MX2008007172A - Matrix-controlled transdermal system comprising salts of ace inhibitor dicarboxylic acids - Google Patents

Abstract

The invention relates to a salt of an ACE inhibitor dicarboxylic acid comprising an organic amine and/or an alkali compound, a transdermal therapeutic system comprising said salt, and a method for producing the transdermal therapeutic system.

Description

TRANSDERMAL SYSTEM CONTROLLED BY MATRIX UNDERSTANDING SALTS FROM ECA INHIBITORS DICARBOXYLIC ACIDS DESCRIPTION OF THE INVENTION The invention relates to a stable transdermal therapeutic system, containing active substance, for the application of ACE inhibitors, whose metabolites represent a dicarboxylic acid. The stable, neutral derivatives of the dicarboxylic acids, ACE inhibitors are obtained by the formation of salts with an organic amine and / or an alkaline compound. Preferred are the stable, neutral derivatives of the dicarboxylic acids inhibiting ECA having an organic amine, and particularly preferred with one molar equivalent of an organic amine. The long-term therapy of hypertonia with angiotensin-converting enzyme inhibitors (ACE inhibitors) is of increasing importance. ACE inhibitors are known for their reliable activity combined with good compatibility. Up to now, only injectable or oral forms of administration of ACE inhibitors have been commercialized, such as tablets or capsules. The disadvantage of the use of injectables is the collaboration with patients. In the oral forms of administration the disadvantage consists in which the patient has to take at least one tablet or capsule each day, and the level of blood plasma is always subject to certain fluctuations. It is almost impossible to guarantee a uniform plasma level with oral administration forms. The transdermal application, in contrast, offers ACE inhibitors a series of advantages: The skin is accessible in an unlimited way, There is no change of environment as in the case of peroral application, The handling is simple and comfortable, It is usually enough single administration for at least 3 days instead of administration several times a day, The patient's collaboration is substantially better, It is allowed to have a long-term continuous therapy, The release of the active substance is performed approximately according to an order kinetics 0, The therapy can be stopped more quickly, a constant plasma level is guaranteed for a longer period, an excessive initial plasma level is avoided, as in the case of intravenous application and Thanks to the avoidance of the same passage, only a lower dosage is required than in the case of oral administration, so there is a lower side effect rate and the danger of excessive or insufficient dosing is lower. Document 0 439 430 describes a transdermal reservoir system with an ACE inhibitor content containing a) a cover layer impermeable to the active substance (closed outer layer), b) a reservoir containing the active substance with a vehicle, respectively, a solvent, as well as optionally a membrane, c) a glue layer and d) a peel off protective layer. As the active substance, a salt of a bipolar ion serves as a bipolar ion, for example, benaceprilate and as a salt-forming component, for example chlorprocaine, choline, diethanolamine, ethylenediamine, methylglucamine, procaine or hydroxides. , hydrogenated carbonates or carbonates of alkali metals, by way of example, of lithium or potassium, and were referred to as examples of disalts, dilithium benaceprilate and dipotassium (table). EP 0 452 837 describes a matrix for adhesives that contends, inter alia, inhibitors of RCT as active substances. As possible ACE inhibitors, mention is made of delapril hydrochloride, enalapril maleate, captopril, alacepril and (R) -3- [(S) -1-carboxy-5- (-piperidyl) -pentyl] -amino-4-oxo acid. -2, 3, -tetrahydro-1, 5-benzothiazepine-5-acetic acid (= dicarboxylic acid). The basic substances are used here only in a very small amount as solubility agents. WO 96/29 999 shows a STT having a matrix based on polyisobutylene or butyl rubber having a content of trandolapril and / or ramipril. In WO 02/03 970 an STT matrix is described whose matrix layer contains an ACE inhibitor in the form of a dicarboxylic acid which was derived to a derivative of the following group: di-ester, di-salt obtainable with bases and mono-salt obtainable with acids. It has been shown, however, that a STT with a di-salt from a base exhibits strong dermal irritation. ACE inhibitors often show low stability and may have different reductive reactions. ACE inhibitors of dicarboxylic acids with the following structural element, for example, can be transposed to form substituted diketopiperazines. By means of a nucleophilic attack of the nitrogen atom, an intramolecular lactam formation occurs in this, as illustrated by the following equation: The intramolecular formation of lactam can be prevented by addition of acids that can block the secondary amino group. The salts of the ECA inhibitors of dicarboxylic acids thus formed with acids (Cf. WO 02/03970) have the disadvantage that there is a greater potential for dermal irritation due to the low pH value. If di-salts of the ECA-inhibiting dicarboxylic acids with bases are used (Cf. WO 02/03970), then an intramolecular formation of lactam is also prevented, but a global formulation with a basic pH value is produced which can also produce skin irritation. The aim of the present invention is the offer of a matrix STT with a content of salts of dicarboxylic acids inhibitors of ECA having a great stability and little potential to irritate the skin. The content of the active substance must be stable over a prolonged period and suffer as little decomposition as possible. The transdermal system must show a large flow, that is, the active substance must be dispensed with a high rate of dermal permeation. The fundamental objective of the invention is achieved by providing a salt, preferably a mono-salt, of an ECA-inhibiting dicarboxylic acid with an organic amine and / or an alkaline compound. The inventive salt can be provided with a monoamine as an organic amine. The inventive salt can be provided, for example, with a primary amine, a secondary amine or a tertiary amine as an organic amine. The inventive salt can be provided with an aliphatic primary C-? 2 amine. The inventive salt can be provided, for example, with butylamine, pentylamine, hexylamine, heptylamine, octylamine, nonylamine, decylamine, undecylamine, dodecylamine or trometamol (= 2-amino-2-hydroxymethyl-1,3-propanediol) as the C4_ amine? 2 primary aliphatic. The inventive salt can also be provided with pyrrolidone or one of its derivatives as a secondary amine. The inventive salt can also be provided with triethanolamine as the tertiary amine. The inventive salt can be provided with an alkaline compound, wherein an alkaline compound in the sense of this compound is any compound that comprises an alkali metal cation. Preferably, the salts of the ECA-inhibiting dicarboxylic acid with an alkali metal cation which are also called alkali salts of the ECA-inhibiting dicarboxylic acid are thus formed. Examples of suitable alkali metal cations are lithium, sodium, potassium, cesium or rubidium cations, of which lithium, sodium and potassium cations are particularly preferred. Also ammonium (NH, j +) is preferred as cation (pseudo cation of alkali metal). Preferably the counter anion of the alkali compound, in particular of the alkali metal cation, proton acceptor characteristics, and the alkali compound is, with particular preference, a salt comprising alkali metal cations of an inorganic or organic acid, strong or weak . Preferred examples are alkali compounds such as alkali metal hydroxides such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alcoholates such as, for example, lithium methanolate, lithium ethanolate, sodium methanolate, sodium ethanolate, potassium methanolate, potassium ethanolate; or alkali metal carbonates such as, for example, sodium hydrogen carbonate or potassium hydrogen carbonate, or alkali metal tartrates such as, for example, sodium tartrate or potassium tartrate, or alkali metal maleates, for example, sodium maleate or potassium maleate. Ammonium hydroxide is preferred as the ammonium compound. The inventive salt may be provided with an alkaline earth compound where an alkaline earth compound, in the sense of this compound, is any compound comprising an alkaline earth metal cation. It is preferred that the salts of the ECA inhibitor dicarboxylic acid be formed with an alkaline earth metal cation, which are also called alkaline earth salts of the ECA inhibitor dicarboxylic acid. Examples of ferrous alkali metal cations are magnesium and calcium cations. Preferably, the counter anion of the alkaline earth compound, in particular of the alkaline earth metal cation characteristic of proton receptor and the alkaline earth compound is particularly preferably a salt comprising alkali metal cations of a strong or weak inorganic or organic acid. . Preferred examples are ferrous alkali compounds such as hydroxides of ferrous alkali metals such as, for example, magnesium hydroxide or potassium hydroxide, or ferrous alkali metal carbonates such as, for example, magnesium carbonate or calcium carbonate. In the case of an inventive salt with an alkaline earth compound, the molar ratio dicarboxylic acid ECA inhibitor: alkaline earth compound is preferably 1: 0.5 to! : less than 1, more preferably 1: 05 to 1: 0.9, in particular 1: 05 to 1: 0.55. The inventive salt comprises a salt having one or more organic amine (s), preferably one, two or three organic amine (s), or one or more alkaline compound (s), preferably one, two or three alkaline compound (s), or one or more alkaline earth (s) compound (s), preferably one, two or three alkaline earth (s) compound (s), as well as arbitrary mixtures of these. Preferably the inventive salt comprises a salt with two organic amines different from each other, or two different alkaline compounds, or two different ferrous alkali compounds from each other, or an organic amine and an alkaline compound, and the like. In the case of the inventive salt, it may be a salt of an ECA-inhibiting dicarboxylic acid from the group of the dicarboxylic acids imidapril, fosinopril, moexipril, perindorpyl, spirapryl, benzepril, cilazapril, lisinopril, quinapril, enalapril, delapril, ramipril and trandolaprilo. Thus, an inventive salt of a trandolapril or ramipril ECA inhibitor dicarboxylic acid may be provided. The molar ratio of the dicarboxylic acid inhibitor of ACE to Amin or dicarboxylic acid ACE inhibitor: alkaline compound for the inventive salt can amount to 1: less than 2. Thus, the molar ratio for the inventive salt of the ECA-inhibiting dicarboxylic acid to Amina or of the ECA-inhibiting dicarboxylic acid: alkaline compound can amount to: 0.5 to 1: less than 2, preferably 1: 0.5 to 1: 1.9, more preferably 1: 0.9 to 1: 1.5, more preferably 1: 1 to 1.5, with particular preference 1: 1.1 and particularly about 1: 1. The fundamental objective of the invention is further achieved by a therapeutic transdermal system having at least one salt of an ECA-inhibiting dicarboxylic acid, at least one organic amine and / or at least one alkaline compound as the active substance. With particular preference, the fundamental objective of the invention is achieved by a therapeutic transdermal system having at least one mono-salt of an ECA-inhibiting dicarboxylic acid, at least one organic amine and / or at least one alkaline compound as active substance, in in particular a mono-salt of an ACE-inhibiting dicarboxylic acid with an organic amine as an active substance. A monoamine as an organic amine can be provided for the inventive therapeutic transdermal system.

Thus, a primary amine, a secondary amine or a tertiary amine as an organic amine can be provided for the inventive therapeutic transdermal system. Thus, an aliphatic primary C-? 2 amine can be provided for the inventive therapeutic transdermal system. Thus, it can be provided for the inventive therapeutic transdermal system butylamine, pentylamine, hexylamine, heptylamine, octylamine, nonylamine, decylamine, undecylamine, dodecylamine or trometamol (= 2-amino-2-hydroxymethyl-l, 3-propanediol) as amine C4_? 2 primary aliphatic. The inventive therapeutic transdermal system may also be provided with pyrrolidone or one of its derivatives as a secondary amine. The inventive therapeutic transdermal system may also be provided with triethanolamine as the tertiary amine. The inventive therapeutic transdermal system may also be provided with an alkaline compound, wherein an alkaline compound in the sense of this compound is any compound comprising an alkali metal cation. Preferably, the salts of the ECA-inhibiting dicarboxylic acid with an alkali metal cation are also formed which are also called alkali salts of the acid dicarboxylic ACE inhibitor. Examples of suitable alkali metal cations are lithium, sodium, potassium, cesium or rubidium cations, of which lithium, sodium and potassium cations are particularly preferred. Also ammonium (NH4 +) is preferred as cation (pseudo cation of alkali metal). Preferably the opposite anion of the alkaline compound, in particular of the alkali metal cation, proton acceptor characteristics, and the alkaline compound is, with particular preference, a salt comprising alkali metal cations of an inorganic or organic acid, strong or weak. Preferred examples are alkaline compounds such as alkali metal hydroxides such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide.; alkali metal alcoholates such as, for example, lithium methanolate, lithium ethanolate, sodium methanolate, sodium ethanolate, potassium methanolate, potassium ethanolate; or alkali metal carbonates such as, for example, sodium hydrogen carbonate or potassium hydrogen carbonate, or alkali metal tartrates such as, for example, sodium tartrate or potassium tartrate, or alkali metal maleates, for example, sodium maleate or potassium maleate. Ammonium hydroxide is preferred as the ammonium compound. The inventive therapeutic transdermal system it may further be provided with an alkaline earth compound where an alkaline earth compound, in the sense of this compound, is any compound comprising an alkaline earth metal cation. It is preferred that the salts of the ECA-inhibiting dicarboxylic acid with an alkaline earth metal cation, which are also termed alkaline earth salts of the ECA-inhibiting dicarboxylic acid, be formed. Examples of ferrous alkali metal cations are magnesium and calcium cations. Preferably, the counter anion of the alkaline earth compound, in particular of the alkaline earth metal cation characteristic of proton receptor and the alkaline earth compound is particularly preferably a salt comprising alkali metal cations of a strong or weak inorganic or organic acid. . Preferred examples are ferrous alkali compounds such as hydroxides of ferrous alkali metals such as, for example, magnesium hydroxide or potassium hydroxide, or ferrous alkali metal carbonates such as, for example, magnesium carbonate or calcium carbonate. In the case of an inventive salt with an alkaline earth compound, the dicarboxylic acid ECA: alkaline compound is preferably 1: 0.5 to: less than 1, more preferably 1: 05 to 1: 0.9, in particular 1: 05 to 1: 0.55.

The inventive therapeutic transdermal system may also be provided with one or more organic amine (s), preferably one, two or three organic amine (s), or one or more alkaline compound (s), preferably one, two or three alkaline compound (s), or one or more alkaline earth (s) compound (s), preferably one, two or three alkaline earth (s) compound (s) , as well as arbitrary mixtures of these. Preferably the inventive salt comprises a salt with two organic amines different from each other, or two different alkaline compounds, or two different ferrous alkali compounds from each other, or an organic amine and an alkaline compound, and the like. The inventive therapeutic transdermal system can also be provided with at least one salt of an ECA-inhibiting dicarboxylic acid from the group of the dicarboxylic acids imidapril, fosinopril, moexipril, perindorpyl, spirapryl, benzepril, cilazapril, lisinopril, quinapril, enalapril, delapril, ramipril and trandolapril. The inventive therapeutic transdermal system can also be provided with at least one mono-salt of an ACE-inhibiting dicarboxylic acid from the group of dicarboxylic acids imidapril, fosinopril, moexipril, perindorpyl, spirapryl, benzepril, cilazapril, lisinopril, quinapril, enalapril, delapril, ramipril and trandolapril. The inventive therapeutic transdermal system may also be provided with a salt of a trandolapril or ramipril ECA inhibitor dicarboxylic acid. Preferably, the inventive therapeutic transdermal system may also be provided with a mono-salt of a trandolapril or ramipril ECA inhibitor dicarboxylic acid. For the inventive therapeutic transdermal system, the molar ratio of the ECA-inhibiting dicarboxylic acid to Amin or of the ECA-inhibiting dicarboxylic acid: alkaline compound for the inventive salt may amount to 1: less than 2. Thus, for the inventive therapeutic transdermal system, the molar ratio for the inventive salt of the ECA-inhibiting dicarboxylic acid to Amina or of the ECA-inhibiting dicarboxylic acid: alkaline compound may amount to: 0.5 to 1: less than 2, preferably 1: 0.5 to: 1.9, more preferably 1: 0.9 to 1: 1.5, more preferably 1: 1 to 1.5, with particular preference 1: 1.1 and particularly approximately 1: 1. The inventive therapeutic transdermal system may be provided with a coating layer impervious to the active substance, one or more self-adhering matrix layers containing the active substance and a removable protective layer. The inventive therapeutic transdermal system may also be provided with a coating layer impermeable to the active substance, - one or more matrix layers containing the active substance, which is (are) provided on the application side with a layer of adhesive glue, and - a removable protective layer. The inventive therapeutic transdermal system can thus be provided with a non-self-adhering matrix layer and a separate layer of an adherent adhesive. For the inventive therapeutic transdermal system, the active substance (s), that is, one or several salts, in particular, one or more mono-salts, of an ACE-inhibiting dicarboxylic acid with at least one organic amine and / or at least one compound alkaline, they may be present in dissolved form in the matrix and / or in the form of emulsion droplets.

For the inventive therapeutic transdermal system, the content of ECA-inhibiting dicarboxylic acid may amount to 2 to 35% by weight, based on the weight of the matrix. Thus, for the inventive therapeutic transdermal system, the content of ECA-inhibiting dicarboxylic acid may amount to 10 to 25% by weight, based on the weight of the matrix. The inventive therapeutic transdermal system may be provided with a pressure sensitive adhesive, based on polyurethane, polyisobutylene, polyvinyl ether, polyacrylate, silicone, styrene block copolymer or a mixture thereof. Thus, the inventive therapeutic transdermal system may be provided with a pressure sensitive adhesive based on isoprene-styrene block copolymer (SIS) or styrene-butadiene-styrene block copolymer. The inventive therapeutic transdermal system may also be provided with a pressure sensitive adhesive based on polyacrylate or polyisobutylene. The inventive therapeutic transdermal system may also be provided with a matrix promoter from the group of polyacrylate, polyisobutylene, silicone, styrene block copolymer or a mixture thereof.

Thus, the inventive therapeutic transdermal system can be provided with a block copolymer of isoprene-styrene (SIS) as a matrix promoter. The inventive therapeutic transdermal system can also be provided with a self-adhesive matrix based on polyacrylate. The inventive therapeutic transdermal system may also be provided with an adhesive adhesive and / or a matrix, based on polyacrylate which is a homopolymer, a copolymer or a terpolymer. Thus, the inventive therapeutic transdermal system may be provided with an adhesive adhesive and / or a polyacrylate-based matrix containing or consisting of different acrylic acid derivatives. Thus, the inventive therapeutic transdermal system can be provided with an adhesive adhesive and / or a polyacrylate-based matrix, consisting of acrylate polymer of at least 50% by weight of an acrylate, methacrylate, alkyl acrylate, alkylmethacrylate or acrylamide monomer, 0-20% by weight of a functional monomer that can copolymerize with acrylate, and 0 to 50% by weight with other monomers. In addition, the inventive therapeutic transdermal system is provided with an agent that promotes the permeation of the group consisting of fatty alcohols saturated and / or unsaturated with 8 to 18 C atoms in each case-Tea tree oil; Cyclic saturated and / or unsaturated ketones; Alkyl-methylsulphoxides; Saturated and / or unsaturated fatty acids with 8 to 18 C atoms in each case; Esters of saturated and / or unsaturated fatty acids with 8 a 18 C atoms in each case; Salts of saturated and / or unsaturated fatty acids with 8 to 18 C atoms in each case; Natural vitamin E; Synthetic vitamin E and / or vitamin E derivatives; Esters of sorbitan fatty acids; Azonas, in particular laurocapram; 1-alkylpyrrolidone; Block copolymers of polyethylene glycol and dimethylsiloxane with groups of cations in an extreme-Polyoxyethylene-10-stearyl ether; Blend of polyoxyethylene-10-stearyl ether and glyceryl laurate; Dodecyl-2- (N, N-dimethylamino) -propanol tetradecanoate and / or dodecyl-2- (N, N-dimethylamino) -propionate; N-acetylprolinate ester (N-acetyl pyrrolidone-2-carboxylic acid ester) with > of 8 C atoms; Nonionic surfactants, in particular lauryl ether; Polyoxyethylene ester; Dimethyl (arylimino) sulfurane; Mixture of analog (s) of oleic acids, and propylene glycol; Mixture of palmitate, octylsalicylate, isopropylmyristate, isopropylpalmitate, octylmethoxycinnamate, larocapram; highly dispersed silicon dioxide (Aerosil) Polyoxyethylene-7-glycerol monococoate (Cetiol HE); 2-octyldodecanol (Eutanol G); and its mixtures. Thus, the inventive therapeutic transdermal system can be provided with Polyoxyethylene-7-glycerol monococoate (Cetiol CIO HE) or 2-octyldodecanol (Eutanol "G) as permeation-promoting agents For the inventive therapeutic transdermal system the glue content of the self-adhesive matrix can amount to 20 to 90% by weight, preferably 30 to 80% by weight and in particular 40 to 60% by weight; the rest active substance (s), optionally permeation agent and optionally filler, in each case referred to the weight of the matrix. Finally, the fundamental objective of the invention is achieved by a method for the production of an inventive therapeutic transdermal system in which the organic amine (s) and the acid (s) are incorporated. dicarboxylic acid (s) ACE inhibitor (s) together with the matrix solution, respectively, suspension and the amine salt (s) is (are) formed (s) in Si tu. With the inventive method for the production of an inventive therapeutic transdermal system, the amine salt (s) of the ECA inhibitor (s) dicarboxylic acid (s) can be incorporated directly into the matrix. The invention also provides a method for the production of an inventive therapeutic transdermal system with which the alkaline compound (s) and the ECA inhibitor (s) dicarboxylic acid (s) are incorporated together into the solution, respectively, matrix suspension and the salt (s) of alkaline compounds is (are) formed (s) in Si in the solution, respectively, matrix suspension. With the inventive method for the production of an inventive therapeutic transdermal system, the salt (s) of alkaline compounds of the ECA inhibitor (s) dicarboxylic acid (s) directly in the matrix can be incorporated. The matrix may be present in the course of each of the inventive methods of production of the inventive therapeutic transdermal system also as a solution or suspension; the solvents respectively Suspension means may optionally be evaporated at a later stage of the method. That is, it has been surprisingly discovered that the salts of the ACE-inhibiting dicarboxylic acid which are formed by transformation with an organic amine and / or an alkaline compound are largely stable against decomposition, in particular against the intramolecular formation of lactam. It has also surprisingly been found that the salts of the ACE-inhibiting dicarboxylic acid which are formed by transformation with a molar equivalent of an organic amine and / or an alkaline compound are largely stable against decomposition, in particular against the intramolecular formation of lactam. The intramolecular formation of lactam is inhibited by a blockage of the carboxyl group X (Cf. the equation) by the amine, respectively, the alkaline compound. Because the carboxylate group X is the most acidic carboxylate group in the ECA inhibitor dicarboxylic acid, it is possible to prevent the intramolecular formation of lactam either by one molar equivalent of amine or alkaline compound. The salts, in particular, the mono-salts of the ECA-inhibiting dicarboxylic acids are present in a neutral area for the skin and thus have a minimum potential for dermal irritation. Amine salts or salts of Alkaline compounds are dispensed from the matrix promoter with great fluidity. The pH value, which is adjusted in the application of the inventive therapeutic transdermal system is preferably located with an inventive salt, in particular, a mono-salt of the ECA-inhibiting dicarboxylic acid with an organic amine and / or an alkaline compound, between 5.0 and 7.5, preferably from 5.0 to 7.0, and with particular preference from 5.0 to 6.8. This pH value can be approximated by shaking the inventive therapeutic transdermal system for a sufficient time in an appropriate amount of water, for example, 25 ml and measuring, for example, after 2 hours the pH value with a usual measurement method. Such an area of pH value is particularly advantageous, since the pH value of the skin is approximately 4.9 to 5.5. Surprisingly it has also been discovered that an inventive therapeutic transdermal system with an inventive salt of an ECA-inhibiting dicarboxylic acid with an organic amine and / or an alkaline compound is particularly stable, for example, in the case of prolonged storage. In addition, an inventive therapeutic transdermal system with an inventive salt of an ECA-inhibiting dicarboxylic acid with an organic amine and / or an alkaline compound is characterized by a flow (a permeation) surprisingly high of the active substance in the application, which is, for example, higher than that of the free ECA inhibitor dicarboxylic acid. These effects are particularly pronounced in the inventive therapeutic transdermal system with the inventive salt of an ACE-inhibiting dicarboxylic acid with an organic amine, in particular an inventive mono-salt of an ECA-inhibiting dicarboxylic acid with an organic amine. The inventive therapeutic transdermal system consists of a layer (1) of impermeable coating for the active substance, of one or more layer (s) (2) of self-adhesive matrix (s) containing (n) the active substance and / or agents of optional permeation or one or more matrix layer (s) (4) that are coated with an adherent adhesive and a removable protective layer (3). In the inventive therapeutic transdermal system, at least one stable amine salt of an ECA-inhibiting dicarboxylic acid based on a reaction of an organic amine with an ECA-inhibiting dicarboxylic acid can be used. As organic amines, the primary, aliphatic amines with 4 to 12 carbon atoms are preferably used. Particularly preferred are the amines with an amino group (monoamine). It can be used, for example, butylamine, pentylamine, hexylamine, heptylamine, octylamine, nonilamma, decylamine, undecylamine, dodecylamine or trometamol (= 2-amino-2-hydroxymethyl-l, 3-propanediol). In particular, trometamol is used as the primary, aliphatic amine. It is also possible to use secondary amines such as pyrrolidone or its derivatives. It is also possible to use tertiary amines such as triethanolamine. The inventive therapeutic transdermal system may contain as an active substance an ACE inhibitor whose active metabolites represent a dicarboxylic acid such as, eg, imidapril, fosinopril, moexipril, perindorpyl, spirapryl, benzepril, cilazapril, lisinopril, quinapril, enalapril, delapril, ramipril and / or trandolaprilo. By a dicarboxylic acid of an ACE inhibitor is meant the active metabolite of the ACE inhibitor in which the carboxylic acid ester group present in the molecule was saponified. Therefore, ACE inhibitors are dicarboxylic acids, e.g., imidaprilat, fosinoprilat, moexiprilat, perindorpilat, spiraprylate, benzeprilat, cilazaprilat, lisinoprilat, quinaprilat, enalaprilat, delaprilat, ramiprilat and / or trandolaprilat. Preference is given to using the salts of alkali compounds or of amines of trandolaprilat and / or ramiprilat as the component of active substance, the amine salts being preferred. The inventive amine salt is a salt, preferably a mono-salt wherein the molar ratio of ECA-inhibiting dicarboxylic acid to amine is less than 1: 2, in particular 1: 0.5 to 1: < 2, preferably 1: 0.5 to 1: 1.9. Preferably a molar ratio of 1: 0.9 to 1: 1.5, in particular 1: 1.1 and especially of approximately 1: 1, is used. The stable amine salts of the ACE-inhibiting dicarboxylic acids can be formed in the solution, respectively, by matrix suspension by incorporating the corresponding organic amines and the ECA-inhibiting dicarboxylic acids together in the matrix. But the stable amine salts of the ECA inhibitor dicarboxylic acids can also be introduced directly into the matrix. The inventive amine salts of the ECA-inhibiting dicarboxylic acids may be present dissolved in the polymer matrix and / or in the form of emulsion droplets. In the inventive therapeutic transdermal system, at least one stable salt of an alkaline compound of an ECA-inhibiting dicarboxylic acid based on a reaction of an alkaline compound with an ECA-inhibiting dicarboxylic acid can be used. As the alkaline compound, compounds comprising an alkali metal cation. Examples of suitable alkali metal cations are lithium, sodium, potassium, cesium or rubidium cations, of which lithium, sodium and potassium cations are particularly preferred. Also ammonium (NH4 +) is preferred as a cation (pseudo cation of alkali metal). Preferably the counter anion of the alkali compound, in particular of the alkali metal cation, proton acceptor characteristics, and the alkali compound is, with particular preference, a salt comprising alkali metal cations of an inorganic or organic acid, strong or weak . Preferred examples are alkali compounds such as alkali metal hydroxides such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alcoholates such as, for example, lithium methanolate, lithium ethanolate, sodium methanolate, sodium ethanolate, potassium methanolate, potassium ethanolate; or alkali metal carbonates such as, for example, sodium hydrogen carbonate or potassium hydrogen carbonate, or alkali metal tartrates such as, for example, sodium tartrate or potassium tartrate, or alkali metal maleates, for example, sodium maleate or potassium maleate. Ammonium hydroxide is preferred as the ammonium compound. The alkaline compound can be used in pure form or in admixture with another suitable component, or with a solvent. The inventive therapeutic transdermal system may contain as an active substance an ACE inhibitor whose active metabolites represent a dicarboxylic acid as, e.g., imidapril, fosinopril, moexipril, perindorpyl, spirapryl, benzepril, cilazapril, lisinopril, quinapril, enalapril, delapril, ramipril and / or trandolapril. By a dicarboxylic acid of an ACE inhibitor is meant the active metabolite of the ACE inhibitor in which the carboxylic acid ester group present in the molecule was saponified. Therefore, ACE inhibitors are dicarboxylic acids, e.g., imidaprilat, fosinoprilat, moexiprilat, perindorpilat, spiraprylate, benzeprilat, cilazaprilat, lisinoprilat, quinaprilat, enalaprilat, delaprilat, ramiprilat and / or trandolaprilat. Preference is given to using the salts of alkali compounds or of amines of trandolaprilat and / or ramiprilat as the component of active substance, the amine salts being preferred. The inventive alkaline compound salt is a salt, preferably a mono-salt in which the molar ratio of ECA-inhibiting dicarboxylic acid to amine is less than 1: 2, in particular 1: 0.5 to 1: <; 2, preferably 1: 0.5 to 1: 1.9. Preferably a molar ratio is used from 1: 0.9 to 1: 1.5, in particular 1: 1.1 and especially of approximately 1: 1. The salts of stable alkali compounds of the ECA-inhibiting dicarboxylic acids can be formed in Si in the solution, respectively, matrix suspension by incorporating the corresponding organic amines and the ECA-inhibiting dicarboxylic acids together in the matrix. However, the stable alkaline compound salts of the ECA-inhibiting dicarboxylic acids can also be introduced directly into the matrix. The inventive alkaline compound salts of the ACE-inhibiting dicarboxylic acids may be present dissolved in the polymer matrix and / or in the form of emulsion droplets. With particular preference the matrix of the inventive therapeutic transdermal system is a non-aqueous matrix, ie a matrix whose content, respectively, remaining water content is less than 2% by weight, preferably less than 1% by weight, with even more preference less than 0.9, preferably approximately 0.7% by weight, relative to the weight of the matrix. The content of ECA-inhibiting dicarboxylic acids can amount to 2-35% by weight, in particular 10-25% by weight, based on the weight of the matrix.

For the adhesive glue layer, a pressure sensitive adhesive, for example, based on polyurethane, based on polyisobutylene, based on polyvinyl ether, based on polyacrylate, based on silicone, based on styrene block copolymer (eg, copolymer) can be selected. of styrene-isoprene-styrene block (SIS) or styrene-butadiene-styrene block copolymer) or a mixture of these. Preferably, adhesives based on acrylate or polyisobutylene are used. For the matrix, the usual matrix promoters such as polyacrylate, polyisobutylene, silicone, styrene block copolymers (e.g., styrene-isoprene-styrene block copolymer (SIS)) or a mixture thereof are used. Preferably a self-adhesive polyacrylate matrix is used in which the matrix promoter and the glue are one. The amine salts of the ECA-inhibiting dicarboxylic acids are dispensed from the matrix promoter, for example, the polyacrylate, with high flux. By a large flow it is understood, for trandolaprilat, 0.25 to 25 μg / cm2 / h, preferably 0.5 to 5 μg / cm2 / h. For ramiprilato, it is understood by a large flow 0.6 to 63 μg / cm2 / h, preferably 1.2 to 12 μg / cm2 / h. The polyacrylate-based glues can be a homopolymer, copolymer or arbitrary terpolymer, containing or consisting of different acrylic acid derivatives. Thus, the polyacrylates can be polymers of one or more monomers of acrylic acids and other copolymerizable monomers. The polyacrylates can also be copolymers of alkyl acrylates and / or alkyl methacrylates and / or secondary monomers or monomers with copolymerizable functional groups. If the number of each type that is added as a monomer is modified it is possible to change the cohesive characteristics of the resultant acrylate polymers. The acrylate polymer generally consists of at least 50% by weight of an acrylate, methacrylate, alkyl acrylate, alkylmethacrylate or acrylamide monomer, 0 to 20% of a functional monomer copolymerizable with acrylate and 0 to 50% of other monomers. In the following, different acrylate monomers are mentioned, as e.g. acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, isooctyl acrylate, isooctilmetacrilato, glycidyl methacrylate, 2-hidroxetilacrilato, methylacrylate, methylmethacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl, decilacrilato, decyl methacrylate, dodecyl acrylate, dodecylmethacrylate, tridecilacrilato and tridecilmetacrilato, which can be polymerized alone or in mixtures.

In addition, functional monomers which are copolymerizable with the aforementioned acrylates, such as, for example, acrylic acid, can be used for the copolymerization., methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, vinyl acetate, hydroxypropylacrylate, acrylamide, dimethyl acrylamide, tert-octylacrylamide, acrylonitrile, dimethyl aminoethyl acrylate, dimethyl aminoethyl methacrylate, tert-butyl aminoethyl acrylate, tert-butyl aminoethyl methacrylate. Further details and examples for the pressure sensitive acrylates which are suitable for the invention are described in Satas Handbook of Pressure Sensitive Adhesive Technology "Acrylic Adhesives", 3rd ed., (D. Satas, ed.), Van Nostrand Reinhold, New York (1999). The adhesive content of the self-adhesive matrix can amount to 20-90% by weight, 30-80% by weight, in particular 40-60% by weight, based on the weight of the matrix. For the release layer, polyester, polyethylene, polypropylene, polysoloxane (for example with a fluorosiliconized coating), polyacrylate, ethylvinyl acetate, polyurethane, thermoplastic polyurethane, polyisobutene or paper, covered most of the time with silicone and / or polyethylene, or a mixture of the above. As an impermeable coating layer, acrylate sheets, acrylonitrile-butadiene-styrene, acrylonitrile copolymer (methyl methacrylate), acrylonitrile copolymer, ethylene ethyl acrylate, ethylene methyl acrylate, ethylene vinyl acetate, ethylene vinyl acetate copolymer, ethylene polymer can be considered vinylalcohol, ionomers, nylon (polyamide), nylon copolymer (polyamide), polybutylene, polycarbonate, polyester, polyethylene terephthalate, thermoplastic polyester copolymer, polyethylene copolymer (high density), polyethylene (high molecular weight, high density), polyethylene ( intermediate molecular weight, high density), polyethylene (linear low density), polyethylene (low density), polyethylene (medium density), polyethylene oxide, polyimide, polypropylene, polypropylene (coated), polypropylene (oriented), polystyrene, polyurethane, polyvinylacetate, polyvinylchloride, polyvinylidene chloride and / or styrene-acrylonitrile which can optionally be metallized or pigmented. As an impermeable coating layer for the active substance, polyurethane, ethylene vinyl alcohol and polyester polymer are preferred. As the permeation promoter, saturated and / or unsaturated fatty alcohols can optionally be used with 8 to 18 C atoms in each case; tea tree oil; Cyclic saturated and / or unsaturated ketones; alkyl methylsulphoxides; saturated and / or unsaturated fatty acids with 8 to 18 C atoms in each case; esters and salts thereof; natural vitamin E; synthetic vitamin E and / or vitamin E derivatives; esters of sorbitan fatty acids; azonas (laurocapram); 1-alkylpyrrolidone; copolymers of polyethylene glycol block and dimethylsiloxane with cation groups at one end; polyoxyethylene-10-stearyl ether; mixture of polyoxyethylene-10-stearyl ether and glyceryl laurate; dodecyl-2- (N, N-dimethylamino) -propanol tetra-decanoate and / or dodecyl-2- (N, N-dimethylamino) -propionate; N-acetylprolinate ester (N-acetyl pyrrolidone-2-carboxylic acid ester) with > of 8 C atoms; nonionic surfactants, e.g. lauryl ether; polyoxyethylene ester; dimethyl (arylimino) sulfurane; mixture of analog (s) of oleic acids, and propylene glycol; padimate mixture O, octylsalicylate, isopropylmyristate, isopropylpalmitate, octylmethoxycinnamate, larocapram; highly dispersed silicon dioxide (Aerosil); polyoxyethylene-7-glycerol monococoate (Cetiol HE); 2-octyldodecanol (Eutanol® G) or a mixture of different individual components. Preferred in the inventive therapeutic transdermal system Polyoxyethylene-7-glycerol monococoate (Cetiol® HE) or 2-octyldodecanol (Eutanol G) as a permeation promoter. As fillers can be used: metal oxides such as zinc oxide, magnesium, calcium or titanium, inorganic salts such as calcium carbonate, magnesium carbonate, sodium carbonate, calcium sulfate, magnesium sulfate or calcium phosphate, clay components such as talc , kaolin, bentonite or polymer fillers. As fillers, zinc oxide and / or aerosil can be used in particular. The inventive therapeutic transdermal system having a self-adhering matrix can be constituted as follows. The upper layer represents the impermeable coating layer for the active substance. Then the matrix layer that the active substance and optionally permeation promoters and / or fillers. The matrix promoter is, in this case, the adhesive glue. Finally comes a removable protective layer. Alternatively, the inventive therapeutic transdermal system may contain a matrix layer which is not self-adhesive and which is provided with a separate adherent adhesive layer. With particular preference the inventive therapeutic transdermal system comprises a matrix layer containing active substance which is a layer of non-aqueous matrix, ie a matrix whose content, respectively, remaining water content is less than 2% by weight, preferably less than 1% by weight, with even more preference less than 0.9, preferably approximately 0.7% by weight, based on the weight of the matrix. The invention is explained below in more detail by the following examples, however, without limiting the scope of the invention to them. The following components are used in particular: as a polyacrylate-based adhesive: Durotak 78-2353; as a glue based on acrylate copolymer and vinyl acetate: Durotak® 87-4098; as a glue based on styrene-butadiene-styrene block copolymer: Durotak 87-6173; as a glue based on polyisobutylene: Durotak 87-6430; as silicone glue: BioPSA Hex 7-4302; As a permeation promoter: Cetiol HE: polyoxyethylene-7-glycerol monocoate. Example 1: Composition of an inventive self-adhesive matrix for a STT having a mono-salt of trandolaprilat and trometamol.

The percents by weight refer to the weight of the matrix. The stoichiometric ratio of trandolaprilat to trometamol is 1: 1.5. Production process: Trandolaprilat and trometamol are dissolved in an appropriate solvent in a mixing vessel. Next, Cetiol HE is added first and then the glue (Durotak) and homogenized. This mixture is applied to a removable and dried sheet. In this matrix, a PET film is then applied as an impermeable coating layer for the active substance. The STTs are then cut with a die and packed into envelopes. Example 2: Composition of an inventive self-adhesive matrix for a STT comprising a mono-salt of trandolaprilat and trometamol The percents by weight refer to the weight of the matrix. The stoichiometric ratio of trandolaprilat to trometamol is 1: 1. Production is carried out analogously to Example 1. Stability: The stability of a transdermal therapeutic system comprising a mono-salt of trandolaprilat with trometamol (ratio of trandolaprilat to trometamol is 1: 1 ) As shown in the table, a STT with a mono-salt trandolaprilat exhibits great stability. Dermal irritation: A transdermal therapeutic system comprising a mono-salt of trandolaprilat with trometamol (ratio of trandolaprilat to trometamol is 1: 1.1) shows an average value for erythema - an inflammatory flushing of the skin due to hyperemia - of 1. A placebo exhibits an average value for erythemas of 1. According to DRAIZE (Evaluation of the safety of chemicals in food, drugs and cosmetics, Association of Food and Drug Officers of the United States, Austin, Texas, 1959) it is permissible to classify erythemas as follows : Accordingly, a transdermal therapeutic system comprising a mono-salt of trandolaprilat shows a small value of erythema, ie, there is no dermal irritation. There is no difference with a placebo. PH value: To determine the pH value of the therapeutic transdermal systems, sections of 10 cm2 laminate were shaken in 25 ml of water for a sufficient time, that is, until a constant pH value was present. The pH value was determined by a usual pH meter.

Example 3: Composition of an inventive self-adhesive matrix for a STT with a salt of ramiprilat and sodium hydroxide (NaOH) in a polyacrylate matrix: The percents by weight refer to the weight of the matrix. The stoichiometric ratio of ramiprilat to sodium hydroxide (NaOH) is 1: 1.3. The production is carried out analogously to example 1. Example 4: The composition of an inventive self-adhesive matrix for a STT with a salt of trandolaprilat and octylamine in a silicone matrix: The percents by weight refer to the weight of the matrix. The stoichiometric ratio of trandolaprilat to octylamine is 1: 1.5. The production is carried out analogously to Example 1 using a fluorosiliconized release sheet. The pH value of the therapeutic transdermal system amounts to 5.0 (determination, see example 2). Example 5: The composition of an inventive self-adhesive matrix for a STT with a trandolaprilat and dodecylamine salt in a block copolymer matrix styrene or a GDP matrix: The percents by weight refer to the weight of the matrix. The stoichiometric ratio of trandolaprilat to dodecylamine is 1: 1.2. The production is carried out analogously to example 1. Example 6: The composition of an inventive self-adhesive matrix for a STT with a salt of trandolaprilat and butylamine in a silicone matrix: The percents by weight refer to the weight of the matrix. The stoichiometric ratio of trandolaprilat to butylamine is 1: 1.5. The production is carried out analogously to the example using a fluorosiliconized release sheet

Claims (48)

1. Exit an ECA inhibitor dicarboxylic acid with at least one organic amine and / or at least one alkaline compound.

2. Salt according to claim 1 characterized by a monoamine as organic amine.

3. Salt according to claim 1 and / or 2 characterized by a primary amine, a secondary amine or a tertiary amine as organic amine.

4. Salt according to claim 3 characterized by a primary aliphatic C-? 2 amine.

5. Salt according to claim 4 characterized by butylamine, pentylamine, hexylamine, heptylamine, octylamine, nonylamine, decylamine, undecylamine, dodecylamine or trometamol (= 2-amino-2-hydroxymethyl-l, 3-propanediol) as amine C-? 2 primary aliphatic.

6. Salt according to claim 3 characterized by pyrrolidone or one of its derivatives as a secondary amine.

7. Salt according to claim 3 characterized by triethanolamine as tertiary amine.

8. Salt according to one of claims 1 to 7, characterized in that the alkaline compound comprises an alkali metal cation.

9. Salt according to claim 8, characterized in that the alkaline compound comprises a cation of lithium, sodium or potassium.

10. Salt according to at least one of the preceding claims characterized by an ECA-inhibiting dicarboxylic acid from the group of the dicarboxylic acids imidapril, fosinopril, moexipril, perindopril, spirapryl, benzepril, cilazapril, lisinopril, quinapril, enalapril, delapril, ramipril and trandolaprilo.

11. A salt according to claim 10 characterized by a trandolapril or ramipril ECA inhibitor dicarboxylic acid.

Salt according to at least one of the preceding claims characterized by a molar ratio of ECA-inhibiting dicarboxylic acid: amine or ECA-inhibiting dicarboxylic acid: alkaline compound of 1: less than 2.

13. Salt according to claim 12, characterized by a molar ratio of ECA inhibitor dicarboxylic acid: amine or ECA inhibitor dicarboxylic acid: alkaline compound of 1: 0.5 to 1: less than 2, preferably 1: 0.5 to 1: 1.9, more preferably 1: 0.9 to 1: 1.5 , more preferably 1: 1.1 and in particular of approximately 1: 1.

14. Monosal according to one of claims 1 to 12, characterized by a molar ratio of ECA-inhibiting dicarboxylic acid: amine or ECA-inhibiting dicarboxylic acid: alkaline compound of about 1: 1.

Therapeutic transdermal system characterized by at least one salt according to one of claims 1 to 14 as active substance.

16. The therapeutic transdermal system according to claim 15, characterized by a monoamine as an organic amine.

17. The therapeutic transdermal system according to claim 15 and / or 16, characterized by a primary amine, a secondary amine or a tertiary amine as an organic amine.

18. Therapeutic transdermal system according to claim 17, characterized by a primary aliphatic C4-i2 amine.

The transdermal therapeutic system according to claim 18, characterized by butylamine, pentylamine, hexylamine, heptylamine, octylamine, nonylamine, decylamine, undecylamine, dodecylamine or trometamol (= 2-amino-2-hydroxymethyl-l, 3-propanediol) as amine C4_ ? 2 primary aliphatic.

20. Transdermal therapeutic system according to claim 17, characterized by pyrrolidone or one of its derivatives as a secondary amine.

21. The therapeutic transdermal system according to claim 17, characterized by triethanolamine as a tertiary amine.

The therapeutic transdermal system according to at least one of the preceding claims, characterized by at least one salt of an ECA-inhibiting dicarboxylic acid from the group of dicarboxylic acids of imidapril, fosinopril, moexipril, perindopril, spirapryl, benzepril, cilazapril, lisinopril, quinapril, enalapril, delapril, ramipril and trandolapril.

23. Therapeutic transdermal system according to claim 22, characterized by a salt of a dicarboxylic acid ECA inhibitor of trandolapril or ramipril.

The therapeutic transdermal system according to at least one of the preceding claims 15 to 23, characterized by a molar ratio of acid: amine or dicarboxylic acid ECA inhibitor: alkaline compound of 1: less than 2.

25. Therapeutic transdermal system according to the claim 24, characterized by a molar ratio of ECA inhibitor dicarboxylic acid: amine or acid ACE inhibitor dicarboxylic acid: alkaline compound of 1: 0.5 to 1: less than 2, preferably 1: 0.5 to 1: 1.9, more preferably 1: 0.9 to 1: 1.5, more frequently 1: 1.1 and in particular of about 1 : 1.

The therapeutic transdermal system according to one of the preceding claims 15 to 24, characterized by a molar ratio of ECA-inhibiting dicarboxylic acid: amine or dicarboxylic acid ACE inhibitor to alkaline compound of approximately 1: 1.

27. Transdermal system Therapeutic according to at least one of the preceding claims 15 to 26, characterized by - a waterproof coating layer for the active substance, - one or more self-adhering matrix layers containing active substance, and - a removable protective layer.

Transdermal therapeutic system according to at least one of the preceding claims 15 to 26, characterized by - an impermeable coating layer for the active substance, - one or more layers of matrix containing active substance, - which is (are) provided (s) ) on the side of the application with a layer of adherent glue, and - a removable protective layer.

The therapeutic transdermal system according to claim 28, characterized by a non-self-adhesive matrix layer and a separate layer of a glue adherent 30.

The therapeutic transdermal system according to at least one of the preceding claims 15 to 29, characterized in that the active substance or substances are dissolved in the matrix and / or present in the form of emulsion droplets.

The therapeutic transdermal system according to at least one of the preceding claims, characterized in that the content of ECA-inhibiting dicarboxylic acid is from 2 to 35% by weight, based on the weight of the matrix.

32. The therapeutic transdermal system according to claim 31, characterized in that the content of ECA-inhibiting dicarboxylic acid is from 10 to 25% by weight, based on the weight of the matrix.

The therapeutic transdermal system according to one of the preceding claims 15 to 32, characterized by a pressure sensitive adhesive based on polyurethane, polyisobutylene, polyvinyl ether, polyacrylate, silicone, styrene block copolymer or a mixture thereof.

34. The therapeutic transdermal system according to claim 33, characterized by a pressure-sensitive adhesive based on styrene-isoprene-styrene block copolymer (SIS) or styrene-butadiene-styrene block copolymer.

35. Transdermal therapeutic system according to claim 33, characterized by a pressure sensitive adhesive based on polyacrylate or polyisobutylene.

36. The therapeutic transdermal system according to one of the preceding claims 15 to 35, characterized by a matrix promoter from the group of polyacrylate, polyisobutylene, silicone, styrene block copolymer or a mixture thereof.

37. Therapeutic transdermal system according to claim 36, characterized by a styrene-isoprene-styrene block copolymer (SIS) as a matrix promoter.

38. The therapeutic transdermal system according to claim 36, characterized by a self-adhesive matrix based on polyacrylate.

39. Therapeutic transdermal system according to one of the preceding claims 15 to 38, characterized by an adhesive adhesive and / or a polyacrylate based matrix which is a homopolymer, copolymer or terpolymer.

40. The therapeutic transdermal system according to claim 39, characterized by an adherent adhesive and / or a polyacrylate-based matrix, containing or consisting of different acrylic acid derivatives.

41. Therapeutic transdermal system according to one of from preceding claims 15 to 40, characterized by an adhesive adhesive and / or a polyacrylate-based matrix, consisting of acrylate polymer of at least 50% by weight of an acrylate, methacrylate, alkyl acrylate, alkylmethacrylate or acrylamide monomer, 0- 20% by weight of a functional monomer that can copolymerize with acrylate, and 0 to 50% by weight with other monomers.

42. The therapeutic transdermal system according to one of the preceding claims 15 to 41, characterized by a permeation promoter of the group consisting of saturated and / or unsaturated fatty alcohols with 8 to 18 C atoms in each case; tea tree oil; cyclic saturated and / or unsaturated ketones; alkyl methylsulphoxides; saturated and / or unsaturated fatty acids with 8 to 18 C atoms in each case; esters of saturated and / or unsaturated fatty acids with 8 to 18 C atoms in each case; salts of saturated and / or unsaturated fatty acids with 8 to 18 C atoms in each case; natural vitamin E; synthetic vitamin E and / or vitamin E derivatives; esters of sorbitan fatty acids; ethoxylated sorbitan fatty acid esters; azones, in particular laurocapram; 1-alkylpyrrolidone; copolymers of polyethylene glycol block and dimethylsiloxane with cation groups at one end; polyoxyethylene-10-stearyl ether; mixture of polyoxyethylene-10-stearyl ether and glyceryl laurate; dodecyl-2- (N, N-dimethylamino) -propanol tetradecanoate and / or dodecyl-2- (N, N-dimethylamino) -propionate; N-acetylprolinate ester (N-acetyl pyrrolidone-2-carboxylic acid ester) with > of 8 C atoms; nonionic surfactants, in particular lauryl ether; polyoxyethylene ester; dimethyl (arylimino) sulfurane; mixture of analog (s) of oleic acids, and propylene glycol; mixture of palmitate, octylsalicylate, isopropylmyristate, isopropylpalmitate, octylmethoxycinnamate, larocapram; highly dispersed silicon dioxide (Aerosil); polyoxyethylene-7-glycerol monococoate (Cetiol HE); 2-octyldodecanol (Eutanol G); and its mixtures.

43. The therapeutic transdermal system according to claim 42, characterized by polyoxyethylene-7-glycerol monococoate (Cetiol "HE) or 2-octyldodecanol (Eutanol G) as a permeation promoter

44. Therapeutic transdermal system according to one of claims 15 to 43 precedents, characterized in that the glue content of the self-adhesive matrix is from 20 to 90% by weight, preferably from 30 to 80% by weight and in particular from 40 to 60% by weight, the rest of the active substance (s), optionally permeation agent and optionally filler, in each case referred to the weight of the matrix

45. Method for the production of a system Therapeutic transdermal according to one of the preceding claims 15 to 44, characterized in that the organic amine (s) and the dicarboxylic acid (s) inhibitor (s) are incorporated. ECA together with the solution of matrix, respectively, suspension and the salt (s) of amine is (are) formed (s) m If you in the solution respectively suspension of matrix.

46. Method for the production of a therapeutic transdermal system according to one of the preceding claims 15 to 44, characterized in that the amine salt (s) of the ECA-inhibiting dicarboxylic acids is (are) incorporated directly into the matrix.

47. Method for the production of a therapeutic transdermal system according to one of the preceding claims 15 to 44, characterized in that the alkaline compound (s) and the dicarboxylic acids inhibitors of ECA are incorporated together in the matrix solution respectively the suspension and the salt (s) of alkaline compounds is / are formed m If you in the matrix solution respectively the solution.

48. Method for the production of a therapeutic transdermal system according to one of claims 15 to 44, characterized in that the salts of the ECA-inhibiting dicarboxylic compound (s) are incorporated directly into the matrix.