Containing estradiol transdermal therapeutic system

 

(57) Abstract:

Containing a biologically active substance transdermal therapeutic system for the controlled delivery of estradiol or its pharmaceutically acceptable derivatives individually or in combination with gestagens, consisting of a substrate associated with it, containing a biologically active material layer of the tank, which is obtained using contact adhesive containing esters of rosin, and peeling of the protective layer. The proposed use of glue not only improves the adhesion of substances, but also gives excellent biopharmaceutical properties - good compatibility with the skin and the ability to permeability, and avoids recrystallization of biologically active substances. 2 C. and 21 C.p. f-crystals, 2 tab.

The invention relates to a transdermal therapeutic system for the controlled delivery of estradiol or its pharmaceutically acceptable derivatives individually or in combination with gestagens, as levonorgestrel, in the skin of a human or animal, its application and how it was received.

Transdermal therapeutic system (TTS) for the treatment of some diseases already are selling is I - are commercially available and have been successfully used in therapy as a therapeutic agent against diseases menopause and more recently against osteoporosis.

Levonorgestrel is a synthetic gestagenna derived, which in combination with orally effective estrogen is still used primarily for contraception. The gestagens, therefore, levonorgestrel, in these drugs function by an appropriate trophic prepare the uterus for possible short-term, quick and "physiological" unwanted bleeding. There is also an indication of a protective effect of the additive gestagen from the danger of endometrial tumors.

Therefore rational for display postmenopausal problems (diseases) to resort to cyclic treatment (processing), that is used occasionally solid combination of drugs of estrogen (such as estradiol) and gestagen (such as levonorgestrel). Especially attractive is this combination of both biologically active substances in the joint, monolithic transdermal therapeutic system that you need when and ability permeation through the skin levonorgestrel especially suitable for this system.

The literature describes an experimental system for transdermal input levonorgestrel (Friend and others , J. Controlled Release, 7, 243-250 /1988/). In addition, according to this estimation for successful transdermal therapy with a fairly small system surface necessary to improve the penetration means (amplifiers), for example, a complex alkalemia esters of short-chain fatty acids (Friend and others J. Controlled Release, 9, 33-40 /1989/).

For transdermal application of estrogen and gestagen already known a number of devices. When applying blockcopolymer styrene with isoprene, a water absorbing polymer domains and amplifier (and agent to help stop irritation in the form of itching) Crotamiton Nakagawa and others (European patent EP-A-0483 370), managed to get a transdermal therapeutic matrix system for a single estradiol. Another concept is the simultaneous application of estradiol and amplifier (ethanol) in a managed membrane tank system (Campbell and others, U.S. patent 4 379 454), which is also applicable in combined dosage form with gestagen - norethisterone (Fank hauser and Schenkel, patent Germany 3 810 896).

Transdermal therapeutic system for administration of estradiol and/ispotentially danger recrystallization biologically active substance over time.

Made up of descriptions of inventions to unaccepted application for patent in Germany 32 05 258 and European patent EP-0 285 563 known introduction of estradiol and ethanol simultaneously in the dosage form in the form of strips. The fabrication of this patch, however, very expensive and not very comfortable in use due to the lack of flexibility.

In the European patent EP-0 285 563 describes a transdermal therapeutic system for the combined use of estrogen and gestagen. The reservoir contains a drug biologically active substances, where necessary, the membrane, and ethanol as improving percutaneous absorption of funds. Since the release of biologically active substances is regulated mainly by the membrane, this transdermal therapeutic system is fundamentally different from the containing biologically active substance patch according to the present invention. Glue in the case described there patch performs only the function of strengthening the patch on the skin. What he can contribute to the regulation of release of the biologically active substance is not its primary goal, but only, perhaps, even an unwanted side effect. While we are talking about so it is of an impermeable substrate and membrane with a layer of glue. Due to its complex structure, the preparation of plaster is very expensive, because the individual components need to obtain separately and then the following workflow to join in the patch.

In the European patent EP-0 275 716 describes, in contrast, proposed according to the invention a single-layer system, two-layer transdermal system for the simultaneous introduction of one or more estrogens, which are dissolved or microdispersion in the polymer layer. The adhesive contains, in addition to biologically active substances, substances that enhance transdermal absorption. Polymer layer and adhesive layer can consist of polyacrylates, silicones or polyisobutylene.

In the European patent EP 0 072 251 describes a flexible absorbent liquid medicinal bandage. Mounted on a flexible substrate, the substrate consists of a hydrophilic matrix based on the hydrophilic high molecular weight polysaccharides and/or polyacrylic system, polyacrylamide, copolymers of ethylene with vinyl acetate and other polymers, and liquid phase on the basis of a solution or emulsion of carbon, proteins and polyhydric alcohols and various biologically active substances, between the ASU glue.

In the European patent EP 0 328 806 describes not containing membrane transdermal therapeutic system, the matrix of which consists of a polyacrylate adhesive, solvent, amplifier penetration and estrogen derivatives thereof, and combinations thereof.

WIPO 87/07 138 describes estradiole patch consisting of a substrate containing a biologically active substance matrix and contact adhesive, which is covered with a peelable protective layer. Preparation of the matrix and contact of the adhesive is carried out in a technologically very expensive workflows by homogenization, degassing, coating, drying and sorting. In one embodiment, the substrate even need to cover a contact adhesive, which leads to further workflow. The connection of separate parts is carried out in a separate worker process. Getting the patch, thus, in General, very expensive and difficult.

From U.S. patent 4 624 665 known systems that contain a reservoir of biologically active substance in microencapsulated form. The tank is placed between the substrate and the membrane. The outer edge system is equipped with a contact adhesive. Design and preparation of this system is very complex the phase which is then further workflow placed between the substrate and the membrane. Additionally, the system then you need to provide a gluing edge and cover with a protective layer.

Next, from European patent EP 0 186 019 known to contain biologically active substance plasters, in which case the weight-based rubber /adhesive resin type is able to swell in water, polymers and which may be released estradiol. However, it was found that the release of estradiol from those containing the biologically active substance patches too small and does not meet therapeutic requirements.

In lined with the description of the invention to unaccepted application for patent in Germany 20 06 969 describes a bandage or an adhesive bandage with a systemic effect, which introduced the contraceptive substances in the adhesive component or adhesive tape. From this description we can conclude that the glue may be an acrylate.

In lined with the description of the invention to unaccepted application for patent in Germany 39 33 460 is described containing estrogen patch with a biologically active substance on the basis of Homo - and/or copolymers with at least one derivative of acrylic or methacrylic acid to ndermining therapeutic, containing matrix systems, which contain the biologically active substance is partially or completely dissolved, there is a potential danger, namely, that the biologically active substance over time recrystallized. This reduces the release of biologically active substances, and containing estrogen patch no longer meets therapeutic requirements.

Another disadvantage of the relevant prior art system is the use of the amplifier, which itself has, in principle, undesirable additional effect on the skin with the risk to cause irritation. Other disadvantages are the expensive design of such systems (the use of multiple containing a biologically active material layers, the application of regulatory membranes), which, as a rule, make the finished product unacceptable to the consumer.

Thus, the object of the invention is to eliminate the above disadvantages and technologically simple to get stable, i.e., without recrystallization, containing estrogen patch, respectively transdermal therapeutic system, the release of the current beginning of and therapeutic use, the skin is treated biologically active substances - estradiol and the progestogen - without affecting the skin substances (amps).

It was unexpectedly found that the problem is solved due to the fact that the containing estrogen contact adhesive is composed predominantly of esters of rosin.

The advantage is the additional application of blockcopolymer of styrene with isoprene and hydrogenated resin acids or derivatives thereof, and the active layer, which, for example, contains a therapeutically number of biologically active substances - estradiol and levonorgestrel.

The combination of both excipients, namely blockcopolymer styrene with isoprene, which serves as the cohesive component and hydrogenated resin acids or their derivatives which act as increase the adhesion of substances, not only provides good adhesive and cohesive rubber (rubber) adhesive, but in addition gives excellent pharmaceutical properties, in particular good skin compatibility and the ability to permeability, and also allows you to avoid recrystallization of biologically active substances.

Thus, the invention relates to a transdermal therapeutic system for the control Studio strobe, flash gestagens, consisting of a substrate associated with it, containing a biologically active material layer of the tank, which is obtained using contact adhesive, and a peelable protective layer, and the contact adhesive contains esters of rosin and excipients.

Complex rosin esters include, for example, methyl ester, esters of glycerin, esters of pentaerythritol, modified maleic acid esters of pentaerythritol, modified maleic acid esters of glycerin, esters of triethylene glycol. The proportion of esters of rosin in containing estradiol contact glue is 55-92 wt. %, preferably 60-90 wt.% and particularly preferably 70-88 wt. %. Next, contact adhesive may contain esters gidrirovannoe rosin.

Particularly preferred esters of rosin are esters of triethylene glycol, esters of glycerin, esters of pentaerythritol gidrirovannoe rosin.

In another embodiment, other components containing estradiol contact adhesive can be polymers that are selected from the group consisting of copolymers of styrene-butadien telena with vinyl acetate, polyvinylpyrrolidone, cellulose derivatives and polymers based on acrylic acid derivatives and methacrylic acid. These polymers are contained in the containing estradiol adhesive mass concentration 6-25 wt.%.

Not subjected to recrystallization containing estradiol patch contains a reservoir of estradiol and its pharmaceutically acceptable derivatives individually or in combination with gestagens in concentrations generally 2-15 wt.%, namely, in a molar ratio of 1:1 to 1:10.

Containing estradiol reservoir may contain at least one component from a group that includes an antioxidant, a softening agent, an antioxidant and amplifiers absorption. Suitable softeners (plasticizers) are known to the expert and are described, for example, in the patent Germany 37 43 949. Containing estradiol tank usually contains a softening agent in an amount of 0-5 wt.%.

Later in containing the biologically active substance layer tank is also included antioxidants at concentrations of 0-1 wt.%. They are known to the expert and are described, for example, in the patent Germany 3743946.

Containing estradiol layer, the tank can be made from solution and from the melt.

In the case where the tank does not have actno adhesive edge. This ensures that the transdermal patch sticks to the skin entire period of use.

Especially preferred design containing transdermal estradiol patch - matrix system, in which case, as is known, the matrix performs the role of regulating the release of biologically active substances, and it follows Vt-law Higuchi. This, however, does not mean that the system with the membrane is also not shown in special cases. When this layer between the tank and a layer of contact adhesive is placed regulating the release of biologically active substances membrane.

The thickness of the transdermal patch is selected depending on therapeutic requirements and accordingly can be adjusted. She is normally in the range of 0.03 to 0.4 mm

Preferred used form next is a monolithic transdermal therapeutic system with a matrix that consists essentially impervious to biologically active substances of the substrate, the actual active matrix layer (which contains a proposed according to the invention are biologically active and excipients), as well as flaking protection the reconstruction and lower the cost of production have improved, also more uniform permeability characteristics of both biologically active substances.

It was unexpectedly found that such consisting predominantly of lipophilic and relatively weakly diffusing polymers and resins formulation leads to levels of biologically active substances in human blood, which cannot be achieved with systems of the prior art with comparable low flow rates.

Rubber (rubber) adhesives are still considered less suitable for administration of estradiol to the skin. So, on the occasion described in the European patent EP-0 186 019 considerations on the application of rubber adhesives (here, with the addition of are able to swell in water substances) object in the European patent EP-a 0 421 454 (S. 2, line 54 and below): sufficient release of estradiol in the case of these minor diffusing and only weakly solvent of the polymer does not occur.

Both significant according to the invention the substance used, namely, block copolymers of styrene with isoprene and hydrogenated resin acids, their derivatives, respectively, have long been successfully used as a classic sticky patches. The term "hydrogenated resin acids" understand soedjito only in chemically modified form, finds wide application in necessities, cosmetics, food packaging, chewing gum, etc. While we are talking about a resinous residue after the distillation of turpentine from the crude gum resin, which comes from various species of pine trees from predominantly subtropically-Mediterranean climatic zones.

The material is brittle, resinous, razmyagchayuschiesya at about 78-80oC with a density of about 1.07 g/ml of Modification of rosin for the purpose of use in transdermal systems is stabilized against the influence of oxygen by hydrogenation, as well as improved resistance to alkali by esterification to esters. By hydrogenation and, if necessary, derivatization substance is suitable for the envisaged purpose. Important used for the purpose of the invention esters are, for example, esters of glycerin, esters of pentaerythritol, methyl ester, as well as other portable skin derivatives gidrirovannoe rosin.

Synthetic rubber polymers play a significant role in the preparation of transdermal therapeutic systems, as plasters for wounds. Their enhan is the compared particularly suitable are copolymers of styrene-isoprene-styrene. Due to the fact that the polymer chain contains the average unit from another mobile long-chain composition of polyisoprene units and both polystyrene end as "anchor points" in the matrix formed three-dimensional mesh, which provides a further constant geometry also during storage. Thus in particular are not limiting molecular weight or the actual ratio between the share of styrene sites and sites branch, Rubezhnoe, Ukraine. On the contrary, it is important to establish the correct stickiness and cohesion. For example, increased the proportion of the resin causes improved prikleivalos to the skin, but also softer consistency of the matrix. As a rule, accept that approximately one-third of blockcopolymer remaining after the addition of biologically active substances, the remainder is biocompatible derivative resin.

Also, although a single-layer structure transdermal therapeutic system has the advantages of simplicity, function, once it is possible to provide such a matrix system according to the invention, for example, a thin additional adhesive layer to the skin. Also for better attachment to the substrate is applied in a thin sticky layer. Such additional layers may consist of a mixture of rubber SNO apply then when they before lamination do not cause biologically active substances, as short-term interim storage of the entire laminate is aligned diffusion.

Example 1. 73,1 g of esters of triethylene glycol gidrirovannoe rosin (Staybelite Ester 3E/ company Hercules) and 9.8 g of esters of glycerol gidrirovannoe rosin (Staybelite Ester 10E/company Hercules) at 100oC for 5 min mix by stirring. Then add 2.5 g of estradiol. Stirred for 30 minutes After heating to 140oC portions add 14.6 g of ethyl cellulose N50 NF (Hercules) and then knead another 2.5 hours, the Coating thus obtained containing the biologically active substance is sticky mass using the device for coating hot melt system (applied using a spray gun) put on peeling the protective layer (Hostaphan RN 100, with one side coated with silicone - firm Kalle) to contain biologically active substance layer tank in the had the weight of a unit area of material 80 g/m2. This layer-tank calandrinia duplicate impermeable substrate (film of the complex polyester thickness: 15 μm). Then stamp the patches with a biologically active substance respecification) knead with both Staybelite Ester - 3E and 10E.

Examples 3-9. The preparation is carried out as described in example 1, but with those specified in the table. 1 (formula cooking) raw materials and quantities.

The analytical part.

The release of biologically active substances from transdermal patch size of 16 cm2determine as described in USP XXII method of Rotating bottle (rotating bottle) in 0.9% sodium chloride solution at 37oC.

To measure the primary permeability in mice skin devoid of hair fix in mice Franx-cell. Skin paste containing estradiol patch area of 2.54 cm2to measure the release of biologically active substances at 37oC (acceptor environment: 0,9% sodium chloride solution) (literature: Umesh V. Banakar. Pharmaceutical dissolution testing. /1st edition - 1991 /)

Test the phenomenon of recrystallization perform visually backlit.

The results are presented in table. 2.

As can be seen from the table. 2, according to the invention achieves clearly better penetration through the skin of a mouse, than found in the comparative example according to the patent Germany 39 33 460. Parallel to this, you can set that in the example according to the invention, the recrystallization is completely absent.

TR 1107 (block copolymers of styrene-isoprene-styrene),

138,0 g Foral< / BR>
85 g (thermoplastic ester resin derived from rosin),

to 200.0 g of benzine (boiling within 80-100oC)

at room temperature in a cylindrical glass vessel is stirred until a uniform suspension, which is then continuously working on the installation for the coating to be applied on the siliconized film of a tough polyester with a thickness of 100 μm so that the result is a layer with a density of 110 g/m2(based on solvent free share). The coating is dried each time for 3 min at 40, 60, 75 and 125oC. the dry layer is applied with a thickness of 12 μm film of a complex of the polyester without air bubbles when the pressure rollers. By stamping with stamp of the firm NACE 1 receive transdermal system area of 20 cm2.

Example 11. Preparation of proposed according to the invention the system.

1.5 g of 17-Estradiol,

1.5 g of levonorgestrel,

70,0 g blockcopolymer styrene-isoprene-styrene,

150,0 g thermoplastic ester resin derived from rosin

in a heated mixer at 150oC in nitrogen atmosphere melted in cicognolo polyester of a thickness of 19 μm is applied to the melt layer thickness of 100 μm. This can be done at 140oC in the device for applying hot melt or about 80-100oC using an extruder. Then siliconized film of a tough polyester with a thickness of 150 μm, pre-coated with a layer of a copolymer based on complex acrylic ester (Durotak280-2516) with a density of 204 m2without air bubbles under the pressure roller is applied to the dried layer (cacheroot). By shtampovaniem with stamp of the firm NACE 1 receive transdermal system area of 20 cm2.

1. Transdermal therapeutic system containing estradiol, which is the process of recrystallization, containing a biologically active substance, for the controlled delivery of estradiol or a pharmaceutically acceptable derivative of estradiol, consisting of a substrate and associated with it, containing a biologically active substance reservoir, made of contact adhesive containing esters of rosin, and the Stripping of the protective layer, characterized in that the adhesive contains esters of rosin in the number 55-92 wt.%.

2. Transdermal therapeutic system according to p. 1, characterized in that the contact adhesive contains complex epidem, that contact adhesive contains esters of rosin in the number of 70-88 wt.%.

4. Transdermal therapeutic system according to p. 1, characterized in that it further comprises a biologically active substance is levonorgestrel, the active layer of the system along with biologically active substances contains block copolymers of styrene with isoprene and hydrogenated resin acids or their derivatives.

5. Transdermal therapeutic system according to PP. 1 to 4, characterized in that esters of rosin selected from the group consisting of methyl esters, esters of glycerin, esters of pentaerythritol-modified maleic acid esters of pentaerythritol-modified maleic acid esters of glycerol and esters of triethylene glycol.

6. Transdermal therapeutic system according to PP. 1 and 2, characterized in that the concentration of estradiol in the active layer is 0.2-2.0 wt.h, preferably 0.7 to 1.4 wt.h.

7. Transdermal therapeutic system according to p. 1 and 4, characterized in that the concentration of levonorgestrel in the active layer is 0.1-1.6 wt.h.

8. Transdermal therapeutic system according to any one of paragraphs. Starmania therapeutic system according to any one of paragraphs.1-8, characterized in that the proportion of blockcopolymer styrene with isoprene in the active layer is 10-45 wt.%, preferably 15-33 wt.%.

10. Transdermal therapeutic system according to any one of paragraphs. 1-9, characterized in that it contains one or both components of the combination - levonorgestrel or estradiol - partially in suspension.

11. Transdermal therapeutic system according to any one of paragraphs. 1-10, characterized in that the estradiol is partly in the form of crystals of estradiol in transdermal therapeutic system, and the crystals estradiol consist essentially of the besieged anhydrate (Anhydrat) estradiol.

12. Transdermal therapeutic system according to any one of paragraphs. 1-11, characterized in that the contact adhesive contains esters gidrirovannoe rosin.

13. Transdermal therapeutic system according to any one of paragraphs. 1-12, characterized in that the contact adhesive contains polymers.

14. Transdermal therapeutic system according to any one of paragraphs. 1-13, characterized in that the contact adhesive contains a polymer concentration 6-25 wt. % and selected from the group consisting of copolymers of stravation - styrene block copolymers sterilizable-styrene, blockcopolymers and polymers based on acrylic acid derivatives and methacrylic acid.

15. Transdermal therapeutic system according to any one of paragraphs. 1-14, characterized in that the layer tank contains estradiol or its pharmaceutically acceptable derivatives individually or in combination with gestagens in concentrations generally 2-15 wt.%, namely, in a molar ratio of 1:1 to 1:10.

16. Transdermal therapeutic system according to any one of paragraphs. 1-15, characterized in that the layer of the reservoir contains at least one component from the group consisting of antioxidants, softeners (plasticizers), antioxidants and amplifiers, absorption and softening agent is contained at a concentration of 0-5 wt.% and an antioxidant in a concentration of 0.1 wt.%.

17. Transdermal therapeutic system according to any one of paragraphs. 1-16, characterized in that the contact adhesive is a contact adhesive dissolved.

18. Transdermal therapeutic system according to any one of paragraphs. 1-17, characterized in that the contact adhesive is a hot melt contact adhesive.

19. Transdermal therapeutic system according to any one of paragraphs. 1-18, characterized in that the layer of the reservoir consists of several layers.

20. Transdermal therapeutic system according to any one of paragraphs. 1-19, characterized in that the layer of redundant fat is eaten.

21. Transdermal therapeutic system according to any one of paragraphs. 1-20, characterized in that between the reservoir layer and a layer of contact adhesive is a membrane that regulates the secretion of biologically active substances.

22. The method of preparation of the transdermal therapeutic system, comprising stirring a mixture of esters of rosin at an elevated temperature until homogenization, the introduction of biologically active substances and at least one polymer at a temperature of dissolution after homogenization, drawing on Stripping the protective layer containing the biologically active substance in the adhesive mass, and duplication on calenders with the substrate, wherein the adhesive contains esters of rosin in the number 55-92 wt.%.

23. The method of preparation of the transdermal therapeutic system according to p. 22, characterized in that the transdermal system is made in the form of strips and used for therapeutic purposes in human medicine and veterinary medicine.

Priority points

Application P 4336557.4 priority 27.10.93 - Application R 4314970.7 priority 06.05.93

1 corresponds to 1

3 - 2

4 - 3

5 - 4

6 - 6

13 - 7

14 - 8

15 - 9, 10

16 - 11

the pattern application PCT/EP 94/01279 - claims claims R 4314970.7 priority 06.05.93

1 corresponds to - 1, 2

2 - 3

3 - 4

5 - 6

12 - 7

13 - 8

14 - 9, 10

15 - 11

16 - 12, 13, 14

17 - 15

18 - 16

19 - 17

20 - 18, 20

21 - 19

22 - 22

23 - 23

 

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