Transdermal therapeutic system with diffusion barrier

Abstract

The present invention relates to a transdermal therapeutic system (1) comprising at least one active substance-containing polymer matrix (3) applied to an active substance carrier layer (2), the matrix containing at least one pressure-sensitive adhesive and at least one pharmacologically active substance absorbable through human or animal skin, and an adhesive carrier layer (6) coated as completely as possible with an active substance-free pressure-sensitive adhesive (7), the adhesive carrier layer (6) being directly bonded to the flat side of the active substance carrier layer (2) facing away from the active substance-containing polymer matrix (3), the adhesive carrier layer (6) peripherally protruding beyond the edge of the active substance carrier layer (2). The system is characterized by the presence of a peripheral region (4) between the active substance-containing polymer matrix (3) and the active substance-free pressure-sensitive adhesive (7) where the thickness of the coating with the active substance-containing polymer matrix (3) and / or the active substance-free pressure-sensitive adhesive (7) is reduced. The present invention further relates to the use of said transdermal therapeutic system and to kits containing it.

Description

[Technical Field]

[0001] The present invention relates to a transdermal therapeutic system (abbreviated "TTS") comprising: an active substance carrier layer having at least one active substance-containing polymer matrix applied thereto, said matrix containing at least one pressure-sensitive adhesive and at least one pharmacologically active substance absorbable through human or animal skin; and an adhesive carrier layer coated as completely as possible with an active substance-free pressure-sensitive adhesive, said adhesive carrier layer being directly bonded by the active substance-free pressure-sensitive adhesive to the flat side of the active substance carrier layer facing away from the active substance-containing polymer matrix, said adhesive carrier layer peripherally protruding beyond the edges of the active substance carrier layer. The present invention further relates to uses of this transdermal therapeutic system and to kits containing it. [Background technology]

[0002] Transdermal therapeutic systems (TTS) are planar pharmaceutical products with a layered structure in which one or more active substances, with or without excipients (such as penetration enhancers), are embedded in an optional pressure-sensitive adhesive polymer matrix. This polymer matrix is ​​typically produced by coating a backing film with an active substance-containing polymer composition and then providing it with a cover film that remains on the skin during application of the transdermal therapeutic system. The backing film serves as a protective layer for the polymer matrix during storage and, in some cases, as an application aid for later use of the transdermal therapeutic system.

[0003] Transdermal therapeutic systems allow for continuous delivery of active substances throughout the application period. Therefore, their concentration-time profile is comparable to that of continuous infusion. Many transdermal therapeutic systems with various active substances and combinations of active substances are currently available on the pharmaceutical market. One of the most important application areas for transdermal therapeutic systems is hormone replacement therapy, especially in menopausal women. In the early days of transdermal hormone replacement therapy, estrogen-containing monotherapy products were primarily used for this purpose. However, recently, transdermal therapeutic systems containing a combination of estrogen (e.g., 17β-estradiol) and progesterone (e.g., norethisterone) have become available. Testosterone, a male hormone, is one of a group of steroid hormones used in hormone replacement therapy, particularly for the treatment of hypogonadism.

[0004] Many commercially available transdermal therapeutic systems are configured as so-called matrix systems, in which the active substance is present in dissolved or suspended form in a polymer matrix with a pressure-sensitive or non-pressure-sensitive adhesive, primarily consisting of a polyacrylate-based pressure-sensitive adhesive.

[0005] Because the pharmacologically active substance contained in the active substance patch of a transdermal therapeutic system is expensive in many applications, the active substance patch is often cut with corners, e.g., square, to minimize loss due to cutting. Because angular patches tend to peel off from the skin, a fixed patch with rounded corners or a completely rounded surface is usually attached over them to securely hold them in place. However, such an arrangement can lead to undesirable migration of the active substance and / or one or more excipients into the pressure-sensitive adhesive matrix of the directly adjacent fixed patch. This can lead to uncontrollable loss of the active substance, as the active substance may not be able to migrate from the pressure-sensitive adhesive matrix to the skin, resulting in failure to achieve the desired dosage of the active substance. Various approaches to combat this migration problem are known in the prior art.

[0006] US2017 / 0290779A1 discloses a patch for skin application, which includes an active reservoir layer, a carrier layer extending beyond the active reservoir layer, and a further carrier layer extending beyond the two layers coated with an adhesive. The reservoir layer may include a pressure-sensitive adhesive and / or a non-adhesive polymer matrix. The production of this layer structure is very complex, and its construction requires a high degree of manufacturing precision.

[0007] WO2016 / 081616A2 describes a patch formulation for transdermal delivery of water-soluble active substances, peptides, proteins, and oligosaccharides. The patch comprises a layer containing an active substance and a polymer matrix, and an adhesive layer, the adhesive layer protruding beyond the active substance / polymer layer. The adhesive layer further comprises an adhesive-free region protruding beyond the active substance / polymer layer.

[0008] EP0755284B1 teaches a topical bandage for dermal and / or transdermal administration of a substance, the bandage comprising a carrier layer coated with an adhesive. The carrier layer further comprises a circular cutout area free of adhesive. The cutout area defines a recess into which an active substance-containing pad is inserted, the pad having a smaller diameter than the cutout area. This results in an intermediate area of ​​reduced layer thickness between the active substance-containing pad and the adhesive layer.

[0009] It can be recognized that the disadvantage of the above two solutions is that coating the carrier layer with different coating materials and coating structures at different times during production is complex and prone to problems. Furthermore, in this structure, the carrier layer must be compatible with all coating materials, which limits the choice of materials. Summary of the Invention

[0010] Starting from the above-mentioned prior art, the object of the present invention is to provide a transdermal therapeutic system of the type mentioned at the beginning, which can be produced more cheaply and at the same time has good adhesive properties to the skin and largely prevents migration of pharmacologically active substances into the adhesive of the fixing patch.

[0011] This object is achieved in a transdermal therapeutic system of the type mentioned at the beginning by providing, between the active substance-containing polymer matrix and the active substance-free pressure-sensitive adhesive of the adhesive carrier layer, a region of reduced thickness of the coating of the active substance-containing polymer matrix and / or the active substance-free pressure-sensitive adhesive, which region acts as a diffusion barrier to prevent the pharmacologically active substance and / or one or more excipients from diffusing laterally into the adhesive of the adhesive carrier layer.

[0012] Therefore, the present invention provides an active substance carrier layer having at least one active substance-containing polymer matrix applied to the active substance carrier layer, said matrix comprising at least one pressure-sensitive adhesive and at least one pharmacologically active substance absorbable through human or animal skin; and an adhesive carrier layer which is as completely coated as possible with an active substance-free pressure-sensitive adhesive, the active substance-free pressure-sensitive adhesive being directly bonded to the flat side of the active substance carrier layer facing away from the active substance-containing polymer matrix, Including, The present invention relates to a transdermal therapeutic system in which the adhesive carrier layer protrudes peripherally beyond the edges of the active substance carrier layer, the system being characterized by the presence of a peripheral region of reduced coating thickness of the active substance-containing polymer matrix and / or the active substance-free pressure-sensitive adhesive between the active substance-containing polymer matrix and the active substance-free pressure-sensitive adhesive.

[0013] The peripheral region with reduced coating thickness is preferably formed by guiding a punching tool over an active substance carrier layer whose entire surface is first coated with an active substance-containing polymer matrix, the tool comprising a hollow cylinder and a cutting blade arranged concentrically directly adjacent to the outside of the hollow cylinder. In this process, the hollow cylinder is first pressed against the coated active substance carrier layer. This causes the adhesive to move laterally, significantly reducing the thickness of the active substance-containing polymer matrix coating in this region. The cutting blade is then used to punch out the active substance carrier layer having a peripheral region with reduced coating thickness with the active substance-containing polymer matrix. This process is particularly advantageous because it allows starting from a carrier material whose entire surface is coated with an active substance-containing polymer matrix as the active substance carrier layer, and the coated active substance carrier layer can be produced in a single operation without losing material or using complex local coating methods. Even if a residual layer thickness of the active substance-containing polymer matrix remains during this process, this is nevertheless sufficient to almost completely prevent the pharmacologically active substance from diffusing into the adhesive of the adhesive carrier layer.

[0014] Therefore, the present invention also provides a method for producing the transdermal therapeutic system of the present invention, comprising the steps of: providing an active substance carrier layer having at least one active substance-containing polymer matrix applied to the active substance carrier layer, said matrix comprising at least one pressure-sensitive adhesive and at least one pharmacologically active substance absorbable through human or animal skin; bonding the adhesive carrier layer, which is as completely coated as possible with the active substance-free pressure-sensitive adhesive, directly to the flat side of the active substance carrier layer facing away from the active substance-containing polymer matrix with the active substance-free pressure-sensitive adhesive; Including, The adhesive carrier layer protrudes peripherally beyond the edge of the active substance carrier layer, and a peripheral region of reduced coating thickness with the active substance-containing polymer matrix and / or the active substance-free pressure-sensitive adhesive exists between the active substance-containing polymer matrix and the active substance-free pressure-sensitive adhesive, and the peripheral region of reduced coating thickness is preferably formed by guiding a punching tool over the material of the active substance carrier layer, the entire surface of which is coated with the active substance-containing polymer matrix, the tool comprising a hollow cylinder and a cutting blade arranged outside the hollow cylinder, more specifically directly adjacent to it, in a concentric manner, wherein the hollow cylinder is first pressed against the coated active substance carrier layer to reduce the coating thickness with the active substance-containing polymer matrix, and then the cutting blade is used to punch out the active substance carrier layer having the peripheral region of reduced coating thickness with the active substance-containing polymer matrix. The cutting blade is preferably first moved to its starting position, and then the hollow cylinder is simply lifted. Punching is preferably carried out from the flat side facing away from the active substance-containing polymer matrix, although it is also possible to punch from the side of the active substance-containing polymer matrix.

[0015] For the final production of the transdermal therapeutic system, the punch blank obtained as described above is bonded to the adhesive side of the adhesive carrier layer with the flat side facing away from the active substance-containing polymer matrix, so that the adhesive carrier layer protrudes peripherally beyond the edge of the active substance carrier layer. The transdermal therapeutic system thus produced is then typically further covered on the adhesive side with a protective layer in the form of a release liner and packaged.

[0016] The present invention further relates to the use of the transdermal therapeutic system of the present invention for the treatment of hypogonadism, Alzheimer's disease, Parkinson's disease, multiple sclerosis, bipolar disorder, muscle tension, severe pain, or high blood pressure, or for hormone replacement therapy, or for contraception, to name a few.

[0017] Another object of the present invention relates to a kit comprising the transdermal therapeutic system of the present invention in an outer package, optionally including instructions for use containing directions for use according to the present invention. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 illustrates intermediate stages in the manufacture of the transdermal therapeutic system of the present invention. [Figure 2] FIG. 2 illustrates the embodiment shown in FIG. 2 of the completed transdermal therapeutic system of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0019] The active substance-containing polymer matrix and the active substance-free pressure-sensitive adhesive can independently be pressure-sensitive adhesive systems suitable for use on the skin and known to those skilled in the art. For the purposes of the present invention, a pressure-sensitive adhesive is an adhesive that is permanently tacky in the range of 0 to 40°C, especially at room temperature, and forms a good bond with slight pressure to different surfaces, especially human skin. This is also called "adhesive." Suitable adhesives are known to those skilled in the art from the field of adhesive tapes, especially medical adhesive tapes or first aid bandages. Suitable pressure-sensitive adhesives have, for example, a glass transition temperature Tg of -10°C or less. The glass transition temperature Tg can be measured by DSC (differential scanning calorimetry) using a Mettler DSC 12E (Mettler Toledo GmbH, Giessen, Germany) at a heating rate of 10 K / min. Usable pressure-sensitive adhesives include those disclosed in DE 10141652 A1. Suitable pressure sensitive adhesives are commercially available, for example, under the brand names Duro-Tak™ and Gelva™ (both from Henkel AG & Co. KGaA).Suitable silicone adhesives (BIO-PSA 7-4101, BIO-PSA 7-4102, BIO-PSA 7-4201, BIO-PSA 7-4202, BIO-PSA 7-4301, BIO-PSA 7-4302, BIO-PSA 7-4401, BIO-PSA 7-4402, BIO-PSA 7-4501, BIO-PSA 7-4502, BIO-PSA 7-4601, BIO-PSA 7-4602), silicone-acrylate hybrid systems (7-6101 SilAc Hybrid PSA, 7-6102 SilAc Hybrid PSA, 7-6301 SilAc Hybrid PSA, 7-6302 SilAc Hybrid PSA), and two-component silicone adhesives (MG7-9700 kit (A&B), MG7-9800 kit (A&B), MG7-9850 Kit (A&B), MG7-9900 Kit (A&B), MG7-1010 Kit (A&B)) are commercially available from Dow Corning, polyisobutylene (Oppanol B10 N, Oppanol B10 SFN, Oppanol B11 SFN, Oppanol B12 N, Oppanol B12 SFN, Oppanol B13 SFN, Oppanol B14 SFN, Oppanol B15 N, Oppanol B15 SFN, Oppanol N50, Oppanol N50 SF, Oppanol N80, Oppanol N100, Oppanol N150) are commercially available from BASF SE, and styrene-isoprene-styrene block copolymers (JSR SIS 5505, JSR SIS 5403, JSR SIS 5506) are commercially available from BASF SE. JSR SIS 5250, JSR SIS 5229, JSR SIS 5002) are commercially available from JSR Life Sciences of Japan, and a suitable polyurethane pressure sensitive adhesive (Transform™ TPU) is available from Lubrizol.

[0020] The transdermal therapeutic system of the present invention comprises an active substance carrier layer and an adhesive carrier layer. The carrier materials used for the active substance carrier layer and the adhesive carrier layer may be the same or different. The carrier may be in the form of a film, woven fabric, sheet, nonwoven fabric, or knitted fabric. The carrier conveniently has sufficient flexibility to allow the system to conform to the contours of the skin. Suitable carrier materials include conventional flexible carrier materials used in pressure-sensitive adhesive tapes, such as polyesters such as polyethylene, especially low-density polyethylene, linear low-density polyethylene, metallocene polyethylene, high-density polyethylene, polypropylene, polyethylene terephthalate, statistically oriented nylon fibers, ethylene-vinyl acetate copolymers, polyurethane, and natural fibers such as rayon. Layered carriers such as polyethylene terephthalate-aluminum-polyethylene composites are also suitable.

[0021] The carrier should be essentially inert to the components of the active substance-containing polymer matrix and the active substance-free pressure-sensitive adhesive. The thickness of the carrier material depends on the desired requirements but is, for example, in the range of 5 to 100 μm.

[0022] The carrier material used is preferably a polyethylene terephthalate film, and the thickness thereof is more preferably in the range of 10 to 40 μm.

[0023] The uncoated side of the active substance carrier layer and especially the adhesive carrier layer may have an outer coating, for example skin-colored, to make the patch less noticeable when worn.

[0024] The surface area of ​​a transdermal therapeutic system depends on the requirements, but is typically between 1.0 and 250 cm. 2 is.

[0025] The active substance-containing polymer matrix and the polymer matrix of the active substance-free pressure-sensitive adhesive can be provided with a protective layer covering the entire surface, and the protective layer is coated, particularly on the flat side facing the active substance-containing polymer matrix, with an adhesion-reducing coating, preferably silicone-treated, and especially fluorosilicone-treated in the case of silicone adhesives. The adhesion-reducing coating facilitates the removal of the protective layer, which is peeled off before applying the TTS to expose the pressure-sensitive adhesive surface. Suitable protective layers include conventional release layers, including known sheet materials such as polyester sheets, polyethylene sheets, polystyrene sheets, or polyethylene-coated paper coated with a suitable fluoropolymer or silicone-based coating.

[0026] The present invention particularly relates to the following embodiments: In a first embodiment, the present invention provides a method for manufacturing a semiconductor device comprising: an active substance carrier layer having at least one active substance-containing polymer matrix applied to the active substance carrier layer, said matrix comprising at least one pressure-sensitive adhesive and at least one pharmacologically active substance absorbable through human or animal skin; and an adhesive carrier layer which is as completely coated as possible with an active substance-free pressure-sensitive adhesive, the active substance-free pressure-sensitive adhesive being directly bonded to the flat side of the active substance carrier layer facing away from the active substance-containing polymer matrix, Including, 1. A transdermal therapeutic system, wherein the adhesive carrier layer protrudes peripherally beyond the edge of the active substance carrier layer, The present invention relates to a transdermal therapeutic system characterized in that there is a peripheral region between the active substance-containing polymer matrix and the active substance-free pressure-sensitive adhesive where the coating thickness of the active substance-containing polymer matrix and / or the active substance-free pressure-sensitive adhesive is reduced.

[0027] In a second embodiment, the present invention relates to a system according to embodiment 1, characterized in that the adhesive carrier layer is coated as completely as possible with an active substance-free pressure-sensitive adhesive and bonded to the active substance carrier layer, and the active substance carrier layer has a peripheral area with a reduced coating thickness of the active substance-containing polymer matrix.

[0028] In a third embodiment, the present invention relates to a system according to embodiment 2, characterized in that the peripheral region with reduced coating thickness is formed or formable by guiding a punching tool onto the material of the active substance carrier layer, the entire surface of which is coated with an active substance-containing polymer matrix, the tool comprising a hollow cylinder and a cutting blade arranged outside the hollow cylinder, more particularly directly adjacent to it in a concentric manner, and the hollow cylinder is first pressed against the coated active substance carrier layer to reduce the coating thickness with the active substance-containing polymer matrix, and then the cutting blade is used to punch out the active substance carrier layer having a peripheral region with reduced coating thickness with the active substance-containing polymer matrix.

[0029] In a fourth embodiment, the present invention relates to a system as described in embodiment 1, characterized in that the adhesive carrier layer has a peripheral region adjacent to the active substance carrier layer where the coating thickness of the active substance-free pressure-sensitive adhesive is reduced.

[0030] In a fifth embodiment, the present invention relates to a system according to any one of the preceding embodiments, characterized in that in the system the active substance-containing polymer matrix is ​​applied directly to the active substance carrier layer and the active substance-free pressure-sensitive adhesive is applied directly to the adhesive carrier layer, and no additional layer is present between the flat side of the active substance carrier layer facing away from the active substance-containing polymer matrix and the active substance-free pressure-sensitive adhesive of the adhesive carrier layer.

[0031] In a sixth embodiment, the invention relates to a system according to any one of the preceding embodiments, characterized in that the active substance-containing polymer matrix and the polymer matrix of the active substance-free pressure-sensitive adhesive are independently selected from acrylates, silicone pressure-sensitive adhesives, polyisobutylenes, SIS copolymers, silicone-acrylate hybrid systems, such as those sold by Dow Corning Healthcare Solutions, and mixtures thereof.

[0032] In a seventh embodiment, the present invention relates to a system according to any one of the preceding embodiments, wherein the pharmacologically active substance is selected from the group consisting of an α-adrenergic agonist, a β-adrenergic agonist, an α-adrenergic antagonist, a β-adrenergic antagonist, an analgesic (sleep-inducing), an analgesic (non-sleep-inducing), an androgen, an anesthetic, an antiallergic, an antiandrogen, an antianginal, an antiarrhythmic, a penicillin, an antidiabetic, an antidementia, an antihistamine, an antimigraine, a hydrogenated ergot alkaloid, a calcium channel blocker, a hormone, a serotonin antagonist, a platelet aggregation inhibitor, an antidepressant, a bronchodilator, an estrogen, a gestagen, a vasodilator, nicotine, or a mixture thereof.

[0033] In an eighth embodiment, the present invention relates to a system according to any one of the preceding embodiments, characterized in that the peripheral area of ​​reduced coating thickness is 20% or less, in particular 15% or less, preferably 0.1 to 12% of the thickness of the polymer matrix of the active substance-containing polymer matrix and / or the active substance-free pressure-sensitive adhesive. In the area of ​​reduced coating thickness, the active substance-containing polymer matrix and / or the active substance-free pressure-sensitive adhesive can be completely removed.

[0034] In a ninth embodiment, the present invention relates to a system according to any one of the preceding embodiments, characterized in that the width of the peripheral region of reduced coating thickness is between 0.05 and 5.0 mm, in particular between 0.1 and 3.0 mm.

[0035] In a tenth embodiment, the invention relates to a system according to any one of the preceding embodiments, characterized in that the peripheral region of reduced coating thickness is essentially undisrupted.

[0036] In an eleventh embodiment, the present invention relates to a system according to any one of the preceding embodiments, characterized in that the coating thickness of the active substance-containing polymer matrix and / or the active substance-free pressure-sensitive adhesive is between 20 and 800 μm, in particular between 40 and 400 μm.

[0037] In a twelfth embodiment, the present invention relates to a system according to any one of the preceding embodiments, in which a protective layer is provided covering the entire surface of the active substance-containing polymer matrix and the polymer matrix of the active substance-free pressure-sensitive adhesive, the protective layer on the flat side facing the active substance-containing polymer matrix being provided with a coating that specifically reduces adhesion, preferably a silicone-treated or fluorosilicone-treated coating.

[0038] In a thirteenth embodiment, the present invention provides a method for producing a transdermal therapeutic system according to any one of embodiments 1 to 12, comprising: providing an active substance carrier layer having at least one active substance-containing polymer matrix applied to the active substance carrier layer, said matrix comprising at least one pressure-sensitive adhesive and at least one pharmacologically active substance absorbable through human or animal skin; bonding the adhesive carrier layer, which is as completely coated as possible with the active substance-free pressure-sensitive adhesive, directly to the flat side of the active substance carrier layer facing away from the active substance-containing polymer matrix with the active substance-free pressure-sensitive adhesive; Including, the adhesive carrier layer projects peripherally beyond the edge of the active substance carrier layer; 1. A method for producing a coated active substance carrier layer comprising a peripheral region (4) with a reduced thickness of the active substance-containing polymer matrix and / or the active substance-free pressure-sensitive adhesive between the active substance-containing polymer matrix and the active substance-free pressure-sensitive adhesive, wherein the peripheral region (4) with a reduced thickness of the coating with the active substance-containing polymer matrix is ​​present between the active substance-containing polymer matrix and the active substance-free pressure-sensitive adhesive, the peripheral region (4) with a reduced thickness of the coating being preferably formed by guiding a punching tool over the material of the active substance carrier layer, the entire surface of which is coated with the active substance-containing polymer matrix, the tool comprising a hollow cylinder and a cutting blade arranged outside the hollow cylinder, more particularly directly adjacent to it in a concentric manner, wherein the hollow cylinder is first pressed against the coated active substance carrier layer to reduce the thickness of the coating with the active substance-containing polymer matrix, and then the cutting blade is used to punch out the active substance carrier layer having the peripheral region (4) with a reduced thickness of the coating with the active substance-containing polymer matrix.

[0039] In a fourteenth embodiment, the present invention relates to the use of a transdermal therapeutic system according to any one of embodiments 1 to 12 for the treatment of humans or animals, in particular for the treatment of hypogonadism, Alzheimer's disease, Parkinson's disease, multiple sclerosis, bipolar disorder, muscle tension, severe pain or hypertension, or for hormone replacement therapy or for contraception.

[0040] In a fifteenth embodiment, the present invention relates to a kit comprising at least one transdermal therapeutic system according to any one of embodiments 1 to 12 in an outer package, and optionally including instructions for use comprising instructions for use according to embodiment 14. [Example]

[0041] The present invention will be described in detail below with reference to the embodiment shown in FIGS. FIG. 1 illustrates intermediate stages in the manufacture of the transdermal therapeutic system of the present invention. FIG. 2 illustrates the embodiment shown in FIG. 2 of the completed transdermal therapeutic system of the present invention.

[0042] 2 shows an embodiment of a transdermal therapeutic system 1 according to the present invention. The transdermal therapeutic system 1 comprises at least one active substance-containing polymer matrix 3 applied to an active substance carrier layer 2, the matrix containing at least one pressure-sensitive adhesive and at least one pharmacologically active substance (in this case, scopolamine) that is absorbable through human or animal skin. The active substance carrier layer 2 has a peripheral region 4 where the active substance-containing polymer matrix is ​​coated to a reduced thickness. The active substance carrier layer 2 is applied on a protective layer 5 that covers the entire surface of the active substance-containing polymer matrix 3, protruding beyond this at the edges and that is provided with a silicone coating to reduce the adhesiveness of the pressure-sensitive adhesive.

[0043] On the flat side facing the active substance-containing polymer matrix 3, the active substance carrier layer 2 is completely covered by an adhesive carrier layer 6, which is directly bonded to the active substance carrier layer 2 by an active substance-free pressure-sensitive adhesive 7. The adhesive carrier layer 6 is coated over its entire surface with the active substance-free pressure-sensitive adhesive 7. As a result of the bonding of the adhesive carrier layer 6 to the active substance carrier layer 2, the peripheral area 4, where the coating thickness is reduced with the active substance-containing polymer matrix, is bent over all around. The pressure-sensitive adhesive of the active substance-containing polymer matrix 3 and the active substance-free pressure-sensitive adhesive 7 are both silicone-based pressure-sensitive adhesives in this example.

[0044] In the manufacture of the transdermal therapeutic system 1 of the present invention, the active substance carrier layer 2 is first coated with an active substance-containing polymer matrix 3, which contains at least one pressure-sensitive adhesive (in this case, a silicone-based pressure-sensitive adhesive) and at least one pharmacologically active substance (in this case, scopolamine) that can be absorbed through human or animal skin. A punching tool comprising a hollow cylinder and a cutting blade positioned concentrically and directly adjacent to the hollow cylinder is guided over the material of the active substance carrier layer 2, whose entire surface is first coated with the active substance-containing polymer matrix 3. In this process, the hollow cylinder is first pressed against the coated active substance carrier layer 2, reducing the thickness of the active substance-containing polymer matrix coating, resulting in a peripheral region 4 with a reduced thickness of the active substance-containing polymer matrix coating. The cutting blade is then used to punch out the active substance carrier layer 2 outside the peripheral region 4 with the reduced coating thickness, and a protective layer 5 with a silicone coating is applied to this, which completely covers the active substance-containing polymer matrix 3 and protrudes beyond its edges. In this process, all or most of the active substance-containing polymer matrix 3 within the hollow cylinder area can be completely removed, depending on the contact pressure of the hollow cylinder and the flexibility of the active substance-containing polymer matrix 3. This results in an intermediate 10, the layer structure of which is shown in Figure 1.

[0045] On the flat side of the intermediate 10 facing the active substance-containing polymer matrix 3, the entire surface of the active substance carrier layer 2 is covered with an adhesive carrier layer 6 that is bonded directly to the active substance carrier layer 2 by an active substance-free pressure-sensitive adhesive 7, resulting in the transdermal therapeutic system 1 of the present invention. Again, a silicone-based pressure-sensitive adhesive is used. As a result of bonding the adhesive carrier layer 6 to the active substance carrier layer 2, the peripheral region 4, where the coating thickness is reduced with the active substance-containing polymer matrix, is curved all the way around, but this does not affect its ability to function as a diffusion barrier.

[0046] After production, the transdermal therapeutic systems 1 thus produced are sealed in individual aluminum-laminated polyester film packages and stored in a climate chamber at 40°C and 75% relative humidity for 6 months. The transdermal therapeutic systems 1 are then removed from the packages and investigated for possible migration of scopolamine. In these investigations, no scopolamine was detected in the active substance-free pressure-sensitive adhesive 7.

[0047] To apply the transdermal therapeutic system 1 of the present invention, the protective layer 5 is peeled off and the remaining layer structure is placed adhesive side down on the desired area of ​​skin and pressure is applied.

[0048] When the transdermal therapeutic system 1 of the present invention was peeled off from the skin after a usage period of 1 to 2 days, and then analyzed, no scopolamine was detected in the active substance-free pressure-sensitive adhesive 7 in the area of ​​the adhesive carrier layer 6 that protruded beyond the active substance carrier layer 2.

Claims

1. an active substance carrier layer (2) having at least one active substance-containing polymer matrix (3) applied to the active substance carrier layer (2), said matrix comprising at least one pressure-sensitive adhesive and at least one pharmacologically active substance absorbable through human or animal skin; an adhesive carrier layer (6) coated as completely as possible with an active substance-free pressure-sensitive adhesive (7), the adhesive carrier layer (6) being directly bonded by the active substance-free pressure-sensitive adhesive (7) to the flat side of the active substance carrier layer (2) facing away from the active substance-containing polymer matrix (3); Including, A transdermal therapeutic system (1) in which the adhesive carrier layer (6) protrudes peripherally beyond the edge of the active substance carrier layer (2), Between the active substance-containing polymer matrix (3) and the active substance-free pressure-sensitive adhesive (7), there is a peripheral area (4) of reduced thickness of coating with the active substance-containing polymer matrix (3), which peripheral area (4) covers the edge of the active substance-containing polymer matrix (3), The active substance carrier layer (2) is characterized in that it has a peripheral area (4) where the thickness of the coating is reduced with an active substance-containing polymer matrix (3), The system is characterized in that the active substance-containing polymer matrix (3) is applied directly to the active substance carrier layer (2) and the active substance-free pressure-sensitive adhesive (7) is applied directly to the adhesive carrier layer (6), and there is no additional layer between the flat side of the active substance carrier layer (2) facing away from the active substance-containing polymer matrix (3) and the active substance-free pressure-sensitive adhesive (7) of the adhesive carrier layer (6). Transdermal therapeutic systems.

2. 2. The transdermal therapeutic system of claim 1, wherein the polymer matrices of the active substance-containing polymer matrix (3) and the active substance-free pressure-sensitive adhesive (7) are independently selected from acrylates, silicone pressure-sensitive adhesives, polyisobutylene, SIS copolymers, silicone-acrylate hybrid systems, and mixtures thereof.

3. 3. The transdermal therapeutic system according to claim 1, wherein the pharmacologically active substance is selected from the group consisting of α-adrenergic agonists, β-adrenergic agonists, α-adrenergic antagonists, β-adrenergic antagonists, analgesics (sleep-inducing), analgesics (non-sleep-inducing), androgens, anesthetics, antiallergic agents, antiandrogens, antianginal agents, antiarrhythmic agents, penicillins, antidiabetic agents, antidementia agents, antihistamines, antimigraine agents, hydrogenated ergot alkaloids, calcium channel blockers, hormones, serotonin antagonists, platelet aggregation inhibitors, antidepressants, bronchodilators, estrogens, gestagens, vasodilators, nicotine, or mixtures thereof.

4. 4. A transdermal therapeutic system according to any one of claims 1 to 3, characterized in that the peripheral area (4) of reduced coating thickness is not more than 20% of the thickness of the polymer matrix of the active substance-containing polymer matrix (3) and / or the active substance-free pressure-sensitive adhesive (7).

5. A transdermal therapeutic system according to any one of claims 1 to 4, characterized in that the width of the peripheral area (4) of reduced coating thickness is between 0.05 and 5.0 mm.

6. A transdermal therapeutic system according to any one of claims 1 to 5, characterized in that the peripheral area (4) of reduced coating thickness is essentially unbroken.

7. 7. The transdermal therapeutic system according to claim 1, wherein the coating thickness of the active substance-containing polymer matrix (2) and / or the active substance-free pressure-sensitive adhesive (7) is between 20 and 800 μm.

8. A transdermal therapeutic system according to any one of claims 1 to 7, wherein a protective layer (5) is provided covering the entire surface of the polymer matrix of the active substance-containing polymer matrix (3) and the active substance-free pressure-sensitive adhesive (7).

9. 9. A transdermal therapeutic system according to any one of claims 1 to 8 for the treatment of hypogonadism, Alzheimer's disease, Parkinson's disease, multiple sclerosis, bipolar disorder, muscle tension, severe pain, or high blood pressure, or for hormone replacement therapy, or for contraception, in animal or human therapy.

10. The transdermal therapeutic system according to any one of claims 1 to 9, which is a patch.

11. A method for producing a transdermal therapeutic system (1) according to any one of claims 1 to 10, comprising: providing an active substance carrier layer (2) having at least one active substance-containing polymer matrix (3) applied to the active substance carrier layer (2), said matrix comprising at least one pressure-sensitive adhesive and at least one pharmacologically active substance absorbable through human or animal skin; and bonding the adhesive carrier layer (6), which is as completely coated as possible with the active substance-free pressure-sensitive adhesive (7), directly to the flat side of the active substance carrier layer (2) facing away from the active substance-containing polymer matrix (3) by means of the active substance-free pressure-sensitive adhesive (7); Including, The adhesive carrier layer (6) projects peripherally beyond the edge of the active substance carrier layer (2), Between the active substance-containing polymer matrix (3) and the active substance-free pressure-sensitive adhesive (7), there is a peripheral area (4) of reduced thickness of coating with the active substance-containing polymer matrix (3), which peripheral area (4) covers the edge of the active substance-containing polymer matrix (3), The active substance carrier layer (2) is characterized in that it has a peripheral area (4) where the thickness of the coating is reduced with an active substance-containing polymer matrix (3), The system is characterized in that the active substance-containing polymer matrix (3) is applied directly to the active substance carrier layer (2) and the active substance-free pressure-sensitive adhesive (7) is applied directly to the adhesive carrier layer (6), and there is no additional layer between the flat side of the active substance carrier layer (2) facing away from the active substance-containing polymer matrix (3) and the active substance-free pressure-sensitive adhesive (7) of the adhesive carrier layer (6). method.

12. 12. The method according to claim 11, wherein the peripheral region (4) of reduced coating thickness is formed by guiding a punching tool over the material of the active substance carrier layer (2), the entire surface of which is coated with the active substance-containing polymer matrix (3), the tool comprising a hollow cylinder and a cutting blade arranged concentrically on the outside of the hollow cylinder directly adjacent to it, the hollow cylinder first being pressed against the coated active substance carrier layer (2) to reduce the coating thickness with the active substance-containing polymer matrix (3), and then the cutting blade is used to punch out the active substance carrier layer (2) having the peripheral region (4) of reduced coating thickness with the active substance-containing polymer matrix (3).

13. A kit comprising at least one transdermal therapeutic system according to any one of claims 1 to 10 in an outer package.

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