New devices for percutaneous introduction of trimegestone

 

The invention relates to medicine, namely to the adhesive polymer matrix applied to the device for percutaneous introduction of progestogenic, and this matrix is composed of a single layer (2) or the following sequential layers: if necessary, layer (1), called anchoring, formed of silicone polymer; a layer (2) formed of silicone polymer enriched Trimegestone and/or one or more pharmaceutically acceptable derivatives and, if necessary, a plasticizer; if necessary, the layer (3), called adhesive formed of silicone polymer. Percutaneous system has the advantage that it can be used for treatment for a long time, completely eliminating overdose. In addition, percutaneous introduction avoids unwanted effects associated with overdose at the hepatic level. 8 C. and 24 C.p. f-crystals, 13 tables. , 5 Il.

The present invention relates to new devices designed for percutaneous introduction of trimegestone and methods of their making.

Percutaneous systems that produce progestogenic, Simi substances, which must be entered for long periods of time.

Esters of these steroids prolonged action or herbal forms with controlled selection, such as implants or microspheres, are used in therapy, but they often have the disadvantage that they are not very easy to use. In addition, they do not make it possible to interrupt the treatment if necessary. Percutaneous system has the advantage that it can be used for treatment for a long time, completely eliminating overdose. In addition, percutaneous introduction avoids unwanted effects associated with overdose at the hepatic level.

Thus, firm-applicant was forced to explore new pharmaceutical composition suitable for administration by percutaneous containing progestogenic known as Trimegestone (alpha-methyl-beta-(2-hydroxy-1-oxo-propyl)östra-4,9-Dien-3-one (21S): 1 - which allows you to keep Trimegestone in conditions ensuring high stability, especially during storage, 2 - which allows you to enter Trimegestone with percutaneous flow, concluded between 0.1 and 3 mg

Thus, the subject invention is an adhesive polymer matrix is applied to the device for percutaneous introduction of progestogenic, characterized in that the matrix is composed of one layer or of the following successive layers: - if necessary, layer (1), called anchoring, formed of silicone polymer layer (2) formed of silicone polymer enriched Trimegestone and/or one or more pharmaceutically acceptable derivatives Trimegestone and, if necessary, a plasticizer, if necessary, layer (3), called adhesive formed of silicone polymer.

Trimegestone is a potent progestogenic described in the European patent 00 is 21, in which the residue of the ester group contains from 1 to 12 carbon atoms. It is, in particular, derived beta-(2-acetoxy-1-oxo-propyl)östra-4,9-Dien-3-one (21S). Similarly we can talk about the following 2-alloctype: isopropionate, propionyloxy, butyryloxy, isobutyryloxy, valeriote, isovalerianic, oxanilate, succinylate, pivaloyloxy, undecanoate, benzoyloxy. These esters receive, in particular, the action of aliphatic or aromatic carboxylic acids or their anhydrides containing 1-12 carbon atoms, Trimegestone.

Esters of Trimegestone, ester residue containing 1 carbon atom, or 3 to 12 carbon atoms, equally are the subject of the present invention.

The firm-the applicant has established that among the many polymers are known to the specialist, able to contain progestogenic, such as Trimegestone, only the organosilicon polymer can satisfy the required conditions of stability, flow and adhesion.

Under organosilicon polymer imply a grid of polydimethylsiloxane links (P. D. M. S.).

Can be used two types of polymers, one with high instant adhesive ability, is the ability, in particular, BIO-PSA7-3045, 7-4201 or 7-4202 (Dow Corning Health Care Centre Europe). Organosilicon polymer is in the form of a transparent solution in an organic solvent, volatile at low temperature, such as hexane, heptane, ethyl acetate, or tetrahydrofuran.

These polymers are resistant to the action of amines, they do not contain acidic silanol groups.

Gluing ability is characterized by the effort of the Department of film and bond strength: this gluing ability increases when moving from low-grade instant adhesive ability to the average instant adhesive capacity, and then to high instantaneous adhesive ability. The option to change this physical characteristic is the ratio of polymer/silicone resin. Under average bonding strength mean ratio 40/60. Under a high bonding strength mean the ratio of 45/55.

The number of Trimegestone introduced in a polymer matrix, such as defined above, made preferably between 1 wt.% and 10 wt.%. This percentage corresponds to the number of the active substance, expressed relative to the dry weight of the mixture after evaporation of the dissolve is used to increase the magnitude of the instantaneous clutch. Use oils such as silicone oil, or Cecily, such as CetiolS (dioctylsebacate). It would be especially high-viscosity silicone oil. We are talking about a polymerized dimethylsiloxane, and in particular, silicone oil 7-9120 Dow Corning (12000 cSt). The amount of plasticizer can be between 1 and 10 wt.%. Preferably, choose from 1 to 3 wt.% plasticizer.

This silicone matrix has a certain number of advantages:
- lack of absorption promoter;
- Trimegestone well chemically stable in the silicon-organic polymer;
- levels flow coupling compatible with therapeutic treatment;
matrix system has the advantage compared to systems with storage tanks, consisting in the absence of risk of rupture, which can lead to an overdose of the active substance;
- Trimegestone not affected in the implementation of the method of manufacture, although it is unstable to moisture and temperature;
- plasters containing Trimegestone, as described above, provide, thus, the diffusion of the active substance, stretched in time. They secrete concentration is high (see pharmacodynamic tests).

Particularly preferred variant of the invention are three types of matrix:
1 - single-layer matrix,
2 - two-layer matrix,
3 - three-layer matrix, which are described below.

1 - single-layer matrix
Particularly preferred variant of the invention is an adhesive polymer matrix imposed on the device for percutaneous introduction of progestogenic, such as defined above, characterized in that the matrix contains a single layer (2) formed of silicone polymer enriched Trimegestone and/or one or more pharmaceutically acceptable derivatives Trimegestone and, if necessary, a plasticizer.

In this case, choose particularly preferably commercial organosilicon polymer having a high instantaneous adhesive ability. In this case, I will be talking about BIO-PSAhaving high instantaneous adhesive ability, and in particular, BIO-PSA7-4301. There is no need to use any promoter absorption.

The subject invention is particularly preferred in ancescao polymer, having a high bonding strength, enriched 1-10 wt. % Of trimegestone and/or one or more pharmaceutically acceptable derivatives of Trimegestone and 0-10 wt.% silicone oil or CetiolS.
The subject of the invention in a particularly preferred variant is the previous single-layer matrix, characterized in that it is composed of 96 wt.% organosilicon polymer BIO-PSAhigh instant adhesive ability, enriched with 3 wt.% Trimegestone and 1 wt.% silicone oil.

2 - two-layer matrix
Similarly, the subject invention is particularly preferably is an adhesive polymer matrix imposed on the device for percutaneous introduction of progestogenic, such as defined above, characterized in that the matrix contains two consecutive layers:
a) the first layer (2) formed of silicone polymer containing Trimegestone and/or one or more pharmaceutically acceptable derivatives of Trimegestone,
b) a second layer (3), an adhesive layer which is in contact with the skin, also formed kremniyorganika choose commercial silicone polymer, high instant adhesive ability. In this case, I will be talking about BIO-PSAhaving high instantaneous adhesive ability, and in particular, BIO-PSA7-4301.

Adding an adhesive layer, which should be on the skin, in a double-layer matrix makes it possible to increase the adhesion, however, without significant changes in flow. Thus, there is no need to use any promoter absorption.

Equally the subject of the invention is particularly preferably is a previous two-layer matrix, characterized in that:
a) the first layer is composed of 90-99 wt.% organosilicon polymer having a high bonding strength,
and 1-10 wt. % Of trimegestone and/or one or more pharmaceutically acceptable derivatives of Trimegestone;
b) the second layer is also formed of silicone polymer having a high bonding strength.

Equally the subject of the invention is particularly preferably is a previous two-layer matrix, characterized in that:
a first layer formed on 97 wt.% organosilicon polymer BIO-PSAhigh instant adhesive ability.

3 - three-layer matrix
Also the subject of the invention is particularly preferably is an adhesive polymer matrix imposed on the device for percutaneous introduction of progestogenic, such as defined above, characterized in that the matrix contains three successive layers:
a) the first layer, called anchoring layer formed of silicone polymer,
b) the second layer (2) formed of silicone polymer containing Trimegestone and/or one or more pharmaceutically acceptable derivatives of Trimegestone,
b) and third layer (3), the adhesive, which should be on the skin, also formed of silicone polymer.

Adding anchoring layer and the adhesive layer enables you to increase the adhesion, however, without significant changes in flow. Thus, there is no need to use any promoter absorption.

As for the adhesive layer, for him especially choose commercial adhesive silicone polymer having a high instantaneous adhesive ability. In this case renest, in particular, BIO-PSA7-4301.

As for the anchoring layer, as well as enriched layer, they particularly choose commercial organosilicon polymer having an average instant adhesive ability, particularly BIO-PSA7-3045, 7-4201 or 7-4202.

Also the subject of the invention, especially preferred is a previous three-layer matrix, characterized in that:
the first layer is formed of silicone polymer, with an average bonding strength,
the second layer consists of 90-99 wt.% organosilicon polymer having an average bonding strength, and 1-10 wt.% Trimegestone and/or one or more pharmaceutically acceptable derivatives of Trimegestone,
- the third layer is formed of silicone polymer having a high bonding strength.

Also the subject of the invention is particularly preferably is a previous three-layer matrix, characterized in that:
the first layer is formed of silicone polymer BIO-PSAwith the average instant adhesive ability,
- second with an average instant adhesive ability, 9 wt.% Trimegestone,
- the third layer is formed of silicone polymer BIO-PSAhigh instant adhesive ability.

Equally the subject of the invention is a device for percutaneous introduction of progestogenic, characterized in that it successively formed:
- protective film (a),
matrix enriched with Trimegestone and/or one or more pharmaceutically acceptable derivatives Trimegestone, such as those defined above,
- detachable protective film (b).

To get serazhidinova system, protective films are used as substrates, which are coated with various layers that make up the patch. When the active substance is sensitive to light, they, if necessary, can be opaque.

Among the protective films preferably choose Scotchpak1109, which is a film having a skin color, impervious and flexible, or Scotchpak1006 (firm ZM Health Care Limited).

Scotchpak1006 consists of 4 with the hazards of medium-density polyethylene and etiennette.

Among other films, well-known specialist and applicable to the present invention, it is possible (similarly, to name Hostaphanseries RN (RN23, RN25, RN75 or RE75).

Used detachable protective film are films designed to protect the adhesive surface intended to be placed on the skin, percutaneous system after manufacture and during storage.

From the detachable protective films, well-known specialist will use preferably a polyester film, one surface of which is treated with fluorocarbons, such as Scotchpak1022 (firm ZM Health Care Limited), or transparent polyester film SiloxB5Y/0 (firm AkrosilTM), one surface of which is subjected to anti-adhesive processing silicones Bio-release from Dow-Corning.

Especially preferred subject of the invention are devices such as described above, containing in series (Fig.1):
- protective film (a),
- single-layer matrix (2), such as described above,
- detachable protective film (b).

Especially preferred subject of izobreteny /> double - layer matrix ((2) and (3)), such as described above,
- detachable protective film (b).

Particularly preferably, the subject invention are devices such as described above, containing in series (Fig.3):
- protective film (a),
three - layer matrix ((1), (2) and (3)), such as described above,
- detachable protective film (b).

Preferably, the protective film are opaque protective film Scotchpak1006, and a detachable protective film are detachable protective film Scotchpak1022.

These percutaneous systems allow you to select Trimegestone with percutaneous flow ex vivo on human skin, concluded between 0.1 and 3 mgcm-2h-1.

Devices such as described above, can be any shape: round, oval, rectangular or square. The area lies between 5 and 50 cm2.

Trimegestone may be associated with estrogen.

Thus, the subject invention equally is a device designed for percutaneous introduction of progestogenic, such as apteekista composed of two parts (a) and (B).

Among the preferred estrogen can be called 17-beta-estradiol, esters of 17-beta-estradiol, such as estradiolvalerate, estradiolcreamas, estradioldiscount and estradiolvalerate, ethinyl estradiol, estrone, estrogen "horse of origin, such as Premarinor a combination of these compounds.

Preferably, the subject invention is a device such as described above, wherein the estrogen is 17-estradiol.

Preferably, the subject invention is a device such as described above, characterized in that the two branches (a) and (B):
- supported the same detachable protective film (b),
and separated from one another by a gap or barrier from 1 to 10 mm,
Department (a) contains the organosilicon polymer matrix, enriched Trimegestone and/or one or more pharmaceutically acceptable derivatives Trimegestone, such as described above,
- Department (B) contains an adhesive polymer matrix, enriched with estrogen,
while each of these matrices, respectively, are covered with a protective film (a) and (a'), the same or different (Fig.4).

The Department is m2.

Detachable protective film supports, thus, two independent compartments, containing, respectively, Trimegestone and estrogenic compound.

Removing once this detachable protective film, get two independent patches that need to be put on the skin or mucous membrane in such a way as to have simultaneous and separate administration of Trimegestone and estrogenic compounds. Similarly, between the two branches (a) and (B) may provide one or more fixtures, the two patches remained United, when the detachable protective film will one day be removed.

Polymer matrix that contains estrogenic compound is chosen among commercial and/or well-known specialist of the polymers. It is, in particular, the polymers or copolymers formed by systems polyisobutylene or polyacrylic chains, copolymers of ethylene and vinyl acetate (EVA) or more organosilicon polymers. If necessary, these polymers can be added hydrophilic polymer and/or absorption promoter and/or a plasticizer and/or other additives known to the expert, to improve criteria flow, adhesion and stabiles the system with the tank.

The size of the gap, making it possible to separate the two areas can be enclosed between 1 and 10 mm, Preferably it lies between 2 and 4 mm

Under the barrier involve physical separator made of a suitable material. Its width is determined depending on the effectiveness of preventing diffusion and method of manufacture. Its width can be made between 1 and 10 mm, Preferably it will be a total of between 1 and 3 mm

When estrogenic compound is estradiol enriched matrix is preferably a single-layer matrix, formed by a mixture of 2-ethylhexyl acrylate and vinyl acetate enriched with estradiol, which, if necessary, add a hydrophilic polymer. In this case, it is especially the copolymer Gelva737, containing 72% 2-ethylhexyl acrylate and 28% vinyl acetate. The hydrophilic polymer is preferably polyvinylpyrrolidone. It is, in particular, Kollidon30 or 90F.

The number of seconds entered in the polymer matrix, such as defined above, made, preferably, between 1 wt.% and 10 wt.%.

The subject of the invention, in CAS 1, composed of
- detachable protective film (b) supporting two branches (a) and (B) separated from one another by a gap or barrier from 1 to 10 mm,
- branch (A), containing a single-layer matrix, covered with a protective film (a) formed of silicone polymer enriched Trimegestone and/or one or more pharmaceutically acceptable derivatives Trimegestone and, if necessary, a plasticizer,
and branch (B), containing a single-layer matrix, covered with a protective film (a') and formed by the copolymer of 2-ethylhexyl acrylate and vinyl acetate enriched with estradiol and, if necessary, a hydrophilic polymer.

DUAL PATCH 2, composed of
- detachable protective film (b) supporting two branches (a) and (B) separated from one another by a gap or barrier from 1 to 10 mm,
- branch (A), containing two-layer matrix, covered with a protective film (a), while
a first layer formed of silicone polymer enriched Trimegestone and/or one or more pharmaceutically acceptable derivatives Trimegestone,
b) a second layer, intended for coupling with the skin, also formed of silicon by polyaluminum 2-ethylhexyl acrylate and vinyl acetate, enriched with estradiol and, if necessary, a hydrophilic polymer.

The subject of the invention are, in particular, devices such as described above, containing:
DUAL PATCH 1A, composed of
- detachable protective film (b) supporting two branches (a) and (B) separated from one another by a gap or barrier from 1 to 10 mm,
- branch (A), containing a single layer of the matrix is covered with an opaque protective film (a) and formed 80-99 wt.% organosilicon polymer having a high bonding strength, enriched 1-10 wt.% Trimegestone and/or one or more pharmaceutically acceptable derivatives, and 0-10 wt.% silicone oil or CetiolS,
and branch (B), containing a single-layer matrix, covered with a protective film (a') and formed 60-99 wt.% Gelva737 enriched 1-10 wt.% estradiol and 0-30 wt.% Kollidon.
DUAL PATCH 2A, composed of
- detachable protective film (b) supporting two branches (a) and (B) separated from one another by a gap or barrier from 1 to 10 mm,
- branch (A), containing TLD the ski polymer, having a high bonding strength, which introduced 1-10 wt.% Trimegestone and/or one or more pharmaceutically acceptable derivatives,
b) a second layer, intended for coupling with the skin, also formed of silicone polymer having a high bonding strength,
and branch (B), containing a single-layer matrix, covered with a protective film (a') and formed 60-99 wt.% Gelva737 enriched 1-10 wt.% estradiol and 0-30 wt.% Kollidon90F.

This "dual patch" allows you to:
to unite in one and the same product Trimegestone and estrogenic compound that when hormone replacement treatment menopause and in particular for the prevention or treatment of osteoporosis should be introduced simultaneously, separately and evenly spaced in time,
- resolve differences in the stability of active substances in the environment of polymers used for enriched layers: Trimegestone unstable in the matrix used for estradiol,
- enter each active ingredient in optimal conditions to obtain pharmaceutically acceptable percutaneous flow, and fully Izbira concerns doses and the day of the introduction of one and the other active substance (pre-dose), still avoiding the purchase and handling two individual patches.

Within ESTRO-progestative combinations of drugs this last point is especially important for hormone replacement treatment menopause, and in particular for the prevention or treatment of osteoporosis or for contraception.

In addition, it has the following advantages: putting on the same detachable protective film two independent matrix, you can easily:
to optimize independently the compositions of mixtures containing active ingredients (the choice of the polymer carrier, the choice of promoter absorption, the choice of the hydrophilic polymer, the choice of plasticizer, optimization of surface density), depending on the desired adhesion and flow,
to optimize independently of the concentration of active substances, depending on the criteria of stability, desirable percutaneous flows, as well as the prescribed doses,
to obtain Department that have the same or different sizes, and this despite the simple method of manufacture.

Equally the subject of the invention is a device ("combined patch"), composed sequentially of the following items:
- casinoaustralia,
- polyester film (b) having the same dimensions as the Department (A), and imposed on him,
- branch (A), formed of silicone polymer matrix, enriched Trimegestone and/or one or more pharmaceutically acceptable derivative such as defined above, with the Department (A) has a size smaller than the size of the Department (B), such as half, and preferably centered with respect to this branch (B),
- detachable protective film (b).

Department (A) has a size smaller than the size of the Department (B), so that the matrix enriched with estrogen, located above the matrix, enriched Trimegestone, could equally be in direct contact with the skin. Thus, the estrogenic compound will diffuse directly through this place. For example, the Department (A) may have a size of 15 cm2and (B) the area of 30 cm2(see Fig.5).

Preferably, the separation (A) is composed of two-layer or three-layer matrix, such as defined above.

"The combined patch" with a two-layer matrix can be used, for example, 4 days, and "combined patch" with a three-layer matrix can be using in the coating. The General principle is as follows.

A solution of silicone polymer in non-polar organic solvent, such as heptane, mixed with the active substance and any other additive and receive a suspension or adhesive solution (2), which is sprinkled on the detachable protective film or a protective film. After, if necessary, prior to evaporation under suction fume hood at room temperature, the film is dried at a temperature of between 40oWith the 100oWith until complete evaporation of the solvent. The operation of this type is repeated in an appropriate manner, depending on the desired number of layers, then cut percutaneous system on the plate, called patches, the area of these patches can vary from 1 to 50 cm2. Under adhesive solution (1) or (3) involve solutions of organosilicon polymer in non-polar organic solvent, such as heptane, which do not contain active substance.

"Single-layer" patch can be made as follows:
1 - detachable protective film (b) pre-applied adhesive solution layer (2) in heptane, which introduced Trimegestone, and if necessary, a plasticizer, then dried,
3 - cut percutaneous system on the plate, the area of which is between 5 cm2and 50 cm2.

The "double" the patch can be made as follows:
1 - pre-applied
a) a detachable protective film (b) solution of the adhesive layer (3) in heptane, then dried,
b) on a temporary detachable protective film (b') solution of the adhesive layer (2) in heptane, which introduced Trimegestone, then dried,
2 - implement the overlay structure adhesive layer (2), enriched Trimegestone/temporary detachable protective film (b')" structure, "adhesive layer (3)/detachable protective film (b)",
3 - carry out the separation of the temporary protective film (b'),
4 - carry out the application of structures "adhesive layer (2)/adhesive layer (3)/detachable protective film (b) on the protective film (a),
5 - cut percutaneous system on the plate, the area of which is between 5 cm2and 50 cm2.

Thus, get the patch, characterized in that it contains (Fig.2):
- protective film (a),
- adhesive layer, enriched with Trimegestone (2),
- adhesive layer between the enriched layer and a detachable protective film (3),
- detachable protective film (b).

"Sandwich" the patch can what are the solution of the adhesive layer (1) in heptane, then dry,
b) on a temporary detachable protective film (b) pre-applied adhesive solution layer (2) in heptane, which introduced Trimegestone, then dried,
b) for detachable protective film (b) pre-applied adhesive solution layer (3) in heptane, then dried,
2 - implement the overlay structure adhesive layer (1)/temporary detachable protective film (b') on the protective film (a),
3 - carry out the separation of the temporary protective film (b'),
4 - perform the overlay structure adhesive layer (2), enriched Trimegestone/temporary detachable protective film (b)" on the structure of the "adhesive layer (1)/protective film (a)",
5 - carry out the separation of the temporary protective film (b'),
6 - finally, perform the last operation of the overlay structure system adhesive layer (3)/detachable protective film,
(b)" structure "enriched layer (2)/adhesive layer (1)/protective film (a)",
7 - cut percutaneous system on the plate, the area of which is between 5 cm2and 50 cm2.

Thus, get the patch, characterized in that it contains (Fig.3):
- detachable protective film (b),
- adhesive layer between the protective film and enriched layer (3),
- adhesive layer is the third layer) (1),
- protective film (a).

Device "dual patch" that allows percutaneous introduction of Trimegestone in combination with estrogen, such as described above can be manufactured as follows:
Phase I: for the manufacture of the patch corresponding to the branch (A),
1 - on a protective film (a) is applied an adhesive layer of silicone polymer enriched Trimegestone, and, if necessary, one or more additives
2 - evaporate the solvent to obtain the ensemble matrix, enriched Trimegestone/protective film (a) corresponding to the branch (A),
3 - carry out the imposing structure of the matrix, enriched Trimegestone/protective film (a)", on detachable protective film (b'),
4 - cut out a patch from 5 to 50 cm2.

Phase II: for the manufacture of the patch corresponding to the branch (B),
1 - on a protective film (a') is applied adhesive polymer layer, enriched estrogenic compound, and, if necessary, one or more additives, such as a hydrophilic polymer, an absorption promoter, or a plasticizer,
2 - evaporate the solvent to obtain the ensemble matrix, enriched with estrogen/protective film (a') corresponding to the branch (B),
4 - cut out a patch from 5 to 50 cm2.

Phase III: for the manufacture of "dual patch"
1 - carry out the removal of detachable protective film (b') with the plaster obtained in phase I,
2 is then transferred to the structure of the matrix, enriched Trimegestone/protective film (a)", on detachable protective film (b),
3 - carry out the removal of detachable protective film (b) with the plaster obtained in phase II,
4 is then transferred to the structure of the matrix, enriched with estrogen/protective film (a') on the previous detachable protective film (b), keeping a safe distance from 1 to 10 mm, or after the introduction of the barrier between the two compartments (a) and (B).

Thus, you receive a "dual patch", characterized in that it contains (Fig.4):
- detachable protective film (b),
- branch (A), formed by the matrix, enriched Trimegestone, such as defined above, and covered with a protective film (a),
- branch (B), formed by the matrix, enriched estrogenic compound and covered with a protective film (a'), with two compartments separated from one another by a gap or barrier from 1 to 10 mm

These methods can be applied equally to esters of Trimegestone, such as defined above.

These These methods, easy to implement and require quite short drying times. Preferably drying is carried out at 60oC for 15 minutes.

The drying is carried out continuously, industrial way.

Conditions of manufacture of the following:
segment I: 35oWith; segment II: 50oWith; segment III: 60oWith segment IV: 80oC.

A method of manufacturing a single-layer patch is particularly simple, since, on the one hand, there is only one layer, then there is no loss of film to transfer the necessary operations naplastovanija and, finally, simplified adjustment towards naplastovany. It is cheap for the reasons mentioned above, but also because it provides high speed of manufacture and requires less of the original product (Trimegestone and excipients). A method of manufacturing a two-layer patch has the advantage in relation to the manufacture of single-layer, namely, that there is no need to make a plasticizer.

Trimegestone has a very high affinity to the progesterone receptor (6-7 times higher than that of progesterone). At the same time it has a very low affinity to the androgen receptor and has no affinity for the estrogen receptor (<0,02). In vivo studies podtverjdeny, androgenic, glucocorticoid, antiglucocorticoid and estrogenic activity. But he has antimineralocorticoid and antiandrogenna activity. Trimegestone in the form of a patch is, therefore, of great interest for therapy.

Plaster containing Trimegestone, according to the invention can be used in the treatment of gynecological disorders caused by luteal insufficiency:
- menstrual disorders and/or disorders of the cycle,
- dysmenorrhea,
- premenstrual syndrome,
- mastodynia, mastitis,
functional bleeding,
- menorrhagia fibromas,
- endometrial hyperplasia,
- disorders premenopause,
- endometriosis
- disorders of menopause,
- contraception
- ovarian dystrophy, by translation of the ovaries in the state of rest,
in the treatment of tumors and cancer.

In combination with estrogen, such as estradiol, progestational drug Trimegestone shows high antiestrogenic activity at the level of the uterus, still not showing any anti-estrogenic activity in bone level. Combination estrogen/Trimegestone according to the invention finds, therefore, used in hormone replacement treatment is new can be called 17-beta-estradiol, esters of 17-beta-estradiol, such as estradiolvalerate, estradiolcreamas, estradioldiscount and estradiolvalerate, ethinyl estradiol, estrone, estrogen "horse of origin, such as Premarinor a combination of these compounds.

Osteoporosis is a pathology that is characterized by quantitative and qualitative weakening of bone tissue, sufficient to lead to vertebral and peripheral fractures, it spontaneously or on the occasion of minor injuries. Although this disease has a multifactorial nature, in women it is the menopause is the predominant factor in bone loss or osteopenia.

This osteopenia manifests as depression and change in the form of spongy bone, resulting in increased fragility of the skeleton and the risk of fractures. Bone loss is greatly accelerated after menopause due to the weakening of ovarian function and reaches 3-5% in the year to slow down after the age of 65.

For therapeutic purposes postmenopausal hormone insufficiency can be compensated for hormone replacement therapy, in which estrogen plays a major role in the protection of bone tissue. the parathas (endometrial hyperplasia, tumors of the mammary glands. . .), which is a big disadvantage and limits its application. Therefore, it should be combined with estrogen progestational drug that can counteract the adverse effects of estrogen on the sexual organs, keeping, however, its positive effects on bone tissue. Combinations of this type are already known and are described, for example, in the following documents: EP-0136011, US 5208225, US 5108995, EP-474374, DE 4019670. However, they have a big disadvantage due to the multiplicity of activities progestative drugs used in combination, and especially their androgenic effects.

The combination of [estrogen/Trimegestone] does not have this inconvenience. In fact, Trimegestone belongs to the class norpregnane progestational drugs, almost devoid of any androgenic activity that entails a good metabolic tolerance.

Combination estrogen/ Trimegestone according to the invention likewise finds its use as a contraceptive. In this case, estrogen particularly preferably is levonorgestrel.

Thus, the subject invention is a device such as described above, for use in the method of introduction of pasona, associated with estrogen, by overlaying the matrix or matrices of the device on the skin or on the mucous membrane of the patient.

Examples of treatment are given below illustrate the invention but do not restrict it.

1) One Trimegestone
Treatment and
The first patch may be imposed from the 16th to the 18th day of the cycle, the second patch from the 19th to the 21st day of the cycle and the third patch from the 22nd to the 25th day of the cycle, or 10 days in the cycle.

Treatment b
The first patch may be imposed from 5-th to 8-th day of the cycle, the second patch from the 9th to the 12th day of the cycle, the third patch from the 13th to the 16th day of the cycle, the fourth patch from the 17th to the 21st day of the cycle, the fifth patch from the 22nd to the 25th day of the cycle, or 21 days in the cycle.

Continuous treatment Trimegestone can also be used.

2) Trimegestone in combination with estradiol
In the framework of hormone replacement treatment menopause and, in particular, in the prevention and treatment of osteoporosis. Estradiol may be in the form of tablets or in the form of a patch.

The introduction of Trimegestone consistently and estradiol continuously:
Treatment and
Introduction estradiol continuously (cycles of 28 days without a break between cycles) at a dose of from 25 to 200 mcg per day and Trimegestone, 14 posedness at a dose of from 25 to 200 mcg per day and Trimegestone, last 14 days of administration of estradiol at a dose of from 0.05 to 2.5 mg per day. Treatment off for 2-3 days per month at the end of each cycle of 28 days.

Treatment
Introduction estradiol 28 days a month at a dose of from 25 to 200 mcg per day and Trimegestone, the first 14 days of administration of estradiol at a dose of from 0/05 to 2.5 mg per day. The treatment appointed or without a break between each cycle of 28 days, or with a break for 2-3 days per month at the end of each cycle.

Treatment g
Introduction estradiol 25 days a month at a dose of from 25 to 200 mcg per day and Trimegestone at a dose of from 0.05 to 2.5 mg per day for 11-14 last days of administration of estradiol. The treatment is interrupted for 5-6 days at the end of each cycle of 25 days.

Continuous introduction of Trimegestone and estradiol
Continuous introduction of estradiol at a dose of from 25 to 200 mcg per day and trimegestone patch at a dose of from 0.05 to 2.5 mg per day. No interruption of treatment.

3) Trimegestone in combination with ethinyl estradiol
In the use as a contraceptive. Appoint a continuous combination trimegestone patch and ethinyl estradiol from 21 to 28 days cycles. Thus, this treatment requires consistent blending 3-8 patches Trimegestone and receiving ethinyl estradiol 21-28 days/experimentalnoy part. The following examples illustrate the invention, but not limit it.

EXAMPLE 1:
A single layer of plaster containing Trimegestone
- Opaque protective film Scotchpak 1006 thickness 702 μm (a),
Layer 94 wt.% organosilicon polymer BIO-PSA, enriched with 3 wt. % Of trimegestone and 1 wt.% silicone oil thickness from 50 to 60 μm (2),
- Detachable protective film Scotchpak 1022 thickness 701 µm (b).

This patch has an area of 20 cm2and allocates ex vivo 0,800,54 mcgh-1cm-2Trimegestone (see Fig.1).

Given the following matrix:
EXAMPLE 1A: (matrix layer)
The area of the patch 20 cm2surface density of 60 g/m2(see tab.1).

EXAMPLE 1B: (matrix layer)
The area of the patch 20 cm2surface density of 60 g/m2(see tab.2)
EXAMPLE 1B: (matrix layer)
The area of the patch 20 cm2surface density of 60 g/m2(see tab.3)
EXAMPLE 1:
The area of the patch 20 cm2, surface density of 40 g/m2(see tab.4)
EXAMPLE 1D:
The area of the patch 20 cm2surface density of 80 g/m2(see 2 (see tab.6)
EXAMPLE 1G: (matrix layer)
The area of the patch 20 cm2surface density of 60 g/m2(see tab.7)
EXAMPLE 1Z: (matrix layer)
The area of the patch 20 cm2, surface density of 40 g/m2(see tab.8)
EXAMPLE 2:
Two-layer plaster containing Trimegestone
- Opaque protective film Scotchpak 1006 thickness 702 μm (a),
Layer 97 wt. % silicone polymer BIO-PSAhigh instant adhesive ability, enriched with 3 wt.% Trimegestone, of a thickness of from 50 to 60 μm (2),
- Adhesive layer BIO-PSAhigh instant adhesive ability, of a thickness of 65 μm (3),
- Detachable protective film Scotchpak 1022 thickness 701 µm (b).

This patch has an area of 20 cm2and allocates ex vivo 1,29of 0.45 ugh-1cm-2Trimegestone (see Fig.2).

Get the following matrix:
EXAMPLE 2A: (matrix double layer)
The area of the patch 20 cm2surface density 60+30 g/m2(see tab.9)
EXAMPLE 3:
Get the transparent protective film Scotchpak 1006 thickness 702 μm (a),
- Sticking layer BIO-PSAwith the average instant adhesive ability, with the thickness of about 33 μm (1),
- Layer of silicone polymer BIO-PSAwith the average instant adhesive ability (91 wt.%), enriched with Trimegestone (9 wt%), thickness from 50 to 60 μm (2),
- Adhesive layer BIO-PSAhigh instant adhesive ability, with the thickness of about 65 μm (3),
Detachable protective film Scotchpak 1022 thickness 701 µm (b).

This patch has an area of 20 cm2and allocates ex vivo 0,590,33 mcgh-1cm-2Trimegestone (see Fig.3).

Get the following matrix:
EXAMPLE 3A: (Matrix sandwich)
The area of the patch 20 cm2surface density of 30.5+61,5+65 g/m2(see tab.10)
EXAMPLE 4:
Plaster containing Trimegestone in combination with estradiol
Dual patch 1B (see Fig.4)
This patch includes the following features:
- detachable protective film (b) Scotchpak- the compartment (A) containing a single-layer matrix with a thickness of approximately 60 μm, coated with an opaque protective film (a) Scotchpak1006 thickness of approximately 70 μm and formed from 96 wt.% BIO-PSAhigh instant adhesive ability, enriched with 3 wt.% Trimegestone and 1 wt. % silicone oil (7-9120, 12000 SST), surface density equal to 6O g/m2,
and branch (B), containing a single-layer matrix with the thickness of about 76 microns, coated with a protective film (a') Scotchpak1109 thickness of approximately 34 μm or HostaphanRN23 and formed from 73 wt.% Gelva737 enriched 2 wt. % estradiol and 25 wt.% Kollidon90F. The surface density equal to 80 g/m2.

Dual patch 2B
This patch includes the following features:
- detachable protective film (b) Scotchpak1022, characterized in that it supports DV is atrica, covered with a protective film (a) Scotchpak1006,
a) the first layer is enriched with 3 wt.% Trimegestone, formed of 97 wt.% organosilicon polymer BIO-PSAhigh instant adhesive ability,
b) a second layer providing adhesion to the skin, formed from silicone polymer BIO-PSAhigh instant adhesive ability.

In this case, the total surface density equal to 90 g/m2,
and branch (B), containing a single-layer matrix, covered with a protective film (a') Scotchpak1109 or HostaphanRN23, formed from 73 wt.% layer of Gelva737 enriched 2 wt.% estradiol and 25 wt.% Kollidon90F. The surface density equal to 80 g/m2.

Tests on the structure of the patch
Were made the following patches:
(I) a two-layer plaster according to the invention, containing 3 wt.% trimegestone, the surface density of the enriched layer = to 59.822.

(II) a two-layer plaster according to the invention, containing 9 wt.% trimegestone, the surface density of the enriched layer = 59,162,77 g/m2surface density of the adhesive layer = 29,72of 3.31 g/m2.

(III) three-layer plaster according to the invention, containing 9 wt.% trimegestone.

(IVa) single-layer patch according to the invention, containing 3 wt.% trimegestone, the surface density = 61,12/5 g/m2(plasticizer: 1 wt.% silicone oil).

(IV) single-layer patch according to the invention, containing 3 wt.% trimegestone, the surface density = 59,10.9 g/m2(plasticizer: 1 wt.% CetiolS).

(IVC) single-layer patch according to the invention, containing 3 wt.% trimegestone, the surface density = 42,93.0 g/m2(without plasticizer).

(Characterise reflexes IVG) single-layer patch according to the invention, containing 3 wt.% trimegestone, the surface density = 63,03,83 g/m2(without plasticizer).

Test adhesion
Principle:
An instant work of adhesion is determined by pin is of (a compressing force: 5 N, duration 60 s) and measuring the energy required to separate two surfaces. This measurement allows to compare different formulations or to follow changes in adhesion depending on time (see tab.11).

As regards two or three layers of plaster, the dose of the active substance contained in the filled matrix, does not change the instant adhesion. The presence of one or two adhesive layers on the filled matrix definitely improves instant adhesion.

Percutaneous flow ex vivo
Principle:
A fragment of the skin is installed in the cell for percutaneous passage of the cell type, Franz. Percutaneous system paste on the skin from the side of the stratum corneum (Horny layer). The active substance is excreted percutaneous system, overcoming the skin barrier and extracted in perceiving the environment. The amount of active substance in this case determined at equal intervals of time.

Method:
Fragments of skin were obtained when plastic surgery (female chest or stomach).

Before cutting the skin stored at 4oWith physiological solution. After removal of the subcutaneous fat, the skin is treated on the dermatome to a thickness of 300 μm, and then stored at -30oTo use.

Skin p is roughly 15 hours. Then the patch placed on the skin. Percutaneous passage of the beginning of the current track by quantitative determination of Trimegestone in perceiving the environment (see tab.12).

TEST the AFFINITY of TRIMEGESTONE TO HORMONAL RECEPTORS
The Affinity Of Trimegestone (Trim.) compare with other conventional Pro gestimation: medroxyprogesterone (MPA), norethisterone (NE), Promegestone (PROM), gestodene (GEST) and levonorgestrel (LNOR). This affinity study on recombinant human hormone progesterone receptor (hPR), androgen (hAN), glucocorticoid (hGR) and estrogen (hER). These receptors receive the superexpression of the system of the insect cells of baculovirus SF9 according to the methods described in particular in European patent application 0629635. Relative values of affinity to adhesion (OSS) as follows (see tab.13).

Pharmacokinetic study of Trimegestone
After applying 4 three-layer patches with an area of 20 cm2(9% of Trimegestone), respectively, 4, 3, 4, and 3 days, plasma concentrations of trimegestone remains stable until the removal of the last patch when the average value of 1.37 mg/ml, Therefore, the flow of Trimegestone has an average value of 0.4 mg/day patch. Level plasmatechnologie hormone (FSH) and luteinizing hormone (LH) decrease accordingly, at 31% and 38% after 14 days of application (antigonadotropin impact of Trimegestone).

In conclusion, patches Trimegestone according to the invention, the blend within 14 days (1 per every three days), emit a constant stream of Trimegestone with stable plasma concentrations of Trimegestone and good local tolerance.

Fig. 1: Structure of a single layer of plaster (20 cm2)
(a) Protective film
(2) Adhesive enriched matrix
(b) Detachable protective film
Fig. 2: Structure of a two-layer patch (20 cm2)
(a) Protective film
(2) Adhesive enriched matrix
(3) Adhesive layer
(b) Detachable protective film
Fig. 3: Structure of three-layer bandage (20 cm2)
(a) Protective film
(1) Anchoring layer
(2) Adhesive enriched matrix
(3) Adhesive layer
(b) Detachable protective film
Fig. 4:
(B) a Compartment containing estradiol (15 cm2)
(A) the Department, containing Trimegestone (a') a Protective film
(a) Protective film
(b) Detachable protective film
Fig. 5:
(B) a Compartment containing estradiol
(A) the Department, containing Trimegestone
(a) Protective film
(b) Detachable protective film

2. The adhesive polymer matrix p. 1, characterized in that it contains 1-10 wt. % Of trimegestone.

3. The adhesive polymer matrix p. 1, characterized in that the matrix contains a single layer (2) formed of silicone polymer containing Trimegestone and/or one or more pharmaceutically acceptable derivatives of Trimegestone and, if necessary, a plasticizer.

4. The adhesive polymer matrix p. 3, characterized in that it consists of 80-99 wt. % silicone polymer having a high bonding strength, 1-10 wt. % Of trimegestone and/or one or nesasana.

5. The adhesive polymer matrix p. 4, characterized in that it consists of 96 wt. % silicone polymer having a high instantaneous adhesive ability 3 wt. % Of trimegestone and 1 wt. % silicone oil.

6. The adhesive polymer matrix p. 1, characterized in that the matrix contains two successive layers: a first layer (2) formed of silicone polymer containing Trimegestone and/or one or more pharmaceutically acceptable derivatives of Trimegestone, b) the second layer (3), an adhesive layer which is in contact with the skin, also formed of silicone polymer.

7. The adhesive polymer matrix p. 6, characterized in that a first layer is composed of 90-99 wt. % silicone polymer having a high bonding strength, 1-10 wt. % Of trimegestone and/or one or more pharmaceutically acceptable derivatives of Trimegestone, b) the second layer is also formed of silicone polymer having a high bonding strength.

8. The adhesive polymer matrix p. 7, characterized in that a first layer composed of 97 wt. % silicone polymer having a high instantaneous adhesive ability, and 3 wt. % Trismegist what capacity.

9. The adhesive polymer matrix p. 1, characterized in that the matrix contains three successive layers: a first layer (1), called anchoring layer formed of silicone polymer, b) a second layer (2) formed of silicone polymer enriched Trimegestone and/or one or more of its pharmaceutically acceptable derivatives, and a third layer (3), an adhesive layer, which should be on the skin, also formed of silicone polymer.

10. The adhesive polymer matrix p. 9, characterized in that the first layer is formed of silicone polymer, with an average bonding strength, the second layer is formed on 90-99 wt. % organosilicon polymer having an average bonding strength, enriched 1-10 wt. % Of trimegestone and/or one or more pharmaceutically acceptable derivative, the third layer is formed of silicone polymer having a high bonding strength.

11. The adhesive polymer matrix under item 9 or 10, characterized in that the first layer is formed of silicone polymer, with an average instant adhesive ability; a second layer formed on 91 wt. % poly silicon is sovan organosilicon polymer, high instant adhesive ability.

12. A device for percutaneous introduction of progestogenic, characterized in that it successively composed of a protective film (a), of a matrix, as defined in paragraph 1 or 2, the detachable protective film (b).

13. The device according to p. 12, characterized in that the matrix is the same as defined in one of the paragraphs. 3-5.

14. The device according to p. 12, characterized in that the matrix is the same as defined in one of the paragraphs. 6-8.

15. The device according to p. 12, characterized in that the matrix is the same as defined in one of the paragraphs. 9-11.

16. The device according to p. 12, characterized in that, in addition, it contains a matrix enriched with estrogen, and this device consists of two parts (a) and (B).

17. The device according to p. 16, wherein the estrogenic compound is chosen among 17-beta-estradiol, esters of 17-beta-estradiol, such as estradiolvalerate, estradiolcreamas, estradioldiscount and estradiolvalerate, ethinyl estradiol, estrone and estrogen "horse of origin, such as Premarinor combinations of these compounds.

18. The device according to p. 16, wherein es is I (a) and (B) supported the same detachable protective film (b), and separated from one another by a gap or barrier from 1 to 10 mm, the Department (a) contains the organosilicon polymer matrix, enriched Trimegestone and/or one or more pharmaceutically acceptable derivatives, such as defined in any of paragraphs. 1-11, Department of (B) contains an adhesive polymer matrix, enriched with estrogen, and each of these matrices is covered, respectively, a protective film (a) and (a'), the same or different.

20. The device according to p. 19, characterized in that Department (a) contains the single-layer matrix, such as defined in paragraph 3, and section (B) contains a single layer of the matrix formed by the copolymer of 2-ethylhexyl acrylate and vinyl acetate enriched with estradiol and, if necessary, a hydrophilic polymer.

21. The device according to p. 19 p. 20, characterized in that Department (a) contains the single-layer matrix, such as defined in paragraph 4 or 5, and division (B) contains a single-layer matrix formed on 60-99 wt. % copolymer of 2-ethylhexyl acrylate (72%) and vinyl acetate (28%), enriched 1-10 wt. % estradiol, and 0-30 wt. % polyvinylpyrrolidone.

22. The device according to p. 19, characterized in that Department (a) contains the two-layer matrix, such as defined in paragraph 6, section (B) with whom Adeola and if necessary, a hydrophilic polymer.

23. The device according to p. 19 or 22, characterized in that Department (a) contains the two-layer matrix, such as defined in paragraph 7 or 8, and division (B) contains a single-layer matrix formed on 60-99 wt. % copolymer of 2-ethylhexyl acrylate (72%) and vinyl acetate (28%), enriched 1-10 wt. % estradiol and 0-30 wt. % polyvinylpyrrolidone.

24. The device according to p. 16, characterized in that it is consistently composed of the following elements: protective film (a) Department (B), formed by the adhesive polymer matrix, enriched with estrogen, such as estradiol, polyester film (b) having the same dimensions as the Department (A), and imposed on him, branch (A), formed of silicone polymer matrix, enriched Trimegestone and/or one or more pharmaceutically acceptable derivative such as defined above, with the Department (A) has a size smaller than the size of the Department (B), such as half, and it is preferably centered with respect to this branch (B), detachable protective film (b).

25. The device according to p. 24, characterized in that the matrix containing Trimegestone, is a two-layer matrix, such as ova for intradermal injection progestogenic, characterized in that the manufacture of the device under item 12 or p. 13 includes the following stages: 1) detachable protective film (b) pre-applied adhesive solution layer (2) in heptane, which introduced Trimegestone, and if necessary, a plasticizer, then dried, 2) exercise overlay structure adhesive layer (2)/ detachable protective film (b) on the protective film (a), (3) cut percutaneous system on the plate, the area of 5-50 cm2.

27. A method of manufacturing a device for percutaneously introducing progestogenic, characterized in that the manufacture of the device under item 12 or 13 includes the following stages: 1) protective film (a) a pre-applied adhesive solution layer (2) in heptane, which introduced Trimegestone, and if necessary, a plasticizer, then dried, 2) exercise overlay structure adhesive layer (2)/ protective film (a) on detachable protective film (b), 3) cut percutaneous system on the plate, the area of 5-50 cm2.

28. A method of manufacturing a device for percutaneously introducing progestogenic, characterized in that the manufacture of the device under item 12 or 14 includes the following stages: 1) pre-applied) on detachable protective film (b) rest (2) in heptane, which introduced Trimegestone, then dried, 2) exercise overlay patterns: "adhesive layer (2) containing Trimegestone/temporary detachable protective film (b')" structure, "adhesive layer (3)/detachable protective film (b)", 3) carry out the separation of the temporary protective film (b'), 4) perform the overlay structure adhesive layer (2)/adhesive layer (3)/detachable protective film (b) on the protective film (a), 5) cut percutaneous system on the plate, the area of 5-50 cm2.

29. A method of manufacturing a device for percutaneously introducing progestogenic, characterized in that the manufacture of the device under item 12 or 15 includes the following stages: (1) (a) on a temporary detachable protective film (b') a pre-applied adhesive solution (1) in heptane, then dried, b) on a temporary detachable protective film (b) pre-applied adhesive solution layer (2) in heptane, which introduced Trimegestone, then dried, in) on detachable protective film (b) pre-applied adhesive solution layer (3) in heptane, then dried, 2) exercise overlay structure adhesive layer (1)/temporary detachable protective film b') on the protective film (a), (3) carry out the separation of the temporary protective film (b'), 4) done by the" structure "of the adhesive layer (1)/protective film (a)", 5) carry out the separation of the temporary protective film (b), 6) finally, perform the last operation of the overlay structure adhesive layer (3)/detachable protective film (b)" on the structure of the "adhesive layer Trimegestone (2)/ adhesive layer (1)/protective film (a), 7) cut percutaneous system on the plate, the area of 5-50 cm2.

30. A method of manufacturing a device for percutaneously introducing progestogenic, characterized in that the manufacture of the device under item 19 includes the following stages: stage 1: preparation of the patch corresponding to the branch (A), 1) protective film (a) is applied an adhesive layer of silicone polymer enriched Trimegestone and, if necessary, one or more additives, 2) evaporate the solvent to obtain the structure of the matrix, enriched trimegestone/protective film (a) corresponding to the branch (A), (3) carry out the imposing structure of the matrix, enriched with trimegestone/protective film (a)", on detachable protective film (b'), 4) cut out a patch from 5 to 50 cm2; phase II: for the manufacture of the patch corresponding to the branch (B), 1) protective film (a') is applied adhesive polymer layer that contains estrogenic compound and, if necessary is ctory matrix, containing estrogen/protective film (a')" corresponding to the branch (B), 3) perform the overlay structure matrix containing estrogen/protective film (a')" detachable protective film (b) 4) cut out a patch from 5 to 50 cm2; stage III: for the manufacture of "dual patch" 1) carry out the removal of detachable protective film (b') with patch from round 1, 2) then transfer structure, the matrix containing Trimegestone/protective film (a)", on detachable protective film (b), 3) carry out the removal of detachable protective film (b) with the patch, obtained in stage II, 4) then transferred to the structure of the matrix containing estrogen/protective film (a')/previous detachable protective film (b), keeping a safe distance from 1 to 10 mm, or after the introduction of the barrier between the two compartments (a) and (B).

31. Device according to any one of paragraphs. 12-16 for use in the method of administration to a patient or Trimegestone and/or one or more pharmaceutically acceptable derivatives of Trimegestone or Trimegestone associated with estrogen, by overlaying the matrix or matrices of the device on the skin or on the mucous membrane above the patient.

32. Esters of Trimegestone in position 21, characterized those who

 

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