The document provides information on transdermal therapeutic systems (TTS). It discusses the advantages and disadvantages of TTS, the structure of skin, permeation through skin, and factors affecting permeation. It also describes the basic components of TTS including polymer matrix, drug, permeation enhancers, and other excipients. Finally, it outlines various formulation approaches used in developing TTS such as membrane permeation controlled systems, adhesive dispersions, matrix diffusion controlled systems, and microreservoir or microsealed dissolution controlled systems.

1. Submitted to: Dr. Ahmed Mahmood Mumtaz
Submitted By: Huzaifa Amjad – 38
Hassan Raza – 36
Affan Umar – 34
Yasir Bashir - 44

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

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

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

5. Disadvantages
■ The drug must have desired physiochemical properties for
penetration through the Stratum Corneum.
■ Skin irritation or contact dermatitis due to excipient and
enhancers of the drug used to increase the percutaneous
absorption. Is the other limitation.
■ The barrier function of the skin changes from one site to
another on the same person. From person to person and with
age.
■ Heat, cold, sweating (perspiring) and showering prevent the
patch form sticking to the surface of the skin for mare than one
day. A new patch has to be applied daily.
■ The patches fall off during bathing and sleeping has resorted
using medical tape to help secure patches.
■ Patches fall off completely during bathing or swimming;
patches sometimes fall off during walking.

6. 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. More than 35 TDD products have now been approved for sale in
US. And approximately 15 active ingredients are approved for use
in TDD products globally.

8. Where as 13 compounds
currently exist to 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 1 is that several of
the compounds
(macromolecules and
vaccines) in development are
outside of the normal niche
of TDD.

9. StructureoftheSkin
■ Anatomically the skin has many histological layers, but it is
divided into three layers:
 Epidermis
 Dermis
 Subcutaneous Tissue

10. Structure of Skin

13. 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.
■ 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.

14. Dermis
■ The dermis is made up of regular network of robust collagen
fibres of fairly uniform thickness with regularly placed cross
striations.
■ This network of 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.

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

16. BiochemistryoftheSkin
-Epidermis
■ The main source of energy for the lower portions of the
epidermis is the glucose and the end product is the lactic acid.
■ Fatty acids are required for the cellular functions of the skin
and cells derives their energy from the degradation of the
phospholipids.
■ The energy derived used for the synthesis of proteins and
construction of the stratum Corneum.
■ Proteolytic enzymes are present in the stratum Corneum and
epidermis consists of specialized organelles like lysosomes.

17. -Dermis
■ Protein synthesis is a key factor in the dermal metabolism.
■ Fibroblast extracellularly deposit large quantities of collagen
and elastin.
■ Protein synthesis occur in hair follicles.
■ The sebaceous gland produce large quantities of lipids and
energy is derived from the intracellular aerobic carbohydrate
metabolism is used for cellular synthetic process.

18. -SkinSurface
■ The skin surface has a population of microorganisms and can
contribute to enzymology.
■ The diversity and abundance varies from individual to
individual.
■ The microorganism alter the skin surface lipid composition via
hydrolysis of secreted sebum

19. PermeationthroughSkin
The permeation through skin occurs by following routes:
■ Transepidermal absorption.
■ Transfollicular (shunt pathway absorption)
■ Clearance by local circulation.

20. PathwaysofpermeationthroughSkin

21. TransepidermalAbsorption
■ Stratum Corneum is the main resistance for absorption through
this route.
■ Permeation involves partitioning of the drug into 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.

22. TransfollicularAbsorption
■ The skin appendages (sebaceous and eccrine glands) are
considered as shunts for by passing the stratum Corneum.
■ Follicular route is important for permeation because 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.

23. ClearancebylocalCirculation
■ 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.

24. FactorsaffectingPermeationthroughSkin
■ 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.
■ 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.

25. BasiccomponentsofTDDS
The components of transdermal drug delivery system include:
■ Polymer matrix or matrices
■ The drug
■ The permeation enhancers
■ Other excipients

26. PolymerMatrix
It releases the drug from the devices and should satisfy the
following criteria:
■ Molecular weight, chemical functionality of the polymer should
be such that specific drug diffuses properly and gets released
through it.
■ It should be stable, non reactive with the drug, easily
manufactured and fabricated by into the desired product.
■ The polymer and its degradation products must be non toxic or
not antagonistic to the host.
■ Synthetic elastomers-polybutadiene, hydrin rubber, poly
siloxane silicone rubber, nitrile, acrylonitrile, butyl rubber,
butadiene neoprene etc.
■ Synthetic polymers-polyvinyl chloride, polyethylene, poly
propylene, polyacrylate, polyamide, polyuria, polyvinyl
pyrrolidone, polymethyl methacrylate.

27. Drug
For successful development of a transdermal drug delivery, the
following are the desirable properties of a drug for transdermal
drug delivery.
■ Physiochemical properties
■ Biological properties

28. PhysiochemicalProperties
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°C)
■ Potent (dose is less than 50mg per day, and ideally less than 10
mg per day).

29. BiologicalProperties
■ The drug should be potent with a daily dose of order of a few
mg per day.
■ The half life of a 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.

30. PermeationEnhancers
■ These are compounds that promote skin permeability by
altering the skin as barrier to the flux of the desired penetrate.
■ The flux of the drug (J) is given by:
𝐉 = 𝐃
𝐝𝐜
𝐝𝐱
D = diffusion co-efficient
C = conc. Of the diffusing species.
X = spatial coordinate

31. ClassificationofPermeableEnhancers
■ Solvents
■ Surfactants
 Anionic surfactants: Dioctyl sulphosuccinate
 Non-ionic surfactants: Pluronic F127, Pluronic F68
 Bile salts: Sodium taurocholate
■ Binary systems: Propylene glycol, oleic acid
■ Miscellaneous chemicals: Urea, calcium thioglycholate

32. OtherExcipients
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.

33. Continued…
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.

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

35. SchematicSkinabsorptionofDrug

36. Continued…
■ Transdermal drug delivery mechanism
■ Passive
■ Matrix (oxytrol)
■ Reservoir (Duragestic)
■ Active
■ Iontophoresis
■ Electroporation
■ Sonophoresis
■ Heat of thermal energy
■ Microneedles

37. FormulationApproachesusedinthedevelopment
ofTDDS
■ Membrane permeation – controlled systems
■ Adhesive Dispersions – type systems
■ Matrix diffusion – controlled systems
■ Microreservoir or microsealed dissolution – controlled systems
■ Poroplastic – type systems
■ Transdermal delivery of macromolecules

38. Membranepermeation–ControlledSystems
■ The drug reservoir is totally encapsulated in a shadow
compartment moulded form a drug – impermeable metallic
plastic laminate and 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 co-
efficient, thickness of the rate limiting membrane and adhesive.
■ Example I) Nitroglycerine releasing transdermal system for
once a day medication in angina pectoris.
Example II) Scopolamine releasing transdermal system for 72
hours prophylaxis of motion sickness.

39. Membrane moderated transdermal drug delivery system

40. Continued…
■ The intrinsic rate of drug release from this type is…
𝐝𝐐
𝐝𝐭
=
𝐂𝐑
𝟏
𝐏𝐦
+ 𝟏
𝐏𝐚
… (1)
where, CR = Drug conc. In the reservoir compartment
Pa & Pm = permeability coefficients of adhesive & the rate
controlling membrane respectively.

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

42. Continued…
■ In case of microporous membrane, the porosity of the
membrane should be taken in to the calculation of Dm and hm
values.
Substituting equation (2) and (3) in (1)…
𝐝𝐐
𝐝𝐭
=
𝐊𝐦 𝐫 𝐊𝐚 𝐦 𝐃𝐦 𝐃𝐚
𝐊𝐦 𝐫 𝐃𝐦 𝐡𝐚+ 𝐊𝐚 𝐦 𝐃𝐚 𝐡𝐚
𝐂𝐑 …… (4)

43. AdhesiveDispersions–TypeSystems
■ 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 for once a day medication of angina pectoris.

44. Adhesive dispersion type Transdermal drug delivery system

45. Continued…
■ The rate of drug release from this type is defined by…
𝐝𝐐
𝐝𝐭
=
𝐊𝐚 𝐫 𝐃𝐚
𝐡𝐚
𝐂𝐑
where, Ka/r = partition coefficient for the interfacial
partitioning of the drug from the reservoir layer to the adhesive
layer.

46. MatrixDiffusion–ControlledSystems
■ It is prepared by homogenously dispersing the drug particles
with a liquid polymer or a highly viscous base polymer
followed by cross linking of the polymer chains or
homogenously blending the drug solids with a rubbery polymer
at an elevated temperature.
■ It can also be prepared by dissolving the drug and polymer in a
common solvent followed by solvent evaporation in a mould at
an elevated temperature or in a vacuum. 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.

47. Matrix diffusion controlled Transdermal Drug Delivery System

48. Continued…
■ Example: Nitroglycerine releasing Transdermal system 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
𝐝𝐭
=
𝐀𝐂𝐩𝐃𝐩
𝟐𝐭
𝟏
𝟐
Where, A = Initial drug loading dose dispersed in polymer
matrix.
Cp & Dp = Solubility and diffusivity of the drug in the polymer
respectively.

49. Microreservoirtypeormicrosealeddissolution-CS
■ This is the combination of reservoir and matrix diffusion type
drug delivery systems.
■ Drug reservoir is formed by first suspending the drug solids in
aqueous solution of a water soluble liquid polymer and then
dispersing the drug suspension homogenously in a lipophilic
polymer such as silicone elastomers by high dispersion
technique.
■ Example: Nitroglycerine-releasing transdermal system for once
a day therapy of angina pectoris.

50. Micro reservoir dissolution controlled transdermal drug delivery system

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

52. TransdermalDeliveryofMacromolecules
■ Macromolecules such as hormones, interferons, bioactive
peptides can be deliver by transdermal delivery system.
■ The devices used for this purpose are divided into two
categories…
■ Devices based on ethylene vinyl acetate copolymers (EVAc)
■ 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.

53. TransdermalPatchDesign

55. EvaluationofTDDS
-EvaluationofAdhesives
Peel adhesion properties:
■ It is the force required to remove an
adhesive coating from a test substrate.
■ It is affected by the molecular weight of
the adhesive polymer, the type & amount
of additives and polymer composition.
■ It is tested by measuring the force
required to pull a single coated tape,
applied to a substrate, to an angle of
180°, no residue on the substrate
indicates ‘Adhesive failure’ signifying a
deficit of cohesive strength in the
coating.

56. Continued…
Tack properties
■ It is the ability of a polymer to adhere to a
substrate with little contact pressure.
■ It is dependant on the molecular weight
and composition of the polymer as well as
the use of tackifying resins in the
polymer.
■ It Includes:
Rolling ball tack test
■ It involves the measurement of the
distance that stainless steel ball travels
along an upward facing adhesive, less
tacky the adhesive, the further the ball
will travel.

57. Continued…
Quick-stick test:
■ The peel force required to break the bond
between an adhesive and substrate at
90°at a speed of 12 inch/min. the force
recorded as the tack value & is expressed
in ounces per inch width with higher
values indicating increasing tack.

58. Continued…
Probe tack test:
■ The force required to pull a probe away
from an adhesive at a fixed rate is
recorded as tack. It is expressed in grams.

59. Continued…
Shear Strength Properties
■ It is affected by molecular weight as well
as the type and amount of tackifier added.
■ Shear strength is determined by
measuring the time it takes to pull an
adhesive coated tape of stainless steel
plate when a specified weight is hung
from the tape in a direction parallel to the
plate.

60. Continued…
In-vitro drug release evaluation:
■ In these studies, excised skin is mounted on skin permeation
cells.
■ Skin of hairless mouse is used rather than human cadaver skin.
■ In-vitro systems 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.
■ 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.

61. Continued…
Keshary-Chien (K.C) cell:
■ It has an effective receptor volume 12ml and a skin surface
area of 3014 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.

62. Continued…
In-vivo drug release 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 usually the forearm or abdomen which
are less hairy sites on the animals body.
■ The compound is applied after light clipper shaving of the site.

63. Continued…
B. Human Volunteers:
■ Procedures for in-vivo evaluation in humans were first
described by Feldmann and Mailbach in 1974.
■ The 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…
% 𝑜𝑓 𝑑𝑜𝑠𝑒 𝑎𝑏𝑠𝑜𝑟𝑏𝑒𝑑 =
𝑡𝑜𝑡𝑎𝑙 𝑟𝑎𝑑𝑖𝑜𝑎𝑐𝑡𝑖𝑣𝑖𝑡𝑦 𝑒𝑥𝑐𝑟𝑒𝑡𝑒𝑑 𝑎𝑓𝑒𝑡𝑟 𝑡𝑜𝑝𝑖𝑐𝑎𝑙 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛
𝑇𝑜𝑡𝑎𝑙 𝑟𝑎𝑑𝑖𝑎𝑐𝑡𝑖𝑣𝑖𝑡𝑦 𝑎𝑥𝑐𝑟𝑒𝑡𝑒𝑑 𝑎𝑓𝑡𝑒𝑟 𝐼.𝑉 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛
× 100

64. Continued…
Other evaluation parameters
■ Thickness
■ Moisture content
■ Folding endurance
■ Tensile strength
T. S =
𝐁𝐫𝐞𝐚𝐤 𝐅𝐨𝐫𝐜𝐞
a. b.
1 +
∆L
L

65. AdvancesinTDDS
Active transdermal Systems
■ Micro structured transdermal systems 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.

66. Continued…
Find an appropriate place to put the patch
■ Choose a dry, unbroken, non-hairy part of your skin, buttocks,
lower abdomen, lower back, and upper arm are good choices. If
the area you choose has body hair, clip the hair close to the skin
with scissors.
■ Make sure that the area is clean. If there is any oil or powder,
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.

67. Continued…
■ Press the patch firmly on your skin with the palm of your hand
for about 30 seconds. Make sure the 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.

69. Reference
■ Y. W. Chien, novel drug delivery systems, 2nd edition, Revised
and expanded, Marcel Dekker, Inc., New York, 1992
■ N. K. Jain, controlled and novel drug delivery, CBS Publishers
and distributors, New Delhi, First edition, 1997
■ Controlled drug delivery devices by Pravin Tyle, Marcel Dekker,
Inc., New York, 1992, page no. 406-408.
■ Mechanisms of Transdermal Drug Delivery by Y. W. Chien,
Marcel Dekker, Inc., New York
■ www.google.com