SI9400023A - Transdermally administered system containing acetylsalicylic acid for thrombosis theraphy and cancer prophilaxys - Google Patents

Abstract

The invention relates to a transdermal anticancer system containing acetylsalicylic as the active substance administration for antithrombotic therapy. for the prophylaxis of the acid and / or its pharmaceutically acceptable salts.

Description

Transdermal administration system containing acetylsalicylic acid for antithrombotic therapy and anti-cancer prophylaxis

FIELD OF THE INVENTION

The field of the invention is the transdermal system for antithrombotic therapy and prophylaxis against cancer containing acetyl .....

salicylic acid.

Technical problem and state of the art

The effect of acetylsalicylic acid (A55) on preventing platelet aggregation and its action in preventing cardiac thrombosis was described in the late 1960s. In the next time it was

There have been a number of clinical studies conducted that have given oral ASS in the following indications:

~ prevention of the first heart attack,

- prevention of re-infarction, ~ treats unstable angina pectoris,

- prophylaxis of thrombosis after the use of vascular or dental prostheses. artificial heart valves, ~ prophylaxis of peripheral arterial thrombosis and

- prophylaxis of thrombosis of cerebral insufficient blood flow.

if the term antithrombotic therapy is used in the following, these indications are substantially widespread.

The results of these therapeutic studies in patients have recently been condensed (V.Fuster et al., Aspirin in the prevention of coronary disease, New Eng. J.Med. 321, 183-185 (1989) and R.

Zichner et al., Towards optimal dosing of acetic acid. Med. Wedge. 84, 43-51 (1989).

Acetylsalicylic acid is often used in medical practice as a non-stereoidal, inflammatory, analgesic and antipyretic active substance. ASS affects platelet function and prevents thrombosis by non-reversible inhibition of thromboxane A2 synthesis (M.Buchanan et al. Aspirin inhibits platelet function independ .....

ent of cyclooxygenase Thrombosis Res. 25, 363-373 (1982).

After oral administration, ASS is rapidly absorbed. The biological half-life in body circulation is however very short, lasting only 15-20 min (M.Rowland et al., Kinetics of acetylsalicylic acid disposition in man, Nature 215, 413-414 (1967)). In normal adults, ASS is rapidly hydrolyzed already in the intestinal tract to salicylic acid (G. Levy, Clinical pharmacokinetics of aspirin, Pediatrics 62, 867-872 (1978)).

However, it must be borne in mind that ASS is itself active in inhibiting platelet function rather than the hydrolysis product of salicylic acid (W. Horsch, Die Salicylate, Pharmazie 34, 585-604 (1979)).

Acetylsalicylic acid (ASS) is widely used in the United States especially by a wide population. Following the publication of Thuna et al., Aspirin Use and Reduced Risk of Fatal Colon Cancer, New Engl. J.Med. 325, 1593-1596 (1991) reduced ASS mortality from colon cancer to about half if ASS was taken fluidly at a minimum of 16 days per month. The survey spread to more than 660,000 people who have taken ASS for at least one year and have lived in all U.S. states, Columbia and Puerto Rico, although it only covered ASS use without providing further information on the type administration and dose, however, it must be assumed that ASS was taken orally and that the responsible substance was not the hydrolysis product of salicylic acid, but ASS itself.

Oral administration is practiced almost exclusively with antithrombotic therapy; conversely, inflammatory retention, analgesic and antipyretic indications have been known to try to apply the active substance via the skin. Thus, reference is made to ASS in US-PS 3, 598, 122 as a possible antipyretic active substance in a membrane-controlled transdermal therapeutic system.

FR-M 1757 describes a dermal topical application of an oil-in-water emulsion containing 5% ASS against acute pain. FR-A 2 297 612 comprises rubbing agents and ointments containing ASS as an analgesic agent.

ASS is combined with corticosteroids in US-PS 4, 012, 508 for topical use in dermatological indications. US-PS 4, 219, 548 describes the topical use of ASS to contain inflammation. The ASS containing gel is topically applied to EP-A 0 055 635 for inflammatory retention, analgesic and antipyretic indications. The subject of US-PS 4,460,368 is the preparation for transdermal application of ASS from an aqueous system to achieve inflammatory retention and analgesic effects. In US-PS 4,665,063, ASS from ethanol solution is topically applied for dermatological disorders. The ASS penetration rate of transdermal administration is achieved in US-PS 4,640,689 with electrical current.

Also, the addition of suitable penetration enhancers according to EP-A 162 239 leads, in transdermal administration, to improved penetration of ASS through the skin. According to JP-OS 61 167 615 ASS is applied using a film to the skin. US-PS 4, 810, 699 describes the combination of ASS with other active agents for transdermal treatment of inflammation, pain and fever.

Special penetration enhancers for transdermal ASS application as pain agent are JP-PS 1 203 336. Further substances of this type for ASS in transdermal inflammatory restraint application are found in JP-PS 1, 242, 521. For the storage of a stable ASS solution for topical application aimed at holding back inflammation and relieving pain are finally subject to US-PS 4, 975, 269.

The described state of the art cannot be summarized or derived from the use of a transdermal system containing ASS and / or its pharmaceutically acceptable salts for the prevention of platelet aggregation in humans and / or for profi .....

anti-cancer laxative.

Many formulations and compositions contain water or hydrophilic solvents that promote the hydrolysis of ASS to salicylic acid. Since it does not develop antithrombotic activity, as explained above, and, on the contrary, exhibits a comparable inflammatory inhibitory and analgesic effect with ASS, it is understandable that the breakdown of ASS in the aforementioned application systems has not been investigated in detail.

Description of solution to a technical problem

Therefore, it has been an object of the present invention to provide, for the administration of ASS In / or its pharmaceutically acceptable salts for antithrombotic therapy and / or for cancer prophylaxis, a delivery system that avoids the disadvantages of oral administration and permits targeted dosing of the unchanged active substance.

The solution to this task is surprising in that it is used to administer acetylsalicylic acid and / or its pharmaceutically acceptable components.

salts for antithrombotic therapy and / or for cancer prophylaxis, preferably a transdermal system containing acetylsalicylic acid or. salts in the matrix that substantially suppress the hydrolysis of acetylsalicylic acid or. Don't let her. In other words, the system is preferably free from substances which, under storage and / or storage conditions. while using acetyl group cleavages.

The transdermal delivery system offers the following benefits in antithrombotic therapy:

1. ASS is administered, in its pharmacologically active form, directly into the body, thereby preventing the metabolism of the substance in the gastrointestinal tract.

2. Reduction of gastrointestinal side effects.

3. Constant therapeutic effect with reduced ASS administration.

4. Reduced risk of overdosage.

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

6. Improved therapeutic loyalty of patients.

The content of ASS in such a unit of administration generally ranges from 5 to 500, preferably 30 to 200 mg, or. the appropriate amount of pharmaceutically acceptable salt. Useful ASS salts are all non-toxic, pharmacologically effective salts such as lithium, sodium, potassium, magnesium and calcium salts or ASS salts with basic organic compounds such as lysine, argline or cetrimones .....

bromide (hexadecyltrimethylammonium bromide). The rate and measurement of the transdermal passage of ASS into the body depends naturally on the amount, type of compound (free acid or salt) and possibly also on the presence of excipients as penetration enhancers. It is advisable to adjust the system to establish an ASS blood level between 0.1 and 1.0 pg / ml. For practical use, the content is adjusted according to the type of indication, body weight (children or adults), matrix permeability, or patch membranes and permeation through the skin.

For antithrombotic therapy and for prophylaxis against cancer, the therapeutically active amount of ASS and / or ASS salts in the blood corresponds to blood ASS values between o, l and 1.0 pg / ml. although ASS is rapidly absorbed after oral administration, ASS hydrolysis is a joke .....

target acid, this type of administration is disadvantageous, especially considering the short biological half-life and the fact that prophylaxis is desired as constant as possible. The transdermal treatment of the invention, in contrast, results in fairly constant and reproducible ASS blood levels that are particularly effective and suitable for cancer prophylaxis in antithrombotic therapy. The transdermal delivery system of the invention provides a constant and reproducible ASS blood level that is effective in antithrombotic therapy.

Under cancer prophylaxis, for example. understands anti-cancer prophylaxis by bula formation, e.g. in the gastrointestinal tract, such as colon cancer.

The transdermal delivery system of ASS and / or ASS salts according to the invention can be realized in a variety of ways, e.g. such as a particularly adhesive adhesive patch, as a film such as spray, cream, ointment or the like.

A preferred form of administration is a adhesive adhesive patch comprising an impermeable back layer, an associated reservoir of active substance of a polymeric matrix, in the absence of other control mechanisms, a membrane for controlling the release of the active substance, a adhesive adhesive device for securing the system to the skin, and, if necessary, a protective layer. which can be removed again before use. In all forms, care must be taken to ensure that the matrix forming the reservoir of the active substance is chosen so as to avoid ASS hydrolysis or at least is strongly retained. Hydrophobic array setup leads to a faster target than hydrophilic.

To hold or. to prevent hydrolysis, substances such as acylating agents, preferably acetylating agents, in particular acetanhydride, e.g. in an amount of 0.01 to 3, preferably 0.1 to 2% by weight with respect to acetylsalicylic acid.

As used according to the invention, transdermal adhesive adhesive patches are all patches known to the person skilled in the art. We can

- 9 delivers far-reaching two fundamental control principles: matrix diffusion control and membrane control, with only the latter having zero order active substance release. The matrix diffusion control patch is e.g. described in DE-PS 33 15 272. It consists of an impermeable backing layer, an associated polymer matrix reservoir containing an active substance at a concentration above the saturation concentration, a adhesive adhesive layer bound to the reservoir and an active substance permeable and of a protective layer covering the adhesive .....

adhesive layer and again removed for use, e.g. made of siliconized polyester film, in particular polyethylene terephthalate. if the reservoir matrix is already adhesive-adhesive itself, the additional adhesive-adhesive layer can be omitted. Systems with less than saturation concentration are also possible.

For membrane-controlled patches, U.S. Patent Nos. 3,742,951, 3,797,494, 3,996,934 and 4,031,894 are indicated. These patches exist, in principle, from the back layer (e.g. polyester film such as aluminizable polyethylene terephthalate or aluminized resin film such as polypropylene, nylon, shelf .....

prolactam representing one of the surfaces, from the membrane, from the adhesive layer permeable to the active substance representing the other surface and finally from the reservoir containing the active substance between the two layers forming the surfaces. Alternatively, the active substance may also comprise a plurality of microcapsules distributed within a permeable adhesive layer. In each case, the active substance is continuously emitted from the reservoir or microcapsules through a membrane in a sticky layer permeable to the active substance in contact with the skin under consideration. In the case of microcapsules, the capsule material also acts as a membrane. For membranes and microcapsules, suitable substances are described e.g. in LJS-PS 3,996,934.

In addition, it must be stated that the control is also possible by means of an electric current, the passage of the active substance through the skin being a step that determines the speed. Such procedures are referred to as electroosmosis, iontophoresis, or electrophoresis.

Patches of any kind may contain, in the case of need, in addition to the matrix forming the reservoir, as well as the active substances, including combinations of ASS and its salts, various types of additional substances, in order to obtain the desired image of the properties. In particular, such additional substances that promote the permeation of ASS and / or its pharmaceutically acceptable salts through the skin should be mentioned. Precise listing of additional substances is not necessary for a person skilled in the art, but for example glycerin, 1,2 .... .

propanediol, monomethyl ether ethylene glycol monoethyl, 2octyldodecanol, laurate, palmitate, stearate or oleate of sorbitol, Cg-CjO - ethoxylated butyric acid glycerides, lower alkyl (Cj to ¢ 3) - lauric acid esters such as propylene glycol monolaurate, lauric, capric acid 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 array, the permeability of the array, or. patch membranes, penetration capability .....

an oil accelerator for the active substance and permeation through the skin.

The invention will be explained by the following examples:

Example

1. A single layer acrylic based system

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

The solution is then applied 300 µm thick to a siliconized, 100 µm thick polyester film. This foil assumes the function of a removable protective layer on the finished system and must be removed before use. The wet film is dried at 50 ° C for 20 min and then has a surface weight of 100 g / m ² .

Then the dried film with 12 pm thick polyester film is lined. Finished patches are stamped from the laminate.

2. A multilayer system

The finished system consists of a removable protective layer, a skin adhesive coating, a non-sticky rezei-voar, an active-impermeable back layer and a good-adhesive primer between the reservoir layer and the back layer, and it is tasked to anchor the non-stick tank on the back layer.

A. Production of a coating for adhesion to the skin

- 100 g of block polymers of polystyrene and polyisoprene (eg Carflex ^R TR - 1107, Shell company),

175 g glycerin ester of partially hydrated rosin and

- 50 g of dioctylcyclohexane is dissolved in 500 g of n-heptane and then 15 g of acetylsalicylic acid and 150 mg of acetanhydride are added. The mass is homogenized by stirring and then coated 100 µm thick on siliconized polyester film, which serves as a removable protective layer on the finished product. The wet film is dried for 20 min at 50 ° C and then has a surface weight of 25 g / m ^.

B. Production of reservoir coating

- 100 g of polystyrene and polyisoprene block polymers (eg charms ™ flex ^R TR-1107 by Shell), and

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

Then 40 g of acetylsalicylic acid and 40 mg of acetanhydride are added and the mass is homogenized by stirring. The mass of the coated 300 pm thick at the thickest as a removable protective layer of a siliconized polyester film and dried for 20 min at 5O ⁰ C. The dried rezei- voarni film has a weight of 100 g / ^m2.

C. Coating

- 100 g of polystyrene and polyisoprene block polymers (eg Shell Chariflex ^R TR-1107),

175 g of glycerin ester of partially hydrated rosin and

- 50 g of dioctylcyclohexane are dissolved in 500 g of n-heptane and 100 pm thick coated analogously to

B thicker than the removable silicone protective layer .....

wound polyester film and dried at 50 ° C for 20 min. The dried film has a surface weight of 25 g / m ² .

D. Composition of the whole system and punching of individual patches

Under B, the reservoir coating produced is tacked onto Coating A for adhesion to the skin and then removed under B called stronger silicone foil. The primer C is then applied in the same way, and after removal of the more strongly siliconized foil under the name of C, a 12 pm thick polyester film is coated.

The resulting patches are extruded from the entire laminate.

3. Membrane system

Hot seal laminate, made of flexible polyester film and of polyethylene / vinyl acetate film copolymer, is sealed according to the dimensions and shapes of later patches on a 50 pm thick membrane of polyethylene / vinyl acetate copolymer containing 19% vi nyl acetate to form a sort of flat. The seam should be 4 mm wide. Before filling the bag without a gap, it is filled with a liquid silicone oil preparation with 10% acetylsalicylic acid and 0.05% acetanhydride.

The diaphragm side of the bags is now attached to a silicone-based adhesive coating on the skin that is suitable, abrasive, .....

yen foil. This foil is identical to the removable protective layer.

The finished systems are so thin that the bag remains on the 3 mm thick sealing edge.

Claims (9)

PATENT APPLICATIONS CLAIMS 1. Transdermal delivery system containing as active ingredient acetylsalicylic acid and / or its pharmaceutically acceptable substances, characterized in that its use is for anti-cancer prophylaxis. Transdermal delivery system according to claim 1, characterized in that it contains between 5 and 500 mg, preferably between 30 and 200 mg of acetylsalicylic acid or. the corresponding pharmaceutically acceptable salts thereof in stable form. Transdermal delivery system according to claim 1 or 2, characterized in that it is in the form of a patch and comprises a impermeable back layer, a reservoir of active substance of a polymeric matrix attached to it, preferably at a concentration above the saturation concentration, in the absence of other control mechanisms a membrane that controls the delivery of the active substances, a preparation for adhesive adhesion to secure the system to the skin and, if necessary, a removable protective layer if necessary. Transdermal delivery system according to claim 1 or 2, characterized in that it is in the form of a cream or ointment. Transdermal delivery system according to claim 1, 2 or 4, characterized in that an electric current is used to promote the permeation of acetylsalicylic acid and / or its pharmaceutically acceptable salts through the skin. Transdermal delivery system according to one or more of claims 1-5, characterized in that it facilitates the permeation of acetylsalicylic acid and / or its pharmaceutically acceptable salts through the skin with the addition of suitable substances. Transdermal administration system according to one or more of Claims 1 to 6, characterized in that it contains acetylsalicylic acid and its salts in a matrix that substantially prevents hydrolysis of acetylsalicylic acid. A method for producing 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 discharged in solid form or in solution or dispersion into the administration system, wherein the usual additional substances may be added. An embodiment according to one or more of claims 1 to 7 and 9, characterized in that it is a cancer prophylaxis system for the formation of bul, especially in the gastrointestinal tract.