Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Patent
1996-07-15
1998-02-10
Phelan, D. Gabrielle
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
424449, A61K 1302
Patent
active
057166366
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/03106, filed Sep. 16, 1994.
The present invention relates to a transdermal therapeutic system for the release of acetylsalicylic acid and optional further substances via the skin to the human body. The system that will be described has an increased chemical hydrolytic stability for the active substance acetylsalicylic acid.
Transdermal therapeutic systems (TTS) have been established on the market in the medicinal therapy of various diseases.
BACKGROUND OF THE INVENTION
It is also known that the active substance acetylsalicylic acid has a basic permeativity through the human skin and is therefore suitable as a component in transdermal therapeutic systems. Rougier et al. (J. Pharm. Sci. Vol. 76, No. 6 451-454, 1987) have already described that the acetylsalicylic acid-absorption rate into the skin depends (to a rather small extent) on the chosen skin area. Chen et al. (Zhongguo Yiyuan Yaoxue Zazhi, Vol. 11, p. 245-247 (1991) give a report on a successful transdermal application of acetylsalicylic acid creams in children suffering from rheumatism.
JP 3 112 926 describes an agent for the percutaneous application, including acetylsalicylic acid, which agent is formed by dissolution in water and addition of water-swellable additives and is finally used in a silicone polymer in dispersed form. In this case, there is a great risk of hydrolysis due to the contact with water.
Acetylsalicylic acid has been introduced for some time and is a therapeutically effective drug having a high therapeutic index. Used in very high doses (more than one gram per day) it is used as an antirheumatic agent, in mean doses (250 to 500 mg) as an antipyretic/analgesic, and in a low dosage (30 to 150 mg per day) as a platelet aggregation inhibitor. Acetylsalicylic acid melts at a low temperature (about 139.degree. C.) and is noticeably volatile at this temperature. Acetylsalicylic acid exists in several polymorphous forms (modifications) which partly melt at only 100.degree. C. and also have different dissolution behavior.
Because of the unstable ester grouping it is susceptible to hydrolysis and transesterification. On the way to a stable administration form the following principles have to be observed in general: formulation components; useful to add potential reaction products, such as acetic acid or water-binding acetic anhydride as stabilizing components; to this acidity promotes stability; e.g., Luzzi and Ma (U.S. Pat. No. 4,228,162) recommend to use dimethylisosorbide as stabilizing solvent.
No indications have been found in literature as to how this galenic problem can be applied to the technique of manufacturing a TTS. First formulations wherein the TTS-matrix--following the state of the art--contained acetylsalicylic acid exclusively in dissolved form proved to be too unstable.
According to U.S. Pat. No. 4,286,592 a pharmaceutic active substance is used in crystalline form in a TTS in order to control the active substance release via an adhesive layer. A special ratio between the particle size of the crystals and the diffusion properties is important in this case. However, this application would only be used by those skilled in the art to limit an active substance flow but not for stabilization purposes with simultaneously maintaining the maximum possible release properties.
It is usual practice in some cases to load transdermal therapeutic systems with active substance to such a concentration that it crystallizes during the production after having been in complete solution initially (EP 0 156 080). By this a particularly long-lasting action is achieved. However, the method involves the disadvantage that it is difficult to control the procedure of crystallization and that, in the absence of crystal nuclei, modifications having a limited storage period are frequently obtained. Thus, the product cannot be manufactured to meet the required pharmaceutical quality. Indications as to stabilize active substances by introducing a high crystalline portion into transdermal therapeutic systems cann
REFERENCES:
patent: 4012508 (1977-03-01), Burton
patent: 4228162 (1980-10-01), Luzzi et al.
patent: 4286592 (1981-09-01), Chandrasekaran
patent: 4460368 (1984-07-01), Allison
patent: 4640689 (1987-02-01), Sibalis
Rougier et al., Journal of Pharmaceutical Sciences, vol. 76, No. 6, Jun., 1987, pp. 451-454.
Hoffmann Gerd
Horstmann Michael
Kindel Heinrich
LTS Lohmann Therapie-Systeme GmbH
Phelan D. Gabrielle
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