SK75495A3 - Transdermal administration system containing acetylsalicylic acid for antithrombotic therapy and the prophylaxis of cancer - Google Patents

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

A transdermal delivery system for antirombotic therapy, respectively, is disclosed. prophylaxis of cancer comprising acetylsalicylic acid and / or pharmaceutically acceptable salts thereof as the active ingredient.

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Transdermal delivery system containing acetylsalicylic acid for antithrombotic therapy and cancer prophylaxis

Technical field

The invention is concerned with the preparation of a transdermal delivery system comprising acetylsalicylic acid for antithrombotic therapy and prophylaxis of cancer.

BACKGROUND OF THE INVENTION

The effect of acetylsalicylic acid (ASK), which results from the inhibition of platelet aggregation and its action in the prophylaxis of cardiac thrombosis, has been described in the late 1960s. A large number of clinical trials have been performed in the next period where acetylsalicylic acid was administered orally in the following indications:

- prevention of a first heart attack

- prevention of recurrent heart attack

- treatment of unstable angina pectoris

- prophylaxis of thrombosis after application of vascular substitutes, resp. artificial heart valves

- - prophylaxis of thrombosis of peripheral arterial vessels

- prophylaxis of cerebral haemorrhage thrombosis As long as the term antithrombotic therapy continues to be used, the above indications are essentially included.

The results of these therapeutic studies in patients have recently been reviewed (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 Dosierung von Acetylsalicylsaeure (Med. Klin. 84: 43-51 (1989)).

Acetylsalicylic acid is often used in medical practice as a non-steroidal active, acting anti-inflammatory, analgesic and antipyretic. ASK 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)).

ASK is rapidly absorbed after oral administration. However, the biological half-life in body circulation is very short, lasting only 15-20 minutes (M. Rowland et al., Kinetics of Acetylsalicylic Acid Disposition in Man, Nature 215, 413-414 (1967)). Thus, in normal adults, ASK is rapidly hydrolysed to salicylic acid already in the stomach and intestinal tract (G. Levy, Clinical pharmacokinetics of aspirin, Pediatrics 62, 867-872 (1978)).

It should be remembered that the active ingredient in inhibiting platelet function is only ASK and not salicylic acid as the product of hydrolysis (W. Horsch, Die Salicylate, Pharmazie 34, 585-604 1979).

Acetylsalicylic acid (ASK) is commonly used in the US by the general population. According to Thun et al., Aspirin Use and Reduced Risk of Fatal Colon Cancer, New Engl. J. Med. 325, 1593-1596 (1991) reduces ASK mortality caused by colon cancer by about half, when ASK is used permanently and resp. at least 16 days per month. The research conducted in all 50 states of the USA, Colombia and Puerto Rico included more than 660,000 people who had been receiving ASK for at least one year. Although the emphasis was only on the use of ASK and no further data on the route of administration and dosage were given, it can still be assumed that ASK was administered orally and that the active substance is not salicylic acid as the hydrolysis product but ASK as such. .

For antithrombotic therapy, oral administration is almost exclusively practiced. However, tests are known in which the active ingredient has also been administered via the skin in anti-inflammatory, analgesic and antipyretic indications. Thus, ASK is mentioned in US 3,598,122 as a possible antipyretic active agent in a membrane transdermal therapeutic system. FR-M 1757 discloses a dermal topical use of an oil-in-water emulsion containing 5% ASK for the treatment of acute pain. FR-A 2 297 612 claims rubbing agents and ointments which contain ASK as an analgesic agent. In combination with corticosteroids, ASK is used in US 4,012,508 for topical use in dermatological indications. US 4,219,548 discloses the topical use of ASK against inflammation. The ASK-containing gel is topically applied in EP-A 0 055 635 and antipyretic application of ASKs in anti-inflammatory, analgesic indications. A device for a transdermal aqueous system for anti-inflammatory and analgesic effects is disclosed in US 4,460,368.

From the ethanolic solution, ASK is topically applied in the US file

4,665,063 in dermatological disorders.

An increase in ASK permeability in transdermal application is achieved in US 4,640,689 by the use of electric current.

Also, the addition of suitable permeation enhancers according to EP-A 162 239 leads to improved skin permeability in transdermal use. by

JP-OS 61 167 615 is an ASK applied to the skin by means of a film. US 4,810, 699 discloses the combination of ASK with other active ingredients for the transdermal treatment of inflammation, pain and temperature. JP 1 203 336 discloses special permeation enhancers for transdermal application of ASK as a pain reliever. Other substances of this type for ASK in transdermal application to suppress inflammation are found in JP 1,242,521. ASK solutions for topical application, which are stable in storage and used to suppress inflammation and alleviate pain, are finally discussed

US 4,975,269.

It is not possible to assume from the prior art that it is contemplated to use a transdermal system that contains ASK and / or its pharmaceutically acceptable salts for suppressing platelet aggregation in humans and / or for the prophylaxis of cancer.

Many compositions and preparations contain water or hydrophilic solvents that accelerate the hydrolysis of ASK to salicylic acid. Since this acid, as already explained above, has no antithrombotic effect but nevertheless exhibits a comparable anti-inflammatory and analgesic effect with ASK, it is understood that the degradation of ASK in said applied systems is not investigated in detail.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide for administration of ASK and / or its pharmaceutically acceptable salts for antithrombotic therapy and / or for the prophylaxis of cancer such delivery system that eliminates the disadvantages of oral administration and allows targeted dosing of the unchanged active ingredient.

The solution to this object is unexpectedly that a transdermal system, preferably one containing acetylsalicylic acid and / or acetylsalicylic acid and / or its pharmaceutically acceptable salts for antithrombotic therapy and / or for the prophylaxis of cancer, is used. a salt thereof in a matrix that substantially suppresses, respectively. it does not allow the hydrolysis of acetylsalicylic acid. In other words, such a system does not contain any substances which, under storage conditions, resp. caused cleavage of the acetyl group during use.

The transdermal delivery system has the following advantages in antithrombotic therapy:

1. ASK is delivered directly to the body's circulation in its pharmacologically active form, thus preventing metabolism in the gastrointestinal tract.

2. Reduction of gastrointestinal side effects.

3. Constant therapeutic effect at reduced doses of ASK.

4. Reduce the risk of overdose.

5. Outpatient treatment of patients without supervision.

6. Improved therapeutic care for patients.

The content of ASK in a delivery unit of this type is generally between 5 and 500, preferably between 30 and 200 mg, respectively. corresponding amounts of pharmaceutically acceptable salts. Pharmaceutically acceptable ASK salts are all non-toxic, pharmacologically active salts such as lithium, sodium, potassium, magnesium and calcium or ASK salts with basic organic compounds such as lysine, arginine or cetrimonium bromide (hexadecyltrimethylammonium bromide). The rate and rate of ASD transdermal passage into the body naturally depends on the amount, type of compound (free acid or salt), and optionally also on the presence of excipients such as permeation enhancers. Preferably, the system is designed such that the blood ASK level is between 0.1 and 1.0 µg / ml. For practical use, the content is preferably tuned according to the type of matrix, recommended patch time, intended indication, body weight (children or adults), matrix permeability, respectively. the membrane of the patch and the skin permeability.

A therapeutically effective amount of ASK and / or ASK-salts in the blood in antithrombotic therapy and prophylaxis of cancer corresponds to a blood ASK level of between 0.1 and 1.0 µg / ml. Although ASK is rapidly absorbed after oral administration, due to the hydrolysis of ASK to salicylic acid, this route of administration is disadvantageous, especially considering the short biological half-life and the fact that constant administration is desirable for prophylaxis.

On the other hand, the proposed transdermal treatment according to the invention yields relatively constant and reproducible ASK values in the blood, which are particularly effective and suitable for the prophylaxis of cancer in antithrombotic therapy. The transdermal delivery system of the invention provides guaranteed constant and reproducible ASK values in the blood that are effective in antithrombotic therapy.

The term prophylaxis of cancer means e.g. anti-cancer with tumor formation, e.g. in the stomach and intestinal tract, such as colon cancer.

The transdermal delivery system for ASK and / or ASK salts of the invention can be implemented in a variety of ways such as e.g. in particular in the form of a self-adhesive patch, film, spray, cream, ointment and the like. Preferred is a self-adhesive patch delivery form comprising an impermeable backsheet, an active substance reservoir of polymer matrix associated therewith, in the absence of other dispensing mechanisms, an active substance delivery membrane, an adhesive device for attaching the system to the skin, and a protective layer removable prior to application. system. In all forms, care must be taken that the matrix binding the active substance reservoir is chosen such that hydrolysis of acetylsalicylic acid is avoided or at least strongly suppressed. In this case, the hydrophobic nature of the matrix leads to a target rather than hydrophilic.

In order to suppress, respectively. to avoid hydrolysis, substances such as acylating agents, preferably acetylating agents, in particular acetic anhydride e.g. in an amount of from 0.01 to% by weight, preferably from 0.1 to 2% by weight, based on acetylsalicylic acid.

The transdermal self-adhesive patches usable according to the invention are all patches known to those skilled in the art. In general, two basic dosing principles can be distinguished: matrix diffusion dosing and membrane controlled dosing, with only the second method being the release of the active ingredient of the zero order. A matrix diffusion dispensing patch is described e.g. DE 33 15 272. It consists of an impermeable backing layer, a polymer matrix containing the reservoir associated therewith at a concentration higher than the saturation concentration, an adhesive reservoir-bonded and permeable layer for the active substance and a protective layer. a layer covering the adhesive layer which is removed in use, e.g. a siliconized polyester film, in particular polyethylene terephthalate. If the reservoir matrix itself is adhesive, the additional adhesive layer may be omitted. However, there are also systems with a lower concentration than the saturation concentration.

Control membrane patches are described, for example, in U.S. Pat. Nos. 3,742,951, 3,797,494, 3, 996,934 and 4,031,894. These patches consist essentially of a backing layer (e.g. a polyester film such as polyethylene terephthalate, which may be aluminized, or an aluminized synthetic resin film such as polypropylene, nylon, polycaprolactam), which represents one of the surfaces, a membrane, an active substance-permeable adhesive layer which represents the second surface and finally from the active substance-containing reservoir which is located between the two surface-forming layers. Alternatively, the active ingredient may also be contained in a plurality of microcapsules that are distributed within the permeable adhesive layer. In any case, the active agent is continuously dosed from the reservoir or microcapsules through the membrane into an adhesive layer permeable to the active agent which is in contact with the skin of the patient. In the case of microcapsules, the capsule material may also act as a membrane. Substances suitable for membranes and microcapsules are described e.g. U.S. Pat. No. 3,996,934.

As a marginal note, it is also possible to control by means of an electric current, whereby the passage of the active substance through the skin is a speed-determining step. Processes of this type are referred to as electroosmosis, iontophoresis or electrophoresis.

If desired, patches of all types may contain, in addition to the reservoir-binding matrix and the active substances, which include combinations of ASK and its salts, additives of various types to achieve the desired properties.

Special mention should be made of those additives which promote the passage of ASK and / or its pharmaceutically acceptable salts through the skin. The exact calculation of the additives is known to those skilled in the art, for example, glycerin, 1,2-propanediol, monomethyl- and / or glycerol. ethylene glycol monoethyl ether, 2-octyldodecanol, laurate, palmitate, sorbitol stearate or oleate, C ₈ -C ₁₀ -ethoxy derivatives of oleic acid glycerides, lower (C ₁ -C ₃ ) esters of lauric acid, such as propylene glycol monolaurate, lauric acid, capric acid, capric acid etc. The amount is generally from 0 to 20 weight percent, preferably from 0.5 to 10 weight percent based on the total amount of matrix components. This amount depends on the type of matrix, the permeability of the matrix, respectively. the membrane of the patch, the dissolution capacity of the active substance permeation enhancers and the skin permeability.

The invention will be illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 Single-layer acrylate-based system

To a 100 g acrylic adhesive solution (e.g., Durotak® 280-2516 National Starch and Chemical) with a solids content of 42% by weight was added 5 g of dioctylcyclohexane, 8 g of acetylsalicylic acid and 40 mg of acetic anhydride and the resulting solution was homogenized with stirring.

The solution is then applied in a layer of 300 microns thick to a siliconized 100 micron thick polyester film. This film takes over the function of a removable protective layer in the finished system and must be removed before use. The wet film is then dried at 50 ° C for 20 minutes to give a basis weight of 100 g / m ² .

Subsequently, the dried film is coated with a 12 micron thick polyester film. Finished patches are punched out of the laminate.

Example 2 Multilayer system

The finished system consists of a removable protective layer, a skin adhesive layer, a non-adhesive reservoir, a back layer impermeable to the active ingredient and a well adhesive base layer, located between the reservoir and a back layer, non-adhesive A. Preparation for the skin, back layer impermeable a base layer to anchor the reservoir to the backing layer of the layer which is adhered to the skin of the polystyrene block polymer (e.g., Cariflex ' TR-1107, from Shell),

100 g and polyisoprene

175 grams of glycerin ester of calophony and partially hydrogenated is added 15 grams of dioctylcyclohexane are dissolved in 500 grams of n-heptane acetylsalicylic acid and 150 micrometers homogenized to siliconized in the finished product to form a layer. The wet film is then dried to give a basis weight of 25 and then mg of acetic anhydride. The mixture is then applied and then applied in a layer of 100 polyester film, which is removable for 20 minutes at 50 ° C, g / m ² .

B. Preparation of a reservoir layer of polystyrene and polyisoprene

100 g of a block polymer of (e.g. Cariflex ^R TR-1107, from Shell) and dioctylcyclohexane are dissolved in 120 g of n-heptane.

Subsequently, 40 g of acetylsalicylic acid and 40 mg of acetic anhydride are added and the mixture is homogenized with stirring. It is then applied in a layer of 300 microns thick to a siliconized polyester film, which is thicker than in the case of a removable protective layer, and dried at 50 ° C for 20 minutes. The dried reservoir film has a basis weight of 100 g / m ² .

C. Preparation of base layer

100 g of polystyrene and polyisoprene block polymer (eg Cariflex ^R TR-1107, from Shell),

175 g of glycerine ester of partially hydrogenated calophony g and dioctylcyclohexane are dissolved in 500 g of n-heptane and applied analogously to procedure B in a 100 micron thick layer on a siliconized polyester film which is thicker than in the removable protective layer and 20 minutes dried at 50 ° C. The dried film has a basis weight of 25 g / m ² .

D. Construction of the final system and construction of individual patches

The reservoir layer obtained according to the layer to be bonded A is then removed as described in Procedure B. Now the base layer of the thicker siliconized system is coated with 12 microns thick. The individual finished patches are then laminated.

in process B, the siliconized film is coated on the thicker skin in the same way as obtained in process C, and after removal of the film in process C, the polyester film is punched out of the obtained

Example 3 Base hot membrane system

The laminate suitable for polyester and flexible polyethylene / vinyl acetate copolymer film is welded to a 50 micron thick polyethylene / vinyl acetate copolymer membrane with a vinyl content of 19% by weight based on the dimensions and shape of the resulting patches to form a flat pouch. The width of the resulting seam should be 4 mm wide. Before the pouches are completely sealed, they are filled with a liquid formulation of silicone oil containing 10% acetylsalicylic acid and 0.05% acetic anhydride. The membrane side of the pouch is now adhered to a layer which is adhered to a silicone-based skin, provided with a suitable non-stick-treated film. This film is identical to the removable protective layer. Finished systems are made by punching, leaving a pouch with a 3 mm wide closing seam.

Industrial usability

The transdermal delivery system of the invention is useful in antithrombotic therapy and prophylaxis of cancer associated with tumor formation, particularly in the stomach and intestinal tract.

Claims (9)

Transdermal delivery system for antithrombotic therapy and / or for the prophylaxis of cancer, comprising as active ingredient acetylsalicylic acid and / or pharmaceutically acceptable salts thereof in a matrix which substantially suppresses the hydrolysis of acetylsalicylic acid, characterized in that the system comprises a removable protective layer, a skin adhesive layer, an active substance containing reservoir, an active substance-impermeable backing layer, and a base layer disposed between the reservoir and the backing layer, wherein the skin-adhesive layer comprises: - a block polymer of polystyrene and polyisoprene - a glycerin ester of partially hydrogenated caffeine - dioctylcyclohexane, with these components - dissolve in n-heptane with the addition of acetylsalicylic acid and acetic anhydride the reservoir layer contains: - a block polymer of polystyrene and polyisoprene - dioctylcyclohexane - acetylsalicylic acid (ASS) - acetic anhydride base layer contains: - a block polymer of polystyrene and polyisoprene - a glycerin ester of partially hydrogenated caffeine dioctylcyclohexane, wherein - in n-heptane Transdermal delivery system and 500 mg, preferably between 30, also these components dissolve the system according to claim 1, comprising between 5 and 200 mg of acetylsalicylic acid, respectively. a corresponding amount of an acceptable salt in a stable form. its pharmaceutical claim 1 or 2, there exists in the form of a backing layer, a matrix associated therewith, preferably when the protective layer of the system is saturated, if necessary with adhesive. 3. The transdermal delivery system of claim 1, wherein the patch a comprises an impermeable reservoir of active agent from a polymer at a concentration greater than the absence of other dispensing mechanisms of the drug delivery membrane, an adhesive device for attaching the system to the skin and removable prior to application. 4. Transdermal delivery characterized by cream or ointment. The system of claim 1, and wherein there is or 2, in the form 5. Transdermal characterized by acetylsalicylic acceptable salts of electric current. the system according to which the acid and / or through the skin is a feeder of claim 4, 1, 2 permeability pharmaceutical supported by use Transdermal delivery system according to claims 1 to 5, characterized by the permeability of the acetylsalicylic pharmaceutically acceptable salts by the addition of suitable substances. or a transdermal delivery system according to one or more of the preceding claims, characterized in that an effective amount of acetylsalicylic acid is incorporated into the delivery system. 7. A process for the preparation of one of the acid systems and / or pharmaceutically acceptable salts thereof in solid form or in solution or dispersion, whereupon conventional additives can be added. 13 The use of a transdermal delivery system according to one or more of claims 1 to 7 in antithrombotic therapy and / or antithrombotic therapy. in the prophylaxis of cancer, particularly in human medicine. Method according to one or more of Claims 1 to 7 and 9, characterized in that the system is intended for the prophylaxis of cancer associated with the formation of tumors, in particular in the stomach and intestinal tract.