SYSTEME THERAPEUTIQUE TRANSDERMIQUE AVEC PROTECTION CONTRE L'HYDROLYSE

TRANSDERMAL THERAPEUTIC SYSTEM WITH PROTECTION AGAINST HYDROLYSIS

Abrégé français

L'invention concerne un système thérapeutique transdermique (TTS) comprenant un principe actif sensible à l'hydrolyse et une couche dorsale imperméable à l'humidité et au principe actif, qui présnte une structure en couches, ainsi qu'une matrix contenant le principe actif et, le cas échéant, une couche protectrice qui recouvre la matrice. Ce système thérapeutique transdermique se caractérise en ce que la matrice contient un constituant hygroscopique.

Abrégé anglais

A transdermal therapeutic system (TTS) comprising an active
substance which is sensitive to hydrolysis, and having a
layer-like structure comprising a backing layer impermeable
to moisture and active substance, a matrix comprising the
active substance, and optionally a protective layer
covering the matrix is characterised in that the matrix contains
a water-binding component.

Revendications

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Claims:
1. Transdermal therapeutic system (TTS) comprising an active substance which
is
sensitive to hydrolysis and having a layered structure comprising a backing
layer
impermeable to moisture and active substance, a matrix comprising the active
substance,
and optionally a protective layer covering the matrix, characterised in that
the matrix
comprises a water-binding component which is a water-binding mineral substance
or a
water-binding non-mineral substance, and wherein the portion of said water-
binding
component in the entire matrix material amounts to at least 1%-wt.
2. The transdermal therapeutic system according to claim 1, characterised in
that the
matrix comprises several layers, and at least one layer contains the water-
binding
component.
3. The transdermal therapeutic system according to claim 1, characterised in
that the
water-binding component is of mineral nature.
4. The transdermal therapeutic system according to claim 1, characterised in
that the
water-binding component is of non-mineral nature.
5. The transdermal therapeutic system according to claim 1 or 2 characterised
in that
the matrix or one of its layers comprises an acrylic acid ester copolymer, a
poly-
isobutylene, an ethylene-vinyl-acetate polymer, or styrene-isoprene block
polymer, or a
synthetic isoprene-isobutylene copolymer, or a hot-melt adhesive.
6. The transdermal therapeutic system according to any one of claims 1 to 5,
characterised in that the active substance is acetylsalicylic acid and is
present in the
matrix in dissolved or dispersed form.
7. The transdermal therapeutic system according to claim 1, characterised in
that the
active substance is bopindolol, and is present in the matrix in dissolved or
dispersed form.

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8. The transdermal therapeutic system according to any one of claims 1 to 7,
characterised in that the water-binding component portion in the entire matrix
material
amounts to 5 to 30%-wt.
9. The transdermal therapeutic system according to any one of claims 1 to 8,
characterised in that the mineral water-binding component is the anhydrate of
an earth
alkaline metal salt or alkali metal salt.
10. The transdermal therapeutic system according to any one of claims 1 to 8,
characterised in that the mineral water-binding component is the semihydrate
or the
anhydrate of calcium sulfate.
11. The transdermal therapeutic system according to any one of claims 1 to 10,
characterised in that the matrix material contains the water-binding component
in a finely
dispersed suspension.
12. The transdermal therapeutic system according to say one of claims 1 to 11,
characterised in that the active substance is present as a dispersion of a
water-free
crystallizate.
13. The transdermal therapeutic system according to any one of claims 1 to12,
characterised in that it is present in the form of a semi-solid preparation.
14. The transdermal therapeutic system according to any one of claims 1 to 13,
characterised in that it is present in the form of a patch and comprises a
suitable backing
layer, an active substance reservoir connected thereto, in the absence of
other control
mechanisms a membrane controlling the release of the active substance, a
pressure-
sensitive adhesive device for affixing the system on the skin, and,
optionally, a protective
layer which is removable prior to application of the system.

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13. The transdermal therapeutic system according to any one of claims 1 to 14,
characterised in that it comprises at least one polymer matrix layer.
16. The transdermal therapeutic system according to claim 15, characterised in
that at
least one of the polymer matrix layers comprises an acrylic acid copolymer.
17. The transdermal therapeutic system according to claim 15, characterised in
that
the active substance reservoir is present in liquid or semi-solid state of
aggregation.
18. The transdermal therapeutic system according to claim 15, characterised in
that
the active substance reservoir contains an oleogel.
19. The transdermal therapeutic system according to any one of claims 1 to 18,
characterised in that it is present in a pack in a gas-tight sealed package or
means of
packaging, and that the package or means of packaging is rendered water vapour-
resistant
to maintain the water-binding capacity of the water-binding additive over the
storage
period.
20. The transdermal therapeutic system according to claim 19, characterised in
that
the package or means of packaging additionally contains a drying agent.

Description

2198092
TRANSDERMAL THERAPEUTIC SYSTEM WITH PROTECTION AGAINST
HYDROLYSIS
In the galenic conversion of a pharmaceutical into a drug
form, the stabilisation of pharmaceuticals or adjuvants
that are sensitive to hydrolysis is a matter of widespread
concern. In the following, the term "hydrolysis" is under-
stood to mean the cleavage of a substance through the
effect of water. This applies, in particular, to the hydro-
lytic cleavage of esters, acetals, ketals, aminals, and the
hydrolytic cleavage of peptide pharmaceuticals.
Generally, protection against hydrolysis can be achieved by
the following methods:
1. Adjusting a particular pH value, which - according to
experimental findings - results in the lowest possible rata
constant for the degradation of the component (1) which is
sensitive to hydrolysis.
2. Forming complex bounds of the active component which
is sensitive to hydrolysis by addition of suitable
reactants (2) capable of complex formation. This leads to
stabilisation in all those cases where the hydrolytic
degradation takes place exclusively in the hydrolysis-
sensitive component which is not present as a complex.
3. Decreasing the solubility of the hydrolysis-sensitive
component in a medium by controlled addition of suitable
substances (3, 4). Examples for this are the pH adjustment
by buffer solutions and the formation of insoluble deriva-
tives that have no propensity for solvolysis.

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2
4. Removing water from the drug form or maintaining as
far as possible an almost water-free environment of the hy-
drolysis-sensitive active component in a drug form (5).
All of the above-mentioned approaches 1-4 are of great im-
portance in the pharmaceutics industry and are more or less
common, depending on the form of drug. Most of these are
only partially suitable for the transdermal application of
pharmaceuticals by so-called transdermal therapeutic
systems. The transdermal availability of a pharmaceutical
is first of all dependent on its physicochemical
properties. Mostly, these are negatively affected by pH
changes, complexation, and by derivatisation, which is why
the above-mentioned methods 1-3 are suitable only in
certain cases.
The safest method is therefore to keep the active ingre-
dient which is embedded (dissolved or dispersed) in a
transdermal therapeutic system in a largely water-free
environment.
The prior art known in respect of this topic can be
described by two methodical approaches:
a) The production of single-dose drugs comprising a
hydrolysis-sensitive pharmaceutical or adjuvant takes place
under exclusion of moisture (water or water vapour) and
employing primary and secondary means of packaging or
packages which represent a migration barrier for the
moisture present in the environment during storage and
which thereby maintain the interior of the package
containing the hydrolysis-sensitive component largely
water-free .

?_ ~ 98092
3
b) The use of water-binding substances within the secon-
dary package in order to bind the moisture entering the
package during storage and thereby to minimise the moisture
content within the primary package.
c) The use of water-binding substances within the primary
package, for example by water-binding drying agents inte-
grated in the lid of the vessel.
By contrast to most other drug forms, in transdermal thera-
peutic systems the primary package has an extremely large
surface area. Furthermore, patch-like transdermal therapeu-
tic systems cannot be bent or folded to keep the surface
area of the package as small as possible. Thus, in such
systems the primary package provides a correspondingly
large boundary surface for the migration of moisture into
the package. For this reason, methods a) to c) are not
always sufficient to ensure the required maximum moisture
content even over prolonged periods of time and under all
kinds of storage conditions, and to stabilise the
hydrolysis-sensitive ingredient.
It is therefore the object of the present invention to
stabilise transdermal therapeutic systems comprising a hy-
drolysis-sensitive active component by the fact that the
intrusion of moisture into the single-dose drug form is
largely prevented by suitable packaging material, and that
moisture which has nevertheless entered the primary package
does not lead to hydrolysis.
According to the invention, this object is achieved by the
fact that the drug form itself contains a water-binding
component. This water-binding component of the drug form in
the transdermal therapeutic system binds moisture which has
entered through the primary package, which moisture does

2198092
4
not lead to the hydrolysis of the hydrolysis-sensitive
active ingredient in the system. This applies in particular
to moisture having entered through the primary package
during storage, for example due to unfavourable storage
conditions.
Here, the manner of incorporation into the drug form and
the degree of dispersion are of no significance for the
function of binding moisture for protection against hy-
drolysis. For the use of a substance as water-binding
ingredient, the state of aggregation of the substance
before and after the incorporation is likewise of no
significance, as long as the water-binding function is
maintained.
In simple semi-solid preparations, such as ointments,
pastes or non-aqueous gals; for example, this can be
achieved by incorporation of the water-binding component,
for example by dispersion in the liquid or semi-solid
starting materials.
In patch-like transdermal systems the water-binding ingre-
dient can be incorporated in the active substance reservoir
itself or in other adhesive or reservoir layers or control-
ling membranes located in front of or behind the active
substance reservoir.
Since in the production of transdermal therapeutic systems
comprising a hydrolysis-sensitive component, water is any-
way largely excluded, it is easily possible to integrate
the incorporation of the water-binding substance in such a
system into the production process.
Further embodiments of the invention are provided in accor-
dance with the subclaims. The system may have several
layers, and at least one layer may contain a water-binding

2~9~092
component. The water-binding component may be of mineral or
non-mineral nature.
One embodiment further provides for the matrix or one of
its layers to contain an acrylic-acid ester copolymer, a
polyisobutylene, an ethylene-vinyl-acetate polymer, or
styrene-isoprene block polymer, or a synthetic isoprene-
isobutylene copolymer, or a hot-melt adhesive.
For example, the active substance may be acetylsalicylic
acid and be present in the matrix in dissolved or dispersed
form.
Further, the active substance may be bopindolol and be
present in the matrix in dissolved or dispersed form.
Advantageously, the water-binding component portion of the
entire matrix material amounts to at least 1%-wt., prefer-
ably up to 30%-wt.
A further embodiment provides that the mineral water-bind-
ing portion is the anhydrate (i.e. the water-free form) of
an earth alkaline metal salt or alkali metal salt.
In the above case, the mineral water-binding component may
be the semihydrate or the anhydrate of calcium sulfate.
It is of advantage if the matrix material contains the
water-binding ingredient in finely dispersed suspension.
Besides, the active substance may be present as a disper-
sion of a water-free crystallisate.
A further essential measure provides that the transdermal
therapeutic system is arranged in a pack in a gastight
sealed means of packaging or package and that the means of

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6
packaging or package is rendered sufficiently water vapour-
resistant to maintain the water-binding capacity of the
water-binding additive over the storage period. In
addition, the package or means of packaging may contain a
drying agent.
In the following the invention will be further illustrated
by means of examples.
Example 1:
Individually dosed acetylsalicylic acid-comprising oleogel
A homogeneous mixture of 26 g acetylsalicylic acid (finely
pulverised) and 10 g micronized calcium sulfate are
dispersed, while stirring, in 26 g Miglyol~ 812. The
resultant dispersion is converted into an oily gel-like
dispersion by successive addition of up to 7 g hydrophobic,
colloidal silicic acid. The dispersion is immediately dosed
into suitable flat bags, the flat bag being subsequently
sealed gastight.
Example 2:
Acetylsalicylic acid-containing transdermal therapeutic
system
g acetylsalicylic acid (finely pulverised) and 15 g
micronised calcium sulfate are processed to yield a
homogeneous powder mixture, which is subsequently worked
into 200 g solvent-containing polyacrylate while stirring.
The resultant suspension is spread onto a siliconised
polyethylene film with a 300 pm doctor knife, and the
solvents are removed by drying for 20 minutes at 80°C. The
adhesive film is covered with a polyester film. The so-

219092
obtained compound is cut to the required size with the aid
of cutting tools, and is introduced in the primary package
or means of packaging in a largely water-free atmosphere
and welded so as to be gastight.