Containing steroid patch, its method of preparation and use


The invention relates to the field of medicine and relates to self-adhesive drug composition for percutaneous use of estrogen combined with progestogen containing 25-90 wt.% self-adhesive acrylate copolymer, 1-15 wt. % of film-forming copolymer of acrylate containing 10-90 wt.% methacrylic acid and 10-90 wt.% of methyl methacrylate, 1-30 wt.% improves adhesion additives in the form of an adhesive resin, 0.2 to 2.0 wt.% estrogen and 1-5 wt.% progestogen. The invention is a percutaneous therapeutic system with a simple matrix structure containing neurohistology providing effective therapy symptoms of menopause composition. 9 C.p. f-crystals, 1 Il.

The invention relates to pharmaceutical compositions intended for transcutaneous use of estrogen combined with progestogen.

The purpose of percutaneous application of active substances is ensuring their overall effect on the body. Taking into account the limited permeability of the skin, the preferred substances suitable for this purpose are substances used in small doses (daily dose 10 mg).

Percutaneous application of an efficient in cases when after oral administration means the second membrane of the gastro-intestinal tract or was withheld by the liver (the primary effect of passing), and/or in cases where the half-life of the active substance from the plasma is small. However, for these purposes are not suitable substances with high allergogennym potential, as well as substances with the local irritant effect. Subject to basic requirements percutaneous application is an alternative to oral administration.

The invention relates to containing the active substance to the device for a specified time at a given speed continuously releasing one or more drugs in a prescribed place. Such a device has the exact program of treatment called therapeutic system. Since the system according to the present invention is a patch applied to the skin in order to achieve overall effect on the body, such a system is called a percutaneous therapeutic system (TTS).

The invention relates to the preparation of high impact, in other words, this drug provides high bioavailability of drugs. This is achieved by a substantial reduction desisting excretion of drugs, mietlicki intestines.

The impact of drug substances may be terminated at any time, with some delay, by simple removal of the drug. Their concentration in the plasma can be installed in therapeutic limits without peaks and troughs. As a result, the product ensures the controllability of the phenomenon of suction.

The preparation according to the invention is highly reliable from the point of view of the implementation of the patient treatment plan, since the reception frequency compared to conventional dosage forms is greatly reduced. In addition, the amount of active substance can be generally reduced. This also decreases the probability associated with dosage side effects or they are completely eliminated, which provides increased reliability of the treatment.

Estradiol, estrone (estrogens or progesterones (a progestogen) is a natural female sex hormone. Sex hormones form the primary and secondary sexual characteristics. They affect the process of growth and body shape, as well as water and mineral balance. In addition, sex hormones determine the nature of the menstrual cycle in women.

The natural sex hormones, their derivatives, and that the personal diseases.

The main field of application of sex hormones is the replacement of hormones in postmenopausal period. Such substitution is to prevent complaints about the symptoms of menopause (hot flushes, dizziness, tachycardia, sweating, anxiety, irritability, poor concentration, sleep disturbance, and so on). In addition, the aim is to prevent changes in the urogenital tract, the cardiovascular changes induced by hyperlipemia, skin atrophy or osteoporosis, as well as further pathological phenomena. For this purpose, the receiving estrogen is carried out in combination with a gestagen.

Can be used, for example, the following estrogens: 17-beta-estradiol, 17-alpha-estradiol, 17-beta-estradiolcreamas, 17-beta-ethinylestradiol, 3,17-beta-estradiolvalerate, 17-beta-estradiolvalerate, 17-beta-estradiolelisaut, 17-beta-astrogeological, 17 diacetylmorphine, norgestimate, mestranol and quinestrol. These estrogens have an aromatic hydroxyl group or their simple esters.

Because natural progesterone gestagen not sufficient for the implementation of substitution therapy pharmacokinetic properties, was synthesized mysteron, ethisterone, melengestrol, norgestrel, levonorgestrel, gestodene, oxyprogesterone, medroxyprogesterone, Echinodermata, 17-alpha-oksiprogesterona, magistralata, lynestrenol, desogestrel, allylestrenol, chlormadinone and chlormadinone. Typical for most compounds the structural feature is the presence of structure 3-ketene-4.

If the receiving estradiol carried out orally, because of its low solubility in water absorbed only a small part, which undergoes significant effect of the first passage. When this occurs, the splitting of a variety of metabolites, not with the properties of estrogen that causes side effects. In addition, oral administration leads to is not caused by physiological causes fluctuations in the hormone levels in the blood. In addition, taking into account the effect of the first passage, it is necessary to take large amounts of estradiol, which leads to more side effects.

The ideal form of reception of estradiol is slow intravenous infusion. However, this method is impractical. Using percutaneous introduction it is possible to achieve almost perfect with the concentrations in plasma, appropriate physiological levels of hormones in the blood Jenin in the period preceding menopause (40-60 picograms/ml). Another advantage of the percutaneous injection compared to oral intake is able to reduce the daily dose to 50grams/day.

The main danger associated with taking estradiol in menopause is over-stimulation of the mucous membrane of the uterus, which entails an increased risk of hyperplasia or rebirth. In addition, therapy is carried out only by estradiol, often accompanied by menstrual disorders. To reduce this risk it is advisable to take estradiol in combination with a gestagen. To prevent hyperplasia dermal application daily, you need to enter about 200-300 grams...of norethisterone or the corresponding number of equivalent, whereas oral administration of the required dose is 0.7-1 mg/day [see Wiseman, R. L. and McTavich, D., "Percutaneous application of estradiol/norethisterone: a Review of pharmacological properties and clinical use women in menopause", drugs&Aging, vol. 4, No.3, 1994, pages 238-256].

From techniques known industrially produced combine with gestagen, especially norethisterone (for example, Estracomb). Their disadvantage is that they have complex designs. So, Estracomb... has two cavities that serve as reservoirs for the active substance. In addition, there are regulatory membrane, providing modified release of the active substance. Given the large space occupied by the cavities, such systems are very thick and, therefore, inconvenient to use.

Examples of matrix systems with a simple design, intended for percutaneous application of estradiol in combination with a gestagen, are described in European patent EP 0695177 B1. In the application WO 96/40087 described matrix system based on a structured polyacrylate intended for percutaneous application of estradiol.

If the storage containing the steroid what matrix type amongst the two problems associated with their stability: active substances susceptible to recrystallization or decomposition.

Recrystallization occurs in excess of the relevant active substance concentration of saturation, resulting in can occur videosmn recrystallization due to its low solubility. In addition, there is the probability of formation of mixed crystals. In this case, the solubility of the mixed crystals is lower than the solubility concentrations up to saturation of the individual components. As a result of recrystallization is reduced thermodynamic activity and rate of permeation of the active substance through the skin. Thus, therapeutic efficacy of the drug is under threat.

Describes the different ways to prevent recrystallization of estradiol. In the system described in U.S. patent US 5676968, the cavity in which the active ingredient, contains the excipients described as inhibitors of crystallization and designed to counter the crystallization process. In particular, the above-mentioned silicon dioxide and substances with macromolecular structure, such as polyvinylpyrrolidone or copolymers with vinyl acetate. In U.S. patent US 5711962 and the application WO 97/23227 described using octyldodecanol to prevent crystallization. In the application WO 96/05814 disclosed system containing as a component of the matrix anhydrous glycerin. Anhydrous glycerin mixed with water in any proportion, hygroscopic and can be used as digiatl water. Thus, anhydrous glycerin is suitable to prevent recrystallization during storage. In the application WO 96/05815 described the addition of mineral substances that bind water to the matrix containing the active substance, resulting in preventing recrystallization of estradiol hemihydrate. As mineral substances mentioned, for example, anhedral calcium sulphate, zinc oxide, magnesium oxide, silicon dioxide, silica gel, talc and other substances. In German patent DE 4237453 proposed the use of dehumidifiers in their original packaging. In the European patent EP 0186019 A1 describes the use of from water swellable polymers that prevent the growth of crystals of the active substance, the concentration of which is greater than its saturation concentration. In the European patent DE 0695177 B1 disclosed a system containing estradiol at a concentration close to the saturation concentration. The saturation concentration is exceeded due to the absorption of water only after the system paste on the skin, thereby increasing thermodynamic activity. The degree of saturation hydrogenated matrix and, thereby, the penetrating ability of the active substance through the skin determines the alpha that is the treatment recrystallization during storage.

During storage steroids (hormones and corticoide) in varying degrees, are split depending on the excipients. You need to take into account a number of mechanisms of decomposition. On the one hand, there saponification reaction leading to the formation of compounds, which are more hydrophilic, on the other hand, the oxidation reaction leading to the formation of unproductive reaction products. In particular, the high sensitivity of different steroids with a partial structure of 3-ketene-4. The cause of this instability, among others, are the group with an acidic. So, in the application WO 97/03629 described system with the carrier, not having acid function and is not purchasing such functions during storage. In German patent 19548332 A1 describes a patch containing the hormone with norethisterone and high storage stability. Stability in this case is achieved through the use of a specific polymer. In the application WO 97/23227 indicated that the decomposition of norethisterone depends on the moisture content in the matrix. Therefore, in the manufacturing process it is advisable to use dry air and to invest in primary packaging ASU is increased, if in the manufacturing process of the active substance dissolved in a solvent mixture consisting of methyl ethyl ketone and ethanol.

In addition to solving the above mentioned problems of stability it is necessary to ensure therapeutic efficacy of what. Therapeutic efficacy is determined depending on the ability to penetrate the skin. To ensure sufficient penetrating power amplifiers often use. Thus, in U.S. patent US 5676968 to increase the penetrating ability of estradiol in the example described the use of 1,2-propane diol and isoprenylated. In the European patent EP 0811381 A1 as the amplifier penetrating ability of estradiol and norethisterone describes the use of fatty alcohols in combination with monoalkyl ether of diethylene glycol. In U.S. patent US 5686097 mentioned the use of monoglycerides and esters of lactic acid to enhance the penetrating power of combination estrogen/progestogen.

However, the use of amplifiers is not always effective. Many of the applied substances cause skin irritation, and therefore often use additional substances, opposing such irritation. In particular, it should be called the city of the sustained fashion effect on the permeation velocity. Its disadvantage is the fact that the glycerol significantly reduces the coupling matrix based on the polyacrylate. The deterioration of coupling is manifested in increased stickiness, plastic deformation, the ability to carry the binder in the protective film, or that the remains of the binder remains on the skin after removal system. For significant improvement in clutch systems with a high content of liquid or mitigating components in U.S. patent US 5306503 proposed to add a so-called film-forming substance.

The aim of the present invention is to provide a transdermal therapeutic system with a simple, so-called matrix structure containing inexpensive composition intended for transcutaneous use of estrogen, particularly estradiol in combination with a gestagen, especially norethisterone, these percutaneous therapeutic system provides effective medical treatment of complaints associated with the symptoms of menopause.

Matrix systems differ in that the active substance is present in the polymer matrix of finely dispersed (dissolved or dispergirovannom). In this case, the matrix plays altoadige substances is largely controlled by the built-in regulating membrane in matrix systems, this function performs the skin. To produce such a matrix containing the active substance, very simply.

This task is solved by using self-adhesive compositions based on polyacrylate for percutaneous application according to the characteristics of the main claim. The preferred option implementation is characterized by the features set forth in the dependent clauses.

Composition based on polyacrylate have very low allergogennym potential and, therefore, also suitable for long term use. In this case, the adhesive ability of the polymers is due to the distribution of molecular weight and the monomers used.

For the manufacture of compositions based on polyacrylate according to the present invention using acrylic and/or alkylacrylate acid, especially methacrylic acid or their derivatives, in particular complex alkalemia esters. In a number of complex alilovic esters of acrylic acid and/or methacrylic acid are esters with 1 to 18 carbon atoms in the alkyl residue, in particular methyl, ethyl, n-butyl, isobutyl, pentyl, 2-ethylbutyl, n-hexyl, heptyl, n-octyl, isooctyl, 2-ethylhexyl, n-decyl, Isodecyl, n-EPA may include additional comonomers. Their examples are acrylic and/or methacrylic amide, complex alkalemia esters of oxyacids and complex polyacrylonitrile esters of acrylic and/or methacrylic acid, nitrogen-containing monomers of acrylic and/or methacrylic acid or their salts, ethylene, vinyl acetate, finalproject, vinylboronate, vinyl pyrrolidone, vinyl chloride, vinyltoluene, Acrylonitrile, styrene and the like.

For manufacturing system according to the invention mainly uses a copolymer of acrylate containing 2-ethyl hexyl acrylate, vinyl acetate, oxidisability and glycidylmethacrylate.

To ensure therapeutic efficacy as amplifiers use glycerin. To this end, in the matrix it is necessary to introduce a significant amount of glycerin. However, in the presence of large quantities of glycerol decreases the coupling matrix. To counteract this deficiency in the matrix based on polyacrylate use additional, non-adhesive polymer with excellent film-forming properties. Such film-forming polymer positive impact on the coupling matrix. As practice shows, for this purpose, suitable polymers based on polyacrylic or polymethacrylic kicker acrylate, containing 10-90 wt. % of methacrylic acid and 10-90 wt. % of methyl methacrylate. As it has been unexpectedly discovered that the addition of the components with an acidic does not increase cleavage members of the hormones with a partial structure of 3-ketene-4. This completely contradicts the results of the tests described in the application WO 97/03629, in contrast to which the use of the above polymer contributes to the stability. The drawing illustrates the effect of Eudragit L100 on the formation of cleavage products of norethisterone. Columns marked with numbers 1 through 3 illustrate a well-known cleavage products (Nordion, 6-beta-oxidoreductase and norethisterone). The Z-axis represents the retention time corresponding to the held liquid chromatography high resolution. The Y axis shows the percentage of cleavage products formed on the General surface performance of high resolution. Second from the right the number on the X-axis illustrates that the composition not containing Eudragit L100, has the largest number of cleavage products. With increasing content of Eudragit L100 (from right to left, from 1 to 10% Eudragit L100 relative to the dry substance) of the amount of fission products increases. What is stored during Doucet mainly metal ions, such as aluminum or titanium.

If the adhesive power of the matrix is decreased by the addition of film-forming polymers, it can be effectively compensated for by the addition of resins, with a strong increase stickiness effect. In the manufacture of compositions according to the invention as increasing the adhesion of substances can be used kanifolnye resin, polyterpene resin, coumaroneindene resin, decentralitralisation resin, hydrocarbon resin, liquid polybutene resin and the like.

Hereinafter the invention will be illustrated by example.

Example Were mixed 1.4 grams of estradiol, 7.5 grams of norethisterone, 105 grams of binders based on acrylate (Durotak387-2287), 46 grams of adhesive resin (e.g., HercolynDE), 10 grams of Eudragit L100, 30 grams of glycerin, 15 grams of acetylacetone and 0.1 gram aluminiumalloy (4 wt. % in ethyl acetate). On impregnated with silicone polyester film (for example, Hostaphanusing plate was coated with the layer of the mixture, the thickness of which in the wet state dostavljenim layer was applied onto a polyester film (for example, Hostaphan). Unit weight per unit area of the adhesive film obtained in this way was about 80,4 grams/m2. Laminate were using the corresponding punch is made of what the desired size. What kept at different temperatures to study their stability.


1. Self-adhesive medicinal composition for percutaneous use of estrogen combined with progestogen containing(a) 25-90 wt.% self-adhesive acrylate copolymer, (b) 1-15 wt.% film-forming copolymer of acrylate containing 10-90 wt.% methacrylic acid and 10-90 wt.% of methyl methacrylate, (c) 1-30 wt.% improves adhesion additives in the form of adhesive resins, (d) 0.2 to 2.0 wt.% estrogen and (e) 1-5 wt.% progestogen.

2. The composition according to p. 1, wherein the self-adhesive acrylate copolymer contains 2-ethyl hexyl acrylate, vinyl acetate, oxidisability and glycidylmethacrylate.

3. The composition according to p. 1, wherein the film-forming copolymer of acrylate contains 10-90 wt.% methacrylic acid and 10-90 wt.% of methyl methacrylate.

4. The composition according to p. 1, characterized in that the additive that increases the stickiness, is proizvodi polyterpene resin.

6. The composition according to p. 1, characterized in that it further contains an additive that improves the grip.

7. The composition according to p. 1, characterized in that the additive that increases the grip is a metal ion, preferably, aluminum or titanium.

8. The composition according to p. 1, wherein the estrogen is a derivative of estradiol, in particular, 17-beta-estradiol.

9. The composition according to p. 1, wherein the gestagen is a derivative of norethisterone, in particular, norethisterone.

10. The composition according to p. 1, characterized in that it contains 1-20 wt.% anhydrous glycerol.


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