DE4240806A1 - Prods for transdermal oestrogen admin - contain 14,17-ethano-1,3,5-oestratriene-3,17-diol - Google Patents

Abstract

Prods for transdermal admin of 14-alpha, 17-alpha-ethano-1,3,5(10)- oestratriene- 3,17-beta-diol (I), opt in combination with one or more progestogens (II), are new. USE/ADVANTAGE - The prods contg (I) alone are useful for hormone replacement therapy of menopausal symptoms, atrophic vaginitis and kraurosis vulvae, for treatment of oestrogen-dependent tumours, for prophylaxis or treatment of osteoporosis, etc. The prods contg (I) and opt (II) are useful for treatment of menopausal symptoms, for prevention of osteoporosis, for regulation and stabilisation of the menstrual cycle, for contraception, etc. The prods provide therapeutically adequate and very uniform skin penetration rates.(cf EP137278 and 275716).

Description

The invention relates to an agent for transdermal application, characterized in that that it is 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol optionally in combination with contains one or more progestogen (s).

14α, 17α-Ethanoestra-1,3,5 (10) -triene-3,17β-diol is a substance of the formula

It is known to be a pharmacologically active compound with exceptional strong estrogenic activity (WO 88/01275).

It has now been found that 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol if necessary in combination with one or more gestagen (s) very good for Production of an agent for the transdermal application of the active ingredient or Mixture of active ingredients can be used.

Medicinally to be administered transdermally have the advantage that they over enable a more even release of the active ingredient over a longer period of time, than this is usually the case with agents to be applied differently - such as orally is possible. These properties can be found in a number of endocrine disorders take advantage of. For steroid hormones that are difficult to dissolve in water, such as The estrogens, however, are usually quite problematic about transdermal systems too create a penetration of the active ingredient through the skin sufficient for therapy guarantee.

It has now been found that it is surprising with the aid of the agent according to the invention which is possible, a therapeutically sufficient, very uniform penetration to achieve the rate of steroid hormones through the skin, while doing so in the known steroid hormones to be administered transdermally to be applied only to a limited extent is possible (EP-A 137278 and EP-A 275716).  

Suitable gestagens for the agent according to the invention are, for example, norethisterone, levonorgestrel, gestodene, 3- keto-desogestrel and their esters. In addition to 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol, the combination preparations according to the invention preferably contain 1 to 3 - in particular 1 to 2 gestagen (s).

The active ingredient or the active ingredient can be used to produce pharmaceutical preparations mixture in suitable volatile solvents and / or penetration enhancers Funds are dissolved or suspended. The solutions or suspensions obtained can be mixed with the usual auxiliaries such as matrix formers and bactericides and if necessary, be filled into conventional dosing containers after sterilization. Other On the other hand, it is also possible to include these solutions or suspensions processing from emulsifiers and water into lotions or ointments. One can also - if necessary with the addition of propellant gas - produce sprays in the usual Dosing containers can be filled.

Suitable volatile solvents are, for example, lower alcohols, ketones or lower carboxylic acid esters such as ethanol, isopropanol, acetone or ethyl acetate, polar ethers, such as tetrahydrofuran, lower hydrocarbons such as cyclohexane or gasoline or Halogenated hydrocarbons, such as dichloromethane, trichloromethane, trichlorotrifluoroethane and trichlorofluoromethane. There is no need to explain that mixtures of these Solvents are suitable.

Suitable penetration-enhancing agents are, for example, mono- or polyvalent ones Alcohols, such as ethanol, 1,2-propanediol or benzyl alcohol, saturated and unsaturated Fatty alcohols with 8 to 18 carbon atoms, such as lauryl alcohol or cetyl alcohol, Hydrocarbons such as mineral oil, saturated and unsaturated fatty acids with 8 to 18 Carbon atoms, such as stearic acid or oleic acid, fatty acid esters with up to 24 carbons Substance atoms or dicarboxylic acid diesters with up to 24 carbon atoms.

Fatty acid esters which are suitable for the agent according to the invention are, for example, those acetic acid, caproic acid, lauric acid, myristic acid, stearic acid and palmitic acid, such as the methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, sec.- Butyl ester, isobutyl ester or tert-butyl ester of these acids. Particularly preferred esters are those of myristic acid, such as their methyl esters and especially theirs Isopropyl ester. Suitable dicarboxylic acid diesters are, for example, diisopropyl adipate, Diisobutyl adipate and diisopropyl sebacate.  

Other penetration-enhancing agents are phosphatidyl derivatives, such as lecithin, Terpenes, amides, ketones, urea and its derivatives or ethers such as Diethylene glycol monoethyl ether. There is no need for a more detailed explanation, that also mixtures these penetration-enhancing agents for producing the agent according to the invention are suitable.

The concentration at which the active ingredient or active ingredient mixture optimally dissolved or suspended in the solvent for 14α, 17α-ethanoestra 1,3,5 (10) -triene-3,17β-diol usually 0.01 to 25 percent by weight. With the progestogens the concentration is naturally dependent on the type of active ingredient used and the aspired individual dose, it must in individual cases by means of the familiar to the expert Preliminary tests, such as determining the achievable blood plasma levels concentrations of active ingredient can be determined with selected agents according to the invention. In general, active ingredient concentrations of 0.01 to 25 weight are also here percent estrogen in the agent according to the invention be sufficient. The weight ratio of 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol to the progestogen (s) in the combination preparations at 5: 1 to 1:20.

The therapeutically required transdermal daily dose for 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol is a maximum of 250 µg; thus, with a TTS area of 25 cm ^2, an average percutaneous flow of 420 ng / cm ² / hour is required. In vitro studies using suitable formulations have shown that this can be exceeded by about 10 times with the agents according to the invention.

A very even application with adjusted dosage of the active ingredient or Active substance mixture can be achieved if the active substance or the mixture in one transdermal therapeutic system (TTS) embedded. Suitable transdermal Therapeutic systems are those that are usually used for the percutaneous application of Active ingredients (Yie W. Chien: "Transdermal Controlled Systemic Medications", Marcel Dekker, Inc., New York and Basel, 1987, Dr. Richard Baker: "Analysis of Transdermal Drug Delivery Patents 1934 to 1984 "and" Analysis of Recent Transdermal Delivery Patents, 1984-1986 and Enhancers "Membrane Technology & Research 1030 Hamilton Court Menlo Park CA 94025 (415) 328-2228).

For example, you can use such a transdermal therapeutic system which one out

• a) an impermeable cover layer, one to three adhering to the top layer, the 14α, 17α-ethanoestra-1,3,5 (10) -triene- 3,17β-diol optionally the progestogen (s) and if desired penetration-containing agents permeable to these components self-adhesive or penetration enhancing agent if desired containing skin pressure sensitive adhesive covered or surrounded matrix layer (s), one removable protective layer, or
• b) one containing a penetration-enhancing agent if desired Pressure sensitive adhesive cover, one to three (each) leaving a pressure-sensitive adhesive border uncovered, by means of a Attach the cover to the pressure sensitive adhesive that 14α, 17α-Ethanoestra-1,3,5 (10) -trien- 3,17β-diol, optionally the progestogen (s) and penetration enhancing Agent-containing matrix layer (s) and a removable protective layer, or
• c) an impermeable cover layer, one to three on or in the top layer, the 14α, 17α-ethanoestra 1,3,5 (10) -triene-3,17β-diol, optionally the gestagen (s) and drug reservoir (s) containing penetration enhancing agents if desired, one to three polymer layer (s) permeable to these components a permeable, possibly containing penetration-enhancing agents Skin pressure-sensitive layer and a peelable protective layer.

A transdermal therapeutic system according to variant a) represents a simple matrix system. It can be, for example, of round, oval or rectangular shape and be made as follows.

A solution or suspension of up to 25% by weight of active ingredient or active ingredient mixture, 0-40 percent by weight of a penetration-enhancing agent, 30-70 Ge percent by weight of a medically customary adhesive filled with a suitable one volatile solvent at 100 percent by weight is impermeable to a plane Painted top layer. After drying, a second and if desired, later even a third, optionally active ingredient, penetrationsver strengthening agent and adhesive-containing layer are applied and dried. Then the matrix system is provided with a removable protective layer.  

If you use a medically customary matrix former that after drying the System does not adhere or does not adhere sufficiently to the skin, so the system can be used applying the peelable protective layer additionally with a skin pressure sensitive adhesive cover or surround.

Suitable solvents and penetration enhancing agents are, for example Liquids of this type already mentioned. Medically customary adhesives are suitable for example polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene Copolymers and natural or synthetic rubbers. As another matrix former cellulose ethers, polyvinyl compounds or silicates come into consideration. To increase The tackiness of the matrix obtained can be the usual additives, such as tackifying resins and oils can be added.

All films that are usually used in transdermal films are suitable as a protective layer therapeutic systems. Such films are siliconized, for example, or fluoropolymer coated.

In this system, for example, 10 to 100 μm thick films made of polyethylene or polyester can be used as a top layer, optionally pigmented or metallized. The drug layer applied thereon preferably has a thickness of 20 to 500 μm. The active ingredients are preferably dispensed over an area of 5 to 100 cm ² .

In the case of multilayer matrix systems, for example, the most impermeable The 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol applied to the top layer of the matrix and, if necessary, the penetration enhancers are introduced while those below located layer or layers the estrogens and optionally also Includes penetration enhancer. On the other hand, it is also possible in such a way transdermal system to arrange several active substance-containing matrices side by side.

A transdermal therapeutic matrix system according to variant b can, for example also be round, oval or rectangular and are made as follows.

A cover is coated with a skin pressure sensitive adhesive. Then you stick on this pro TTS one to three punched out areas with an impermeable cover provided, the 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol, optionally the or the matrix layers containing the gestagen (s) and penetration-enhancing agents so that that the cover has a sufficient edge for attachment to the skin and at  several areas also has sufficient gaps and provides them with a removable protective layer. The materials used in this matrix system can be the same as in those of variant a.

A transdermal therapeutic reservoir system according to variant c can, for example also be round, oval or rectangular and are represented as follows:

An impermeable film is deformed by heat and / or tension so that one to three Bulges of 0.1 to 3 ml are created. This is with an active ingredient Solution or suspension containing 1-50 percent by weight of active ingredient or Active ingredient mixture filled with a penetration-enhancing agent. The active ingredient The solution or suspension can also be thickened with up to 10 percent by weight of matrix former his.

A welded-on or glued-on serves to cover the reservoir towards the skin permeable polymer layer on which a permeable skin pressure sensitive adhesive layer and a removable protective layer is attached.

In this system, the penetration-enhancing agents mentioned above can be used be applied. A 20 to 200, for example, is used as the permeable polymer layer µm thick film made of cellulose esters, cellulose ethers, silicones or polyolefin bindings used. The diffusion gene can be varied by varying this polymer layer speed of the active ingredient or mixture of active ingredients within wide limits vary.

The same materials used for the adhesive and protective layer are suitable transdermal therapeutic system according to variant a are described.

In the manufacture of transdermal therapeutic systems with two or three active ingredient-containing matrix layers or pharmaceuticals arranged side by side reservoirs, it is often useful in the one 14α, 17α-Ethanoestra-1,3,5 (10) -trien- 3,17β-diol and in the other to introduce the gestagen (s). In such cases not only can the active ingredient-containing matrix systems or drug reservoirs different active ingredients but also different ones contain penetration enhancing agents.  

In the case of the matrix systems according to variant a or b, one has to have an adequate one Care should be taken to ensure that the active ingredients diffuse into each other To prevent the area. In the case of the reservoir systems according to variant c, it is possible to to provide individual reservoirs with differently permeable polymer layers in order to thus adapting the diffusion flow of the individual active ingredients to the respective needs.

Further features of the transdermal systems according to the invention are based on the attached, not to scale drawings explained.

Fig. 1 shows a cross section through a simple round matrix system according to variant a without the removable protective layer. It consists of the impermeable cover layer 1 and the drug-containing matrix layer 2 .

Fig. 2 shows a cross section through a matrix system according to variant b without the removable protective layer. Fig. 3 shows the supervision of this system. The system consists of the cover 3 , which is provided with an adhesive layer 4 . Two drug-containing matrix layers 6 and 8 are attached to this pressure-sensitive adhesive layer by means of impervious covers 5 and 7 .

Fig. 4 shows a cross section through a round einkammeriges reservoir system according to variant c without the removable protective layer. It consists of the impermeable cover layer 9 , the drug reservoir 10 , the permeable polymer layer 11 and the skin pressure-sensitive adhesive layer 12 .

Fig. 5 shows a cross section through a circular two-chamber reservoir system according to variant c without the removable protective layer. It consists of the impermeable cover layer 13 , the two semicircular drug reservoirs 14 and 15 , the permeable polymer layer 16 and the skin pressure-sensitive adhesive layer 17th

In addition to transdermal therapeutic systems, other galenic systems are also suitable Preparations for the transdermal application of 14α, 17α-ethanoestra-1,3,5 (10) -triene- 3,17β-diol.

An emulsion gel for transdermal application consists, for example, of the active ingredient or mixture of active ingredients, penetration-enhancing agents, emulsifiers (where ambiphilic Representatives of the penetration-enhancing agents can serve as emulsifiers) and optionally matrix formers. A typical recipe consists of 0.1-25  Weight percent active ingredient or mixture of active ingredients, 0-10 weight percent emulsifier, 0-5 Weight percent matrix formers, 0 to 50 weight percent penetration enhancing 100% water and water. The agent is emulsified in the usual way, and if necessary with the usual antioxidants, preservatives etc. transferred.

Single-phase gels are obtained, for example, by dissolving or suspending the active ingredient or the active ingredient mixture in solvents such as water, lower alcohols or Mixtures of the same, optionally with the addition of penetration-enhancing agents and thickening with matrix formers.

Typical formulations for such gels contain 0.01-25 percent by weight of active ingredient or Active ingredient mixture, 1-20 percent by weight matrix former, 0 to 40 percent by weight penetration-enhancing agents supplemented with the solvent to 100 percent by weight.

If desired, these gels can also contain antioxidants, preservatives, etc. contain.

A typical spray formulation is, for example:

1-25 percent by weight of active ingredient or mixture of active ingredients, 0-20 percent by weight Matrix former, 0-60% by weight penetration enhancing agents supplemented with Solvents and possibly blowing agents to 100%. If you use compressed gas packs, the blowing agent can be omitted.

The 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol-containing agents according to the invention for transdermal application can be used to treat the same diseases are used, such as the previously known agents, for example to be administered orally, the contain highly effective estrogens. In addition, the invention if necessary, progestogen-containing preparations also for conception prevention Find. The agents according to the invention have particular advantages in the treatment of Diseases that require long-term treatment with a relatively high dosage of active ingredients require. Here the application frequency can be significantly reduced and one substantially uniform blood plasma levels can be achieved. It is also advantageous that gastrointestinal side effects are not expected and the first liver passage is circumvented.  

These benefits leave the progestogen-free monotherapeutics of the present invention as appear particularly suitable. For example, for hormone replacement therapy menopausal symptoms, atrophic vaginitis, caurosis vulvae, treatment estrogen-dependent tumors for osteoporosis prophylaxis or treatment, or for Treatment of other diseases that require estrogen replacement therapy is.

The transdermal use of progestogens in sequential or continuous Combination with 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol offers special Advantages, for example for the treatment of menopausal complaints, for prevention osteoporosis, for cycle regulation and cycle stabilization, for transdermal Contraception and for the treatment of other diseases in which a combined Estrogen / progestogen replacement is indicated.

The following exemplary embodiments serve to explain the invention in more detail. The following commercial products were used in them:

Polyester film of 0.074 mm thickness (Skotchpak®1009 from the manufacturer 3M; Polypropylene film (Celgard®2500) from Celanese, liner film Skotchpak® 1022 and 1360 from the manufacturer 3M; Transfer adhesive 9871 from the manufacturer 3M, polyacrylate Sichello®J 6610-21 adhesive from Henkel KG, polyacrylate adhesive from Type Gelva®788 from the manufacturer Monsanto, silicone adhesive of type X-7-2960 des Manufacturer Dow Corning and hydroxypropyl cellulose type Klucel®HXF des Manufacturer Hercules.  

example 1

In 62.4 g of a 50% solution of silicone adhesive in gasoline are stirred successively

0.8 g 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol
8.0 g of 1,2 propanediol

registered. After degassing the mixture, the mixture is applied to polyester film by means of a coating device in such a way that, after removal of the volatile solvent, a uniform film of 40 g / m ^{2 of} solids is formed. It is then laminated with a fluoropolymer-coated polyester liner. The laminate thus obtained is divided into round individual plasters with an area of 10 cm ² by means of a punching device and packed in aluminum foil. Fig. 1 shows a cross section through this plaster without polyester liner. The patch adheres to the skin after the liner film has been removed.

The content determination gives an even distribution of active ingredient of 0.08 mg / cm ² on average.

Example 2

In 170 g of a 50% solution of polyacrylic ester adhesive in acetone / gasoline successively

5.0 g of 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol and
10.0 g isopropyl myristate

dissolved with stirring. After degassing the mixture, the solution is applied to a polyester film by means of a coating device in such a way that, after removal of the volatile solvents, a uniform film of 100 g / m ^{2 of} solids is formed. It is then laminated with a siliconized, active ingredient-free liner film. The laminate obtained in this way is divided into individual plasters with an area of 10 cm ² by means of a punching device and packed in aluminum foil. The patch adheres to the skin after the liner film has been removed.

The content of 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol is on average 0.5 mg / cm ² .

Example 3

112 g of a 50% solution of polyacrylic ester adhesive in acetone / gasoline successively

3.5 g of 3-keto-desogestrel
3.5 g of 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol and
7.0 g of 1,2-propanediol with 10% 1-dodecanol

dissolved or suspended with stirring. After degassing the mixture, the mixture is applied to polyester film by means of a coating device in such a way that, after removal of the volatile solvents, a uniform film of 70 g / m ^{2 of} solid material is formed. It is then laminated with a siliconized, active ingredient-free liner film. The laminate obtained in this way is divided into individual plasters with an area of 10 cm ² by means of a punching device and packed in aluminum foil. The patch adheres to the skin after the liner film has been removed.

The content of 3-keto-desogestrel and 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol is equally 0.35 mg / cm ² .

Example 4

Analogously to Example 1, two different segment-like matrix systems are produced, which have the shape shown in FIGS. 2 and 3. The matrix system I consists of the matrix layer 8 provided with a polyester film 7 of the following composition

1.0 mg 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol
5.0 mg isopropyl myristate and
44 mg of acrylic adhesive solid

and has an area of 5 cm ² .

The matrix system II consists of the matrix layer 6 provided with a polyester film 5 of the following composition

2.0 mg gestoden
10.0 mg isopropyl myristate and
88 mg of acrylic adhesive solids

and has an area of 10 cm ² .

Both matrix systems are glued to a cover film coated with skin pressure sensitive adhesive, as shown in FIG. 3. After lamination and punching out, plasters of the type shown in FIGS. 2 and 3 are produced.

Example 5

A 7.4 cm diameter polyester film is deformed by means of tension and heat so that a round bulge of 10 cm ² area is formed. This is with 1 ml of a Sus pension from

2.5 mg of norethisterone acetate and
2.5 mg 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol

filled in 1,2-propanediol, which contains 10% lauric acid. A polypropylene or Cellulose acetate butyrate film is welded on at the edge. Depending on the pressure per unit of time the sealing temperature is between 70 ° C and 100 ° C. On the permeable poly Pressure sensitive adhesive film is transferred. The patch is provided with a liner and packed in aluminum foil.

Fig. 4 shows a cross section through a plaster of this type without a liner.

Example 6

Analogously to Example 5, a polyester film is deformed in such a way that two semicircular bulges, each separated by a web, of 7.5 cm ^{2 in} area are formed.

Reservoir I is filled with 0.75 ml of a suspension of

1.5 mg 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol in 1,2-propanediol

and reservoir II with 0.75 ml of such a

3.0 mg levonorgestrel in 1,2-propanediol

filled. The plaster is completed as described in Example 5. Fig. 5 shows a cross section through such a plaster without a liner.

Example 7

In 76.78 g of ethanol (96 vol%) or isopropanol are successively

0.2 g 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol
0.02 g gestoden
10.0 g of 1,2-propanediol and
10.0 g isopropyl myristate

solved. Then you add 3 g of hydroxypropyl cellulose to the solution and remove the Air. After 2 hours of swelling, the gel is tripled in aluminum tubes Bottled interior protective paint.

The content determination results in a homogeneous active ingredient distribution in the gel with values of 95% at 105% of the setpoint.

Example 8

20.00 g of 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol are in 1000 g Dissolved isopropyl myristate, sterile filtered and in aseptic conditions in Dispensed 5 ml medication bottles.

Claims (13)

1. Agent for transdermal application, characterized in that it contains 14α, 17α- ethanoestra-1,3,5 (10) -triene-3,17β-diol, optionally in combination with one or more gestagen (s). 2. Means for transdermal application according to claim 1, characterized in that that as progestin (s) norethisterone, levonorgestrel, gestodene, 3-keto-desogestrel or Esters of these compounds can be used. 3. Means for transdermal application according to claim 1 and 2, characterized characterized in that the agent is a transdermal therapeutic system (TTS). 4. Means for transdermal application according to claim 3, characterized in that the transdermal therapeutic system

• a) an impermeable top layer, one to three adhering to the top layer, the 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol, optionally the gestagen (s) and, if desired, penetration-enhancing agents containing self-adhesive matrix layer (s) which are permeable to these components or which are covered or surrounded by a skin pressure-sensitive adhesive, if appropriate containing a penetration-enhancing agent, a removable protective layer, or
• b) a pressure-sensitive adhesive provided with a penetration-enhancing agent if desired, one to three (each) leaving a pressure-sensitive adhesive border uncovered and fastened to the pressure-sensitive adhesive by means of an impermeable cover, the 14α, 17α-ethanoestra-1,3,5 (10) -triene -3,17β-diol, optionally containing the gestagen (s) and penetration-enhancing agents matrix layer (s) and a removable protective layer, or
• c) an impervious top layer, one to three on or in the top layer, the 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol, optionally the gestagen (s) and, if desired, penetration-enhancing Medicament reservoir (s) containing agents, one to three polymer layer (s) permeable to these components, a permeable skin pressure-sensitive adhesive layer optionally containing penetration-enhancing agents, and a removable protective layer.

5. means for transdermal application according to claim 4, characterized in that it contains an active substance-containing matrix layer or a drug reservoir. 6. Means for transdermal application according to claim 4, characterized in that that there are two or three active substance-containing matrix layers or drug reservoirs contains. 7. Means for transdermal application according to claim 6, characterized in that that the active ingredient-containing matrix layers or the drug reservoirs contain different active ingredients. 8. Use of 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol optionally in Combination with one or more progestogen (s) for the production of an agent for the transdermal application of the active ingredient or mixture of active ingredients. 9. Use of 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol in combination with one or more gestagen (s) for the preparation of an agent according to claim 8, characterized in that as progestin (s) norethisterone, levonorgestrel, Gestoden, 3-keto-desogestrel or esters of these compounds can be used. 10. Use of 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol optionally in Combination with one or more progestogen (s) for the production of an agent according to claims 8 and 9, characterized in that the agent transdermal therapeutic system (TTS). 11. Use of 14α, 17α-ethanoestra-1,3,5 (10) -triene-3,17β-diol optionally in Combination with one or more progestogen (s) for the production of an agent according to claim 10, characterized in that it is a transdermal therapeutic system according to claims 4 to 7. 12. Use of progestogen-free agents for transdermal application according to Claims 1 to 7 for hormone replacement therapy for menopausal symptoms, atrophic vaginitis, craurosis vulvae, for the treatment of estrogen-dependent tumors,  for osteoporosis prophylaxis or treatment, or for the treatment of others Diseases for which estrogen substitution is indicated. 13. Use of means for transdermal application according to claim 1 to 7, optionally in combination with progestogen-containing agents for treatment climacteric complaints, for the prevention of osteoporosis, for cycle regulation, for cycle stabilization, transdermal contraception and treatment of others Diseases where combined estrogen / progestogen replacement is indicated.