DE4305881C1 - Transdermal therapeutic system for topical and systemic application of active agents - includes cpd(s) from which nitrogen oxide is released by human or animal metabolism or cpds which release nitrogen oxide in organism - Google Patents

Abstract

Transdermal therapeutic system for topical and systemic application of active agents includes at least one compound chosen from cpds. (A), from which nitrogen oxide is released by human or animal metabolism and cpds (B) which release NO in the organism. Nitrate esters and molsidomin are specifically excluded. Pref. compsn. contains arginine or a deriv., a cpd. with a gp. SNO, (a) or (b), a cpd. of formula (I), a sodium nitroprusside, or nitroso iron (II) sulphate, R1 and R2 = 1-12C alkyl without an branch, or benzyl, or NR1R2 = pyrrolidino, piperidino, piperazino or morpholine; an M<x+> = a cation; and x = the valency of the cation. USE/ADVANTAGE - The compsn. is used to treat NO- deficiency, high blood pressure, arterial spasms, platelet aggregation arteriosclerosis, to influence immunological and inflammatory process, to improve transfer of around signals in the central and peripheral nervous system, to relax the corpus cavernosum and to combat tumour cells. The compsn. releases the active agent steadily over a long time.

Description

The present invention relates to a transdermal therapeutic System (TTS) for systemic and topical Administration of active substances which are suitable, the Nitric oxide (NO) concentration in human and animal Increase organism.

Many researches have been done in recent years reveal that the NO plays a very important role as a mediator both physiological and pathophysiological Processes in the body. The role of the NO extends focus on the regulation of arterial vascular tone, platelet aggregation, influencing immunological and inflammatory processes, changes of the arterial walls, which function as a messenger the transmission of excitations of the central and peripheral Nervous system. In this respect, NO is also included in pathophysiological changes in these anatomical Structures or organ systems, such as B. high blood pressure, Coronary stenoses, arteriosclerosis; beyond there is Indications of involvement in immunological and inflammatory Processes as well as in the fight against Tumor cells.

When researching the regulation of vascular tone was in In recent years, NO has found a very intense, but is an unstable vasodilator, also called an "endothelium derived relaxing factor (EDRF) ". Physiologically the endothelial biosynthesis of the NO takes place, among other things by converting L-arginine to citrulline. Meanwhile the formation of NO was also found in many other tissues proven. It was also shown  that the effect of a number of well-known drugs such as nitrate compounds (GTN, ISDN) and Sydnonimine (e.g. molsidomine) in the treatment of coronary circulatory disorders relies on the donation of NO.

In addition to the vasodilator and antithrombotic NO has an effect in the central and peripheral nervous system Function of a neutron transmitter, as in the was found in recent years. The quick diffusion through cell membranes enables the significant role as inter- and intracellular mediator.

The knowledge of these processes has meanwhile become first Patents suppressed, e.g. B. in terms of use of NO donors in the treatment of high blood pressure (U.S. Patent No. 5,039,705); on the other hand, too Patents issued which block the NO production in the body (US Patent No. 5,059,712 and US Patent No. 5,028,627).

In any case, it is desirable to have the active ingredients Release NO - a substance that lasts only seconds Half-life in the organism - to be applied so that a continuous, controlled drug function via a longer period can be guaranteed. This is however, not on the conventional application routes or can only be realized with serious disadvantages. So z. B. oral administration has the disadvantage that by enzymatic cleavage and metabolism in the context of gastrointestinal absorption is not the active agent or is not only available in the desired concentration, which can only be compensated for by unacceptably high doses could. The system is reached directly with injections, however, drug delivery is only possible as a bolus. Continuous infusion brings the advantage of controlled Active ingredient intake over a long period of time, but is in  limited their application in that they are permanent Monitoring requires and also the freedom of movement of the Severely restricts patients.

It was therefore an object of the present invention to provide an administration system to provide for active substances from which metabolism in the human or animal organism NO is released, or for active substances that are in the donate NO to human or animal organism, whereby the system avoids the disadvantages mentioned above and a targeted dosage of the active ingredient allowed.

The solution to this problem is that the above Active substance types mentioned (except esters of nitrous Acid and nitric acid and molsidomine) with the help of a transdermal therapeutic system. A therapeutic system is a drug-containing one Device or dosage form, which one or several drugs at a predetermined rate continuously over a set period of time on a set Place of application (HEILMANN "Therapeutic Systems", F. Enke Verlag Stuttgart, 1984, p. 26). Therapeutic Systems are for both topical and systemic Applications can be used and are accordingly different designed.

A transdermal therapeutic system (TTS) is under characterized by the following advantages:

• - The active ingredient arrives in its pharmacologically active Form directly into the body's circulatory system, which increases metabolism in the gastrointestinal tract is avoided.
•  - Reduction of gastrointestinal side effects.
• - Consistent therapeutic effect with against other administration of minimized dose.  
• - Special suitability for active ingredients with a very short pharmacodynamic phase.
• - Outpatient treatment of patients without the need constant surveillance.
• - Improved patient compliance.

To implement the TTS according to the invention various options, such as pressure-sensitive adhesive Plasters, films, sprays, creams, ointments and the like. The form of administration of the pressure-sensitive adhesive is particularly preferred Band Aid. They usually consist of one impermeable backing layer, an associated drug reservoir with a mostly polymeric matrix, in the absence other control mechanisms one the delivery of the Active ingredient-controlling membrane, a pressure sensitive adhesive device to attach the system to the skin and if necessary one of the application of the system as ready to use Medicinal removable protective layer.

The transdermal pressure sensitive adhesives useful in this invention Patches are all patches that the specialist is made of are known in the art. You can largely assign two basic control principles: Matrix diffusion control and membrane control, being only the latter a zero order drug release owns. A patch with matrix diffusion control will e.g. B. described in DE-PS 33 15 272. It consists of one impermeable backing layer, an associated, specially constructed reservoir made of a polymer matrix, that the active ingredient in a concentration above the Contains saturation concentration, one with the reservoir associated pressure-sensitive adhesive layer permeable to the active ingredient and a covering the pressure sensitive adhesive layer for Use removable protective layer. Is the reservoir matrix self-adhesive, so the additional Pressure sensitive adhesive layer can be dispensed with.  

For plasters with membrane control is an example U.S. Patent 3,598,122. These patches exist basically a backing that is one of the surfaces represents one permeable to the active ingredient Adhesive layer, which represents the other surface, and ultimately a reservoir that holds the active ingredient between the contains the two surface-forming layers. Alternatively, the active ingredient can also be used in a large number of microcapsules contained within the permeable Adhesive layer are distributed. In any case, the Active ingredient from the reservoir or the microcapsules a membrane in the adhesive layer permeable to the active ingredient, those in contact with the skin of the person to be treated stands, continuously released. In the case of microcapsules the capsule material can also act as a membrane.

In addition, it should be pointed out that a controller is possible with the help of electric current, whereby the passage of the active ingredient through the skin determines the rate Represents step. Such operations are called electroosmosis, iontophoresis or electrophoresis designated. The plasters, of whatever type, can be used if necessary in addition to the matrix forming the reservoir and the active ingredient or combinations of active ingredients and various additives included to the desired property image receive. Such additives are particularly mentioned, the diffusion of the active ingredient in the reservoir and / or the Affect permeation of the active ingredient through the skin. Such additives are known to those skilled in the art known. Let the active ingredients to be used according to the invention divide in principle into two groups. The one Group includes those chemical compounds that are in their Molecule contain a suitable nitrogen atom from which can be formed by the metabolism NO. The other  Group is formed by such chemical compounds which already contain the NO in their molecule.

The first group includes:

• - Arginine, especially L-arginine and their pharmaceutical acceptable salts.
• - Functional derivatives of arginine, especially of L-arginines in which the guanidino group is unsubstituted remains, and their pharmaceutically acceptable Salts.
• - Functional analogues of arginine, especially that of L-arginine, with one accessible to metabolism Guanidino group and their pharmaceutically acceptable Salts.

The second group includes:

• - Furoxane with the characteristic group and their pharmaceutically acceptable salts. The synthesis of such compounds is described in W. Sliwa and A. Thomas, Heterocycles 23/2 (1985) pp. 399-416.
• - S-nitrosothiols with the identifying group -S-N = O. The synthesis of such compounds is described in US-PS 5,116,861.
• - Sydnonimine with the group and their pharmaceutically acceptable salts. An overview of this substance class can be found in EP-A 04 99 831.
  The molsidomine, a representative of this class of substances, does not fall within the scope of the present invention.
• - Compounds of the formula where R₁ and R₂, which may be the same or different, are a straight-chain or branched alkyl radical having 1-12 carbon atoms, with no branching on the α-C atom of the alkyl group, or may be a benzyl radical, or wherein the two groups R₁ and R₂ together with the nitrogen atom to which they are attached in the formula shown form a pyrrolidino, piperidino, piperazino or morpholino ring, M ^{+ x is} a pharmaceutically acceptable cation and x indicates the valence of the cation.
  With regard to this connecting group, reference is expressly made to US Pat. No. 5,039,705.
• Inorganic salts containing reversibly bound NO, such as, for example, nitroprusside sodium and Nitroso iron (II) sulfate.

An effective one is used to produce the TTS according to the invention Amount of active substance in solid form, in solution or in Dispersion introduced into the system, with usual additives can be used. The choice of ingredients, the structure, the design and the active ingredient concentrations depend on the nature of the active ingredient and the desired effect, so that no generally applicable Information is possible.

The exclusive use of the TTS according to the invention lies in the manufacture of ready-to-use pharmaceuticals, preferably in plaster form, for the elimination of nitrogen oxide Deficiency in the human or animal organism. The consequences of this deficiency are:

• - Hypertension and / or vascular spasms in arteries.
• - platelet aggregation.
• - Disruption of immunological processes.
• - Inflammatory processes.
• - atherosclerosis.
• - Disturbance in the transmission of excitation signals in the central and peripheral nervous system.
• - Development of tumor cells.
• - Malfunctions of the corpus cavernosum

The manufacture of ready-to-use medicinal products in plaster form requires the definition of the following parameters, which are from Expert to be adapted to the intended use can:

• - Choice of active ingredient
• - Active ingredient combination
• - Release control
• - release rate
• - Composition of the reservoir
• - stabilization
• - Enhancer additive
• - thickness of the layers
• - Design of the back layer
• - sizing

Claims (23)

1. Transdermal therapeutic system for the topical and systemic administration of active substances, characterized in that at least one of the active substances is selected from compounds from which nitric oxide is released by the metabolism in the human and animal organism, with the exception of esters of nitrous acid and nitric acid and molsidomine, and from those compounds that emit nitrogen oxide in the human and animal organism. 2. Transdermal therapeutic system according to claim 1, characterized in that the active ingredient arginine, a functional derivative of arginine, a pharmaceutical acceptable salt of arginine and / or its functional Derivatives and / or a functional analogue of Arginine and / or a pharmaceutically acceptable salt of it is. 3. Transdermal therapeutic system according to claim 2, characterized in that the active ingredient L-arginine, a functional derivative of L-arginine, a pharmaceutical acceptable salt of L-arginine and / or its functional derivatives and / or a functional one Analog of L-arginine and / or a pharmaceutical acceptable salt of it is.   4. Transdermal therapeutic system according to claim 1, characterized in that the active ingredient is a compound from the group of furoxanes, which is the characteristic group exhibit. 5. Transdermal therapeutic system according to claim 1, characterized in that the active ingredient is a compound from the group of S-nitrosothiols, which is the characteristic group -S-N = O included. 6. Transdermal therapeutic system according to claim 1, characterized in that the active ingredient is a compound from the group of Sydnonimine, except molsidomine, by the group is marked. 7. Transdermal therapeutic system according to claim 1, characterized in that the active ingredient is a compound of the formula is, where R₁ and R₂, which may be the same or different, are a straight-chain or branched alkyl radical having 1-12 carbon atoms, with no branching on the α-C atom of the alkyl group, or may be a benzyl radical, or wherein the two groups R₁ and R₂ together with the nitrogen atom to which they are attached in the formula shown form a pyrrolidino, piperidino, piperazino or morpholino ring, M ^{+ x is} a pharmaceutically acceptable cation and x indicates the valence of the cation. 8. Transdermal therapeutic system according to claim 1, characterized in that the active ingredient is an inorganic Salt is the reversibly bound nitrogen oxide contains. 9. Transdermal therapeutic system according to claim 8, characterized in that the active ingredient nitroprusside sodium or whose hydrate is. 10. Transdermal therapeutic system according to claim 8, characterized in that the active substance nitroso iron (II) sulfate is. 11. Transdermal therapeutic system according to one of the several of claims 1-10, characterized in that it is in plaster form and an impermeable Backing layer, an associated drug reservoir, in the absence of other control mechanisms, the Delivery of the active ingredient-controlling membrane, a pressure-sensitive adhesive device for fastening the system on the Skin and if necessary one before the application of the System includes removable protective layer. 12. Transdermal therapeutic system according to claim 11, characterized in that the permeation of the active ingredient  or the active ingredients through the skin Use of electrical current is affected. 13. Transdermal therapeutic system according to claim 11 or 12, characterized in that the diffusion and / or the permeation of the active ingredient or ingredients in the reservoir through the skin by adding suitable substances is affected. 14. Transdermal therapeutic system according to one or several of claims 11-13, characterized in that the active ingredient or ingredients in microencapsulated Form. 15. Process for the preparation of a transdermal therapeutic Systems according to one or more of the preceding Claims, characterized in that a effective amount of the active ingredient or ingredients in solid form or in solution or in dispersion in that System is introduced, with usual additives can be used. 16. Use of a transdermal therapeutic system according to one or more of claims 1 to 14 for Manufacture of a ready-to-use drug for Remedying nitric oxide deficiency in human or animal organism. 17. Use of a transdermal therapeutic system according to claim 16 for the manufacture of a ready-to-use Medicines to fight high blood pressure and / or vascular spasms in arteries. 18. Use of a transdermal therapeutic system according to claim 16 for the manufacture of a ready-to-use  Medicinal product for the prophylaxis and therapy of Platelet aggregation. 19. Use of a transdermal therapeutic system according to claim 16 for the manufacture of a ready-to-use Medicinal product to influence immunological and inflammatory processes. 20. Use of a transdermal therapeutic system according to claim 16 for the manufacture of a ready-to-use Medicinal product for the prophylaxis and therapy of Arteriosclerosis. 21. Use of a transdermal therapeutic system according to claim 16 for the manufacture of a ready-to-use Medicinal product to facilitate the transfer of Excitation signals in the central and peripheral nervous system. 22. Use of a transdermal therapeutic system according to claim 16 for the manufacture of a ready-to-use Medicinal product to fight tumor cells. 23. Use of a transdermal therapeutic system according to claim 16 for the manufacture of a ready-to-use Medicinal product to relax the corpus cavernosum.