FI120719B - A process for the preparation of a transdermal system containing acetylsalicylic acid - Google Patents

Description

Process for the preparation of a transdermal system containing acetylsalicylic acid - Acetylsalicylsyra

The invention relates to a process for the preparation of a transdermal therapeutic delivery system containing acetylsalicylic acid which can be used for thrombotic therapy and cancer prevention.

The antiplatelet effect of acetylsalicylic acid (ASS) has been described in the past 60 years. In the years that followed, a large number of clinical trials have been conducted in which orally administered ASs have been linked to the following 10 indications:

Prevention of first myocardial infarction.

Prevention of new heart attacks.

Treatment of unstable angina pectoris.

Blockage of blockages after the placement of vascular prostheses, for example, after an artificial heart-15 valve.

Inhibition of peripheral arterial obstruction.

Prevention of blockages in cerebrovascular insufficiency.

When used hereinafter, the term "antithrombotic therapy" refers mainly to these indications.

*** *** *** *** *** *** · *** 20 *** ***: ***: 20 Recent summaries of the results of these therapeutic studies in patients (· 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. Clin., 84.43-51 (1989).

In medical practice, acetylsalicylic acid is often associated with non-steroidal, anti-inflammatory, analgesic and anti-pyretic agents. ASS acts on T-platelet function and prevents blockages by irreversibly inhibiting the synthesis of thromboxane A2 (M. Buchanan et al., "Aspirin inhibitory platelet function indepen-"): Thrombosis Res. , 25, 363-373 (1982)). ASS is absorbed rapidly after oral administration. However, it has a very short half-life in the circulation of 30, only 15-20 min (M. Rowland et al., "Kinetics of Acetylsalicylic Acid Disposition in Man", Nature 215. 413-414 (1967).

: ***: In a normal adult human, ASS is rapidly hydrolyzed to gastric salicylic acid by G. Levy, "Clinical Pharmacokinetics of Aspirin" (Pediatrics 62, 867-872 (1978)).

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However, it has to be kept in mind that the ASS itself, and not its hydrolyzing product, salicylic acid, is active in antifouling activity. (W. Horch, "Die Salicylate", Pharma-34. 585-604 (1979)).

Acetylsalicylic acid is widely used by large sections of the population, especially in the US. 5 According to Thun et al., "Aspirin Use and Reduced Risk of Fatal Colon Cancer", New Engl. J. Med., 325. 1539-1596 (1991), assays a reduction in colon cancer mortality of about half when used continuously and for at least 16 days per month. The study involved more than 660,000 people who had used ASS for at least one year and were from 10 of the 50 US states, Colombia and Puerto Rico. However, even if only the use of ASS is considered, without further information on the quality and dose of the preparation, it can be assumed that the ASS has been taken orally and that the active compound is not the product of hydrolysis of salicylic acid but ASS itself.

15 In antithrombotic therapy, oral administration is almost always used; in contrast, attempts to apply the active ingredient to the skin are already known in the anti-inflammatory, analgesic and antipyretic indications. Thus, ASS is mentioned in U.S. Patent 3,598,122 as a potential anti-pyretic agent in a membrane-controlled transdermal system. FR-M-1757 20 describes a topical dermal application of an oil-in-water emulsion for acute pain: use containing 5% ASS. FR-A-2 297 612 discloses requirements for an ointment and an ointment containing ASS as an analgesic. US- ···: v. U.S. Patent No. 4,012,508 discloses the use of ASS in combination with corticosteroids for topical dermatological indication. U.S. Patent 4,219,548 describes · ·: *. · * 25 topical use of ASS for anti-inflammatory use. EP-A-0 055 635 uses an AAS-containing gel for topical anti-inflammatory, analgesic and antipyretic indication. Instead, U.S. Patent 4,460,368 discloses a device comprising an aqueous system for transdermal use of ASS, which is intended to achieve an anti-inflammatory and analgesic effect. In U.S. Patent No. 4,665,063, ASS is used locally in ethanol solution for dermatological disorders. U.S. Patent No. 4,640,689 achieves an increase in the penetration rate of ASS ··· .... in transdermal use with electric current.

The addition of a suitable penetration accelerator according to EP-A-162 239 resulted in improved transdermal penetration of ASS in transdermal use. 35 In accordance with JP-OS-61 167 615, AS $ is applied by a film to the skin. US 4,810,699 describes the use of a combination of ASS and other active ingredients 3 for the transdermal treatment of inflammation, pain and fever. JP-A-1 203 336 includes a special penetration accelerator for the transdermal use of ASS as an analgesic. JP-A-1 242 521 further describes compounds in this field for trans-dermal applications of ASS Tu-5. In contrast, U.S. Pat. No. 4,975,269 discloses a storage stable solution of ASS. for local anti-inflammatory and analgesic applications.

From the foregoing prior art, it cannot be inferred or implied that it would draw attention to the use of transdermal systems such that the use of ASS and / or its pharmaceutically acceptable salt would include the prevention of platelet thrombosis and / or cancer in humans.

Many formulations and compositions contain water or a hydrophilic solvent that accelerates the hydrolysis of ASS to salicylic acid. Since these do not contain an antithrombotic effect as described above, but on the contrary exhibit a verifiable anti-inflammatory and analgesic effect of ASS, it is to be understood that the release of ASS in these applications has not been studied in detail.

Therefore, it was an object of the present invention to provide a delivery system for the use of ASS and / or a pharmaceutically acceptable salt thereof for anti-thrombotic therapy and / or cancer prevention which is devoid of oral applications. disadvantages and would allow targeted administration of the active ingredients.

··· • ·: · ν The solution to this task is surprisingly such that a transdermal system is fitted to a salicylic acid and / or its pharmaceutical formulation for antithrombotic treatment and / or cancer prevention, preferably *: one containing acetylsalicylic acid or a salt in a matrix which substantially reduces or does not allow the acetylsalicylic acid to be hydrolyzed at all. In other words, the system is essentially free of material that causes weapons. ·· *. style grouping under storage conditions or during use.

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The essential features of the invention are set forth in the appended claims: ·; 30 seats.

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The transdermal delivery system provides the following O benefits for antithrombotic therapy: 1. The AS is released into the bloodstream in its pharmacologically active form, which saves the digestive system's metabolism.

2. Reduction of side effects in the intestinal tract.

3. The therapeutic effect is constant with reduced ASS administration.

5 4. Reduced risk of overdose.

5. Patient care without supervision.

6. Improved reliability of patient care.

The concentration of ASS in such a preparation is generally 5 to 500, preferably 30 to 200 mg, or the equivalent amount of a pharmaceutically acceptable salt. Salts useful herein are all non-toxic, pharmacologically acceptable salts such as lithium, sodium, potassium, magnesium and calcium salts, or salts of ASS with basic organic compounds such as lysine, arginine, or cetrimonium bromide (hexadecyltrimethylammonium) . The rate and amount of transdermal delivery of ASS to the body will, of course, depend on the amount and quality of the compound (free acid 15 or salt) and sometimes also the presence of excipients such as penetration accelerators. The system is suitably adjusted to set the ASS blood values between 0.1 and 1.0 pg. For practical implementation, consideration will be given to the appropriate concentration of ASS in matrix grade, recommended duration of the patch, intended indication, body weight (child or adult), matrix permeability or 20 membrane of the patch, and penetration through the skin.

• ·: A therapeutically effective amount of thrombotic therapy and cancer prevention! ...: The amount of ASS and / or ASS salt in the blood contains 0.1 to 1.0 pg / ml of ASS in the blood. Although ASS is rapidly absorbed by oral administration, the release of such a preparation is disadvantageous due to the hydrolysis of ASS to • salicylic acid, especially considering the short biological half-life and the desirability of constant rate release in contraception. In contrast, the transdermal treatment proposed in accordance with the invention can maintain a relatively constant and reproducible amount of ASS in the blood, which is particularly effective in antithrombotic therapy and is suitable for the prevention of cancer. In contrast, the transdermal delivery system ** '* obtained in accordance with the invention certainly provides a uniform and reproducible amount of ASS in the blood, which is effective in antithrombotic therapy.

t t ·

For example, cancer prevention is understood to be one that targets, for example, C. *: a cancer with abscesses, such as colon cancer.

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According to the invention, the transdermal ASS and / or ASS salt delivery system can be implemented with an adhesive patch or flat bag. Most preferred is an adhesive patch dosage form comprising an impermeable backing layer, a reservoir of the active ingredient 5 bound to the hydrophobic polymer matrix, in the absence of another delivery mechanism that delivers the active agent to the delivery membrane, In addition, in all forms, it should be noted that the matrix containing the active ingredient is selected so that no hydrolysis of ASS occurs, or at least 10 is significantly reduced. Here, the hydrophobic composition of the matrix leads more easily to the goal than the hydrophilic one.

To displace or reduce the hydrolysis, agents such as acylating agents, preferably acetylating agents, especially acetic anhydride, for example 0.01-3, preferably 0.1-2 wt.%, May be added based on the amount of acetylsalicylic acid.

The transdermal skin adhesive patches obtained according to the invention are all patches known to those skilled in the art. They further allow, in principle, the organization of two delivery principles: transfer by matrix diffusion and transfer by membrane, with only the latter having the release of the active ingredient without carrying out the transfer. DE-A-3 315 272 describes a patch in which transfer is by matrix diffusion. It consists of an impermeable backing layer, an adhesive polymer matrix stock attached thereto, containing the active ingredient in excess of the saturation concentration: Y, an active material permeable adhesive layer attached to the stock, and: ** a protective layer covering the adhesive layer with a removable film, consists of polyester, in particular polyethylene terephthalate. If the storage matrix is self-adhesive, the additional attachment layer may be dispensed with. This is also a system that allows ... less than a saturation concentration.

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For patches where membrane transfer is referred to, ·· *. 30, for example, U.S. Patent 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 foil consisting of • ·. A polyester such as polyethylene terephthalate which may be aluminized, or an aluminum * · foil consisting of an artificial resin such as polypropylene, nylon or polycaprolactam) forming an outer surface, membrane, an agent-permeable adhesive layer forming a second surface, and finally a stock containing the active agent and located between the two layers forming the outer surface 6. Alternatively, the active ingredient may be contained in a plurality of microcapsules distributed within the permeable adhesive layer. In all cases, the active ingredient is continuously transferred from the storage or microcapsules through the membrane to the permeable adhesive layer which is in contact with the skin to be treated. In the case of a microcapsule, the capsule material may also act as a membrane. Suitable membranes and microcapsules are described in U.S. Patent No. 3,996,934.

In addition, the transfer is also possible by means of an electric current, whereby the rate determining step is the penetration of the active ingredient into the skin. Such a reaction occurs by electro-osmosis, ionophoresis or electrophoresis.

Such prior art patches may, if necessary, contain a stock-forming matrix and an active ingredient which includes combinations of ASS and its salt, and various other additives to achieve the desired properties. Particular mention should be made of additives that promote the percutaneous penetration of ASS 15 and / or its pharmaceutically acceptable salts. The exact calculation of the additives is unnecessary for one skilled in the art, however, for example, glycerin, 1,2-propanediol, monomethyl or monoethyl ether of ethane glycol, 2-octyldodecanol, laurate, palmitate, sorbitol stearate or oleate, Ce. lower alkyl-20 1 (C 1 -C 3) esters such as propylene glycol monolaurate, lauric, capric, oleic acid: * ·, etc. The amount generally rises from 0 to 20, preferably from 0.5 to 10% by weight: calculated from the total matrix shares. It depends on the type of matrix, the permeability of the matrix or the membrane of the patch, the ability of the penetration accelerator to dissolve, and the penetration through the skin.

The invention is illustrated by the following examples: 1. Acrylate-based single-layer system «·· '· [' 100 g acrylate adhesive solution (e.g. OurotakR 280-2516 National Starch and * ···) * Chemical) with a fat content of 42% by weight, 5 g of dioctylcyclohexane, 8 g of acetylsalicylic acid and 40 mg of acetic anhydride are added and the solution is homogenized by stirring.

• · «: / ·: Apply 300 μητ.η on siliconized 100 µm polyester foil. This foil takes over the finished system, which acts as a removable protective layer and must be removed if necessary 7 before use. The moist film is dried for 20 minutes at 50 ° C and then has a basis weight of 100 g / m 2.

Finally, the dried film is coated with 12 µm thick polyester foil. Finished patches are stamped from this laminate.

5 2. Multilayer system

The finished system consists of a removable protective layer, a skin adhesive strip, a non-adhesive storage, an active agent impermeable backing layer and a highly adhesive bottom strip between the storage layer and the backing layer, which serves to anchor the non-10 adhering stock to the backing layer.

A. Preparation of a Skin Adhesive Strip 100 g of block polymers of polystyrene and polyisoprene (e.g., Cariflex® TR-1107, Fa. Shell), 175 g of glycerol esters of partially hydrogenated rosin and 50 g of dioctylcyclohexane are dissolved in 500 g of n-heptane and finally g of acetylsalicylic acid and 150 mg of acetic anhydride. The pulp is homogenized by blending and then applied to the siliconeized polyester foil to serve as a removable protective layer in the finished product. The moist film is dried for 20 minutes at 50 ° C and then weighs: 25 g / m2. v. 20 B. Preparation of Strip Strip: · 100 g of block polymer made of polystyrene and polyisoprene (e.g., Cariflex * TR-1107, Fa. Shell) and 20 g of dioctylcyclohexane are dissolved in 120 g. n-heptane. Finally, 40 g of acetylsalicylic acid and 40 mg of acetic anhydride are added and the mass is homogenized by stirring. The pulp is re - applied at 300 µm on 25 thick starches which are siliconized with polyester foil. and dry for 20 minutes at 50 ° C. The dried stock film has a basis weight of 100 g / m 2. C. Preparation of the base plate: • 100 g of block polymers of polystyrene and polyisoprene (for example, 30 Cariflex® TR-1107, Fa. Shell), 175 g of glycerol esters of partially hydrogenated rosin and 50 g of dioctylcyclohexane are dissolved in 500 g of n-heptane and applied in analogy to point B on a silicone-bonded polyester foil with 8 removable protective layers and dried for 20 minutes at 50 ° C. The dried stock weight is 25 g / m 2 D. Formation of joint system and stamping of individual patches

The storage strip obtained in step B is coated on the skin adhesive layer of step A and finally the starch siliconized foil mentioned in step B is removed. Now, the same is done for the base layer C, and after removing the silicone foil mentioned in C, a 12 µm thick polyester foil is coated.

The finished patch is stamped from a common laminate.

3. Membrane System 10 A flexible polyester foil heat sealable laminate and a polyethylene / vinyl acetate copolymer foil are brought into line with the size and shape of a subsequent patch so that a 50 µm thick membrane made of a polyethylene / vinyl acetate copolymer with vinyl 19% seamed so that the quality includes a flat bag. The seam width-15 should be 4 mm. Before the bag is completely sealed, it is filled with a preparation of running silicone oil and 10% acetal salicylic acid and 0.05% acetic anhydride. The membrane sides of the bag are now covered with a suitable silicone-based adhesive foil, located on a silicone-based skin adhesive strip. This foil is identical to the removable protective layer 20.

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The finished system is stamped to leave a 3 mm strong seal edge in the bag.

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Claims (14)

A process for the preparation of a transdermal therapeutic system in the form of a patch, comprising a reservoir based on a hydrophobic polymer matrix and containing as active substance (s) acetylsalicylic acid and / or pharmaceutically acceptable salts thereof. characterized in that the reservoir is produced by preparing a mixture containing the matrix (s) polymer (s), acetylsalicylic acid and / or pharmaceutically acceptable salts thereof, an acylating agent and organic (organic) solvent, and the resulting pulp is applied to a carrier and it is dried to form a reservoir layer. Method according to claim 1, characterized in that the matrix-forming polymers are selected from the group of acrylic-based adhesive polymers. Process according to claim 1, characterized in that the matrix-forming polymers are selected from the group consisting of block copolymers of polystyrene and polyisoprene. Process according to any one of claims 1-3, characterized in that the acylating agent is an acetylating agent, preferably acetanic anhydride. A process according to any of the preceding claims, characterized in that the acylating agent is added at a concentration of 0.01-3% by weight based on the amount of Y \ acetylsalicylic acid. t · I Method according to any of the preceding claims, characterized in that the process further comprises a step in which the mixture is added to one or more substances which promote penetration through the skin. 25 Process according to any of the preceding claims, characterized in that the carrier is a polyester film which acts as a removable protective layer, and the reservoir is coated after another drying with another polyester film. • · · • Process according to any of the preceding claims, characterized in that the reservoir contains acrylic-based adhesive, acetylsalicylic acid, acetanhydride and dioctylcyclohexane and that one side of the reservoir is coated with a removable protective layer, preferably a polyester foil, and the other side is of the reservoir. background layer, preferably a polyester film. 9. A process according to any preceding claim, characterized in that the reservoir layer is prepared from a mixture containing a block copolymer of polystyrene and polyisoprene, acetylsalicylic acid, acetanhydride and dioctylcyclohexane, and the method further comprises the steps of: of the matrix layer, a base layer is laminated on the other side of the matrix layer, an impermeable protective layer for the active substance is laminated on the base layer, the layer adhering to the skin is coated with a removable protective layer. 10. A process according to claim 9, characterized in that the skin-adhering layers contain polystyrene and polyisoprene (s) copolymer (s), partially hydrogenated rosin, dioctylcyclohexane, acetylsalicylic acid and acetanhydride (s). Process according to claim 9 or 10, characterized in that the base layer contains block copolymer (s) of polystyrene and polyisoprene, glycerol esters (esters) of partially hydrogenated rosin and dioctylcyclohexane. A process for the preparation of a transdermal therapeutic system in the form of a flat bag containing as active substance (s) acetylsalicylic acid. . and / or pharmaceutically acceptable salts thereof, characterized in that the process comprises the steps of: mixing the silicone oil with acetylsalicylic acid and acetanic anhydride to obtain an active ingredient preparation:. - the paste is filled with the prepared preparation and closed. ··· · t ·· A method according to claim 12, characterized in that the strip is made of 25. a heat-sealable laminate consisting of a flexible polyester film and. a polyethylene / vinyl acetate copolymer film; and a polyethylene / vinyl acetate copolymer membrane, said laminate and membrane being bonded together by heat sealing. • · • · \ * ·: 30 14. A method according to claim 13, characterized in that the method further comprises a step wherein the membrane side of the strip is laminated with an adhesive layer, preferably a silicone-based adhesive layer, and the adhesive layer is coated with a removable protective layer, preferably a polyester film.