Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Therapeutic preparation for the transdermal application of active
substances through the skin
SPECIFICATION
The present invention relates to a therapeutic preparation for the
transdermal application of active substances through the skin
comprising additives causing an increase in the percutaneous ab-
sorption rate of active substances which can normally only insuf-
ficiently be absorbed transdermally.
One of the major problems of administration forms comprising per-
cutaneously absorbable active substances, for example, transder-
mal therapeutic systems, is to overcome the skin's natural perme-
ability barrier. It serves the epidermal protective function of the
skin and is formed by wide laminated lipid bilayers in the intercel-
lular spaces of the epidermis, it is a barrier resisting any attempt of
percutaneous absorption.
In order to overcome this problem, permeation-promoting addi-
tives, so-called classical enhancers, have already been added to
therapeutic preparations for the transdermal application of active
substances for some time now. These enhancers increase the per-
cutaneous absorption rate of lipophilic or hydrophilic medicinal
substances over a longer period of time. However, it turned out
that a number of active substances nevertheless have an insuffi-
cient percutaneous absorption rate. Occasionally, the area of a
transdermal therapeutic preparation has been enlarged to achieve
a therapeutically effective active substance flow through the skin
into the organism. However, this also results in a number of disad-
vantages; on the one hand, such a patch becomes unnecessarily
expensive both with respect to costs and production and, on the
other hand, patients find a large transdermal patch disagreeable.
When a larger skin area is covered, partial detachment of the
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patch may easily occur through play of muscles or other move-
ments of the body, this impairs the controlled active substance
flow to a considerable extent.
The mode of action of classical enhancers has not yet been re-
searched down to the last detail. However, the enhancers con-
ventionally used today are attributed physicochemical mechanisms
of action; for example, an increase of the lipid solubility through ..
modified distribution coefficients of the active substance in the
epidermal lipid bilayers, or a reduction of the diffusion coefficient
owing to an entropy decrease in the liquid-crystalline condition of
the cutaneous lipids through steric effects and polar interactions
between enhancer and cutaneous lipid.
Furthermore, it is known that the structure of the skin can also be
modified by the fact that a direct intervention in biochemical re-
generation processes, for example in the epidermis, influences the
permeability barrier of the skin. For example, a work of Proksch
tJ. Hautarzt, 1955, V. 46 N 2, pp. 76-80) describes that the topi-
cal application of the specific HMG-CoA-inhibitor LOVASTATIN
results in a decrease of the cholesterol level in the skin with a si-
multaneous increase in the transepidermal loss of water and the
DNA-synthesis in the epidermis; this disturbs the natural perme-
ability barrier of the skin.
The use of lipid-lowering substances in transdermal therapeutic
systems is mentioned in DE 36 34 016. However, this specifica-
tion of lipid-lowering substances in combination with other active
substances exclusively serves therapeutic objectives; it is not in-
tended to increase the percutaneous absorption rate of active sub-
stances which can normally only insufficiently be absorbed trans-
dermally.
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It is the object of the present invention to advance a therapeutic
preparation of the kind mentioned in the introductory part of claim
1 and to improve it in such a manner that it changes the structure
of the skin to such an extent that an increased absorption of me-
dicinal agents Bs achieved as a result of a reduced diffusion resis-
tance of the skin, in particular of the epidermis, so that even ac-
tive substances that can normally only insufficiently be absorbed
have a considerably improved rate of permeation.
In order to achieve this object, the present invention proposes that
the additives to increase the percutaneous absorption rate of a
_ preparation be HMG-CoA-reductase-inhibitors.
Thus, the effect mentioned in the work of Proksch, i.e., a distur-
bance of the skin's natural permeability barrier - which, according
- -- --to .this publication,. exclusively serves therapeutic purposes by
combining lipid-lowering substances with other active substances -
is selectively used to increase the percutaneous absorption rate of
lipophilic or hydrophilic medicinal_ agentsover a longer period by
using HMG-CoA-reductase-inhibitors with at least 0.1 but a maxi-
mum of 20 ~=wt, as permeation-promoting additives.
In contrast to classical enhancers, the present invention is based
on a biochemical principle of action with respect to the surpris-
ingly achieved permeation promotion. With a disturbed permeabil-
ity barrier in the epidermis, this principle forms a "window" over a
longer period through which medicinal agents being problematic
owing to their physicochemical properties, for example, having
molecular masses of more than 400 dalton, a high melting point,
low water-solubility or a low distribution coefficient, water/oil, can
actually overcome, in fact with added force, the skin passage
transdermally.
The suppression of the epidermal biolipid synthesis which is
caused by HMG-CoA-reductase-inhibitors also prevents that natu-
ral repair mechanisms of the epidermis to restore a disturbed
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permeability barrier, which are usual when enhancers having fat-soluble
properties are
used, fail to succeed. For this reason, the permeation-promoting effect, the
so-called
"window" within the permeability barrier, is of longer duration and thus also
of practical
significance in the transdermal therapy of medicinal substances.
The problem of skin-irritating side effects, which prevent the practical use
of many
potential enhancers and in particular also apply to HMG-CoA-reductase-
inhibitors, such
as LOVASTATIN, SIMUASTATIN, MEVASTATIN, and PROVASTATIN, is qualified
according to the present invention by the fact that a maximum of 20%-wt. of
the possible
lipid-lowering substances are used in transdermal application systems (TTS).
The present invention will be illustrated by means of the measuring results
shown in Figs.
1 and 2.
Examples of normally insufficiently absorbable active substance, in addition
to morphine
include:
Theophylline, L-thyroxine, ergotamine, D,L-kawain, D, L-warfarin.
21305083.1
CA 02235617 1998-04-23
FIG. 1 shows the influence of the lipid-lowering substance LO-
VASTATIN on the permeation rate of morphine base, using ex-
cised guinea pig skin
(released in 0.9% salt solution at T=37°C, n=3, +/- SD)
The example proves that the addition of the lipid-lowering sub-
stance LOVASTATIN, even in small amounts (2%-wt.), can double
the permeation rate after 24 h.
An increase is maintained even beyond this period (up to 48 h)
with about 80%.
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FIG. 2 shows the influence of the lipid-lowering substance LO-
VASTATIN on the permeation rate of D,L-kavain., using excised
guinea pig skin
(released in isotonic phosphate buffer pH 7.4 at T=37°C, n=3,
+/- SD)
The example proves that the addition of the lipid-lowering sub-
stance LOVASTATIN, even in small amounts (2%-wt.), can
achieve an increase in the permeation rate of an active substance
that is poorly absorbable transdermally by 70% after 24 h.
An increase is maintained even beyond this period (up to 52 h)
with 50%.
