Note: Descriptions are shown in the official language in which they were submitted.
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Acetylsalicylic acid-containing transdermal
therapeutic system with absorption enhancement
The invention relates to an acetylsalicylic acid-containing
transdermal therapeutic system with an essentially active
ingredient- and moisture-impermeable backing layer, an
active ingredient reservoir and, where appropriate, a
redetachable protective layer.
Transdermal therapeutic systems (TTS) have already been
launched on the market in the medicinal treatment of a
number of disorders.
The ability in principle of the active ingredient acetyl-
salicylic acid to permeate through the human skin and thus
be suitable as ingredient of transdermal therapeutic
systems is also known. Thus, Rougier et al. (J. Pharm. Sci.
176, 451-454, 1987) have already described the (rather low)
dependence of the rate of acetylsalicylic acid uptake into
the skin on the selected area of skin.
Acetylsalicylic acid is a relatively safe medicinal
substance with a high therapeutic index. In very high doses
(more than one gram a day) it is used as antirheumatic
agent, in intermediate doses (250-500 mg) as
antipyretic/analgesic and in low dosage (30 to 150 mg per
day) as platelet aggregation inhibitor. Acetylsalicylic
acid is a substance which melts at a low temperature (about
139°C) and shows marked volatility at this temperature.
Because of the unstable ester group, acetylsalicylic acid
is susceptible to hydrolysis and transesterification.
Various stabilization methods have therefore already been
considered, such as elimination of water, alcohols and
esters as possible partners in a transesterification or
hydrolysis reaction; addition of acetic acid or acetic
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anhydride or adjustment to pH 2-3. US-A 4,228,162 also
mentions dimethylisosorbide as stabilizing solvent.
A major impediment of the development of acetylsalicylic
acid-containing pharmaceutically effective transdermal
therapeutic systems is moreover the low permeability, by
comparison with the high therapeutic daily dose reguired,
of the active ingredient through the skin. A large number
of permeation accelerants have therefore already been
proposed as additives, such as atones, carboxylic esters,
surface-active substances etc.
US-A 5,164,416 also indicates limonene as permeation-
enhancing substance for acetylsalicylic acid but, according
to this, its use is restricted to the simultaneous addition
of a possibly irritating alkaline additive. Furthermore the
permeation rates which can be achieved for acetylsalicylic
acid - following this teaching - are still insufficiently
high.
It has now been found, surprisingly, that combined addition
of limonene and dimethylisosorbide in particular ratios of
amounts leads to a considerable improvement, which was not
predictable, in acetylsalicylic acid permeation through the
skin.
Accordingly, the transdermal therapeutic system according
to the invention of the type mentioned at the outset is
essentially characterized by a content of limonene and
dimethylisosorbide in a mixing ratio of at least 50:50
(g/g) limonene to dimethylisosorbide in the active
ingredient-active region.
This solution to the problem is surprising inasmuch as the
route to a medicinal form with better bioavailability leads
for the skilled person via basic substances which are good
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solvents, whereas limonene shows an extremely low
solubility for acetylsalicylic acid - even on addition of
dimethylisosorbide.
Particular features of the invention are evident from the
claims and the following description.
The principle according to the invention can be utilized
both in matrix systems and in reservoir/membrane systems.
It is also immaterial which polymers, resins and possibly
other additives are added as long as the formulation is
suitable for delivering the basic substances acetyl-
salicylic acid, limonene and dimethylisosorbide to the
skin.
In the simplest case it is possible for all three charac-
terizing starting materials to be dispersed or dissolved in
a solution of basic polymers, and for the mixture to be
coated onto a suitable substrata, as a rule a siliconized
thermoplastic sheet and, after evaporation of the solvent
contents, where appropriate intensified by input of heat,
to be covered with another sheet which forms the later rear
side of the transdermal therapeutic system. Transdermal
therapeutic systems are obtained from such a laminate by
cutting out flat structures with the required geometric
shape (circle, rounded rectangle etc.).
However, further embodiments may comprise forming a
two-layer matrix consisting of a layer on the skin side,
which contains the active ingredient in dispersed or
dissolved form, and a second layer facing away from the
skin, which contains limonene and dimethylisosorbide in the
desired mixing ratio. These design variants ate, however,
only the simplest of a number of possible conceptions of
the system known to the skilled person. Thus, matrix
systems with more than two layers are, of course, possible
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and, where appropriate, further active ingredients can be
provided.
Suitable basic polymers for the system according to the
invention are, in particular, acrylate copolymers,
styrene/diene copolymers, silicone polymers, mixtures of
polyisobutylene with suitable thermoplastic resins. This
list is far from complete but indicates the wide applica-
bility of the principle according to the invention.
The mixing ratio of limonene to dimethylisosorbide is, in
particular, in the range from 50:50 to 99:1, preferably
from 85:15 to 95:5 and specifically in the region of 90:10.
It is moreover possible and expedient to provide a limonene
content which is of the order of magnitude of the acetyl-
salicylic acid concentration.
Example 1:
20 g of micronized acetylsalicylic acid
30 g of limonene and
1 g of dimethylisosorbide
are dissolved or dispersed in 600 g of an acrylate
copolymer solution (solids content: 50% g/g).
The composition is coated onto a siliconized polyester
sheet (100 ~t~m thick) to result in a layer with a weight per
unit area of 150 g per ma. Drying takes place under mild
conditions by storing at room temperature in the air for
hours. The matrix obtained in this way is laminated with
another sheet (polyester sheet 15 dun thick), and punches
are used to cut out circles with a size of 20 cm2.
This results in transdermal therapeutic systems which can
be applied to the skin directly after detachment of the
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siliconized polyester sheet in order to produce the desired
therapeutic effect.
Example 2:
1.) 20 g of micronized acetylsalicylic acid are dispersed
in 160 g of an acrylate copolymer solution (solids content:
50% g/g). The composition is coated onto a siliconized
polyester sheet (100 ~tm thick) to result in a layer with a
weight per unit area of 52 g/ma. Drying takes place by
storing at room temperature in the air for 10 hours. The
matrix obtained in this way is laminated with another sheet
(polyester sheet 15 ~tm thick).
2.) 20 g of micronized acetylsalicylic acid are dispersed
in 160 g of an acrylate copolymer solution (solids content:
50% g/g). The composition is coated onto a siliconized
polyester sheet (100 Etm thick) to result in a layer with a
weight per unit area of 93 g/m~. Drying takes place by
storing at room temperature is the air for 10 hours.
A circular disc of fabric (cotton) 2.5g cma in size is
applied to the adhesive area of the laminate from (2).
8.5 mg of a mixture of 10% (g/g) dimethylisosorbide and 90%
(g/g) limonene, which has previously been saturated with
acetylsalicylic acid by stirring at room temperature for
hours and then filtering, are applied dropwise to the
disc of fabric. Laminate from (1) and disc of fabric are
covered on the adhesive side with layer (2) so as to result
in a sandwich of polyester sheet (15 Eun), 52 g/ma poly-
acrylate with acetylsalicylic acid, doped disc of fabric
2.54 cmZ and 93 g/ma polyacrylate with acetylsalicylic
acid, which is then covered on the adhesive side by a
siliconized polyester protective sheet with an abhesive
action.
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7.10 cm~ circles are cut of this laminate in such a way
that the disc of fabric is located in the middle. After
application to excited rat skin, the permeation is
determined in vitro.
The average permeation found after 48 hours was
632.6 ~,tg/cma acetylsalicylic acid.
Example 3 (example comparing with Example 2):
Layer 1 and 2 are produced in accordance with Example 2.
A circular disc of fabric (cotton) 2.54 cm2 in size is
applied to the adhesive area of the laminate from (2).
8.5 mg of pure dimethylisosorbide which has previously been
saturated with acetylsalicylic acid by stirriag at room
temperature for 5 hours and then filtering, are applied
dropwise to the disc of fabric. Laminate from (1) and disc
of fabric are cut out into 7.10 cma specimens in analogy to
Example 2. A determination of the permeation of excised rat
skin was also carried out in the same way.
The average permeation found after 48 hours was
130.4 ~g/cma acetylsalicylic acid.
Example 4: (example comparing with Example 2):
Layer 1 and 2 are produced in accordance with Example 2.
A circular disc of fabric (cotton) 2.54 cma in size is
applied to the adhesive area of the laminate from (2).
8.5 mg of pure limonene which has previously been saturated
with acetylsalicylic acid by stirring at room temperature
for 5 hours and then filtering, are applied dropwise to the
disc of fabric. Laminate from (1) and disc of fabric are
cut out into 7.10 cmZ specimens in analogy to Example 2. A
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determination of the perzneation of excised rat skin was
also carried out in the same way.
The average permeation found after 48 hours was
253.3 ~,g/cma acetylsalicylic acid.
Example 5: (example comparing with Example 2):
Layer 1 and 2 are produced in accordance with Example 2.
A circular disc of fabric (cotton) 2.54 cma in size is
applied to the adhesive area of the laminate from (2). No
dropwise application of medium takes place. Laminate from
(1) and disc of fabric are cut out into 7.10 cma specimens
in analogy to Example 2. A determination of the permeation
of excised rat skin was also carried out in the same way.
The average permeation found after 48 hours was 52.9 ~.g/cma
acetylsalicylic acid.
Comparison of the permeation results for Examples 2 to 5
clearly shows the superiority of the system according to
the invention.
