ARTICLE
Auteur(s) : Cristina Padula1, Sara
Nicoli1, Vincenzo Aversa1, Paolo
Colombo1, Françoise Falson2, Fabrice
Pirot2, Patrizia Santi1
1Dipartimento Farmaceutico, Università degli Studi di
Parma, Viale G.P. Usberti 27/A, 43100 Parma, Italy
2Institut des Sciences pharmaceutiques et biologiques,
Université Claude Bernard, Lyon, France
accepté le 27 Mars 2007
Throughout the past 2 decades, the transdermal patch has become a
proven technology that offers a variety of significant clinical
benefits over other dosage forms. Since the first transdermal patch
containing scopolamine was approved in 1981 to prevent the nausea
and vomiting associated with motion sickness, the Food and Drug
Administration (FDA) has approved, throughout the past 25 years,
transdermal patch products containing fentanyl, nitroglycerin,
estradiol, ethinyl estradiol, norelgestromin, norethindrone
acetate, testosterone, clonidine, nicotine, lidocaine, prilocaine,
oxybutynin. More recently, patches containing methylphenidate – for
the treatment of attention deficit hyperactivity disorder – and
selegiline – for treating major depressive disorder – were approved
by the FDA. Growth in demand for prescription drug patches is being
driven by both technology and demographic factors.
Transdermal drug delivery systems: structure
The first type of transdermal delivery system, introduced into the
market a long time ago, was the so-called plaster, formed by a
thick layer of an adhesive hydrogel containing the active supported
on a tissue or woven-non-woven. Today, patches have a typical
multilayered structure, composed of more than one layer of material
superimposed on each other. Despite structural differences, all
patches have a support or backing layer, a drug deposit or
reservoir, an adhesive and a protective layer or release liner to
be removed before patch application.
The backing layer is always impermeable to the active contained
and often also to water vapor. The adhesive layer allows the
delivery system to stay in intimate contact with the skin surface
for the intended period of time and must be drug-permeable.
According to their design, transdermal patches can be divided
into matrix and reservoir types (figure 1). In the
reservoir systems, the active is in the form of a solution, gel or
solid polymeric matrix, in contact with the skin through a
polymeric membrane which modulates the delivery of the active. The
membrane is coated with an adhesive layer which guarantees the
contact with the skin. This type of system offers the big advantage
of formulation flexibility and of drug release control although,
from the fabrication point of view, is the most difficult and
expensive to produce.
Matrix systems represent a simplification of reservoir systems.
In this case, the drug deposit is not encapsulated in a separate
compartment, but is directly dissolved or dispersed in a polymeric
matrix, coated with the adhesive. Since there is no controlling
membrane, the release of the drug is governed by the permeability
of the skin. Although simple to make, these systems show a limited
formulative flexibility compared to reservoir systems.
Finally, the drug-in-adhesive systems are characterized by a
further formulative simplification, because the active is included
directly into the adhesive layer. These systems are particularly
appreciated by patients, because they are thin, flexible,
comfortable and conformable.
The technology Patch-non-Patch®[1]
With the aim of further simplifying the formulation and improving
the appearance of the patch without reducing its performance, we
recently proposed a new design of transdermal drug delivery
platform, called Patch-non-Patch®. The trade name
suggests that the system is a patch without the typical
characteristics of conventional patches. In fact, the
Patch-non-Patch® is a monolaminated bioadhesive film in
which the usual constituents of transdermal patches (backing, drug
and adhesive) have been condensed in one single layer.
The main characteristics of the film is that it is not
self-adhesive in the dry state but becomes adhesive only when
applied on wet skin. This characteristic is due to the presence of
a small amount of adhesive, unable to make the system
self-adhesive, but capable of restoring the adhesiveness in contact
with a small amount of water on the skin surface.
The application of the patch on the skin surface is performed in
a peculiar way, in three steps (figure 2): (i) wetting the
skin with water; (ii) depositing the film on the wet surface by
applying a light pressure and (iii) peeling away the liner.
The film adheres to the skin and in few minutes dries out,
becoming almost invisible and perfectly following the skin
irregularities. The film itself is typically highly water
permeable, as demonstrated by in vitro [2] and in vivo tests [3]
thus reducing the problems of skin irritation produced by occlusion
[4]. The removal is performed directly by gentle peeling off or by
washing with warm water.
The preparation of the system is made using the typical
lamination techniques and apparatus. A water solution, or
suspension, of the components (film-forming polymer, adhesive,
plasticizer, active) is coated on a release liner and then
oven-dried. Because only water is needed for its preparation, there
is a considerable advantage in terms of organic solvent use and
elimination.
Various actives have been included in this film that for the
typical structure was denominated Patch-non-Patch®. In
general, due to the structure of the patch, drugs destined to short
time application or dermal treatments are preferred. Lidocaine [2,
5], caffeine [3, 6], ibuprofen lysine, diclofenac, estradiol [7],
oxybutynin [8], progesterone, levothyroxine, sumatriptan, nicotine
[9] and bupropion [9] are some of the substances studied.
Patch-non-Patch®: examples of application
The drug release kinetics observed with the
Patch-non-Patch® is similar for all the molecules that
were studied and this is probably due to the application procedure.
In fact, the delivery of the active from the patch shows a very
short time lag, probably due to the presence of water on the skin
surface. In a previous paper [2] we have shown that lidocaine
release from the transdermal film is subordinated to the hydration
of the polymeric component by the water used in its application. In
other words, the transdermal film – applied on the wet skin surface
– absorbs water, swells and then drug release takes place. As shown
in figure 3A,
which reports the permeation profiles of lidocaine across rabbit
and pig skin, the profiles were not linear with time, but typically
showed a fast initial permeation, followed by a reduced flux later.
The data relative to lidocaine presented in the figure demonstrate
also that, although the total amount of lidocaine permeated may be
slightly different using different skin types, the kinetics is
always the same. In particular, for most of the drugs studied, the
permeation profiles became linear when plotted versus the square
root of time, as indicated in figure 3B suggesting that
the film acts as a matrix controlling the release of the drug. This
behavior has the consequence that the release rate of the drug is
particularly high at short application times. Additionally, a very
short lag-time was observed with most of the drugs studied. Taken
together, these results indicate the possibility of achieving a
faster onset of action in vivo compared to the commercial
formulations.
Another typical feature of the system is that the percentage of
drug permeated is unusually high, reaching even 60% after
24 h, as in the case of caffeine permeation across rabbit ear
skin [6]. The performance of the system is typically comparable or
better than the existing commercial formulations: figure 4 reports the amount
of caffeine permeated across the skin from the
Patch-non-Patch®, from a commercial patch containing
caffeine (Medicell Patch®, Sant’Angelica, Torino, Italy)
and from a topical gel containing the same drug
(Percutafeine®, Pierre Fabre, Paris, France, applied at
finite dose). Both commercial formulations gave a very low
permeation of caffeine, whereas the Patch-non-Patch®
showed a much higher performance.
Skin retention following Patch-non-Patch® application
was studied as well with some actives.
This was done in vitro by dosing the total amount of drug
accumulated into the skin after a predetermined period of time. In
the case of sumatriptan [10] skin retention was lower from the film
than from the respective solution whereas in the case of
levothyroxine [11] the result was comparable to a commercial cream.
These results suggest that the extent of drug accumulation into the
skin depends on the drug, although more molecules should be studied
before drawing more general conclusions.
When tested in vivo, by means of the tape stripping technique,
the Patch-non-Patch® demonstrated a lidocaine stratum
corneum accumulation comparable to the corresponding water
solution, suggesting that the matrix did not reduce to a
significant extent the diffusivity of the specific drug lidocaine.
Since it is water-based, the patch is electrically conductive and
can, therefore, constitute a useful reservoir for iontophoresis
application. In the case of lidocaine, the amount transported into
the stratum corneum after iontophoresis was practically doubled, as
assessed by tape stripping [2].
Water plays an important role in the application and functioning
of the Patch-non-Patch®. It was shown that the presence
of water on the skin surface is necessary not only for skin
adhesion but also for the performance of the system, because in the
absence of water the stratum corneum skin accumulation was
significantly reduced, as assessed using the tape stripping
technique [2]. In a subsequent paper [10] it was shown that the
absolute amount of water used for film application is not so
critical, because it did not affect sumatriptan in vitro skin
penetration when varying from 7.5 to 30 μL/cm2.
The evaporation kinetics of water from the patch was evaluated
in vivo, by measuring the TEWL (trans epidermal water loss), on the
patch applied on an impermeable surface, such as parafilm, kept at
the same temperature as the skin surface. The result obtained,
illustrated in figure
5, shows that water used for patch application (12
μL/cm2) evaporated from the patch during the first hour
of application. When the same experiment was performed on the skin
the kinetics was comparable, indicating that also in vivo the
amount of water used for film application evaporates during the
first hour of application and then the film remains in the dried
form on the skin surface. The same experiment showed also that the
film is not occlusive on the skin surface up to 24 hour of
application [3]. Water evaporation from the skin surface has been
also evoked as the reason why the permeation profiles tend to
flatten in the later times of the experiment. This was particularly
evident in the case of sumatriptan [10] and oxybutynin [8], while
it was less pronounced with lidocaine [2] and caffeine [6].
Second generation: the occlusive
Patch-non-Patch®
Occlusion (i.e. the application of an impermeable backing on the
surface of the formulation to avoid water evaporation) is known to
improve drug penetration [4], although to a different extent
according to the physico-chemical properties of the permeant. The
second generation of the Patch-non-Patch® is
characterized by being occlusive on the skin, thus limiting the
evaporation of water, both that used for film application and that
produced by the TEWL. In the case of sumatriptan [10] and
oxybutynin [8], drug transport increased dramatically with
occlusion, while lidocaine was less sensitive to the effect of
occlusion [12]. The oxybutyinin bioadhesive film can be a promising
and innovative therapeutic system for the transdermal
administration of oxybutynin. When the film was applied in
occlusive conditions the release profiles were much higher than in
non-occlusive conditions, reaching 50% of drug permeated after
24 h, as can be seen in figure 6. Compared to the
commercial patch Oxytrol®, the film was more efficient
up to 24 h of application [8].
Conclusion
From the results presented, it appears that the technology
Patch-non-Patch® has the potentiality to be successfully
applied to the pharmaceutical and cosmetic market. On the skin the
film is flexible, invisible and adapts to all skin irregularities.
The system has been shown to be highly efficient, releasing a high
percentage of the active included in most cases. Additionally, the
inclusion of other excipients can modulate drug delivery, thus
improving the versatility of the product. Finally, the second
generation Patch-non-Patch®, made occlusive on the skin
surface, can further broaden the potential application.
Acknowledgements
Lisapharma S.p.A. (Como, I) is gratefully acknowledged for
supporting this work.
References
1 http://patchnonpatch.awardspace.com.
2 Padula C, Colombo G, Nicoli S,
Catellani PL, Massimo G, Santi P. Bioadhesive film
for the transdermal delivery of lidocaine: in vitro and in vivo
behavior. J Control Release 2003; 88(2): 277-85.
3 Nicoli S, Colombo P, Santi P. Release and
permeation kinetics of caffeine from bioadhesive transdermal films.
AAPS J 2005; 7(1): E218-E223.
4 Zhai H, Maibach HI. Occlusion vs. skin barrier
function. Skin Res Technol 2002; 8(1): 1-6.
5 Fauth C, Wiedersberg S, Neubert RH,
Dittgen M. Adhesive backing foil interactions affecting the
elasticity, adhesion strength of laminates, and how to interpret
these properties of branded transdermal patches. Drug Dev Ind Pharm
2002; 28(10): 1251-9.
6 Nicoli S, Amoretti V, Colombo P, Santi P.
Bioadhesive transdermal film containing caffeine. Skin Pharmacol
Physiol 2004; 17(3): 119-23.
7 Padula C, Rizzo P, Amoretti V, Colombo P, Santi 4th P. World
Meeting on Pharmaceutics, Biopharmaceutics, Pharmaceutical
technology, Firenze, 2002.
8 Nicoli S, Penna E, Padula C, Colombo P,
Santi P. New transdermal bioadhesive film containing
oxybutynin: In vitro permeation across rabbit ear skin. Int J Pharm
2006; 325(1-2): 2-7.
9 Cella S, Nicoli S, Santi P. Controlled Release
Society. Miami. 2005.
10 Femenia-Font A, Padula C, Marra F,
Balaguer-Fernandez C, Merino V, Lopez-Castellano A,
Nicoli S, Santi P. Bioadhesive monolayer film for the in
vitro transdermal delivery of sumatriptan. J Pharm Sci 2006; 95(7):
1561-9.
11 Pappani A, Padula C, Marra F, Santi P. 5th World Meeting on
Pharmaceutics, Biopharmaceutics ad Pharmaceutical Technology,
Geneva (CH), 2006.
12 Padula C, Nicoli S, Colombo P, Santi P. Single-layer
transdermal film containing lidocaine: modulation of drug release.
Eur J Pharm Biopharm (in press). 11.
|
Printable version
Version PDF
