CA2150033A1 - Transdermal administration system containing acetylsalicylic acid for antithrombotic therapy and the prevention of cancer - Google Patents
Transdermal administration system containing acetylsalicylic acid for antithrombotic therapy and the prevention of cancerInfo
- Publication number
- CA2150033A1 CA2150033A1 CA002150033A CA2150033A CA2150033A1 CA 2150033 A1 CA2150033 A1 CA 2150033A1 CA 002150033 A CA002150033 A CA 002150033A CA 2150033 A CA2150033 A CA 2150033A CA 2150033 A1 CA2150033 A1 CA 2150033A1
- Authority
- CA
- Canada
- Prior art keywords
- asa
- acetylsalicylic acid
- application system
- skin
- transdermal application
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
Abstract
The invention concerns a transdermal administration system for antithrombotic therapy and the prevention of cancer, the system containing as its active ingredient acetylsalicylic acid and/or phrmaceutically acceptable salts thereof.
Description
. ~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.
~50033 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 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 21~0D33 . , 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.
. ~ 21~Q33 , 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.
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.
~50033 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 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 21~0D33 . , 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.
. ~ 21~Q33 , 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 I
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 2t~0033 , 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.
2150~33 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 r 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 ~lS0033 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.
2?~0033 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 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 ~ .
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.
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 2t~0033 , 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.
2150~33 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 r 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 ~lS0033 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.
2?~0033 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 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 ~ .
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.
Claims (9)
1. Transdermal application system for antithrombotic therapy and/or for the prophylaxis against cancer contain-ing as active substance acetylsalicylic acid and/or phar-maceutically acceptable salts thereof in a matrix substan-tially suppressing the hydrolysis of acetylsalicylic acid, characterized in that said system comprises a detachable protective layer, a skin-adhesive spread, an active sub-stance-containing reservoir, an active substance-impermeable backing layer and a base layer located between reservoir and backing layer, whereby said skin-adhesive spread contains:
- block copolymer of polystyrene and polyisoprene - glycerol ester(s) of partially hydrogenated colophony - dioctylcyclohexane, whereby said components are present - dissolved in n-heptane with added ASA and acetic anhydride, said reservoir spread contains:
- block copolymer of polystyrene and polyisoprene - dioctylcyclohexane - acetylsalicylic acid (ASA) - acetic anhydride, and said base spread contains:
- block copolymer of polystyrene and polyisoprene - glycerol ester(s) of partially hydrogenated colophony - dioctylcyclohexane, whereby said components are likewise present - dissolved in n-heptane.
- block copolymer of polystyrene and polyisoprene - glycerol ester(s) of partially hydrogenated colophony - dioctylcyclohexane, whereby said components are present - dissolved in n-heptane with added ASA and acetic anhydride, said reservoir spread contains:
- block copolymer of polystyrene and polyisoprene - dioctylcyclohexane - acetylsalicylic acid (ASA) - acetic anhydride, and said base spread contains:
- block copolymer of polystyrene and polyisoprene - glycerol ester(s) of partially hydrogenated colophony - dioctylcyclohexane, whereby said components are likewise present - dissolved in n-heptane.
2. The transdermal application system according to claim 1, characterized in that it contains between 5 and 500 mg, preferably between 30 and 200 mg, of acetyl-salicylic acid or the corresponding amount of a pharma-ceutically acceptable salt thereof, respectively, in stable form.
3. The transdermal application system according to claim 1 or 2, characterized in that it is present in the form of a plaster and comprises an impermeable backing layer, an active substance reservoir connected thereto and made of a polymer matrix, preferably in a concen-tration above the saturation concentration, where other control mechanisms are not present a membrane control-ling the release of the active substance, a pressure-sensitive adhesive device for fixing the system to the skin and, if required, a protective layer which may be detached prior to the application of the system.
4. The transdermal application system according to claim 1 or 2, characterized in that it is present in the form of a cream or ointment.
5. The transdermal application system according to claim 1, 2 or 4, characterized in that the permeation of the acetylsalicylic acid and/or its pharmaceutically accep-table salts through the skin is enhanced by employing electric current.
6. The transdermal application system according to one or more of claims 1 - 5, characterized in that the permea-tion of acetylsalicylic acid and/or its pharmaceutical-ly acceptable salts through the skin is enhanced by adding suitable substances.
7. The process for the manufacture of the transdermal application system according to one or more of the preceding claims, characterized in that an effective amount of acetylsalicylic acid and/or its pharmaceutic-ally acceptable salts, in solid form or dissolved or dispersed, are introduced into the application system, whereby common additives may be added thereto.
8. The use of the transdermal application system according to one or more of claims 1 to 7 in antithrombotic ther-apy or the prophylaxis against cancer, respectively, especially in human medicine.
9. Embodiment according to one or more of claims 1 to 7 and 9, characterized is that the system is intended to be used in the prophylaxis against cancer involving the formation of tumors, especially in the gastrointestinal tract.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4241128.9 | 1992-12-07 | ||
| DE4241128A DE4241128C2 (en) | 1991-12-20 | 1992-12-07 | Use of a transdermal administration system which contains acetylsalicylic acid and / or pharmaceutically acceptable salts thereof as active ingredient |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2150033A1 true CA2150033A1 (en) | 1994-06-23 |
Family
ID=6474576
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002150033A Abandoned CA2150033A1 (en) | 1992-12-07 | 1993-11-18 | Transdermal administration system containing acetylsalicylic acid for antithrombotic therapy and the prevention of cancer |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0671916A1 (en) |
| JP (1) | JP3799502B2 (en) |
| AU (1) | AU694410B2 (en) |
| CA (1) | CA2150033A1 (en) |
| CZ (1) | CZ149495A3 (en) |
| FI (1) | FI120719B (en) |
| HR (1) | HRP931474A2 (en) |
| HU (1) | HUT75680A (en) |
| IL (1) | IL107867A (en) |
| NO (1) | NO952234D0 (en) |
| NZ (1) | NZ258129A (en) |
| PL (1) | PL174770B1 (en) |
| SK (1) | SK75495A3 (en) |
| ZA (1) | ZA939126B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7910597B2 (en) | 2006-11-28 | 2011-03-22 | Shire Llc | Substituted quinazolines |
| US8304420B2 (en) | 2006-11-28 | 2012-11-06 | Shire Llc | Substituted quinazolines for reducing platelet count |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004064841A1 (en) * | 2003-01-23 | 2004-08-05 | Shire Holdings Ag | Formulation and methods for the treatment of thrombocythemia |
| EP1716854A4 (en) | 2004-02-16 | 2010-01-20 | Teikoku Seiyaku Kk | External preparation for treating painful skin wound |
| JP6720257B2 (en) * | 2018-09-05 | 2020-07-08 | テックフィールズ インコーポレイテッド | NSAIA prodrugs with very fast skin and membrane penetration rates and novel pharmaceutical uses thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2496459A1 (en) * | 1980-12-19 | 1982-06-25 | Astier Laboratoires Docteur P | PHARMACEUTICAL COMPOSITION IN THE FORM OF A GEL CONTAINING ACETYLSALICYLIC ACID |
| IL68965A (en) * | 1983-06-13 | 1987-02-27 | Rafa Labor Ltd | Topical pharmaceutical preparation comprising acetylsalicylic acid for the treatment of dermatological disorders |
| HRP921157A2 (en) * | 1991-12-20 | 1994-10-31 | Lohmann Therapie Syst Lts | Transdermal system of applying acetilsalicilyc acid in antithrombosys therapy |
-
1993
- 1993-11-18 NZ NZ258129A patent/NZ258129A/en unknown
- 1993-11-18 CA CA002150033A patent/CA2150033A1/en not_active Abandoned
- 1993-11-18 EP EP94900819A patent/EP0671916A1/en not_active Ceased
- 1993-11-18 CZ CZ951494A patent/CZ149495A3/en unknown
- 1993-11-18 JP JP51371294A patent/JP3799502B2/en not_active Expired - Fee Related
- 1993-11-18 HU HU9501641A patent/HUT75680A/en unknown
- 1993-11-18 PL PL93309285A patent/PL174770B1/en unknown
- 1993-11-18 SK SK754-95A patent/SK75495A3/en unknown
- 1993-11-18 AU AU55632/94A patent/AU694410B2/en not_active Ceased
- 1993-12-03 HR HR931474A patent/HRP931474A2/en not_active Application Discontinuation
- 1993-12-03 IL IL10786793A patent/IL107867A/en not_active IP Right Cessation
- 1993-12-06 ZA ZA939126A patent/ZA939126B/en unknown
-
1995
- 1995-06-06 NO NO952234A patent/NO952234D0/en unknown
- 1995-06-07 FI FI952805A patent/FI120719B/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7910597B2 (en) | 2006-11-28 | 2011-03-22 | Shire Llc | Substituted quinazolines |
| US8304420B2 (en) | 2006-11-28 | 2012-11-06 | Shire Llc | Substituted quinazolines for reducing platelet count |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5563294A (en) | 1994-07-04 |
| HRP931474A2 (en) | 1994-12-31 |
| JPH08504198A (en) | 1996-05-07 |
| ZA939126B (en) | 1994-08-05 |
| CZ149495A3 (en) | 1996-03-13 |
| NO952234L (en) | 1995-06-06 |
| PL309285A1 (en) | 1995-10-02 |
| EP0671916A1 (en) | 1995-09-20 |
| NZ258129A (en) | 1999-10-28 |
| IL107867A (en) | 1998-08-16 |
| AU694410B2 (en) | 1998-07-23 |
| FI952805A0 (en) | 1995-06-07 |
| SK75495A3 (en) | 1996-05-08 |
| JP3799502B2 (en) | 2006-07-19 |
| IL107867A0 (en) | 1994-04-12 |
| NO952234D0 (en) | 1995-06-06 |
| HU9501641D0 (en) | 1995-08-28 |
| FI120719B (en) | 2010-02-15 |
| PL174770B1 (en) | 1998-09-30 |
| HUT75680A (en) | 1997-05-28 |
| FI952805A (en) | 1995-06-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued | ||
| FZDE | Discontinued |
Effective date: 20021118 |