1. TRANSDERMAL DRUG
DELIVERY
Arya Soman
first year M.Pharm

2. Content
• Anatomy of skin
• Mechanism of skin permeation
• TDDS
• Advantages & disadvantages
• Factors affecting skin permeation
• Design of TDDS
• Technologies for developing TDDS
• Kinetic evaluation of TDDS
• Optimization of TDDS
• Advance in TDDS researches.
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3. ANATOMY OF SKIN
• Skin is a multilayered organ
• It is composed of three tissue layers mainly
 The epidermis
 The dermis
 Subcutaneous fat tissue
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4. Basic diagram of skin structure.
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5. • Outer layer of the skin
• Composed of stratified squamous epithelial cells. These are held
together mainly by highly convoluted interlocking bridges which are
responsible for the unique integrity of skin .
 Microscopic section of epidermis shows two main parts mainly
1.Stratum corneum
2.Stratum germinativum
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6. DERMIS
• It is composed of network of collagen & elastic fibers
embedded in a mucopolysaccharide matrix, which
contain blood vessels, lymphatic & nerve endings, there
by providing physiological support for epidermis
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7. SUBCUTANEOUS TISSUE
• This is a sheet of fat containing areolar
tissue, known as superficial fascia, attaching
the dermis to underlying structure.
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8. MECHANISM OF SKIN
PERMEATION
• It consist of series of step in sequence…
Sorption of a parenteral molecule on to the surface layers of stratum corneum
Diffusion through it & viable epidermis & finally at the papillary layers of dermis
The molecule is taken up into the microcirculation for subsequent systemic distribution
The viable tissue layers & the capillaries are relatively permeable & the peripheral
circulation is sufficiently rapid so that for the great majority of penetrant, diffusion
through the stratum corneum is often the rate limiting step
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9. Process of transdermal permeation.
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10. TRANSDERMAL DRUG DELIVERY
SYSTEM
• Transdermal drug delivery is defined as self
contained, discrete dosage forms which, when
applied to the intact skin, deliver the
drug, through the skin at controlled rate to the
systemic circulation. Transdermal drug delivery
system (TDDS) established itself as an integral
part of novel drug delivery systems.
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11. ADVANTAGES OF TDDS
1. Avoidance of significant presystemic metabolism & the need
therefore a lower daily dose.
2. Recent inter & intra patient variability.
3. Drug input can be terminated simply by removal of patch.
4. Drug levels can be maintained in the systemic circulation, with in
the therapeutic window for a prolonged period of time.
5. Thus the duration of drug action can be extended & frequency of
dosing is decreased.
6. Improved patient compliance & acceptability of the drug therapy.
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12. DISADVANTAGES
1. It is limited only to potent drug molecule.
2. Pharmacokinetic & pharmacodynamic characteristics of
the drug must be such that relatively sustained & slow
input provided by transdermal delivery produces
desirable therapeutic effect.
3. Drugs with short biological half lifes that are subject to
large first pass metabolism.
4. Drugs must not be locally irritating or sensitizing.
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13. FACTORS AFFECTING SKIN PERMEATION
– Age
– Physicochemical properties of penetrant (pKa, molecular size,
stability, binding affinity, solubility, partition coefficient)
– Integrity and thickness of stratum corneum
– Density of sweat glands and follicles
– Skin hydration
– Metabolism
– Vehicle effects 13

14. DESIGN OF TRANSDERMAL
SYSTEM
The components are :
1. Polymer matrix
2. The drug
3. Enhancers
4. Excipients
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5. Adhesive

15. 15

16. 1.POLYMER MATRIX
• They are film or membrane with or without micro pores & consist of
gelatin, gum acacia, ethyl cellulose, starch, shellac, natural
rubber, neoprene, polystyrene, pvp…….
• The polymer must fulfill the following requirements.
1. It must allow the diffusion of drug substance at desirable rates.
2. It should be an inert drug carrier.
3. It must not decompose on storage or during the life of the device.
4. The polymer and its decomposed products should not be toxic
5. The cost of polymer should not be excessively high
6. The polymer must be easy to manufacture & fabricate into the desired
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products.

17. • The selection of polymer depends on
i. Proper diffusion & release of drug.
ii. Compatibility
iii. Non toxic
iv. Stability on storage
v. Cost of storage
• The polymer which are most widely used in TDDS :
a. Polypropylene. f. Polyethylene terphthalate
b. Poly vinyl carbonate g. Hydroxypropyl cellulose
c. Cellulose acetate nitrate h. polyester
d. Polyacrylonitrile i. EVA poymer
e. Ethylene vinyl acetate {EVAc} copolymer
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18. 2. DRUG
• Judicious choice of drug.
• The important drug properties that affect its diffusion
from devices as well as across the skin include:
a. Molecular weight
b. Chemical functionality
c. Physical properties
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19. It is generally accepted that the best drug candidates for
transdermal patches must be :
• Non ionic
• Low molecular weight{less than 500 Dalton}
• Adequate solubility in oil & water
• Low melting point{less than 200ºc}
• Potent{dose is less than 50 mg per day &ideally less than
10 mg per day}
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20. • The drug should be non irritating & non allergic to human
skin.
• The main factors that control drug absorption are
1. Solubility
2. Partition coefficient
3. Particle size
4. Diffusion coefficient
5. Ionized or unionized form
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21. 3. EXCIPIENTS & ENHANCERS
• It is an integral part of most of the transdermal formulation
because of the barrier properties of stratum corneum.
• The penetration enhancers have been classified broadly into 3
main categories:
1. Lipophilic solvent : increases the permeation of
lipophilic drugs eg. Dimethyl sulfoxide
2. Two component system : mainly composed of oleic acid &
propylene glycol. The system affect the multilaminate
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hydrophilic layers as well as the continuous path of skin.

22. 3. Surface-active agents :enhance the permeation of hydrophilic
drugs
• In commercially available transdermal products, use of
enhancers is not indicated, however many excipients may be
additionally incorporated which could facilitate & support the
permeation. They include : Propylene glycol
Glycerol
Ethanol
Silicone fluids
Isopropyl palmitate 22

23. 4. ADHESIVES & PACKAGING
• pressure sensitive polymeric adhesive .
• The adhesive system should posses following characteristics:
1. It should not cause an irritation, sensitization or imbalance in
the normal skin flora.
2. It should adhere to the skin strongly & should be easily
removable without leaving any unwashable remains.
3. It should have intimate contact with the skin at both
macroscopic & microscopic levels.
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24. 5.BACKING MEMBRANE
 It is an impermeable membrane that protect the
product during the use on the skin & prevent the drug
from leaving the dosage form through the top.
 It contain formulation through out the shelf life &
during wear period.
 Must be compatible with formulation.
eg: metallic plastic laminate, plastic backing with
adsorbent pad adhesive foam pad. 24

25. 6.RELEASE LINER
• During storage the patch is covered by a
protective liner that is removed & discharged
immediately before the application of the patch to
the skin.
• It is there fore regarded as a part of primary
packing material rather than a part of dosage form
for delivering the drug.
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26. TECHNOLOGIES FOR DEVELOPING
TRANSDERMAL DELIVERY
• Based on the components the delivery systems could be
essentially be classified as :
a) Membrane moderated
b) Adhesive diffusion controlled
c) Matrix dispersion type
d) Micro reservoir type
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27. 1.MEMBRANE MODERATED TDDS
[RESERVOIR TYPE]
• The drug reservoir is encapsulated in a shallow
compartment moulded from a drug impermeable metallic –
plastic lamination whilst the drug delivery side is covered
by controlling polymeric membrane.
• The drug molecules are released only through the rate
controlling membrane.
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28. Drug mixed with polymer
solution
Drug suspended in
polymer solution
Volume controlled
injection pump system
Molding as TDDS using
primary packing material
Packing machinery using
secondary packing material
Transdermal therapeutic
system
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29. • The rate of drug release from this type of
TDDS can be tailored by varying the polymer
composition, permeability coefficient &
thickness of the rate controlling membrane.
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30. 30

31. • The intrinsic rate of drug release from this type
of systems is defined as following:
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32. 2.ADHESIVE DISPERSION TYPE
TDDS
• It is the simplified form of membrane moderated drug delivery system
• It is prepared by directly dispensing the drug in an adhesive polymer & then
spreading the medicated adhesive by solvent film casting method over a flat sheet
of drug impermeable metallic or plastic backing membrane, this forms a thin drug
reservoir layer.
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33. 33

34. • The drug reservoir layer is then covered by a
non medicated rate controlling adhesive
polymer of constant thickness to produce an
adhesion diffusion controlling drug delivery
system.
• The rate of drug release is defined by:
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35. 3.MATRIX DIFFUSION CONTROLLED TDDS
[MONOLITHIC DEVICE]
• It is formed by homogenously dispersing the drug in a mixture of
hydrophilic – Lipophilic polymer{matrix} & the medicated
polymer is moulded on the medicated disc of defined surface
area & thickness .
• It is then glued over an occlusive base plate consisted of
compartment fabricated using an impermeable plastic backing.
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36. 36

37. • The adhesive polymer is applied along the
circumference to form an adhesive rim around
the medicated disc.
• The rate of drug release from this type of
TDDS is defined as follows:
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38. MICRORESERVOIR TYPE TDDS
• It has features of both reservoir & matrix dispersion
type drug delivery system.
• The drug reservoir is formed by suspending the drug
solid in an aq. Solution of water soluble polymer.
• The drug suspension is dispersed homogenously in a
Lipophilic polymer, by high shear mechanical agitation
to form thousands of unleachable microspheres of drug.
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39. 39

40. 40

41. EVALUTION OF TDDS
• It is evaluated by using a 2 – compartment diffusion cell
assembly under identical conditions.
• It is carried out by mounting the freshly excised skin from
either human or hairless mouse on diffusion cell assembly.
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42. • Franz – diffusion cell is being commercialized & widely employed
for studying the skin permeation profile by finite dosing technique.
• The full thickness abdominal skin freshly excised from either human
cadaver or hairless mouse is mounted between the donor & receptor
compartment .
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43. • The drug delivery systems are then applied with their drug releasing
surface being in intimate contact with the stratum corneum surface of the
skin.
• The permeation profile of the drug is assessed by sampling the receptor
solution at predetermined intervals for definite duration & assessing the
drug concentration in the sample using a sensitive analytical method.
• The release profile can also be investigated by using the same
experimental setup with out skin.
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44. OPTIMIZATION OF TDDS
• To formulate a TDDS one should take into consider:
 The rate of drug delivery to the skin surface
 Rate of skin absorption of the drug.
• This is particularly important because of stratum
corneum is known to be highly permeable to most
drugs.
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45. • A TDDS should ideally be designed to have a skin
permeation rate determined the rate of drug
delivery from the TDDS , not by the skin
permeability to the drug to be delivered.
• In such a case, transdermal bioavailability of a
drug become less dependent upon the intra & or
inter – patient variability in the skin permeation.
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46. • The rate of transdermal permeation of a
drug at steady state (Rp)ss is
mathematically related both i.e..., the
actual rate of drug delivery from a TDDS
(Rd)a to the skin surface & to maximum
achievable rate of skin absorption (Ra)m
by the following equation
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47. ADVANCES IN TRANSDERMAL
CONTROLLED DRUG DELIVERY RESEARCH
• Transdermal rate controlled drug delivery offers
the following potential biomedical benefits :
1. Avoid the risks & inconveniences of i.v therapy.
2. Bypass the variation in the absorption &
metabolism associated with oral administration.
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48. 3. Permit continuous drug administration & the use of
drugs with a short biological half lifes.
4. Increase the bioavailability & efficacy of drugs
through the bypass of hepatic first pass elimination.
5. Decrease the chance of over or under dosing through
the prolonged, preprogrammed delivery of drug at the
required therapeutic rate.
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49. 5. Provide a simplified therapeutic regime leading to better patient
compliance.
6. Permit a rapid termination of the medication, if needed , by simply
removing the TDDS from the skin surface.
7. The intensity of interest in the potential biomedical applications of
rate controlled transdermal drug administration has been
demonstrated by a substantial increase in the R & D activities in
many health care institutions aiming to develop viable TDDS for
the prolonged continuous transdermal infusion of therapeutic agent
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50. 50

51. Table 1 Transdermal Controlled-
Release Products and Devices
Drug Trade Name Type of Devices Indication
Scopolamine Transderm-Scop Reservoir Motion sickness
Nitroglycerine Transderm-Nitro Reservoir Angina
Nitro-Dur Monolithic
Nitrodisc Monolithic
Estradiol Estraderm Reservoir and Hormone
ethanol treatment
enhancer
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52. Table 2 transdermal products under
development
Drug Trade name Producer-Marketer
Minocycline Sunstar American Cyanamide, Takeda
Estradiol+Noret Estracombi Ciba-Geigy, Alza
histerone TIS
DHEA Pharmedic
Fentanyl
Triamcinolone Whitby Pharm.
acetonide
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53. REFERRENCE
• Controlled drug delivery by Lee, 2nd edition
revised & expanded.
• Textbook of pharmaceutics by Aulton 2nd
edition.
• Novel drug delivery by Y.M.Chein, 2nd edition.
• www.google.com
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54. THANK
YOU
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