Transdermal drug delivery systems

By:
Kasturi Banerjee
M. Pharm- Pharmaceutics (1st Year)
KLE Society’s College of Pharmacy, Bengaluru
TRANSDERMAL
DRUG DELIVERY
SYSTEMS

Contents
*Conceptual origin of TDDS
*Introduction
*History
*Advantages
*Disadvantages
*Basic Components of TDDS
*Formulation approaches used in the development of TDDS
*Evaluation of TDDS
*Advances in TDDS
*References
2

The potential of using intact skin as the site for continuous
transdermal infusion of drug has been recently recognized
beyond the boundary of local medication.
The development of female syndromes in male operators
working in the production of estrogen-containing
pharmaceutical dosage forms challenged the old theory
that the skin is a perfectly impermeable barrier.
It triggered the research curiosity of several biomedical
scientists to evaluate the feasibility of transdermal
delivery of systemically active drugs.
CONCEPTUAL ORIGIN OF
TRANSDERMAL DRUG DELIVERY
3

The findings, accumulated over the years, have
practically revolutionized the old concept of an
impermeable skin barrier and also motivated a number
of pharmaceutical scientists to develop patch-type drug
delivery systems for the rate-controlled transdermal
administration of drugs to achieve systemic
medication.
Over a decade of intensive research and development
efforts, several rate-controlled transdermal drug
delivery systems have been successfully developed and
commercialized.
4

Transdermal drug delivery (TDD) systems have recently
been developed, aiming to achieve the objective of
systemic medication through topical application to the
intact skin surface.
They were exemplified first with the development of a
scopolamine-releasing TDD system (Transderm-Scop) for
72hr prophylaxis or treatment of motion-induced nausea,
then by the successful marketing of nitroglycerin-releasing
TDD systems (Deponit, Nitrodisc, Nitro-Dur, Transderm-
Nitro and others) and an isosorbide dinitrate-releasing TDD
system (Frandol tape) for once-a-day medication of angina
pectoris, as well as a clonidine-releasing TDD system
(Catapres-TTS) for the weekly therapy of hypertension and
of an estradiol-releasing TDD system (Estraderm) for the
twice-a-week treatment of postmenopausal syndromes.
Introduction
5

History
The first transdermal patch was approved in 1981 to
prevent the nausea and vomiting associated with motion
sickness.
The FDA 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, ehinylestradiol,
norethindroneacetate, testosterone, clonidine, nicotine,
lidocaine, prilocaine and scopolamine.
Two new, recently approved transdermal patch products
are: a contraceptive patch containing ethinylestradiol and
nor elgestromin and a patch to treat overactive bladder
containing oxybutinin.
6

Product Name Drug Manufacturer Indication
Alora Estradiol Thera Tech/ P&G Post Menstrual
Syndrome
Androdem Testosterone Thera Tech/ GSK Hypogonadism in
males
Catapres-TTS Clonidine Alza/Boehinger
Ingelheim
Hypertension
Climaderm Estradiol Ethical Holdings/
Wyeth-Ayerest
Postmenstrual
syndrome
Climara Estradiol 3M
Pharmaceuticals/
Berlex Labs
Postmenstrual
syndrome
CombiPatch Estradiol/
Norethindrone
Noven , Inc./Aventis Hormone
replacement
therapy
Deponit Nitroglycerin Schwarz-Pharma Angina pectoris
Duragesic Fentanyl Alza/Janssen
Pharmaceuticals
Moderate/severe
pain
Nicoderm Nicotine Alza/GSK Smoking cessation
Transderm Scop Scopolamine Alza/Norvatis Motion sickness
12

More than 35 TDDS products have now
been approved for sale in the US and
approximately 16 active ingredients are
approved for use in TDDS products globally.
13

It delivers a steady infusion of drug over an extended
period of 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 inter 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.
Advantages
14

At times the maintenance of the drug concentration
within the diphase is not desired. Application and removal
of transdermal patch produce the optimal sequence of
pharmacological effect.
When compared to oral delivery system and intravenous
delivery system transdermal drug delivery system shows
more advantages-
IV Oral TDDS
Reduced first-pass effects Yes No Yes
Constant drug levels Yes No Yes
Self-administration No Yes Yes
Unrestricted patient activity No Yes Yes
15

The drug must have desired physicochemical
properties for penetration through stratum corneum
and if the drug dose required for therapeutic value
is more than 10 mg/day, the transdermal delivery
will be very difficult.
Only relatively potent drugs are suitable candidates
for TDDS because of the natural limits of drug entry
imposed by the skin’s impermeability.
Skin irritation or contact dermatitis due to excipient
and enhancers of the drug used to increase the
percutaneous absorption is the other limitation.
Disadvantages
16

Clinical need is another area that has to be
examined carefully before a decision is made to
develop a transdermal product.
The barrier function of the skin changes from one
site to the other on the same person, from person to
person and with age.
Heat, cold, sweating and showering prevent the
patch from sticking to the surface of the skin for
more than one day. A new patch has to be applied
daily.
17

The criteria for a drug molecule to be suitable for
TDDS are:
Drug molecule should have molecular size less than
400 daltons.
Particular log P value should be between the range
of 2-4.
Should have low melting point.
Dose of the drug should range within 10-20mg.
Criteria for Selection of a
Drug for TDDS
18

The components of transdermal devices include:
1. Polymer matrix or matrices
2. The drug
3. Permeation enhancers
4. Other excipients
Basic Components of
Transdermal Drug Delivery
Systems
19

The Polymer controls the release of the drug from the
device.
Possible useful polymers for transdermal devices are:
a) Natural Polymers:
e.g. Cellulose derivatives, Zein, Gelatin, Shellac, Waxes,
Proteins, Gums and their derivatives, Natural rubber,
Starch etc.
b) Synthetic Elastomers:
e.g. Polybutadieine, Hydrin rubber, Polysiloxane, Silicone
rubber, Nitrile, Acrylonitrile, Butyl rubber,
Styrenebutadieine rubber, Neoprene etc.
1.
20

c) Synthetic Polymers:
e.g. Polyvinyl alcohol, Polyvinyl chloride, Polyethylene,
Polypropylene, Polyacrylate, Polyamide, Polyurea,
Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy
etc.
21

For successfully developing a transdermal drug delivery
system, the drug should be chosen with great care.
The following are some of the desirable properties of a
drug for transdermal delivery.
Physicochemical properties:
1. The drug should have a molecular weight less than
approximately 1000 daltons.
2. The drug should have affinity for both – lipophilic and
hydrophilic phases. Extreme partitioning characteristics
are not conducive to successful drug delivery via the skin.
3. The drug should have low melting point.
4. Along with these properties the drug should be potent,
having short half life and be non irritating.
2.
22

These are compounds which promote skin permeability by
altering the skin as a barrier to the flux of a desired
penetrant.
These may conveniently be classified under the following
main headings:
a) Solvents
• These compounds increase penetration possibly by
swallowing the polar pathway and/or by fluidizing lipids.
• Examples include water; alcohols – methanol and ethanol;
alkyl methyl sulfoxides – dimethyl sulfoxide, alkyl homologs
of methyl sulfoxide dimethyl acetamide and dimethyl
formamide; pyrrolidones – 2 pyrrolidone, N-methyl, 2-
purrolidone; laurocapram (Azone), miscellaneous solvents –
propylene glycol, glycerol, silicone fluids, isopropyl
palmitate.
3.
23

b) Surfactants
• These compounds are proposed to enhance polar pathway
transport, especially of hydrophilic drugs.
• The ability of a surfactant to alter penetration is a
function of the polar head group and the hydrocarbon
chain length.
• Anionic Surfactants: e.g. Dioctyl sulphosuccinate, Sodium
lauryl sulphate, Decodecylmethyl sulphoxide etc.
• Nonionic Surfactants: e.g. Pluronic F127, Pluronic F68,
etc.
• Bile Salts: e.g. Sodium taurocholate, Sodium
deoxycholate, Sodium tauroglycocholate.
• Binary system: These systems apparently open up the
heterogeneous multilaminate pathway as well as the
continuous pathways.e.g. Propylene glycol-oleic acid and
1, 4-butane diol-linoleic acid.24

c) Miscellaneous chemicals
• These include urea, a hydrating and keratolytic agent;
N, N-dimethyl-m-toluamide; calcium thioglycolate;
anticholinergic agents.
• Some potential permeation enhancers have recently
been described but the available data on their
effectiveness sparse.
• These include eucalyptol, di-o-methyl-ß-cyclodextrin
and soyabean casein.
25

a) Adhesives:
• The fastening of all transdermal devices to the skin has
so far been done by using a pressure sensitive adhesive
which can be positioned on the face of the device or in
the back of the device and extending peripherally.
• Both adhesive systems should fulfil the following
criteria:
i. Should adhere to the skin aggressively, should be easily
removed.
ii. Should not leave an unwashable residue on the skin.
iii.Should not irritate or sensitize the skin.
4.
26

• The face adhesive system should also fulfil the
following criteria:
i. Physical and chemical compatibility with the drug,
excipients and enhancers of the device of which it
is a part.
ii. Permeation of drug should not be affected.
iii.The delivery of simple or blended permeation
enhancers should not be affected.
27

b) Backing membrane:
• Backing membranes are flexible and they provide a
good bond to the drug reservoir, prevent drug from
leaving the dosage form through the top, and accept
printing.
• It is impermeable substance that protects the product
during use on the skin e.g. metallic plastic laminate,
plastic backing with absorbent pad and occlusive base
plate (aluminium foil), adhesive foam pad (flexible
polyurethane) with occlusive base plate (aluminium foil
disc) etc.
28

Composition relatively invariant in use.
System size reasonable.
Defined site for application.
Application technique highly reproducible.
Delivery is (typically) zero order.
Delivery is efficient
Desirable Features for
Transdermal Patches
29

a. Asymmetric TPX membrane method:
A prototype patch can be fabricated for this a heat
sealable polyester film (type 1009, 3m) with a concave
of 1cm diameter will be used as the backing membrane.
Drug sample is dispensed into the concave membrane,
covered by a TPX {poly (4-methyl-1-pentene)}
asymmetric membrane, and sealed by an adhesive.
[(Asymmetric TPX membrane preparation): These are
fabricated by using the dry/wet inversion process.
TPX is dissolved in a mixture of solvent (cyclohexane)
and nonsolvent additives at 60°c to form a polymer
solution.
Various Methods for
Preparation of TDDS:
30

b. Circular teflon mould method:
Solutions containing polymers in various ratios are used in an
organic solvent.
Calculated amount of drug is dissolved in half the quantity of
same organic solvent.
Enhancers in different concentrations are dissolved in the other
half of the organic solvent and then added.
Di-N-butylphthalate is added as a plasticizer into drug polymer
solution.
The total contents are to be stirred for 12 hrs and then poured
into a circular teflon mould.
The moulds are to be placed on a leveled surface and covered
with inverted funnel to control solvent vaporization in a laminar
flow hood model with an air speed of 0.5 m/s.
 The solvent is allowed to evaporate for 24 hrs. The dried films
are to be stored for another 24 hrs at 25±0.5°C in a desiccators
containing silica gel before evaluation to eliminate aging
effects.
The type films are to be evaluated within one week of their
preparation. 31

c. Mercury substrate method:
In this method drug is dissolved in polymer solution along with
plasticizer.
The above solution is to be stirred for 10- 15 minutes to produce
a homogenous dispersion and poured in to a levelled mercury
surface, covered with inverted funnel to control solvent
evaporation.
d. By using “IPM membranes” method:
In this method drug is dispersed in a mixture of water and
propylene glycol containing carbomer 940 polymer and stirred for
12 hrs in magnetic stirrer.
The dispersion is to be neutralized and made viscous by the
addition of triethanolamine.
Buffer pH 7.4 can be used in order to obtain solution gel, if the
drug solubility in aqueous solution is very poor.
The formed gel will be incorporated in the IPM membrane.32

e. By using “EVAC membranes” method:
In order to prepare the target transdermal therapeutic
system, 1% carbopol reservoir gel, polyethelene (PE),
ethylene vinyl acetate copolymer (EVAC) membranes
can be used as rate control membranes.
If the drug is not soluble in water, propylene glycol is
used for the preparation of gel.
Drug is dissolved in propylene glycol, carbopol resin will
be added to the above solution and neutralized by using
5% w/w sodium hydroxide solution.
The drug (in gel form) is placed on a sheet of backing
layer covering the specified area.
A rate controlling membrane will be placed over the gel
and the edges will be sealed by heat to obtain a leak
proof device 33

f. Aluminium backed adhesive film method:
Transdermal drug delivery system may produce unstable
matrices if the loading dose is greater than 10mg.
Aluminium backed adhesive film method is a suitable
one.
For preparation of same, chloroform is choice of solvent,
because most of the drugs as well as adhesive are
soluble in chloroform.
The drug is dissolved in chloroform and adhesive
material will be added to the drug solution and
dissolved.
A custom made aluminium former is lined with
aluminium foil and the ends blanked off with tightly
fitting cork blocks.
34

g. By using free film method:
Free film of cellulose acetate is prepared by casting on mercury
surface.
A polymer solution 2% w/w is to be prepared by using
chloroform.
Plasticizers are to be incorporated at a concentration of 40%
w/w of polymer weight.
5ml of polymer solution was poured in a glass ring which is
placed over the mercury surface in a glass petri dish.
The rate of evaporation of the solvent controlled by placing an
inverted funnel over the petri dish.
The film formation is noted by observing the mercury surface
after complete evaporation of the solvent.
The dry film will be separated out and stored between the
sheets of wax paper in a desiccator until use.
Free films of different thickness can be prepared by changing
the volume of the polymer solution.
35

For a systemically active drug to reach a target tissue remote
from the site of drug administration on the skin surface, it must
possess physicochemical properties that facilitate the sorption
of drug by the stratum corneum, the penetration of drag
through the viable epidermis, and also the uptake of drug by
microcirculation in the dermal papillary layer.
The rate of permeation
𝒅𝑸
𝒅𝒕
across various layers of skin tissues
can be expressed mathematically as
𝒅𝑸
𝒅𝒕
=Ps(Cd-Cr) ….(i)
where, Cd and Cr are, respectively, the concentrations of a skin
penetrant in the donor phase and Ps is the overall permeability
coefficient of the skin tissues to the penetrant.
Mechanisms of Rate-Controlled
TDD
36

Ps is defined by
Ps = Ks/d Dss
hs
……(ii)
where,
Ks/d is the partition coefficient for the interfacial
partitioning of the penetrant molecule from a
transdermal drug delivery system onto the stratum
corneum;
Dss is the apparent diffusivity for the steady-state
diffusion of the penetrant molecule through the skin
tissues; and
hs is the overall thickness of the skin tissues for
penetration.
37

The permeability coefficient Ps for a skin penetrant can be
considered a constant value if the Ks/d, Dss, and hs in terms
of equation (ii) are essentially constant under a given set
of conditions.
Analysis of equation (i) suggests that to achieve a constant
rate of drug permeation one needs to maintain a condition
in which the drug concentration on the surface of stratum
corneum Cd is consistently and substantially greater than
the drug concentration in the body Cr; i.e., Cd > Cr.
Under such conditions equation (i) can be reduced to
𝒅𝑸
𝒅𝒕
=PsCd ……(iii)
and the rate of skin permeation
𝒅𝑸
𝒅𝒕
should be a constant, if
the magnitude of Cd value remains fairly constant throughout
the course of skin permeation.
38

Fig: Relationship among the rate of skin permeation Rp of a drug, the
rate of drug delivery Rd from a TDD system, and the rate of drug
absorption Ra by the skin.
39

To maintain the Cd at a constant value, it is necessary to
deliver the drug at a rate Rd that is either constant or
always greater than the rate of skin absorption Ra; i.e.,
Rd > Ra.
By making Rd greater than Ra, the drug concentration 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 Ce
s; i.e., Cd ≥ Ce
s.
A maximum rate of skin permeation (dQ/dt)m, as
expressed by Equation (iv), is thus achieved:
(
𝒅𝑸
𝒅𝒕
)m= PcCe
s …….(iv)
Apparently, the magnitude of (dQ/dt)m is determined by
the permeability coefficient Ps of the skin to the drug and
the equilibrium solubility of the drug in the stratum
corneum Ce
s. 40

This concept of stratum corneum-limited skin permeation
was investigated by depositing various doses of pure
radiolabeled nitroglycerin, dissolved in a volatile organic
solvent, onto rhesus monkey skin with a controlled
surface area.
Analysis of the urinary recovery data indicated that the
rate of skin permeation dQ/dt increases with the
increase in nitroglycerin dose Cd applied on a unit surface
area of the skin.
It appears that a maximum rate of skin permeation
(1.585 mg/cm2/day) is achieved when the applied dose of
nitroglycerin reaches a level of 4.786 mg/cm2 or greater.
41

Fig: Linear relationship between the skin permeation rate of
nitroglycerin dQ/dt determined from the daily urinary recovery data
and the nitroglycerin dose applied to the rhesus monkey skin (Cd).42

The kinetics of skin permeation can be more precisely
analyzed by studying the permeation profiles of drug across
a freshly excised skin specimen mounted on a diffusion cell,
such as the Franz diffusion cell.
A typical skin permeation profile is shown in Figure 25 for
nitroglycerin.
The results indicated that nitroglycerin penetrates through
the freshly excised abdominal skin of hairless mouse at a
zero-order rate of 19.85 ± 1.71 /xg/cm2/hr, as expected
from equation (iv), when the pure nitroglycerin in oily liquid
form is directly deposited on the surface of stratum
corneum (in this case the skin permeation of drug is under
no influence from either an organic solvent or a rate-
controlled drug delivery system).
Using a hydrodynamically well-calibrated horizontal skin
permeation cell the same observations were also made in a
series of long-term skin permeation kinetic studies for
estradiol. 43

1.Polymer membrane permeation-
controlled TDD systems:
Transderm-Scop system (scopolamine-releasing TDD
system)
Transderm-Nitro system (nitroglycerin- releasing TDD
system)
Catapres-TTS system (clonidine-releasing TDD system)
 Estraderm system (estradiol-releasing TDD system)
Technologies for Developing
TDDS
44

2. Adhesive polymer dispersion TDD
systems:
Deponit system (nitroglycerin-releasing
TDD system)
Frandol tape (isosorbide dinitrate-releasing TDD
system)
Minitran system (nitroglycerin-releasing TDD system)
Nitro-Dur II system (nitroglycerin-releasing TDD
system)
49

3. Nonadhesive polymer dispersion
TDD systems:
Nitro-Dur system (nitroglycerinreleasing TDD
system)
NTS system (nitroglycerin-releasing TDD system)
51

4. Microreservoir dissolution-controlled
TDD systems:
Nitrodisc system (nitroglycerin-releasing TDD system)
Transdermal contraceptive system (progestin-
estrogen-releasing TDD system)
52

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.
In the drug reservoir compartment the drug solids are
dispersed homogeneously in a solid polymer matrix (e.g.,
polyisobutylene), suspended in a unleachable, viscous
liquid medium (e.g., silicone fluid) to form a paste-like
suspension, or dissolved in a releasable solvent (e.g., alkyl
alcohol) to form a clear drug solution.
1. Polymer Membrane
Permeation- Controlled TDD
Systems
54

The rate-controlling membrane can be either a microporous
or a nonporous polymeric membrane, e.g., ethylene-vinyl
acetate copolymer, with a specific drug permeability.
On the external surface of the polymeric membrane a thin
layer of drug-compatible, hypoallergenic pressure-sensitive
adhesive polymer, e.g., silicone adhesive, may be applied to
provide intimate contact of the TDD system with the skin
surface.
The rate of drug release from this TDD system can be
tailored by varying the composition of the drag reservoir
formulation and the permeability coefficient and/or
thickness of the rate-controlling membrane.
55

The intrinsic rate of drug release from this type of TDD
system is defined by
….(v)
where,
• CR is the drug concentration in the reservoir compartment;
• Km/r and Ka/m are the partition coefficients for the
interfacial partitioning of drug from the reservoir to the
membrane and from the membrane to the adhesive,
respectively;
• Dm and Da are the diffusion coefficients in the rate-
controlling membrane and in the adhesive layer,
respectively; and
• hm and ha are the thickness of the rate-controlling
membrane and the adhesive layer, respectively.56

Fig: Cross-sectional view of a polymer membrane permeation-
controlled TDD system showing various major structural components,
with a liquid drug reservoir (top) or a solid drug reservoir (bottom).
57

In this approach the drug reservoir is formed by
homogeneously dispersing the drug solids in a
hydrophilic or lipophilic polymer matrix, and the
medicated polymer formed is then moulded 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.
2. Polymer Matrix Diffusion-
Controlled TDD Systems
58

Fig: Cross-sectional view of a polymer matrix diffusion-controlled
TDD systems showing various major structural components.
59

The rate of drug release from this polymer matrix drug
dispersion-type TDD system is defined as
……(vi)
where,
• Ld is the drug loading dose initially dispersed in the polymer
matrix; and
• Cp and Dp are the solubility and diffusivity of the drug in
the polymer matrix, respectively.
• Because only the drug species dissolved in the polymer can
release, Cp is practically equal to CR.
60

At steady state a Q versus t1/2 drug release profile is
obtained is defined by
……(vii)
Alternatively, the polymer matrix drug dispersion-type TDD
system can be fabricated by directly dispersing the drag 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.
61

The release profiles of drug from this type of TDD system
also follow a Q versus t1/2 pattern, as expected from the
matrix diffusion process.
Fig: Cross-sectional view of an adhesive polymer drug
dispersion-type TDD system showing various major
structural components.
62

To overcome the non-zero-order (Q versus t1/2) drug
release profiles, polymer matrix drug dispersion-type
TDD systems can be modified to have the drug loading
level varied in an incremental manner, forming a
gradient of drug reservoir along the diffusional path
across the multi-laminate adhesive layers.
The rate of drug release from this type of drug reservoir
gradient-controlled TDD system can be expressed by
….(viii)
3. Drug Reservoir Gradient-
63

In this system the thickness of diffusional path through
which drug molecules diffuse increases with time, i.e.,
ha(t).
To compensate for this time-dependent increase in
diffusional path as a result of drug depletion due to
release, the drug loading level in the multi-laminate
adhesive layers is also designed to increase
proportionally, i.e., Ld(ha).
This, in theory, should yield, a more constant drug
release profile.
This type of TDD system is best illustrated by the
development of a nitroglycerin- releasing TDD system,
the Deponit system.
64

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 is formed by first
suspending the drug solids in an aqueous solution of a
water-miscible drug solubilizer, e.g., polyethylene
glycol, and then homogeneously dispersing the drug
suspension, with controlled aqueous solubility, in a
lipophilic polymer, by high shear mechanical force, to
form thousands of unleachable microscopic drug
reservoirs.
4. Microreservoir Dissolution-
65

This 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 and a fixed thickness.
A TDD system is then produced by mounting the medicated disk
at the center of an adhesive pad.
Fig: Cross-sectional view of a drug reservoir gradient-controlled
TDD system showing various major structural components.66

The rate of drug release from a microreservoir drug delivery
system is defined by
…..(ix)
where,
• A = a/b. a is the ratio of the drug concentration in the bulk
of elution solution over the drug solubility in the same
medium, and b is the ratio of the drug concentration at the
outer edge of the polymer coating membrane over the drug
solubility in the same polymer composition;
• B is the ratio of the drug concentration at the inner edge of
the interfacial barrier over the drug solubility in the
polymer matrix. 67

• Kl, Km, and Kp are the partition coefficients for the
interfacial partitioning of drug from the liquid
compartment to the polymer matrix, from the polymer
matrix to the polymer coating membrane, and from the
polymer coating membrane to the elution solution (or skin),
respectively;
• Dl, Dp and Ds are the drug diffusivities in the liquid
compartment, polymer coating membrane, and elution
solution (or skin), respectively;
• Sl, and Sp are the solubilities of the drug in the liquid
compartment and in the polymer matrix, respectively; and
• hl, hp, and hd are the thickness of the liquid layer
surrounding the drug particles, the polymer coating
membrane around the polymer matrix, and the
hydrodynamic diffusion layer surrounding the polymer
coating membrane, respectively.68

Fig: Cross-sectional view of a microreservoir dissolution-controlled
TDD system showing various major structural components.
69

The release and skin permeation kinetics of drug from
these technologically different TDD systems can be
evaluated using a two-compartment diffusion cell
assembly under identical conditions.
This is carried out by individually mounting a skin
specimen excised from either a human cadaver or a live
animal on a vertical diffusion cell, such as the Franz
diffusion cell and its modifications, or a horizontal
diffusion cell, such as the Valia-Chien skin permeation
cell.
EVALUATIONS OF TRANSDERMAL
DRUG DELIVERY KINETICS
70

Each unit of the TDD system is then applied with its
drug-releasing surface in intimate contact with the
stratum corneum surface of the skin.
The skin permeation profile of the drug is followed by
sampling the receptor solution at predetermined
intervals until the steady-state flux is established and
assaying drug concentrations in the samples by a
sensitive analytic method, such as high-performance
liquid chromatography (HPLC).
The release profiles of drug from these TDD systems
can also be investigated in the same diffusion cell
assembly without a skin specimen.
71

Using a Franz diffusion cell assembly, the mechanisms
and the rates of drug release from these technologically
different TDD systems were evaluated and compared.
The results indicated that nitroglycerin is released at a
constant rate profile (Q versus t) from the TDD systems
like the Transderm-Nitro system [a polymer membrane
permeation-controlled TDD system] and the Deponit
system [a drug reservoir gradient-controlled TDD
system].
The release rate of nitroglycerin from the Transderm-
Nitro system (0.843 ± 0.035 mg/cm2/day) is almost
three times greater than that from the Deponit system
(0.324 ± 0.011 mg/cm2/day).
A.
72

Fig: The vertical-type in vitro skin permeation system; the Franz diffusion cell
is shown along with the Keshary-Chien skin permeation cell.
73

This suggests that diffusion through the rate-controlling
adhesive polymer matrix in the Deponit system plays a
greater rate-limiting role over the release of nitro
glycerin than does permeation through the rate-
controlling polymer membrane in the Transderm-Nitro
system.
On the other hand, the release profiles of nitro-
glycerin from the Nitrodisc and Nitro-Dur systems are
not constant but are observed to follow a linear Q
versus t1/2 pattern as expected from matrix diffusion-
controlled drug release kinetics.
The release flux of nitroglycerin from the Nitro-Dur
system (a polymer matrix diffusion-controlled TDD
system) is almost twice greater than that from the
Nitrodisc system (a microreservoir dissolution-
controlled TDD system; 4.124 ± 0.047 versus 2.443 ±
0.136 mg/cm2/day1/2).
74

Fig: The hydrodynamically well-calibrated horizontal skin permeation
system used for studying the controlled release and skin permeation of
drugs from transdermal drug delivery (TDD) systems.
75

1.Animal Skin Model
The skin permeation studies of these TDD systems
suggested that all four systems give a constant rate of
skin permeation.
The highest rate of skin permeation was observed with
the Nitrodisc system (0.426 ± 0.024 mg/cm2/ day),
which is, however, statistically no different from the
rate of skin permeation for pure nitro-glycerin (0.476
± 0.041 mg/cm2/day).
B.
76

Fig: Comparative release profiles of nitroglycerin from various TDD systems into saline solution
under sink conditions at 37°C. The release flux of nitroglycerin was: Nitrodisc system (2.443 ±
0.136 mg/cm2/day), Nitro-Dur system (4.124 ± 0.047 mg/cm2/day), Transderm-Nitro system
(0.843 ± 0.035 mg/cm2/day), and Deponit system (0.324 ± 0.011 mg/cm2/day).
77

For the Nitro-Dur system practically the same rate of
skin permeation (0.408 ± 0.024mg/cm2/day) was
obtained initially and 12hr later; however, the rate
slowed to 0.248 ± 0.018mg/cm2/day.
On the other hand, the rate of skin permeation of
nitroglycerin from the Transderm-Nitro system (0.388 ±
0.017 mg/cm2/day) was found to be one-third lower
than the rate achieved by pure nitroglycerin or one
quarter slower than that of the Nitrodisc system.
The lowest rate of skin permeation was obtained by the
Deponit system (0.175 ± 0.016 mg/cm2/day), which
achieved only one-third the skin permeation rate for
pure nitroglycerin.
78

A comparison made between the rate of skin permeation
and the rate of release suggests that under sink
conditions all TDD systems deliver nitroglycerin at a rate
greater than its rate of permeation across the skin
(Rd > Ra).
For example, nitroglycerin was delivered by the
Transderm-Nitro system, which is a polymer membrane
permeation-controlled drug delivery system, at a rate
(0.843 mg/cm2/day) 2.5 times greater than its rate of
permeation across the skin (0.338 mg/cm2/day).
Likewise, the rate of delivery by the Deponit system,
which is a multi laminate adhesive dispersion-type drug
delivery system with the slowest rate of nitroglycerin
delivery (0.324 mg/cm2/day), was found to be almost
two fold faster than the rate of skin permeation (0.175
mg/cm2/day). 79

The same observations were also true for the Nitrodisc
and Nitro-Dur systems.
This phenomenon is an indication that the stratum
corneum plays a rate-limiting role in the transdermal
delivery of drugs, including the relatively skin-
permeable nitroglycerin, as a result of its extremely
low permeability coefficient.
The difference in skin permeation rates among the
various TDD systems could be attributed to the variation
in formulation design that affects the magnitude of the
partition coefficient [ks/d].
80

The permeation of nitroglycerin across the skin of
human cadaver was also investigated for various
nitroglycerin-releasing TDD systems using the Valia-
Chien skin permeation cell assembly.
The results indicated that the skin permeation of
nitroglycerin through human cadaver skin following the
delivery from all the TDD systems evaluated also
follows the same zero-order kinetic profile as observed
with hairless mouse abdominal skin.
It has been found that differences in the type and
thickness of a skin specimen and variation in the
hydrodynamics of in vitro skin permeation cells could
affect interspecies correlation in skin permeation
rates.
2.
81

Fig: Comparative permeation profiles of nitroglycerin from various TDD systems across human
cadaver dermatomed skin. The rate of skin permeation was: Nitrodisc system (26.4± 0.5
µg/cm2/hr), Transderm-Nitro system (36.9 ± 0.9 /µg/cm2/hr), Nitro-Dur II system 37.6 ± 5.0
/µg/cm2/nr), NTS-5 system (39.2 ± 1.2 /µg/cm2/hr), and Deponit system (19.1± 0.8 µg/cm2/hr).
82

Table: Interspecies Correlation in the In Vitro Transdermal
Controlled Delivery of Drugs from TDD Systems
Similarly, the skin permeation rates of progesterone and its
hydroxy derivatives across human cadaver skin are also
correlated with that across hairless mouse skin.83

The transdermal bioavailability of nitroglycerin
resulting from the 24-32hr topical applications of
various TDD systems in human volunteers in figures
given later.
The results suggest that a prolonged, steady-state
plasma level of nitroglycerin was achieved and
maintained throughout the duration of TDD system
applications for at least 24hr as a result of continuous
transdermal infusion of drug at a controlled rate from
the TDD systems.
C.
84

Table: Interspecies Correlation in Transdermal Permeation Rates
of Nitroglycerin
85

Fig: Correlation of the permeation rates of progesterone and its
hydroxy 1 derivatives across the skin of human cadaver (hcs) and of
hairless mouse (him) of approximately the same thickness.
86

Fig: Plasma profiles of nitroglycerin in 12 healthy male volunteers;
each received 1 unit of Nitrodisc system (16 cm2) on the chest for 32
hr. A mean steady-state plasma level (Cp)ss of 280.6 ± 18.7 pg/ml was
obtained.
87

Fig: Plasma profiles of nitroglycerin in 14 healthy human subjects;
each received 1 unit of Transderm-Nitro system (20 cm2) for 24 hr. A
(Cp)ss value of 209.8 ± 22.8 pg/ml was attained.
88

Fig: Comparative plasma profiles of nitroglycerin in 24 healthy male
volunteers; each received randomly 1 unit of Nitro-Dur system I or II
(20 cm2) over the chest for 24 hr. A (Cp)ss value of 182 ± 114 (I) and 224
± 172 (II) pg/ml was achieved.
89

Fig: Plasma profiles of nitroglycerin in six healthy male volunteers;
each received 1 unit of the Deponit system (16 cm2) over the chest
for 24 hr. A (Cp)ss value of 125 ± 50 pg/ml was obtained.
90

Fig: Antianginal effect of nitroglycerin delivered by a transdermal patch using
the maximal exercise performance achieved by sublingual nitroglycerin
(measured at 5 min) as the positive control and the time course for the
improvement in exercise performance.
91

Fig: Clinical pharmacokinetic profiles of estradiol (E2) delivered
transdermally by the Estraderm system (E2, 0.10 mg/day) for a 72 hr
application compared to oral administration of Estrace tablets (E2, 2
mg/day), once a day, and of Premarin tablets (conjugated estrogens,
1.25 mg/day), once a day.
93

The in vivo rate of transdermal permeation (Q/t)iv can be
calculated from the steady state plasma level (Cp)ss data
using the relationship
where,
• Ke and Vd are the intrinsic first-order rate constant for
elimination and the apparent volume of distribution for the
drug, respectively, and
• As is the drug-releasing surface area of the TDD device in
contact with the skin.
D.
94

Fig:
Systemic bioavailability
of estradiol and serum
levels of estrone in
postmenopausal women
(n = 23) following the
transdermal delivery of
estradiol from the
Estraderm system with
various daily dosage
rates and oral
administration of various
daily doses of
conjugated estrogens
from Premarin tablets.
The serum levels of
estradiol and estrone in
the premenopausal
women (n = 15) are also
shown for comparison.
95

The results indicate that the in vivo rates of
transdermal permeation calculated show a good
agreement with the in vitro data determined from
either the epidermis or the dermatomed skin of
human cadaver.
In view of the uncertainty involved in the availability
of human cadaver skin and the variability in the
source of its supply, the in vivo-in vitro agreement
achieved, suggests that hairless mouse skin could be
an acceptable skin model as an alternative to human
cadaver skin in studying the transdermal permeation
kinetics of systemically active drugs and for
prediction of the in vivo rate of transdermal drug
delivery in humans.
96

Fig:
Comparative effect on
bone metabolism in
postmenopausal women
(n = 23) following the
transdermal delivery of
estradiol from the
Estraderm system with
various daily dosage
rates and oral
administration of
various daily doses of
from Premarin tablets.
The calcium levels in
the urine and the
urinary calcium-
creatinine ratios in
premenopausal women
(n = 15) are also shown
for comparison.97

1. Interaction studies:
Excipients are integral components of almost all
pharmaceutical dosage forms.
The stability of a formulation amongst other factors
depends on the compatibility of the drug with the
excipients.
The drug and the excipients must be compatible with
one another to produce a product that is stable, thus it
is mandatory to detect any possible physical or
chemical interaction as it can affect the bioavailability
and stability of the drug.
Other Evaluation Parameters
98

2. 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.
3. Weight uniformity:
The prepared patches are to be dried at 60°c for 4hrs
before testing.
A specified area of patch is to be cut in different parts
of the patch and weigh in digital balance.
The average weight and standard deviation values are
to be calculated from the individual weights.
99

4. Folding endurance:
A strip of specific are is to be cut evenly and repeatedly
folded at the same place till it broke.
The number of times the film could be folded at the same
place without breaking gave the value of the folding
endurance.
5. Percentage Moisture content:
The prepared films are to be weighed individually and to be
kept in a desiccator containing fused calcium chloride at
room temperature for 24 hrs.
After 24 hrs the films are to be reweighed and determine
the percentage moisture content from the below mentioned
formula.30
Percentage moisture content = [Initial weight- Final weight/
Final weight] ×100. 100

6. Percentage Moisture uptake:
The weighed films are to be kept in a desiccator at
room temperature for 24 hr containing saturated
solution of potassium chloride in order to maintain 84%
RH.
After 24 hr the films are to be reweighed and
determine the percentage moisture uptake from the
below mentioned formula.
Percentage moisture uptake = [Final weight- Initial
weight/ initial weight] ×100.
101

7. Water vapour permeability (WVP) evaluation:
Water vapour permeability can be determined with
foam dressing method the air forced oven is replaced
by a natural air circulation oven.
The WVP can be determined by the following formula
WVP=W/A
Where, WVP is expressed in g/m2 per 24hrs, W is the
amount of vapour permeated through the patch
expressed in g/24hrs and A is the surface area of the
exposure samples expressed in m2.
102

8. Drug content:
A specified area of patch is to be dissolved in a
suitable solvent in specific volume.
Then the solution is to be filtered through a filter
medium and analyse the drug contain with the
suitable method (UV or HPLC technique).
Each value represents average of three different
samples.
103

9. Uniformity of dosage unit test:
An accurately weighed portion of the patch is to be cut
into small pieces and transferred to a specific volume
volumetric flask, dissolved in a suitable solvent and
sonicate for complete extraction of drug from the patch
and made up to the mark with same.
 The resulting solution was allowed to settle for about
an hour, and the supernatant was suitably diluted to
give the desired concentration with suitable solvent.
The solution was filtered using 0.2μm membrane filter
and analysed by suitable analytical technique (UV or
HPLC) and the drug content per piece will be
calculated.
104

10. Polariscope examination:
This test is to be performed to examine the drug
crystals from patch by polariscope.
A specific surface area of the piece is to be kept on the
object slide and observe for the drugs crystals to
distinguish whether the drug is present as crystalline
form or amorphous form in the patch.
11. Thumb tack test:
It is a qualitative test applied for tack property
determination of adhesive.
The thumb is simply pressed on the adhesive and the
relative tack property is detected.
105

12. Shear Adhesion test:
This test is to be performed for the measurement of the
cohesive strength of an adhesive polymer.
It can be influenced by the molecular weight, the degree
of crosslinking and the composition of polymer, type and
the amount of tackifier added.
An adhesive coated tape is applied onto a stainless steel
plate; a specified weight is hung from the tape, to affect
it pulling in a direction parallel to the plate.
Shear adhesion strength is determined by measuring the
time it takes to pull the tape off the plate.
The longer the time take for removal, greater is the
shear strength.
106

13. Peel Adhesion test:
In this test, the force required to remove an adhesive
coating form a test substrate is referred to as peel
adhesion.
Molecular weight of adhesive polymer, the type and
amount of additives are the variables that determined
the peel adhesion properties.
A single tape is applied to a stainless steel plate or a
backing membrane of choice and then tape is pulled
from the substrate at a 180º angle, and the force
required for tape removed is measured
107

14. Flatness test:
Three longitudinal strips are to be cut from each film
at different portion like one from the center, other
one from the left side, and another one from the
right side.
The length of each strip was measured and the
variation in length because of non-uniformity in
flatness was measured by determining percent
constriction, with 0% constriction equivalent to 100%
flatness
108

15. Percentage Elongation break test:
The percentage elongation break is to be determined
by noting the length just before the break point, the
percentage elongation can be determined from the
below mentioned formula.
Elongation percentage = L1-L2/ L2 ×100
where, L1is the final length of each strip and L2 is
the initial length of each strip.
109

16. Rolling ball tack test:
This test measures the softness of a polymer that
relates to talk.
In this test, stainless steel ball of 7/16 inches in
diameter is released on an inclined track so that it
rolls down and comes into contact with horizontal,
upward facing adhesive.
The distance the ball travels along the adhesive
provides the measurement of tack, which is
expressed in inch.
110

17. Quick Stick (peel-tack) test:
In this test, the tape is pulled away from the
substrate at 90ºC at a speed of 12 inches/min.
The peel force required to break the bond between
adhesive and substrate is measured and recorded as
tack value, which is expressed in ounces or grams
per inch width.
111

18. Probe Tack test:
In this test, the tip of a clean probe with a defined
surface roughness is brought into contact with
adhesive, and when a bond is formed between
probe and adhesive.
The subsequent removal of the probe mechanically
breaks it.
The force required to pull the probe away from the
adhesive at fixed rate is recorded as tack and it is
expressed in grams.
112

19. Skin Irritation study:
Skin irritation and sensitization testing can be
performed on healthy rabbits (average weight 1.2 to
1.5 kg).
The dorsal surface (50cm2) of the rabbit is to be
cleaned and remove the hair from the clean dorsal
surface by shaving and clean the surface by using
rectified spirit and the representative formulations
can be applied over the skin.
The patch is to be removed after 24 hr and the skin is
to be observed and classified into 5 grades on the
basis of the severity of skin injury.
113

20. Stability studies:
Stability studies are to be conducted according to
the ICH guidelines by storing the TDDS samples at
40±0.5°c and 75±5% RH for 6 months.
The samples were withdrawn at 0, 30, 60, 90 and
180 days and analyze suitably for the drug content.
114

To formulate a TDD system one should take into consideration
the relationship between the rate of drug delivery Rd to the
skin surface and the maximum achievable rate of drug
absorption Ra by skin tissue.
This is particularly important because the stratum corneum is
known to be highly impermeable to most drugs.
A TDD system should ideally be designed to have a skin
permeation rate determined by the rate of drug delivery from
the TDD system, not by the skin permeability.
In such a case the transdermal bioavailability of a drug
becomes less dependent upon any possible intra- and/or
interpatient variabilities in skin permeability.
OPTIMIZATION OF
TRANSDERMAL CONTROLLED
DRUG DELIVERY
115

The rate of skin permeation of a drug at steady state
(Rp)ss is mathematically related to the actual rate of
drug delivery from a TDD system (Rd)a to the skin
surface and the maximum achievable rate of skin
absorption (Ra)m by the relationship
The actual rate of drug delivery from a TDD system to
the skin surface, which acts as the receptor medium in
the clinical applications, can thus be determined from
116

If we consider the rate of skin permeation of pure
nitroglycerin, which is free of any influence by the
formulation or vehicle, as the value for (Ra)m, the actual
delivery rate of nitroglycerin from various TDD systems can
be determined.
Using a matrix diffusion-controlled TDD system the
relationship between the rate of skin permeation and the
rate of drug delivery from the TDD system can be
established.
The skin permeation rate of a drug at steady state, (Rp)ss, is
related to the drug delivery rate from a matrix-type TDD
system, (Q/t1/2), as follows
(Rp)ss =
m(Q/t1/2)2
1+n(Q/t1/2)2
where, m and n are composite constants and defined as
117

Fig:
Comparative effect
on vaginal cytology
in postmenopausal
women (n = 23)
following the
transdermal delivery
of estradiol from the
Estraderm system
with various daily
dosage rates and oral
administration of
various daily doses of
from Premarin
tablets. The
percentage of
superficial cells and
parabasal cells in the
premenopausal
women (n = 15) is
also shown for
comparison.118

Fig:
Comparative
effect on hepatic
protein activity in
postmenopausal
women (n = 23)
following the
transdermal
delivery of
estradiol from the
Estraderm system
with various daily
dosage rates and
oral
administration of
various daily
doses of
conjugated
estrogens from
Premarin tablets.
The serum levels
of various hepatic
proteins in the
premenopausal
women in = 15)
are also shown for
comparison.
119

Table: Comparison in In Vitro and In Vivo Transdermal Permeation
Rates
120

Table: Intersubject Variability in Human Cadaver Skin Permeability
121

Table: Delivery Rate of Nitroglycerin from Various TDD
Systems
122

Fig: The hyperbolic relationship between the skin permeation rate and the square
of the release flux of nitroglycerin delivered by the matrix diffusion-controlled
TDD system. It was observed that when the (Q/t1/2)2 value is equal to or less than
48 /µg2/cm4/hr, the skin permeation rate of nitroglycerin is controlled by the
delivery system; when the (Q/t1/2)2 value is greater than 48 µg2/cm4/hr, the skin
permeation rate becomes limited by the stratum corneum permeability.
123

Transdermal drug delivery is hardly an old technology, and
the technology no longer is just adhesive patches.
Due to the recent advances in technology and the
incorporation of the drug to the site of action without
rupturing the skin membrane transdermal route is becoming
the most widely accepted route of drug administration.
It promises to eliminate needles for administration of a
wide variety of drugs in the future.
TDDS have great potentials, being able to use for both
hydrophobic and hydrophilic active substance into promising
deliverable drugs.
To optimize this drug delivery system, greater
understanding of the different mechanisms of biological
interactions, and polymer are required.
TDDS realistic practical application as the next generation
of drug delivery system.
Conclusion
124

1. Jain, N. K., Controlled and Novel Drug Delivery, CBS
Publishers, and Distributors, 2002, 107.
2. Chien, YW, Novel drug delivery systems, Drugs and the
Pharmaceutical Sciences, Vol.50, Marcel Dekker, New
York, NY;1992;797.
3. Guy, RH.; Hadgraft, J., editors. New York: Marcel
Dekker; Transdermal Drug Delivery, 2003.
References
125

Describe components of a TDDS.
What are the merits and limitations of a TDDS?
Explain the rationale behind the use of TDDS to regulate
systemic availability of drugs.
Explain different methods of formulating a transdermal
patch.
Discuss the basic components of TDDS.
Explain the factors affecting permeation of drug through
skin.
Explain the mechanism of permeation and permeation
enhancers used in transdermal patches.
Explain the mechanism of drug absorption by transdermal
route.
Explain the techniques for formulation of TDDS.
FAQs
126

How will you design a transdermal patch?
How do you design a TDDS for administering nicotine?
Write the role of permeation enhancers in TDDS.
Write notes on:
• Reservoir type TDDS
• Mechanism of transdermal permeation
• Permeation enhancers
• Evaluation of TDDS
Discuss the evaluation techniques for transdermal
patches.
Explain the method of evaluation of transdermal patch
using a suitable model.
127

Explain formulation approaches (techniques) for
TDDS. Briefly discuss evaluation methods for TDDS.
Discuss the advantages of transdermal absorption.
How are such products designed and evaluated?
Explain factors affecting permeation through skin.
Write a note on permeation enhancers.
Explain method of evaluation of TDD patch using a
suitable model.
Importance of in-vitro methods of evaluation of TDDS.
Most Commonly Asked
Questions:
128

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