Note: Descriptions are shown in the official language in which they were submitted.
. ~150033
A TRANSDERMAL APPLICATION SYSTEM CONTAINING ACETYLSALICYLIC
ACID FOR ANTITHROMBOTIC THERAPY AND CANCER PROPHYLAXIS
D E S C R I P T I O N
The platelet aggregation-preventing effect of acetyl-
salicylic acid (ASA) and its effect in the prevention of
cardiac thrombosis was described in the late 60s.
Subse~uently, a large number of clinical studies have been
conducted whereby ASA was administered orally in the case
of the following indicatio~s:
prevention of first-instance cardiac infarction,
prevention of reinfarction,
treatment of unstable angina pectoris, -
prophylaxis against thrombosis after transplan-
tation of vascular prostheses or artificial car-
diac valves
prophylaxis against thrombosis of the peripheral
arterial vessels
prophylaxis against thrombosis of cerebral inade-
~uate circulation
Where in the following the term ~anti-thrombotic therapy~'
i6 used, this substantially comprises the above indica-
tions.
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In recent years, the results of these therapeutic tests on
patients have been summed up (V. Fuster et al., "Aspirin in
the prevention of coronary disease", New Engl. J. Med. 321,
183-185 ~1989) and R. Zichner et al., "Zur optimalen Dosie-
rung von Acetylsalicylsaeure", Med. Klin. 84, 43-51
(1989)).
Acetylsalicylic acid has freguently been employed in
medical practice as a non-steroid anti-inflammatory, anal-
gesic and antipyretic active substance. ASA influences
platelet function and prevents thrombosis by irreversibly
inhibiting the thromboxane A2 synthesis (M. BUchAn~n et
al.,"Aspirin inhibits platelet function independent of
cyclooxygenase", Thrombosis Res. 25, 363-373 (1982)). `
~ `~
After oral administration ASA is ~uickly absorbed.
However, its biological half-life in the systemic circula-
tion is very short, it lasts only 15 - 20 minutes (M. Row-
land et al., "Kinetics of acetylsalicylic acid disposition
in man~', Nature 215, 413-414 (1967)). In normal ad!ults ASA -
is guickly hydrolized to salicylic acid in the gastrointes-
tinal tract. (G. Levy, "Clinical pharmacokinetics of
aspirin", Pediatrics 62, 867-872 (1978)).
It should be emphasized, however, that it is ASA itself
which is active in inhibiting platelet function, and not
its hydrolysis product, salicylic acid (W. Horsch, "Die
Salicylate", Pharmazie 34, 585-604 (1979)).
Acetylsalicylic acid (ASA) is continually taken by large
parts of the population especially in the USA. According
to a paper by Thun et al., ~Aspirin Use and Reduced Risk of
Fatal Colon Cancer~, New Engl. J. Med. 325, 1593-1596
(1991), ASA reduces mortality caused by colonic cancer by
around 50%, provided ASA is taken continually, i.e. on at
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least 16 days per month. The study involved more than
660,000 persons living in all 50 states of the USA, the
District of Columbia and Puerto Rico, who had taken ASA for
a period of at least one year. This study refers only to
the use of ASA and fails to provide further information as
to the manner and form of administration and dosage.
Nevertheless, it is to be assumed that ASA was administered
orally and that the substance having the above-described
effect was not the hydrolysis product salicylic acid but
ASA itself
In antithrombotic therapy oral ~m;n; stration is practised
almost exclusively; in the case of anti~inflammatory, anal-
gesic and antipyretic indications, however, attempts have
already become known to apply the active substance via the
skin. Thus, US Patent 3,598,122 mentions ASA as a possible
f antipyretic active substance in a membrane-controlled
transdermal therapeutic system. FR-M 1757 describes the
dermal topical application of an oil-in-water emulsion con-
taining 5% of ASA against acute pain. FR-A 2 297 612
claims lin;ments and ointments containing ASA as analgetic
agent. In US Patent 4,012,508 ASA is employed-in combina-
tion with corticosteroids for topical application in the
case of dermatological indications. US Patent 4,219,548
describes a topical application of ASA for the checking of
inflammatory processes. In European Patent 0 055 635 an
ASA-containing gel is applied topically in the case of
anti-inflammatory, analgesic and antipyretic indications.
US Patent 4,460,368 discloses a device for the transdermal
application of ASA out of an aqueous system for achieving
anti-inflammatory and analgesic effects. In US Patent
4,665,063, ASA is topically applied against dermatological
disturbances by using a solution in ethanol. In US Patent
4,640,689 an increase in the penetration rate of ASA in
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. ,
transdermal application i8 achieved by employing electric
current.
Addition of suitable penetration enh~ncers, as in ~uropean
Patent 0 162 239, also leads to an improved penetration of
ASA through the skin. In Japanese Publication 61 167 615
ASA is applied to the skin by means of a film. US Patent
4,810,699 describes combinations of ASA with other active
substances for the transdermal treatment of inflammations,
pain and fever. Japanese Patent 1,203,336 relates to
special penetration enhAncers for the transdermal applica-
tion of ASA as an analgesic. Further substances of this
kind for ASA in transdermal application for the checking of
inflammatory processes, are cont~;ne~ in Japanese Patent
1,242,521. Finally, US Patent 4,975,269 relates to
storage-stable solutions of ASA for topical application
aiming at checking inflammatory processes and relieving
f pain.
The mentioned prior art does not contain any indication,
nor can it be derived therefrom, that the use of a trans- --
dermal system has been considered which contains A-SA and/or
pharmaceutically acceptable salts thereof to prevent plate-
let aggregation in humans and/or for the prophylaxis
against cancer.
Many formulations and compositions contain water or hydro-
phile solvents which accelerate the hydrolysis of ASA to
salicylic acid. Since, as explained hereinabove, salicylic
acid has no antithrombotic effect but shows an anti-
inflammatory and analgesic effect comparable to that of
ASA, it becomes clear that the decomposition of ASA in the
above mentioned application systems has not been studied in
detail.
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,
It has therefore been the object of the present invention
to provide an application system for the application of ASA
and/or its pharmaceutically acceptable salts for antithrom-
botic therapy and/or for the prophylaxis against cancer
which avoids the disadvanta~es inherent in oral application
and allows for target-specific dosage of the unchanged
active substance.
This object has surprisingly been solved by employing a
transdermal system for administering acetylsalicylic acid
and/or the pharmaceutically acceptable salts thereof for
antithrombotic therapy and/or for the prophylaxis against
cancer, said system preferably containing acetylsalicylic
acid or the said salts in a matrix substantially suppr'es-
sing or preventing the hyd~olysis of acetylsalicylic acid.
In other words, the system preferably is free of substances
which - under storage conditions or during application -
lead to a separation of the acetyl group.
A transdermal administration system offers the foll,owing
advantages in antithrombotic therapy: -
1. ASA is directly introduced into the systemic circula-
tion in its pharmacologically active form, thus avoid-
ing metabolism in the gastrointestinal tract.
2. reduction of gastrointestinal side effects
3. constant therapeutic effect with reduced doses of ASA
4. reduced risk of overdosage
5. treatment of outpatients without the need of
observation
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6. improved patient compliance during treatment.
The content of ASA in such an administration unit is gener-
ally 5 - 500 mg, preferably 30 - 200 mg, or the correspond-
ing amount of a pharmaceutically acceptable salt. ASA
salts suitable for this purpose are all those which are
non-toxic and pharmacologically effective, such as lithium,
sodium, potassium, magnesium and calcium salts or salts of
ASA with basic organic compounds, such as lysine, arginine
or cetrimide (hexadecyltrimethylammonium bromide). The
speed and extent of the transdermal permeation of ASA into
the body is, naturally, dependent on the given amount, the
type of compound (free acid or salt) and possibly also on
the presence of auxiliary substances, such as penetration
enhancers. Advantageously,~the system is adjusted such that
an ASA blood level of between 0.1 and 1.0 ~g/ml is ob-
tained. For practical application, the content is advan-
tageously adjusted to the type of matrix, the recommended
period of time during which the plaster is worn, the inten-
ded indication, the body weight (child or adult), the per- -
meability of the matrix or membrane of the plaster~, and the
permeation through the skin.
In antithrombotic therapy and in the prophylaxis against
cancer, a therapeutically effective amount of ASA and/or
ASA salts in the blood corresponds to blood level values of
ASA of between 0.1 and 1.0 ~g/ml. Although, after oral ad-
ministration, ASA is ~uickly absorbed, this mode of admin-
istration is disadvantageous due to the hydrolysis of ASA
to salicylic acid, especially when taking into account the
short biological half-life and the fact that for prophy-
laxis an administration is aimed at which remains as cons-
tant as possible. By contrast, the transdermal treatment
as proposed in the present invention secures rather cons-
tant and reproducible blood levels of ASA which are espe-
cially effective in antithrombotic therapy and suitable for
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,
cancer prophylaxis. A delivery system according to the
invention, however, ensures constant and reproducible ASA
blood levels which are active in antithrombotic therapy.
The term cancer prophylaxis implies, for example, the
prophylaxis against cancer involving formation of tumors
for example in the gastrointestinal tract, such as colonic
cancer.
The transdermal application system for ASA and/or ASA salts
according to the present invention, may be realised in
numerous ways, for example in the form of a plaster, in
particular a pressure-sensitive adhesive one, a film, a
spray, a cream, ointment and the like. The preferred form
of administration is that of a pressure-sensitive adhesive
plaster comprising an impermeable backing layer, an active
J substance reservoir connected thereto and consisting of a
polymer matrix, where other control mechanisms are not
present a membrane controlling the release of active
substance, a pressure-sensitive adhesive device for fixing --
the system to the skin and, i~ re~uired, a protective layer
which may be detached prior to the application of the sys-
tem. With all forms of administration, the matrix forming
the reservoir must be chosen such that hydrolysis of ASA iS
precluded or is at least greatly reduced. A hydrophobic ad-
justment of the matrix is more suitable for this purpose
than a hydrophilic one.
For reducing or suppressing the hydrolysis, substances may
be added such as acylating agents, preferably acetylating
agents, and in particular acetic anhydride, for instance in
an amount of 0.01 to 3, preferably 0.1 to 2%-wt, relative
to acetylsalicylic acid.
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The transdermal pressure-sensitive adhesive plasters
suitable for this invention are all those known to the per-
son skilled in the art from the prior art. For the most
part, these plasters can be assigned to two basic control
principles: matrix diffusion control and membrane control,
whereby only the latter allows for an active substance
release of zero order. A matrix diffusion control plaster
is described, for example, in German Patent No. 33 15 272.
It consists of an impermeable backing layer, a reservoir
made up of a polymer matrix connected thereto and contain-
ing the active substance in a concentration which is above
the saturation concentration, a pressure-sensitive adhesive
layer connected to the reservoir and permeable to the ac-
tive substance, and a protective layer which covers the
pressure-sensitive adhesive layer, e.~. a siliconised film
of ~olyester, in particular of polyethylene terephtalate,
and may be detached for application of the system. If the
reservoir matrix itself is pressure-sensitive adhesive, the
additional pressure-sensitive adhesive layer need not be
present. However, systems with a saturation which is below
the saturation concentration are possible as well.--
Examples for plasters with membrane control include US Pat-
ents 3,742,951, 3,797,494, 3,996,934 and 4,031,894. These
plasters, in principle, consist of a backing layer (e.g. a
film of polyester, such as polyethylene terephtalate, which
may be aluminized, or an aluminised film of a synthetic
resin, such as polypropylene, nylon, polycaprolactam),
which forms one of the surfaces, a membrane, an adhesive
layer permeable to the active substance which forms the
other surface and, finally, a reservoir containing the
active substance between the two layers forming the sur-
faces. Alternatively, the active substance may also be
contained in a plurality of microcapsules dispersed within
the permeable adhesive layer. In all cases, the active
substance is continuously released from the reservoir or
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the microcapsules, through a membrane, into the adhesive
layer which is permeable to the active substance and which
is in contact with the skin of the person to be treated. If
microcapsules are present, the capsule material may also
~erve as a membrane. Substances suitable for membranes and
microcapsules are described, for example, in US Patent
3,996,934.
In addition, it should be pointed out that control is also
possible by means of electric current, whereby the velocity
is determ;ne~ by the phase in which the active substance
permeates the skin. Such processes are referred to as
electroasmosis, iontophoresis or electrophoresiæ.
All types of plasters may,~if required, contain various
additives in addition to the matrix forming the reservoir
f and the active substance, the latter also including combi-
nations of ASA and the salts thereof, in order to achieve
the desired properties. To be mentioned in particular are
those additives enh~ncing the permeation of ASA andJor its
pharmaceutically acceptable salts through the skin~. The
various suitable additives are known to the man skilled in
the art, a detailed list is therefore unnecessary; however,
glycerin, 1,2-propane diol, the monomethyl or monoethyl
ether, respectively, of ethylene glycol, 2-octyl dodecanol,
the laurate, palmitate, stearate or oleate of sorbite, C8-
C10-ethoxylated oleic acid glycerides, lower alkyl(Cl to C3)
esters of lauric acid, such as propylene glycol mono-
laurate, lauric, capric, oleic acid, etc., are mentioned by
way of example. The amount used is generally 0 to 20%-wt.,
preferably 0.5 to 10%-wt., relative to the total matrix
components. Said amount is dependent on the type of
matrix, the permeability of the matrix or membrane, respec-
tively, of the plaster, the dissolving capacity of the
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penetration enhancer for the active substance, and the per-
meation through the skin.
The present invention will be illustrated but not limited
by the following examples:
Examples:
1. Acrylate-based Single-Layer System
5 g dioctyl cyclohexane, 8 g acetylsalicylic acid and 40 mg
acetic anhydride are added to 100 g of a solution of an
acrylic adhesive (e.g. Durotak~ 280-2516 National Starch
and Chemical) having a sol-ids content of 42%-wt., and the
solution is homogenized by agitating.
The solution is thereafter spread at a thickness of 300 ~m
on a 100 ~m thick polyester film. In the finished system,
this film takes over the function of the detachable protec- -
tive layer and must be removed prior to use. The ~oist
film is dried for 20 minutes at 50C and thereafter has a
weight per area of 100 g/m2.
The dried film is subseguently laminated with a 12~m thick
polyester film and the finished plasters are punched out of
the laminate.
2. Multilayer System
The finished system comprises a detachable protective
layer, a spread of skin adhesive, a non-adhesive reservoir,
a backing layer impermeable to active substance and a base
spread, having good viscous properties, which is located
21aQQ33
between the reservoir layer and the backing layer and per-
forms the function of fixing the non-adhesive reservoir to
the backing layer.
A. Manufacture of the Skin ~dhesive Spread
100 g of a block polymer consisting of polystyrene and
polyisoprene (e.g. Cariflex~ TR-1107, by Shell),
175 g of a glycerol ester of partially hydrogenated colo-
phonium
and
50 g of dioctyl cyclo~ex~n~
f are dissolved in 500 g n-heptane and, subsequently, 15 g
acetylsalicylic acid and 150 mg acetic anhydride are added
thereto. The mass is homogenized by agitating and then
spread on a siliconized polyester film at a thickness of --
lOO~m, the polyester film serving in the finished product
as a detachable protective layer. The moist film is dried
for 20 minutes at 50C and thereafter has a weight per area
of 25 g/m2.
B. Manufacture of the Reservoir Spread
100 g of a block polymer consisting of polystyrene and
polyisoprene (e.g. Cariflex ~R-1107, by Shell)
and
20 g dioctyl cyclohexane are dissolved in 120 g n-heptane.
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Thereafter, 40 g acetylsalicylic acid and 40 mg acetic an-
hydride are added, and the mass is homogenized by agitat-
ing. The resulting mass is spread at a thickness of 300~m
on a protective polyester film which is siliconized to a
higher degree than the detachable protective layer, and is
dried for 20 minutes at 50~. The dried reservoir layer
has a weight per area of 100 g/m2
C. Manufacture of the Base Spread
100 g of a block polymer consisting of polystyrene and
polyisoprene (e.g. Cariflex TR-1107, by Shell),
175 g of a glycerol ester of partially hydrogenated
colophonium
f
and
50 g of dioctyl cyclohexane
are dissolved in 500 g n-heptane and, analogous to B,
spread, at a thickness of 100 ~m, onto a polyester film
which has been siliconized to a higher degree than the
detachable protective layer, and is dried for 20 minutes at
50C
The dried film has a weight per area of 25 g/m2
D. Assembly of the Entire System and Punching of the
Individual Plasters
The reservoir spread resulting from B is laminated onto the
skin adhesive spread A; the foil mentioned under B which is
siliconized to a higher degree is thereafter removed. Then
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the base spread C is applied in the same manner and after
removal of the film mentioned under C which has a higher
degree of siliconization, a 12-~m-thick polyester film is
laminated thereon.
The finished plasters are punched out of the assembled
laminate.
3. Membrane System
A heat-sealing laminate consisting of a flexible polyester
film and a film of a polyethylene/vinylacetate copolymer is
sealed against a 50-~m-thick membrane of a poly-
ethylene/vinylacetate copolymer, having a vinyl acetate
content of 19%, in the ~;men~ions and shapes correspo~;ng
f to those of the intended plasters and in such a manner that
a kind of flat bag is obtained. The sealing seam is to be
4 mm in width. Before the bag is sealed in such a manner
that no gaps remain, it is filled with a preparation of
silicone oil with 10% acetylsalicylic acid and 0.0-5% acetic
anhydride.
The membrane side of the bag is then laminated on a sili-
cone-based skin adhesive spread, which is located on a
suitable foil having been rendered adhesive. This foil is
identical with the detachable protective layer.
The finished systems are punched out in such a manner that
a bag having a sealing border of 3 mm in width remains.
