Transdermal drug delivery system

1. Transdermal Drug Delivery
System
By:
Kailash V.Vilegave
Pharmaceutics dept
S.S.Jondhle college of pharmacy Asangaon

2. • Anatomy of Skin
• Mechanism of percutaneous absorption
• Kinetics of Skin permeation
• Factors affecting Skin permeation
• Basic components of Transdermal drug delivery systems
• Formulation approaches used in development of TDDS
• Evaluation of Transdermal products.
Contents :

3. Definition :
Transdermal drug delivery systems (TDDS) are topically
administered medicaments in the form of patches, which when
applied to intact skin, allows the delivery of contained drugs into the
systemic circulation via permeation through skin layers at a
predetermined and controlled rate.
Transdermal patches typically involve a liquid, gel, solid matrix
or pressure sensitive adhesive carrier into which the drug is
incorporated.
This approach of drug delivery is more pertinent in case of
chronic disorders (hypertension, diabetes) which require long term
dosing to maintain therapeutic drug concentrations.

4. Advantages over conventional drug delivery systems :
1. Improves patient compliance, provides capacity for multi-day
therapy with a single application. No pills to remember.
2. Slow & steady infusion of a drug over an extended period of
time results in more consistent plasma concentrations. Adverse
effects or therapeutic failures (due to peaks & valley) frequently
associated with intermittent dosing can be avoided.
3. Transdermal delivery can increase the therapeutic value of
many drugs by avoiding specific problems associated with the
drug like
– G.I irritation,
- Low absorption,
- Decomposition due to hepatic first pass effect
- Formation of metabolites that cause side effects,
- Short half life necessitating frequent dosing etc.

5. 4. Dose of drug required is low than is necessary for drug dose given
orally.
5. Avoid GIT drug absorption difficulties caused by GI Ph,
enzymatic activity & drug interactions with food, drink or other
orally administered drugs.
6. Substitutes for oral administration of medication when the route
is unsuitable as in case of vomiting or diarrhea.
7. Provide ease of rapid administration of medication in
emergencies like unconsciousness, non responsive cases etc.
8. Avoid risk & inconveniences of Parenteral therapy :
- necessitates no hospitalization of patients.
- close medical supervision of the medicament is not needed.
- non invasive in nature.

6. Advantages over other Novel DDS :
1. Vast surface area for drug administration.
2. Administration site can be varied/rotated conveniently
according to the patient needs.
3. Self administration is possible with these systems.
4. The drug input can be terminated at any point of time by
removing the patch.

7. 1. The drug must have some desirable physicochemical properties
for penetration through skin like balanced hydrophilic &
lipophilic nature, low molecular weight etc.
2. If the drug dose required for therapeutic value is more than 10
mg/day, the transdermal delivery will be very difficult if not
possible. This means only potent drugs can be administered.
3. Skin irritation or contact dermatitis due to the drug, excipients
& enhancers of the drug used to increase percutaneous
absorption is another limitation.
4. Some drugs that undergo local dermal metabolism cannot be
administered.

8. 5. The barrier function of the skin changes from one site to another
on the same person, from person to person with age.
6. Requires careful disposal as patch may still contain active
medication.
7. Technical difficulties are associated with adhesion of system to
different skin types & under various environmental conditions.
8. High cost of such a system.

9. Skin site for transdermal drug delivery
 Skin is one of the most extensive & readily accessible organ of
the human body.
 Surface area of skin on an average adult body is
 2 m2 or 3000 inch2.
 Thickness – 2.97 +/- 0.28 mm.
 Receives about 1/3rd of blood circulation of the body.
 Function – To keep our inside in & outside out.
Anatomy of Skin
Microscopically skin is a multilayered organ broadly composed of
three tissue layers :
 The Epidermis
 The Dermis
 Subcutaneous fatty tissue.

10. Blood
Vessels

11. Epidermis : Outermost layer of skin
• Composed of stratified squamous epithelial cells.
• Microscopic sections of epidermis show 2 main parts :
a. the Stratum Corneum (Horny layer)
b. the Stratum Germinativum (Viable epidermis).
a. Stratum Corneum :
• Forms the outermost layer of epidermis (skin)
• Consists of many layers of compacted, flattened, dehydrated,
keratinized cells in stratified layers.
• These cells have lost their nuclei & are physiologically rather
inactive.

12. b) Stratum Germinativum :
It is the regenerative layer of epidermis.
Stratum Germinativum
Contains basal cell layer or basal cells
Multiply & produces cells that undergo slow upward migration
These cells form Stratum corneum & are continuously replenished
in this way, for every 2 weeks.

13. This process of regeneration of Stratum corneum is made
possible by the 3 layers of Stratum Germinativum :
• Stratum Spinosum (prickly layer)
• Stratum Granulosum (granular layer)
• Stratum Lucidum (clear layer).
TISSUE WATER
CONTENT
FUNCTION
Stratum corneum 20 % To maintain flexibility
& softness.
Stratum Germinativum 70% Regenerates new
Stratum corneum.

14. 2. Dermis :
• It is a gel like structure.
• Made up of network of robust collagen fibers of uniform thickness
. with regularly spaced cross-striations.
• Function – responsible for elastic properties of skin.
• This layer contains blood vessels, lymphatics & nerve endings.
3. Subcutaneous fatty tissue :
Beyond our scope.

15. Mechanism of percutaneous absorption
 Principle mechanism is passive diffusion of drug through the
skin.
 The mechanism of permeation can involve :
a. Passage through epidermis itself (transepidermal absorption).
b. Diffusion through hair follicles & eccrine/sweat glands (called as
transfollicular or shunt pathway absorption)
ab b
Hair follicle
Sebaceous gland
eccrine/sweat
gland

16. a. Transepidermal absorption :
Within the stratum corneum molecules can penetrate either
Transcellularly or Intercellularly.
Transcellularly means diffusion occurs through the cells of Stratum
corneum.
Polar compounds, ions/electrolytes pass through the Stratum
corneum by Transcellularly.
Intercellularly means diffusion occurs through the intercellular
lipoidal route. Intercellular space present between the Stratum
corneum cells are filled with lipid rich amorphous materials.
Lipid molecules diffuse through Stratum corneum easily by
intercellular route.

17. Further steps in skin permeation is described schematically in next
slide.

18. Diffusion of drug through patch to skin surface
Transepidermal route Transfollicular route
Partitioning of drug into Stratum
Corneum
Partitioning into Sebum
Diffusion through protein-lipid
matrix of stratum corneum
Diffusion through lipids in
sebaceous pore
Partitioning into viable epidermis
Diffusion through cellular mass of epidermis
Diffusion through fibrous mass of upper dermis
Capillary uptake & systemic dilution of drug.

19. Eccrine glands are numerous, but absorption through them is not
possible because
 their orifices are tiny.
 moreover they are either evacuated or so profusely active that
molecules cannot diffuse inwardly against the glands output.
gland

20. Kinetics of transdermal permeation
 Knowledge of skin permeation kinetics is vital for successful
development of transdermal therapeutic system.
 Transdermal permeation of drug involves the following steps :
a. Sorption by stratum corneum
b. Penetration of drug through viable epidermis.
c. Uptake of drug by capillary network in the dermal papillary
layer.
The rate of permeation dQ/dt across various layers of
skin tissue is given by :
dQ
dt
Where, Cd & Cr – concentrations of skin penetrant (drug) in the
donor compartment (e.g. – drug contn on the surface of stratum
corneum) as delivered from a TDD system & in the receptor
compartment (e.g. – systemic circulation/body).
= PS (Cd – Cr) (1)

21. PS – Overall permeability coefficient of skin tissues to the
penetrant.
The permeability coefficient is given by relationship :
PS
Where, KS – Partition coefficient for the interfacial partioning of the
penetrant molecule from a TDDS onto the stratum
corneum.
DSS – Apparent diffusivity for the steady state diffusion of
the penetrant molecule through the skin tissues.
hS – Overall thickness for skin tissues for penetration.
As KS, DSS, and hS are constants under given conditions, the
permeability coefficients (PS) for a skin penetrant can be considered
to be a constant.
From eqtn (1) it is clear that a constant rate of drug permeation can
be obtained only when Cd >> Cr, that is the drug concentration at
Ks DSS
hs
= 2.

22. the surface of stratum corneum (Cd) is consistently & substantially
greater than the drug concentration in the body (Cr).
Hence the eqtn (1) becomes :
dQ
dt
• Now the rate of skin permeation (dQ/dt) is constant provided the
magnitude of Cd remains fairly constant, throughout course of skin
permeation.
• For keeping Cd constant
- the drug should be released from the device at a constant rate
(Rr) or
- the drug should be released from the device at rate (Rr) always
greater than the rate of skin uptake (Ra) i.e. Rr >>Ra.
Since Rr is greater than Ra, the drug contn on the skin surface (Cd) is
maintained at a level equal to or greater than the equilibrium (or
saturation) solubility of the drug in the Stratum Corneum (CS) i.e.
Cd >> CS.
= PS Cd 3

23.  Therefore a maximum rate of skin permeation (dQ/dt)m is
obtained and is given by equation :
dQ
dt
From the above equation, it can be seen that maximum rate of
skin permeation depends on :
- skin permeability coefficient (PS) and
- its equilibrium solubility in stratum corneum (CS).
Thus skin permeation appears to be stratum corneum limited.
( )m
= PS CS (4)

24. Factors affecting Transdermal permeability :
1. Physicochemical properties of parent molecule
a. Solubility & partition coefficient
b. PH conditions
c. Penetrant concentrations.
2. Physicochemical properties of drug delivery system
a. Release characteristic
b. Composition of drug delivery systems
c. Enhancement of transdermal permeation
3. Physiological & pathological conditions of skin
a. Reservoir effect of horny layer
b. Lipid film
c. Skin hydration
d. Skin temperature
e. Effect of vehicle
4. Biological factors :
a. Skin age b. Skin condition
c. Regional site d. Skin metabolism
e. Circulatory effect species differences

25. 1. Physicochemical properties of parent molecule
a. Solubility and partition coefficient
 Solubility character of a drug greatly influences its ability to
penetrate skin.
 partition coefficient has profound influence on transfer of drug
from vehicle to skin.
 Drug solubility determines the concentration presented on
absorption site, thus can effect the rate and extent of drug
absorption.
 Skin permeation can be increased by increasing the lipophillic
character of drug, so that drug readily penetrates through
S.corneum but may not penetrate viable epidermis because of
its reduced water solubility. Therefore a balance in lipophillic
& hydrophilic nature is required for optimum skin
permeation.
 A lipid water partition coefficient of 1 or more is generally
required for optimal skin permeation.

26. b. PH condition
• Application of a solution whose pH value are very high or very
low can be destructive to skin, hence moderate ph is favorable.
• The flux of ionizable drugs can be affected by changes in ph as it
alters the ratio of charged and uncharged species and their
transdermal permeability.
c. Penetration concentration
• As skin permeation follows passive diffusion, concentration is the
driving force in penetration of drug through skin.
• Higher the concentration of dissolved drug in vehicle faster is the
absorption.
• Above saturation point, excess solid drug functions as a reservoir
& helps to maintain a constant drug release for prolonged period of
time

27. 2. Physicochemical properties of drug delivery system
a. Release characteristic
Solubility of drug in the vehicle determines release rate. The
mechanism of drug release depends on :
 Whether drug molecules are dissolved or suspended in the
delivery system.
 Interfacial partition coefficient of drug from delivery system to
skin tissue.
 PH of vehicle.
b. Composition of drug delivery systems
 It not only affects the rate of drug release but also permeability
of S.corneum by means of hydration mixing with skin lipids or
other sorption promoting effects.
e.g. : Methyl salicylate is more lipophilic than its parent acid.
When applied to skin from fatty vehicle, the methyl
salicylate yielded higher skin absorption than salicylic acid.

28. ncement of transdermal permeation
 Majority of drugs will not penetrate the skin at rates sufficiently
high for therapeutic efficiency, hence addition of permeation
enhancers is required to increase skin permeation.
3. Physiological & pathological conditions of skin
a. Reservoir effect of horny layer
 The horny layer can sometimes act as a depot & modify
transdermal permeation characteristics of some drugs.
 Reservoir effect is due to the irreversible binding of part of
applied drug with skin.
 This binding can be reduced by the treatment of skin surface
with anionic surfactants.
b. Lipid film
 Lipid films on skin surface act as protective layer to prevent
removal of moisture from skin and helps in maintaining barrier
function of S.corneum.

29. • Defatting of this film will decrease transdermal absorption.
c. Skin hydration
• It enhances permeability.
• It can be achieved simply by covering or occluding skin with
plastic sheeting, leading to accumulation of sweat, condensed water
vapors which increases hydration & porosity of skin due to opening
up of dense, closely packed cells of skin.
d. Skin temperature
It is directly proportional to skin penetration due to
• Thermal energy required for diffusivity.
• Solubility of drug in skin tissue.
• Increased vasodilatation of skin vessels.
• Occlusions on skin surface increase the temperature by 2 to 30C
which causes an increase in molecular motion and skin permeation.
e. Effect of vehicle
• It influences the percutaneous absorption by its potential effect on
physical states of drug & skin. Eg: greases, paraffin bases are most
occlusive while W/O bases are less.

30. Basic components of transdermal drug delivery systems
The components of transdermal devices include :
1. Polymer matrix or matrices
2. The drug
3. Permeation enhancers
4. Other Excipients - a) Adhesives
b) Backing membrane
c) Protective liner.

31. 1. Polymer matrix :
The polymer controls the release of drug from the device.
The following criteria should be satisfied for a polymer to be used in
a transdermal system :
a. Molecular weight, glass transition temperature & chemical
functionality of the polymer should be such that the specific
drug diffuses properly & gets released through it.
b. The polymer should be stable, non reactive with the drug.
c. Easily manufactured & fabricated into the desired product &
must be inexpensive.
d. The polymer & its degradation products must be non toxic or
non antagonistic to the host.
e. The mechanical properties of the polymer should not deteriorate
excessively when large amounts of active agent are incorporated
into it.

32. Possible useful polymers for transdermal devices, can be classified
based on :
a. Nature of origin as :
 Natural polymers
Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums
& their derivatives, natural Rubber, Starch etc.
 Synthetic elastomers
Polybutadiene, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile,
Acrylonitrile, Butyl rubber, Styrene – butadiene rubber,
Neoprene etc.
 Synthetic polymers
Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene,
Polyacrylate, Polyamide, Polyurea, PVP,
Polymethylmethacrylate, Epoxy, EVA, Polyisobutylene.

33. b. Pore size as :
 Macroscopic films :
Membranes of large pore size of average diameter 0.1 to 1μm.
E.g. : polymethacrylonitrile.
 Microscopic films :
Smaller pore size of average diameter 100 to 500 Ao.
E.g. :Mesopore silica mixed matrix membrane.
 Non – porous films :
Size between 10 to 100 Ao.
E.g. : Ethylene – vinyl alcohol copolymer membrane.
In these cases spacing between the macromolecular chain of polymer
becomes controlling factor for release of drugs.

34. 2. The drug :
Drug should be choosen with great care.
Following are some of the desirable properties of a drug for
transdermal delivery :
Physicochemical properties
a. The drug should have a molecular weight less than
approximately 1000 daltons.
b. The drug should have a balanced hydrophilic & lipophilic
nature. Extreme partitioning characteristics are not conducive
to successful drug delivery via skin.
c. Should have a low melting point.
Biological properties
a. The drug should be potent with a daily dose of the order of a
few mg/day.
b. The half life (t1/2) of the drug should be short.
c. The drug must not induce a cutaneous irritant or allergic
response.

35. d. Suitable candidates for transdermal delivery may be drugs, that –
 Degrade in the GI tract e.g – Nitroglycerine
 Inactivated by hepatic first pass effect e.g - β blockers, Ca2+
channel blockers etc.
 Which have low bioavailability e.g – Nicorandil
 Which cause severe local side effects when administered orally
e.g. – Tenoxicam.
e. Transdermal patches are usually suitable for chronic therapy.
e.g. – hypertension, diabetes, angina pectoris etc.,
f. Tolerance to the drug must not develop under the near zero
order release profile of transdermal delivery.
g. Drugs which cause adverse effects to non target tissues can also
be formulated for transdermal delivery.

36. 3. Permeation enhancers / Penetration enhancers
These are the compounds which promote skin permeability by
altering the skin as a barrier to the flux of desired penetrant.
Kinetics
The flux J, of drugs across the skin can be written as –
Where, D – diffusion coefficient of the drug & is a function of the
size, shape and flexibility of the diffusing molecule
as well as the membrane resistance.
C – Concentration of diffusing species
X – Space co-ordinate measured normal to the section.
J = D
dC
dX

37.  The concentration gradient is thermodynamic in origin.
 Diffusion coefficient is related to the size & shape of pearmeant
and the energy required to make a hole for diffusion.
 Thus enhancement of flux across the membrane depends on :
-- Thermodynamics (lattice energies, distribution coefficients)
-- Molecular size and shape
-- Reducing the energy required to make a molecular hole in the
membrane.
This is the approach or principle employed in permeation enhancers.

38. Desirable properties for penetration enhancers :
 They should be non-toxic, non-irritating and non allergenic.
 They would ideally work rapidly, and the activity and duration of
effect should be both predictable and reproducible.
 They should have no pharmacological activity within the body—
i.e. should not bind to receptor sites.
 The penetration enhancers should work unidirectionally, i.e.
should allow therapeutic agents into the body whilst preventing
the loss of endogenous material from the body.
 When removed from the skin, barrier properties should return
both rapidly and fully.
 Should be appropriate for transdermal formulation i.e. compatible
with both excipients & drugs.
 They should be cosmetically acceptable with an appropriate skin
‘feel’.

39. Potential mechanisms of action :
i. Act on the stratum corneum intracellular keratin, denature it or
modify its conformation causing swelling and increased hydration.
ii. Affect the desmosomes that maintain cohesion between
corneocytes (stratum corneum cells).

40. iii. Modify the intercellular lipid domains to reduce the barrier
resistance of the bilayer lipids.
iv. Alter the solvent nature of the stratum corneum to modify
partitioning of the drug into the tissue, most enhancers are good
solvents.
E.g. – Pyrrolidones can increase the amount of permeant present
within the skin.

41. Classification of Permeation enhancers
a. Solvents :
i. Polar compounds : methanol, ethanol, water.
ii. Alkyl methyl sulfoxides : dimethyl methyl sulfoxide, alkyl
homologous of methyl sulfoxides, dimethyl acetamide &
dimethyl formide.
iii. Pyrrolidones : 2-pyrrolidone, N-methyl-2-pyrrolidone
iv. Azone (laurocaprum)
v. Miscellaneous solvents : propylene glycol, glycerol, silicone fluids,
Isopropyl palmitate.
b. Surfactants :
 The ability of surfactants to alter penetration is a function of
polar head group & the hydrocarbon chain length.

42.  These compounds are however, skin irritants therefore a
balance between penetration enhancement & irritation has to
be considered.
i. Anionic surfactants : dioctyl sulphosuccinate, sodium lauryl
sulphate, decodecylmethyl sulphoxide
ii. Cationic surfactants : more irritant, not used
iii. Non ionic surfactants : have least potential for irritation. Eg:
pluronic F127, pluronic F68.
iv. Bile salts : sodium taurocholate, sodium deoxycholate,sodium
tauroglycocholate.
c. Binary systems :
Egs : propylene glycol – oleic acid
1,4-butane diol – linoleic acid.
d. Miscellaneous chemicals :
i. Urea – a hydrating & keratolytic agent.
ii. N,N-dimethyl-m-toluamide & calcium thioglycolate.

43. iii. Others are di-O-methyl-β –cyclodexdrin & soyabean casein.
e. Natural compounds :
Terpenes & terpenoides, isolated from natural essential oils are
currently under investigation as safe non irritating penetration
enhancers.
Class Drugs
Terpene enhancers :
Mentha oil :
L-menthol, D-limonene, Menthone.
Eucalyptus oil :
1-8-cineole, carvone
Chenopodium & Ylang Ylang oils
5-flurouracil,
Indomethacin,
Zidovudine,
Diclofenac sodium
5-flurouracil

44. 4. Other excipients :
a. Adhesives :
 The fastening of all transdermal devices to the skin has so far
been done by using a pressure sensitive adhesive.
 Face adhesive system adhesive positioned on the face of
the device.
 Peripheral adhesive system adhesive positioned in the
back of the device & extending peripherally.
Face adhesive system
Adhesive rim Polymer matrix
Occlusive base plate
Peripheral adhesive system

45. Both adhesive systems should fulfill the following criteria :
 Should not irritate or sensitize the skin or cause an imbalance in
the normal skin flora during its contact time with the skin.
 Should adhere to the skin aggressively during the dosing interval
without its position being disturbed by activities such as bathing,
exercise etc.
 Should be easily removed.
 Should not leave an unwashable residue on the skin.
 Should have an excellent contact with the skin at macroscopic &
microscopic level.
The face adhesive system should also fulfill the following criteria :
 Should be inert, has physical & chemical compatibility with the
drug, excipients & enhancers of the device of which it is a part.
 Permeation of drug should not be affected.
Egs : Polyisobutylenes, acrylics & silocones.

46. b. Backing membrane :
 Backing membranes are flexible and they provide a good bond to
the drug reservoirs, prevent drug from leaving the dosage form
through the top & accept printing.
 It is impermeable substance that protects the product from
external environment during use on the skin.
Egs : Metallic plastic laminate,
Plastic backing with absorbent pad & occlusive base plate
. (aluminium foil),
Adhesive foam pad (flexible polyurethane) with occlusive base
plate (aluminium foil disc) etc.

47. c. Liner :
 It protects the patch during storage.
 The liner is removed prior to use.

48. Technologies for developing Transdermal drug
delivery systems
Several technologies have been successfully developed to provide
rate control over the release & skin permeation of drugs.
These technologies can be classified into 3 basic approaches :
A) Polymer membrane permeation-controlled TDD system :
Adhesive layer
Silicone adhesive Rate controlling polymeric membrane
EVA Co-polymer
Drug – Impermeable metallic
Plastic laminate
Drug reservoir

49. Fabrication of drug reservoir compartment :
Drug solids Drug solids
 The rate controlling membrane can be either a microporous or a
nonporous polymeric membrane. E.g. : Ethylene-Vinyl acetate
copolymer.
Dispersed homogeneously
in a solid polymer matrix in a solid polymer matrix
Eg - Polyisobutylene
Dispersed homogeneously
Eg - Polyisobutylene
Homogenous dispersion Homogenous dispersion
Suspended in a unleachable,
Viscous liquid medium
E.g – Silicone fluid
Paste like suspension
Dissolved in a
releasable solvent
E.G – Alkyl alcohol
Clear drug solution

50.  Adhesive polymer used on external surface of membrane is a drug
compatible, hypoallergenic polymer like silicone adhesive.
 Drug release rate from this system can be tailored by :
- Varying the composition of drug reservoir formulation.
- Permeability coefficient of drug through polymer.
- Thickness of the rate controlling membrane.
The rate of drug release is defined by :
dQ
CR = drug concentration in the reservoir compartment.
Km/r = partition coeff. of drug from reservoir to membrane.
Ka/m = partition coeff. of drug from membrane to adhasive.
Dm = diffusion coefficients of drug in rate controlling membrane.
Da = diffusion coefficients of drug in the adhesive layer.
Hm = thickness of rate controlling membrane
Ha = thickness of adhesive layer.
dt
= CR
Km/r Ka/m Da Dm
Km/r Dm ha + Ka/m Da hm

51.  This system is applied in the development of :
Transderm – Nitro system, Transderm – Scop system,
Catapress TTS system, Estraderm system & Duragesic system.
B) Polymer matrix diffusion controlled TDD Systems :
This system can be formulated by 2 approaches :
First approach :
Adhesive Rim
Drug Reservoir
Drug / polymer matrix
Drug - Impermeable
Plastic backing
Absorbent PadOcclusive Baseplate
(aluminum foil)

52. The rate of drug release from this type of TDD system is defined as :
dQ
dt
Ld = drug loading dose initially dispersed in the polymer matrix.
Cp = solubility of drug in polymer matrix.
Dp = diffusivity of drug in polymer matrix.
At steady state, a Q versus t1/2 drug release profile is obtained as
defined by the equation :-
Q
t1/2
Egs. : Nitro – Dur system
NTS system.
=
Ld Cp Dp
2t( )1/2
(1)
= [ (2Ld – Cp) Cp Dp ] (2)
1/2

53. Second approach : polymer matrix drug dispersion type TDDS
The release profile of drug from this system follows the same equation (2) as shown above.
Egs. : The Minitran system
The Nitro – Dur II system
Frandol tape.
Drug Loaded pressure sensitive adhesive
E.g. : Polyacrylate
Impermeable film
Release Liner

54. C) Drug reservoir gradient-controlled TDD system :
 This system was fabricated to overcome the Q versus t1/2 (non zero
order) drug release profile as shown by polymer matrix drug
dispersion type TTD system.
Drug Reservoir
Gradient Adhesive
Layers
R1 > R2 > R3 > Rn
R1
R2
R3
Rn
Drug
Drug – Impermeable laminate

55. The rate of drug release from this system is given by :
dQ Ka/r Da
dt ha (t)
In this system the thickness of diffusional path through which the
drug molecules diffuse increases with time i.e hd(t), as a result of
drug depletion in each adhesive layer due to release.
To compensate for this time dependent increase in diffusional
path, the drug loading level in the multilaminate adhesive layers is
also designed to increase proportionally i.e Ld(ha).
This, in theory, should yield, a more constant drug release profile.
E.g. : Nitroglycerine releasing TDD system the DEPONIT System.
Ld (ha)=

56. Method Advantage Disadvantage
Penetration
enhancers
Increase penetration through
skin &give both local &
systemic effect
Skin irritation,
Immunogenic, only for
low molecular weight
drugs
Physical methods
e.g. Iontophoresis
Increase penetration of
intermediate size charged
molecule
Only for charged drugs,
transfer efficiency is low
(less than 10%)
Liposomes Phospholipid vesicle,
biocompatible,biodegradable
Less skin penetration,less
stable
Proliposome Phospholipid vehicle, more
stable than liposomes
Less penetration,cause
aggregation & fusion of
vesicles
Nisosomes Non-ionic surfactants vesicles,
greater stability
Less skin penetration
easy handling
Proniosomes
Transfersomes &
Protransfersomes
Will convert into niosome in
situ,stable
More stable, high penetration
due to high deformability,
biocompatible, biodegradable
But will not reach upto
deeper skin layer
None, but for some
limitations.

57. Evaluation of TDD systems
1. Evaluation of adhesive :
Pressure sensitive adhesives are evaluated for the following
properties :
A) Peel adhesion properties :
 Peel adhesion is the force required to remove an adhesive
coating from the test substance.
 It is important in transdermal devices because the adhesive
should provide adequate contact of the device with the skin &
should not damage the skin on removal.
 Peel adhesion properties are affected by :
- Molecular weight of the adhesive polymer
- The type & amount of adhesives added in it.
- Polymer composition.

58. Procedure :
It is tested by measuring the force required to pull a single coated
tape, applied to a substrate, at a 1800 angle.
Result :
No residue on the substrate indicates “adhesive faliure” which is
desirable for transdermal devices.
Reminents on the substrate indicate “cohesive faliure” signifying a
deficit of cohesive strength in the coating.
Pull at
1800
Adhesive rim
Backing film
Standard panel or Substrate

59. B) Tack properties :
Tack is the ability of the polymer to adhere to the substrate with
little contact pressure.it is important in transdermal devices which
are applied with finger pressure.
Tack is dependent on :
- The molecular weight of polymer adhesive
- Composition of polymer
- The use of tackifying resins in the polymer.
Tests for tack include :
a. thumb tack test :
This is a subjective test in which evaluation is done by pressing the
thumb briefly on to the adhesive.
Experience is required for this test.
b. Rolling ball tag test :
This test involves the measurement of the distance that a stainless
steel ball travels along an upward facing adhesive .

60. The less tacky the adhesive, the farther the ball will travel.
c. Quick-stick (or peel tack) test :
The peel force required to break the bond between an adhesive &
substrate is measured by pulling the tape away from the substrate
at 900 at a speed of 12 inch/min.
7 / 1611 Ball
Adhesive film
22.50 Slope
Backing MembraneAdhesive film
Stainless steel plate

61. d. Probe tack test :
Here the force required to pull a probe away from an adhesive at a
fixed rate is recorded as tack (grams).
C) Shear strength properties :
It is a measurement of the cohesive strength of an adhesive polymer.
For a polymer the adequate cohesive strength will mean that the
device will not slip on application & will leave no residue on
removal.
Probe
Force guage
annular
Weight
Adhesive film

62. Shear strength is affected by :
- Molecular weight of polymer.
- The type & amount of tackifier added.
Method :
2) Thickness :
The thickness of the patch is measured by using a digital screw
gauge.
Weight
Adhesive coated tape
Stainless steel plate

63. 3) In-vitro drug release evaluation
Uses of In-Vitro studies :
a. Information such as time needed to attain steady state
permeation & the permeation flux at steady state can be
obtained from In-vitro studies of the developed TDDS.
b. Used to optimize the formulation before more expensive In-vivo
studies are performed.
c. Studies on skin metabolism can also be performed.
Excised skin used are – Human Cadaver skin.
Hairless Mouse skin.

64. Several designs of In-vitro membrane pearmeation apparatus are in
existance which include :
a) Valia – Chien (V-C) cell
b) Ghannam – Chien (G-C) membrane permeation cell
c) Jhawer – Lord (J-L) rotating disc system.
d) Franz diffusion cell
e) Keshary – Chien (K-C) cell.
Name of
the cell
Surface area
of skin
Vol. of fluid
in
compartment
Stirrer Speed
V – C cell 0.645 Cm2 3.5 ml Star head magnet 600 rpm
G – C cell 139 Cm2 140 – 250 ml Bar shaped magnet 60 – 100 rpm
F – D cell 1.57-4.71 Cm2 10 – 12 ml Rod shaped 600 rpm
K – C cell 3.14 Cm2 12 ml Star shaped 600 rpm

65. 4) In-Vivo evaluation
A) Animal models :
Animal species used for In-vivo testing include --- Mouse, rat,
Guinea pig, Rabbit, Rhesus Monkey, Dog, Cat ….etc.
 Small, hairy animals (Rat, Rabbit) are not good predictive
models for human in-vivo TDD delivery.
 Penetration values obtained with these animals are higher than
those seen in man.
 The Rhesus Monkey is the most reliable model for In-vivo
evaluation in man.
Method – standard radiotracer methodology is used.
Application site – Forearm or abdomen which are least hairy sites on
the animal body.

66. B) Human models :
a) Feldmann and Maibach model :
 The percentage of dose absorbed transdermally is calculated as:
 Completion time of test is 5 to 7 days.
Limitations :
 No detailed kinetic analysis of data is possible since the
radioactivity detected is a mixture of parent chemical &
metabolites.
 The origin of metabolites is unknown.
Drugs successfully analyzed – Steroids, Pesticides, Cosmetics.
% Dose absorbed =
Total radioactivity excreted after topical
administration
X 100
Total radioactivity excreted after i.v
administration

67. 5) Cutaneous toxicological evaluations :
Contact Irritant dermatitis :
It results from direct toxic injury to cell membranes, cytoplasm on
nuclei.
Manifestations include :
 Inflammation
 Cutaneous erythema
 Itching.
Ten day primary irritation test :
 A panel of 10 subjects has the test agent applied daily for two
weeks at the site to be used in clinical situations.
 The test agent is left in place over the weekend between the first &
second five days of repeated application.
 Prior to the re-application of the agent daily, adverse reactions like
erythema & scaling are graded daily on a -

68. 0 to 3 scale of none, mild, moderate & server or a
0 to 6 scale to permit more discrimination.
Results :
i) A system which results in no erythema or scaling (0 rating) is
safe.
ii) Materials which induce marked irritation (+2 or +3) are likely
to induce significant contact irritation during clinical use.
iii) For border line cases (+1 rating) the test is repeated using
increased number of subjects & greater application time.

69. Marketed brand
name
Therapeutic
agent
Company Therapeutic indication
Transderm-scop scopolamine Ciba 72 hr prophylaxis of
motion induced nausea.
Nitro-Dur system,
Nitrodisc Deponit
Minitran
Nitroglyc-erine Key serale Bolar
pharma-schwarz
3M Riker
Once-a-day Medication of
Angina pectoris
Frandol tape Isosorbide
dinitrite
Toaeiyo-
Yamanouchi
Once-a-day Medication of
Angina pectoris
Catapres-TTS clonide Boehringer -
Ingelheim
Weekly therapy of
hypertension
Estraderm, Estran,
combitram Estradiol
Ciba
Samyang
Twice a week treatment of
post menapausal
syndromes
Duragesic fentanyl Mylan
pharmaceuticals
Twice a week analgesic in
cancer patients
Nicostop Nicotine To quit smoking
Rheumastop Diclofenac To relieve pain caused by
rheumatic arthritis

70. Oxttrol Oxybutynin Watson pharma Overactive bladder
Marketed brand
name
Therapeutic
agent
Company Therapeutic indication
Neupro Rotigotine Schwarz pharma Parkinsonism

71. Refrences
1. Controlled & Novel drug delivery by N.K.Jain
2. Novel drug delivery systems by Y.W.Chien
3. Modern Pharmaceutics by Banker & Rhodes
4. Artificial “Penetration enhancers” by Ardian C.
Williams, Brian W. Barry; Adv. Dr. Delivery Reviews.
5. Internet sources.

72. Oral Controlled Drug Delivery System
ThaNK you !
72NKV