WO1994013302A1

WO1994013302A1 - Transdermal administration system containing acetylsalicylic acid for antithrombotic therapy and the prevention of cancer

Info

Publication number: WO1994013302A1
Application number: PCT/EP1993/003231
Authority: WO
Inventors: Frank Becher; Thomas Kissel
Original assignee: Lts Lohmann Therapie-Systeme Gmbh & Co. Kg
Priority date: 1991-12-20
Filing date: 1993-11-18
Publication date: 1994-06-23

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 pharmaceutically acceptable salts thereof.

Description

A transdermal delivery system containing acetylsalicylic acid for antithrombotic therapy and cancer prophylaxis

DESCRIPTION

The antiplatelet effect of acetylsalicylic acid (ASA) and its effectiveness in preventing cardiac thrombosis was described in the late 1960s. A large number of clinical studies were subsequently carried out in which ASA was used orally for the following indications:

Prevention of a first heart attack

Prevention of a pure attack

Treatment of unstable angina pectoris

Thrombosis prophylaxis after the use of vascular prostheses or artificial heart valves

Thromboprophylaxis of the peripheral arterial vessels

Thrombosis prophylaxis of insufficient cerebral blood flow

If the term "antithrombotic therapy" is used in the following, these indications are essentially included.

The results of these therapeutic studies in patients have recently been summarized (V. Fuster et al., "Aspirin in the prevention of coronary disease", New Engl. J. Med. 221, 183-185 (1989) and R Zichner et al, "For the optimal dosage of acetylsalicylic acid", Med. Klin. __4.43-51 (1989)).

In medical practice, acetylsalicylic acid is often used as a non-steroidal anti-inflammatory, analgesic and antipyretic agent. ASA affects platelet function and prevents thrombosis by irreversibly inhibiting thromboxane A2 synthesis (M. Buchanan et al., "Aspirin inhibits platelet function independent of cyclooxygenase", Thrombosis Res. 25, 363-373 (1982)). ASA is quickly absorbed after oral administration. However, the biological half-life in the body circulation is very short, it only lasts 15-20 minutes (M. Rowland et al., "Kinetics of acetylsalicylic acid disposition in man", NatureZIS, 413-414 (1967)). In normal adults, ASA is quickly hydrolyzed to salicylic acid in the gastrointestinal tract (G. Levy, "Clinical pharmacokinetics of aspirin", Pediatrics __2. 867-872 (1978)).

However, it should be noted that ASA itself and not the hydrolysis product salicylic acid is active in inhibiting platelet function (W. Horsch, "Die Salicylate", Pharmazie 2A.585-604 (1979)).

Acetylsalicylic acid (ASA) is continuously ingested by large sections of the population, particularly in the USA. According to a work by Thun et al., "Aspirin Use and Reduced Risk of Fatal Colon Cancer", New Engl. J. Med..225. 1593-1596 (1991), ASA reduced the mortality caused by colon cancer to about half when ASA was taken continuously, at least 16 days a month. The investigation included more than 660,000 people who had taken ASA for at least one year and lived in all 50 states in the United States, the Columbia District, and Puerto Rico. Although reference was only made to the use of ASA without further details regarding the mode of administration and the dose, it can nevertheless be assumed that the ASA had been taken orally and that the substance responsible for the action is not the hydrolysis product salicylic acid, but ASA itself.

In antithrombotic therapy, oral administration is practiced almost exclusively; on the other hand, attempts have already been made to apply the active ingredient via the skin for the anti-inflammatory, analgesic and antipyretic indications. For example, ASS is mentioned in US Pat. No. 3,598,122 as a possible antipyretic active substance in a membrane-controlled transdermal therapeutic system. FR-M 1757 describes the dermal topical application of an oil-in-water emulsion which contains 5% ASA for acute pain. FR-A 2 297 612 claims rubbing agents and ointments which contain ASA as an analgesic agent. Combined with corticosteroids, ASS is used in US Pat. No. 4,012,508 for topical use in dermatological indications. US Pat. No. 4,219,548 describes a topical application of ASA for anti-inflammation. An ASS-containing gel is applied topically in EP-A 0055635 for anti-inflammatory, analgesic and antipyretic indications. A device for the transdermal application of ASA from an aqueous system to achieve anti-inflammatory and analgesic effects is the subject of US Pat. No. 4,460,368. ASS is applied topically from ethanolic solution in US Pat. No. 4,665,063 against dermatological disorders. An increase in the penetration rate of ASA in the case of transdermal application is achieved in US Pat. No. 4,640,689 with electric current.

The addition of suitable penetration accelerators according to EP-A 162 239 also leads to improved penetration of the ASA through the skin in the case of transdermal use. According to JP-OS 61 167 615, ASS is applied to the skin with the aid of a film. US Pat. No. 4,810,699 describes combinations of ASA with other active substances for the transdermal treatment of inflammation, pain and fever. Special penetration accelerators for the transdermal application of ASA as a pain reliever are contained in JP-PS 1 203 336. Further substances of this type for ASA in transdermal application for inhibiting inflammation can be found in JP-PS 1, 242,521. Storage-stable solutions from ASS for topical application with the aim of reducing inflammation and relieving pain are the subject of US Pat. No. 4,975,269.

The state of the art described cannot be deduced and it cannot be inferred from the fact that the use of a transdermal system, the ASA and / or its pharmaceutically acceptable salts for the prevention of platelet aggregation in humans and / or for the prophylaxis against cancer is considered contains.

Many formulations and compositions contain water or hydrophilic solvents that accelerate the hydrolysis of ASA to salicylic acid. Since, as already explained above, this has no antithrombotic effect, but shows anti-inflammatory and analgesic effects comparable to ASA, it is understandable that the breakdown of ASA has not been investigated in detail in the application systems mentioned.

It was therefore an object of the present invention to provide an administration system for the application of ASA and / or its pharmaceutically acceptable salts for antithrombotic therapy and / or for prophylaxis against cancer, which avoids the disadvantages of oral administration and allows a targeted dosage of the unchanged active ingredient.

The solution to this problem surprisingly consists in the fact that a transdermal system is used for the administration of acetylsalicylic acid and / or its pharmaceutically acceptable salts for antithrombotic therapy and / or for prophylaxis against cancer, preferably one which contains acetylsalicylic acid or the salts contains in a matrix that substantially suppresses or does not permit the hydrolysis of acetylsalicylic acid. In other words, the system is preferably free of substances which, under the storage conditions or during use, cause the acetyl group to be split off. A transdermal delivery system offers the following advantages in anti-thrombotic therapy:

1. ASA, in its pharmacologically active form, is given directly to the body's circulation, thereby avoiding metabolism in the gastrointestinal tract.

2. Reduction of gastrointestinal side effects

3. Constant therapeutic effect with reduced ASA administration.

4. Reduced risk of overdose.

5. Outpatient treatment of patients without the need for surveillance.

6. Improved patient therapy adherence

The ASA content in such an administration unit is generally 5 to 500, preferably 30 to 200 mg or the corresponding amount of a pharmaceutically acceptable salt. The ASS salts that can be used here are all non-toxic, pharmacologically active salts such as the lithium, sodium, potassium, magnesium and calcium salts or salts of ASS with basic organic compounds such as lysine, arginine or cetrimonium bromide (hexadecyltrimethylam onium bromide). The rate and extent of the transdermal transfer of ASA into the body naturally depends on the amount, the type of compound (free acid or salt) and, if appropriate, also on the presence of auxiliaries such as penetration accelerators. The system is expediently adjusted in such a way that an ASA blood level value between 0.1 and 1.0 μg / ml is established. For practical use, the content is expediently based on the type of matrix, the recommended wearing time of the F-Tlaster, the intended indication, the body weight (children or adults), the permeability of the matrix or membrane of the patch and the permeation through the skin Voted.

An amount of ASA and / or ASA salts in the blood that is therapeutically effective in antithrombotic therapy and prophylaxis against cancer corresponds to ASA blood level values between 0.1 and 1.0 μg / ml. Although ASA is rapidly absorbed after oral administration, this type of administration is unfavorable, especially because of the hydrolysis of ASA to salicylic acid if the short biological half-life and the fact that the most constant possible administration is desirable for prophylaxis. By contrast, the transdermal treatment proposed according to the invention gives fairly constant and reproducible ASA blood level values which are particularly effective in anthrhrombotic therapy and are suitable for cancer prophylaxis. By contrast, a transdermal delivery system according to the invention ensures constant and reproducible ASA blood levels which are effective in antithrombotic therapy.

With cancer prophylaxis e.g. understood one against cancer with tumor formation, e.g. in the gastrointestinal tract, such as colon cancer.

The transdermal administration system for ASA and / or ASA salts according to the invention can be implemented in a variety of ways, e.g. as a particularly pressure-sensitive adhesive plaster, as a film, as a spray, cream, ointment and the like. Preferred is the form of administration of the pressure-sensitive adhesive plaster, which has an impermeable backing layer, an associated active substance reservoir made of a polymer matrix, in the absence of other control mechanisms, a membrane that controls the release of the active substance, a pressure-sensitive adhesive device for attaching the system to the skin and, if necessary includes a protective layer that can be removed before the system is applied. In all forms, care must be taken that the matrix forming the active substance reservoir is selected in such a way that the hydrolysis of ASA is avoided or at least strongly suppressed. A hydrophobic setting of the matrix leads to the goal here rather than a hydrophilic one.

In order to suppress or suppress the hydrolysis, substances such as acylating agents, preferably acetylating agents, in particular acetic anhydride, e.g. in an amount of 0.01 to 3, preferably 0.1 to 2 wt .-%, based on acetylsalicylic acid.

The transdermal pressure-sensitive adhesive plasters which can be used according to the invention are all plasters which are known to the person skilled in the art from the prior art. They can largely be assigned to two basic control principles: matrix diffusion control and membrane control, only the latter having a zero-order release of active ingredient. An F-raster with matrix diffusion control is described for example in DE-PS 33 15 272. It consists of an impermeable backing layer, an associated reservoir made of a polymer matrix, which contains the active ingredient in a concentration above the juicing concentration, a pressure-sensitive adhesive layer connected to the reservoir, permeable to the active ingredient, and a protective layer covering the adhesive layer, which can be removed again for use, e.g. a siliconized film made of polyester, especially polyethylene terephthalate. If the reservoir matrix itself is already pressure sensitive, you can use the additional adhesive layer can be dispensed with. However, systems with lower than the saturation concentration are also possible.

For plasters with membrane control, reference is made, for example, to US Pat. Nos. 3,742,951, 3,797,494, 3,996,934 and 4,031, 894. These plasters basically consist of a backing layer (e.g. a film made of a polyester such as polyethylene terephthalate, which can be aluminized, or an aluminized film made of a synthetic resin such as polypropylene, nylon, polycaprolactam), which is one of the surfaces, a membrane, one for the Active substance permeable adhesive layer that represents the other surface and ultimately a reservoir that contains the active substance between the two layers forming the surfaces. Alternatively, the active ingredient can also be contained in a large number of microcapsules which are distributed within the permeable adhesive layer. In any case, the active ingredient is continuously released from the reservoir or the microcapsules through a membrane into the adhesive layer which is permeable to the active ingredient and which is in contact with the skin of the person to be treated. In the case of microcapsules, the capsule material can also act as a membrane. Substances suitable for membranes and microcapsules are e.g. in U.S. Patent 3,996,934.

In addition, it should also be pointed out that control by means of electric current is also possible, the passage of the active ingredient through the skin being the rate-determining step. Such processes are called electroosmosis, iontophoresis or electrophoresis.

If necessary, the plasters, regardless of their type, can contain various additives in addition to the matrix forming the reservoir and the active ingredient, which also includes combinations of ASA and their salts, in order to obtain the desired property profile. Additives that promote the permeation of ASA and / or their pharmaceutically acceptable salts through the skin should be particularly mentioned. A precise list of the additives is unnecessary for the person skilled in the art in this field, but mention may be made, for example, of glycerol, 1, 2-propanediol, the monomethyl or monoethyl ether of ethylene glycol, 2-octyldodecanol, the laurate, palmitate, stearate or oleate of sorbitol, C ₈ -

C ₁₀ ethoxylated oleic acid glycerides, lower alkyCC to C ₃ ) esters of lauric acid, such as propylene glycol monolaurate, lauric, capric, oleic acid etc. The amount is generally from 0 to 20, preferably from 0.5 to 10,% by weight. %, based on the total components of the matrix. It depends on the type of matrix, the permeability of the matrix or membrane of the patch, the dissolving power of the penetration accelerator for the active ingredient and the permeation through the skin. The invention is illustrated by the following examples:

Examples:

1. One-layer system based on acrylate.

5 g of dioctylcyclohexane, 8 g of acetylsalicylic acid and 40 mg of acetic anhydride are added to 100 g of a solution of an acrylic adhesive (eg Durotak ^R 280-2516 National Starch and Chemical,) with a solids content of 42% by weight, and the solution is homogenized by stirring.

The solution is then spread 300 μm thick on a siliconized, 100 μm thick polyester film. In the finished system, this film takes over the function of the removable protective layer and must be removed before use. The moist film is dried at 50 ° C. for 20 minutes and then has a weight per unit area of 100 g / m ² .

The dried film is then laminated with a 12 μm thick polyester film. The finished plasters are punched out of the laminate.

2. Multi-layer system

The finished system consists of a removable protective layer, a skin adhesive layer, a non-adhesive reservoir, an active substance-impermeable back layer and a well-adhesive primer layer which is located between the reservoir layer and the back layer and has the task of anchoring the non-adhesive reservoir on the back layer.

A. Preparation of the skin adhesive coat

100 g of a block polymer made of polystyrene and polyisoprene (e.g. Cariflex ^R TR-1107, Shell),

175 g of a glycerol ester of partially hydrogenated rosin

and

50 g dioctylcyclohexane

are dissolved in 500 g of n-heptane and then 15 g of acetylsalicylic acid and 150 mg of acetic anhydride are added. The mass is homogenized by stirring and then spread 100 μm thick on a siliconized polyester film serving as a removable protective layer in the finished product. The moist film is dried at 50 ° C. for 20 minutes and then has a weight per unit area of 25 g / m ² .

B. Production of the reservoir line

100 g of a block polymer made of polystyrene and polyisoprene (e.g. Cariflex TR-1 107, Shell)

and

20 g of dioctylcyclohexane are dissolved in 120 g of n-heptane.

Then 40 g of acetylsalicylic acid and 40 mg of acetic anhydride are added and the mass is homogenized by stirring. The mass is spread 300 μm thick on a polyester film that is more siliconized than the removable protective layer and dried for 20 minutes at 50 ° C. The dried reservoir film has a basis weight of 100 g / m ² . C. Preparation of the primer coat

100 g of a block polymer made of polystyrene and polyisoprene (e.g. Cariflex TR-1107, Shell),

175 g of a glycerol ester of partially hydrogenated rosin

and

50 g dioctylcyclohexane

are dissolved in 500 g of n-heptane and 100 μm thick, analogously to B, coated on a polyester film that is more siliconized than the removable protective layer and dried at 50 ° C. for 20 minutes. The dried film has a weight per unit area of 25 g / m ² .

D. Structure of the overall system and punching the individual plasters

The reservoir coat obtained under B is laminated onto the skin gash line A and then the more siliconized film mentioned under B is removed. Now the primer coat C is applied in the same way and a 12 μm thick polyester film is laminated on after removing the more siliconized film mentioned under C.

The finished plasters are punched out of the total laminate.

3. Membrane system

A heat-sealable laminate made of a flexible polyester film and a film made of a polyethylene / vinyl acetate copolymer is sealed against a 50 μm thick membrane made of a polyethylene / vinyl acetate copolymer with a vinyl acetate content of 19% in accordance with the dimensions and shapes of the later plasters Kind of flat bag arises. The sealing seam should have a width of 4 mm. Before the bag is completely sealed, it is filled with a liquid preparation made from a silicone oil with 10% acetylsalicylic acid and 0.05% acetic anhydride. The membrane side of the pouch is then laminated onto a silicone-based skin adhesive layer located on a suitable, abhesively finished film. This film is identical to the removable protective layer.

The finished systems are punched out so that a bag with a 3 mm thick sealing edge remains.

Claims

PATENT CLAIMS

1. Trαnsdermαles administration system which contains acetylsalicylic acid and / or pharmaceutically acceptable salts thereof as active ingredient, characterized in that it is intended for antithrombotic therapy and / or for prophylaxis against cancer.

2. Transdermal administration system according to claim 1, characterized. that it contains between 5 and 500 mg, preferably between 30 and 200 mg of acetylsalicylic acid or the corresponding amount of a pharmaceutically acceptable salt thereof in stable form.

3. Transdermal administration system according to claim 1 or 2, characterized in that it is in F-flaster form and an impermeable backing layer, an associated drug reservoir from a polymer matrix, preferably in a concentration above the saturation concentration, in the absence of other control mechanisms, the release of the active ingredient controlling membrane, a pressure sensitive adhesive device for attaching the system to the skin and, if necessary, a removable protective layer before application of the system.

4. Transdermal delivery system according to claim 1 or 2, characterized in that it is present as a cream or ointment.

5. Transdermal administration system according to claim 1, 2 or 4, characterized in that the permeation of acetylsalicylic acid and / or its pharmaceutically acceptable salts through the skin is promoted by the use of electric current.

6. Transdermal administration system according to one or more of claims 1-5, characterized in that the permeation of acetylsalicylic acid and / or its pharmaceutically acceptable salts is promoted by the addition of suitable substances.

7. The transdermal delivery system according to one or more of claims 1 to 6, characterized in that it contains the acetylsalicylic acid and its salts in a matrix which substantially suppresses the hydrolysis of the acetylsalicylic acid.

8. A method for producing a transdermal administration system according to one or more of the preceding claims, characterized in that a 8. A process for the production of a transdermal administration system according to one or more of the preceding claims, characterized in that an effective amount of acetylsalicylic acid and / or its pharmaceutically acceptable salts is introduced into the administration system in solid form or in solution or in dispersion, with customary additives being added can be.

9. Use of a transdermal administration system according to one or more of claims 1 to 7 in antithrombotic therapy or prophylaxis against cancer, in particular in human medicine.

10. Embodiment according to one or more of claims 1 to 7 and 9, characterized in that the system for the prophylaxis against cancer with tumor formation, in particular in the gastrointestinal tract is intended.