug uptake & glandular secretions
Vitamin D Production Converts UV to vitamin D₃
Immune Surveillance
Detects and defends against
pathogens
Storage Holds fat & water
Aesthetic & Emotional
Impacts appearance and
communication
20

21. 1. Biological Factors
A. Skin Condition
B. Skin Age
C. Blood Flow
D. Site of application
E. Skin Metabolism
F. Species Differences
G. Race
FACTORS INFLUENCING FERMAL PENETRATION OF
DRUGS
2. Physicochemical
Factors
A. Drug Solubility
B. Ionization
C. Hydrogen bonding
D. Melting point
E. Skin Hydration
F. Skin Temperature
G. Skin pH
H. Diffusion
Coefficient
I. Drug Concentration
J. Partition Coefficient
K. Molecular Size
3. Excipient factors
A. Nature of base
B. Miscibility with skin
secretion
C. Effect on skin function
D. Alteration of the skin
permeability
4. Environmental factors
A. Sunlight
B. Cold season
C. Air pollution

22. Skin Condition
• Epidermal barrier may not be intact in diseased or damaged skin. So, the rate of percutaneous
absorption most compounds is limited by diffusion through the stratum corneum.
• Persons with diseased or damaged skin may be at special risk for the toxic effects of
environmental pollutants as a result of increased percutaneous absorption.
• Any skin condition like mechanical injury (cuts, wounds, abrasions) or other insults such as
sunburn, that compromises the capability of the stratum corneum to serve as a permeability
barrier, including psoriasis, eczema, rashes, or dermatitis, may also result in increased
percutaneous absorption in affected individuals.
• If organ thickened with corns, calluses and warts, drug permeation is decreased.
Skin Age
• Skin of young and elder people have more permeation than skin of adults.
• Children's having greater surface area per unit body weight is more prone to toxic effects of
drugs and chemicals.
• Some functional and structural changes take place in skin that affect the transdermal
absorption of molecules into it.

23. Blood Flow
• Altered peripheral circulation affects the transdermal absorption.
• Prolonged skin exposure to organic solvents is known to result in vasodilation in areas that come into
contact with these compounds.
• Rise in blood flow decreases the retention time of a penetrant in the dermis and elevates the concentration
gradient across the skin.
Site of application
• Thickness of skin, nature of stratum corneum and density of appendages vary site to site. These factors
affect significantly penetration.
• The compound applied on the forehead, permeation is twice then applied on arm or abdomen.
Skin Metabolism
Skin metabolises about 5% of the topically applied drugs.
Steroid hormones, chemical carcinogens, and others are metabolised in the skin which regulates the
therapeutic efficacy of topical compounds (especially prodrugs) and their carcinogenic effect on the skin.
Species Differences
• Mammalian (humans and laboratory animals) skin shows variation with respect to horny layer thickness,
sweat gland, hair follicle densities, and pelt condition.
• The reactions between penetrants and the skin may undergo alteration due to the biochemical differences
between the human and animal skin.

24. Race
Racial differences in skin function have been investigated. Study reported that, an
increase in intracellular cohesion in black skin, while higher lipid content in black
skin.
Drug Solubility
The permeation of the lipid-soluble drugs is more through the hair follicle. The
penetration of hydrophilic drugs is more beneath the stratum corneum.
Ionization
If the drug molecules are ionised state, the rate of penetration is less through the
stratum corneum. If the drug molecules are in a non-ionised state, the rate of
penetration is more through the intracellular route.
Hydrogen bonding
Skin components (lipids, proteins, aqueous regions, enzymes etc.) and drug
penetrants (weak acids/bases, ionized/unionized species, neutral molecules etc.)
may interact with each other and form hydrogen bonds, or weak Van der Waals
forces, it may influence skin penetration of a permeating drug.

25. Melting point
High melting points and high enthalpy of melting, organic substances have lower aqueous
solubility properties, because solvents can't enter the crystalline structure of such molecules
to dissolve them.
Lowering the melting point of a drug would hence cause an increase in its solubility in the
stratum corneum and ultimately in its permeation across the skin.
Skin Hydration
When skin gets saturated with water. the tissue Swells, softens, wrinkles, and permeability of
drug is significantly increased. So use of humectant is done in transdermal delivery.
Skin occlusion with wraps or impermeable plastic films prevents the loss of surface water from
the skin and this causes increased level of hydration in the subcutaneous thereby decreasing
the protein network density and the diffusional path length, this increases skin penetration.
Skin Temperature
• Permeation of molecules across the skin is a passive process.
• An increase in skin temperature, kinetic energy of the drug molecules is increased therefore
molecules move faster through the stratum corneum.
• An increasing temperature would also cause structural alterations in the stratum corneum
and underlying tissue and result in a faster movement of the drug through the different skin
layers.
• It is observed that reduction in temperature results in a decrease in diffusion coefficient.

26. Skin pH
• Dissociation of weak acids and bases occur at different degrees based on their pH and pka or
pkb values. Thus, the amount of unionised drug (dependent on pH) in the applied phase
defines the effective membrane gradient.
• On the contrary, the ionised molecules partially penetrate the stratum corneum, as their
aqueous solubility in saturated or nearly-saturated solutions is greater than the neutral species.
Thus, they may contribute to the total flux. The stratum corneum resists changes in pH upto
the range of 3-9.
Diffusion Coefficient
• The speed, at which the molecule diffuses through the skin, depends on the state of matter of
medium.
• According to ficks law of diffusion, the diffusion coefficient is directly proportional and is
dependent on the steady state flux across stratum corneum.
• The diffusion is lowest within compact stratum corneum matrix in skin.
Drug Concentration
• The solute flux is proportional to the concentration gradient through the entire barrier phase.
Saturation of the donor solution is required for maximum flux in a thermodynamically stable
situation.

27. Partition Coefficient
• The partition coefficient of drug is an important factor for affecting the penetration of drug.
• Drugs with high partition coefficient are not ready to leave the lipid portion of skin. Also,
drugs with low partition coefficient will not be permeated.
• Compounds having Log P value 1-3, represents its ability to dissolve in both oil and water,
showing good skin penetration and permeability
Molecular Size
Drug penetration is inversely related to molecular weight; small molecules penetrate faster than
large ones. Drug with molecular weight 500 Dalton are difficult to penetrate through stratum
corneum.
High molecular weight of compound like proteins and polysaccharides, are absorbed poorly.
Nature of the Vehicle (Base)
Fat base (e.g. wool fat, wool alcohol) and fixed oils penetrate more readily through the skin when
compared to mineral oil base (e.g. liquid paraffin).
o/w emulsion type of bases (PEG base) releases the medicaments more readily than the w/o type
of emulsion bases or hydrocarbon bases (White or yellow soft paraffin)

28. Miscibility with skin secretions
• Water-soluble bases (Poly ethylene glycol (PEG)) and o/w bases (Emulsifying wax)
mix readily with skin secretions, so the drug is more rapidly and completely
released to the skin.
• But the greasy bases (white and yellow soft paraffin) are not miscible with skin
secretions. Therefore, the penetration of the drug is also less.
Effect on skin functions
• Greasy bases (Hard paraffin) may interfere with skin function like heat, radiation
and sweat excretions. So the penetration of the drug is less, but emulsion bases (o/w
type: sodium lauryl sulphate) may not interfere with the skin function, and also
penetration is more.
Alteration of the skin permeability
• Penetration can be increased by dissolving the medicament in an organic liquid
such as Dimethyl formamide (DMF), Dimethyl sulfoxide (DMSO). They increase
the hydration of the skin and increase the permeability of the drug.

29. MECHANISM OF DRUG PENETRATION THROUGH SKIN

30. 30

31. Steps involved in drug penetration through skin
1. Dissolution within and release from the formulation.
2. Partitioning into the outermost layer of the skin, stratum corneum
3. Diffusion through the stratum corneum.
4. Partitioning from the stratum corneum into the aqueous viable epidermis,
5. Diffusion through the viable epidermis and into the upper dermis.
6. Uptake into the local capillary network and eventually the systemic circulation
Intracellular/ Transcellular pathway
• Trans-cellular pathway means transport of (molecules across epithelial cellular membrane).
• Transport of small molecules, active transport of ionic and polar compounds, and endocytosis and
transcytosis of macromolecules.
• Under normal conditions the transcellular route is not considered as the preferred way of dermal
invasion the reason being the very low permeability through the corneocytes and the obligation to
partition several times from the more hydrophilic corneocytes into the lipid intercellular layers in the
stratum corneum and vice versa.
• The transcellular pathway can gain an importance when a penetration enhancer is used.

32. 𝐝𝐐
𝐝𝐭
=
𝐃𝐀𝐊𝐩
𝐡
(C1-C2)
dQ/dt - Rate of drug diffusion (amount/time).
D - Diffusion coefficient of the drug through the membrane (area/time)
A - Surface area of the absorbing membrane for drug diffusion (area)
KP - partition coefficient (CGIT – C)
C1 - C2 - Difference in the concentration of drug in the absorbing site and the plasma
h - Thickness of the membrane (length)
Since under usual conditions of absorption, D, A, KP, h are constants, so, they can be replaced by
a combined constant P called as permeability coefficient.
Permeability refers to the ease with which a drug can penetrate or diffuse through a membrane.
Moreover, due to sink conditions, the concentration of drug in plasma C2 is very small in
comparison to drug in the absorbing site C1.
𝑑𝑄
𝑑𝑡
= 𝑃𝐶1
Thus, passive diffusion follows first-order kinetics. Since a large concentration gradient always
exists at the absorption site for passive diffusion, the rate of drug absorption is usually more rapid
than the rate of elimination.

33. Paracellular/ Intercellular pathway
• In para-cellular route drug molecules transport around or between the cells.
• Tight junctions or similar situations exist between the cells.
• The principal pathway taken by a permeate is decided mainly by the partition
coefficient (log k).
• Hydrophilic drugs partition preferentially into the intercellular domains, whereas
lipophilic permeants (o/w log k >2) traverse the stratum corneum via the intracellular
route.
• The intercellular route is considered to yield much faster absorption due to the high
diffusion coefficient of most drugs within the lipid

34. Trans follicular route/ Macro route
• Penetration of drug through skin appendageal route comprises transport via eccrine
sweat glands, apocrine sweat glands and hair follicles with their associated sebaceous
glands.
• These routes circumvent penetration through the stratum corneum and are
Considerable role. therefore, known as "shunt" routes.
• Trans-follicular route is considered to be of minor importance because of its
relatively small area, approximately 0.1 % of the total skin area.
• In contrast, in the initial stages s of a skin absorption process and in the case of large
hydrophilic compounds and ions invasion through the appendages may play a
Considerable role.

35. 1. Drug
2. Polymer matrix/drug reservoir
3. Permeation enhancers
4. Pressure-sensitive adhesives (PSA)
5. Backing laminates
6. Release liner
7. Other excipients like plasticizers and solvents
35
BASIC COMPONENTS OF TDDS

36. DRUG
➢Drug should be chosen with great care.
➢Transdermal patches offer many advantages to drugs that
undergo
BIOLOGICAL PROPERTIES :
➢Drug should be potent.
➢Short half life.
➢Non allergic and non irritant.
➢Extensive first pass metabolism.
➢Should not have any binding capacity to skin proteins.
Drug suitable for TDDS, like nicardipine hydrochloride,
captropril, Atenolol, Metoprolol tartarate, Clonidine,
Indapamide, Propranolol hydrochloride, Carvedilol, and
Verapamil hydrochloride etc..
36

37. 37

38. POLYMER MATRIX/DRUG RESERVOIR
➢Polymers are the backbone of TDDS, which control the
release of the drug from the device.
➢Polymer matrix can be prepared by dispersion of drug in a
liquid or solid state synthetic polymer base.
➢Polymers used in TDDS should have biocompatibility and
chemical compatibility with the drug and other components
of the system, such as penetration enhancers and PSAs
➢Polymer must be following:
❖Molecular weight, and chemical functionality of the polymer
-should be such that specific drug diffuses properly and gets
released through it.
❖Stable, non reactive with the drug.
❖Easily manufactured and fabricated into the desired product.
❖Inexpensive, degradation products of polymer – nontoxic.
38

39. 39

40. 40

41. 41

42. 42

43. 43

44. 44

45. 45

46. 46

47. 47

48. 48

49. 49

50. 50

51. 51

52. 52

53. 53

54. 54

55. 55

56. 56

58. 58

60. 60

61. 61

62. 62

63. 63

64. 64

65. 65

66. 66

67. 1. Polymer Membrane Permeation controlled TDDS
2. Polymer Matrix Diffusion Controlled TDDS
3. Adhesive Dispersion TDDS
4. Drug Reservoir Gradient Controlled TDDS
5. Micro reservoir Dissolution Controlled TDD
67
FORMULATION APPROACHES USED IN
THE DEVELOPMENT OF TDDS

68. POLYMER MEMBRANE PERMEATION-CONTROLLED
TDDS
➢In this system the drug reservoir is sandwiched between a drug-
impermeable backing laminate and a rate-controlling polymeric
membrane.
➢The drug molecules are permitted to release only through the rate-
controlling polymeric membrane.
68

69. • Dispersed on solid polymer matrix eg:
polyisobutylene
• Suspended in unleachable viscous
liquid medium eg: silicone fluid
• Dissolved in solvent-alkyl alcohol
Drug reservoir
compartment
• Microporous, nonporous
• eg: ethylene vinyl acetate copolymer
Rate controlling
membrane
• Thin layer of adhesive
• Drug compatible, hypo allergic
• eg: silicone adhesive
Adhesive layer
69

70. ➢Rate of drug release depends on varying :
❖Composition of the drug reservoir formulation
❖Permeability coefficient and/or thickness of the rate-controlling
membrane. The intrinsic rate of drug release defined by
❖CR - Drug concentration in the reservoir compartment.
❖Km/r & Ka/m -Partition coefficient of the drug molecule from
reservoir to the membrane & from membrane to adhesive.
❖Dm & Da -Diffusion coefficients in the rate controlling membrane and
in adhesive layer.
❖hm & ha -Thickness of rate controlling membrane and adhesive layer.
Eg: Transderm-Nitro system once-a-day angina pectoris.
Transderm-Scop system for 3-day protection of motion
sickness .
70

71. POLYMER MATRIX DIFFUSION-CONTROLLED TDDS
i.Drug in adhesive system
➢In this approach the drug reservoir is formed by homogeneously
dispersing the drug solids in a hydrophilic or lipophilic polymer
matrix,(silicone elastomers, polyurethanes, polyvinyl alcohol),
medicated polymer formed is then molded into medicated disks with a
defined surface area and controlled thickness.
➢This drug reservoir-containing polymer disk is then mounted onto an
occlusive baseplate in a compartment fabricated from a drug-
impermeable plastic backing
➢In this system the adhesive polymer is applied along the
circumference of the patch to form a strip of adhesive rim surrounding
the medicated disk.
➢The rate of drug release from this polymer matrix drug dispersion-
type TDD system is defined as
71

72. ❖Ld - Drug loading dose initially dispersed in polymer matrix
❖Cp & Dp - Solubility and diffusivity of drug in matrix
72

73. ii.Polymer matrix drug dispersion-type:
➢Dispersing the drug in a pressure-sensitive adhesive polymer, e.g.
polyacrylate, and then coating the drug-dispersed adhesive polymer
by solvent casting or hot melt
Onto a flat sheet of a drug-impermeable backing laminate to form a
single layer of drug reservoir.
➢This yields a thinner and/or smaller TDD patch.
73

74. 74
ADHESIVE DISPERSION TDDS
• This is a simplified form of the membrane permeation controlled
system.
• The drug reservoir is formulated by directly dispensing the drug in an
adhesive polymer e.g. poly (isobutylene) or poly(acrylate)
• Adhesive and then spreading the medicated adhesive, by solvent
casting or hot melt, on to a flat sheet of drug impermeable metallic
plastic backing to form a thin drug reservoir layer.
• On top of drug reservoir layer, thin layers of non medicated, rate
controlling adhesive polymer of a specific permeability and constant
thickness are applied to produce an adhesive diffusion controlled
system.

75. Ka/r – Partition coefficient for the interfacial partition of the drug
from the reservoir layer to adhesive layer.
Da - Diffusion coefficient in rate controlling membrane
ha - Thickness of rate controlling membrane
CR - Drug concentration in reservoir compartment
75
CR

76. DRUG RESERVOIR GRADIENT-CONTROLLED TDDS
➢Polymer matrix drug dispersion-type TDD systems can be modified,
drug reservoir- drug loading level is varied in an incremental manner,
forming a gradient of drug reservoir along the diffusional path across
the multi laminate adhesive layers.
76

77. MICRORESERVOIR DISSOLUTION-CONTROLLED
TDDS
➢This type of drug delivery system can be considered a
hybrid of the reservoir- and matrix dispersion-type drug
delivery systems.
➢In this approach the drug reservoir
formed by
First suspending the drug solids
Water-miscible drug solubilizer e.g., polyethylene glycol
Homogeneously dispersing the drug suspension, with
controlled aqueous solubility, in a lipophilic polymer
by high shear
mechanical force
Form thousands of unleachable microscopic drug
reservoirs.
77

78. Thermodynamically unstable dispersion is quickly stabilized
by immediately
Cross-linking the polymer chains in situ, which produces a medicated
polymer disk with a constant surface area, fixed thickness
Depending upon the physicochemical property of the drug and the
desired rate of drug release, the device can be further coated with a
layer of biocompatible polymer to modify the mechanism and the rate
of drug release
TDD system is then produced by mounting the medicated disk at the
center of an adhesive pad.
78

79. ➢The rate of drug release from a microreservoir drug delivery system
is defined by
➢B -Ratio of the drug concentration at the inner edge of the interfacial
barrier over the drug solubility in the polymer matrix.
➢Kl, Km, Kp -Partition coefficient for interfacial partitioning of drug
from the liquid compartment to the polymer matrix, from polymer
matrix to the polymer coating membrane, from the polymer coating
membrane to the elution solution.
➢Dl, Dp, Ds -Drug diffusivities in the liquid compartment, polymer
coating membrane, and elution solution.
➢Sl, Sp - Solubilities of the drug in the liquid compartment & in the
polymer matrix
79

80. ➢A=a/b
➢a - ratio of drug concentration in bulk of elution solution
over drug solubility in the same medium.
➢b - ratio of drug concentration at the outer edge of the
polymer coating membrane over the drug solubility in same
polymer.
➢hi-Thickness of the liquid layer surrounding the drug
particles,
➢hp -Thickness of polymer coating membrane surrounding the
polymer matrix,
➢hd -Thickness of hydrodynamic diffusion layer surrounding
the polymer coating membrane, respectively.
➢Eg: Combination of a potent progestin and a natural
estrogen at different daily dosage rates for weekly fertility
regulation in females . 80

81. Evaluation of tdds
These evaluation are predictive of transdermal dosage form
and it classified into following :
I. Physicochemical evaluation
• Thickness
• Weight uniformity
• Folding endurance
• Percentage moisture content
• Percentage moisture uptake
• Drug content determination
• Content uniformity test
• Flatness
• Tensile strength
• Evaluation of adhesive
81

82. • Thickness of the patch
➢The thickness of the drug-loaded patch is measured in different
points by using a digital micrometer, and determines the average
thickness and standard deviation for the same to ensure the thickness
of the prepared patch.
➢
• Weight uniformity
➢The prepared patches are to be dried at 60°C for 4h before testing.
➢A specified area of patch is to be cut in different parts of the patch
and weighed in a digital balance.
➢The average weight and standard deviation values are to be
calculated from the individual weights.
82

83. • Folding endurance
➢It determines the folding capacity of film.
➢A strip of the specific area is to be cut evenly and repeatedly folded at
the same place till it breaks.
➢The number of times the film can be folded at the same place without
breaking gives the value of the folding endurance.
• Percentage moisture content
➢The prepared films are to be weighed individually and are to be kept
in a desiccator containing fused calcium chloride at room temperature
for 24hr.
➢After 24hr, the films are to be reweighed to determine the percentage
moisture content. Formula
Percentage moisture content:
= Initial weight - Final weight ×100
Final weight
83

84. • Percentage moisture uptake
➢The weighed films are to be kept in a desiccator at room
temperature for 24hr, which contains a saturated solution of
potassium chloride in order to maintain 84% RH.
➢After 24hr, the films are to be reweighed to determine the
percentage moisture uptake from the below-mentioned formula:
Percentage moisture uptake
= Final weight -Initial weight ×100
Initial weight
84

85. 85
Drug content determination
Accurately weighed portion of film
(100mg) is dissolved in 100ml of
suitable solvent & shaken continuously
for 24 hr, then sonicated
After sonication and subsequent
filtration, drug in solution is estimated
spectrophotometrically by appropriate
dilution

86. Content uniformity test
10 patches are selected and content
is determined for individual patches.
If 9 out of 10 patches have content
between 85% to 115% of specified
value, patches pass the test.
If 3 patches range 75% to 125%, then
additional 20 patches are tested .If
these 20 patches have range 85%-
115%,then patches pass the test.
86

87. • Flatness
➢A transdermal patch should possess a smooth surface and
should not constrict with time. This can be demonstrated
with flatness study.
➢For flatness determination, one strip is cut from the centre
and two from each side of patches.
➢The length of each strip is measured and variation in length
is measured by determining percent constriction.
➢Zero percent constriction is equivalent to 100 percent
flatness.
➢% constriction = L1 –L2 X 100
L1
L2= Final length of each strip
L1 = Initial length of each strip
87

88. • Tensile strength
➢To determine tensile strength, polymeric films are sandwiched
separately by corked linear iron plates.
➢One end of the films is kept fixed with the help of an iron screen
and other end is connected to a freely movable thread over a pulley.
➢The weights are added gradually to the pan attached with the
hanging end of the thread.
➢A pointer on the thread is used to measure the elongation of the
film.
➢The weight just sufficient to break the film is noted.
88

89. Tensile strength = F 1 + L
a×b l
F– Force required to break
a- Width of film; b- thickness of film
L- Length of film
l- Elongation of film at break point
89

90. • Evaluation of adhesive
a. Peel adhesion test
b. Tack properties
b.1 Thumb tack test
b.2 Probe tack test
b.2 Rolling ball test
b.3 Quick stick (Peel tack) test
a. Peel adhesion test
➢In this test, the force required to remove an adhesive
coating from a test substrate is referred to as peel adhesion.
90

91. ➢Molecular weight of the adhesive polymer, and amount of
additives are the variables that determine the peel adhesion
properties.
➢ A single tape is applied to a stainless steel plate or a backing
membrane of choice and then the tape is pulled from the substrate
at a 180º angle, and the force required for tape removal is
measured.
91

92. b. 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.
b.1 Thumb tack test:
➢It is a qualitative test.
➢The force required to remove thumb from adhesive is a measure of
tack.
b.2 Probe tack test
➢Force required to pull a probe away from an adhesive at a fixed rate
is recorded as tack.
92

93. b.3 Rolling ball test
➢This test involves measurement of the distance that stainless steel
ball travels along an upward facing adhesive.
➢The less tacky the adhesive, the further the ball will travel.
Rolling ball test Quick stick test
93
b.4 Quick stick (Peel tack) test
➢ The peel force required breaking the bond between an
adhesive and substrate is measured by pulling the tape
away from the substrate at 90 at the speed of 12
inch/min.

94. In vitro evaluation
• 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 are to be cut into a definite shape, weighed and
fixed over a glass plate with an adhesive.
➢The glass plate was then placed in 900mL 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 25-50 rpm. Samples (5-mL aliquots) can be withdrawn
at appropriate time intervals up to 24 h and analyzed by a UV
spectrophotometer or HPLC. The experiment is to be performed in triplicate,
and the mean value can be calculated.
94

95. 95

96. • In vitro skin permeation studies
➢An in vitro permeation study can be carried out by using diffusion
cells (Franz diffusion cell).
➢Membrane prep: Full-thickness abdominal skin of male Wistar rats
weighing 200–250 g was selected.
➢Hair from the abdominal region is to be removed carefully by using a
electric clipper .
➢The dermal side of the skin was thoroughly cleaned with distilled
water to remove any adhering tissues or blood vessels
➢Condition: Equilibrated for 1 hr 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.
➢The temperature of the cell was maintained at 32 ± 0.5°C using a
thermostatically controlled heater.
96

97. ➢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(prepared film).
➢Definite volume of sample 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 the filtering medium, and can be
analyzed spectrophotometrically or by using HPLC.
97

98. In vivo studies
• HUMAN MODEL :
➢Involves collection of pharmacokinetics and pharmacodynamic data
following application of the patch to human volunteers.
• ANIMAL MODEL:
➢The most common animal species used for evaluating transdermal
DDS are mouse, hairless rat, hairless dog, hairless rhesus monkey,
rabbit, guinea pig etc..
➢Hairless animals are preferred over hairy animals in both in vitro and
in vivo.
98

99. THANK YOU
99