WO2009007334A2

WO2009007334A2 - Transdermal therapeutic systems which contain the substance anastrozole

Info

Publication number: WO2009007334A2
Application number: PCT/EP2008/058743
Authority: WO
Inventors: Christian Brätter
Original assignee: Braetter Christian
Priority date: 2007-07-10
Filing date: 2008-07-07
Publication date: 2009-01-15
Also published as: DE102007032468A1; EP2178523A2; WO2009007334A3

Abstract

The invention relates to a transdermal therapeutic system (TTS) which comprises a back layer impermeable to the substance, an adhesive layer (layer holding the substance) which contains an adhesive component and the substance anastrozole or the physiologically acceptable hydrate thereof, solvate or salt dissolved in a concentration of 0.1% (m/m) to 30% (m/m), relative to the weight of the adhesive layer, and a removable layer in contact with the skin which is removed before application of the TTS. The invention likewise relates to the use of said TTS.

Description

Transdermal therapeutic systems containing the active substance anastrozole

DESCRIPTION

The invention relates to a transdermal therapeutic system (TTS) containing the aromatase inhibitor anastrozole. This TTS allows delivery of anastrozole in therapeutically effective amounts over a period of at least 12 hours. The invention also encompasses the use of a TTS 'according to the invention alone or in combination therapy for the therapy of breast cancer or related tumors.

Anastrozole, like other aromatase inhibitors of the 1 / - / - 1, 2,4-triazole group (eg letrozole, fadrozole and vorozole), is already approved for oral use in the pharmaceutical market. This currently available oral therapy with aromatase inhibitors is associated with significant pharmacokinetic problems and / or compliance issues. Gastrointestinal side effects have also been described. In particular, a lack of compliance can jeopardize the therapeutic success in the treatment of cancer.

Transdermal preparations for drugs with antiestrogen-like effect have been described. For example, WO 93/19746 A1 mentions topical preparations for the estrogen receptor antagonist toremifene and its salts. Toremifen does not interfere with the denovo-Estrogensynthese, but blocks rather the estrogen receptor. Furthermore, the excipients of WO 97/019746 are dosage forms for topical application. The site of action is therefore local, i. 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.

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

The document 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 backbone is condensed to a bicyclic benzotriazole, while anastrozole has only a simple 1 / - / - 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.

Because of the divergent physico-chemical properties, it has been difficult to use anastrozole in the form of a transdermal therapeutic system (TTS).

TTS are dosage forms which, when applied to the skin, release the active ingredient continuously at a predetermined rate over a defined time interval. Such TTSs consist of a drug-impermeable backing layer, a drug-containing layer, an adhesive layer which may be identical to the drug-containing layer, and a release liner which is removed prior to application of the system. Optionally, a control membrane for defining the rate of release may be incorporated into the system.

There is a need for other dosage forms for anastrazole which have a lower level of side effects compared to, for example, oral administration. These should be superior to the previously known preparations. It is therefore the object of the present invention to provide a transdermal therapeutic system (TTS) for the administration of anastrazole, which shows significantly reduced side effects compared to the previously known dosage forms.

The object is achieved by a transdermal therapeutic system (TTS) according to claim 1. Further preferred embodiments emerge from the subclaims.

In other words, the object is achieved by a transdermal therapeutic system (TTS) for transdermal administration, which comprises a drug-impermeable backing layer, an adhesive layer containing an adhesive component and the active substance anastrozole or its physiologically compatible hydrate, solvate or salt dissolved in a concentration of 0, 1% (m / m) to 30% (m / m), based on the weight of the adhesive layer, comprises (active substance-containing layer) and a skin-side peel-off layer which is removed before the application of the TTS. Optionally, other ingredients may be included. Anastrozole itself is particularly preferably used as active ingredient.

Such a TTS for the active ingredient anastrozole should release the drug in therapeutic doses so that it can achieve its desired pharmacological effects.

The TTS according to the invention makes it possible to release the active ingredient over a time interval of at least 12 hours, preferably 24 hours and most preferably 48 hours or longer. This can be expected a significant improvement for a corresponding therapy. Also, by transdermal application of the drug, a nearly constant concentration level of the drug in the plasma can be achieved. Thus, the plasma concentration spikes that occur as a result of oral therapy and are responsible for typical drug-specific side effects are avoided. Likewise, the gastrointestinal side effects are reduced. Overall, improved therapy with anastrozole is therefore to be expected.

The adhesive component of the TTS according to the invention comprises at least one polymer as a pressure-sensitive adhesive, which is selected from the group of acrylates, methacrylates or the acrylate methacrylates or their copolymers, the group of silicones, the group of polystyrenes, the group of polyisobutylenes or the group of celluloses and cellulose derivatives, optionally containing functional groups in the polymer chains. These functional groups can be selected from the group of amino and hydroxy groups and their amides and esters.

The at least one polymer of the adhesive component is preferably a copolymer of an acrylate, methacrylate or acrylate methacylate with vinyl acetate, with an acrylate-vinyl acetate copolymer being particularly preferred

Preferred acrylates are the DuroTak adhesives (National Starch, USA). For the acrylate methacrylates Eudragite (from Rohm Pharma Polymers, Germany) should be mentioned as a preferred variant. In the context of the silicones are preferably the bio-PSA adhesives (Dow Corning, USA) to call. Preferred acrylate copolymers, such as acrylate vinyl acetates, are the Gelva adhesives (Solutia, USA). A preferred example of adhesives with functional groups is the Eudragit E 100, which contains amino functions in the side chains.

The active ingredient may be contained in dissolved and / or suspended (dispersed) form in the TTS according to the invention, the dissolved form being preferred.

All the following concentration data based on the mass or the weight of the adhesive layer are understood to refer to the adhesive layer after the necessary drying (for removal of process solvent) i. on the dry adhesive layer.

The active ingredient itself is in the TTS 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 of between 1% and 10% (m / m, based on the mass of the adhesive layer).

In addition to the active substance anastrozole and the adhesive component (adhesive component), ie the at least one polymer, the adhesive layer may also contain further ingredients, for example for stabilizing the system or for improving the release of active ingredient. In general, the further ingredients may be present in the TTS according to the invention in concentrations between 0.01% (m / m) and 50% (m / m), based 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 or / and glycerol, and most preferably propylene glycol. In a particularly preferred variant of the TTS according to the invention, the at least one aliphatic alcohol is selected from the group of propylene glycol, 1,2-butanediol and / or dodecanol.

According to the invention, the at least one alcohol is present in a concentration of 0.5% (m / m) to 50% (m / m), based on the weight of the adhesive layer, with a concentration of 0.5% (m / m). to 20% (m / m), 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 preferable.

In a further preferred embodiment, the TTS can be used as further 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 selected to contain at least one chemical permeation enhancer. When using all the above-mentioned polymers, the incorporation of the at least one chemical permeation enhancer had a positive effect. Only in the case of a polymer from the group of silicones was it found that with the incorporation of various permeation enhancers a continuous permeation of anastrozole could be maintained only over a very short time interval.

The at least one chemical permeation enhancer is preferably selected from the group of the alcohols, the N-alkylpyrrolidones, the 2-alkylpyrrolidones, the N-alkylazacycloheptanones, the polyoxyethylene sorbitan esters or the sorbitan esters. addiction is. It is particularly preferred to select it from the group of N-methylpyrrolidone, N-dodecylpyrrolidone, 2-methylpyrrolidone, 2-ethylpyrrolidone and 2-dodecylpyrrolidone, N-dodecylazacycloheptanone, the polyoxyethylene sorbitan esters with fatty acids or the sorbitan esters with fatty acids. Suitable polyoxyethylene sorbitan esters with fatty acids are, in particular, the compounds known briefly as polysorbates or under the trade name Tween. Preferred here are Tween 20 (polyoxyethylene (20) sorbitan monolaurate), 40 (polyoxyethylene (20) sorbitan monopalmitate), 60 (polyoxyethylene (20) sorbitan monostearate) and 80 (polyoxyethylene (20) sorbitan monooleate). Most preferred is Tween 80. The sorbitan esters with fatty acids are known by the name Span. Preferred are Span 20 (sorbitan monolaurate), 40 (sorbitan monopalmitate), 60 (sorbitan monostearate), 80 (sorbitan monooletate), with Span 20 being most preferred.

Furthermore, the at least one chemical permeation enhancer can be a straight-chain hydrocarbon radical having 10 to 18 carbons, preferably 12 carbon atoms, and a polar head group selected from the group consisting of hydroxyl and carbonyl groups and also β-, γ- or δ-lactones.

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 a concentration of 0.5% (m / m) to 20% (m / m), 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.

As further ingredients cosolvents may be included to increase the solubility of the active ingredient. These cosolvents improve the solubility parameters for the active substance anastrozole in the patch or - after release - in the skin.

Furthermore, as a further ingredient at least one crystallization inhibitor to avoid the crystallization or precipitation of dissolved active ingredient may be included. It is preferred that the at least one crystallization inhibitor belongs to the group of polymers, in particular vinylpyrrolidones and acrylates. In particular, it is preferred that the at least one crystallization inhibitor belongs to the group of polyvinyl nylpyrrolidone having a molecular weight in the range of 2,500 to 750,000 daltons.

According to the invention may be included as additional ingredients in addition adjuvants for stabilizing the active ingredient, i. to protect it from decomposition. Accordingly, it is preferred that at least one antioxidant is included. The at least one antioxidant preferably belongs to the group of PHB esters, p-hydroxytoluene derivatives, ubiquinones, vitamins or vitamins.

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 pouches are preferably made of a sealable multilaminate film containing inside a sealable polymer layer and then an aluminum layer. To the outside, a further polymer or paper layer can be applied, which is preferably printable.

The TTS according to the invention which comprises an active-substance-impermeable backing layer, an adhesive layer which comprises an adhesive component and the active substance Ana strozo I or its physiologically tolerated hydrate, solvate or salt dissolved in a concentration of 0.1% (m / m) to 30% (m / m), based on the weight of the adhesive layer, comprises (drug-containing layer) and a skin-side release layer, which is removed before the application of the TTS, is used for the therapy of breast cancer or related tumors, alone or in combination therapy. Optionally, other ingredients may be included. Preferred is the use for the treatment of anti-estrogen-sensitive tumors. Likewise, the TTS according to the invention can be used for the treatment of the prostate adenoma, alone or in combination therapy. A further use according to the invention is the stimulation of foil proliferation as a measure of in vitro fertilization or as a measure of in vivo fertilization. The TTS according to the invention likewise finds application in the treatment of hypogonadism and its consequences, in particular lack of libido and erectile dysfunction. Another use of the invention is in the treatment of gynecomastia. In a preferred embodiment, the TTS according to the invention is used for the treatment of Benign Prostatic Hyperplasia, which are associated with increased estrogen action, alone or in combination therapy. In other words, it is used to treat Benign Prostatic Hyperplasia that respond to anti-tumor therapy. Likewise, the use is to Tumor prophylaxis according to the invention. This means the use in long-term use to reduce the risk of breast cancer and to prevent recurrences. In other words, the TTS according to the invention is used for the prevention of tumor formation.

The application is made by sticking to the skin of the human body, preferably by sticking to the abdomen, the chest, the lateral trunk, the back, the shoulders, the upper arms or the thighs.

In the following, the invention will be explained by way of examples without being limited thereto.

EXAMPLES

example 1

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

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 skin-side 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 ⁰ C, so that a temperature of 32 ⁰ 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 analyzed 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 flow, the x-intercept as lag time. In addition, average flows were calculated based on 24 and 48 hours. The permeation profile of anastrozole is shown in Figure 1.

Obviously, anastrozole permeates the skin tissue in clearly measurable quantities. A constant release of the drug (steady state) could be maintained for at least 24 hours. The drug flux in the 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 components was as follows: anastrozole to silicone 1; 99, or in the case of using permeation enhancers anastrozole: permeation enhancer: silicone 1: 10: 89. After a homogenization phase, the adhesive solution was applied to a fluoropolymerized PET film by means of a doctor blade and the film subjected to a controlled drying program to remove the process solvents To remove 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 analogously to the procedure described in Example 1, are shown in FIGS. 3 to 5.

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 differ significantly in their physicochemical properties and thus their mechanisms of action, led to the surprising result that a continuous permeation of anastrozole could be maintained only over a very short time interval. The continuous flow of anastrozole through the skin membrane After only about eight hours and was close to zero after a few more hours.

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 ^ J ₃ 24 / IJ ₃ 24 / II J ₃ 48

Without CPE ^v 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 the silicone TTS described in Example 2, a TTS based on an acrylate-vinyl acetate (Gelva® 7883, Solutia Inc., USA) was likewise produced. The composition of the adhesive layer was determined as follows: anastrozole 2.5%, dodecanol 10%, polymer 87.5% (data in% by weight (m / m).) Anastrozole and dodecanol were dissolved in a mixture of 2-propanol and 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 The profile determined from the permeation test is in Figure 6 shown.

The result clearly shows that anastrozole permeates the excised skin of the hairless mouse. Interestingly, the continuous release of anastrozole starts immediately after application of the TTS and continues throughout the duration of the experiment maintained. The steady-state transdermal flux of anastrozole was determined to be 1.72 (0.41) μg / cm ² / h, permitting skin penetration up to 42 μg / cm ² within one day. The average flow in relation to the first 24-hour interval was 1.75 μg / cm ² / h.

Description of the pictures

Fig. 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.

Fig. 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.

Fig. 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.

Fig. 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.

FIG. 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.

FIG. 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.

Claims

1. Transdermal therapeutic system (TTS), comprising a drug-impermeable backing layer, an adhesive layer, the te an adhesive Komponen- and the active ingredient anastrozole or its physiologically acceptable hydrate, solvate or salt dissolved in a concentration of 0.1% (m / m) to 30% (m / m), based on the weight of the adhesive layer, contains (active substance-containing layer) and a skin-side peel-off layer, which is removed before the application of the TTS.

2. TTS according to claim 1, characterized in that the adhesive component comprises at least one polymer selected from the group of the acrylates, the methacrylates or the acrylate methacrylates or their copolymers, the group of silicones, the group of polystyrenes, the group the polyisobutylenes or the group of celluloses and cellulose derivatives is selected, wherein optionally functional groups are contained in the polymer chains, which are selected from the group of amino and hydroxy group and their amides and esters.

3. TTS according to any one of claims 1 or 2, characterized in that the at least one polymer of the adhesive component is a copolymer of acrylate, methacrylate or acrylate methacylate with vinyl acetate.

4. TTS according to any one of claims 1 to 3, characterized in that the active ingredient in a concentration of 0.5% (m / m) to 20% (m / m), based on the weight of the adhesive layer is contained and a concentration from 1% (m / m) to 10% (m / m), based on the weight of the adhesive layer is most preferred.

5. TTS according to any one of claims 1 to 4, characterized in that as a further ingredient at least one aliphatic alcohol is contained.

6. TTS according to any one of claims 1 to 5, characterized in that the at least one aliphatic alcohol is selected from the group of linear aliphatic alcohols having a terminal OH function, preferably with a a chain length between 2 and 14 carbon atoms, and most preferably ethanol and / or dodecanol.

7. TTS according to any one of claims 1 to 6, characterized in that the at least one aliphatic alcohol contains more than one OH function and is preferably propylene glycol, 1, 3-butanediol and / or glycerol, and is most preferably propylene glycol.

8. TTS according to any one of claims 1 to 7, characterized in that the at least one aliphatic alcohol is propylene glycol, 1, 2-butanediol and / or dodecanol.

9. TTS according to any one of claims 1 to 8, characterized in that the at least one alcohol is present in a concentration of 0.5% (m / m) to 50% (m / m), based on the weight of the adhesive layer, wherein a concentration of 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), is most preferred based on the weight of the adhesive layer.

10. TTS according to any one of claims 1 to 9, characterized in that as a further ingredient 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 selected, at least one chemical permeation enhancer is included.

1 1. TTS according to one of claims 1 to 10, characterized in that the at least one chemical permeation enhancer is selected from the group of alcohols, the N-alkylpyrrolidone, the 2-alkylpyrrolidone, the N-alkyl-azacycloheptanone, the Polyoxyethylensorbitanester or sorbitan.

12. TTS according to any one of claims 1 to 11, 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 ester with fatty acids.

13. TTS according to any one of claims 1 to 12, characterized in that the at least one chemical permeation enhancer of a straight-chain hydrocarbon radical having 10 to 18 carbon atoms and a polar head group selected from the group of hydroxyl and carbonyl group and ß-, Y- or δ Lactone.

14. TTS according to any one of claims 1 to 13, characterized in that the at least one chemical permeation enhancer of a straight-chain hydrocarbon radical having 12 carbon atoms and a polar head group selected from the group of hydroxyl and carbonyl group and ß-, y- o- δ-lactone exists.

15. TTS according to any one of claims 1 to 14, characterized in that 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 wherein a concentration of 0.5% (m / m) to 20% (m / m) based on the weight of the adhesive layer is preferable and a concentration of 1% (m / m) to 10% (m / m ), based on the weight of the adhesive layer is most preferred.

16. TTS according to any one of claims 1 to 15, characterized in that as further ingredients in addition cosolvents are included to increase the solubility of the active ingredient.

17. TTS according to any one of claims 1 to 16, characterized in that as a further ingredient at least one crystallization inhibitor to prevent the crystallization of dissolved active ingredient is included.

18. TTS according to any one of claims 1 to 17, characterized in that the at least one crystallization inhibitor to the group of polymers, in particular belongs to vinylpyrrolidones and acrylates.

19. TTS according to any one of claims 1 to 18, characterized in that the at least one crystallization inhibitor belongs to the group of polyvinylpyrrolidones having a molecular weight in the range of 2,500 to 750,000 daltons.

20. TTS according to any one of claims 1 to 19, characterized in that as further ingredient at least one antioxidant is contained.

21. TTS according to any one of claims 1 to 20, characterized in that the at least one antioxidant belongs to the group of PHB esters, p-hydroxytoluene derivatives, ubiquinones, vitamins or vitamin derivatives.

22. Transdermal therapeutic system (TTS) according to any one of claims 1 to 21, comprising a drug-impermeable backing layer, an adhesive layer which has an adhesive component and the active ingredient anastrozole or its physiologically acceptable hydrate, solvate or salt dissolved in a concentration of 0.1 % (m / m) to 30% (m / m), based on the weight of the adhesive layer, contains (drug-containing layer) and a skin-side release layer, which is removed prior to the application of the TTS, for the treatment of breast cancer or related tumors, alone or in combination therapy.

23. TTS according to any one of claims 1 to 22 for the treatment of antiestrogen-sensitive tumors.

24. TTS according to any one of claims 1 to 23 for the treatment of prostate adenoma, alone or in combination therapy.

25. TTS according to any one of claims 1 to 24 for the stimulation of Follikelprolifera- tion as a measure of in vitro fertilization.

26. TTS according to any one of claims 1 to 25 for the stimulation of follicle proliferation as a measure of in vivo fertilization.

27. TTS according to any one of claims 1 to 26 for the treatment of hypogonadism and its consequences, in particular lack of libido and erectile disfunction tion.

28. TTS according to any one of claims 1 to 27 for the treatment of gynecomastia.

29. TTS according to any one of claims 1 to 28 for the treatment of Benigner Prostatahyperplasie responsive to an anti-drug therapy, alone or in combination therapy.

30. TTS according to any one of claims 1 to 29 for the prevention of tumor formation.