DE102007032468A1 - Transdermal therapeutic systems containing the active substance anastrozole - Google Patents

Abstract

The invention relates to a transdermal therapeutic system (TTS) comprising an active substance impermeable backing layer, an adhesive layer which contains an adhesive component, the active ingredient anastrozole or its physiologically compatible hydrate, solvate or salt and optionally further ingredients (active substance-containing layer), and a skin-side peel-off layer, which is removed before the application of the TTS. Likewise, the invention relates to the use of this TTS.

Description

The The invention relates to a transdermal therapeutic system (TTS), which contains the aromatase inhibitor anastrozole. This TTS allows the delivery of anastrozole in therapeutic effective quantities over a period of at least 12 Hours. The invention also includes the use of an inventive TTS 'alone or in combination therapy for the treatment of breast cancer or related tumors.

anastrozole Like other aromatase inhibitors, it is the 1H-1,2,4-triazole group (eg letrozole, fadrozole and vorozole) already in oral dosage form authorized in the pharmaceutical market. These present available oral therapy with aromatase inhibitors with significant pharmacokinetic problems and / or compliance issues afflicted. Gastrointestinal side effects have also been described. In particular, a lack of compliance can be helpful in the therapy of Cancer endanger the success of therapy.

Transdermal preparations for drugs with antiestrogen-like effect have been described. So mentioned the WO 97/019746 topical preparations for the estrogen receptor antagonist toremifene and its salts. Toremifene does not interfere with denovo-estrogen synthesis but rather blocks the estrogen receptor. Furthermore, the excipients of the WO 97/019746 Dosage forms for a topical application. The site of action is therefore local, ie limited to the site of application and surrounding tissue. The application is in a topical application, for example in the form of ointments, creams, powders, suspensions, emulsions or solutions.

The EP 0 943 333 also describes systems which are to be used for topical application. Here, the focus is on the active ingredient formestane, which differs significantly from the anastrozole structurally and thus in its physicochemical as well as in its pharmacodynamic properties. A systemic effect is undesirable here.

The font WO 97/29735 mentions transdermal therapeutic systems for the administration of the aromatase inhibitor exemestane. Exemestane has a steroid backbone and thus differs significantly in the physicochemical properties of the triazole derivative anastrozole, requiring a different approach and formulation strategy. Also, exemestane, unlike anastrozole, acts as an irreversible enzyme inhibitor.

The document WO 97/06788 comprises a transdermal therapeutic system with a reservoir for administering the active substance vorozole. Vorozole is significantly different from the active substance anastrozole. Thus, the triazole skeleton is condensed to a bicyclic benzotriazole, while anastrozole has only a simple 1H-1,2,4-triazole skeleton. The physico-chemical properties, which significantly influence the skin permeability of the drug, thus differ in particular in solubility parameters, which requires different development strategies.

by virtue of the deviating physico-chemical properties it was so far not obvious, anastrozole in the form of a transdermal therapeutic Systems (TTS).

TTS are dosage forms, which, applied to the skin, the contained Active ingredient continuously in predefined speed release a defined time interval. Such TTS consist of a drug-impermeable backing layer, a the drug-containing layer, an adhesive layer, which may be the same as the layer containing the drug, and a release liner which is removed prior to application of the system becomes. Optionally, a control membrane can be used to define the release rate in the system can be installed.

It there is a need for further dosage forms for anastrazole, which, for example, a lower degree of side effects for oral administration. These should consider the previously known preparations be.

It is therefore the object of the present invention, a transdermal provide therapeutic system (TTS) for the administration of anastrazole, which compared to the previously known dosage forms shows significantly reduced side effects.

Solved The task is accomplished by a transdermal therapeutic system (TTS) according to claim 1. Further preferred embodiments emerge from the dependent claims.

In In other words, the task is performed by a transdermal therapeutic System (TTS) for transdermal application dissolved, which a drug-impermeable backing layer, a Adhesive layer, which is an adhesive component, the active ingredient anastrozole or its physiologically acceptable Hydrate, solvate or salt and optionally other ingredients contains (active substance-containing layer) and a skin-side Peel-off layer which is removed before application of the TTS, includes. Anastrozole itself is particularly preferred as the active ingredient used.

One Such TTS for the active ingredient anastrozole should be the Release active ingredient in therapeutic doses, giving this its achieve desired pharmacological effects.

The TTS according to the invention makes it possible to use the Active substance over a time interval of at least 12 hours, preferably 24 hours and most preferably 48 hours or longer release. This leaves a clear Expect improvement for appropriate therapy. Also, by a transdermal application of the drug almost constant concentration level of the drug in the plasma be achieved. Thus, the plasma concentration peaks which as a result of oral therapy occur and for typical drug-specific side effects are responsible, avoided. Likewise, the gastrointestinal side effects are reduced. In sum, therefore, is an improved therapy with anastrozole expected.

The Adhesive component of the invention TTS comprises at least one polymer as a pressure-sensitive adhesive, which from the group of acrylates, methacrylates or acrylate methacrylates or their copolymers, the group of silicones, the group of Polystyrenes, the group of polyisobutylenes or the group of Cellulo sen and cellulose derivatives is selected, wherein optionally contain functional groups in the polymer chains are. These functional groups can be selected be from the group of amino and hydroxy group and their amides and esters.

Prefers it is the at least one polymer of the adhesive component a copolymer of an acrylate, methacrylate or acrylate methacylate with vinyl acetate, with an acrylate-vinyl acetate copolymer being especially As preferred acrylates, the Duro Tak Kleber (National Starch, USA). For the acrylate methacrylates are the Eudragite (Röhm Pharma Polymers, Germany) as a preferred variant. In the context of the silicones are preferably the bio-PSA adhesive (Dow Corning, USA). As preferred acrylate copolymers, such as Acrylate vinyl acetates are the Gelva adhesive (Solutia, USA) in Question. As a preferred example of adhesive with functional Groups should be mentioned the Eudragit E 100, which amino functions in the side chains.

Of the Active substance may be dissolved and / or suspended (dispersed) Form may be included in the TTS according to the invention, the dissolved form being preferred.

All following concentration data based on the mass or Weight of the adhesive layer are understood in terms of the adhesive layer after the necessary drying (for Removal of process solvent) d. H. on the dry Adhesive layer.

Of the Active substance itself is in the TTS according to the invention in a concentration between 0.1% and 30% (m / m, based on the Mass of the adhesive layer), preferably in concentrations between 0.5% and 20% (m / m, based on the mass of the adhesive layer) and most preferably a concentration between 1% and 10% (m / m, based on the mass of the adhesive layer).

Next the active ingredient anastrozole and the adhesive component (adhesive component) d. H. the at least one polymer may be the adhesive layer contain further ingredients, for example for stabilization system or to improve drug release.

As a general rule can the other ingredients in the inventive TTS in concentrations between 0.01% (m / m) and 50% (m / m), based be included on the weight of the adhesive layer.

The further ingredients include, for example, at least one aliphatic alcohol. The at least one aliphatic alcohol is preferably selected from the group of linear aliphatic alcohols having a terminal OH function, preferably having a chain length of from 2 to 14 carbon atoms, such as ethanol or dodecanol. Most preferably these are ethanol or / and dodecanol. The at least one aliphatic alcohol may also contain more than one OH function and is then preferably propylene glycol, 1,3-butanediol and / or glycerol, and most preferably propylene glycol. In a special preferred variant of the TTS according to the invention is the at least one aliphatic alcohol selected from the group of propylene glycol, 1,2-butanediol and / or dodecanol.

According to the invention the at least one alcohol in a concentration of 0.5% (m / m) up to 50% (m / m), based on the weight of the adhesive layer, with a concentration of 0.5% (m / m) to 20% (m / m), is preferred based on the weight of the adhesive layer and a concentration of 1% (m / m) to 10% (m / m), based on the Weight of the adhesive layer is most preferred.

In In another preferred embodiment, the TTS as additional ingredients in addition to the adhesive component, which comprises at least one polymer selected from the group of Acrylates, methacrylates or acrylate methacrylates or their Copolymers, the group of polystyrenes, the group of polyisobutylenes or the group of celluloses and cellulose derivatives is at least one chemical permeation enhancer contain. When using all the above polymers had the Incorporation of the at least one chemical permeation enhancer a positive effect. Only in the case of a polymer from the Group of silicones revealed that when incorporating various Permeation enhancer continuous permeation of Anastrozole maintained only over a very short time interval could be.

Of the at least one chemical permeation enhancer is preferred from the group of the alcohols, the N-alkylpyrrolidones, the 2-alkylpyrrolidones, the N-alkylazacycloheptanone, the polyoxyethylene sorbitan ester or the sorbitan ester is selected. It is particularly preferred him from the group of N-methylpyrrolidone, N-dodecylpyrrolidone, 2-methylpyrrolidone, 2-ethylpyrrolidone and 2-dodecylpyrrolidone, N-dodecylazacycloheptanone, the polyoxyethylene sorbitan ester with fatty acids or the Select sorbitan esters with fatty acids. When Polyoxyethylene sorbitan esters with fatty acids are in particular the briefly known under polysorbates or under the trade name Tween Connections in question. Tween 20 (polyoxyethylene (20) sorbitan monolaurate) are preferred here, 40 (polyoxyethylene (20) sorbitan monopalmitate), 60 (polyoxyethylene (20) sorbitan monostearate) and 80 (polyoxyethylene (20) sorbitan monooleate). Maximum Tween 80 is preferred. The sorbitan esters with fatty acids are known by the name Span. Span 20 (sorbitan monolaurate) is preferred here, 40 (sorbitan monopalmitate), 60 (sorbitan monostearate), 80 (sorbitan monooletate), Span 20 being most preferred.

Farther it may be the at least one chemical permeation enhancer a straight chain hydrocarbon radical of 10 to 18 carbons, preferably 12 carbon atoms, and a polar head group selected from the group of hydroxyl and carbonyl group and β, γ- or δ-lactones act.

According to the invention the at least one chemical permeation enhancer in a concentration of 0.5% (m / m) to 40% (m / m), based on the Weight of the adhesive layer, containing one concentration from 0.5% (m / m) to 20% (m / m), based on the weight of the adhesive layer is preferred and a concentration of 1% (m / m) to 10% (m / m), highest based on the weight of the adhesive layer is preferred.

When additional ingredients can additionally cosolvents to increase the solubility of the active ingredient be. These cosolvents improve solubility parameters for the active substance anastrozole in the plaster or also - after Release - in the skin.

Farther may contain as further ingredient at least one crystallization inhibitor to avoid the crystallization or precipitation of be dissolved drug. It is preferred that the at least one crystallization inhibitor belongs to the group of Polymers, in particular the vinylpyrrolidones and acrylates belongs. In particular, it is preferred that the at least one crystallization inhibitor to the group of polyvinylpyrrolidones having a molecular weight in the range heard from 2,500 to 750,000 daltons.

According to the invention as additional ingredients additional auxiliary substances for stabilization of the active ingredient, d. H. to protect it from decomposition. Accordingly, it is preferred that at least one antioxidant be included is. Preferably, this includes at least one antioxidant to the group of PHB esters, p-hydroxytoluene derivatives, ubiquinones, vitamins or vitamin derivatives.

The TTSs of the invention are individually packaged in a sealed bag to protect the system from external influences such as moisture and light. These bags are preferably made of a sealable multilaminate film having inside a sealable polymer layer and then a Aluminum layer contains. To the outside, a further polymer or paper layer can be applied, which is preferably printable.

The TTS according to the invention, which is a drug-impermeable Backsheet, an adhesive layer, which is a Adhesive component, the active ingredient anastrozole or its physiologically acceptable hydrate, solvate or salt and optionally contains further ingredients (active substance-containing Layer) and a skin-side peel-off layer which before application TTS is included for the treatment of breast cancer or related tumors, used alone or in combination therapy. Preferred is the use for the treatment of antiestrogensensitiven Tumors. Likewise, the TTS invention for the treatment of the prostate adenoma, alone or in combination therapy be used. Another invention Use is the stimulation of follicular proliferation as a measure in vitro fertilization or as a measure of in vivo Fertilization. Likewise, the inventive TTS in the treatment of hypogonadism and its consequences, in particular Lack of libido and erectile dysfunction application. Another invention Use is in the treatment of gynecomastia. In a preferred embodiment of the invention TTS for the treatment of Benign Prostatic Hyperplasia, which in connection with increased estrogenic activity, alone or in Combination therapy used. In other words, it becomes a treatment of Benign prostatic hyperplasia, which indicates an anti-tumoral therapy respond, used. Likewise, the use for tumor prophylaxis according to the invention. This means the use in long-term use for the reduction of breast cancer risk as well as for Avoidance of recurrences. Ie. in other words, that the erfindungsge Permitted TTS is used to prevent tumor formation.

The Application is by sticking to the skin of the human Body, preferably by sticking on the belly, the chest, the lateral trunk, the back, the shoulders, the upper arms or the thighs.

following the invention is explained by way of examples, without to limit it to.

EXAMPLES

example 1

A saturated aqueous solution of anastrozole was produced. An HPLC analytical assay provided a solubility of 32 mg anastrozole per 100 mL. by virtue of saturation is the thermodynamic activity, which is the driving force for the permeation process, maximum.

This solution was tested for the permeation of the drug through the excised skin of the hairless mouse, a scientifically widespread and accepted model membrane. The excised skin was carefully freed of adherent fatty tissue, divided into segments of sufficient size and then placed with the skin outside up in static Franz diffusion cells filled with the skin permeation medium so that it was in contact with the underside of the skin. The skin permeation medium consisted of a pH 7.4 phosphate buffered solution with additions of polyethylene glycol 400 and 2-hydroxypropyl-beta-cyclodextrin to ensure sink conditions for the drug. The water-jacketed cells were tempered with water of 38 ° C, so that a temperature of 32 ° C at the permeation surface of the skin resulted. The medium was stirred continuously with a magnetic stirrer at 500 rpm. 150 μL of the saturated anastrozole solution was applied to the skin. Samples were taken at defined times and collected in HPLC vials. The removed sample volume was replaced by fresh and tempered skin permeation medium. This dilution was taken into account in the calculation of cumulatively permeated amounts of anastrozole. At the end of the permeation experiment, the samples were assayed for anastrozole content by a selective HPLC analytical method with UV detection. The cumulated permeated amounts were plotted against time in a Cartesian coordinate system. The slope of the linear part of the profile was defined as a steady state flux, the x-axis intercept as lag time. In addition, average flows were calculated based on 24 and 48 hours. The permeation profile of anastrozole is in 1 shown.

Obviously, anastrozole permeates the skin tissue in clearly measurable quantities. Constant release of the drug (steady state) could be maintained for at least 24 hours. The drug flux at steady state was calculated to be 2.30 (0.47) μg / cm ² / h.

Example 2

TTS on the basis of a silicone adhesive (Bio PSA ^® 7-4301, Dow Corning, USA) were prepared by the solvent casting method. Anastrozole was dissolved in ethyl acetate, optionally together with potential permeation enhancers, and then added to the silicone polymer dissolved in n-heptane. The mass ratio of the solid constituents was as follows: anastrozole to silicone 1:99, or in the case of the use of permeation enhancers Anastrozole: permeation enhancer: silicone 1:10:89. After a homogenization phase, the adhesive solution was knife coated onto a fluoropolymerized PET film and the film subjected to a controlled drying program to remove the process solvents ethyl acetate and n-heptane. Subsequently, the dried film was laminated with a PE membrane. The average weight of the adhesive layer containing anastrozole was determined to be about 55 mg per 10 cm ² . The TTS were examined by polarization microscopy immediately after production and immediately before a permeation experiment. All TTS had a homogeneous and crystal-free appearance.

As permeation Brij ^® 30, dodecanol and dimethyl isosorbide were examined. The results from the permeation experiments, which were carried out in analogy to the procedure described in Example 1, are described in FIGS 3 to 5 shown.

Surprisingly, the test series shows that anastrozole from a non-optimized TTS without the addition of a permeation enhancer already permeates the model skin in vitro to a significant extent. Interestingly, continuous permeation of anastrozole begins without any appreciable delay (lag time) and persists for a time interval of about 32 hours. The steady state flux could be determined to be 2.07 (0.13) μg / cm ² / h and thus surprisingly only slightly below that of a saturated solution with maximum thermodynamic activity (see Example 1).

The Incorporation of various permeation enhancers which in their physicochemical properties and thus their mechanisms of action clearly different from each other, led to the surprising Result that continuous permeation of anastrozole only over a very short time interval could be maintained. Of the continuous flow of anastrozole through the dermal membrane has already disappeared after about eight hours and was close to zero after a few more Hours.

• ¹ CPE: Chemical permeation enhancer, chemischer Permeationsverstärker J_ss = steady state Fluss von Anastrozol, J_a 24/I = Durchschnittsfluss von Anastrozol in den ersten 24 Stunden, J_a 24/II = Durchschnittsfluss von Anastrozol in den zweiten 24 Stunden, J_a 48 = Durchschnittsfluss von Anastrozol in den ersten 48 Stunden.

In contrast, the permeation enhancer-free control formulation allowed a significantly increased average flow in the first 24 hours, in the second 24 hours, as well as in the total interval of 48 hours (Student's t-test, P <0.05). Table 1 summarizes the permeation data for all silicone TTS tested. Table 1: Permeation parameters for the silicone TTS, calculated from the respective permeation profiles. formulation J _ss J _a 24 / I J _a 24 / II J _a 48 Without CPE ¹⁾ 2.07 (0.13) 2.34 (0.21) 0.51 (0.19) 1.42 (0.06) + Brij ^® 30 3.98 (0.31) 1.88 (0.13) 0.01 (0.19) 0.95 (0.08) + Dimethylisosorbide 2.29 (0.39) 0.88 (0.26) 0.07 (0.11) 0.47 (0.15) + Dodecanol 8.44 (2.63) 1.86 (0.82) 0.02 (0.02) 0.94 (0.39)

• ¹ CPE: Chemical permeation enhancer, chemical permeation enhancer J _ss = steady state flow of anastrozole, J _a 24 / I = average flow of anastrozole in the first 24 hours, J _a 24 / II = average flow of anastrozole in the second 24 hours, J _a 48 = average flow of anastrozole in the first 48 hours.

Example 3

Analogous to those described in Example 2 silicone TTS was also a TTS based on an acrylate-vinyl acetate (Gelva ^® 7883, Solutia Inc., USA). The composition of the adhesive layer was determined as follows: anastrozole 2.5%, dodecanol 10%, polymer 87.5% (in terms of solids% (m / m)) Anastrozole and dodecanol were dissolved in a mixture of 2-propanol and ethyl acetate ( After a homogenization phase, the TTSs were prepared analogously to Example 2. The absence of crystals and the homogeneity of the TTSs were demonstrated by polarization microscopic investigations Profile is in 6 shown.

The result clearly shows that anastrozole permeates the excised skin of the hairless mouse. Interestingly, continuous release of anastrozole starts immediately after application of the TTS and is maintained throughout the duration of the experiment. The steady-state transdermal flux of anastrozole was determined to be 1.72 (0.41) μg / cm ² / h, allowing up to 42 μg / cm ^{2 to} permeate the skin within a day. The average flow based on the first 24-hour interval was 1.75 μg / cm 2 / h.

Description of the pictures

1 : Permeation profile of anastrozole from a saturated aqueous solution through the excised skin of the hairless mouse. Shown are the single curves and the mean curve +/- standard deviation of n = 3 experiments.

2 : Permeation profile of anastrozole from a silicone TTS without permeation enhancer through the excised skin of the hairless mouse. Shown are the single curves as well as the mean curve +/- standard deviation of n = 4 experiments on 2 mice.

3 : Permeation profile of anastrozole from a silicone TTS with an additional 10% Brij ^® 30 through the excised skin of the hairless mouse. Shown are the single curves as well as the mean curve +/- standard deviation of n = 4 experiments on 2 mice.

4 : Permeation profile of anastrozole from a silicone TTS with an additional 10% dimethylisosorbide through the excised skin of the hairless mouse. Shown are the single curves as well as the mean curve +/- standard deviation of n = 4 experiments on 2 mice.

5 : Permeation profile of anastrozole from a silicone TTS with an additional 10% dodecanol through the excised skin of the hairless mouse. Shown are the single curves as well as the mean curve +/- standard deviation of n = 4 experiments on 2 mice.

6 : Permeation profile of anastrozole from an acrylate-vinyl acetate TTS with an additional 10% dodecanol through the excised skin of the hairless mouse. Shown are the single curves as well as the mean curve +/- standard deviation of n = 4 experiments on 2 mice.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• WO 97/019746 [0003, 0003]
• EP 0943333 [0004]
• WO 97/29735 [0005]
• WO 97/06788 [0006]

Claims (36)

Transdermal therapeutic system (TTS), comprising a drug-impermeable backing layer, a Adhesive layer, which is an adhesive component, the active ingredient anastrozole or its physiologically acceptable Hydrate, solvate or salt and optionally other ingredients contains (active substance-containing layer) and a skin-side Peel-off layer which is removed before application of the TTS. TTS according to claim 1, characterized in that the active ingredient is anastrozole. TTS according to one of the claims 1 and 2, characterized in that it contains the active ingredient a time interval of at least 12 hours, preferably 24 hours and most preferably releases for 48 hours or more. TTS according to one of the claims 1 to 3, characterized in that the adhesive component comprises at least one polymer selected from the group of acrylates, the methacrylates or the acrylate methacrylates or their copolymers, group of silicones, group of polystyrenes, group the polyisobutylenes or the group of celluloses and cellulose derivatives is selected, where appropriate, functional groups contained in the polymer chains which are selected are from the group of amino and hydroxy groups and their amides and esters. TTS according to one of the claims 1 to 4, characterized in that the at least one polymer of Adhesive component is a copolymer of an acrylate, methacrylate or acrylate methacylate with vinyl acetate. TTS according to one of the claims 1 to 5, characterized in that the at least one polymer of Adhesive component is an acrylate vinyl acetate copolymer. TTS according to one of the claims 1 to 6, characterized in that the active ingredient dissolved and / or suspended. TTS according to one of the claims 1 to 7, characterized in that the active ingredient dissolved is present. TTS according to one of the claims 1 to 8, characterized in that the active ingredient in a concentration from 0.1% (m / m) to 30% (m / m), based on the weight of the adhesive layer with a concentration of 0.5% (m / m) to 20% (m / m), is preferred based on the weight of the adhesive layer and a concentration of 1% (m / m) to 10% (m / m), based on the Weight of the adhesive layer is most preferred. TTS according to one of the claims 1 to 9, characterized in that as a further ingredient at least one aliphatic alcohol is included. TTS according to one of the claims 1 to 10, characterized in that the at least one aliphatic Alcohol from the group of linear aliphatic alcohols with a terminal OH function is selected, preferred having a chain length between 2 and 14 carbon atoms, and most preferably is ethanol and / or dodecanol. TTS according to one of the claims 1 to 11, characterized in that the at least one aliphatic Alcohol contains more than one OH function and is preferred Propylene glycol, 1,3-butanediol and / or glycerol is and most preferably is propylene glycol. TTS according to one of the claims 1 to 12, characterized in that the at least one aliphatic Alcohol is propylene glycol, 1,2-butanediol and / or dodecanol. TTS according to one of the claims 1 to 13, characterized in that the at least one alcohol in a concentration of 0.5% (m / m) to 50% (m / m), based on the Weight of the adhesive layer is included, with a concentration from 0.5% (m / m) to 20% (m / m), based on the weight of the adhesive layer is preferred and a concentration of 1% (m / m) to 10% (m / m), based on the weight of the adhesive layer is most preferred is. TTS according to one of claims 1 to 14, characterized in that as a further ingredient ne the adhesive component which comprises at least one polymer which is selected from the group of acrylates, methacrylates or acrylate methacrylates or their copolymers, the group of polystyrenes, the group of polyisobutylenes or the group of celluloses and cellulose derivatives, at least one chemical permeation enhancer is. TTS according to one of the claims 1 to 15, characterized in that the at least one chemical Permeation enhancer is selected from the group the alcohols, the N-alkylpyrrolidones, the 2-alkylpyrrolidones, the N-alkyl-azacycloheptanone, the polyoxyethylene sorbitan ester or the sorbitan ester. TTS according to one of the claims 1 to 16, characterized in that the at least one chemical Permeation enhancer is selected from the group of N-methylpyrrolidone, N-dodecylpyrrolidone, 2-methylpyrrolidone, 2-ethylpyrrolidone and 2-dodecylpyrrolidone, N-dodecylazacycloheptanone, the polyoxyethylene sorbitan ester with fatty acids or the Sorbitan esters with fatty acids. TTS according to one of the claims 1 to 17, characterized in that the at least one chemical Permeation enhancer from a straight-chain hydrocarbon radical having 10 to 18 carbon atoms and a polar head group from the group of hydroxyl and carbonyl group as well as β-, γ- or δ-lactone. TTS according to one of the claims 1 to 18, characterized in that the at least one chemical Permeation enhancer from a straight-chain hydrocarbon radical selected with 12 carbon atoms and a polar head group from the group of hydroxyl and carbonyl group as well as β-, γ- or δ-lactone. TTS according to one of the claims 1 to 19, characterized in that the at least one chemical Permeation enhancer in a concentration of 0.5% (m / m) up to 40% (m / m), based on the weight of the adhesive layer, with a concentration of 0.5% (m / m) to 20% (m / m), is preferred based on the weight of the adhesive layer and a concentration of 1% (m / m) to 10% (m / m), based on the Weight of the adhesive layer is most preferred. TTS according to one of the claims 1 to 20, characterized in that as further ingredients additional cosolvents to increase the solubility of the active ingredient are included. TTS according to one of the claims 1 to 21, characterized in that as further ingredient at least one crystallization inhibitor to prevent crystallization is contained by dissolved active substance. TTS according to one of the claims 1 to 22, characterized in that the at least one crystallization inhibitor to the group of polymers, in particular the vinylpyrrolidones and acrylates belongs. TTS according to one of the claims 1 to 23, characterized in that the at least one crystallization inhibitor to the group of polyvinylpyrrolidones having a molecular weight in the range heard from 2,500 to 750,000 daltons. TTS according to one of the claims 1 to 24, characterized in that as further ingredient at least one antioxidant is included. TTS according to one of the claims 1 to 25, characterized in that the at least one antioxidant to the group of PHB esters, p-hydroxytoluene derivatives, ubiquinones, vitamins or vitamin derivatives. Use of a transdermal therapeutic system (TTS) according to one of claims 1 to 26, comprising an active substance-impermeable backing layer, an adhesive layer which is an adhesive component, the active ingredient anastrozole or its physiologically acceptable Hydrate, solvate or salt and optionally other ingredients contains (active substance-containing layer) and a skin-side Peel-off layer which is removed before application of the TTS, for the treatment of breast cancer or related tumors, alone or in Combination therapy. Use of a TTS according to a of claims 1 to 27 for the treatment of antiestrogensensitiven Tumors. Use of a TTS according to a of claims 1 to 28 for the treatment of prostate adenoma, alone or in combination therapy. Use of a TTS according to a of claims 1 to 29 for stimulating follicular proliferation as Measure of in vitro fertilization. Use of the TTS according to a of claims 1 to 30 for stimulating follicular proliferation as a measure of in vivo fertilization. Use of a TTS according to a of claims 1 to 31 for the treatment of hypogonadism and their consequences, in particular lack of libido and erectile dysfunction. Use of a TTS according to a of claims 1 to 31 for the treatment of gynecomastia. Use of a TTS according to a of claims 1 to 32 for the treatment of benign prostatic hyperplasia, which respond to anti-tumor therapy, alone or in Combination therapy. Use of a TTS according to a of claims 1 to 34 for the prevention of tumor formation. Use of a TTS according to a of claims 1 to 35, characterized in that the Application by sticking on the belly, the chest, the lateral Hull, back, shoulders, upper arms or Thighs done.