KR100496109B1 - Transdermal Systems Containing Two Active principles in Separate Compartments, Their Method of Preparation and Application as Medicine - Google Patents

Abstract

The present invention,

A compartment (A) containing a matrix comprising the active ingredient (I), a compartment (B) containing a matrix comprising the active ingredient (II),

Each matrix is respectively coated with the same or different protective films; Characterized in that compartment (A) is separated from compartment (B) by an empty space of 1 to 10mm, compartments (A) and (B) are supported by the same peeling protective film (b),

A device for transdermal administration of an active ingredient (I) and an active ingredient (II), consisting of two compartments (A) and (B).

Description

Transdermal Systems Containing Two Active principles in Separate Compartments, Their Method of Preparation and Application as Medicine}

Example 1:

Patches containing trimegeston in combination with estradiol

Dual Patch 1b

This double patch,

A Scotchpack® 1022 peeling protective film for supporting two compartments (A) and (B), each separated at a spacing of 2 to 4 mm,

-Strong instantaneous adhesion silicone polymer 96% w / coated with Scotchpack® 1006 opaque protective film, containing 3% w / w of trimegeston and 1% of silicone fluid (7-9120, 12000 cSt) compartment (A) comprising a monolayer matrix consisting of w and having a gram number of 60 g / m 2, and

Gelbar® coated with Scotchpack® 1109 or Hostaphan® RN23 protective film and containing 2% w / w of estradiol and 25% of collidone® A compartment (B) comprising a monolayer matrix composed of 737 layers 73% w / w and having a gram number of 80 g / m 2.

Dual Patch 2b

This double patch,

A Scotchpack® 1022 peeling protective film for supporting two compartments (A) and (B), each separated at a spacing of 2 to 4 mm,

A gram number consisting of 97% w / w of silicone polymer having a two-layer matrix coated with Scotchpack® 1006 protective film and loaded with trimegestone 3% w / w and having strong instantaneous adhesion; b) a first layer of g / m ² , b) a compartment attached to the skin, consisting of a silicone polymer with strong adhesion, consisting of a second layer of 30 g / m 2, with a total number of grams of 90 g / m 2 ( A), and

Gelbar® 737 layer 73% w / w, coated with Scotch Pack 1109 or Hostaphan RN23 protective film, containing 2% w / w of estradiol and 25% of Collidone® 90F Comprising a monolayer matrix consisting of, characterized in that the compartment (B) having a gram number of 80g / ㎡.

Example 2: Amount of Active Ingredient in Each Compartment

The amount (x) of the active ingredient can be expressed by the following general formula.

x (mg / patch) = p.M / 100 = p.G.S / 100

Where

G (mg / cm 2) represents the total number of grams of the coated mass (sum of the number of grams of each coating layer in case of a multilayer patch),

S is the surface area of the patch (cm 2),

p is the percentage of active ingredient in the set of coated mass (% w / w),

Therefore, the coated mass M (mg / patch) is calculated as M = G.S.

Compartment (A) Compartment (B) G (mg / cm 2) 6 8 p (%) 3 2 S (㎠) 5 5 S (㎠) 50 50 Min x (mg / patch) 0.9 0.8 Max x (mg / patch) 9 8

Reference to Figure 1:

(B) a compartment containing the active ingredient (II)

(A) a compartment containing the active ingredient (I)

(a) protective shield

(a ') shield

(b) Peeling protective film

The present invention relates to a novel device for the administration of the active ingredient in combination with other active ingredients via the transdermal route and to a method of making the same.

The Applicant discloses a novel method for preventing or treating a disease requiring double treatment by the active ingredient (I) and the active ingredient (II) combined in a single entity that can be administered simultaneously, separately and for a period of time. To study the herbal form,

The problem of differences in the stability of the active ingredients in the polymers used in the loaded layer is solved,

Each active ingredient is administered under optimal conditions under which a pharmaceutically acceptable transdermal fluid is obtained and all interactions between the compound and the matrix of the other compound can be avoided,

There is no need to purchase and process two separate patches, to meet the defined requirements regarding the dosage and date of administration of each active ingredient (dosage precursor).

In the estrogen-progestogen combination, the last of the above is particularly important in the case of prophylactic hormone replacement therapy and especially in the prevention or treatment of osteoporosis, as well as in contraception.

To the best of our knowledge, the herbal forms used to deliver the two active ingredients simultaneously, separately and for a period of time are not available in the form proposed in this patent application.

According to the state of the art in the art, the active ingredient

Present in two separate patches, or

Or are mixed in the same matrix,

Present in the nested matrix, or

Present in adjacent matrices on the same protective film.

If the active ingredient is present in two separate patches, the prescription requiring simultaneous application of the two patches may not be strictly followed, but if these two patches are present in a single unit, the patient will apply them simultaneously. This avoids all the risks of skipping applications. This also makes it easier to simultaneously change two patches during a long treatment period that requires replacement of the patches. Thus, it avoids all the risks that one or more of the active ingredients will be over or unadministered compared to the other.

If the compounds are mixed in the same matrix, problems of stability may appear. Moreover, there may be problems of interaction or competition that modify the flow of one of the active ingredients to be superior to the other active ingredients.

If each component is located in the nested matrix, the above-described problems may appear the same.

If the matrices are adjacent, there may be a problem of moving or distributing from one matrix to another, so there may be a risk that the flow and / or stability of one of the active ingredients may change to be superior to the other active ingredient.

Therefore, the present invention

A compartment (A) containing an adhesive polymer matrix comprising the active ingredient (I), to which one or more additives can optionally be added,

A compartment (B) containing an adhesive polymer matrix comprising the active ingredient (II), to which one or more additives can optionally be added, wherein each matrix is the same or different protective films (a) and (a ' Rapidly coated with;

Compartment (A) is separated from compartment (B) by an empty space of 1 to 10 mm, compartments (A) and (B) are supported by the same peeling protective film (b),

A device for transdermal administration of active ingredient (I) and active ingredient (II), comprising two compartments (A) and (B) (see FIG. 1).

In each polymer matrix containing the active ingredient, hydrophilic additives and / or absorbent accelerators and / or plasticizers and / or any other additives known to those skilled in the art for improving fluidity, adhesion and transdermal system stability properties. Can be added.

According to the invention, the surface area of compartment A is 5 to 50 cm ^2, and the surface area of compartment B is 5 to 50 cm ² .

In order to more easily distinguish the two patches or for the reason of the required dosage, the surfaces of each matrix (A) and (B) may be different.

The apparatus described above may be in any form. Each compartment (A) or (B) can also be of any shape, including round, oval, rectangular or square.

The peeling protective film (b) is characterized by supporting two separate compartments (A) and (B) each containing the active ingredient (I) and the active ingredient (II).

Once this release protective film is removed, two separate patches are applied to the skin or mucosa so that the administration of the active ingredient (I) and the active ingredient (II) is developed simultaneously, individually or over a period of time.

According to the invention, one or more fastening means may be present between the two compartments A and B so that the two patches are connected once the peeling protective film b is removed.

By "bipatch" as the subject of the present invention, it is also possible to administer any combination of medicaments known to those skilled in the art to provide dual treatment.

In addition, the present invention extends to a "double patch" that not only enables the administration of a combination with a synergistic or compensatory effect for a single therapeutic purpose, but also allows the parallel administration of each active ingredient with individual therapeutic purposes .

Accordingly, the "dual patch", which is the object of the present invention, simply solves various problems present in the mixed patch of the prior art, and suggests an appropriate countermeasure against the above-mentioned goal. In addition, by applying two separate matrices to the same release protective film

Individual optimization of formulations containing the active ingredients (selected support polymers, selected absorption promoters, selected hydrophilic polymers, selected plasticizers, optimal grams), as a function of the required adhesion and flow properties

-Individual optimization of the active ingredient concentration as a function of the required stability and percutaneous flow properties and prescription dosage

-Acquisition of compartments of the same or different size by a simple manufacturing process

This facilitating advantage is provided.

Peeling protective film (b)

The release protective film used is a film to protect the adhesive surface fixed to the skin from the transdermal system after manufacture and during storage.

Among the peeling protection films known to those skilled in the art, preferred are polyester films such as Scotchpak® 1022 (manufactured by 3M Health Care Limited) treated with fluorocarbons on one side, or Dow Corning. It is a transparent polyester film Silox® B5Y / O (Akrosil ^™ ), one side of which is anti-adhesion treated using Bio release silicones.

Adhesive polymer matrix

Adhesive polymer matrices containing the active ingredient are selected from a number of polymers that are commercially available and / or known to those skilled in the art. These are in particular polymers or copolymers comprising a network of polyisobutylene or polyacrylic chains, ethylene and vinyl acetate (EVA) copolymers or silicone polymers. Suitably, any additive known to those skilled in the art of transdermal systems may be added to these polymers.

These matrices can be monolayer or multilayer. Compartments A and B may also include storage systems.

Of the polyisobutylene chains used herein, mention is made of Mark Vistanex® (EXXON) or Oppanol® (BASF).

Among the acrylic polymers to mention

Acrylic polymer Gelva® 737 and 788 comprising a mixture of 2-ethylhexyl acrylate and vinyl acetate;

Acronal® acrylic copolymers, in particular Acronal® V205 and DS 3405,

-Durotak® self crosslinked acrylic solution, in particular Durotak® 126-1753, 280-2516, 380-1054,

Eudragit® acrylic and methacryl ester copolymers, in particular Eudragit® RL100 and S100,

There is an aqueous dispersion of neutral methacrylate Eudragit® NE 30D.

Among the silicone polymers which may be mentioned are those having strong instantaneous adhesion (BIO PSA® 7-4301), and those having moderate instantaneous adhesion (BIO PSA® 7-3045, 7-4201 or 7-4202; DOW Corning Health Care Center Europe product).

Adhesion is characterized by peel strength and adhesion strength. This adhesive strength increases from grade "low viscosity" to "medium viscosity" followed by "high viscosity". The parameter used to control this physical property is the ratio of silicone polymer / resin.

Medium adhesion means the ratio of 40/60. Strong adhesive strength means a ratio of 45/55.

Absorption accelerator

Absorption accelerators optionally used are commercially available and / or a certain number of accelerators known to those skilled in the art, in particular diethylene glycol monoalkyl ethers, polyethylene glycol esters of saturated polyglycolated glycerides including glycerides and fatty acids having 6 to 14 carbon atoms. , Monoalkylates having 8 to 12 carbon atoms, 1,2-propane-diol and ethanol, or a combination of these components.

Hydrophilic adhesive

The hydrophilic adhesive optionally used is selected from any number of polymers commercially available and / or known to those skilled in the art, including guar gum, xanthan gum and polyvinyl pyrrolidone.

Plasticizer

The purpose of any plasticizer optionally used is to improve the present bonding process. In particular, they are silicone fluids or cethiol S (dioctyl cyclohexane) or glycerol triacetate.

empty place

The empty space used for separating the two compartments (A) and (B) can be 1 to 10 mm. Preferred sizes are 2 to 4 mm.

Protective films (a) and (a ')

The protective film used is a support layer to which different layers constituting the patch are applied so that a permanent system is obtained. One of the products from 3M's Scotch Pack®, more specifically Scotch Pack® 1109, a membrane that is colored, occluded and flexible, or Scotch Pack® 1006, or pest Products from Hoechst's Hostaphan®, more specifically RN (RN23, RN50 or RN75), are preferably used. The matrix can of course be covered by the same or different protective films.

More specifically, the present invention relates to a device for transdermal administration as described above, wherein compartment A contains a progestogen-like compound and compartment B contains an estrogen compound.

More specifically, the present invention is a progestogen-like agonist is noethin drone (17α) -17-hydroxy-19-norpregin-4-ene-20-yn-3-one, norgestimate ( 17α) -17- (acetyloxy) -13-ethyl-18,19-dinonorgeun-4-ene-20-yn-3-one-3-oxime, norgesterone (17α) -17-hydroxy -19-norpregna-5 (10), 20-dien-3-one, trimegston 17α-methyl-17β- (2-hydroxy-1-oxo-propyl) -estra-4,9-diene- 3-one (21S), promegestone (17β) -17-methyl-17- (1-oxopropyl) estra-4,9-dien-3-one, 13-ethyl-17-hydroxy-18,19 Lenororgestrel type (-) of dinorpregine-4-ene-20-yn-3-one (norgestrel), ST 1435 16-methylene-17α-acetoxy-19-nor-4-pregnene -3,20-dione, hydroxyprogesterone (6α) -17-hydroxy-6-methylpregin-4-ene-3,20-dione, gestoden (17α) -13-ethyl-17-hydroxy -18,19-dinorpregna-4,15-diene-20-yn-3-one, dienoguest 17-hydroxy-3-oxo-19- Le-17α-pregna-4,9-diene-21-nitrile, desogestrel (17α) -13-ethyl-11-methylene-18,19-dinonorpregine-4-ene-20-yne-17 -Ol, ketodesogestrel (17α) -13-ethyl-11-methylene-18,19-dinorpregan-4-ene-20-yn-3-one-17-ol, noethysterone acetate ( 17α) -17-acetoxy-19-norpregin-4-ene-20-yn-3-one, demegestone 17-methyl-19-norpregna-4,9-diene-3,20-dione And a device as described above, characterized in that it is selected from these compound combinations.

More specifically, the present invention relates to a device as described above, wherein the progestogen-like compound is trimegstonone.

Trimegeston (17α-methyl-17β- (2-hydroxy-1-oxo-propyl) -estra-4,9-dien-3-one (21S)) is a potent progester described in European Patent EP-0007823. It is a strogen-like agonist.

More specifically, the present invention provides estrogen compounds in which estrogens and estrogens derived from “horses” such as 17-β-estradiol, ethynyl estradiol, Premarin®, and combinations of these compounds A device as described above, characterized in that it is selected from water.

More specifically, the present invention relates to a device as described above, wherein the estrogen compound is estradiol.

When the estrogen compound is estradiol, the matrix contained is preferably a monolayer matrix comprising 2-ethylhexyl acrylate and vinyl acetate copolymer, to which a hydrophilic polymer can be optionally added. More specifically, this is a Gelva® 737 copolymer containing 72% 2-ethylhexylacrylate and 28% vinyl acetate.

Preferred hydrophilic polymers are polyvinylpyrrolidone. More specifically, this is Kollidon® 30 or 90F.

The amount of estradiol incorporated into the polymer matrix as defined above is from 1% w / w to 10% w / w. This percentage corresponds to the dry weight of the coating after solvent evaporation.

When the progestogen-like compound is trimegeston, the matrix loaded is preferably

A monolayer matrix comprising a silicone polymer to which a plasticizer, such as a silicone fluid, is optionally added, or

a) a first layer comprising a silicone polymer comprising trimegoneton, and

  b) a second layer comprising a silicone polymer, attached to the skin

It is a two-layer matrix consisting of.

In either case, the matrix is preferably composed of a polydimethylsiloxane chain network tissue with strong adhesion, such as BIO PSA® 7-4301.

The amount of trimegeston incorporated into the polymer matrix as defined above is from 1% w / w to 10% w / w. This percentage corresponds to the dry weight of the coating after solvent evaporation.

Since the trimegestone (17α-methyl-17β- (2-hydroxy-oxo-propyl) -estra-4,9-dien-3-one (21S)) is not stable in the matrix used for estradiol, the present invention Devices of interest are particularly suitable for the case of administering trimegeston in combination with estradiol.

More specifically, the present invention

A peeling protective film (b) supporting two compartments (A) and (B) separated by an empty space of 1 to 10 mm,

A compartment (A) which is covered with a protective film (a) and comprises a single-layer matrix composed of a silicone polymer containing trimegonestone and optionally a plasticizer, and

A compartment (B) coated with a protective film (a '), consisting of a 2-ethylhexyl acrylate and a vinyl acetate copolymer, comprising a monolayer matrix comprising estradiol and optionally a hydrophilic polymer

Double patch 1 including; And

A peeling protective film (b) supporting two compartments (A) and (B) separated by an empty space of 1 to 10 mm,

A two-layer matrix composed of a protective film (a), a) a first layer made of a silicone polymer with strong adhesion, containing trimegonestone, b) a second layer attached to the skin, and also made of a silicone polymer Compartment (A), and

A compartment (B) coated with a protective film (a '), consisting of a 2-ethylhexyl acrylate and a vinyl acetate copolymer, comprising a monolayer matrix comprising estradiol and optionally a hydrophilic polymer

Characterized in that the dual patch 2 comprising a, as described above.

More specifically, the present invention

A peeling protective film (b) supporting two compartments (A) and (B) separated by an empty space of 1 to 10 mm,

Strong adhesion silicone, covered with an opaque protective film (a) and containing 1 to 10% w / w of trimegeston and silicone fluid or Cetiol® S 0 to 10% w / w Compartment (A) comprising a monolayer matrix composed of polymer 80-99% w / w, and

Gelba® 737 60-99% w coated with protective film (a ') and containing 1-10% w / w of estradiol and 0-30% w / w of Kollidon® compartment containing monolayer matrix composed of / w (B)

Double patch 1a comprising a; And

A peeling protective film (b) supporting two compartments (A) and (B) separated by an empty space of 1 to 10 mm,

A first layer composed of 90-99% w / w of a silicone polymer with strong adhesion, covered with a protective film (a) and containing a) 1-10% w / w of trimegone, b) attached to the skin And a compartment (A) comprising a two-layer matrix composed of a second layer of silicone polymer also having a strong adhesion, and

Gelbar® 737 60-99% w / w, coated with protective film (a ') and containing 1-10% w / w of estradiol and 0-30% w / w of collidone® Compartment containing configured monolayer matrix (B)

It relates to a device as described above, comprising a dual patch 2a comprising.

According to the present invention, the transdermal flow rate of estradiol is 0.1 to 2.5 μg / cm 2 / h and the transmembrane flow rate of 0.1 to 3 μg / cm 2 / h.

The invention also relates to a method of manufacturing the device as described above.

The production technique of the transdermal system of the present invention is a coating method. The general principle is as follows:

Step I: Preparation of Patches Corresponding to Compartment (A)

1.cover the silicone adhesive polymer layer comprising the active ingredient (I) and optionally at least one additive such as a hydrophilic polymer, an absorption promoter or a plasticizer on the protective film (a),

2. The solvent is evaporated until a set of "matrix / protective membranes (a) with active ingredient (I)" corresponding to compartment (A) is obtained,

3. A set of "matrix / protective film (a) containing active ingredient (I)" is laminated together on the peeling protective film (b '),

4. Cut into 5-50 cm 2 patches.

Step II: Preparation of Patches Corresponding to Compartment (B)

1.covering an adhesive polymer layer comprising the active ingredient (II) and optionally at least one additive such as a hydrophilic polymer, an absorption accelerator or a plasticizer, on the protective film (a '),

2. The solvent is evaporated until a set of "matrix / protective film (a ') with active ingredient (II) corresponding to compartment (B) is obtained,

3. A set of "matrix / protective film (a ') containing active ingredient (II)" is laminated together on the peeling protective film (b' '),

4. Cut into 5-50 cm 2 patches.

Step III: Preparation of "Dual Patch"

1. Peel off the peeling protective film (b ') from the patch obtained in step I,

2. Transfer the set of "matrix / protective film (a) with active ingredient (I)" to the peel protective film (b),

3. Peel off the peeling protective film (b ') from the patch obtained in step II,

4. The set of "matrix / protective film (a ') containing active ingredient (II)" is transferred to the peeling protective film (b) while maintaining a distance of 1 to 10 mm between the compartments (A) and (B).

In this way,

Peeling protective film (b),

A compartment (A) consisting of a matrix loaded with the active ingredient (I) and covered with a protective film (a), and

A compartment (B) consisting of a matrix loaded with the active ingredient (II) and covered with a protective film (a '),

A "double patch" is obtained, characterized in that the two compartments are separated by an empty space of 1 to 10 mm (see Figure 1).

When used in combination with estrogens, progesterone trimeston shows a strong antiestrogenic effect on the uterus without showing any antiestrogenic effect on bone structure.

Thus, the trimegestone / estradiol combination as described herein can be used simultaneously, separately or over a period of time for hormone replacement therapy and for the prevention or treatment of osteoporosis for menopause. It can be used to prevent the effects and symptoms of menopause, such as redness, sweating, vaginal atrophy and dryness, decreased long-term bone structure mass, which increases the risk of urinary symptoms and fractures, and loss of the cardiovascular protective effects provided by estrogen. .

The estrogen / progesterone combinations described herein can also be used as contraceptives.

Finally, the present invention relates to a device as described above for use in a method of delivery of several medicaments by applying two matrices of the device to the skin or mucous membrane of a patient.

<Therapeutic example using double patch>

The following therapeutic examples illustrate the invention but do not limit it. In each dual patch, adhesion lasts 4-7 days.

1. Trimegeston in combination with estradiol

Hormone replacement therapy for menopause, especially the prevention or treatment of osteoporosis

1.1 Sequential Administration of Trimegestone and Continuous Administration of Estradiol

Treatment a.

Continuous administration of estradiol at a dose of 25 to 200 μg / day (28-day cycle without rest between cycles), and trimegeston at a dose of 0.05 to 2.5 mg / day for the last 14 days of each 28-day cycle Was administered continuously. Thus, the trimegestone / estradiol doublepatch according to the present invention was used for the last 14 days (ie 2 to 4 doublepatches).

Treatment b.

Estradiol was administered for 28 days per month at a dose of 25-200 μg / day, and trimegestone at a dose of 0.05-2.5 mg / day for the last 14 days of estradiol administration. Treatment was discontinued for three days each month at the end of each 28-day cycle. Thus, the trimegestone / estradiol doublepatch according to the present invention was used for the last 14 days (ie 2 to 4 doublepatches).

Treatment c.

Estradiol was administered for 28 days per month at a dose of 25-200 μg / day, and trimegonestone patches at a dose of 0.05-2.5 mg / day for the first 14 days of estradiol administration. Treatment was administered without a break between each 28-day cycle or with a break of 2-3 days per month at the end of each cycle. Thus, the trimegestone / estradiol doublepatch according to the present invention was used for the last 14 days (ie 2 to 4 doublepatches).

Treatment d.

Estradiol was administered 25 days per month at a dose of 25-200 μg / day, and trimegestone at a dose of 0.05-2.5 mg / day for the last 11-14 days of estradiol administration. Treatment was discontinued for 5-6 days per month at the end of the 25-day cycle.

Thus, the trimegestone / estradiol doublepatch according to the invention was used for the last 11-14 days (ie 2-4 doublepatches).

1.2 Continuous Administration of Trimegestone and Estradiol

Trimergestone was continuously administered transdermally with estradiol at a dose of 25-200 μg / day and 0.05-2.5 mg / day. There was no time off for treatment. Thus, the trimegestone / estradiol doublepatch according to the present invention was used for 28 days (ie 4 to 8 doublepatches).

2. Trimegeston in combination with ethynylestradiol

Use as a contraceptive

Trimegestone was administered continuously by the transdermal route in combination with ethynylestradiol for 21 to 28 days per cycle. Therefore, this treatment requires the continuous application of three to eight trimegstones / ethynylestradiol doublepatches.

Examples of double patches according to the present invention are shown in the experimental column below. The following examples illustrate the invention but do not limit it.

Claims (10)

A compartment (A) containing an adhesive polymer matrix comprising the active ingredient (I), to which one or more additives can optionally be added, A compartment (B) containing an adhesive polymer matrix comprising the active ingredient (II), to which one or more additives can optionally be added, wherein each matrix is the same or different protective films (a) and (a ' Rapidly coated with; Compartment (A) is separated from compartment (B) by an empty space of 1 to 10 mm, compartments (A) and (B) are supported by the same peeling protective film (b), Device for transdermal administration of active ingredient (I) and active ingredient (II), consisting of two compartments (A) and (B). The device for transdermal administration according to claim 1, wherein the compartment (A) contains a progestogen-like compound and the compartment (B) contains an estrogen compound. 3. The method of claim 2, wherein the progestogen-like compound is noethyne drone (17α) -17-hydroxy-19-norpregin-4-ene-20-yn-3-one, norgestimate (17α) ) -17- (acetyloxy) -13-ethyl-18,19-dinonorgeun-4-ene-20-yn-3-one-3-oxime, norgesterone (17α) -17-hydroxy- 19-Norpregna-5 (10), 20-dien-3-one, trimegstone 17α-methyl-17β- (2-hydroxy-1-oxo-propyl) -estra-4,9-diene-3 -One (21S), promegestone (17β) -17-methyl-17- (1-oxopropyl) estra-4,9-dien-3-one, 13-ethyl-17-hydroxy-18,19- Lenororgestrel-type (-) of dinorpregine-4-ene-20-yn-3-one (norgestrel), ST 1435 16-methylene-17α-acetoxy-19-nor-4-pregnene- 3,20-dione, hydroxyprogesterone (6α) -17-hydroxy-6-methylpregin-4-ene-3,20-dione, gestoden (17α) -13-ethyl-17-hydroxy- 18,19-dinorpregna-4,15-diene-20-yn-3-one, dienoguest 17-hydroxy-3-oxo-19-nor-17α-prop REGNA-4,9-diene-21-nitrile, desogestrel (17α) -13-ethyl-11-methylene-18,19-dinonorpregan-4-ene-20-yne-17-ol, ketodeso Cerrel (17α) -13-ethyl-11-methylene-18,19-dinonorgeun-4-ene-20-yn-3-one-17-ol, noreosterone acetate (17α) -17- Acetoxy-19-norpregin-4-ene-20-in-3-one, demegestone 17-methyl-19-norpregna-4,9-diene-3,20-dione and combinations of these compounds Apparatus characterized in that selected from water. The device according to claim 2 or 3, wherein the progestogen-like compound is trimegstonone. The device of claim 2, wherein the estrogen compound is selected from 17-β-estradiol, ethynyl estradiol, estrone and estrogen from “horse”, and combinations of these compounds. The device according to claim 2 or 3, wherein the estrogen compound is 17-β-estradiol. The method according to claim 1 or 2, Compartment (A) contains a monolayer matrix composed of a silicone polymer, comprising trimeston and optionally a plasticizer, The compartment (B) contains a monolayer matrix composed of 2-ethylhexyl acrylate and vinyl acetate copolymer, comprising estradiol and optionally a hydrophilic polymer. The method according to claim 1 or 2, Compartment (A) comprises a) a first layer consisting of a silicone polymer comprising trimegestone, b) a skin attached to the skin, and also a two layer matrix consisting of a second layer consisting of silicone polymer, The compartment (B) contains a monolayer matrix composed of 2-ethylhexyl acrylate and vinyl acetate copolymer, comprising estradiol and optionally a hydrophilic polymer. 1.cover the silicone adhesive polymer layer comprising the active ingredient (I) and optionally at least one additive such as a hydrophilic polymer, an absorption promoter or a plasticizer on the protective film (a), 2. The solvent is evaporated until a set of "matrix / protective membranes (a) with active ingredient (I)" corresponding to compartment (A) is obtained, 3. A set of "matrix / protective film (a) containing active ingredient (I)" is laminated together on the peeling protective film (b '), 4. Manufacturing step I of a patch corresponding to compartment A, comprising cutting into a patch of 5 to 50 cm 2, 1.covering an adhesive polymer layer comprising the active ingredient (II) and optionally at least one additive such as a hydrophilic polymer, an absorption accelerator or a plasticizer, on the protective film (a '), 2. The solvent is evaporated until a set of "matrix / protective film (a ') with active ingredient (II) corresponding to compartment (B) is obtained, 3. A set of "matrix / protective film (a ') containing active ingredient (II)" is laminated together on the peeling protective film (b' '), 4. Preparation step II of a patch corresponding to compartment (B), comprising cutting into patches of 5 to 50 cm 2, and 1. Peel off the peeling protective film (b ') from the patch obtained in step I, 2. Transfer the set of "matrix / protective film (a) with active ingredient (I)" to the peel protective film (b), 3. Peel off the peeling protective film (b ") from the patch obtained in step II, 4. The step of transferring the "matrices / protective film (a ') with active ingredient (II)" set to the peeling protective film (b) while maintaining a distance of 1 to 10 mm between the compartments (A) and (B) A method of manufacturing an apparatus according to any one of claims 1 to 8, characterized in that it comprises step III of manufacturing a "dual patch". The device according to claim 1 or 2, which is used in a method of delivering several kinds of medicines by applying two matrices of the device to the skin or mucous membrane of a patient.