Deuterated active substances in transdermal application

Details Deuterated active substances in transdermal application Deuterated active substances in transdermal application

1996-08-15

1999-04-20

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...

424434, 424448, 514946, 514947, 514969, A61F 1300

Patent

active

058956603

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The present invention relates to the transdermal application of deuterated drugs. Although the transdermal application of drugs undoubtedly has great advantages, there is the disadvantage that the amount of drug that can be absorbed via the skin is limited. Thus, when the therapy by dermal application began, attempts were made at the same time to find a way of increasing the capacity of drugs to penetrate through the skin. The development of penetration enhancers which are added to drugs for dermal application was regarded as a solution for this problem first. These substances change subjacent skin structures, at least for a short time, and can result in undesired side effects in unfavorable cases. Other possibilities of increasing the absorption of active substances is to remove the stratum corneum by a laser treatment or by repeated sticking and tearing-off adhesive strips, the so-called "stripping". The drawback of this method is the fact that not only the desired penetration of the active substance into the human body is facilitated but also that of all other substances as well as of micro-organisms, such as bacteria and fungus spores. Another way of improving the dermal absorption is to use current. As is known to medical experts, this process, known under the term "iontophoresis", cannot be applied without pain. The same applies to the so-called "spiked patch". This administration form is fixed to the body by means of cannulae penetrating the horny layer of the skin. The active substance release takes place through said cannulae which simultaneously serve as fixation aids.
The dermal application of so-called "pro-drugs" seems at first to be an interesting alternative. In this case structural elements of drugs which are considered to be particularly unfavorable for the dermal absorption, e.g., phenolic hydroxyl groups, are derivatized, e.g., esterified. The characteristic feature of the chemical modification of pro-drugs is the fact that the derivatization is extremely unstable so that the drug underlying the pro-drug is quickly and completely formed in vitro. However, it is known to the skilled artisan that this actually neat idea can only rarely be realized in practice, since the intended quick and complete metabolic degradation does not take place in vivo. Thus, some toxicological questions arise with respect to the pro-drugs which still require extensive pharmacologic studies.
By way of trial, radioactively labeled drugs were applied transdermally in the past, in order to facilitate the determination of the extremely low blood levels frequently occurring after transdermal application; an exchange of radioactive components under in-vivo-conditions was not intended to take place.


DESCRIPTION OF THE INVENTION

Accordingly, it is the object of the present invention to provide a drug composition for the transdermal application of active substances, which allows an increased absorption rate for active substances and avoids the drawbacks known from methods according to the art. According to the present invention this object is achieved in a surprising manner by means of a drug for the release of active substances to the skin, which has an increased deuterium portion as compared to the natural isotope distribution.
This solution is most surprising since deuterated compounds, as compared to corresponding non-deuterated substances, should actually have a worse or--at best--the same diffusion behavior owing to their increased molecular weight.
Within the meaning of the present invention deuterated compounds mean those compounds in which at least one or several hydrogen atoms are replaced by deuterium.
The subject matter of the present invention are compounds which are not labeled isotopically and are required for studies on biosynthesis and biodegradation of natural substances, works on the metabolism of drugs and other chemicals in plant and animal organisms, since these have to be stable. However, in the present invention a re-exchange reaction is very well possible in such a

REFERENCES:
patent: 3598122 (1971-08-01), Zaffaroni
patent: 4473585 (1984-09-01), Abrahamsson
patent: 4529600 (1985-07-01), Dawson
patent: 4898855 (1990-02-01), Baggiolini
patent: 5075337 (1991-12-01), Cordi
Aldrich's Catalogue Handbook of Fine Chemicals, pp. 126 and 1024, 1992.
Sigma's Biochemicals and Organic Compounds for Research and Diagnostics, pp. 1637-1638, 1992.
Heilmann, "Therapeutische Systeme -Konzept und Realisation programmierter Arzneiverabreichung", 4th Edition Ferdinand Enke Verlag Stuttgart 1984, page 26.

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