NO315149B1 - Adhesive polymer matrix applied to a device for transdermal administration of a progestomimetic compound, device for transdermal administration of a progestomimetric compound, and method of preparing the device - Google Patents

Abstract

Devices intended for transdermal administration, characterized in that they contain:. - a protective film (a) ,. a single-layer, two-layer or three-layer matrix filled with trimegeston and possibly a matrix filled with estrogen ,. a peelable protective film (b). A process for their preparation and their use as medicaments is also described.

Description

The present invention relates to an adhesive polymer matrix applied to a unit for transdermal administration of a progestomimetic compound, unit for transdermal administration of a progestomimetic compound and method for manufacturing the unit.

Transdermal systems that deliver a progestomimetic compound are of great therapeutic interest.

Progestomimetic steroids are then also active ingredients that must be administered for long periods of time.

The retarding esters of these steroids or the galenic forms which provide controlled release, such as implants or microspheres, are used therapeutically, but often have the disadvantage that they are not easy to use. They also do not allow a quick interruption of the treatment if necessary.

A transdermal system has the advantage that it can be used for long-term treatment under the limitation of over-dosage. Application of the transdermal administration can also avoid unwanted effects, such as overloading the liver.

The applicant has thus investigated a new pharmaceutical compound which can be administered transdermally, containing a progestomimetic compound known under the name trimegestone (17-alpha-methyl-17-beta-(2-hydroxy-1-oxopropyl)-estra-4,9-diene- 3-on (21S)): 1 - which can contain trimegestone under good stability conditions, especially during storage, 2 - which allows the administration of trimegestone in a transcutaneous flow of between 0.1 and 3 ug/cm<2>/h,

3 - which allows the delivery of the necessary

dose of the active ingredient while maintaining a size (surface area) that is more acceptable than plasters according to known techniques,

4 - which has a simple and cheap production process

5 - which allows adhesion compatible with the required duration, especially for menopausal hormone replacement therapy, i.e. for 3 to 7 days, 6 - which provides an amount suitable for the flow and adhesion criteria.

According to the present invention, an adhesive polymer matrix applied to a unit for transdermal administration of a progestomimetic compound is thus provided, characterized in that the matrix contains the following successive layers: - possibly a layer (1) known as an anchoring layer, consisting of a silicone polymer, - a layer (2) consisting of a silicone polymer filled with trimegestone and one or more pharmaceutically acceptable derivatives, and optionally a plasticizer, - optionally a layer (3) known as an adhesion layer, consisting of a silicone polymer.

Trimegestone is a powerful progestomimetic compound described in European patent EP-0007823.

Pharmaceutically acceptable derivatives mean esters in position 21 of trimegestone where the ester residue contains from 1 to 2 carbon atoms. This is particularly the 17-beta-(2-ace-toxy-1-oxo-propyl)-estran-4,9-dien-3-one-(21S) derivative. The ester can also be made up of the following 2-acyloxy groups: isopropionyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, oxalyloxy, succinyloxy, piva-loyloxy, undecanoyloxy, benzoyloxy. These esters are produced in particular by the action of aliphatic or aromatic carboxylic acids or anhydrides containing from 1 to 12 carbon atoms on trimegestone.

Among the many polymers known in the art which are capable of containing a progestomimetic compound, such as trimegestone, the applicant has determined that only one silicone polymer is capable of satisfying the necessary conditions for stability, flow and adhesion.

By silicone polymer is meant a network of poly-dimethylsiloxane (PDMS) chains.

Two types of polymer can be used, one with a strong, instant adhesive power, and especially "BIO-PSA" 7-4301, and the other with a medium, instant adhesive power, and especially "BIO-PSA" 7-3045, 7- 4201 or 7-4202. (Dow Corning Health Care Center Europe). The silicone polymer exists in the form of a clear solution in an organic solvent which is volatile at low temperatures, such as hexane, heptane, ethyl acetate or tetrahydrofuran.

These polymers are amino-resistant and contain no acidic silanol groups.

Adhesive force is characterized by peeling force and adhesive force: the adhesive force increases when passing from low instantaneous adhesive force to medium instantaneous adhesive force. The parameter used to modulate this physical characteristic is the silicone polymer/resin ratio. With medium adhesive power, a ratio of 40/60 is meant. In the case of strong adhesive force, a ratio of 45/55 is meant.

The amount of trimegestone incorporated into a polymer matrix as defined previously is between 1% by weight and 10% by weight. This percentage corresponds to the amount of active ingredient expressed as a percentage of the dry weight of the mixture after evaporation of the solvent. Trimegestone is then in a state of suspension in the silicone matrix.

The purpose of plasticizers is to increase the immediate adhesion value. Oils such as silicone fluid or Cetiols such as "Cetiol" S (dioctylcyclohexane) are used. More specifically, it will be present as a silicone fluid with a high viscosity. This will be polymerized dimethylsiloxane and specifically 7-912 0 silicone fluid {12,000 cSt) from DOW Corning. The amount of plasticizer can vary from 1 to 10% by weight. There can be, for example, from 1 to 3% by weight of softening agent1.

This silicone matrix has many advantages:

- No absorption promoter,

- Trimegestone is chemically well stabilized in the silicone polymer, - Flow and adhesion levels are compatible with therapeutic treatment, - Compared to reservoir systems, the matrix system has the advantage that it poses no risk of breaking down a membrane, which could lead to an overdose of the active ingredient. - Trimegestone is not affected during the production process, although it is unstable to humidity and temperature.

The piasters containing Trimegeston, as described above, thus allow a distribution of the active ingredient over time. The concentration is stable over time, without any peaks {cf. pharmacodynamic tests).

It is further particularly preferred that said adhesive polymer matrix contains an amount of trimegestone of between 1 and 10% by weight. Furthermore, it is preferred that said adhesive contains a single layer (2) consisting of a silicone polymer filled with trimegestone and one or more pharmaceutically acceptable derivatives and possibly a plasticizer. It is further preferred that said adhesive consists of 80 to 99% by weight of a silicone polymer with a strong adhesive power filled with 1 to 10% by weight trimegestone and one or more pharmaceutically acceptable derivatives and with 0 to 10% by weight silicone fluid or dioctylcyclohexane, and further more preferably 96% by weight silicone polymer with a strong, instant, adhesive power filled with 3 wt% trimegestone and 1 wt% silicone fluid.

In another embodiment, it is preferred that said adhesive polymer matrix contains 2 successive layers, where a) a first layer (2) consisting of a silicone polymer filled with trimegestone and one or more pharmaceutically acceptable derivatives, b) a second layer (3), adhesion layer , in contact with the skin and also consisting of a silicone polymer. Further preferred is an adhesive where a) the first layer consists of 90 to 99% by weight of a silicone polymer with a strong adhesive force, filled with 1 to 10% by weight trimegestone and one or more pharmaceutically acceptable derivatives, b) the second layer also consists of a silicone polymer with a strong adhesive force. Most preferred is an adhesive polymer matrix where a) the first layer consists of 97% by weight of a silicone polymer with a strong, instant, adhesive force, filled with 3% by weight trimegestone, b) the second layer also consists of a silicone polymer with a strong, instant, adhesive power.

The present invention also relates to an adhesive polymer matrix containing three successive layers where a) a first layer (1) known as an anchoring layer consisting of a silicone polymer, b) a second layer (2) consisting of a silicone polymer filled with trimegestone and one or more pharmaceutically acceptable derivatives, c) a third layer (3), the adhesion layer, which is in contact with the skin and also consists of a silicone polymer. It is further preferred that the first layer consists of a silicone polymer with a medium adhesive power, the second layer consists of 90 to 99% by weight of a silicone polymer with a strong adhesive power and filled with 1 to 10% by weight trimegestone and one or more pharmaceutically acceptable derivatives, and the third layer consists of a silicone polymer with a strong adhesive force. It is further most preferred that the first layer consists of a silicone polymer with a medium, instant adhesive power, the second layer consists of 91% by weight of a silicone polymer with a medium, instant, adhesive power and filled with 9% by weight trimegestone, and the third layer consists of a silicone polymer with a strong, instant, adhesive power.

Another object of the invention is also a device for the transdermal administration of a progestomimetic compound, characterized in that it successively consists of:

a protective film (a),

a matrix added as defined

in claim 1 or 2,

a removable protective film (b).

In even further embodiments, it is preferred that said matrix in the unit for transdermal administration is as defined in claims 3-11.

The protective films used are support materials on which the different layers that make up the patch are coated to achieve a non-dissociable system. They may be opaque if the active ingredient is photosensitive.

Among the protective films, "Scotchpak" 1109 is preferably chosen because this is a skin-colored, dense and flexible film, or "Scotchpak" 1006 (3 M Health Care Limited). "Scotchpak" 1006 consists of 4 layers:

a) a skin-colored pigmented layer

b) an aluminum layer

c) a polyethylene terephthalate layer

d) a medium density polyethylene and ethylene acetate layer.

Among the other protective films known to those skilled in the art that can be used in the present invention, mention may also be made of the "Hostaphan" RN series {RN23, RN25, RN75 or RE75).

The removable protective films used are films intended to protect the adhesive side to be attached to the skin against the transdermal system after production and during storage.

Among the peelable protective films known to those skilled in the art may be mentioned a polyester film in which one surface is treated with fluorocarbons, such as "Scotchpak" 1022 {3 M Health Care Limited) or a transparent polyester film "Silox" B5Y/0 ("Akrosil") in which one of the surfaces has been treated against adhesion with Dow-Corning Bio-release silicones.

The protective films may be opaque "Scotchpak" 1006 protective films and the peelable protective films are preferably "Scotchpak" 1022 peelable protective films.

These transdermal systems allow the delivery of trimegestone to human skin at a transcutaneous current ex vivo of between 0.1 and 3 µg/cm<2>/h.

The devices as described above can have any shape: round, oval, rectangular or square. They have a surface area of between 5 and 50 cm<2>.

Trimegestone can be combined with an estrogen. A further object of the present invention is thus also a unit for transdermal administration of a progestomimetic compound, characterized in that it also contains a matrix with added estrogen, in that the unit consists of 2 sections

(A) and (B) .

As the preferred estrogens can be mentioned 17-S-estradiol, the esters of 17-S-estradiol, such as estradiol valerate, -cyprionate, -decanoate and -acetate, ethinylestradiol, estrone, an estrogen of "horse origin", such as "Premarin" or a combination of these compounds.

More specifically, an object of the invention is the unit as described above, characterized in that the estrogenic compound is 17-p<->estradiol.

More specifically, an object of the invention is a unit as described above, characterized in that the two sections (A) and

(B)

is supported by the same removable protective film (b),

and separated by a void or barrier of 1 to 10 mm,

section (A) contains a silicone polymer matrix added with trimegestone and one or more pharmaceutically acceptable derivatives, as described above,

section (B) contains an adhesive polymer matrix filled with oestrogen, - and each of these matrices is resp. covered by a protective film (a) and (a') which are identical or different (Fig. 4). Section (A) has, for example, a surface area of between 5 and 50 cm<2> and section (B) has, for example, a surface area of between 5 and 50 cm<2>.

It is further preferred that section (A) contains a single-layer matrix as defined in claim 3, and section

(B) contains a single-layer matrix consisting of 2-ethylhexyl acrylate and vinyl acetate copolymer filled with estradiol and

optionally a hydrophilic polymer. More preferably, section (A) contains a single-layer matrix as defined in claim 4 or 5, and section (B) contains a single-layer matrix consisting of 60 to 99% 2-ethylhexyl acrylate (72%) and vinyl acetate (28%) copolymer filled with 1 to 10% by weight estradiol and 0 to 30% by weight polyvinylpyrrolidone. In a further other embodiment, it is preferred that section (A) contains a two-layer matrix as defined in claim 6, section (B) contains a single-layer matrix consisting of a 2-ethylhexyl acrylate and vinyl acetate copolymer filled with estradiol and optionally a hydrophilic polymer. Furthermore, it is preferred that section (A) contains a two-layer matrix as defined in claim 7 or 8, and section (B) contains a single-layer matrix consisting of 90 to 99% by weight of a 2-ethylhexyl acrylate (72%) and vinyl acetate (28%) ) copolymer filled with 1 to 10% by weight estradiol and 0 to 30% by weight polyvinylpyrrolidone.

According to the present invention, it is also preferred that the unit according to the present invention successively consists of the following elements:

a protective film (a),

a section (B) consisting of an adhesive polymer matrix filled with an estrogen such as estradiol,

a polyester film (C) with the same dimensions as section (A) and situated on top of this,

a section (A) consisting of a silicone polymer matrix filled with trimegestone and various pharmaceutically acceptable derivatives as defined above, where section (A) has a smaller size than section (B), e.g. half the size and is preferably centered in relation to section (B),

a removable protective film (b). More specifically, it is preferred that the matrix containing trimegestone is a two-layer matrix as defined in claim 6 or a three-layer matrix as defined in claim 9.

The removable, protective film therefore supports two separate sections (A) and (B) which respectively contains trimegestone and an estrogen compound.

When this peelable protective film has been removed, two separate patches are produced which are applied to the skin or mucous membranes, so that the administration of trimegestone and the estrogen compound is simultaneous and separate. There may also be one or more fixing means between the two sections (A) and (B) in order for the two plasters to stick together when the peelable, protective film is removed.

The polymer matrix containing the estrogen compound is selected from the 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 also silicone polymers. If necessary, a hydrophilic polymer and/or an absorbent promoter and/or a plasticizer and/or other additives known to those skilled in the art and which can improve flow, adhesion and stability criteria for transdermal systems can be added to these copolymers.

This matrix can be simple or consist of several layers. A reservoir system can also be used.

The open area used to separate the two sections can be from 1 to 10 mm. More specifically, the size of the open area can be from 2 to 4 mm.

By "barrier" is meant a physical separation consisting of a suitable material. The width of the barrier is defined by its ability to stop distribution and by the manufacturing process. The width of the barrier can be between 1 and 10 mm. It will preferably be between 1 and 3 mm wide.

When the estrogen compound is estradiol, the matrix can be a single-layer matrix comprising a 2-ethylhexyl acrylate and vinyl acetate mixture with added estradiol and to which a hydrophilic polymer can optionally be added. Specifically, it may be the "Gelva" 737 copolymer containing 72% 2-ethylhexyl acrylate and 28% vinyl acetate. Optionally, the hydrophilic polymer can be, for example, polyvinylpyrrolidone. Specifically, this "Kollidon" is 30 or 90F.

The amount of estradiol incorporated into a polymer matrix as defined above can be between 1% by weight and 10% by weight.

More specifically, the present invention also provides units according to claims 12 to 16, characterized in that they are used in a delivery process, either of trimegestone and one or more pharmaceutically acceptable derivatives, or of trimegestone combined with an oestrogen, to a patient by application of the matrix/ the matrices in the device on the patient's skin or mucous membranes.

The devices as described above can, for example, have the following characteristics:

Double patch 1, comprehensive

a peelable protective film (b) supporting two sections (A) and (B) separated by an open area or barrier of 1 to 10 mm,

section (A) containing a single layer matrix covered by a protective film (a) and consisting of a silicone

polymer added trimegestone and one or more pharmaceutically acceptable derivatives and optionally a plasticizer, and

section {B) containing a single layer matrix covered with a protective film (a<1>) consisting of a 2-ethylhexyl acrylate and vinyl acetate copolymer added with estradiol and optionally a hydrophilic polymer.

Double patch 2, comprehensive

a peelable protective film (b) supporting two sections (A) and (B) separated by an open area or barrier of 1 to 10 mm,

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

a) the first layer consists of a silicone polymer added with trimegestone and one or more pharmaceuticals

acceptable derivatives,

b) the second layer, the layer that adheres to the skin, also consists of a silicone polymer,

and section (B) containing a single-layer matrix covered with a protective film (a<1>) consisting of a 2-ethylhexyl acrylate and vinyl acetate copolymer added with estradiol and optionally a hydrophilic polymer.

More specifically, the above-mentioned units may contain:

Double plaster la, extensive

a peelable protective film (b) supporting two sections (A) and (B) separated by an open area or barrier of 1 to 10 mm,

section (A) containing a single-layer matrix covered by an opaque, protective film (a) and consisting of 80 to 99% by weight of silicone polymer with a strong adhesive force, added with 1 to 10% by weight of trimegestone and one or more pharmaceutically acceptable derivatives and with 0 to 10% by weight silicone fluid or Cetiol S,

section (B) containing a single layer matrix covered with a protective film (a<1>) and consisting of 60 to 99% by weight "Gelva" 737 added with 1 to 10% by weight estradiol and 0 to

30% by weight "Kollidon".

Double patch 2a, extensive

a peelable protective film (b) supporting two sections (A) and (B) separated by an open area or barrier of 1 to 10 mm,

section (A) containing a two-layer matrix covered by a protective film (a), a) the first layer consists of 90 to 99% by weight of a silicone polymer with a strong adhesive force, added 1 to 10% by weight trimegestone and one or more pharmaceutically acceptable derivatives, b) the second layer, the layer that adheres to the skin, also consists of a silicone polymer with a strong

adhesive force,

and section (B) containing a single-layer matrix covered by a protective film (a<1>) and consisting of 60 to 99% by weight "Gelva" 737 added with 1 to 10% by weight estradiol and 0 to 30% by weight "Kollidon".

This "double patch":

allows the combination in a single unit of trimegestone and the estrogen compound to be administered simultaneously, separately and for a certain time for hormone replacement therapy in connection with the menopause and in particular for the prevention or treatment of osteoporosis,

solves problems with stability differences between active ingredients in polymers used for layers containing added substances: trimegestone is not stable in the matrix used for estradiol,

allows the administration of each active ingredient under optimal conditions to obtain a pharmaceutical transcutaneous flow and avoids any interaction between one compound and the matrix of the other compound,

allows adaptation to the stipulated requirements regarding doses and administration day for each active ingredient

(advance dosing), while the purchase and manipulation of two individual plasters is avoided.

In connection with an estrogen-progesterone combination, the last point is particularly important for hormone replacement therapy in connection with the menopause and especially the prevention or treatment of osteoporosis, as well as contraceptive treatment.

It also offers the following advantage: by applying two separate matrices on the same removable protective film, it is easy to: separately optimize the formulations containing the active ingredients (selection of the support polymer, selection of an absorption promoter, selection of the hydrophilic polymer, selection of a plasticizer, optimization of quantity ratio) as a function of the required adhesion and flow criteria,

separately optimize the concentrations of the active ingredients as a function of required stability and transcutaneous flow criteria, and prescribed doses,

obtain sections of identical or different size using a simple manufacturing process.

It also describes a unit ("combination patch") successively consisting of the following components:

a protective film (a),

a section (B) consisting of an adhesive polymer matrix added with an estrogen, such as estradiol,

a polyester film (C) with the same dimensions as section (A) and located on top of this,

a section (A) consisting of a silicone polymer matrix added to trimegestone and various pharmaceutically acceptable derivatives as defined above, section (A) having a smaller size than section (B), e.g. half the size and is preferably centered in relation to section (B),

a removable protective film (b).

Section (A) is smaller than section (B), so that the matrix containing estrogen located above the matrix containing trimegestone can also be in direct contact with the skin. The estrogen compound will thus diffuse directly from this location. Section (A) can e.g. have a surface area of 15 cm<2> and section (B) can have a surface area of 30 cm<2> {see fig. 5).

The "Combiplasteret" with a two-layer matrix, can e.g. used for 4 days and the "combi patch" with a three-layer matrix, can e.g. used for 7 days.

The production technique for transdermal systems is coating. The general principle is as follows: A silicone polymer solution is mixed in an apolar, organic solvent, such as heptane, with the active ingredient and possibly any other additive, and a suspension or solution of adhesive (2) is obtained which is spread (coated) on a removable protective film or a protective film. After any preliminary evaporation under a fume hood at ambient temperature, the film is dried at a temperature between 40 and 100 °C until the solvent has evaporated completely. Such a method is repeated a suitable number of times, depending on the number of layers required and then the transdermal system is cut into pieces, called patches, where the surface area of these patches is between 1 and 50 cm<2>. Adhesive solution (1) or (3) refers to silicone polymer solutions in an apolar, organic solvent, such as heptane, to which no active ingredient has been added. An aim of the present invention is consequently also the production of units according to claim 12 or 13, characterized in that 1 - a solution of adhesive layer (2) in heptane filled with trimegestone and possibly a plasticizer, is first applied to a removable, protective film ( b) and then dried, 2 - the "adhesive layer (2)/removable protective film (b)" set is laminated together on the protective film (a) , 3 - the transdermal systems are cut into pieces with a surface area of between 5 and 50 cm<2>.

In this way, a "double plaster" is obtained, which is characterized by the fact that it contains (fig. 1):

- a protective film (a)

- an adhesive layer (2) with added trimegestone and possibly a plasticiser, - a removable, protective film (b).

According to the present invention, the manufacturing process can also be carried out as follows: 1 - a solution of adhesive layer in heptane filled with trimegestone and possibly a plasticizer (2), first applied to a protective film (a) and then dried, 2 - the "adhesive layer (2)/protective film (a)" set is laminated together on a removable protective film (b), 3 - the transdermal system is cut into pieces with a surface area of between 5 and 50 cm<2>.

Units according to the present invention can also be produced as follows: 1

a) a solution of adhesive layer (3) in heptane is first applied to a removable protective film (b) and

then dried,

b) a solution of adhesive layer (2) in heptane, filled with trimegestone, on a temporarily removable, protective

film (b<1>) and then dried,

2 - the "adhesive layer (2) filled with trimegestone/- temporary removable protective film (b')" set, is laminated together on the "adhesive layer (3)/removable protective film (b)" set, 3 - the temporary protective film (b') is removed, 4 - the "adhesive layer (2)/adhesive layer (3)/removable protective film (b)" set is laminated on a protective film (a), 5 - the transdermal systems are cut into pieces with a surface area of between 5 and 50 cm<2>.

In this way, the "double patch11" is obtained, which is characterized by the fact that it contains (fig. 2):

- a protective film (a)

- an adhesive layer coated with trimegestone (2),

- an adhesive layer between the trimegestone layer and the removable, protective film (3),

- a removable, protective film (b).

Further other units of the present invention can be produced by

1

a) a solution of adhesive layer (1) in heptane is first applied to a temporary, removable, protective

film (b<1>) and then dried,

b) a solution of adhesive layer (2) in heptane, filled with trimegestone, is first applied to a temporary

removable protective film (b<11>) and then dried,

c) a solution of adhesive layer (3) in heptane is first applied to a removable, protective film (b) and

then dried,

2 - the "adhesive layer (1)/temporary peelable protective film (b')" set is laminated together on a protective film (a), 3 - the temporary protective film (b<1>) is removed, 4 - the "adhesive layer (2) coated with trimegestone/temporary adhesive layer (b'')" set is laminated together on the "adhesive layer Cl)/protective film (a)" set, 5 - the temporary protective film ( b'1) <f>ironed, 6 - "adhesive layer {3)/removable protective film (b)" sets are laminated together on the "filled layer (2)/adhesive layer (1)/protective film (a) "set, 7 - the transdermal system is cut into pieces with a surface area of between 5 and 50 cm<2>.

In this way, a plaster is obtained which is characterized by the fact that it contains (fig. 3):

- a removable, protective film (b),

- an adhesive layer between the protective film and the preparation-added layer (3),

- an adhesive layer with added trimegestone (2),

- an adhesive layer between the preparation-added layer and the protective film (anchor layer) (1),

- a protective film (a).

Furthermore, the device allowing the transdermal administration of trimegestone combined with an estrogen according to the present invention can preferably be prepared as follows: Step I: For the preparation of the patch corresponding to section

(A)

1 - the adhesive silicone polymer layer filled with

trimegestone and optionally one or more additives, are coated on the protective film (a), 2 - the solvent is evaporated until the "matrix filled with trimegestone (I)/protective film (a)" set, which corresponds to section (A), is obtained, 3 - the "trimegestone coated matrix/protective film (a)" kit is laminated together on a removable protective film (b'),

4 - a patch of 5 to 50 cm<2> is cut out.

Step II: For the preparation of the patch corresponding to section

(B)

1 - the adhesive polymer layer filled with an estrogen-gene 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<1>), 2 - the solvent is evaporated until "matrix filled with estrogen/protective film (a<1>)" set, corresponding to section (B), is obtained, 3 - "matrix filled with estrogen/protective film (a')" set is laminated together on peelable protective film

<b") ,

4 - a patch of 5 to 50 cm<2> is cut out.

Step III: For making the "double patch"

1 - the peelable protective film (b') is removed from the patch prepared in step 1, 2 - the "matrix filled with trimegestone/protective film (a)" kit is transferred to a peelable protective film (b) , 3 - the peelable , protective film (b11) is removed from the patch prepared in step 2, 4 - the "matrix filled with estrogen/protective film (a<1>)" kit is transferred to the peelable protective film (b) described above, maintaining a distance of 1 to 10 mm or after placing a barrier between sections (A) and (B).

In this way, a "double plaster" is obtained, which is characterized by the fact that it contains (fig. 4):

- a removable, protective film (b),

- a section (A) consisting of a matrix added to trimegestone, as defined above, and covered by a protective film (a) - a section (B) consisting of a matrix added to an estrogen compound and covered by a protective film (a<1> ), where the two sections are separated from each other by an open area or barrier of 1 to 10 mm.

All these procedures can also be applied to the esters of trimegestone, as defined above.

These different processes are in all cases less expensive than the production process using reservoir systems. The processes are easy to carry out and require relatively short drying times. The drying is preferably carried out at 60 °C for 15 min.

The drying is carried out as a continuous industrial process. The production conditions are as follows: stage I: 35 °C, stage II: 50 °C, stage III: 60 °C and stage IV: 80 °C.

The production process for a single-layer plaster is particularly simple because, on the one hand, there is only a single layer, which does not entail any loss of film in relation to simultaneous lamination processes, and adjustments are simplified in relation to a simultaneous lamination. The process is cheap for the reasons mentioned above, but also because it allows a high production rate and it requires less raw material (trimegestone and excipients). The production process for a two-layer plaster has the advantage over a single-layer plaster in that it does not ■require a plasticiser.

Trimegestone has very good affinity for the progesterone receptor (6 to 7 times the affinity of progesterone). It also has a very weak affinity for the androgen receptor and no affinity for the estrogen receptor (<0.02). Investigations in vivo have confirmed the investigations in vitro. Trimegestone is a potent progestomimetic compound without mineralocorticoid, androgenic, glucocorticoid, antiglucocorticoid and estrogenic activity. On the other hand, it has an antimineral-corticoid and antiandrogen activity. Trimegestone in the form of a patch is therefore of great interest in therapeutic medicine.

Units containing trimegestone according to the present invention can be used in the treatment of gynecological problems caused by a failure of the corpus luteum: - menstrual problems and/or problems in connection with the menstrual cycle,

- dysmenorrhea,

- premenstrual syndrome,

- mastodynia, mastopathy,

- functional bleeding,

- menorrhagia caused by fibroids,

- endometrial hyperplasia,

- premenopausal problems,

- endometriosis,

- monopause problems,

- contraception,

- ovarian dystrophies due to inactivity of the ovaries,

- treatment of tumors and the uterus.

In combination with an estrogen, such as estradiol, the progestomimetic compound, trimegestone, shows a strong anti-estrogenic activity at the uterine level, while it shows no anti-estrogenic activity at the bone structure level. The combination estrogen/trimegestone according to the present invention can therefore be used in hormone replacement therapy in connection with the menopause and especially in the prevention or treatment of

osteoporosis.

Among the preferred estrogens may be mentioned 17-beta-estradiol, the esters of 17-beta-estradiol, such as estradiol valerate, -cyprionate, -decanoate and -acetate, ethinylestradiol, estrone, estrogen of "equine origin", such as premarin (premarins), or a combination of these compounds.

With respect to osteoporosis, this is a pathology characterized by a quantitative and qualitative reduction of bone substance, sufficient to lead to vertebral or peripheral fractures, in a spontaneous manner or in cases resulting from minimal trauma. Although this disease is caused by many basic factors, it is the menopause which, in women, constitutes the dominant factor in bone loss or osteopenia.

Osteopenia is manifested by a loss and a modification of the structure of the spongy bone substance and the consequence of this is that the fragility of the skeleton and the risk of fractures increase. Bone loss increases strongly after menopause due to the suppression of ovarian function and reaches 3 to 5% per years before it decreases after the age of 65.

For therapeutic purposes, the postmenopausal hormone deficiency can be compensated for by means of a hormone replacement therapy where estrogen plays a major role in maintaining bone mass. However, long-term estrogen therapy is sometimes accompanied by unwanted effects on the genital system (endometrial hyperplasia, breast tumors...) which constitute a major disadvantage and limit the use of the therapy. It is therefore appropriate that estrogen is combined with a progestational hormone capable of counteracting the side effects of estrogen on genital targets while maintaining its beneficial effect on bone. Combinations of this type are already known and are e.g. described in the following patents or patent applications EP-0136011, US5208225, US5108995, EP-474374, DE4019670. However, they have a significant disadvantage due to the many activities associated with the progestational hormones used in the combinations and especially their androgenic effects.

The combination does not have this disadvantage. Trimegestone, which belongs to the norpregnane class of progestational hormones, has practically no androgenic activity, which leads to a good metabolic tolerance.

The estrogen/trimegestone combination according to the present invention can also be used as a contraceptive. The estrogen gene will then be ethinylestradiol in particular.

The processing examples below illustrate the invention without limiting it.

1) Trimegestone alone

Treatment a

A first patch can be applied from the 16th to the 18th day of the cycle, a second patch from the 19th to the 21st day of the cycle and a third patch from the 22nd to the 25th day of the cycle, i.e. 10 days per cycle.

Treatment b

A first patch can be applied from the 5th. to the 8th day of the cycle, a second patch from the 9th to the 12th day of the cycle, a third patch from the 13th to the 16th day of the cycle, a fourth patch from the 17th to the 21st day in the cycle and a fifth patch from the 22nd to the 25th day of the cycle, i.e. 21 days per cycle.

Continuous trimegestone treatment can also be used.

2) Trimegestone combined with estradiol

Used as hormone replacement therapy for the menopause and especially in the prevention or treatment of osteoporosis. The estradiol can be available in the form of a tablet or patch.

Sequential administration of trimegestone and continuous administration of estradiol:

Treatment a

Continuous administration of estradiol (28-day cycles without interruption between cycles) at a dose of 25 to 200 µg per day and of trimegestone in the last 14 days of each 28-day cycle, at a dose of 0.05 to 2.5 mg per day.

Treatment b

Administration of estradiol 28 days per months at a dose of 25 to 200 ug per day and of trimegestone in the last 14 days of the administration of estradiol, at a dose of 0.05 to 2.5 mg per day. The treatment is stopped for 2 to 3 days per months at the end of each 28-day cycle.

Treatment c

Administration of estradiol 28 days per months at a dose of 25 to 200 ug per day and of trimegestone in the first 14 days of the administration of estradiol, at a dose of 0.05 to 2.5 mg per day. The treatment is administered either without interruption between each 28-day cycle, or with an interruption of 2 to 3 days per cycle. months at the end of each cycle.

Treatment d

Administration of estradiol 25 days per months in a dose of 25 to 200 ug per day and of trimegestone in a dose of 0.05 to 2.5 mg per day for the last 11 to 14 days of estradiol administration. Treatment is stopped for 5 to 6 days at the end of the 25-day cycle.

Continuous administration of trimegestone and estradiol

Continuous administration of estradiol at a dose of 25 to 200 ug per day and of the trimegestone patch in a dose of 0.05 to 2.5 mg per day. There is no interruption in treatment.

3) Trimegestone combined with ethinylestradiol

In connection with use as a contraceptive.

The trimegestone patch in combination with ethinylestradiol is administered continuously for 21 to 28 days per cycle. This treatment requires successive application of 3 to 8 tri-megestone patches and administration of ethinylestradiol for 21 to 28 days/cycle, especially in the form of a patch or

pills.

Examples of plasters according to the present invention are shown in the following and in the experimental part. The following examples illustrate the invention without limiting it.

Example 1

Single-layer patch containing trimegestone

- A Scotchpak 1006 opaque protective film with a thickness of 70 ± 2 Jim (a) ,

- A layer of 94% by weight BIO-PSA silicone polymer added

3% by weight trimegestone and 1% by weight silicone fluid, thickness from 50 to 60 µm (2), - A Scotchpak 1022 removable protective film, thickness 70 ± 1 p (b).

This patch has a surface area of 20 cm<2> and delivers eJcs vivo 0.80 ± 0.54 ug/h/cm<2> trimegestone (see Fig. 1). The following matrices have been produced:

Example la: (one-layer matrix)

Plaster surface area 20 cm<2>, quantity 60 g/m<2>

Example 2

Two-layer patch containing trimegestone

- A Scotchpak 1006 opaque protective film with a thickness of 70 ± 2 um (a), - A layer of 97% by weight BIO-PSA silicone polymer with a strong adhesive power, added with 3% by weight trimegestone, thickness from 50 to 60 um (2 ), - A "BIO-PSA" adhesive layer with a strong, instant adhesive force, thickness 65 µm (3), - A Scotchpak 1022 removable protective film with a thickness of 70 ± 1 µm (b).

This plaster has a surface area of 20 cm<2> and delivers ex vivo 1.29 + 0.45 ug/h/cm<2> trimegestone (see fig. 2). The following matrix was produced:

Example 2a: (two-layer matrix)

Plaster surface area 20 cm2, quantity 60 + 30 g/m<2>

Example 3

The following "three-layer" plaster was prepared:

This patch consists of the following successive layers:

- A Scotchpak 1006 opaque protective film with a thickness of 70 ± 2 um (a), - A "BIO-PSA" anchoring layer with a medium, instant adhesive force, thickness approx. 33 um (1), - A layer of "BIO- PSA" silicone polymer with a medium, instant adhesive power (91% by weight) added trimegestone (9% by weight), thickness from 50 to 60 µm (2), - A "BIO-PSA" adhesive layer with a strong, instant adhesive power, thickness approx. 65 um (3), - A Scotchpak 1022 removable protective film with a thickness of 70 ± 1 um (b).

This patch has a surface area of 20 cm<2> and delivers ex vivo 0.59 ± 0.33 ug/h/cm<2> trimegestone (see Fig. 3). The following matrix was produced:

Example 3a: (three-layer matrix)

Plaster surface area 20 cm<2>, quantity 30.5 + 61.5 + 65 g/m<2>

Example 4

Patches containing trimegestone combined with estradiol Double patch lb (see fig. 4)

This double plaster has the following characteristics: - a "Scotchpak" 1022 removable, protective film (b), thickness approx. 70 µm, characterized by supporting two sections (A) and (B), separated from each other by an open area of 2 to 4 mm. - section (A) contains a single-layer matrix, thickness approx. 60 um, covered by a "Scotchpak" 1006 opaque protective film (a), thickness approx. 70 um and consisting of 96% by weight "BIO PSA" with a strong, instant adhesive power, added with 3% by weight trimegestone and 1% silicone fluid (7-9120, 12000 cSt). The amount is equal to 60 g/m<2>. - and section (B) containing a single-layer matrix, thickness approx. 76 um, covered by a "Scotchpak" 1109 protective film (a<1>) thickness approx. 34 um, or "Hostaphan" RN23 and consisting of 73% by weight "Gelva" 737 added with 2% by weight estradiol and 25% by weight "Kollidon" 90F. The amount is equal to 80 g/m<2>.

Double patch 2b

This double patch has the following characteristics: - a "Scotchpak" 1022 removable protective film (b) characterized by supporting two sections (A) and (B), separated from each other by an open area of 2 to 4 mm. - section (A) containing a two-layer matrix covered with a "Scotchpak" 1006 protective film (a),

a) the first layer to which 3% by weight trimegestone has been added is made up of 97% by weight of a "BIO PSA" silicone polymer

with a strong, instant, adhesive power,

b) the second layer, the layer that adheres to the skin, consists of a "BIO PSA" silicone polymer with a strong,

adhesive force;

The total amount is thus 90 g/m<2>,

- and section (B) containing a single layer matrix covered by a "Scotchpak" 1109, or "Hostaphan" RN23 protective film (a<*>) and consisting of 73% by weight of a "Gelva" 737 layer added with 2% by weight of estradiol and 25% by weight "Kollidon" 90F. The amount is equal to 80 g/m<2>.

Tests on the plaster structure

The following patches were produced:

(I) A two-layer patch according to the invention containing 3% by weight trimegestone, the amount in the filled layer = 59.82 ± 1.77 g/m<2>, the amount in the adhesive layer = 29.76 ± 3.67 g/m< 2>. (II) A two-layer plaster according to the invention containing 9% by weight trimegestone, the weight in the filled layer = 59.16 ± 2.77 g/m<2>, the amount in the adhesive layer = 29.72 ± 3.31 g/m< 2>. (III) A three-layer patch according to the invention containing 9% trimegestone.

(IVa) A single-layer patch according to the invention containing 3% by weight of trimegestone, amount = 61.1 ± 2.5 g/m<2> (with a plasticizer: 1% by weight of silicone fluid).

(IVb) A single-layer patch according to the invention containing 3% by weight trimegestone, amount = 59.1 ± 0.9 g/m<2> (with a plasticizer: 1% by weight "Cetiol" S).

(IVc) A single-layer patch according to the invention containing 3% by weight of trimegestone, amount = 42.9 ± 3.0 g/m<2> (without a plasticizer).

(IVd) A single-layer patch according to the invention containing 3% by weight of trimegestone, amount = 63.0 + 3.83 g/m<2> (without a plasticizer).

Adhesion test:

Principle:

The instantaneous adhesion force is evaluated by placing a patch (surface area = 5 cm<2>) in contact with a steel surface (1 cm<2>) under known pressure conditions (compression force: 5 N, duration 60 s) and by measuring the energy required to separate the two surfaces. This measurement can be used to compare different formulas or to monitor the development of the adhesion over time.

With regard to the two-layer or three-layer patch, the amount of active ingredient contained in the filled matrix will not modify the immediate adhesion.

The presence of one or two adhesive layers on the filled matrix significantly improves immediate adhesion.

Transcutaneous permeation ex vivo

Principle:

A skin fragment is mounted on a Franz cell-type cell for transcutaneous transfer. The transdermal system is attached to the skin on the stratum corneum side. The active ingredient is released by the transdermal system, penetrates the skin barrier and is recovered in the collection medium. The amount of active ingredient is dosed at regular time intervals.

Method:

The skin fragments originate from plastic surgery (breast or abdomen).

The skin is stored at 4 °C in a survival fluid until dissected. After removal of the subcutaneous fat, the skin is cut into a 300 µm thick slice and stored at -30 °C until use.

The skin is mounted on the receiving section of the cell. The skin and the receiving medium must be kept for approx. 15 h to reach equilibrium. The patch is then placed on the skin. The transcutaneous passage of the active ingredient is monitored by the dose of trimegestone in the receiving medium.

The presence of one or two additional layers does not significantly modify transcutaneous permeation.

Test on the affinity of trimegestone towards hormonal receptors

The affinity of trimegestone was compared to other common progestomimetic compounds: medroxyprogesterone (MPA), norethisterone (NE), promegestone (PROM), gestodene (GEST) and levonorgestrel (LNOR). This affinity was tested on recombinant human progesterone (hPR), androgen (hAN), glucocorticoid (hGR) and estrogen (hER) hormonal receptors. These receptors are obtained by overexpression in an insect cell-baculovirus SF9 system in accordance with the methods described in particular in European patent application 0 62 9 635. The relative binding affinities (RBA) are as follows:

Pharmacokinetic investigation of trimegestone

After application of the 4 three-layer 20 cm<2> plasters (9% trimegestone) in each 4, 3, 4 and 3 days, the concentration of trimegestone in plasma remains stable until the last patch is removed, with an average value of 1.37 mg/ml. The through-flow of trimegestone therefore has an average value of 0.4 mg/day/patch. No changes in the plasma concentration levels of estradiol and estrone were observed. The plasma concentrations of FSH and LH are, in turn, reduced by 31 and 38% after 14 days of application (antigonadotropic effect of trimegestone).

In conclusion, the trimegestone patches according to the present invention, applied for 14 days (1 every 3 days), provide a constant stream of trimegestone with stable plasma concentrations of trimegestone and good local tolerance.

Figure no. 1: Construction of single-layer plaster (20 cm<2>)

(a) Protective film

(2) Filled adhesive layer

(b) Removable protective film

Figure no. 2: Construction of a two-layer plaster (20 cm<2>)

(a) Protective film (2) Filled adhesive layer

(3) Adhesive layer

(b) Removable protective film

Figure no. 3: Construction of a three-layer plaster (20 cm<2>)

(a) Protective film (1) Anchoring layer

(2) Filled adhesive matrix

(3) Adhesive layer

(b) Removable protective film

Figure No. 4:

(B) Section containing estradiol (15 cm<2>)

(A) Section containing trimegestone (20 cm<2>)

(a1) Protective film

(a) Protective film (b) Removable protective film

Figure No. 5:

(B) Section containing estradiol (A) Section containing trimegestone

(a) Protective film

(b) Removable protective film (c) Polyester film

Claims (31)

1. Adhesive polymer matrix applied to a unit intended for transdermal administration of a progestomimetic compound, characterized in that the matrix contains the following successive layers: - possibly a layer (1) known as an anchoring layer, consisting of a silicone polymer, - a layer (2) consisting of a silicone polymer filled with trimegestone and one or more pharmaceutically acceptable derivatives, and optionally a plasticizer, - optionally a layer (3) known as an adhesion layer, consisting of a silicone polymer. 2. Adhesive polymer matrix according to claim 1, characterized in that it contains an amount of trimegestone of between 1 and 10% by weight. 3. Adhesive polymer matrix according to claim 1, characterized in that it contains a single layer (2) consisting of a silicone polymer filled with trimegestone and one or more pharmaceutically acceptable derivatives and optionally a plasticizer. 4. Adhesive polymer matrix according to claim 3, characterized in that it consists of 80 to 99% by weight of a silicone polymer with a strong adhesive force filled with 1 to 10% by weight trimegestone and one or more pharmaceutically acceptable derivatives and with 0 to 10% by weight of silicone fluid or dioctylcyclohexane. 5. Adhesive polymer matrix according to claim 4, characterized in that it consists of 96% by weight silicone polymer with a strong, immediate, adhesive force filled with 3% by weight trimegestone and 1% by weight silicone fluid. 6. Adhesive polymer matrix according to claim 1, characterized in that it contains 2 successive layers: a) a first layer (2) consisting of a silicone polymer filled with trimegestone and one or more pharmaceutically acceptable derivatives, b) a second layer (3), adhesion layer , in contact with the skin and also consisting of a silicone polymer. 7. Adhesive polymer matrix according to claim 6, characterized in that a) the first layer consists of 90 to 99% by weight of a silicone polymer with a strong adhesive force, filled with 1 to 10% by weight trimegestone and one or more pharmaceutically acceptable derivatives, b) the second layer also consists of a silicone polymer with a strong adhesive force. 8. Adhesive polymer matrix according to claim 7, characterized in that a) the first layer consists of 97% by weight of a silicone polymer with a strong, immediate, adhesive force, filled with 3% by weight trimegestone, b) the second layer also consists of a silicone polymer with a strong, instant, adhesive power. 9. Adhesive polymer matrix according to claim 1, characterized in that it contains three successive layers: a) a first layer (1) known as an anchoring layer consisting of a silicone polymer, b) a second layer (2) consisting of a silicone polymer filled with trimegestone and one or more pharmaceutically acceptable derivatives, c) a third layer (3), the adhesion layer, which is in contact with the skin and also consists of a silicone polymer. 10. Adhesive polymer matrix according to claim 9, characterized in that the first layer consists of a silicone polymer with a medium adhesive power, the second layer consists of 90 to 99% by weight of a silicone polymer with a strong adhesive force and filled with 1 to 10% by weight trimegestone and one or more pharmaceutically acceptable derivatives, the third layer consists of a silicone polymer with a strong adhesive force. 11. Adhesive polymer matrix according to claim 9 or 10, characterized in that the first layer consists of a silicone polymer with a medium, instant, adhesive power, the second layer consists of 91% by weight of a silicone polymer with a medium, instant adhesive power and filled with 9% by weight trimegestone, the third layer consists of a silicone polymer with a strong, instant, adhesive power. 12. Device for transdermal administration of a progestomimetic compound, characterized in that it successively consists of: a protective film (a), a matrix as defined in claim 1 or 2, a removable, protective film (b). 13. Device according to claim 12, characterized in that the matrix is as defined in any of claims 3 to 5. 14. Device according to claim 12, characterized in that the matrix is as defined in one of claims 6 to 8. 15. Device according to claim 12, characterized in that the matrix is as defined in any of claims 9 to 11. 16. Device according to claim 12, characterized in that it also contains a matrix filled with estrogen, as the unit consists of 2 sections (A) and (B) . 17. Device according to claim 16, characterized in that the estrogen compound is selected from 17-13-estradiol, esters of 17-S-estradiol, such as estradiol valerate, -cyprionate, -decanoate and -acetate, ethinyl estradiol, estrone and an estrogen of "equine origin", such as " Premarin" or a combination of these compounds. 18. Device according to claim 16, characterized in that the estrogen compound is 17-S-estradiol. 19. Device according to claim 16, characterized in that the two sections (A) and (B) - are supported by the same removable, protective film (b), - and are separated from each other by an open area or a barrier of 1 to 10 mm, - section (A ) containing the silicone polymer matrix filled with trimegestone and one or more pharmaceutically acceptable derivatives, as defined in any of claims 1 to 11, - section (B) containing an adhesive polymer matrix filled with estrogen, - and each of these matrices is respectively covered by a protective film (a) and (a<1>) which are identical or different . 20. Device according to claim 19, characterized in that: - section (A) contains a single-layer matrix as defined in claim 3, - and section (B) contains a single-layer matrix consisting of 2-ethylhexyl acrylate and vinyl acetate copolymer filled with estradiol and optionally a hydrophilic polymer. 21. Unit according to claim 19 or 20, characterized in that: - section (A) contains a single-layer matrix as defined in claim 4 or 5, - and section (B) contains a single-layer matrix consisting of 60 to 99% 2-ethylhexyl acrylate- (72 %) and vinyl acetate (28%) copolymer filled with 1 to 10% by weight estradiol and 0 to 30% by weight polyvinylpyrrolidone. 22. Device according to claim 19, characterized in that: - section (A) contains a two-layer matrix as defined in claim 6, - section (B) contains a single-layer matrix consisting of a 2-ethylhexyl acrylate and vinyl acetate copolymer filled with estradiol and optionally a hydrophilic polymer. 23. Unit according to claim 19 or 22, characterized in that: - section (A) contains a two-layer matrix as defined in claim 7 or 8, - and section (B) contains a single-layer matrix consisting of 90 to 99% by weight of a 2-ethylhexyl acrylate - (72%) and vinyl acetate (28%) copolymer filled with 1 to 10% by weight estradiol and 0 to 30% by weight polyvinylpyrrolidone. 24. Device according to claim 16, characterized in that it successively consists of the following elements: a protective film (a), a section (B) consisting of an adhesive polymer matrix filled with an estrogen such as estradiol, a polyester film (C) with the same dimensions as section (A) and situated on top of this, a section (A) consisting of a silicone polymer matrix filled with trimegestone and various pharmaceutically acceptable derivatives as defined above, where section (A) has a smaller size than section (B), e.g. half the size and is preferably centered in relation to section (B), a removable protective film (b). 25. Device according to claim 24, characterized in that the matrix containing trimegestone is a two-layer matrix as defined in claim 6 or a three-layer matrix as defined in claim 9. 26. Unit according to any one of claims 12 to 16, characterized in that it is used in a delivery process, either of trimegestone and one or more pharmaceutically acceptable derivatives, or of trimegestone combined with an oestrogen, to a patient by application of the matrix(es) in the unit on the patient's skin or mucous membranes. 27. Method for manufacturing units according to claim 12 or 13, characterized in that: 1 - a solution of an adhesive layer (2) in heptane, filled with trimegestone and possibly a plasticizer, is first applied to a removable, protective film (b) and then dried, 2 - "adhesive layer (2)/ removable protective film (b)" set is laminated together on the protective film (a), 3 - the transdermal systems are cut into pieces with a surface area of between 5 and 50 cm<2>. 28. Method for manufacturing units according to claim 12 or 13, characterized in that: 1 - a solution of adhesive layer (2) in heptane filled with trimegestone and possibly a plasticizer is first applied to a protective film (a) and then dried, 2 - "adhesive layer (2)/protective film (of - the set is laminated together on a removable, protective film (b) , 3 - the transdermal systems are cut into pieces with a surface area of between 5 and 50 cm<2>. 29. Method for manufacturing units according to claim 12 or 14, characterized in that: 1 a) a solution of adhesive layer (3) in heptane is first applied to a removable, protective film (b) and then dried, b) a solution of adhesive layer (2) in heptane filled with trimegestone is applied to a temporary peelable protective film (b<1>) and then dried, 2 - "adhesive layer (2) filled with trimegestone/- temporary peelable protective film (b')" set, laminated together on "adhesive layer (3 )/removable protective film (b)" set, 3 - the temporary protective film (b<1>) is removed, 4 - "adhesive layer (2)/adhesive layer (3)/removable protective film (b )" kit is laminated on a protective film (a), 5 - the transdermal systems are cut into pieces with a surface area of between 5 and 50 cm<2>. 30. Method for manufacturing units according to claim 12 or 15, characterized in that: l a) a solution of adhesive layer (1) in heptane is first applied to a temporary, removable, protective film (b<1>) and then dried, b) a solution of adhesive layer (2) in heptane, filled with trimegestone, is first applied to a temporary removable protective film (b<11>) and then dried, c) a solution of adhesive layer (3) in heptane is first applied to a removable protective film (b) and then dried, 2 - the "adhesive layer (1)/temporary peelable protective film (b1)" set is laminated together on a protective film (a), 3 - the temporary protective film (b<1>) is removed, 4 - " adhesive layer (2) filled with trimegestone/- temporary adhesive layer (b' 1) 11 - the set is laminated together on the "adhesive layer (1)/protective film (a)" set, 5 - the temporary protective film (b< 1>1) is removed, 6 - "adhesive layer (3)/removable protective film (b)" set is finally laminated together on "filled layer (2)/- adhesive layer (1)/protective film (a)" -set, 7 - the transdermal ones systems are cut into pieces with a surface area of between 5 and 50 cm<2>. 31. Method for manufacturing the device according to claim 19, characterized in that: Step I: For the production of the plaster as to corresponds to section (A) 1 - the adhesive silicone polymer layer filled with trimegestone and possibly one or more additives is coated on the protective film (a), 2 - the solvent is evaporated until "matrix filled with trimegestone (I)/protective film (off-set, which corresponds to section (A), is obtained, 3 - the "trimegestone coated matrix/protective film (a)" kit is laminated together on a peelable protective film (b<1>), 4 - a patch of 5 to 50 cm <2> is cut out Step II: For making the patch that corresponds section (B) 1 - the adhesive polymer layer filled with an 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'), 2 - the solvent is evaporated until "matrix filled with estrogen/protective film (a')" set, corresponding to section (B), is obtained, 3 - the "matrix filled with estrogen/protective film (a')" set is laminated together on peelable protective film {b<> >'), 4 - a patch of 5 to 50 cm<2> is cut out. Step IIIrFor the preparation of the "double patch" 1 - the peel-off protective film (b<1>) is removed from the patch prepared in step 1, 2 - the "trimegestone-filled matrix/protective film (a)" kit is transferred to a peel-off protective film film (b), 3 - the peelable, protective film (b<11>) is removed from the patch prepared in step 2, 4 - the "matrix filled with estrogen/protective film (a<1>)" set is transferred to the above described , removable protective film (b), while maintaining a distance of 1 to 10 mm or after placing a barrier between sections (A) and (B).