Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Patent
1998-03-12
1999-10-26
Brouillette, D.Gabrielle
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
424448, A61F 1300
Patent
active
059723769
DESCRIPTION:
BRIEF SUMMARY
Tetrahydroaminoacridine (tacrine) is used as a centrally active choline esterase inhibitor in the case of Alzheimer's disease. Its choline esterase inhibition lasts for approximately 15 hours, i.e. considerably longer than the half-life of tacrine which is in the region of 1.5 to 3.5 h. The daily recommended dose varies between 30 and 160 mg, the therapeutic blood level being in the range of 5 to 70 ng/ml and the bioavailability in the region of 10 to 30%. In the case of patients who suffer from Alzheimer's disease and are being treated over a prolonged period with several doses of tacrine per day, a clinical improvement in the memory and the functional autonomy can be observed.
Tacrine is used orally in the form of the hydrochloride (Cognex.RTM.). Since the oral administration of tacrine must take place in the form of multiple dosages, because of its short elimination half-life, while on the other hand the release of the active substance should remain constant over a long period, a transdermal administration would represent a more effective drug therapy. An additional problem is posed by the strong first pass metabolisation and the greatly varying pharmacokinetics of tacrine which lead to a poor adjustability of the patients, the occurrence of blood plasma peaks and an increase in the secondary effects and the toxicity, particularly to the liver. The hepatotoxic effect of tacrine occurs in the case of approximately half of the patients, an increase in the ALT (alanine aminotransferase) values to as much as 20 times the upper normal limit being observed. By way of a continuous transdermal administration of tacrine, more constant and lower therapeutically effective plasma levels and consequently reduced secondary effects, particularly on the liver, might be obtained, in particular since the high first pass effect and the low bioavailability should no longer occur.
In EP-B-0 332 147, a transdermal system is described with a content of salt of this compound as active substance and
Migliol increases the flow of substance through the skin of mice in this transdermal system in comparison with a formulation without Migliol. Optionally, a permeation accelerator in the form of a solvent can be added, e.g. alcohol. However, alcohol irritates the skin, dries it and damages it. The use of ethanol should be assessed critically since it interferes with the natural lipid layer of the skin and dries it and irritates it. In addition, it is stated in EP-B-O 499 662 that the release control of the active substance in the case of plaster according to EP-B-O 332 147 is not an optimal one.
According to EP-B-O 499 662, a two-layer composite laminate is provided as transdermal system which consists of substance in a partially cured elastomer and solvent and an active substance in a macroporous moulded body with a pore size of 10 to 100 .mu.m.
As an example of an active substance, 1,2,3,4-tetrahydro-9-acridinamine (THA=tacrine) is mentioned, inter alia. Alcohols, for example ethanol, are suggested as solvents for components A and B. However, ethanol again dries the skin, irritates and damages it.
Moreover, the spongy transdermal system known from EP-B-O- 499 662 is thick and inflexible and consequently not very practical for application by the patient since the system is exposed as a result of its height, easily involuntarily removable and does not adjust well to body movements.
The transdermal system known from EP-B-O 499 662 is produced by component component B is obtained which forms layer II obtained is cut into plasters of the desired size.
This production process is difficult to understand, complicated and, moreover, leads to a poorly reproducible blood level, possibly as a result of the partial curing of the elastomer which is difficult to control. If, moreover, an elevated temperature of e.g. 160.degree. C. is used with this highly costly process over several minutes, the active substance may be degraded as a result. Apart from the question of how an aluminium foil should be laminated onto a macroporous sponge, the questio
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patent: 4861800 (1989-08-01), Buyske
patent: 5019395 (1991-05-01), Mahjour et al.
patent: 5312817 (1994-05-01), Snorrason
Fischer Wilfried
Sendl-Lang Anna
Brouillette D.Gabrielle
Hexal, A.G.
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