Transdermal therapeutic system containing sex steroids

 

(57) Abstract:

The invention relates to medicine. Describes transdermal therapeutic system containing sex steroids and, if necessary, the penetration enhancers and inhibitors of crystallization, which are characterized in that they contain dimetridazole, except for systems that contain including biologically active substance, non-leaking gel-phase or 3-keto-desogestrel. These systems have a uniform speed of penetration of steroid hormones through the skin. 2 S. and 11 C.p. f-crystals, 3 ill., 3 table.

The invention relates to transdermal therapeutic systems containing sex steroids and, if necessary, the penetration enhancers and inhibitors of crystallization, which are characterized in that they contain dimetridazole, except for systems that contain including biologically active substance of non-leaking gel-phase or 3-keto-desogestrel.

According to the invention, under the sex steroids need to understand is preferably a progestogen and/or estrogens, although in principle to obtain proposed according to the invention suitable means other sex steroids, as androgens, antiestrogens or antigestagen staden, levonorgestrel, desogestrel, norethisterone and norethisterone. To obtain proposed according to the invention means are also suitable 3-keto - desogestrel, as can be concluded from the still unpublished at the priority date of this application PCT/EP 93/02224.

Suitable estrogens for proposed according to the invention means are, for example, estradiol, estriol, ethinyl-estradiol, mestranol, 14,17 - ethanoate-1,3,5 (10)-triene - 3,17 - diol [WIPO 88/01275], 14,17 - ethanoate-1,3,5 (10)-triene - 3,16,17 - triol (WIPO 91/08219) and their esters (European patent A-163596), as estradiol - dipropionate, estradiol-digestant and estradiol-dodecanoate. Proposed according to the invention a combination of drugs together, at least one gestagen contain preferably 1 to 3, in particular 1-2, estrogen.

European patent B-0 137 278, which relates to transdermal therapeutic systems, in which the biologically active substance is introduced into non-leaking gel phase contains a General indication that the solvent can also be used dimetridazole, and from this measure cannot be concluded that the use of this tool in percutaneous therapeutic systems can be osobitim, they make possible a more uniform release of biologically active substances over a longer period of time than is usually possible in the case of input differently, as, for example, oral, funds. These properties can be preferably used in a number of endocrine diseases. For sparingly soluble in water steroid hormones, such as, for example, gestagen, however, usually very problematic manufacturing percutaneous systems that provide adequate therapy for the penetration of biologically active substances through the skin.

Currently, it is found that using the proposed according to the invention means that contains, along with sex steroid (sex steroids) advanced dimetridazole, unexpectedly can be achieved therapeutically sufficient, a very uniform rate of penetration of steroid hormones through the skin, while it is in the case of known, containing steroid hormones, percutaneous funds used only in relation to possible (European patents NN A-137278 and A-275 716), which necessitates the use of relatively large systems.

Dimetridazole is a substance form organic compounds (H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kasmetic und angrenzende Gebiete, ed. Canton Aulendorf, 1989). This ability is used, for example, in U.S. patent 4082881 to various topical compositions, but not in percutaneous systems, to maintain the dissolved high concentrations of organic medicines. In U.S. patent 4814173 dimetridazole used as a solvent for various medicines, however, is not sex steroids, in solutions, emulsions, and hard built percutaneous therapeutic systems based on silicone contact against the skin adhesives.

It is now established that dimetridazole capable of dissolving large amounts of a number of sex steroids. The choice of these steroids are presented in table 1. In particular dimethylselenide in a distinctly higher concentrations can be dissolved levonorgestrel, which in most standard indifferent foundations of drugs for percutaneous application only slightly soluble.

Moreover, dimetridazole lowers the solubility of gestagens and estrogens. It has a great additional benefit for the development of combined percutaneous systems, tsoknyi ratios from about 5:1 to 1:5 together can be distributed in the form of a molecular dispersion in the matrix. This ensures that both biologically active substances are simultaneously in the system with high thermodynamic activity.

Dimetridazole, as described in the patent DDR A-217989 in an appropriate volume mixed with normal to obtain percutaneous systems contact against the skin adhesives.

Now found that certain mixed system of contact for skin glue and dimethylselenide, compared to systems without dimethylselenide, have distinctly higher solubility in relation to sex steroids. These new systems, the structure of which is shown in Fig. 1, in contrast specified in European patent A-0 137 278, contains sex steroid soloprenuer systems are single phase and are distinguished by the fact that they stick to the skin. Also on the basis of their simple structure, they stand out against designated in the international application WO -89/04179 topical compositions, in particular listed there contain biologically active substance patches. They can do easier than the above percutaneous system, and they have more favorable bearing properties due to yanikoski molecules, dimethylindole has also enhance the penetration properties. Thus, while in vitro studies of penetration was unexpectedly found that indifferent basis of medicinal dimetridazole - has a strong, promotes penetration properties in relation to sex steroids (see. table 2).

In the proposed according to the invention means are usually used 1-40 wt. % and preferably 5-25 wt.% dimethylselenide, based on the entire phase of biologically active substances.

Thanks suitable combination of dimethylselenide with other known penetration enhancers can even further increase achieved in vitro percutaneous flow (discharge) sex steroids (see table 3).

Using the proposed according to the invention means you can get a percutaneous therapeutic system with high concentrations of dissolved molecular dispersions of sex steroids. The application of these new systems reach particularly high effective concentration gradient between the drug and the skin. High concentration gradient and strong, promotes penetration of the action dimethylselenide on hand.

In a single case, the addition of inhibitors of crystallization in the matrix of the above systems, as described in international application WO-93/087795, can improve the stability during storage proposed according to the invention percutaneous systems.

Very uniform introduction of fixed dose biologically active substances or mixtures of biologically active substances can be achieved when the biologically active substance or a mixture of biologically active substances administered in transdermal therapeutic system (TTS) and in this case specifically to the matrix system. Suitable matrix systems are those that are usually used for percutaneous administration of biologically active substances (Yie W. Chien: "Transdermal Controlled Systemic Medications Marcel Dikker, Inc., New York and Basel, 1987; Dr. Richard Baker," Analysis of Transdermal Drug Delivery Patents, 1934-1984" and "Analysis of Recent Transdermal Delivery Patents, 1984-1986 and Enhancers" Membrane Technology and Research 1030 Hamilton Court Menlo Park CA 94025/415/328-2228).

For example, it is possible to apply such transdermal therapeutic system, which consists of:

a) impermeable upper (outer) layer; from one to three matrix layer, adherent to the upper layer, containing a progestogen and/or estrogen, and dimetridazole and desirable sucheninov self-adhesive, coated or covered or surrounded by the contact against the skin glue, containing desirable in the case of enhancing the penetration means, and a removable protective layer; or

b) coating supplied containing desirable in the case of enhancing the penetration means a contact adhesive, one or two matrix layers, leaving open the trim of contact adhesive, toughened by using coating on contact adhesive containing a progestogen and/or estrogen and dimetridazole and if necessary enhance the penetration means and inhibitors of crystallization of the matrix layer; and a removable protective layer.

Transdermal therapeutic system according to variant (a) is a simple matrix system. It can be, for example, round, oval or rectangular shape and it is prepared as follows:

the solution with the amount of biologically active substances or mixtures of biologically active substances up to 25 wt.%, 1-40 wt.% dimethylselenide or mixture of dimethylselenide and other reinforcing penetration means, 30-70 wt.% conventional medicine glue, supplemented with prihodova volatile solvent to 100 wt.%, smear on a flat impermeable top layer. After drying, this layer can apply a second and desirable in case p is th tools and glue, layer and dried. Then matrix system provide removable protective layer.

If you use conventional medicine, forming a matrix material, which after drying system does not stick or insufficiently adheres to the skin, then the system before applying the removable protective layer is further possible to cover or surround with contact glue.

Suitable volatile solvents are, for example, lower alcohols, ketones or esters of lower carboxylic acids, as ethanol, isopropanol, acetone, or ethyl acetate; polar ethers, like tetrahydrofuran; lower hydrocarbons like cyclohexane or benzene; or galoidovodorodami as dichloromethane, trichloromethane, trichlorotrifluoroethane and Trichlorofluoromethane. You do not need any explanation, which is also suitable mixture of these solvents.

Suitable reinforcing penetration means are, for example, one - or polyhydric alcohols as ethanol, 1,2-propandiol or benzyl alcohol; saturated and unsaturated fatty alcohols with 8 to 18 carbon atoms, as lauric alcohol and cetyl alcohol; hydrocarbons, such as mineral oil; saturated and unsaturated fatty acids range from 8-18 atoms of plastics technology: turning & is laroda up to 24 or complex diesters of dicarboxylic acids with the number of carbon atoms up to 24-X.

As usual in medicine adhesives are suitable, for example, polyacrylates, silicones, polyurethanes, block copolymers, styrene-butadiene copolymers, natural or synthetic rubbers, such as, for example, polyisobutylene and in particular polyacrylates. As other, forming a matrix of materials taking into account ethers of cellulose, polyvinyl compounds or silicates. To improve the adhesiveness to the resulting matrix can be added conventional additives, such as, for example, giving the adhesiveness of the resin and oil.

Esters of fatty acids of the series, which is suitable for the proposed according to the invention means are, for example, those of acetic acid, Caproic acid, lauric acid, myristic acid, stearic acid and palmitic acid, as, for example, a complex of methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, isobutyl, tert. -butyl or monoglycerides acid esters of these acids. Particularly preferred esters are those of myristic acid or oleic acids as their methyl esters and in particular isopropyl esters. Suitable complex diesters of dicarboxylic acids are n penetration means are derivatives of phosphatidic, as lecithin, terpenes, amides, ketones, urea and its derivatives, or ethers, such as, for example, dimethylindole and diethylethylenediamine ether. Don't need any more detailed explanation of what to get proposed in the invention means are also suitable mixture of these enhance the penetration of funds.

As inhibitors of crystallization, which in particular cases can improve the stability during storage proposed according to the invention systems are suitable, for example, additives highly dispersed silicon dioxide or macromolecular substances, such as polyvinylpyrrolidone (e.g., Kollidon 12 PF Kollidon 17 PF, Kollidon 25 and Kollidon 30 BASF), crosslinked polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, ethylcellulose, gelatin, starch (derivatives) and dextran.

As the protective layer, any suitable film that is usually used in the case of transdermal therapeutic systems. Such films, for example, siliconserver or coated with fluorocarbon resin.

As the upper (outer) layer in the case of this system can be applied, for example, a thickness of 10-100 μm film of polyethylene or complex polyester, optionally pigmented or metallic. Namesnik substances are usually removed in the area of 1-100 cm2and preferably between 5-100 cm2.

In the case of multilayer matrix systems, for example, deposited on impervious top layer of the matrix, you can enter a gestagen, dimetridazole and if necessary amplifiers penetration, while underneath, a layer or layers contains estrogen together with dimethylisoxazol and if necessary also the penetration enhancers. On the other hand, however, in such a percutaneous system can be placed next few containing biologically active substance matrix systems.

Percutaneous therapeutic matrix system according to variant b) may be, for example, round, oval or rectangular and can be accessed as follows:

On the floor put the contact in relation to skin glue. Then, for one what, paste one or two vyshtampovannyj area (square) provided with an impermeable coating containing a progestogen, dimetridazole, if necessary estrogen or estrogen and, if necessary, enhance the penetration means matrix layers so that the coating has sufficient land to harden on the skin and in the case of multiple habitats is also sufficient Prohm is them, as in the matrix system variant (a).

In the case of this system, along with dimethylisoxazol you can apply the above to enhance the penetration means. As permeable polymer layer is used, for example, a thickness of 20-200 μm film of cellulose ethers, ethers of cellulose, silicones or polyolefin compounds. By changing this polymer layer in a wide range you can adjust the speed of diffusion of the biologically active substance or mixture of biologically active substances.

As an adhesive and a protective layer suitable such materials are described in the case of percutaneous therapeutic system according to option a).

In the preparation of transdermal therapeutic systems with two, adjacent, containing biologically active substance matrix layers or tanks drugs, it is often advisable one to enter the gestagen and the other estrogen. In such cases, containing biologically active substance matrix system or tanks medicines may include not only different biologically active substances, but also an additional variety that enhance the penetration of Sal between habitats, in order to prevent diffusion of the biologically active substances to another, depending on the circumstances, the area.

Further characteristics of the proposed according to the invention percutaneous systems are explained based attached, not seasoned in the scale figures.

In Fig.1 presents a cross section of a simple round of the matrix system according to variant (a) without the detachable protective layer. It consists of impermeable top layer 1 and containing the drug matrix layer 2.

In Fig.2 presents a cross section of the matrix system according to variant b) without the detachable protective layer.

In Fig.3 shows a longitudinal section of the system. The system consists of a cover 3, which is provided with a layer of contact adhesive 4. On this layer of contact adhesive with impermeable coatings 5 and 7 two hardened containing the drug matrix layer 6, and 8.

Proposed according to the invention, containing a progestogen means for percutaneous application can be used for the treatment of such diseases, as is already known, for example, is applied orally, the funds that contain highly effective progestogen. Moreover, the label for contraception and for replacement therapy in postmenopausal women. Special advantages offered according to the invention means are in the treatment of diseases that require long-term treatment with a relatively high dosage of biologically active substances. In this case, it is possible to significantly reduce the frequency of application and achieve a much more uniform level (drugs) in the blood plasma. Further, it is preferable that one should not expect gastrointestinal side effects and in the case of containing estrogen combined drugs bypass the first passage through the liver and the dose of estrogen can be reduced.

These advantages make containing progestogen monotherapeutic means of the present invention is particularly suitable for the treatment of, for example, endometriosis, gestagen-dependent tumors, benign diseases of the breast or premenstrual syndrome.

Percutaneous application of estrogen, if necessary, in successive or continuous combination with a gestagen, gives special advantages, for example, for the treatment of menopausal difficulties, to prevent osteoporosis, to regulate the cycle and to stabilize the loop.

The following examples of domestic the BR> the film of the complex polyester (polyester film) with a thickness 0,074 mm ( Skotchpak1009) manufacturer 3M; polypropylene film ( Celgard2500) manufacturer Celanese; lining film Skotchpak1022 and 1360 manufacturer 3M; molding glue 9871 manufacturer 3M; adhesive based on complex polyacrylic ester type SichellaJ 6610-21 manufacturer Henkel KG; silicone adhesive type X-7-2960 manufacturer Dow Cornind and hydroxypropylcellulose Klucel typeHXF manufacturer Hercules; polyisobutylene type OppanolB 15 SF BASF AG; dimetridazole type ArlasolveDMI firm ICI Surfactions; polyvinylpyrrolidone type Kollidon 12 PF, as well as copolymers of vinyl acetate with vinyl pyrrolidone type Kollidon VA 64 BASF AG,

Example 1

In the 62.4 g of a 50% aqueous solution of silicone glue in gasoline under stirring consistently contribute 0.8 g of desogestrel, 8.0 g of dimethylselenide. After obezvozhivanija initial mixture, the mixture using a device for coating applied to the film of the complex of the polyester in such a way that after removal of the volatile solvent is formed a uniform film with a layer of solids of 40 g/m2. Then cacheroot using coated with fluoropolymer lining of clinically separate patches area of 10 cm2and Packed in aluminum foil. In Fig.1 shows a cross-section of the patch without the lining of the complex polyester. The patch after removal of the backing film sticks to the skin.

Quantitative analysis gives a uniform distribution of biologically active substances in the medium, equal to 0.08 mg/cm2.

Example 2

170 g of a 50% aqueous solution of glue on the basis of complex polyacrylic ester in a mixture of acetone with benzene under stirring consistently dissolve 5.0 g of gestodene and 10.0 g of dimethylselenide. After obezvozhivanija initial mixture, the solution by means of a device for coating applied to the film of the complex of the polyester in such a way that after removal of the volatile solvent is formed a uniform film with a layer of a solid substance 100 g/m2. Then cacheroot using siliconized, not containing biologically active substances lining film. The thus obtained laminate using a stamping device is divided into individual separate patches area of 10 cm2and Packed in aluminum foil. After removal of the backing film of the patch adheres to the skin.

The content of gestodene sostavilokolo ether in a mixture of acetone with benzene under stirring consistently dissolve, accordingly, suspended, 3.5 g of estradiol, 3.5 g of levonorgestrel and 7.0 g of dimethylselenide with 10% lauric acid. After obezvozhivanija initial mixture, the mixture using a device for coating applied to the film of the complex of the polyester in such a way that after removal of the volatile solvent is formed a uniform film with a layer of solids 70 g/m2. Then cacheroot using siliconized, not containing biologically active substances, lining film. Thus, the obtained laminate using a stamping device is divided into individual patches area of 10 cm2and Packed in aluminum foil. After removal of the backing film of the patch adheres to the skin. The content of estradiol and levonorgestrel uniform and is 0.35 mg/cm2.

Example 4

Analogously to example 1, get two different segmental matrix system, which are shown in Fig. 2 and 3 form. Matrix system 1 is supplied from a film of the complex polyester 7 matrix layer 8 of the following composition: 1.0 mg of norethisterone, 5.0 mg of dimethylselenide and 44 mg of acrylate adhesive; and has an area of 5 cm2.

Matricin is ethinyl estradiol, 10.0 mg of dimethylselenide and 88 mg of acrylate adhesive; and has an area of 10 cm2. Both the matrix system thickness coated with a contact adhesive canvas, as shown in Fig. 3. After laminating and vyshtampovanny so get the patch specified in Fig. 2 and 3 of a kind.

Example 5

In 112 g of a 50% aqueous solution of plastic of polyisobutylene ( OppanolB 15 SF BASF AG] in a mixture of acetone with gasoline consistently and with stirring contribute 3.5 g of ethinyl estradiol, 3.5 g of desogestrel and 7.0 g of isopropylmyristate and proceed as described in example 3.

Example 6

100 g of a 50% aqueous solution of glue on the basis of complex polyacrylic ester in a mixture of ethyl acetate with isopropanol under stirring consistently dissolve 1.0 g of gestodene, 8.0 g of dimethylselenide and 9.0 g Kollidon 12 PF. After obezvozhivanija initial mixture, the mixture using a device for coating applied to the film of the complex of the polyester in such a way that after removal of the volatile solvent is formed a uniform film with a layer of solids of 80 g/m2. Then cacheroot using siliconized, not containing biologically active substances lining film. The thus obtained lamas who live in aluminium foil. The patch, after removal of the backing film, adheres to the skin.

Example 7

100 g of a 50% aqueous solution of glue on the basis of complex polyacrylic ester in a mixture of ethyl acetate with isopropanol under stirring consistently dissolve 1.0 g of gestodene, 2.0 g of estradiol, 8.0 g of dimethylselenide and 9.0 g Kollidon 12 PF. After obezvozhivanija initial mixture, the mixture using a device for coating applied to the film of the complex of the polyester in such a way that after removal of the volatile solvent is formed a uniform film with a layer of solids of 80 g/m2. Then cacheroot using siliconized, not containing biologically active substances lining film. The thus obtained laminate using a stamping device is divided into individual patches with an area of 15 cm2and Packed in aluminum foil. The patch after removal of the backing film sticks to the skin.

Example 8

100 g of a 50% aqueous solution of glue on the basis of complex polyacrylic ester in a mixture of ethyl acetate with isopropanol under stirring consistently dissolve 1.0 g of levonorgestrel, 8.0 g of dimethylselenide and 9.0 g Kollidon 12 PF. After obezvozhivanija initial mixture, the mixture with the help of volatile solvent forms a uniform film with a layer of solids of 80 g/m2. Then cacheroot using siliconized, not containing biologically active substances lining film. The thus obtained laminate using a stamping device is divided into individual separate patches with an area of 20 cm2and Packed in aluminum foil. After removal of the backing film of the patch adheres to the skin.

Example 9

100 g of a 50% aqueous solution of glue on the basis of complex polyacrylate ester in a mixture of ethyl acetate with isopropanol under stirring consistently dissolve 1.0 g of levonorgestrel, 1,0 estradiol, 8.0 g of dimethylselenide and 9.0 Kollidon 12 PF. After obezvozhivanija initial mixture, the mixture using a device for coating applied to the film of the complex of the polyester in such a way that after removal of the volatile solvent is formed a uniform film with a layer of solids of 80 g/m2. Then cacheroot using siliconized, not containing biologically active substances lining film. The thus obtained laminate using a stamping device is divided into individual patches with an area of 20 cm2and Packed in aluminum foil. After removal of the backing film plasters prismes ethyl acetate to isopropanol with stirring consistently dissolve 2.0 g of estradiol, 8.0 g of dimethylselenide and 9.0 g Kollidon VA 64. After obezvozhivanija initial mixture, the mixture using a device for coating applied to the film of the complex of the polyester thus that is formed after removal of the volatile solvent, a uniform film with a layer of solids of 80 g/m2. Then cacheroot using siliconized, not containing biologically active substances lining film. The thus obtained laminate using a stamping device is divided into individual patches with an area of 15 cm2and Packed in aluminum foil. After removal of the backing film of the patch adheres to the skin.

Example 11

170 g of a 38% aqueous solution of glue on the basis of complex polyacrylic ester in a mixture of ethyl acetate with isopropanol under stirring consistently dissolve 0.9 g of levonorgestrel, 1.8 g of estradiol, 19,0 g dimethylselenide, 4.5 g of lauric acid and 13.5 g Kollidin VA 64. After obezvozhivanija initial mixture, the mixture using a device for coating applied to the film of the complex of the polyester in such a way that after removal of the volatile solvent is formed a uniform film with a layer of a solid substance 100 g/m2. Then casinoprism the resulting laminate using a stamping device is divided into individual patches with an area of 20 cm2and Packed in aluminum foil. After removal of the backing film of the patch adheres to the skin.

Example 12

170 g of a 38% aqueous solution of glue on the basis of complex polyacrylic ester in a mixture of ethyl acetate with isopropanol under stirring consistently dissolve 0.9 g of levonorgestrel, 19,0 g dimethylselenide, 4.5 g of lauric acid and 13.5 g Kollidon VA 64. After obezvozhivanija initial mixture, the mixture using a device for coating applied to the film of the complex of the polyester in such a way that after removal of the volatile solvent is formed a uniform film with a layer of a solid substance 100 g/cm2. Then cacheroot using siliconized, not containing biologically active substances lining film. The thus obtained laminate using a stamping device is divided into individual patches with an area of 20 cm2and Packed in aluminum foil. After removal of the backing film of the patch adheres to the skin.

Example 13

170 g of a 38% aqueous solution of glue on the basis of complex polyacrylic ester in a mixture of ethyl acetate with isopropanol under stirring consistently dissolve 0.9 g of gestodene, 1.8 g of estradiol, 19,0 g dimethylazobenzene coatings applied to the film of the complex of the polyester thus, after removal of the volatile solvent is formed a uniform film with a layer of a solid substance 100 g/m2. Then cacheroot using siliconized, not containing biologically active substances lining film. The thus obtained laminate using a stamping device is divided into individual patches with an area of 20 cm2and Packed in aluminum foil. After removal of the backing film of the patch adheres to the skin.

Example 14

170 g of a 38% aqueous solution of glue on the basis of complex polyacrylic ester in a mixture of ethyl acetate with isopropanol under stirring consistently dissolve 0.9 g of gestodene, 19,0 g dimethylselenide, 4.5 g of lauric acid and 13.5 g Kollidon VA 64. After obezvozhivanija initial mixture, the mixture using a device for coating applied to the film of the complex of the polyester in such a way that after removal of the volatile solvent is formed a uniform film with a layer of a solid substance 100 g/m2. Then cacheroot using siliconized, not containing biologically active substances lining film. The thus obtained laminate using a stamping device is divided into an individual who adheres to the skin.

Example 15

170 g of a 38% aqueous solution of glue on the basis of complex polyacrylic ester in a mixture of ethyl acetate with isopropanol under stirring consistently dissolve 0.9 g of levonorgestrel, 1.8 g of estradiol, 19,0 g dimethylselenide, 4.5 g of lauric acid and 13.5 g Kollidon 12 PF. After obezvozhivanija initial mixture, the mixture using a device for coating applied to the film of the complex of the polyester in such a way that after removal of the volatile solvent is formed a uniform film with a layer of a solid substance 100 g/m2. Then cacheroot using siliconized, not containing biologically active substances lining film. The thus obtained laminate using a stamping device is divided into individual patches with an area of 20 cm2and Packed in aluminum foil. After removal of the backing film of the patch adheres to the skin.

Example 16

170 g of a 38% aqueous solution of glue on the basis of complex polyacrylic ester in a mixture of ethyl acetate with isopropanol under stirring consistently dissolve 0.9 g of levonorgestrel, 19,0 g dimethylselenide, 4.5 g of lauric acid and 13.5 g Kollidon 12 PF. After obezvozhivanija initial mixture, the mixture with the help of the device is of storytale formed a uniform film with a layer of a solid substance 100 g/m2. Then cacheroot using siliconized, not containing biologically active substances lining film. The thus obtained laminate using a stamping device is divided into individual patches with an area of 20 cm2and Packed in aluminum foil. After removal of the backing film of the patch adheres to the skin.

Example 17

170 g of a 38% aqueous solution of glue on the basis of complex polyacrylic ester in a mixture of ethyl acetate with isopropanol under stirring consistently dissolve 0.9 g of gestodene, 1.8 g of estradiol, 19,0 g dimethylselenide, 4.5 g of lauric acid and 13.5 g Kollidon 12 PF. After obezvozhivanija initial mixture, the mixture using a device for coating applied to the film of the complex of the polyester in such a way that after removal of the volatile solvent is formed a uniform film with a layer of a solid substance 100 g/m2. Then cacheroot using siliconized, not containing biologically active substances lining film. The thus obtained laminate using a stamping device is divided into individual patches with an area of 20 cm2and Packed in aluminum foil. After removal of the backing film plaga ether in a mixture of ethyl acetate with isopropanol under stirring consistently dissolve 0.9 g of gestodene, 19,0 g dimethylselenide, 4.5 g of lauric acid and 13.5 g Kollidon 12 PF. After obezvozhivanija initial mixture, the mixture using a device for coating applied to the film of the complex of the polyester in such a way that after removal of the volatile solvent is formed a uniform film with a layer of a solid substance 100 g/m2. Then cacheroot using siliconized, not containing biologically active substances lining film. The thus obtained laminate using a stamping device is divided into individual patches with an area of 20 cm2and Packed in aluminum foil. After removal of the backing film of the patch adheres to the skin.

1. Transdermal therapeutic system containing sex steroids and, if necessary, the penetration enhancers and inhibitors of crystallization, characterized in that they contain 1 to 40 wt.% dimethylselenide counting on all phase of biologically active substances with the exception of systems that contain including biologically active substance, non-leaking gel-phase or 3-keto-desogestrel.

2. Transdermal therapeutic system according to p. 1, characterized in that they contain 5 to 25 wt.% dimethylselenide in the calculation of the different topics as sex steroid they contain a progestogen and/or estrogen.

4. Transdermal therapeutic system according to p. 3, characterized in that as progestogen they contain gestodene, levonorgestrel, desogestrel, norethisterone or norethisterone.

5. Transdermal therapeutic system according to p. 3, characterized in that as oestrogen (estrogen) they contain estradiol, estriol, 17-ethinylestradiol, mestranol, 14, 17-ethanoate-1,3,5(10)-triene-3,17-diol, 14, 17-ethanoate-1,3,5(10)-triene-3,16, 17-triol or esters of these compounds.

6. Transdermal therapeutic system according to PP.1 - 5 for percutaneous contraceptive for endometriosis treatment, for the treatment of gestagen-dependent tumors and for the treatment of premenstrual syndrome.

7. Transdermal therapeutic system according to PP.1 to 5, if necessary in combination with estrogen means, for the treatment of menopausal difficulties, for protection from osteoporosis, to regulate the cycle, in order to stabilize the loop and percutaneous contraceptive.

8. Transdermal therapeutic system containing matrix layer, including sex steroids and dimetridazole, characterized in that the system is ¾ gestagen and/or estrogen and dimetridazole and in the desirable case, enhance the penetration means and inhibitors of crystallization, covered or surrounded by the contact against the skin adhesive containing, in a desirable way, enhance the penetration means, and a removable protective layer; or b) cover, provided with a contact adhesive containing, in a desirable way, tools that enhance the penetration of one or two matrix layers, leaving open the trim of contact adhesive, reinforced with an impervious coating over the contact adhesive containing a progestogen and/or estrogen and dimetridazole and, in the desirable case, means amplifying penetration, and inhibitors of crystallization, and remove the protective layer.

9. Transdermal therapeutic system according to p. 8, characterized in that it contains including biologically active substance matrix layer.

10. Transdermal therapeutic system according to p. 9, characterized in that it contains two or three including biologically active substance matrix layer.

11. Transdermal therapeutic system according to p. 10, characterized in that it contains a biologically active substance matrix layers include different biologically active substances.

12. Crossability from gestagen tumors and for the treatment of premenstrual syndrome.

13. Transdermal therapeutic system according to PP.8 - 11, if necessary in combination with estrogen means for the treatment of menopausal difficulties, for protection from osteoporosis, to regulate the cycle, in order to stabilize the loop and percutaneous contraceptive.

 

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The invention relates to pharmaceutical industry and can be used for the treatment of diseases of musculoskeletal system

Medical bandage // 2125859
The invention relates to medicine, namely to polymeric dressing materials used in surgery for the treatment of wounds, burns, skin lesions of varying severity

FIELD: medicine.

SUBSTANCE: material has two layers - the first one and the second one. The first one has staple viscose fibers. The second one is manufactured from staple easily fusible thermoplastic synthetic fibers. Both layers are joined to each other under water jet treatment. The second layer fibers partially penetrate into the first layer and fixed therein. The second layer surface is melted and turned outward. It becomes smooth under temperature and pressure treatment. The non-woven material has high absorbing capacity.

EFFECT: low risk of traumatic complications.

5 cl, 2 dwg

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