Transdermal application system containing acetylsalicylic...

Details Transdermal application system containing acetylsalicylic... Transdermal application system containing acetylsalicylic...

1994-08-04

2001-07-24

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

C424S449000, C424S448000

Reexamination Certificate

active

06264978

ABSTRACT:

The platelet aggregation-preventing effect of acetylsalicylic acid (ASA) and its effect in the prevention of cardiac thrombosis was described in the late 60s. Subsequently, a large number of clinical studies have been conducted whereby ASA was administered orally in the case of the following indications:
prevention of first-instance cardiac infarction,
prevention of reinfarction,
treatment of unstable angina pectoris,
prophylaxis against thrombosis after transplantation of vascular prostheses or artificial cardiac valves
prophylaxis against thrombosis of the peripheral arterial vessels
prophylaxis against thrombosis of inadequate cerebral circulation
Where in the following the term “anti-thrombotic therapy” is used, this substantially comprises the above indications.
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 Dosierung von Acetylsalicylsaeure”, Med. Klin. 84, 43-51 (1989)).
Acetylsalicylic acid has frequently been employed in medical practice as a non-steroid anti-inflammatory, analgesic and antipyretic active substance. ASA influences platelet function and prevents thrombosis by irreversibly inhibiting the thromboxane A2 synthesis (M. Buchanan et al., “Aspirin inhibits platelet function independent of cyclooxygenase”, Thrombosis Res. 25, 363-373 (1982)).
After oral administration ASA is quickly absorbed. However, its biological half-life in the systemic circulation is very short, it lasts only 15-20 minutes (M. Rowland et al., “Kinetics of acetylsalicylic acid disposition in man”, Nature 215, 413-414 (1967)). In normal adults ASA is quickly hydrolyzed to salicylic acid in the gastrointestinal 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 administration is practised almost exclusively; in the case of anti-inflammatory, analgesic and antipyretic indications, however, attempts have already become known to apply the active substance via the skin. Thus, U.S. Pat. No. 3,598,122 mentions ASA 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 containing 5% of ASA against acute pain. FR-A 2 297 612 claims liniments and ointments containing ASA as analgetic agent. In U.S. Pat. No. 4,012,508 ASA is employed in combination with corticosteroids for topical application in the case of dermatological indications. U.S. Pat. No. 4,219,548 describes a topical application of ASA for the checking of inflammatory processes. In EP-A 0 055 635 an ASA-containing gel is applied topically in the case of anti-inflammatory, analgesic and antipyretic indications. U.S. Pat. No. 4,460,368 discloses a device for the transdermal application of ASA out of an aqueous system for achieving antiinflammatory and analgesic effects. In U.S. Pat. No. 4,665,063, ASA is topically applied against dermatological disturbances by using a solution in ethanol. In U.S. Pat. No. 4,640,689 an increase in the penetration rate of ASA in transdermal application is achieved by employing electric current.
Addition of suitable penetration enhancers, as in EP-A 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. U.S. Pat. No. 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 application of ASA as an analgesic. Further substances of this kind for ASA in transdermal application for the checking of inflammatory processes, are contained in Japanese Patent 1,242,521. Finally, U.S. Pat. No. 4,975,269 relates to storage-stable solutions of ASA for topical application aiming at checking inflammatory processes and relieving pain.
The mentioned prior art does not contain any indication, nor can it be derived therefrom, that the use of a transdermal system has been considered which contains ASA and/or pharmaceutically acceptable salts thereof to prevent platelet aggregation in humans and/or for the prophylaxis against cancer.
Many formulations and compositions contain water or hydrophilic 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.
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 antithrombotic therapy and/or for the prophylaxis against cancer which avoids the disadvantages 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 suppressing or preventing the hydrolysis 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 following advantages in antithrombotic therapy:
1. ASA is directly introduced into the systemic circulation in its pharmacologically active form, thus avoiding 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
6. improved patient compliance during treatment.
The content of ASA in such an administration unit is generally 5-500 mg, preferably 30-200 mg, or the corresponding 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 &mgr;g/ml is obtained. For practical applicat

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