approaches of Transdermal drug delivery system

1. Formulation approaches used in the
development of TDDS their
Evaluation & Permeation enhancers
Presented by….
NIVEDITHA G
M. Pharm 1st Year
Dept. of Pharmaceutics
NARGUND COLLEGE OF PHARMACY
Seminar on…..

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Table of Contents…..
 Formulation approaches used in the development of
TDDS
 Evaluation of TDDS
 Permeation Enhancers
 Advances in TDDS
 References.

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Schematic Skin absorption of drug

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Formulation Approaches used in the development
of TDDS
1. Membrane permeation – controlled systems.
2. Adhesive dispersion – type systems.
3. Matrix diffusion – controlled systems.
4. Microreservoir type or Microsealed dissolution – controlled
systems.
5. Poroplastic – type systems.
6. Transdermal delivery of Macromolecules.

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1. Membrane permeation – controlled
systems
 The drug reservoir is totally encapsulated in a shallow
compartment moulded from a drug – impermeable metallic
plastic laminate & 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
coefficient, thickness of the rate limiting membrane &
adhesive.
 Example:- i) Nitroglycerine-releasing Transdermal system
(Transderm-nitro) for once a day medication in angina
pectoris.
ii) Scopolamine-releasing Transdermal system (Transderm-
scop) for 72 hrs. prophylaxis of motion sickness.

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Fig. Membrane moderated Transdermal drug delivery system

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

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

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Continued…
 In case of microporous membrane, the porosity of the
membrane should be taken in to the calculation of Dm & hm
values,
Substituting eq. (2) & (3) in eq. (1)…
dQ
dt
Km/r Ka/m Dm Da
Km/r Dm ha Ka/m Da ha
CR
…………...(4)

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2. Adhesive dispersion – type systems
 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 (Frandol tape) for once a day medication
of angina pectoris.

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Fig. Adhesive dispersion type Transdermal drug delivery system

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Continued…
 The rate of drug release in this system is defined by…
Where, Ka/r = Partition coefficient for the interfacial partitioning
of the drug from the reservoir layer to adhesive layer.
dQ
dt
Ka/r Da
ha
CR

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3. Matrix diffusion – controlled systems
i) It is prepared by homogeneously dispersing the drug particles with
a liquid polymer or a highly viscous base polymer followed by
cross linking of the polymer chains or homogeneously blending
the drug solids with a rubbery polymer at an elevated temp.
ii) It can also be prepared by dissolving the drug & polymer in a
common solvent followed by solvent evaporation in a mould at an
elevated temp. or in a vaccum. 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.

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Fig. Matrix diffusion controlled Transdermal drug delivery system

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Continued…
 Example: Nitroglycerine-releasing Transdermal system
(Nitro- Dur & Nitro- Dur II ) 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…
Where, A = Initial drug loading dose dispersed in the polymer
matrix.
Cp & Dp = Solubility & diffusivity of the drug in the polymer
respectively.
dQ
dt
ACp Dp
2t
1/2

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4. Microreservoir type or Microsealed dissolution –
controlled systems
 This is the combination of reservoir & matrix diffusion type
drug delivery systems.
 Drug reservoir is formed by first suspending the drug solids in
an aqueous solution of a water soluble liquid polymer & then
dispersing the drug suspension homogeneously in a lipophilic
polymer such as silicone elastomers by high dispersion
technique.
 Example: Nitroglycerine-releasing Transdermal system
(Nitro disc) for once a day therapy of angina
pectoris.

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rim
Fig. Micro reservoir dissolution-controlled transdermal drug delivery system

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

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6. Transdermal delivery of Macromolecules
 Macromolecules such as Hormones, interferon's, bioactive
peptides can be deliver by Transdermal delivery system.
 The devices used for this purpose are divided in to two
categories….
a. Devices based on ethylene vinyl acetate copolymers
(EVAc).
b. 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.

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Evaluation of TDDS
1. Evaluation of Adhesive :
A. Peel adhesion properties:-
i) It is the force required to remove an
adhesive coating from a test
substrate.
ii) It is affected by molecular wt. of the
adhesive polymer, the type &
amount of additives & polymer
composition.
iii) It is tested by measuring the force
required to pull a single coated
tape, applied to a substrate, at an
angle of 1800, no residue on the
substrate indicates ‘Adhesive
failure’ signifying a deficit of
cohesive strength in the coating.
Fig. Peel adhesion test for
adhesive evaluation

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B. Tack properties:-
i) It is the ability of polymer to
adhere to a substrate with little
contact pressure.
ii) It is dependent on the
molecular wt. & composition of the
polymer as well as the use of
tackifying resins in the polymer.
iii) It includes….
a. Thumb tack test
b. Rolling ball tack test :
It involves the measurement of
the distance that a stainless steel
ball travels along an upward-
facing adhesive, less tacky the
adhesive, the further the ball will
travel.
Fig. Rolling ball tack test for
adhesive evaluation

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c. Quick- stick (peel tack)
test :
The peel force required to
break the bond between an
adhesive & substrate at 900 at
a speed of 12 inch/min. The
force recorded as the tack
value & is expressed in ounces
(or grams) per inch width with
higher values indicating
increasing tack.
Fig. Quick stick test for
adhesive evaluation

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d. Probe tack test :
The force required to pull a probe away from an adhesive
at a fixed rate is recorded as tack. (expressed in grams)
Fig. Probe tack test for adhesive
evaluation
Probe
Force gauge

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C. Shear strength properties
i) It is affected by molecular wt. as well
as the type & amount of tackifier added.
ii) Shear strength is determined by
measuring the time it takes to pull an
adhesive coated tape of stainless steel
plate when a specified wt. is hung from the
tape which pulls the tape in a direction
parallel to the plate.
Fig. Shear strength test
for adhesive evaluation

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2. In-vitro drug release evaluation :
i) In these studies, excised skin is mounted on skin permeation cells.
ii) Skin of hairless mouse is used rather than human cadaver skin.
iii) In-vitro system 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.
iv) 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, Jhawer-Lord (J-L) rotating disc cell, Franz diffusion
cell & Keshary-Chien (K-C) cell.

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 Keshary-Chien (K-C) cell : It has an effective receptor
volume 12 ml & a skin surface area of 3.14 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.
Fig. K-C cell for permeation study

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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 generally the forearm or abdomen
which are less hairy sites on the animals body.
 The compound is applied after light clipper shaving of the site.
3. In-vivo evaluation :

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B. Human volunteers:-
 Procedures for in-vivo evaluation in humans were first
described by Feldmann & Mailbach in 1974.
 They 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 after topical administration
Total radioactivity excreted after I. V. administration
x 100

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 Various modifications have been made for above method…
A. “Reservoir” technique:- It involves a simple, short exposure
of the skin to the compound (radio labelled) under study
followed by removal of the striatum corneum by tape striping
& analysis of the content of the compound in the striatum
corneum. From this it is possible to predict amount of drug
that will penetrate over a long period of time.
 Limitations:
i) Invasive nature of the technique due to the tape striping
required.
ii) The single measurement obtained which does not allow
detailed kinetic analysis & the administration of large dose of
radioactive material is required.
B. “Mass balance” technique.

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4.Cutaneous toxicological evaluations:-
a. Contact dermatitis:-
1) Contact irritant dermatitis:-
 Two types of protocols are used…
i) Ten-day primary irritation test
ii) Twenty-one day irritation test
2) Laser Doppler
3) Evaporative water loss measurements
4) Contact allergic dermatitis
b. Growth of microorganisms
1) Localized superficial infections
2) Miliaria (prickly heat)

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Permeation Enhancers
 These are the compounds which promotes skin permeability
by altering the skin as a barrier to the flux of desired
penetrant.
 The flux ‘J’ of drugs across the skin can be written as….
Where, D = Diffusion coefficient,
c = conc. of diffusing species
x = spatial coordinate
J = D
dc
dx

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 Ideal properties of Permeation enhancers:-
i) They should be non-toxic, non-irritating & non-allergenic.
ii) They would ideally work rapidly & the activity & duration of
effect should be both predictable & reproducible.
iii) They should have no pharmacological activity within the
body.
iv) When removed from skin, barrier properties should return
both rapidly & fully.
v) They should be compatible with both excipients & drugs.
vi) They should be cosmetically acceptable with an
appropriate skin feel.

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 The flux ‘J’ of a drug through skin can be approximated by
Fick’s second law of diffusion.
Where, m = cumulative mass of permeant that passes per unit
area through the membrane in time ‘t’.
C0 = conc. of diffusant in the first layer of the membrane
at the skin surface contacting the source of the
penetrant.
h = membrane thickness.
δC
δ t
D
δ2C
δ x2
…………..(1)
dm
dt
=
=
DC0
h
………….(2)

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 It is difficult to measure C0 but C0’ which is the conc. of
diffusant in the donor phase, C0 & C0’ is related by…
 Substituting eq. (3) into eq. (2) gives…
C0 = PC0’ ……………(3)
dm DC0’ P
dt
=
h
…………...(4)

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 Classification of Permeation enhancers:-
a. Solvents
b. Surfactants
i) Anionic surfactants: Dioctyl sulphosuccinate, Sodium
lauryl sulphate.
ii) Non-ionic surfactants: Pluronic F127, Pluronic F68
iii) Bile salts : Sodium taurocholate,Sodium
deoxycholate.
c. Binary systems : Propylene glycol-oleic acid
d. Miscellaneous chemicals : Urea, Calcium thioglycholate.

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Advances in TDDS
 Active Transdermal Systems:-
 Microstructured Transdermal System (MTS) is a state-of-the-art
microneedle 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.

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References
 Y. W. Chien, Novel drug delivery systems, 2nd edition, Revised
& expanded, Marcel Dekker, Inc., New York, 1992.
 N. K. Jain, Controlled & Novel drug delivery, CBS Publishers
& Distributors, New Delhi, First edition, 1997.
 Controlled drug delivery devices by Pravin Tyle, Marcel
Dekker, Inc., New York, 1992, pg. no. 406 – 408.
 Mechanisms of Transdermal drug delivery system by Y. W.
Chien, Marcel Dekker, Inc., New York.
 www.google.com

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