U.S. patent application number 10/838995 was filed with the patent office on 2004-10-21 for device for and method of increasing the transdermal permeation of drugs.
Invention is credited to Adam, Bernd, Falkenhausen, Christian von, Koch, Andreas, Matusch, Rudolf.
Application Number | 20040208918 10/838995 |
Document ID | / |
Family ID | 7908799 |
Filed Date | 2004-10-21 |
United States Patent
Application |
20040208918 |
Kind Code |
A1 |
Koch, Andreas ; et
al. |
October 21, 2004 |
Device for and method of increasing the transdermal permeation of
drugs
Abstract
The invention relates to a device and a method for increasing
the transdermal permeation of medicaments. The invention is
characterized in that a constituent which effects a local increase
in temperature and/or an increase in blood flow of the skin is
administered in addition to the transdermally applied active
substance.
Inventors: |
Koch, Andreas; (Melsbach,
DE) ; Falkenhausen, Christian von; (Meckenheim,
DE) ; Matusch, Rudolf; (Marburg, DE) ; Adam,
Bernd; (Treysa, DE) |
Correspondence
Address: |
FROMMER LAWRENCE & HAUG
745 FIFTH AVENUE- 10TH FL.
NEW YORK
NY
10151
US
|
Family ID: |
7908799 |
Appl. No.: |
10/838995 |
Filed: |
May 5, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10838995 |
May 5, 2004 |
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09979251 |
Nov 19, 2001 |
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6756052 |
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09979251 |
Nov 19, 2001 |
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PCT/EP00/04460 |
May 17, 2000 |
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Current U.S.
Class: |
424/449 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/485 20130101; A61K 9/7092 20130101; A61K 9/703 20130101;
A61K 9/7084 20130101; A61K 31/565 20130101; A61K 9/7038 20130101;
Y10S 514/947 20130101 |
Class at
Publication: |
424/449 |
International
Class: |
A61K 009/70 |
Foreign Application Data
Date |
Code |
Application Number |
May 21, 1999 |
DE |
199 23 427.2 |
Claims
1-19 (cancelled)
20. A method for increasing the transdermal absorption rate of an
active substance to a person in need thereof said method comprises:
a) releasing the active substance in a controlled manner from a
transdermal therapeutic system (TTS) to the skin of a person, b)
providing a local temperature increase of the skin by applying at
least one substance to the skin which increases i. the rate of
penetration of said active substance into the skin, ii. the travel
of said active substance through the different layers of the skin,
iii. the transport of said active substance through the blood
capillary system of the dermis, and/or iv. the transport of the
active substance through the blood vessels of the hypodermis, and
c) allowing said active substance to enter the circulation.
21. The method according to claim 20 wherein said active substance
is a pharmaceutically active substance that is capable to exert a
systemic action.
22. The method according to claim 20 wherein said active substance
is selected from the group consisting of opiates, morphine,
diamorphine, buprenorphine, fentanyl, estrogens,
17.beta.-estradiol, hormones, testosterone, norethisterone,
gestagens, peptides, insulin, analgetics and alkaloids.
23. The method according to claim 20 wherein said transdermal
therapeutic system comprises one or more of an active substance
impermeable backing layer, an active substance reservoir, an active
substance release controlling membrane, an adhesive layer
containing active substance, and a redetachable protective
layer.
24. The method according to claim 20 wherein said method provides a
long-term effect throughout the duration of the transdermal
administration of said active substance.
25. A method according to claim 20 wherein said method extends over
a period of at least 8 hours.
26. A method for reducing the period between the application of a
transdermal therapeutic system (TTS) to the skin of a person and
the onset of a pharmacological effect of an active substance said
method comprises: a) releasing the active substance in a controlled
manner from said TTS to the skin of said person, b) providing a
local temperature increase of the skin by applying at least one
substance to the skin which increases i. the rate of penetration of
said active substance into the skin, ii. the travel of said active
substance through the different layers of the skin, iii. the
transport of said active substance through the blood capillary
system of the dermis, and iv. the transport of the active substance
through the blood vessels of the hypodermis, and c) allowing said
active substance to enter the circulation.
27. A method according to claim 26 wherein said active substance is
a pharmaceutically active substance that acts systematically.
28. A method according to claim 26 wherein said active substance is
selected from the group consisting of opiates, morphine,
diamorphine, buprenorphine, fentanyl, estrogens,
17.beta.-estradiol, hormones, testosterone, norethisterone,
gestagens, peptides, insulin, analgetics and alkaloids.
29. A method according to claim 26 wherein said transdermal
therapeutic system comprises one or more of an active substance
impermeable backing layer, an active substance reservoir, an active
substance release controlling membrane, an adhesive layer
containing active substance, and a redetachable protective
layer.
30. A method according to claim 26 wherein said method provides a
short-term effect up to the onset of the pharmacological effect of
said active substance.
Description
[0001] The invention relates to a device for and to a method of
increasing the dermal and/or transdermal permeation of drugs.
[0002] The transdermal administration of pharmaceutical active
substances has been known from the time of the first commercial use
of a scopolamine transdermal therapeutic system (Scopoderm TTS).
Other active substances (nitroglycerine, estradiol, clonidine,
isosorbide dinitrate, fentanyl, nicotine, norethisterone etc.) as
well are now offered in the form of such a TTS. These active
substance patches are adhered to the skin of a patient. The active
substance is then released in a controlled manner from the TTS to
the skin of the patient, travels through the various layers of the
skin, and, finally, enters the circulation.
[0003] A problem with this mode of administration of a substance
having a systemic action is very frequently that the path taken by
the active substance through the differently constructed layers of
the skin is very long and the transport of the active substance
until it enters the circulation is time-consuming. There are a
number of reasons for this. First, the skin possesses a natural
barrier function against the penetration of foreign substances into
the body. Secondly, substances having a very large molecular radius
possess only a low diffusion coefficient. The latter is a measure
of the ability of a substance to travel within a medium; in the
case in hand, therefore, the permeation behavior within the skin
layers. And, finally, physico-chemical interactions (for example,
polar interactions, dipole-dipole interactions, etc.) between the
active substance and the various constituents of the different skin
layers may lower the rate of diffusion of an active substance in
the skin.
[0004] All of these phenomena may result in the percutaneous and
subsequent absorption of the active substance taking place so
slowly that a pharmacological effect occurs only with considerable
time delay. This period between the application of a TTS to the
skin of the patient and the onset of the pharmacological effect is
referred to by the skilled worker as the lag time.
[0005] Almost logically, therefore, enhancing the percutaneous
permeation of a transdermally administerable active substance has
been the subject of extensive research work, especially by the
pharmaceutical industry. It has led to the use of a very wide
variety of substances which improve skin penetration (known as
enhancers) and to the development of specific substances, e.g.,
Azone.RTM.. Enhancers include alcohols, amides, amino acids,
derivatives of Azone.RTM., essential oils, fatty acids and fatty
acid derivatives such as fatty acid esters, macrocyclic compounds,
phospholipids, pyrrolidones, sulfoxides, and others.
[0006] When such enhancers are given, the increase in skin
penetration (or, more precisely, the acceleration of an active
substance's entry into and travel through the various skin layers
and thus, ultimately, the raising of the transdermal absorption
rate as well) is essentially achieved by virtue of the fact that
these enhancers penetrate the uppermost layers of the skin, where
they alter the structure of the skin in such a way that its barrier
function is no longer fully effective. This mode of action is
explained at the molecular level as follows: the enhancers
incorporate themselves into biological membranes and alter the
natural structure of lipids and proteins--causing them, for
example, to swell. The active substance applied to the skin is then
able to travel more easily, i.e. more quickly, through the
different layers of the skin.
[0007] The use of the prior art enhancers, however, also possesses
many disadvantages. First of all, the enhancer must not be toxic
and must not cause any physiological side effects. Further, there
must be no chemical or physical incompatibilities between enhancer
and both the active substance and the other materials constituting
the TTS. Finally, the enhancer must be present in the TTS in an
amount such that the permeation-intensifying effect is retained
over the entire period of its application (generally from 16 to 24
hours, although there are also 3-day plasters already available).
An inevitable result of this, however, is often that said enhancer
is administered to the patient likewise in amounts such as to cause
a systemic effect.
[0008] It is an object of the present invention to accelerate the
penetration of an active substance into the skin and/or the travel
of this active substance through the different layers of the skin
and/or the transport of this active substance through the blood
capillary system of the dermis and/or the blood vessels of the
hypodermis in such a way that absorption through the skin takes
place more rapidly and thus a reduction in the lag time is
achieved. In particular, practical transdermal application should
be made accessible to active substances which by their nature
exhibit a long lag time for absorption through the skin.
[0009] This object is achieved by a device which comprises a
component which brings about a local temperature increase in the
skin and/or increases the circulation. The device of the invention
can be, for example, an ointment, a solution, a suspension, an
emulsion, a foam, a paste, a gel or a patch, a patch of this kind
being a preferred embodiment.
[0010] The invention further provides a method which comprises
achieving an increase in the rate of penetration of an active
substance into the skin and/or of travel of this active substance
through the different layers of the skin and/or of transport of
this active substance through the blood capillary system of the
dermis and/or the blood vessels of the hypodermis by means of a
local temperature increase and/or an increase in the circulation of
the skin. In this way, ultimately, the transdermal absorption rate
of said active substance is increased and the lag time to the onset
of a pharmacological effect of said active substance is
reduced.
[0011] The use of substances which bring about a local temperature
increase in the skin for the purpose of increasing the rate of
penetration of an active substance into the skin and/or of travel
of this active substance through the different layers of the skin
and/or of transport of this active substance through the blood
capillary system of the dermis and/or the blood vessels of the
hypodermis is likewise provided by the present invention. It is
possible to achieve either a short-term effect (that is, up to the
onset of the pharmacological effect) or a long-term effect (that
is, throughout the duration of transdermal administration of the
active substance in question).
[0012] Further elucidation of the invention is aided by the
following definitions:
[0013] Skin refers to the uninjured, i.e., undamaged, unshaved skin
of a mammal, especially that of a human, said skin having its
normal hair cover. For the purposes of this invention, the term
skin does not include mucous membrane. Normal skin consists
essentially of three layers: the epidermis (situated externally),
the dermis, and the hypodermis (which is situated below). The
hypodermis is also referred to as the subcutis. The epidermis in
turn is composed of the stratum corneum, stratum lucidum, stratum
granulosum, stratum spinosum and stratum germativum. The dermis
contains, inter alia, the blood capillary system. The hypodermis
houses the blood vessels.
[0014] Penetration refers to the penetration of an active substance
into the outer layers of the skin, especially into those of the
epidermis. Permeation refers to the travel of the active substance
through the skin, especially through the epidermis (including the
stratum corneum) and the dermis.
[0015] The term dermal administration as used in the present
description means that an active substance is applied to the skin
and develops a local or regional (i.e., topical) action in the
epidermis and/or dermis. Transdermal administration in the present
description means that an active substance is applied to the skin,
passes through the epidermis and/or dermis into the blood stream or
into the lymph system, is distributed from there throughout the
body, and develops a systemic action at the target site.
Transdermal absorption is used to denote the takeup of an active
substance by the under-skin blood vessels following transdermal
administration, thereby permitting a systemic action of the active
substance taken up.
[0016] Active substances for the purposes of the present invention
are essentially pharmaceutical and/or cosmetic active substances
which serve to prevent, alleviate, heal or reveal disorders. They
include substances which are able to exert a topical and/or
systemic action. Active substances are known to the skilled worker
and can be found in standard works, such as, for example, the
German "Red List" (pharmaceutical active substances) and "Green
List" (cosmetic active substances). Further active substances are
specified in U.S. Pat. No. 4,557,934 and in the sources cited
therein (col. 10, lines 18-35). In order to avoid repetition, the
content of that patent insofar as it refers to active substances is
considered part of the disclosure of the present invention by
reference. In principle, the nature of the active substance is not
critical to the present invention. The term active substance should
therefore not be interpreted in a manner which restricts the
subject matter of the invention.
[0017] Active substances which by their nature exhibit a long lag
time on absorption through the skin include the following: opiates
such as, for example, morphine, diamorphine, buprenorphine;
fentanyl, estrogens such as, for example, 17.beta.-estradiol;
hormones such as, for example, testosterone, norethisterone,
gestagens; peptides such as, for example, insulin; analgesics; and
alkaloids. This type of systemic active substance can be made
amenable to transdermal administration in a particularly
advantageous way by means of the subject matter of the
invention.
[0018] The component which brings about a local temperature
increase and/or an increase in the circulation of the skin is a
substance or substance mixture which when applied to the skin
results in local heating of the skin. Such substances include
especially rubefacientia, vasodilators, and hyperemic
substances.
[0019] Rubefacientia are substances which as a consequence of
hyperemia have a skin irritant and/or skin reddening action.
Rubefacientia are therefore a particular group of hyperemic
substances. They include, for example, pelargonic acid vanillyl
amide, cayenne pepper oil resin, capsicum extract, capsicum
tincture, cayenne pepper extract, cayenne pepper, and
capsaicin.
[0020] Vasodilators are vessel widening substances which bring
about a widening of the blood vessels by, for example, relaxing the
vessel musculature. This is often accompanied by a lowering of
blood pressure. This also takes place, of course, in the peripheral
blood vessels, so producing increased blood flow through the area
affected. Vasodilators include nicotinic acid; derivatives of
nicotinic acid such as, for example, nicotinyl alcohol, benzyl
nicotinate, nicotinamide, etc.; adenosine compounds; xanthine,
derivatives of xanthine such as caffeine, etc.; arnica extract,
arnica blossom extract, pyridyl-3-carbinol and its salts, camomile,
phytolacca, guaia gum, cinnabaris, creosotum, Luffa operculata, and
tincture of Rhus toxicodendron.
[0021] Hyperemic substances are substances which increase
circulation. The increase in circulation is brought about by
increased blood afflux (reactive hyperemia) or reduced blood efflux
(restriction hyperemia). This can have various causes. Hyperemic
substances include essential oils, menthol, camphor, nicotinic
esters, salicylic esters, hydroxyethyl salicylate, methyl
salicylate, and ortho-carbamoylphenoxyacetic acid.
[0022] The heat effect in the skin is, therefore, brought about
essentially by an improvement in the circulation to the peripheral
blood vessels (capillary system). It is not based on a heat effect
in the form, for example, of thermal conduction, ultrasound,
thermal radiation, etc., being exerted on the skin from the
outside. There is no transport of energy from an external energy
source into the skin.
[0023] Devices of the abovementioned kind are produced in a known
manner where the device in question is an ointment, solution,
suspension, emulsion, foam, paste, aerosol, or gel. All that must
be done is to incorporate the component which brings about a local
temperature increase in the skin into the active substance
composition in an appropriate process step. Said ointment,
solution, suspension, emulsion, foam, paste, aerosol or gel can be
applied to the skin area in question directly prior to application
of the active substance TTS. It can also be applied to the skin
around the TTS following application of the latter.
[0024] Owing to the difficulty in controlling the amount applied in
this case of the component which brings about a local temperature
increase of the skin, and owing to any concomitant adhesion
problems of the TTS on the skin, the preferred embodiment is, as
stated, a patch.
[0025] A patch of this kind, i.e., a dermal or transdermal
therapeutic system, can comprise the following structural elements:
an active substance impermeable backing layer, an active substance
reservoir, an active substance release controlling (semipermeable
or microporous) membrane, an adhesive layer containing active
substance, and a redetachable protective layer (known as the
release liner).
[0026] In accordance with the invention, the component which brings
about a local temperature increase and/or circulation increase in
the skin can be present in the active substance reservoir and/or in
the adhesive layer containing active substance. Alternatively, in
order to avoid incompatibilities but also as a preferred
embodiment, the component which brings about a local temperature
increase of the skin can also be present in a structural element of
the device which is spatially separate from the structural elements
containing active substance.
[0027] The simplest embodiment of this case is a pressure sensitive
adhesive layer which comprises the component that brings about a
local temperature increase and/or increase in circulation in the
skin and which is equipped with a backing layer impermeable to said
component. In this embodiment, the device consists of two separate
devices, namely an active substance release device and the device
containing the component which brings about a local temperature
increase and/or circulation increase in the skin. The active
substance release device, an active substance TTS for example, is
applied first of all to the skin of the patient. Then the device
containing the component which brings about a local temperature
increase of the skin is placed atop it and judicially fixed--for
example, by means of a pressure sensitive adhesive layer located on
the bottom, pressure sensitive adhesive strips located on the edge
of the device, or a further, cover patch.
[0028] Likewise preferred is an embodiment in which an outer
segment containing the component which brings about a local
temperature increase and/or circulation increase in the skin is
disposed around an inner segment which contains the active
substance intended for transdermal administration. The form of the
inner segment is in principle not critical; it can be circular,
rectangular or square. The form of the outer segment is likewise in
principle not critical; it can also be circular, rectangular or
square. Alternatively, the outer segment can be disposed around the
inner segment in the form of a ring or as two or more sections
which are, for example, rectangular or semicircular. This
embodiment is particularly suitable since it profits from the
formation of a horizontal concentration gradient in the epidermis
and in the dermis/subcutis. Although this so-called lateral
diffusion can be derived from the structure of the stratum corneum
with its lamellar lipid-water bilayers, this phenomenon has,
surprisingly, to date not been considered by those skilled in the
art for a practical implementation in terms of increasing the rate
of penetration into the skin and/or of travel through the skin, in
particular for increasing the transdermal absorption rate of an
active substance applied to the skin.
[0029] In this advantageous embodiment, the outer segment overhangs
the inner segment to a considerable extent; for example, by several
millimeters (e.g.: from 5 to 25) or by the length of the diameter
of the inner segment. In this way, the principle responsible for
the increase in the transdermal absorption rate of the active
substance acts on an area which projects beyond the mere release
area of the transdermally administered active substance.
[0030] The area of the pressure sensitive adhesive layer, or of the
outer segment, which contains the component which brings about a
local temperature increase and/or increase in the circulation of
the skin is generally smaller than 100 cm.sup.2.
[0031] A preferred embodiment of this kind can likewise be produced
by processes known to the skilled worker, as described, for
example, in DE 37 14 140, DE 38 09 978 and DE 4110027. In order to
avoid repetition, the relevant section of the disclosure contents
of these documents has not been reproduced here but is considered
to be incorporated by reference. It is clear that when producing
the outer segment the component which brings about a local
temperature increase of the skin must be incorporated into the
matrix forming the outer segment, in the appropriate working step.
The spatial separation of the segments containing the component
which brings about a local temperature increase and/or circulation
increase in the skin from the segments containing the active
substance intended for transdermal administration is achieved by
horizontal or vertical barrier layers or material voids.
[0032] Depending on the amount of the component which brings about
a local temperature increase and/or circulation increase in the
skin, the action of the device of the invention may extend over a
relatively long period: for example, about 8, 16, 24, 48 or even 72
hours. The device of the invention is applied to the skin of the
patient under normal conditions, i.e., at normal--that is, not
increased--external skin temperature. Alternatively, the device of
the invention can be applied before and during an iontophoresis
treatment.
[0033] Within the device, the amount of the substance which is able
to bring about a local temperature increase and/or circulation
increase in the skin depends on whether the desire is for a
short-term effect, until the onset of the pharmacological effect,
or a long-term effect, throughout the duration of the transdermal
administration of the active substance in question.
[0034] It is also guided in each specific case by the specific
properties of the substance. In general, therefore, the amount of
this substance within the device is between 0.5 and 20% by
weight.
[0035] The device of the invention is preferably free from
permeation enhancers, i.e., substances which by intervening in the
structure of the skin achieve an improvement in the skin permeation
of a dermally administered active substance, but may, if desired,
comprise such substances. A list of these substances can be found
from the article by D. W. Osborne and J. J. Hill on "Skin
penetration enhancers cited in the technical literature" on the
Internet website http://pharmtech.com/techni-
cal/osborne/osborne.htm.
[0036] The examples which follow serve to elucidate the mode of
action of the invention.
EXAMPLE 1
[0037] Three samples of a commercially available estradiol active
substance patch (Vivelle.RTM.) were each applied centrally to
circular specimens of complete human skin, measuring 4.52 cm.sup.2.
The skin samples thus prepared were placed for 72 h in modified
Franz cells, there being no acceptor medium, so as to avoid
artefacts as a result of back-diffusion into the cells. After the
end of this time, the active substance patches were removed and the
skin below the application site was punched out exactly. Further
circular segments were punched out from the skin sample, each
situated further and further from the core segment, that is, the
actual release area of the TTS.
[0038] The skin samples obtained in this way were subsequently
extracted with methanol for 16 h and assayed for residual
estradiol. A horizontal concentration profile was found which was
also statistically significant. The results of the residue assay
are given in Table 1. The horizontal concentration profile found is
reproduced in FIG. 4.
1 TABLE 1 Skin segment R1 R2 R3 R4 Residual content in
.mu.g/cm.sup.2 8.62 5.16 0.23 0.06 Key: R1 = skin segment directly
below the TTS application area (= 1.13 cm.sup.2) R2 = 1st skin
segment outside the TTS core segment (= 1.41 cm.sup.2) R3 = 2nd
skin segment outside the TTS core segment (= 1.98 cm.sup.2) R4 =
3rd skin segment outside the TTS core segment (= 2.54 cm.sup.2)
EXAMPLE 2
[0039] An in vivo animal experiment was performed on two groups of
rats each containing n=6 animals. Each of the animals from both
groups had adhered to it a TTS containing a poorly absorbable
active substance (morphine base).
[0040] In the animals of the first experimental group, a cover
patch containing an effective amount of a component which brings
about a local temperature increase of the skin (ABC patches from
Beiersdorf, Hamburg (DE)) was applied over the actual active
substance release TTS. The effective substances of said cover patch
are capsaicin and arnica extract. The areal skin contact of the
cover patch in comparison to that of the active substance release
TTS was 3 to 1.
[0041] The animals of the second experimental group (the control
group) received as cover patch a self-adhesive occlusive film
without a component which brings about a local temperature increase
of the skin (Opraflex from Lohmann, Neuwied (DE)). The areal skin
contact of the cover patch in comparison to that of the active
substance release TTS was likewise 3 to 1.
[0042] After the end of the 24-hour period of wear, the patch
dressings were removed and were assayed for residues of morphine
base. The results are summarized in Table 2 and show that the use
of a cover patch containing an effective amount of a component
which brings about a local temperature increase of the skin
increased the transdermal absorption rate from 5.7 to 26.4%.
2TABLE 2 TTS Initial amount Residue Released Experimental group
with Opraflex cover patch Verum 1 546.7 .mu.g/cm.sup.2 506.6
.mu.g/cm.sup.2 40.1 .mu.g/cm.sup.2 Verum 2 546.7 .mu.g/cm.sup.2
514.2 .mu.g/cm.sup.2 32.5 .mu.g/cm.sup.2 Verum 3 546.7
.mu.glcm.sup.2 538.8 .mu.g/cm.sup.2 7.9 .mu.g/cm.sup.2 Verum 4
546.7 .mu.g/cm.sup.2 528.0 .mu.g/cm.sup.2 18.7 .mu.g/cm.sup.2 Verum
5 546.7 .mu.g/cm.sup.2 494.9 .mu.g/cm.sup.2 51.8 .mu.g/cm.sup.2
Verum 6 546.7 .mu.g/cm.sup.2 510.0 .mu.g/cm.sup.2 36.7
.mu.g/cm.sup.2 Mean: 515.4 .mu.g/cm.sup.2 31.3 .mu.g/cm.sup.2 This
gives a relative absorption rate of 5.72%. Experimental group with
ABC-Wrme-Pflaster N cover patch Verum 1 546.7 .mu.g/cm.sup.2 364.7
.mu.g/cm.sup.2 182.0 .mu.g/cm.sup.2 Verum 2 546.7 .mu.g/cm.sup.2
354.6 .mu.g/cm.sup.2 192.1 .mu.g/cm.sup.2 Verum 3 546.7
.mu.g/cm.sup.2 442.9 .mu.g/cm.sup.2 103.8 .mu.g/cm.sup.2 Verum 4
546.7 .mu.g/cm.sup.2 447.9 .mu.g/cm.sup.2 98.8 .mu.g/cm.sup.2 Verum
5 546.7 .mu.g/cm.sup.2 446.8 .mu.g/cm.sup.2 99.9 .mu.g/cm.sup.2
Verum 6 546.7 .mu.g/cm.sup.2 359.0 .mu.g/cm.sup.2 187.7
.mu.g/cm.sup.2 Mean : 402.7 .mu.g/cm.sup.2 144.1 .mu.g/cm.sup.2
This gives a relative absorption rate of 26.4%.
[0043] This result is all the more surprising since this method of
improving the permeation of a transdermally administerable active
substance through the skin is neither a chemical nor another
invasive process which permanently damages the skin. Therefore,
there is no intervention in the structure of the skin, especially
the epidermis, and so neither is there any need to activate the
"self-repair" mechanism of the skin.
[0044] On the basis of a local temperature increase and/or
circulation increase of the skin, therefore, the device and the
method bring about an increase in the rate of penetration into the
skin and/or an increase in the travel through the skin and/or an
increase in the transdermal absorption rate of an active substance
applied to the skin.
[0045] Embodiments of the invention are elucidated using FIGS. 1 to
3.
[0046] FIG. 1 shows an embodiment in which the component which
brings about a local temperature increase and/or circulation
increase in the skin is present in the same reservoir and in the
same pressure sensitive adhesive layer as the active substance
intended for transdermal administration. The reference symbols have
the following meanings: 11=skin, 12=active substance impermeable
backing layer, 13=reservoir containing the active substance
intended for transdermal administration and, if appropriate, the
component which brings about a local temperature increase and/or
circulation increase in the skin, 14=semipermeable or microporous
membrane for controlling active substance release, 15=pressure
sensitive adhesive layer containing the active substance intended
for transdermal administration and the component which brings about
a local temperature increase and/or circulation increase in the
skin.
[0047] FIG. 2 shows an embodiment in which the component which
brings about a local temperature increase and/or circulation
increase in the skin is spatially separated by a vertical barrier
layer from the reservoir and from the pressure sensitive adhesive
layer containing the active substance intended for transdermal
administration. The reference symbols have the following meanings:
21=active substance impermeable backing layer, 22=reservoir
containing the active substance intended for transdermal
application but free from the component which brings about a local
temperature increase and/or circulation increase in the skin,
23=pressure sensitive adhesive layer containing the active
substance intended for transdermal administration but free from the
component which brings about a local temperature increase and/or
circulation increase in the skin, 24=pressure sensitive adhesive
layer containing the component which brings about a local
temperature increase and/or circulation increase in the skin,
25=vertical barrier layer.
[0048] FIG. 3 shows an embodiment in which the component which
brings about a local temperature increase and/or circulation
increase in the skin is spatially separated by a horizontal barrier
layer from the reservoir and from the pressure sensitive adhesive
layer containing the active substance intended for transdermal
administration. The reference symbols have the following meanings:
31=active substance impermeable backing layer, 32=reservoir or
pressure sensitive adhesive layer containing the active substance
intended for transdermal administration but free from the component
which brings about a local temperature increase and/or circulation
increase in the skin, 33=pressure sensitive adhesive layer
containing the component which brings about a local temperature
increase and/or circulation increase in the skin, 34=horizontal
barrier layer, 35=skin.
* * * * *
References