Computational and Theoretical Polymer Science 10 (2000) 391–401

Processes of drug transfer with three different polymeric systems with

transdermal drug delivery
E.M. Ouriemchi, J.M. Vergnaud*
Laboratory of Materials and Chemical Engineering, Department of Chemistry, University of Saint-Etienne, 23 Dr P. Michelon, Saint-Etienne 42023, France
Received 6 July 1998; received in revised form 1 September 1999; accepted 11 October 1999

Abstract
The transdermal drug delivery exhibits two main advantages over the conventional oral delivery, by-passing the hepatic first-pass, and
maintaining the plasma drug level at a plateau over a long period of time. The role of the transdermal therapeutic systems is to apply a
constant drug concentration on the skin for a long time, while the skin acts as a membrane. Thus the drug transfer through the skin reaches a
constant rate under stationary conditions after a short time under transient conditions. Three transdermal therapeutic systems are considered:
a monolithic device made of a polymer containing the drug; this monolithic device in contact with a drug reservoir; a porous polymer
containing the drug. The monolithic device can maintain a constant drug delivery only when the diffusivity of the drug through this polymer
is very high. In association with a reservoir, this device becomes more efficient. The system made of a porous polymer with convective
transfer of the drug appears to be more effective, providing a constant drug concentration on the skin surface, which is responsible for a
constant rate of drug transfer through the skin and a constant plasma drug level over a long period of time. 䉷 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: Transdermal therapeutic system; Polymer; Diffusion; Convection; Modeling

1. Introduction on the system and on the pharmacokinetic parameters of the

A transdermal therapeutic system (TTS) delivers the drug
systematically into the circulatory system of the patient
through the skin. Its main role is to apply the drug to the
patient’s skin at a given concentration. Working by a
process of molecular diffusion, the TTS must release the
drug into the skin to the subcapillary plexus at a rate,
which remains constant as long as the diffusion gradient
between the system and the skin is maintained. As soon as
the TTS is applied to the skin, a relatively large quantity of
drug is delivered, saturating the binding sites of the skin,
penetrating the barriers of the stratum corneum, the living
epidermis and the dermis, and then reaching the blood-
stream in the stage of absorption. The drug concentration
in the plasma, then, increases up to a level which remains
constant as long as the TTS is maintained and delivers the
drug at a constant rate; this fact results from the stages of
absorption in the plasma compartment and elimination of
the drug, which are controlled by first-order kinetics [1].
Thus, after a transient period of a few hours, which depends
* Corresponding author. Tel.: ⫹ 33-04-77481568; fax: ⫹ 33-04-
77251817.
E-mail address: vergnaud@univ-st-etienne.fr (J.M. Vergnaud).
1089-3156/00/$ - see front matter 䉷 2000 Elsevier Science Ltd. All rights reserved.
PII: S1089-315 6(00)00003-9
drug, stationary conditions are attained with a state of equi-
librium between absorption in the plasma and elimination of
the drug. When the TTS is removed, the plasma concentra-
tion falls at a rate which is determined by the half-life of the
drug and its rate of elimination [1].
By now, TTS has gone mainstream and several com-
panies are established, dedicated to advance transdermal
controlled-release technologies. Although polymer matrix
bandage formulations for topical delivery of antibiotics
have been known since at least as early as the 1950s, it is
about 25 years since Alza’s first controlled-release trans-
dermal delivery system patents were issued. The Alza
patents were the first to describe the use of membranes to
control the rate of drug delivery to the skin. In 1979, the first
commercial transdermal nitroglycerin systems went on sale:
Transderm-Nitro QD in the USA from Alza-Ciba Geigy, or
Nitro-Dur from Key Pharmaceuticals [2]. Since then only a
few more drugs have been found that can be delivered trans-
dermally.
It is now well established that TTS offer a unique com-
bination of therapeutic advantages:
(i) The drug metabolism is reduced because the liver is
initially bypassed.
392 E.M. Ouriemchi, J.M. Vergnaud / Computational and Theoretical Polymer Science 10 (2000) 391–401
Nomenclature
Cx;t Drug concentration at position x and time t
Cin Initial concentration of drug
DTT Diffusivity of the drug in the polymer device
Ds Diffusivity of the drug in the skin
Ft Rate of drug transferred through the skin at time t
h Coefficient of convective transfer of drug out of the skin after removal of the TTS
ka Rate constant of absorption of the drug in the plasma (h ⫺1)
ke Rate constant of elimination of the drug out of the plasma (h ⫺1)
LTT Thickness of the polymer device
Ls Thickness of the skin
Mt Amount of drug transferred through the skin
T Time
Vp Plasmatic volume of the rat
x Position in the TTS-skin system
X Amount of drug in the dermis
Y Amount of drug in the plasma
(ii) The risk of overdosage when the drug enters the
plasma is avoided. In contrast with the oral dosage form
which gives rise to a maximum of the drug concentration
or peak, the plasma drug level when delivered by TTS
increases regularly up to a plateau. The side effects asso-
ciated with these drug concentration peaks are thus
reduced.
(iii) Variables which can affect the gastro-intestinal (GI)
absorption of oral dosage forms are circumvented.
Especially, the time over which the drug is delivered
can exceed the GI tract time.
Despite the obvious advantages of TTS and the consider-
able research and development expense in the transdermal
product development and skin research field, progress to
bring more TTS to market has been very slow [2]. It is
clear that for most drugs, with a few exceptions, like, alka-
loids such as nicotine, the skin plays the role of a significant
barrier that must be overcome, as the drug has to reach the
bloodstream. The skin is relatively impermeable to most
substances and for that reason it had been considered an
inappropriate site for the administration of drug until 1980
[3]. Another disadvantage is that the thickness of skin varies
in different parts of the body as well as among individuals.
The stratum corneum is the principal barrier against many
substances, in contrast with the living epidermis and the
dermis [4]. The stratum corneum can be described as a
heterogeneous two-phase membrane with lipophilic and
hydrophilic elements, and this layer determines the rate of
drug penetration.
Two main ways are followed to increase the permeability
of the stratum corneum to drugs: using enhancers or trans-
dermal iontophoresis. Only a short literature survey is made
here on these subjects to give an idea of the problems and
their potential solutions. Some chemicals can play the role
of enhancers by increasing the permeability of the skin to
the drug, acting either on the diffusivity or the solubility of
the drug [5–9].
In fact the problem of understanding the mechanism of
transfer through the epidermis is highly complex [10]. The
other way of increasing the permeability of the skin consists
of using the transdermal iontophoresis by applying a poten-
tial electrical gradient between the skin site and another
place on the body with two electrodes. The electrode on
the skin site bears the same charge of the drug ion, and
the movement of these ions through the skin is brought
about by using an appropriate direct/alternating current
between the two electrodes. Of course the technique of
transdermal iontophoresis is useful for drugs which are
predominantly ionized [11–13]. It must be noted that
some interactions may occur between penetration enhancers
and iontophoresis [14].
The TTS with the patch also plays a role. On the whole,
the TTS systems can be divided into two broad categories
with the monolithic and the reservoir systems. In a mono-
lithic system, the TTS has three layers, an impermeable
backing, an intermediate polymer matrix containing the
drug, and a skin adhesive layer, which is attached to a
release liner before using. In this type of system, the matrix
polymer is designed to control the drug diffusion from the
system. Initially the drug is uniformly distributed through-
out the polymer matrix. When the system is placed on the
skin, the drug permeates into the skin, provoking a decrease
in the drug concentration on the surface in contact with the
skin. It stands to reason that the value of the diffusivity of
the drug through the polymer as compared to that in the
skin, plays a major role on the rate of drug transport through
the skin and on the plasma drug level. With the reservoir
system, the impermeable backing layer is sealed to a rate-
controlling membrane layer. The volume between the back-
ing and membrane is the reservoir. The drug is usually
contained within the reservoir in a liquid or gel carrier
 E.M. Ouriemchi, J.M. Vergnaud / Computational and Theoretical Polymer Science 10 (2000) 391–401
Fig. 1. Scheme of the process (up). Scheme of the three TT system (down):
(1) TTS with polymer and diffusion. (2) TTS with polymer and reservoir.
(3) TTS with porous polymer and convection.
phase. The membrane is adhered to the skin adhesive. The
drug release is controlled by the rate-controlling membrane
layer, which can be achieved either by diffusion or by
convection.
The first objective of this paper is to calculate the rate of
drug transferred through the skin with these different
systems. The results can be expressed in terms of profiles
of drug concentration developed through the TTS and the
skin and of kinetic of drug transfer through the skin. The
theoretical results are compared to some experimental
results obtained through in vitro experiments which are
clearly and precisely defined [15]. Thus the effect of the
TTS system and of the nature of the polymers used as the
rate-controlling membrane can be evaluated.
As the purpose of these systems is to deliver the drug in
the plasma, the plasma drug level is assessed by using a
numerical model taking the known facts into account [16]:
the diffusion of the drug through the TTS and the skin, the
stage of absorption into the plasma and the stage of elim-
ination. This model is tested by comparing the plasma drug
level assessed with that obtained from experiments using
Metoprolol as the drug [15,16]. This way of calculating
the plasma drug level has been developed for oral dosage
forms with controlled release [17–19]. In vitro/in vivo
correlations have also been made for the transdermal deliv-
ery [6,20] in the same way as for oral dosage forms with
controlled release [21–23]. It must be said that some authors
393
of the report on oral dosage forms concluded that no mean-
ingful correlations were obtained at that time [24,25]. It is
worth noting that the model used in this paper is similar to
that built for calculating the drug transfer from the plasma to
blister fluid [26] which is the problem of drug transfer in the
opposite direction; the transfer from the plasma into the
blister fluid was considered as a diffusional transfer through
the tissues and the diffusivity as a ratio of the tissue (thick-
ness) 2 evaluated, has the (time) ⫺1 equation of dimension
and thus is similar to a rate constant of elimination. The
drug concentration in the blister fluid and its change with
time was found to be in good agreement with those obtained
from experiments [27]; the drug concentration follows that
of the plasma with a lag time, meaning that the diffusional
transfer is reversible. In the same way, a similar model with
the two stages of absorption into and elimination of the drug
out of the plasma was built and successfully tested for intra-
muscular delivery of Aspegic [28]; the drug transfer by
diffusion through the tissue was thus successfully expressed
by a first-order kinetics of absorption, and the rate constant
of absorption was found to be the same as that used for oral
dosage forms.
2. Theoretical
The process of drug transfer is considered firstly through
the TT systems in contact with the skin, as it is determined
through in vitro tests. Secondly, the plasma drug level is
calculated.
2.1. Drug transfer through the transdermal therapeutic
system and skin
The following three TT systems are examined in succes-
sion: the TT diffusional system made of a polymer contain-
ing the drug; the TT system made of a reservoir and a
diffusional membrane; the TT system consisting of a porous
polymer with a convectional drug transfer (Fig. 1).
2.1.1. Transdermal therapeutic system with a polymer alone
2.1.1.1. Assumptions. The following assumptions are
made:
(i) The drug concentration is initially uniform in the poly-
mer membrane.
(ii) The TT system and skin are in good contact.
(iii) Initially, the skin is free from drug.
(iv) The drug concentration on the skin surface is the
same with the three TT systems, in order to make compar-
ison more easily. Moreover the drug concentration in the
polymer is also the same in the three TT systems.
(v) The process of drug transfer is controlled by diffusion
either in the TTS and skin with constant diffusivities in
both these media.
(vi) The drug concentration at the inside of the skin is
394 E.M. Ouriemchi, J.M. Vergnaud / Computational and Theoretical Polymer Science 10 (2000) 391–401

very low, as the drug is absorbed in the plasma with a skin is:
first-order kinetics. DCin C L
Mt ˆ t ⫺ in s
Ls 6
2.1.1.2. Mathematical treatment. The equation of !
2Cin Ls X∞
…⫺1†n n2 p 2
unidirectional diffusion is: ⫺ exp ⫺ 2 Dts …3†
p 2
nˆ1 n 2 Ls
2C 22 C
ˆD 2 …1† When the drug transfer proceeds, the amount Mt tends to the
2t 2x asymptotical line
with a diffusivity DTT and Ds in each medium. !
DCin L2s
Mt ˆ t⫺ …4†
Ls 6Ds
2.1.2. Transdermal therapeutic system with a polymer and
which intercepts the time-axis at:
reservoir
L2s
2.1.2.1. Assumptions. The assumptions from (i) to (vi) still tˆ : …5†
6Ds
hold, with another one resulting from the presence of the
reservoir which maintains the drug concentration constant
on the external surface of the TTS. 2.2. Drug transfer into the plasma

(vii) The drug concentration is constant on the side of 2.2.1. Assumptions

TTS opposite to the skin. The following assumptions are made:
(i) The drug is delivered in the dermis at a rate which
2.1.2.2. Mathematical treatment. The problem is resolved depends on time Ft :
with a numerical model. In fact this model, able to give the (ii) The drug is then absorbed in the plasma through a
rate Ft of drug crossing the skin at time t, is extended to the first-order kinetics with the rate constant of absorption ka
drug transfer in the plasma, as shown in Section 2.2. [16]. This assumption is the same as that made for the
drug transfer in the plasma with the other ways of drug
delivery, oral [17–19], intramuscular [28], which proved
2.1.3. Transdermal therapeutic system with the process of successful.
convective transfer (iii) The drug in the plasma is eliminated through a first-
order kinetics with the rate constant of elimination ke.
2.1.3.1. Assumptions. The following assumptions are:
(i) The drug concentration is maintained constant 2.2.2. Mathematical treatment
throughout the TTS. The following stages are considered in succession.
(ii) The skin is initially free from drug. The amount of drug in the dermis, X, is expressed by:
(iii) Good contact is obtained between the TTS and skin.
dX
(iv) The drug concentration on the side of the skin oppo- ˆ F t ⫺ Ka X …6†
site to the TTS is maintained to a low value, as the drug is dt
absorbed in the plasma with a first-order kinetics. The amount of drug in the plasma, Y, is obtained with:
dY
ˆ ka X ⫺ Ke Y …7†
2.1.3.2. Mathematical treatment. This is the well-known dt
problem of the membrane with a constant concentration A problem appears for calculating the plasma drug level
maintained on each side [29] (the skin of thickness Ls is after removal of the patch [16]. Three assumptions have
thus maintained between Cin and 0). been tested previously:
The drug concentration through the skin is given by:
(i) By putting ka ˆ 0 at the time of the patch removal,
  meaning that the drug located in the skin remains in it.
X
Cx;t ˆ Cin 1 ⫺ (ii) By keeping ka constant and the gradient of concen-
Ls
tration equal to zero at the external surface of the skin;
! this means that all the drug located in the skin is delivered
2Cin X
∞
1 npx n2 p 2
⫺ sin exp ⫺ 2 Dt …2† into the plasma.
p nˆ1 n Ls Ls (iii) Another assumption was made by telling that only a
part of the drug initially located in the skin is delivered
and the amount of drug which emerges at the inside of the into the plasma, the other part being eliminated through
 E.M. Ouriemchi, J.M. Vergnaud / Computational and Theoretical Polymer Science 10 (2000) 391–401
Table 1
Parameters concerned with the Metoprolol transfer [15,16]
Skin Ds ˆ 2:2 × 10⫺8 cm2 =s Ls ˆ 0:038 cm
TTS Cin ˆ 0:036 g=cm3 h ˆ 6 × 10⫺6 cm=s
Drug ka ˆ 1:1=h ke ˆ 0:78=h V ˆ 51
the external side of the skin. It is expressed by the relation:
2C
t ⱖ tr xˆ0 D ˆ hCi;t …8†
2x
where h is a coefficient of convective transfer of the drug out
of the skin and Ci; t is the drug concentration on the external
surface of the skin and tr is the time of patch removal.
2.2.3. Numerical treatment
As no analytical solution exists, the problem of drug
transfer in the plasma is resolved by using a numerical
method [16].
3. Experimental
Experiments described in a previous paper by other work-
ers [15] are summarized.
Metroprolol (MP) was chosen for the drug, because it is
subjected to extensive hepatic first-pass metabolism following
oral administration and has a short biological half-life [15].
The patch was prepared in the Ghosh laboratory by
mixing MP with a polyacrylate adhesive, and a uniform
layer 0.12 cm thick was made on Scotch Pack 1006 (3M
Company, USA). The system was cured at room tempera-
ture. This laminate was covered by a release liner Scotch
Pack 1022 (3M Company). For transdermal application
10 cm 2 pieces were cut out.
In vitro permeation through the full-thickness hairless rat
skin was determined [15] using a Valia-Chien glass diffu-
sion, leading to the kinetics of transfer through the skin,
expressed in Eq. (3).
Bioavailability studies were made on various rats by
measuring the plasma concentration–time profile after
either an intravenous (IV) injection or an oral administration
of MP.
Transdermal administration of MP via the patch was
made by application of the patch for 25 h and removal of
the device, leading to a plasma concentration–time history
[15].
4. Results
The three types of TT systems are investigated, by
considering in succession the profiles of drug concentration
developed through the TTS and the skin, the kinetics of drug
transferred through the skin, and the plasma drug level asso-
ciated with the drug delivery with each TT system. Thus
395
attention is focused on the process of drug transfer through
the TT system, and the consequence not only upon the
kinetics of drug delivered to the patient, but also upon the
plasma drug level.
In order to simplify the presentation of the results, the
partition factor K which can appear at the TTS-skin inter-
face, meaning that the drug concentration on the skin
surface is K times that on the TTS surface, is taken as 1 in
all cases.
The parameters determined from the early paper by
Ghosh et al. [15], are shown in Table 1.
From the kinetics of drug transfer through the skin, by
considering the slope of the asymptote and the intercept of
this asymptote with the time-axis, using Eqs. (6) and (7),
and the knowledge of the thickness of the skin of
0.038 cm, the values of the diffusivity through the
skin Ds and the constant concentration Cin in TTS are
evaluated [16].
4.1. Transdermal therapeutic system with diffusion-process
control without reservoir
This is perhaps the simplest TT system, where the drug is
located in a polymer matrix. Thus the drug diffuses through
the polymer matrix and through the skin with a constant
diffusivity which can be the same or different.
4.1.1. Drug transfer through the transdermal therapeutic-
skin system
The results are expressed in two ways: with the profiles of
drug concentration developed through the TTS-skin system,
and with the kinetics of drug transfer in the dermis.
The profiles of drug concentration are drawn in the TTS-
skin system (Fig. 2) when the diffusivities are different in
the TTS and the skin (diffusivity in the TTS ˆ 4:4 ×
10⫺6 cm2 =s†: The kinetics of drug transfer into the dermis
are drawn (Fig. 3) for different values of the diffusivity in
the TTS (1: DTT ˆ 4:4 × 10⫺5 cm2 =s; 2: DTT ˆ
4:4 × 10⫺6 cm2 =s; 3: DTT ˆ 4:4 × 10⫺7 cm2 =s; 4: DTT ˆ
2:2 × 10⫺8 cm2 =s†:
The following observations are drawn from these curves:
(i) The profiles of drug concentration developed through
the TTS-skin system (Fig. 2) afford a further insight into
the nature of the process of drug transfer controlled by
diffusion.
(ii) The drug concentration progresses continuously
through the skin, under transient conditions. After a
time around 1 h, the drug reaches the dermis (Fig. 2).
(iii) After a time higher than 6 h, the drug concentration
becomes nearly uniform in the TTS and tends to be linear
through the skin.
(iv) The drug concentration decreases regularly with time
in the TTS, as well as on the skin surface in contact with
the TTS. This is the main result shown in Fig. 2.
(v) The kinetics of drug transfer in the dermis exhibit a
typical pattern which follows the drug concentration
396 E.M. Ouriemchi, J.M. Vergnaud / Computational and Theoretical Polymer Science 10 (2000) 391–401

Fig. 2. Profiles of drug concentration through the TTS and skin, with a polymer alone. Initial drug concentration: 0.036 g/cm 3. Thickness of the patch: 0.12 cm,
of the skin: 0.038 cm. DTT ˆ 4:4 × 10⫺6 cm2 =s: Ds ˆ 2:2 × 10⫺8 cm2 =s:

profiles in the TTS-skin system. For instance, with the
value of the diffusivities in the TTS of 4:4 × 10⫺6 used in
Fig. 2, the kinetics (2) in Fig. 3 follows that obtained in
experiments [15], only at the beginning of the process
when the concentration in the TTS and on the skin surface
has not decreased so much below the value of Cin ˆ
0:036 g=cm3 :
(vi) When the concentration in the TTS has decreased
significantly below this concentration of 0.036 g/cm 3,
the slope in Fig. 3, which represents the kinetics of
drug transfer continuously decreases.
(vii) The effect of the value of the diffusivity on the
kinetics of drug transfer in the dermis also appears (Fig.
3), with the obvious statement: the higher the diffusivity
in the TTS, the higher the kinetics of drug delivery in the
dermis.
(viii) As proved previously [16], after removal of the
patch, the third assumption with Eq. (8) is able to give
a good agreement between the experimental and calcu-
lated plasma drug level. The value of the coefficient of
convective transfer h is shown in Table 1. This assump-
tion means that after the removal of the patch, only a part

Fig. 3. Kinetics of drug transfer through the skin, for various values of the diffusivity in the polymeric device: DTT; 4:4 × 10⫺5 cm2 =s …1†; 4:4 × 10⫺6 cm2 =s …2†;
4:4 × 10⫺7 cm2 =s …3†; 2:2 × 10⫺8 cm2 =s …4†: Ds ˆ 2:2 × 10⫺8 cm2 =s: Ls ˆ 0:038 cm:
 E.M. Ouriemchi, J.M. Vergnaud / Computational and Theoretical Polymer Science 10 (2000) 391–401
Fig. 4. Plasma drug profiles obtained with the polymeric device, and various diffusivity in the polymer: experiments: S Calculated (full line) with the
diffusivity DTT: 4:4 × 10⫺5 cm2 =s …1†; 4:4 × 10⫺6 cm2 =s …2†; 4:4 × 10⫺7 cm2 =s …3†; 2:2 × 10⫺8 cm2 =s …4†: Drug: Metopolol. ka ˆ 1:1=h: ke ˆ 0:78=h: Vp ˆ 51:
of the drug previously located in the skin is delivered into
the plasma.
4.1.2. Plasma drug profiles
The plasma drug concentrations are drawn in Fig. 4 for
various values of the diffusivity of the drug through the
TTS, leading to the following comments:
(i) At the beginning of the process, e.g. up to 3 h, the
kinetics determined by calculation follow that obtained
from experiment.
(ii) After this time interval of 3 h, when the drug
concentration on the TTS surface in contact with the
skin has decreased significantly, the plasma drug
profiles obtained by calculation are below that obtained
from experiment.
(iii) The effect of the diffusivity in the TTS on the
plasma drug profile is a consequence of the results
shown in Figs. 2 and 3.
(iv) After removal of the TTS from the skin, the plasma
drug level decreases, resulting from the kinetics of elim-
ination. Only a part of the drug located in the skin is deliv-
ered into the plasma [16], the other part leaves the skin by
following Eq. (8).
4.2. Transdermal therapeutic system controlled by diffusion
with a reservoir
The process of drug transfer is to some extent similar to
that shown without the reservoir, with the main difference
that the reservoir maintains a constant concentration on the
external surface of the polymer in the TTS.
397
4.2.1. Drug transfer through the therapeutic transdermal-
skin system
The results are expressed in terms of the profiles of
concentration attained under stationary conditions in the
TTS-skin system (Fig. 5) and of the kinetics of drug transfer
through the skin (Fig. 6).
The profiles of the concentration attained under the
nearly stationary conditions through the TTS-skin thick-
ness are drawn (Fig. 5) for various values of the diffu-
sivity in the TTS and for a constant drug concentration
…Cin ˆ 0:036 g=cm3 † on the external surface of the TTS.
The kinetics of drug transfer through the skin are also
drawn (Fig. 6) for the same values of the diffusivity in
the TTS and the experimental values [15] are also
shown.
A few comments are worth noting from these curves:
(i) Of course, the linear gradients of drug concentration
are inversely proportional to the values of the diffusivity
in the TTS. Thus the drug concentration remains nearly
uniform in the TTS when the diffusivity is very high
(curve 1).
(ii) The drug concentration is not uniform in the TTS, and
thus the drug concentration on the skin surface decreases
during the process for lower values of the diffusivity.
(iii) The kinetics of drug transfer concentration through
the skin calculated with the higher values of the diffu-
sivity in the TTS (curves 1 and 2) are in rather good
agreement with the experimental kinetics (Fig. 6).
(iv) When the diffusivity is too low in the TTS, the
concentration on the skin surface decreases, and the
kinetics of drug transfer is below the experimental
kinetics (Fig. 6—curve 3).
398 E.M. Ouriemchi, J.M. Vergnaud / Computational and Theoretical Polymer Science 10 (2000) 391–401

Fig. 5. Profiles of drug concentration through the TTS and skin, with a polymer device and reservoir, under stationary condition, for various values of the
diffusivity in the polymer: Cin ˆ 0:038 g=cm3 : DTT: 4:4 × 10⫺5 cm2 =s …1†; 4:4 × 10⫺6 cm2 =s …2†; 4:4 × 10⫺7 cm2 =s …3†: Ds ˆ 2:2 × 10⫺8 cm2 =s: Ls ˆ 0:038 cm:
LTT ˆ 0:12 cm:

4.2.2. Plasma drug level with the diffusional therapeutic
transdermal system and reservoir
The plasma drug levels are drawn (Fig. 7) for the various
values of the diffusivity in the TTS.
The obvious results appear from these curves:
(i) The plasma drug level obtained by calculation with the
two high values of the diffusivity in the TTS are nearly
similar to that obtained by experiments, from the begin-
ning to the end of the process (curves 1 and 2).
(ii) With the lower values of the diffusivity of the drug in
the TTS (curve 3), the plasma drug level is similar to that
obtained from experiment at the beginning of the process,
e.g. up to 3 h. After this time, the plasma drug level
increases more slowly, and reaches a plateau at a lower
level than in experiment.
(iii) After a time of 25 h, the TTS system is removed, and
in all cases, the plasma drug level falls resulting from the
drug elimination out of the plasma.
(iv) In the same way as for the simple monolithic device,
after removal of the TTS from the skin, the plasma drug
level decreases.

Fig. 6. Kinetics of drug transfer through the skin, with a polymer device and reservoir, for various values of the diffusivity in the polymer: Cin ˆ 0:038 g=cm3 :
DTT: 4:4 × 10⫺5 cm2 =s …1†; 4:4 × 10⫺6 cm2 =s …2†; 4:4 × 10⫺7 cm2 =s …3†: Ds ˆ 2:2 × 10⫺8 cm2 =s: Ls ˆ 0:038 cm: LTT ˆ 0:12 cm:
 E.M. Ouriemchi, J.M. Vergnaud / Computational and Theoretical Polymer Science 10 (2000) 391–401 399

Fig. 7. Plasma drug profiles obtained with the polymeric device, and reservoir, for various values of the diffusivity in the polymer: Cin ˆ 0:038 g=cm3 : Drug:
Metoprolol. ka ˆ 1:1=h: ke ˆ 0:78=h: Vp ˆ 51: DTT: 4:4 × 10⫺5 cm2 =s …1†; 4:4 × 10⫺6 cm2 =s …2†; 4:4 × 10⫺7 cm2 =s …3†: Ds ˆ 2:2 × 10⫺8 cm2 =s: Ls ˆ 0:038 cm:
LTT ˆ 0:12 cm:

4.3. Transdermal therapeutic system with drug convection
The main principle with this TTS-skin system is that the
convective transfer of the drug is so high through the TTS
that the drug concentration on the skin surface is maintained
constant, at least for a period of time over which the mean
drug concentration in the TTS remains nearly constant.
4.3.1. Drug transfer through the therapeutic transdermal-
skin system
The results are expressed by the profiles of drug concen-
tration developed through the TTS-skin system and by the
kinetics of drug transfer through the skin.
The kinetics of drug transfer through the skin are drawn
(Fig. 9) for various values of the constant drug concentration
in the TTS, ranging from 0.01 to 0.075 g/cm 3.
These curves lead to the following results:
(i) Of course, when the drug transfer in the TTS is controlled
by convection, the drug concentration is maintained
constant on the surface of the skin in contact with the TTS.
(ii) The usual profiles of concentration develop through the

Fig. 8. Profiles of drug concentration through the TTS and skin, with drug convective transfer, under transient and stationary conditions. C ˆ 0:036 g=cm3 :
Ds ˆ 2:2 × 10⫺8 cm2 =s: Ls ˆ 0:038 cm: LTT ˆ 0:12 cm:
400 E.M. Ouriemchi, J.M. Vergnaud / Computational and Theoretical Polymer Science 10 (2000) 391–401
Fig. 9. Kinetics of drug transfer through the skin, with the convective TTS, and various values of the constant drug concentration in the TTS. LTT ˆ 0:12 cm:
Ls ˆ 0:038 cm: Cin: (1) 0.075 g/cm 3; (2) 0.05 g/cm 3; (3) 0.036 g/cm 3; (4) 0.01 g/cm 3.
skin, at less times under transient conditions; and after a
sufficiently long time, the stationary state is attained with
a linear profile (Fig. 8).
(iii) The kinetics of drug transfer through the skin are drawn
for various values of the constant drug concentration in the
TTS ranging from 0.075 to 0.01 g/cm 3 (Fig. 9). Of course,
the higher the constant drug concentration in the TTS, the
higher the rate of drug transfer through the skin. In fact, as
shown in Eq. (4), when the process has reached the station-
ary state, the rate of drug transfer is proportional to this drug
concentration in the TTS.
4.3.2. Plasma drug level with the drug transfer in the TTS
controlled by convection
The plasma drug profiles are calculated with this TTS-
skin system with constant drug concentration in the TTS,
with various values of this constant drug concentration in
the TTS (Fig. 10).
Some facts deserve notice:
(i) A good agreement is observed between the theoretical
and experimental plasma drug levels, when the constant
drug concentration in the TTS is 0.036 g/cm 3 (curve 3).
(ii) The plasma drug level largely depends on the value of
the constant drug concentration in the TTS. In fact, the
drug level at the plateau is proportional to the drug
concentration in the TTS applied to the skin surface.
(iii) The lag time, or time necessary for the drug to cross
the skin and to reach the blood stream is the same, what-
ever the drug concentration in the TTS. In fact, the lag
time depends only on the characteristics of the skin, e.g.
its thickness and the drug diffusivity.
(iv) After removal of the TTS, the plasma drug level falls
in all cases, and Eq. (8) applies, meaning that only a part
of the drug located in the skin is delivered in the plasma.
5. Conclusions
It arises from the literature survey that the transdermal way
of drug delivery is of great interest, as it enables us to by-pass
the hepatic first-pass through which some drugs are affected,
and to provide the drug in the body with a constant rate over a
long period of time. However, some drawbacks appear, result-
ing essentially from the low permeability of the skin.
The process of drug transfer consists of the following
stages: diffusion through the skin which plays the role of a
membrane, absorption of the drug in the plasma and elim-
ination. Then a plateau is reached for the plasma drug level,
and maintained over a time, which depends on the ability of
the transdermal therapeutic system to maintain a constant
drug concentration on the external surface of the skin. Of
course, the level of this plateau can be adjusted to the best
therapeutic drug concentration in the plasma.
Thus, the TTS plays an important role, as it should
provide the drug with a given constant concentration on
the skin surface over a long period of time. The three
usual TTS have been considered: the simple monolithic
made of a polymer containing the drug, the process being
controlled by diffusion of the drug through the polymer; the
monolithic device associated with a drug reservoir; and the
porous system through which the drug is transferred by
convection. The advantages and drawbacks of these three
TTS have been examined in succession.
The monolithic device is very simple, but the diffusivity
of the drug through the polymer matrix must be very high.
Even in this case, the system is not able to provide a constant
 E.M. Ouriemchi, J.M. Vergnaud / Computational and Theoretical Polymer Science 10 (2000) 391–401
Fig. 10. Plasma drug profiles with the convective TTS, and various values of the constant drug concentration in the TTS. LTT ˆ 0:12 cm: Ls ˆ 0:038 cm: Cin:
(1) 0.075 g/cm 3; (2) 0.05 g/cm 3; (3) 0.036 g/cm 3; (4) 0.01 g/cm 3. Drug: Metoprolol, ka ˆ 1:1=h: ke ˆ 0:78=h: Vp ˆ 51:
drug concentration on the skin surface over a long period of
time. As a result, the rate of drug transfer through the skin is
not constant, and decreases regularly with time.
The addition of a drug reservoir to the polymer matrix is
able to reduce the main drawback of the first TTS. The
reservoir maintains a constant drug concentration on the
surface of the polymer in contact with it. When the diffu-
sivity of the polymer is high, the drug diffuses strongly
through this matrix leading to a nearly uniform drug concen-
tration through the polymer. Thus this polymer matrix is
able to provide a nearly constant drug concentration on
the skin surface. And following this improvement, the rate
of the drug transfer through the skin is almost constant, and
the plasma drug level can reach the plateau at the desired
level and can be maintained over a long period of time. Of
course, the effect of the diffusivity of the drug through the
polymer matrix is of great importance.
The third TTS with a convective drug transfer through the
porous polymer can play the role of both the reservoir and
the polymer matrix regulating the drug transfer. This system
is able to provide a constant concentration of drug on the
skin surface over a long period of time. Associated with this
fact, the plasma drug level reaches a plateau at the desired
concentration over a long period of time. The study of the
effect of the drug concentration maintained on the skin
surface shows the effect of enhancers which increase the
solubility of the drug in the skin.
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