KR100498199B1 - Novel Devices for Transdermal Administering of Trimegestone - Google Patents

Abstract

The present invention provides a transdermal administration comprising a protective film (a), a single layer containing trimegestone, a matrix of two or three layer structure and an optional matrix containing estrogen, and a peelable protective film (b). The apparatus for this, the manufacturing method of these apparatus, and its use as a medicine are described.

Description

Novel Devices for Transdermal Administering of Trimegestone

<Example 1>

<Trimegestone-containing monolayer patch>

-Scotchpack 1006 opaque protective film (a) with a thickness of 70 ± 2 μm,

A layer 2 of 50-60 μm thick, 94% w / w BIO-PSA silicone polymer with 3% w / w of trimegonestone and 1% w / w of silicone fluid, and

Scotchpack 1022 peelable protective film (b) having a thickness of 70 ± 1 μm.

The surface area of this patch is 20 cm 2, and 0.80 ± 0.54 μg / h / cm 2 of trimegestone is delivered in vitro (see FIG. 1).

The following matrix was prepared:

<Example 1a>

(Single layer matrix)

Patch surface area 20 cm 2, Gram number 60 g / m 2

ingredient % w / w Mg / patch Trimegeston BIO-PSA ^R 7-4301 Silicone Fluid 7-9120 3961 3.6115.21.2 gun 100 120

<Example 1b>

(Single layer matrix)

Patch surface area 20 cm 2, Gram number 60 g / m 2

ingredient % w / w Mg / patch Trimegeston BIO-PSA ^R 7-4301 Silicone Fluid 7-9120 3943 3.6112.83.6 gun 100 120

<Example 1c>

(Single layer matrix)

Patch surface area 20 cm 2, Gram number 60 g / m 2

ingredient % w / w Mg / patch Trimegeston BIO-PSA ^R 7-4301 Silicone Fluid 7-9120 3925 3.6110.46.0 gun 100 120

Example 1d

Patch surface area 20 cm 2, Gram number 40 g / m 2

ingredient % w / w Mg / patch Trimegeston BIO-PSA ^R 7-4301 Silicone Fluid 7-9120 3943 2.475.22.4 gun 100 80

<Example 1e>

Patch surface area 20 cm 2, Gram number 80 g / m 2

ingredient % w / w Mg / patch Trimegeston BIO-PSA ^R 7-4301 Silicone Fluid 7-9120 3943 4.8150.44.8 gun 100 160

<Example 1f>

(Single layer matrix)

Patch surface area 20 cm 2, Gram number 40 g / m 2

ingredient % w / w Mg / patch Trimegeston BIO-PSA ^R 7-4301 Cetiol ^R S 3943 2.475.22.4 gun 100 80

<Example 1g>

(Single layer matrix)

Patch surface area 20 cm 2, Gram number 60 g / m 2

ingredient % w / w Mg / patch Trimegeston BIO-PSA ^R 7-4301 Cetiol ^R S 3943 3.6112.83.6 gun 100 120

<Example 1h>

(Single layer matrix)

Patch surface area 20 cm 2, Gram number 40 g / m 2

ingredient % w / w Mg / patch Trimegeston BIO-PSA ^R 7-4301 Cetiol ^R S 3943 4.8150.44.8 gun 100 160

<Example 2>

<Trimageton-containing 2-layer patch>

-Scotchpack 1006 opaque protective film (a) with a thickness of 70 ± 2 μm,

A strong adhesive BIO-PSA ^R silicone polymer 97% w / w, containing 3% w / w of trimegestone, layer 2 having a thickness of 50 to 60 μm,

A BIO-PSA ^R adhesive layer 3 having a thickness of 65 μm with strong instantaneous adhesion, and

Scarpak 1022 peelable protective film (b) having a thickness of 70 ± 1 μm.

This patch has a surface area of 20 cm 2 and delivers 1.29 ± 0.45 μg / h / cm 2 of trimegestone in vitro (see FIG. 2).

The following matrix was prepared:

<Example 2a>

(2-layer matrix)

Patch surface area 20 cm 2, Gram number 60 + 30 g / m 2

layer ingredient % w / w Mg / patch Drug-containing layer Trimegeston BIO-PSA ^R 7-4301 397 3.6116.4 Layer bonded to the skin BIO-PSA ^R 7-4301 100 60 gun - 180

<Example 3>

The following "three layer" patches were prepared:

This patch

-Scotchpack 1006 opaque protective film (a) with a thickness of 70 ± 2 μm,

A BIO-PSA ^R fixed layer (1) having a thickness of about 33 μm with moderate instantaneous adhesion,

A layer 2 of 50 to 60 μm thick, of a moderate instantaneous adhesion BIO-PSA ^R silicone polymer (91% w / w) containing trimegonestone (9% w / w), and

A BIO-PSA ^R adhesive layer 3 having a thickness of about 65 μm with strong instantaneous adhesion, and

-Scotchpack 1022 peelable protective film with thickness of 70 ± 1 μm (b)

It consists of successive layers.

The surface area of this patch is 20 cm 2, and 0.59 ± 0.33 μg / h / cm 2 of trimegestone is ex vivo delivered (see FIG. 3).

The following matrix was prepared:

<Example 3a>

(3-layer matrix)

Patch surface area 20 cm 2, Gram number 30.5 + 61.5 + 65 g / m 2

layer ingredient % w / w Mg / patch Fixed layer BIO-PSA ^R 7-4201 100 61 Drug-containing layer Trimegeston BIO-PSA ^R 7-4201 991 11.07111.93 Layer bonded to the skin BIO-PSA ^R 7-4301 100 130 gun - 314

<Example 4>

<Timegestone-containing patch mixed with estradiol>

<Duplicate Superposition 1b (see Fig. 4)>

This double patch is

A Scotchpack ^R 1022 peelable protective film (b) having a thickness of about 70 μm, characterized by supporting two compartments (A) and (B) separated from each other by an empty space of 2 to 4 mm,

Strong instantaneous adhesion, coated with Scotchpack ^R 1006 opaque protective film (a), approximately 70 μm thick, containing 3% w / w of trimegstone and 1% w / w of silicone fluid (7-9120, 12000 cSt) Compartment (A) of about 60 μm in thickness containing a monolayer matrix, composed of BIO-PSA ^R 96% w / w (gram count is 60 g / m 2), and

Coated with Scotchpack ^R 1109 protective film (a ') or Hostaphan ^R RN23 having a thickness of about 34 μm, containing 2% w / w estradiol and 25% w / w collidone ^R 90F Compartment (B), about 76 μm thick, containing a monolayer matrix, consisting of 73% w / w Gelbar ^R 737 (grams are 80 g / m 2)

Has the features.

<Double superposition 2b>

This double patch is

A Scotchpack ^R 1022 peelable protective film (b), characterized by supporting two compartments (A) and (B) separated from each other by an empty space of 2 to 4 mm,

A compartment containing a two-layer matrix (A), covered by a Scotchpack ^R 1006 protective film (a),

a) a first layer composed of 97% w / w BIO-PSA ^R silicone polymer with strong instantaneous adhesion and containing 3% w / w of trimegestone,

b) a second layer adhered to the skin, consisting of BIO-PSA ^R silicone polymer with strong adhesion (hence the total number of grams is 90 g / m 2), and

73% w / w gel bar covered with Scotchpack ^R 1109 or Hostaphan ^R RN23 protective film (a ') and containing 2% w / w estradiol and 25% w / w collidone ^R 90F Compartment B containing monolayer matrix, consisting of ^R 737 layers (grams are 80 g / m 2)

Has the features.

<Test on the bonding structure>

The following patches were prepared:

(I) two-layer patch according to the invention containing 3% w / w of trimegestone, grams of drug-containing layer = 59.82 ± 1.77 g / m 2, grams of adhesive layer = 29.76 ± 3.67 g / m 2.

(II) Two-layer patch according to the invention containing 9% w / w of trimegestone, grams of drug-containing layer = 59.16 ± 2.77 g / m 2, grams of adhesive layer = 29.72 ± 3.31 g / m 2.

(III) The three-layer patch according to the present invention containing 9% w / w of trimegestone.

(IVa) monolayer patch according to the invention, containing 3% w / w of trimegestone, grams = 61.1 ± 2.5 g / m 2 (for plasticizers: 1% w / w of silicone fluid).

(IVb) monolayer patch according to the invention containing 3% w / w of trimegestone, grams = 59.1 ± 0.9 g / m 2 (for plasticizers: 1% w / w of Cetiol ^R S).

(IVc) monolayer patch according to the invention containing 3% w / w of trimegestone, grams = 42.9 ± 3.0 g / m 2 (without plasticizer).

(IVd) monolayer patch according to the invention, containing 3% w / w of trimegestone, gram count = 63.0 ± 3.83 g / m 2 (without plasticizer).

<Adhesion test>

principle:

The instantaneous adhesive strength is such that the adhesive (surface area = 5 cm 2) is placed in contact with the steel surface (1 cm 2) under known pressure conditions (compression force: 5 N, time: 60 seconds) and the energy required to separate the two surfaces. Evaluate by measuring. This measurement can be used to compare different formulations or to monitor adhesion development over time.

Patch type Adhesive Strength (Nm) x 10 ^-3 (I) 2nd floor 3% 56.4 ± 5.0 (II) 2nd floor 9% 52.1 ± 4.2 (III) 3rd floor 9% 49.4 ± 7.5 (IVa) monolayer 3% + 1% silicone fluid 33.5 ± 1.6 (IVb) monolayer 3% + 1% cethiol ^R S 31.1 ± 2.0 (IVc) monolayer 3% (G ≒ 40 g / m 2) 10.2 ± 1.7 (IVd) single layer 3% (G ≒ 60 g / ㎡) 35.6 ± 2.6

In the case of two-layer or three-layer patches, the active ingredient contained in the drug-containing matrix does not modify the instantaneous adhesion. The presence of one or two layers of adhesive layers on the drug contained matrix significantly improves instantaneous adhesion.

Ex vivo transdermal flow

principle:

Skin fragments are prepared on cells of Franz cell type for transdermal delivery. The percutaneous system is fixed to the skin on the stratum corneum plane. The active ingredient is released by the transdermal system and recovered in the receiving medium across the skin barrier. The active ingredient amount is then administered at regular time intervals.

Way:

Skin fragments are supplied from a plastic surgeon (thoracic or abdominal).

The skin is stored in 4 ° C. survival until partitioning. After subcutaneous fat is removed, the skin is cut into sheets of 300 μm thick and stored at −30 ° C. until use.

The skin is prepared on a receiving compartment of cells. Skin and receiving media need to be left to stand for about 15 hours to achieve equilibrium. The patch is then placed on the skin. Transdermal passage of the active ingredient is monitored by administering trimegonestone in the receiving medium.

Patch type Flow ^{(10 -6 · g · h -1} · ㎝ -2) (I) 2nd floor 3% 1.29 ± 0.45 (II) 2nd floor 9% 1.07 ± 0.75 (III) 3rd floor 9% 0.59 ± 0.33 (IVa) monolayer 3% + 1% silicone fluid 0.80 ± 0.54 (IVb) monolayer 3% + 1% cethiol ^R S 0.68 ± 0.22 (IVc) monolayer 3% (G ≒ 40 g / m 2) 0.34 ± 0.24 (IVd) single layer 3% (G ≒ 60 g / ㎡) 1.42 ± 0.87

The presence of one or two additional layers does not significantly modify transdermal flow.

<Test of the affinity of trimegonestone compared to the hormone receptor>

The affinity of trimegonestones for other common progesterone-like agonists, such as methoxyprogesterone (MPA), noethysterone (NE), promegestone (PROM), gestodine (GEST) and levonorgestrel (LNOR) ). This affinity was tested for recombinant human hormone receptors of progesterone (hPR), androgen (hAN), glucocorticoid (hGR) and estrogen (hER). These receptors were obtained in particular by overexpression in the insect cell-baculovirus SF9 system according to the method described in EP 0 629 635. Relative binding affinity (RBA) is as follows:

Receptor Relative binding affinity Trimegeston Medroxyprogesterone Norethysterone Promegestone Gustodine Levonorgestrel Progesterone 588 298 134 469 868 323 Glucocorticoids 13 58 1.4 8 38 7.5 Androgen 2.5 36 55 3 71 58 Estrogen <0.02 <0.02 <0.15 <0.02 <0.02 <0.02

Pharmacokinetic Study of Trimegeston

Four 20 cm 2 three-layer patches (9% of trimegestone) were applied for 4 days, 3 days, 4 days and 3 days, respectively, and then the plasma tree was removed until the last patch with an average value of 1.37 mg / ml was removed. Megestone concentration remains stable. Therefore, the average value of trimegestone flow is 0.4 mg / day / patch. The plasma concentration levels of estradiol and estrone did not change. For these parts, the plasma concentrations of FSH and LH drop to 31% and 38%, respectively, 14 days after application (antigonadotropic effect of trimegestone).

In conclusion, the trimegestone patch according to the present invention applied for 14 days (once every 3 days) delivers trimegestone at a stable flow rate with stable trimegestone plasma concentration and good local resistance.

1: Single layer patch (20 cm 2) structure

(a) a shield,

(2) a drug-containing adhesive layer and

(b) Peelable protective film.

Fig. 2: Two-layer patch (20 cm 2) structure

(a) a shield,

(2) a drug-containing adhesive layer,

(3) adhesive layer and

(b) Peelable protective film.

Figure 3: Three-layer patch (20 cm 2) structure

(a) a shield,

(1) a fixed bed,

(2) a drug-containing adhesive matrix,

(3) adhesive layer and

(b) Peelable protective film.

Figure 4:

(B) estradiol containing compartments (15 cm 2),

(A) trimeston containing compartment (20 cm 2),

(a ') shield,

(a) a protective film and

(b) Peelable protective film.

Figure 5:

(B) estradiol containing compartments,

(A) a trimeston containing compartment,

(a) a shield,

(b) a peelable protective film and

(c) polyester film.

The present invention relates to novel devices for the administration of trimegestone via the transdermal route and methods of making these devices.

Transdermal systems that deliver progestomimetic agonists are of significant therapeutic importance.

In fact, progesterone-like steroids are active ingredients that need to be administered over a long period of time.

Although delayed ester or herbal formulations of such steroids, such as implants or microspheres with controlled release, are used therapeutically, they often exhibit disadvantages that are quite difficult to use. In addition, such preparations cannot be quickly discontinued if necessary. The advantage of the percutaneous system is that it can be used for prolonged treatment while limiting overdose. Transdermal routes can be used to rule out undesirable effects such as liver overloading.

Accordingly, Applicants may administer by the transdermal route, containing a progesterone-like agonist known under the name Trimegestone,

1.under good stability conditions, especially during storage, may contain trimegestons,

2. Trimegestone is administered at a transdermal flow rate of 0.1 to 3 μg / cm 2 / h,

3. Delivering the required dosage of the active ingredient while maintaining an acceptable size (surface area) over prior art patches,

4. It is manufactured by simple and inexpensive manufacturing method,

5. to allow adhesion appropriate for the required period, particularly during hormone replacement therapy during menopause, ie for 3 to 7 days,

6. Providing suitable grammage for flow and adhesion standards

A new pharmaceutical compound (17α-methyl-17β- (2-hydroxy-1-oxo-propyl) -estra-4,9-dien-3-one (21S)) was studied.

Therefore, the object of the present invention

An optional layer (1) known as a fixed layer consisting of a silicone polymer,

A layer (2) consisting of trimegonestone and / or a silicone polymer comprising at least one pharmaceutically acceptable derivative and optionally a plasticizer, and

An optional layer consisting of a silicone polymer, known as an adhesive layer (3)

An adhesive polymer matrix applied to a device for transdermal administration of a progesterone-like agonist, characterized in that it contains at least one continuous layer.

Trimegestone (see formula below) is a potent progesterone-like agonist described in EP-0007823.

A pharmaceutically acceptable derivative means an ester of position 21 of trimegston, wherein the carbon number of the portion of the trimegston ester except for trimegestone is 1 to 12 carbon atoms. In particular, the derivative is a 17β- (2-acetoxy-1-oxo propyl) estra-4,9-dien-3-one (21S) derivative. The derivative may also be a 2-acyloxy group: isopropionyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, oxalyloxy, succinyloxy, pi Valoyloxy, undecanoyloxy, benzoyloxy. These esters are especially prepared by reacting aliphatic or aromatic carboxylic acids or anhydrides having 1 to 12 carbon atoms with trimegonestones.

Esters of trimegonestone having 1 to 3 or 3 to 12 carbon atoms in the trimeghone ester except for trimegonestone are also an object of the present invention.

Among the many polymers known to those skilled in the art, which may contain progesterone-like agonists such as trimeston, the applicant has determined that only silicone polymers can satisfy the required stability, flow and adhesion conditions. .

Silicone polymer refers to a network of polydimethylsiloxane (PDMS) chains.

Two kinds of polymers can be used, one with strong instantaneous adhesion, especially BIO-PSA ^R 7-4301, the other with moderate instantaneous adhesion, especially BIO-PSA ^R 7-3045, 7-4201 Or 7-4202 from Dow Corning Health Care Center Europe. The silicone polymer takes the form of a clear solution in an organic solvent such as hexane, heptane, ethyl acetate or tetrahydrofuran which is volatile at low temperatures.

These polymers are amino resistant and do not have any acid silanol groups.

Adhesion is characterized by peel and adhesion: the adhesion increases from low instantaneous adhesion to medium instantaneous adhesion. The parameter used to control the physical properties is the silicone polymer / resin ratio. Moderate adhesion means a ratio of 40/60. Strong adhesion means a ratio of 45/55.

The amount of trimegstones incorporated into the polymer matrix as already defined is 1 to 10% w / w. The ratio corresponds to the amount of active ingredient expressed as the ratio of the dry weight of the mixture after solvent evaporation. The trimegeston is then in suspension in the silicone matrix.

The purpose of the plasticizer is to increase the instantaneous adhesion value. Oils such as silicone fluids or cethiols such as Cetiol ^R S (dioctylcyclohexane) are used. More specifically, high viscosity silicone fluids will be used. Polymerized dimethylsiloxane, particularly specifically Dow coating product 7-9120 silicone fluid (12000 cSt), will be used. The amount of plasticizer can vary from 1 to 10% w / w. Preferably, 1 to 3% w / w of plasticizer will be selected.

The silicon matrix provides a number of advantages:

-No absorption accelerator,

-Trimegeston is chemically stable among silicone polymers,

-Flow level and adhesion level are suitable for therapeutic treatment,

The matrix system offers the advantage that, in comparison with the storage system, it does not involve the risk of membrane destruction which can lead to overdose of the active ingredient,

-The process is unstable with respect to humidity and temperature when carrying out the manufacturing process, but trimesgestone is not affected.

Thus, the trimegestone-containing patch as previously described allows the active ingredient to be distributed, ie spread over time. The concentration is time stable with no peaks (see pharmacokinetic test).

More specifically, the object of the present invention is to

1- monolayer matrix,

2- two-layer matrix,

3- 3-layer matrix

Three kinds of matrix.

<1- monolayer matrix>

A more particular object of the present invention is a progesterone as defined above, characterized in that it contains a single layer (2) consisting of trimegestone and / or a silicone polymer comprising at least one pharmaceutically acceptable derivative and optionally a plasticizer. Adhesive polymer matrix applied to the device for transdermal administration of similar agents.

More specifically, it will then be desirable to select commercially available adhesive silicone polymers with strong instantaneous adhesion. It would then be desirable to select BIO-PSA ^R , in particular BIO-PSA ^R 7-4301, which has strong instantaneous adhesion.

It is not necessary to use any absorption promoter.

A quite particular object of the present invention is a powerful preparation comprising from 1 to 10% w / w of trimegestone and / or one or more pharmaceutically acceptable derivatives and from 0 to 10% w / w of silicone fluid or cethiol ^R S Said single layer matrix, characterized in that it consists of 80-99% w / w of silicone polymer of adhesion.

A fairly specific object of the present invention is characterized in that the composition consists of 96% w / w of a strong adhesion BIO-PSA ^R silicone polymer containing 3% w / w of trimegonestone and 1% w / w of silicone fluid. It is a single layer matrix.

<2-layer Matrix>

A more particular object of the present invention is also

a) a first layer (2) comprising a silicone polymer comprising trimestonone and / or one or more pharmaceutically acceptable derivatives, and

b) a second adhesive layer in contact with the skin and composed of a silicone polymer (3)

It is an adhesive polymer matrix applied to a device for transdermal administration of a progesterone-like agonist, characterized in that it contains a continuous layer of two layers.

It will be more particularly preferable to select commercially available adhesive silicone polymers with strong instantaneous adhesion for the drug containing layer and the adhesive layer. It would then be desirable to select BIO-PSA ^R , in particular BIO-PSA ^R 7-4301, which has strong instantaneous adhesion.

Addition of an adhesive layer that should be present on the skin in a two-layer structure increases adhesion and fluidity was not significantly modified. Therefore, there is no need to use an absorption accelerator.

A quite particular object of the invention is also more particularly

a) the first layer consists of 90-99% w / w of a strong adhesion silicone polymer comprising 1-10% w / w of trimegonestone and / or one or more pharmaceutically acceptable derivatives,

b) the second layer is also composed of a silicone polymer with strong adhesion

Said two-layer matrix characterized by the above-mentioned.

A quite special object of the present invention is also

a) the first layer consists of 97% w / w of a strongly adhesive BIO-PSA ^R silicone polymer comprising 3% w / w of trimegestone,

b) the second layer is also composed of a BIO-PSA ^R silicone polymer with strong instantaneous adhesion

Said two-layer matrix characterized by the above-mentioned.

<3-layer 3-layer matrix>

A more particular object of the present invention is also

a) a first layer (1) known as a fixed layer consisting of a silicone polymer,

b) a second layer (2) consisting of a silicone polymer comprising trimestonone and / or one or more pharmaceutically acceptable derivatives, and

c) a third adhesive layer in contact with the skin and composed of a silicone polymer (3)

An adhesive polymer matrix applied to a device for transdermal administration of a progesterone-like agonist as defined above, characterized in that it contains three continuous layers of.

The adhesion was increased by adding a pinned layer and an adhesive layer, but the fluidity was not significantly modified. Thus, there is no need to use any absorption accelerator.

As for the adhesive layer, it will be more particularly preferable to select a commercially available adhesive silicone polymer having strong instantaneous adhesion. Subsequently, BIO-PSA ^R , in particular BIO-PSA ^R 7-4301, which has strong instantaneous adhesion will be chosen. It is more particularly preferable to select silicone polymers having moderate instantaneous adhesion, in particular BIO-PSA ^R 7-3045, 7-4201 or 7-4202, for the fixed and inclusive layers.

A quite special object of the present invention is also

The first layer consists of a silicone polymer with moderate adhesion,

The second layer consists of 90 to 99% w / w of a strongly adherent silicone polymer comprising 1 to 10% w / w of trimegestone and / or one or more pharmaceutically acceptable derivatives,

The third layer consists of a silicone polymer with strong adhesion

Said three-layer matrix characterized by the above-mentioned.

A quite special object of the present invention is also

The first layer consists of a BIO-PSA ^R silicone polymer with moderate instantaneous adhesion,

The second layer consists of 91% w / w of a BIO-PSA ^R silicone polymer of moderate instantaneous adhesion, comprising 9% w / w of trimegeston,

The third layer consists of BIO-PSA ^R silicone polymer with strong instantaneous adhesion

Said three-layer matrix characterized by the above-mentioned.

The object of the present invention is also,

-Protective film (a),

A matrix comprising trimegeston and / or one or more pharmaceutically acceptable derivatives as previously defined, and

-Peel-off protective film (b)

Is a device for transdermal administration of a progesterone-like agonist, characterized in that it is continuously configured.

The protective film used is a support on which the different layers constituting the patch are coated, to obtain a non-separable system. These membranes may be opaque if the active ingredient is photosensitive.

Scotchpak ^R 1109, or Scotchpack ^R 1006 (3M Health Care Limited), in the case of a flexible membrane that is colored and blocked in the protective film, is preferably selected. Scotch Pack ^R 1006

a) a colored surface layer,

b) aluminum layer,

c) polyethylene terephthalate layer, and

d) moderate density polyethylene and ethylene acetate layers

It consists of four floors.

Among the remaining protective films applicable to the present invention, known to those skilled in the art, Hostaphan ^R RN series (RN23, RN25, RN75 or RE75) may be mentioned.

The peelable protective film used is a film for protecting the adhesive surface to be fixed on the skin from the percutaneous system during post-production storage.

One surface of a peelable protective film known to those skilled in the art is a polyester film treated with a fluorocarbon such as Scotch Pack ^R 1022 (3M Health Care Limited), or a bio-release silicone, a Dow coating product. It would be desirable to select a transparent polyester film Silox ^R B5Y / O (Akrosil ^{trade name} ) which treated one surface for adhesion.

More particularly, the object of the present invention

-Protective film (a),

A single layer matrix (2) as already described, and

-Peelable protective film (b)

It is an apparatus as described above containing continuously (FIG. 1).

More particularly, the object of the present invention

-Protective film (a),

Two-layer matrices (2) and (3) as already described, and

-Peelable protective film (b)

It is an apparatus as described above containing successively (FIG. 2).

More particularly, the object of the present invention

-Protective film (a),

A three-layer matrix ((1), (2) and (3)) as previously described, and

-Peelable protective film (b)

It is an apparatus as described above containing successively (FIG. 3).

The protective film is preferably an opaque Scotch Pack ^R 1006 protective film, and the peelable protective film is preferably a Scotch Pack ^R 1022 peelable protective film.

These transdermal systems deliver trimegstones on human skin at ex vivo transdermal flow rates of 0.1 to 3 μg / cm 2 / h.

The device as already described may be of any type, ie, round, oval, rectangular or square. The surface area of these devices is 5 to 50 cm 2.

Trimegestone can be mixed with estrogen.

Accordingly, an object of the present invention is also a device for transdermal administration of a progesterone-like agonist, which also contains a matrix comprising estrogen and is composed of two compartments (A) and (B).

Preferred estrogens include 17β-estradiol; Esters of 17β-estradiol such as estradiol valerate, cyprionate, decanoate and acetate; Ethynyl estradiol, estrone; Mention may be made of "horse" estrogens, such as Premarin ^R , or mixtures of these compounds.

More particularly, an object of the present invention is a device as defined above, wherein the estrogen compound is estradiol.

More particularly, it is an object of the present invention that two compartments (A) and (B)

Supported by the same peelable protective film (b),

Separated from each other by an empty space or barrier of 1 to 10 mm,

The compartment (A) contains a silicone polymer matrix comprising a trimegeston and / or one or more pharmaceutically acceptable derivatives as previously described,

Said compartment (B) contains an adhesive polymer matrix comprising estrogen,

The matrix is each covered by the same or different protective films (a) and (a '), respectively.

It is a device as already described, characterized in that (Fig. 4).

The surface area of compartment A is 5-50 cm 2, and the surface area of compartment B is 5-50 cm 2.

Thus, the peelable protective film supports two separate compartments (A) and (B) each containing a trimegonestone and an estrogen compound.

Once the peelable protective film is removed, two separate patches are applied that are applied to the skin or mucosa to administer the trimegestone and estrogen compounds simultaneously or separately. In addition, once the peelable protective film is removed, one or more fastening means may be present between the two compartments (A) and (B) to keep the two patches bound.

Polymer matrices containing estrogen compounds are selected from polymers that are commercially available and / or known to those skilled in the art. These matrices are, in particular, polymers or copolymers comprising a network of polyisobutylene or polyacrylic chains, ethylene and vinyl acetate (EVA) copolymers or also silicone polymers. In some cases hydrophilic polymers and / or absorption accelerators and / or plasticizers and / or other additives known to those skilled in the art, which can improve flow standards, adhesion criteria and transdermal stability criteria, these copolymers Can be added to.

The matrix may be a single layer structure or a multi layer structure. Storage systems can also be used.

The empty space used to separate the two compartments may be 1 to 10 mm. Preferred sizes are 2 to 4 mm.

By "barrier" is meant a physical separator composed of a suitable material. The width of the barrier is limited to the ability of the barrier and the method of manufacture to interrupt the distribution. The width of the barrier can be 1 to 10 mm. The barrier will preferably have a width of 1 to 3 mm.

If the estrogen compound is estradiol, the matrix comprised will preferably be a single layer matrix comprising a mixture of 2-ethylhexyl acrylate and vinyl acetate with estradiol to which a hydrophilic polymer can optionally be added. More specifically, the compound will be a Gelva ^R 737 copolymer containing 72% 2-ethylhexyl acrylate and 28% vinyl acetate. Preferred hydrophilic polymers are polyvinylpyrrolidone. More specifically the polymer will be Kollidon ^R 30 or 90F.

The amount of estradiol incorporated in the polymer matrix as already defined is preferably 1 to 10% w / w.

More specifically, the object of the present invention is a device as already described which exhibits the following features:

Double superposition 1

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

A compartment (A) containing a single layer matrix, which is covered by a protective film (a) and composed of a trimegonestone and / or a silicone polymer comprising one or more pharmaceutically acceptable derivatives and optionally a plasticizer, and

Compartment (B) containing a monolayer matrix, covered by protective film (a ') and composed of 2-ethylhexyl acrylate and vinyl acetate copolymer comprising estradiol and optionally a hydrophilic polymer

Including;

Double superposition 2

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

A compartment (A) containing a two-layer matrix covered by a protective film (a),

a) a first layer consisting of a silicone polymer comprising trimestonone and / or one or more pharmaceutically acceptable derivatives,

b) a second layer adhered to the skin and also composed of a silicone polymer, and

Compartment (B) containing a monolayer matrix, covered by protective film (a ') and composed of 2-ethylhexyl acrylate and vinyl acetate copolymer comprising estradiol and optionally a hydrophilic polymer

It includes.

More particularly, the object of the present invention

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

-Covered with an opaque protective film (a), 1 to 10% w / w of trimegestone and / or one or more pharmaceutically acceptable derivatives and 0 to 10% w / w of silicone fluid or cethiol ^R S Compartment (A) containing a single layer matrix, consisting of 80-99% w / w of a strong adhesion silicone polymer containing

- a protective film (a ') consisting of a coating is 1 to 10% w / w of estradiol and 0 to 30% w / w Kollidon ^R gelba ^R 737 of 60 to 99% w / w that includes the single Compartment containing layer matrix (B)

Double patch 1a containing

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

A compartment containing a two-layer matrix, covered by a protective film (a) (A)

a) a first layer consisting of 90-99% w / w of a strongly adherent silicone polymer comprising 1-10% w / w of trimegonestone and / or one or more pharmaceutically acceptable derivatives,

b) a second layer composed of a silicone polymer adhered to the skin and having strong adhesion, and

- and covered with a protective film (a '), consisting of 1 to 10% w / w of estradiol and 0 to 30% w / w Kollidon ^R 90F gelba ^R 737 of 60 to 99% w / w that includes the Compartment containing monolayer matrix (B)

It is an apparatus as already described containing the double patch 2a containing.

The "double patch" is

Allowing mixtures in a single body of trimegeston and estrogen compounds to be administered separately, simultaneously, over time during the prophylaxis or treatment of hormone replacement therapy associated with menopause, in particular osteoporosis,

Solves the problem of differences in the active ingredient stability in the polymer used in the drug containing layer (trimegestone is unstable in the matrix used in estradiol),

Administering each active ingredient under optimal conditions to obtain a pharmaceutically acceptable transdermal flow to eliminate all interactions between the compound and the rest of the compound matrix,

To comply with regulatory requirements regarding the dosage and date of administration (preliminary administration) of each active ingredient, excluding the purchase and manipulation of two separate agents.

The last point in the paragraph of the estrogen-progestogen mixture is that it is particularly important for hormone replacement therapy associated with menopause, especially for the prevention or treatment of osteoporosis and contraception.

In addition, by applying two separate matrices on the same peelable protective film

Easy to individually optimize formulations containing the active ingredient as a function of the necessary adhesion and flow criteria (selection of support polymers, selection of absorption promoters, selection of hydrophilic polymers, selection of plasticizers, optimization of grams),

It is easy to optimize the active ingredient concentration separately as a function of the required stability criteria and transdermal flow criteria and as a prescribed dosage,

It is easy to obtain compartments of the same or different size by a simple manufacturing method

It provides an advantage.

The object of the present invention is also,

Protective film (a),

Compartment (B) consisting of an adhesive polymer matrix containing estrogens such as estradiol,

Polyester film (c) having the same size as compartment (A) and disposed on top of compartment (A),

Consisting of a matrix of silicone polymers as defined above containing trimegonestone and / or various pharmaceutically acceptable derivatives, the size being smaller than compartment (B), for example half the size of compartment (B), A compartment (A) preferably located centrally with respect to the compartment (B), and

Peelable protective film (b)

It is an apparatus ("combipatch") comprised continuously with the component of the.

Compartment (A) is smaller in size than compartment (B) such that a matrix containing estrogens disposed on a matrix containing trimegonestones can also be in direct contact with the skin. Thus, the estrogen compound will diffuse directly from that location. For example, the surface area of compartment A may be 15 cm 2, and the surface area of compartment B may be 30 cm 2 (see FIG. 5).

Preferably, compartment (A) consists of a two-layer or three-layer matrix as already defined.

A "combi patch" with a two-layer matrix can be used for 4 days, for example, and a "combi patch" with a three-layer matrix can be used for 7 days, for example.

The manufacturing technique for the percutaneous system which is the object of the present invention is a coating. The general principle is as follows:

The silicone polymer solution is mixed with the active ingredient and any other additives in a nonpolar organic solvent such as heptane to obtain a suspension or solution of the adhesive 2 which is sprayed (coated) onto the peelable protective film or protective film. The film is optionally pre-evaporated under a fumigation hood at ambient temperature until it is completely evaporated and then dried at 40-100 ° C. This type of process is repeated in the appropriate order according to the number of layers required, followed by cutting the percutaneous system into pastilles designated as patches, with a surface area of 1 to 50 cm 2. Adhesive solution (1 or 3) means a silicone polymer solution that does not contain the active ingredient in a nonpolar organic solvent such as heptane.

A "single layer" patch can be prepared as follows:

The solution in heptane of the adhesive layer (2) containing 1-trimegestone and optionally plasticizer is first applied to the peelable protective film (b) and then dried,

2- "adhesive layer (2) / peelable protective film (b)" set is laminated on the protective film (a) simultaneously,

3- Cut the percutaneous system to a pastille having a surface area of 5 to 50 cm 2.

In this way

-Protective film (a),

-An adhesive layer (2) containing trimegeston and optionally a plasticizer and

-Peelable protective film (b)

A "double supernatant" is obtained which contains (Fig. 1).

The preparation method can also be carried out as follows:

A solution in heptane of the adhesive layer (2) containing 1-trimegestone and optionally a plasticizer is first applied to the protective film (a) and then dried,

2- "adhesive layer (2) / protective film (a)" set is laminated on the peelable protective film (b) simultaneously,

3- Cut the percutaneous system to a pastille having a surface area of 5 to 50 cm 2.

A "two layer" patch can be prepared as follows:

1- a) A solution in heptane of the adhesive layer (3) is first applied to the peelable protective film (b) and then dried,

b) a solution in heptane of the adhesive layer 2 containing trimegestone is first applied to the temporary peelable protective film b 'and then dried;

2- A set of " adhesive layer (2) / temporary peelable protective film (b ') " containing trimetheston is simultaneously laminated on the “adhesive layer (3) / peelable protective film (b)” set,

3- Peel off the temporary protective film (b '),

4- A layer of "adhesive layer (2) / adhesive layer (3) / peelable protective film (b)" is simultaneously laminated on the protective film (a),

5- Percutaneous system is cut to a pastille having a surface area of 5 to 50 cm 2.

In the above manner

-Protective film (a),

An adhesive layer containing trimegeston (2),

An adhesive layer (3) between the drug containing layer and the peelable protective film and

-Peelable protective film (b)

A "double supernatant" is obtained which contains (Fig. 2).

A "three layer" patch can be prepared as follows:

1- a) A solution in heptane of the adhesive layer (1) is first applied to a temporary peelable protective film (b ') and then dried,

b) a solution in heptane of the adhesive layer 2 containing trimegestone is first applied to the temporary peelable protective film b " and then dried;

c) the solution in heptane of the adhesive layer 3 is first applied to the peelable protective film (b) and then dried;

2- A set of "adhesive layer (1) / temporary peelable protective film (b ')" is simultaneously laminated on protective film (a),

3- Peel off the temporary protective film (b '),

4- Laminate sets of "adhesive layer (2) / temporary adhesive layer (b") "containing trimegestone on the" adhesive layer (1) / protective film (a) "set simultaneously,

5- Peel off the temporary protective film (b "),

6- In the final co-lamination process, the "adhesive layer (3) / peelable protective film (b)" set is co-laminated on the "drug containing layer (2) / adhesive layer (1) / protective film (a)" set,

The 7-cutaneous system is cut to a pastille having a surface area of 5 to 50 cm 2.

In this way

A peelable protective film (b),

An adhesive layer between the protective film and the drug containing layer (3),

An adhesive layer containing trimegeston (2),

An adhesive layer (fixed layer) between the drug containing layer and the protective film (1) and

-Shield (a)

To obtain a patch characterized in that it contains (Fig. 3).

A "double patch" device for transdermal administration of trimegston mixed with estrogen as previously described can be prepared as follows:

Step I : for the preparation of a patch corresponding to compartment (A)

A silicone polymer adhesive layer comprising 1-trimegestone and optionally one or more additives is coated on the protective film (a),

The solvent is evaporated until a set of "matrix (I) / protective film (a) with trimegestone" corresponding to 2-compartment (A) is obtained,

3- A set of " matrix / protective film (a) with trimegonestone " was co-laminated on the peelable protective film (b '),

4- 5-50 cm 2 patch is cut,

Step II : for the preparation of a patch corresponding to the compartment (B)

A polymer adhesive layer comprising a 1-estrogen compound and optionally one or more additives such as a hydrophilic polymer, an absorption promoter or a plasticizer is coated on the protective film (a '),

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

3- A set of "matrix / protective film (a ') containing estrogen" is simultaneously laminated on the peelable protective film (b'),

4- 5-50 cm 2 patch is cut,

Step III : for the manufacture of "double super"

1- Peelable protective film (b ') is peeled from the patch obtained in step I,

2- transfer a set of "matrix / protective film (a) with trimegonestone" onto the peelable protective film (b),

3- A peelable protective film (b ") is peeled off from the patch obtained in step II,

After considering a distance of 4- 1 to 10 mm, or arranging a barrier between compartments (A) and (B), a set of " matrix / protective film (a ') containing estrogen " b) transfer onto bed.

In this way

A peelable protective film (b),

A compartment (A) consisting of a matrix containing trimegonestones as previously defined and covered by a protective film (a), and

A compartment (B) consisting of a matrix containing an estrogen compound and covered by a protective film (a ')

And the two compartments are separated from each other by an empty space or barrier of 1 to 10 mm to obtain a "double patch" (FIG. 4).

In addition, these procedures can all be applied to esters of trimegston as already defined.

These different methods are in all cases cheaper than manufacturing methods using reservoir systems. These methods are simple to carry out and require a relatively short drying time. Preferably, it is dried for 15 minutes at 60 ℃.

Drying is carried out as a continuous industrial process. Preparation conditions are as follows: Section I: 35 ° C., Section II: 50 ° C., Section III: 60 ° C. and Section IV: 80 ° C.

The production method for monolayer patching is particularly simple, on the other hand, when only a single layer is present, no transfer film required during the co-lamination process is lost at all and finally the adjustments associated with co-lamination are simplified. This method is inexpensive, as well as for the reasons mentioned above, because it allows for high speed production and requires smaller amounts of raw materials (trimegestone and excipients). The method for producing a two-layer patch is advantageous over a single layer that does not require plasticizer feed.

The affinity of trimegestone is significantly better than the progesterone receptor (6-7 times the affinity of progesterone). In addition, the affinity of trimegstonone is significantly weaker than the androgen receptor and is absent compared to the estrogen receptor (<0.02). In vivo studies have confirmed in vitro studies. Trimegestone is a potent progesterone-like agonist with no electrolyte corticoids, androgens, glucocorticoids, anti-glucocorticoids, and estrogen activity. On the other hand, trimegeston has antielectrolyte corticoid and antiandrogen activity. Thus, trimegeston in patch formulations is a therapeutic of considerable interest.

The trimegestone-containing patch according to the invention is a gynecological problem due to luteal insufficiency, namely

Problems with menstruation and / or menstrual cycles,

-Irregular menstruation,

Premenstrual symptoms,

-Breast pain, mastopathy,

-Functional bleeding,

-Excessive menstruation of the fibroids,

Endometrial hyperplasia,

-Premenopausal problems,

Endometriosis,

-Menopause problems,

-Contraception,

Ovarian dystrophy due to ovarian inactivity,

Tumors and Uterus

Can be used for the treatment of

Premenstrual trimegestone, when mixed with estrogens such as estradiol, exhibits potent antiestrogenic activity at the uterine level, but no antiestrogenic activity at the bone structure level. Thus, the estrogen / trimegestone mixtures according to the invention can be used in hormone replacement therapy associated with menopause, in particular in the prevention or treatment of osteoporosis.

17β-estrodiol among preferred estrogens; Esters of 17β-estrodiol such as estrodiol valerate, cyprionate, decanoate and acetate; Ethynyl estradiol, estrone; Mention may be made of "horse" estrogens such as premarin ^R , or mixtures of these compounds.

Pathology for osteoporosis is characterized by quantitative and qualitative degradation of the bone material, which is sufficient to cause vertebral fractures or peripheral fractures in spontaneously or sometimes with minimal trauma. There are many causes of the disease, but in women, menopause is the dominant factor in bone loss or osteopenia.

This osteopenia manifests as sparsity and modification of the cavernous bone composition, resulting in increased skeletal fragility and fracture risk. Bone loss is strongly increased after menopause due to suppression of ovarian function, reaching 3-5% per year before ageing after age 65.

If estrogens play an important role in the protection of bone material for therapeutic purposes, postmenopausal hormone deficiency can be supplemented by alternative hormone therapy. However, long-term eestrogenotherapy sometimes involves undesirable effects on the genitals (endometrial hyperplasia, breast cancer ...) and constitutes an important disadvantage, limiting its use. As a result, it is appropriate to mix premenstrual hormones with estrogen that can maintain beneficial effects on bone while countering estrogen side effects on reproductive targets. Mixtures of this type are already known and are described, for example, in the following patents or patent applications EP-0136011, US5208225, US5108995, EP-474374, DE4019670. However, a significant disadvantage of these mixtures is due to the overlap in activity associated with premenstrual hormones used in the mixtures, in particular the androgen effect of these mixtures.

The mixture does not exhibit such disadvantages. In fact, trimegstones belonging to the norpregnane class of premenstrual hormones have virtually no androgen activity, leading to good metabolic resistance.

The estrogen / trimegestone mixture according to the invention can also be used as a contraceptive. The estrogen will then be quite particularly ethynylestradiol.

Accordingly, it is an object of the present invention to apply a matrix (s) of the device as described above onto the patient's skin or mucous membranes, thereby admixing the trimeston and / or one or more pharmaceutically acceptable derivatives, i.e., a tree mixed with estrogen. Device for use of megestone as a method of delivery to a patient.

The following therapeutic examples are described without limiting the invention.

1) trimegeston alone

Therapy a

The first preparation may be applied from 16 days to 18 days of the cycle, the second preparation may be applied from the 19th to 21st days of the cycle, and the third preparation may be applied from the 22nd to 25th days of the cycle, ie for 10 days / cycle. .

Therapy b

From the 5th day to the 8th day of the cycle for the first preparation, from the 9th to the 12th day of the cycle for the second preparation, from the 13th to the 16th day of the cycle for the third preparation, the 17th to 21st day of the cycle for the fourth preparation And the fifth patch can be applied from day 22 to day 25 of the cycle, ie for 21 days / cycle.

In addition, trimegeston therapy can be used continuously.

2) Trimegestone mixed with estradiol

Hormone replacement therapy for menopause, in particular with regard to the prevention or treatment of osteoporosis.

Estradiol may be a tablet formulation or a patch formulation.

Subsequent Administration of Trimegestone and Continuous Administration of Estradiol:

Therapy a

Consecutive administration of 25-200 μg / day of estradiol (28-day cycles without interruption between cycles) and 0.05-2.5 mg / day of trimegone during the last 14 days of each 28-day cycle

Therapy b

Dosage of 0.05-2.5 mg / day of trimezone during 28 days / 1 month of estradiol at a dose of 25-200 μg / day and the last 14 days of administration of estradiol. This therapy is discontinued for 2-3 days / 1 month at the end of each 28-day cycle.

Therapy c

Administration of a dose of 0.05-2.5 mg / day of trimegone during 28 days / 1 month of estradiol at a dose of 25-200 μg / day and the initial 14 days of administration of estradiol. This therapy is administered without interruption between each 28-day cycle, or with interruption for 2-3 days / 1 month at the end of each cycle.

Therapy d

Dosage of 0.05-2.5 mg / day of trimezone during 25 days / 1 month of estradiol at a dose of 25-200 μg / day and the last 11-14 days of estradiol administration. This therapy is discontinued for 5-6 days at the end of the 25-day cycle.

Continuous Dosage of Trimegeston and Estradiol

Continuous administration of estradiol at a dose of 25-200 μg / day and trimegestone patch of 0.05-2.5 mg / day. There is no interruption to this therapy.

3) Trimegestone mixed with ethynyl estradiol

About use as a contraceptive.

Trimegestone patch mixed with ethynylestradiol is administered continuously for 21 to 28 days per cycle. This therapy requires continuous application of three to eight trimegestone patch, in particular administration of 21 to 28 days / cycle of ethynyl estradiol in the patch or tablet formulation.

Example preparations according to the invention are shown in the experimental section hereafter. The following examples illustrate the present invention without limiting it.

Claims (32)

An optional fixed layer consisting of silicone polymer (1), A layer (2) consisting of trimegonestone and / or a silicone polymer comprising at least one pharmaceutically acceptable derivative and optionally a plasticizer, and Optional adhesive layers consisting of silicone polymers (2006.01) An adhesive polymer matrix applied to a device for transdermal administration of a progesterone-like agonist (progestomimetic), characterized in that it contains at least one continuous layer. The adhesive polymer matrix according to claim 1, which contains 1 to 10% w / w of trimegstone. Adhesive matrix according to claim 1, characterized in that it contains a single layer (2) consisting of trimegestone and / or a silicone polymer comprising at least one pharmaceutically acceptable derivative and optionally a plasticizer. 4. A composition according to claim 3, comprising from 1 to 10% w / w of trimegestone and / or one or more pharmaceutically acceptable derivatives and from 80 to 80 containing from 0 to 10% w / w of silicone fluid or dioctylcyclohexane An adhesive polymer matrix comprising 99% w / w of strong adhesion silicone polymer. The adhesive polymer matrix of claim 4, wherein the adhesive polymer matrix comprises 3% w / w of trimegonestone and 96% w / w of strong instantaneous adhesion silicone polymer containing 1% w / w of silicone fluid. The method of claim 1, a) a first layer (2) comprising a silicone polymer comprising trimestonone and / or one or more pharmaceutically acceptable derivatives, and b) a second adhesive layer in contact with the skin and composed of a silicone polymer (3) An adhesive polymer matrix comprising two consecutive layers of the polymer. The method of claim 6, a) the first layer consists of 90-99% w / w of a strong adhesion silicone polymer comprising 1-10% w / w of trimegonestone and / or one or more pharmaceutically acceptable derivatives, b) the second layer is also composed of a silicone polymer with strong adhesion Adhesive polymer matrix, characterized in that. The method of claim 7, wherein a) the first layer consists of 97% w / w of a strong instantaneous adhesion silicone polymer containing 3% w / w of trimegestone, b) the second layer is also composed of a silicone polymer having strong instantaneous adhesion Adhesive polymer matrix, characterized in that. The method of claim 1, a) a first fixed layer (1) consisting of a silicone polymer, b) a second layer (2) consisting of a silicone polymer comprising trimestonone and / or one or more pharmaceutically acceptable derivatives, and c) a third adhesive layer in contact with the skin and composed of silicone polymer (3) An adhesive polymer matrix comprising a continuous layer of three layers. The method of claim 9, The first layer consists of a silicone polymer with moderate adhesion, The second layer consists of 90 to 99% w / w of a strongly adherent silicone polymer comprising 1 to 10% w / w of trimegestone and / or one or more pharmaceutically acceptable derivatives, The third layer consists of a silicone polymer with strong adhesion Adhesive polymer matrix, characterized in that. The method according to claim 9 or 10, The first layer consists of a silicone polymer having moderate instantaneous adhesion, The second layer consists of 91% w / w of a medium instantaneous adhesion silicone polymer containing 9% w / w of trimegonestone, The third layer consists of a silicone polymer with strong instantaneous adhesion Adhesive polymer matrix, characterized in that. continuously -Protective film (a), The matrix (2) as defined in claim 1 or 2, and -Peelable protective film (b) Apparatus for transdermal administration of a progesterone-like agent, characterized in that consisting of. The device of claim 12, wherein the matrix is defined in any one of claims 3 to 5. 13. The device of claim 12, wherein the matrix is defined in any of claims 6-8. 13. The device of claim 12, wherein the matrix is defined in any of claims 9-11. 13. An apparatus according to claim 12, further comprising a matrix comprising estrogen, consisting of two compartments (A) and (B). The method of claim 16, wherein the estrogen compound is 17β-estradiol; Esters of 17β-estradiol such as estradiol valerate, cyprionate, decanoate and acetate; A device characterized in that it is selected from ethynyl estradiol, estrone, "horse" estrogens such as Premarin ^R , and mixtures of these compounds. The device of claim 16, wherein the estrogen compound is selected from 17β-estradiol. The method of claim 16 wherein the two compartments (A) and (B) Supported by the same peelable protective film (b), Separated from each other by an empty space or barrier of 1 to 10 mm, Said compartment (A) contains a matrix of silicone polymers comprising a trimegeston and / or at least one pharmaceutically acceptable derivative as defined in any one of claims 1 to 11, Said compartment (B) contains an adhesive polymer matrix comprising estrogen, These matrices are each covered by the same or different protective films (a) and (a '), respectively. Device characterized in that. The method of claim 19, Compartment (A) contains a monolayer matrix as defined in claim 3, Compartment (B) contains a monolayer matrix consisting of 2-ethylhexyl acrylate-vinyl acetate copolymer comprising estradiol and optionally a hydrophilic polymer Device characterized in that. The method of claim 19 or 20, Compartment (A) contains a monolayer matrix as defined in claim 4 or 5, 60-99% w / w 2-ethylhexyl acrylate (72%) with compartment (B) containing 1-10% w / w estradiol and 0-30% w / w polyvinylpyrrolidone ) Containing a single layer matrix composed of vinyl acetate (28%) copolymer Device characterized in that. The method of claim 19, Compartment (A) contains a two-layer matrix as defined in claim 6, Compartment (B) contains a monolayer matrix consisting of 2-ethylhexyl acrylate-vinyl acetate copolymer comprising estradiol and optionally a hydrophilic polymer Device characterized in that. The method of claim 19 or 22, Compartment (A) contains a two-layer matrix as defined in claim 7 or 8, 60-99% w / w 2-ethylhexyl acrylate (72%) with compartment (B) containing 1-10% w / w estradiol and 0-30% w / w polyvinylpyrrolidone ) Containing a single layer matrix composed of vinyl acetate (28%) copolymer Device characterized in that. The method of claim 16, Protective film (a), Compartment (B) consisting of an adhesive polymer matrix containing estrogens such as estradiol, Polyester film (c) having the same size as compartment (A) and disposed on top of compartment (A), Consists of the above-described silicone polymer matrix containing trimegeston and / or various pharmaceutically acceptable derivatives, the size being smaller than the compartment (B), for example half the size of the compartment (B), preferably Is located centrally with respect to compartment (A), and Peelable protective film (b) Apparatus characterized in that it is continuously configured with the components of. 25. An apparatus according to claim 24, wherein the trimegstone containing matrix is a two layer matrix as defined in claim 6 or a three layer matrix as defined in claim 9. The solution in heptane of the adhesive layer (2) containing 1-trimegestone and optionally plasticizer is first applied to the peelable protective film (b) and then dried, 2- "adhesive layer (2) / peelable protective film (b)" set is laminated on the protective film (a) simultaneously, 3- cut percutaneous system into pastilles with a surface area of 5 to 50 cm 2 Method according to claim 12 or 13, characterized in that the manufacturing method. The solution in heptane of the adhesive layer (2) containing 1-trimegestone and optionally plasticizer is first applied to the peelable protective film (b) and then dried, 2- "adhesive layer (2) / protective film (a)" set is laminated on the peelable protective film (b) simultaneously, 3- cutting the percutaneous system into pastilles with a surface area of 5 to 50 cm 2 Method according to claim 12 or 13, characterized in that the manufacturing method. 1- a) A solution in heptane of the adhesive layer (3) is first applied on the peelable protective film (b) and then dried, b) a solution in heptane of the adhesive layer 2 containing trimegestone is first applied onto the temporary peelable protective film b 'and then dried; 2- A set of " adhesive layer (2) / temporary peelable protective film (b ') " containing trimetheston is simultaneously laminated on the “adhesive layer (3) / peelable protective film (b)” set, 3- Peel off the temporary protective film (b '), 4- A layer of "adhesive layer (2) / adhesive layer (3) / peelable protective film (b)" is simultaneously laminated on the protective film (a), 5- cut percutaneous system with pastille having a surface area of 5 to 50 cm 2 Method according to claim 12 or 14, characterized in that the manufacturing method. 1- a) A solution in heptane of the adhesive layer (1) is first applied to a temporary peelable protective film (b ') and then dried, b) a solution in heptane of the adhesive layer 2 containing trimegestone is first applied to the temporary peelable protective film b " and then dried; c) the solution in heptane of the adhesive layer 3 is first applied to the peelable protective film (b) and then dried; 2- A set of "adhesive layer (1) / temporary peelable protective film (b ')" is simultaneously laminated on protective film (a), 3- Peel off the temporary protective film (b '), 4- Laminate sets of "adhesive layer (2) / temporary adhesive layer (b") "containing trimegestone on the" adhesive layer (1) / protective film (a) "set simultaneously, 5- Peel off the temporary protective film (b "), 6- In the final co-lamination process, the "adhesive layer (3) / peelable protective film (b)" set is co-laminated on the "drug containing layer (2) / adhesive layer (1) / protective film (a)" set, 7- cut percutaneous system with pastilles having a surface area of 5 to 50 cm 2 Method according to claim 12 or 15, characterized in that the manufacturing method. Step I: for the preparation of a patch corresponding to compartment (A) A silicone polymer adhesive layer comprising 1-trimegestone and optionally one or more additives is coated on the protective film (a), The solvent is evaporated until a set of " matrix (I) / protective film (a) with trimegestone ”corresponding to 2-compartment (A) is obtained, 3- A set of " matrix / protective film (a) with trimegonestone " was co-laminated on the peelable protective film (b '), 4- 5-50 cm 2 patch is cut, Step II: For Preparation of Patches Corresponding to Compartment (B) A polymer adhesive layer comprising a 1-estrogen compound and optionally one or more additives such as a hydrophilic polymer, an absorption promoter or a plasticizer, is coated on the protective film (a '), The solvent is evaporated until a set of "matrix / protective film (a ') with estrogen corresponding to 2-compartment (B) is obtained, 3- A set of "matrix / protective film (a ') containing estrogens is co-laminated on the peelable protective film (b"), 4- 5-50 cm 2 patch is cut, Step III: for the formation of "double super" 1- Peelable protective film (b ') is peeled from the patch obtained in step I, 2- transfer the set of "matrix / protective film (a) with trimegonestone" to the peelable protective film (b), 3- A peelable protective film (b ") is peeled off from the patch obtained in step II, After considering a distance of 4- 1 to 10 mm, or arranging a barrier between compartments (A) and (B), a set of " matrix / protective film (a ') containing estrogen " b) transferred to 20. A method of manufacturing the device according to claim 19, characterized in that. 17. The tree of any of claims 12 to 16, wherein the matrix (s) of the device are applied to the skin or mucous membranes of the patient, thereby admixing the trimeston and / or one or more pharmaceutically acceptable derivatives, or estrogens. Device for use in the process of delivering megestone to a patient. An ester at position 21 of a trimegeston, characterized in that it has 1 or 3 to 12 carbon atoms in the trimeston ester, excluding the trimeston.