A transdermal therapy system containing the active ingredient rotigotine and at least one non-amine-resistant silicone adhesive.

Abstract

This invention relates to a transdermal therapeutic system (TTS) for the administration of the active ingredient rotigotine and its preparation method. The transdermal therapeutic system (TTS) comprises a matrix layer containing: rotigotine; one or more non-amine-resistant silicone adhesives in an amount greater than 50% by weight, based on the total weight of the pressure-sensitive adhesives in the matrix layer; and paraffin. The transdermal therapeutic system according to the invention is particularly suitable for the treatment of Parkinson's disease.

Description

Summary of the Invention

[0001] This invention relates to a transdermal therapeutic system (TTS) for the administration of the active ingredient rotigotine and its preparation method, wherein the transdermal therapeutic system (TTS) comprises one or more non-amine-resistant silicone adhesives. The transdermal therapeutic system according to the invention is particularly suitable for the treatment of Parkinson's disease. Background Technology

[0002] Rotigotine is the INN of the compound (-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-1-naphthol with the following structural formula:

[0003]

[0004] Currently, two polymorphs of rotigotine are known: polymorph I and polymorph II (WO 2009 / 068520). Polymorph I and polymorph II can be distinguished by their respective physicochemical parameters, such as powder X-ray diffraction patterns, Raman spectroscopy, and melting points. As described in WO 2009 / 068520, polymorph II is thermodynamically more stable than polymorph I and is also said to have improved processability.

[0005] Rotigotine is a known dopamine receptor agonist that has been successfully used to treat Parkinson's disease. The efficacy of rotigotine and the diseases in which rotigotine may be preferably used are described, for example, in WO 2002 / 089777, WO 2005 / 092331, WO2005 / 009424, WO 2003 / 092677 and WO 2005 / 063237.

[0006] Oral administration of rotigotine / fluticasone combination therapy presents problems due to its short half-life and high first-pass effect. Therefore, some publications recommend transdermal administration of rotigotine, and a product called [redacted] is available on the market. The corresponding medication.

[0007] A transdermal therapeutic system for administering rotigotine was described long ago in WO 94 / 07468. In the system described there, the active ingredient is used as a hydrochloride salt in a two-phase matrix, which is essentially formed of a hydrophobic polymeric material existing as a continuous phase, in which a hydrated silicate is dispersed to absorb the hydrophilic drug salt. However, the transdermal therapeutic system described there is difficult to prepare, and the penetration of the active ingredient from the skin through such a system is problematic. Therefore, the transdermal therapeutic system described in WO 94 / 07468 is not suitable for commercial use.

[0008] Numerous publications describe improved transdermal therapy systems. For example, WO 99 / 49852 discloses a transdermal therapy system having a matrix based on a non-aqueous polymeric adhesive system of acrylate or silicone bases, which is substantially free of inorganic silicate particles. In its simplest embodiment, the matrix system represents a single-phase matrix system. The matrix is ​​essentially composed of an acrylate adhesive or a silicone adhesive, and in the case of a silicone adhesive, the matrix may further contain, for example, copolymers of polyvinylpyrrolidone, vinylpyrrolidone, and vinyl acetate, polyethylene glycol, glycerol, fatty acid esters of glycerol, or copolymers of ethylene and vinyl acetate.

[0009] WO 2004 / 012730, WO 2004 / 012719, and WO 2004 / 058247 disclose transdermal therapeutic systems for administering rotigotine, having a self-adhesive matrix saturated with an active ingredient and containing the active ingredient as a plurality of micro-reservoirs or amorphous particles. The matrix is ​​a self-adhesive matrix based on a silicone adhesive.

[0010] WO 02 / 089778 also discloses a silicone-based transdermal therapeutic system for administering rotigotine. Importantly, this transdermal therapeutic system has a depth of 10-40 cm. 2 The surface area contains 0.1-3.15 mg / cm³ 2 Rotigotine is the active ingredient.

[0011] A crucial aspect of formulating transdermal therapy systems using the active ingredient rotigotine is avoiding crystallization of the active ingredient within the system. Crystallized active ingredients can cause numerous problems, including impaired drug delivery rates and adversely affected adhesive properties of the adhesive matrix. Unfortunately, this crystallization is a common issue with rotigotine in existing technologies. Currently, the only transdermal therapy system on the market is UCB's product... In this formulation, rotigotine is embedded in a polymer matrix. However, the first formulation was not proven to be stable and resulted in crystal formation in the product, which is why a recall was necessary.

[0012] Therefore, WO 2012 / 072650 recommends introducing an active ingredient into a non-adhesive matrix and providing an adhesive layer on the non-adhesive matrix, the adhesive layer preferably being self-adhesive and preferably composed of a "pressure-sensitive polymer adhesive", preferably composed of an amine-resistant silicone adhesive.

[0013] WO 2012 / 084969 discloses a transdermal therapeutic system for administering rotigotine, wherein the adhesive matrix is ​​composed of polystyrene, polyisobutylene and mixtures thereof, and contains, in addition to the active ingredient, at least one cross-linked polyvinylpyrrolidone or a copolymer of vinylpyrrolidone and vinyl acetate.

[0014] Publication WO 2011 / 076879 describes the use of polyvinylpyrrolidone (PVP) at a specific weight ratio to rotigotine, because this weight ratio unexpectedly stabilizes the amorphous form of rotigotine and prevents recrystallization of rotigotine in solid dispersions such as self-adhesive matrices of transdermal therapeutic systems. Therefore, WO 2011 / 076879 recommends using PPVP at a weight ratio of about 9:3.5 to about 9:6 to stabilize the amorphous form of rotigotine in a solid dispersion in a dispersant, preferably comprising at least one pressure-sensitive silicone adhesive.

[0015] Finally, publication WO 2011 / 057714 describes a method for preventing drug crystallization in a polymer membrane. This polymer membrane of WO 2011 / 057714 is particularly suitable for preparing transdermal therapeutic systems, where one of the two preferred drugs is rotigotine. Here, in the preparation of the polymer membrane, a spread, solvent-containing coating material (coating material) containing a matrix-forming polymer or polymer mixture and at least one drug is dried at a temperature sometimes at least 10°C higher than the melting temperature of the drug contained in the coating material.

[0016] Another important aspect of formulating transdermal therapy systems is the selection of pressure-sensitive adhesives. When choosing a pressure-sensitive adhesive, various factors must be considered, particularly optimal adhesive strength, separation force and tackiness, sustained release of the active ingredient, storage stability, and minimal adhesive residue and skin irritation. Furthermore, the pressure-sensitive adhesive must not react with the active ingredient.

[0017] "Adhesive strength" (or "adhesive strength") describes the force required to peel a transdermal therapy system (TTS) from a test surface to which it has been attached, i.e., the property of resisting peeling from the surface. "Separation force" refers to the force required to peel the TTS from the protective film (4). "Adhesiveness" (or "stickiness") is the property of adhering to a solid surface, i.e., the property of adhering to a solid surface with a short contact time and very slight pressure.

[0018] Various pressure-sensitive adhesives, particularly silicone adhesives, have been proposed for transdermal therapeutic systems containing the active ingredient rotigotine, but also, for example, polyacrylate, polyisobutylene, and polystyrene-based polymer adhesives.

[0019] Polyisobutylene and polystyrene, and mixtures thereof, are used, for example, in transdermal therapeutic systems for administering rotigotine as per WO 2012 / 084969. Compared to many pharmaceutical active ingredients, polyisobutylene generally has poor solution properties. Furthermore, they have the disadvantage that they only exhibit sufficient adhesiveness in mixtures with lower molecular weight polyisobutylenes, and can then exhibit high so-called cold flow. Meanwhile, polystyrene typically requires significant amounts of plasticizers and tackifiers.

[0020] In contrast, pressure-sensitive silicone adhesives exhibit high flexibility, low surface tension, and minimal performance variation over a wide temperature range. Finally, silicone adhesives offer high air and water permeability, good skin tolerance, and resistance to external influences (such as moisture, UV radiation, and stability under acidic and alkaline conditions).

[0021] In the case of pressure-sensitive silicone adhesives used in transdermal therapy systems, a distinction can generally be made between two forms: “non-amine-resistant” silicone adhesives and “amine-resistant” silicone adhesives. “Non-amine-resistant” silicone adhesives also contain free silanol groups. These silanol groups interact slightly with amine groups in active ingredients such as rotigotine, thereby potentially leading to degradation products of the active ingredient. Furthermore, this reaction can significantly impair the properties of the adhesive layer in the transdermal therapy system, for example, by reducing tack and / or by drying during storage (see, for example, US patent applications US RE35,474 and US4,591,622).

[0022] For this reason, in the prior art, transdermal therapy systems using silicone adhesives containing the active ingredient rotigotine typically use only amine-resistant silicone adhesives, not non-amine-resistant ones. In "amine-resistant" silicone adhesives, the silanol groups are protected by protective groups such as trimethylsilyl (TMS) groups.

[0023] Therefore, for example, in the currently available transdermal therapy systems... In this process, only amine-resistant silicone adhesives are used. Here, it is a single-layer laminate, with the matrix layer being a two-phase system in the form of a solid dispersion. The inner phase is formed by the active ingredient dissolved in the polymer, and the outer phase is formed by the amine-resistant silicone adhesive acting as a dispersant.

[0024] Similarly, in WO 99 / 49852, due to the fundamental properties of rotigotine, amine-resistant adhesives are used in silicone adhesives containing this active ingredient. As described in WO 99 / 49852, such amine-resistant silicone adhesives are characterized by the absence of free silanol functional groups (i.e., silanol groups).

[0025] According to WO 02 / 089778, the silicone-based transdermal therapy system disclosed therein must also contain at least one amine-resistant silicone compound as a major component. Here, the silicone compound is typically a pressure-sensitive adhesive or a mixture thereof, forming a matrix in which other components of the transdermal therapy system are embedded.

[0026] According to WO 2004 / 012730 (and according to WO 2004 / 012719 and WO 2011 / 076879), particularly preferred pressure-sensitive adhesives for use in the transdermal therapeutic systems disclosed therein are of the type that form a network of soluble polycondensed polydimethylsiloxane (PDMS) / resin, wherein hydroxyl groups are protected, for example with trimethylsilyl (TMS) groups.

[0027] According to WO 2004 / 058247, in a preferred embodiment of the invention, the matrix polymer is silicone, preferably an amine-resistant silicone or a mixture of silicones. Similarly, according to WO 2004 / 058247, the matrix polymer is an amine-resistant silicone or a mixture of amine-resistant silicones. Finally, also according to WO2011 / 057714, amine-resistant polysiloxanes are particularly preferred.

[0028] However, such amine-resistant silicone adhesives, such as those used in commercially available products, often lead to unsatisfactory results, particularly in terms of bond strength and adhesiveness.

[0029] Therefore, despite the existence of all known transdermal therapeutic systems containing the active ingredient rotigotine, a further requirement exists for transdermal therapeutic systems that deliver rotigotine with satisfactory adhesive strength and tackiness (adhesion) and excellent storage stability, i.e., the active ingredient does not crystallize during storage. However, the transdermal therapeutic system should ensure sufficient skin permeability for the active ingredient, be as simple to manufacture as possible, and simultaneously allow for administration of the active ingredient for at least one day of the desired duration of dosing. Furthermore, for cost reasons and given the requirements of drug regulatory authorities in some countries (e.g., to avoid misuse), the residual concentration of the active ingredient in the transdermal therapeutic system after its use should not be excessively high. Summary of the Invention

[0031] To address this problem, the present invention proposes a transdermal therapy system as defined in the claims.

[0032] The inventors of this invention have surprisingly discovered that in transdermal therapeutic systems (TTS) containing the active ingredient rotigotine, by adding a small amount of paraffin to the matrix layer, improved performance can still be achieved compared to TTS using amine-resistant silicone adhesives, despite the use of silicone adhesives that still have a relevant amount of free silanol groups (i.e., non-amine-resistant silicone adhesives). In particular, there is a significant increase in adhesive strength and tackiness, as well as improved storage stability.

[0033] Furthermore, the inventors have surprisingly discovered that in transdermal therapeutic systems containing more than 50% by weight (based on the total weight of the pressure-sensitive adhesive in the matrix layer (2)) of the active ingredient rotigotine and one or more non-amine-resistant silicone adhesives, no crystallization of the active ingredient occurs when the matrix layer in the dispersed phase of the solid dispersion uses a rotigotine and polyvinylpyrrolidone weight ratio of 9:6.4, particularly 9:7 or smaller. Conversely, at larger rotigotine and polyvinylpyrrolidone weight ratios, for example 9:5 or greater, there is a risk of crystal formation after prolonged storage at temperatures of 25°C or higher. Therefore, such a high rotigotine to polyvinylpyrrolidone weight ratio according to the invention is certainly possible, but not preferred.

[0034] Finally, it was surprisingly found that in the transdermal therapeutic system according to the invention, it is not necessary to raise the drying temperature during the coating process to at least 10°C above the melting point of rotigotine to prevent subsequent crystallization of rotigotine.

[0035] As a result, the present invention provides a transdermal therapeutic system comprising a backing layer (1), a drug-containing matrix layer (2), and a protective foil (4) to be removed before use, wherein the drug is rotigotine and wherein the matrix layer (2) contains one or more non-amine-resistant pressure-sensitive silicone adhesives in an amount exceeding 50% by weight based on the total weight of the pressure-sensitive adhesives in the matrix layer (2), and contains paraffin in an amount of at least 0.1% by weight based on the total weight of the matrix layer (2).

[0036] This invention also relates to the use of a transdermal therapeutic system for treating diseases requiring transdermal administration of rotigotine, particularly for treating Parkinson's disease. Finally, this invention relates to a method for preparing the transdermal therapeutic system according to the invention. Attached Figure Description

[0037] Figure 1 (A) A single-layer formulation of a transdermal therapeutic system having a backing layer (1), a matrix layer (2), and a protective foil (4). (B) A two-layer formulation of a transdermal therapeutic system having a backing layer (1), a matrix layer (2), at least one additional pressure-sensitive adhesive layer (3) initially without active ingredients, and a protective foil (4).

[0038] Figure 2Separation force of various single-layer and double-layer formulations during storage at 40°C / 75% RH (relative humidity) for 0 to 3 months.

[0039] Figure 3 Adhesive strength (adhesive strength) of various single-layer and double-layer formulations during storage at 40°C / 75% RH (relative humidity) for 0 to 3 months.

[0040] Figure 4 (A) Determine the optimal polymer adhesive ratio for the silanol-reduced silicone adhesive BIO-PSA SRS7-4501 (medium tack) : SRS7-4601 (high tack) while considering separation force, adhesion, and adhesive properties. (B) Determine the optimal polymer adhesive ratio for the non-silanol-reduced silicone adhesive BIO-PSA 7-4501 (medium tack) : 7-4601 (high tack) while considering separation force, adhesive strength, and adhesive properties.

[0041] Figure 5 Adhesiveness (stickiness) of various single-layer and double-layer formulations stored at 40°C / 75% RH (relative humidity) for 0 to 3 months.

[0042] Figure 6 A) Cumulative permeation of rotigotine over 24 hours in a monolayer formulation with constant rotigotine content and variable PVP K90 content. B) The difference between BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 (Dow) at constant rotigotine and PVP K90 contents. The cumulative permeation of rotigotine in 24 hours for different monolayer formulations with different mixing ratios.

[0043] Figure 7 (A) Cumulative penetration of rotigotine over 24 hours in a monolayer formulation with a non-amine-resistant silicone adhesive containing reduced silanol and 2% paraffin. (B) Cumulative penetration of rotigotine over 24 hours in a monolayer formulation with a non-amine-resistant silicone adhesive containing reduced silanol and 1-2% paraffin.

[0044] Figure 8 A) Cumulative permeation of rotigotine over 24 hours in a two-layer formulation. B) Cumulative release of rotigotine over 6 hours in a single-layer formulation.

[0045] Figure 9 In the bilayer formulation, the cumulative release of rotigotine over 6 hours after each in vitro dissolution (in vitro release of the active ingredient), wherein the amount released after coating to 50 g / m³ is as follows. 2Previously, only the material containing the active ingredient matrix layer (2) was stirred, and then coated to 50 g / m³. 2 Previously, the same material was separately homogenized. 618_617ROTTDS: Two-layer formulation; 589ROTTDS: Single-layer formulation; Stirring: Stirring only; Homogenization: Stirring and homogenizing. Detailed Implementation

[0046] In its simplest embodiment, the transdermal therapeutic system according to the invention comprises a backing layer (1), a matrix layer (2) containing active ingredients following the backing layer (1), and a protective foil (4) following the matrix layer (2) to be removed before use (see See) Figure 1 (A)). One or more additional layers may be disposed between the various layers of the transdermal therapeutic system according to the invention, i.e., between the backing layer (1) and the matrix layer (2) and / or between the matrix layer (2) and the protective foil (4). For example, in a preferred embodiment of the invention, at least one additional pressure-sensitive adhesive layer (3) initially free of active ingredients may be present between the matrix layer (2) and the protective foil (4).

[0047] The matrix layer (2) of the transdermal therapy system according to the present invention is a pressure-sensitive adhesive layer containing the active ingredient rotigotine, and according to the present invention, the pressure-sensitive adhesive layer must contain more than 50% by weight of one or more non-amine-resistant pressure-sensitive silicone adhesives and at least 0.1% by weight of paraffin, based on the total weight of the matrix layer (2).

[0048] The inventors have surprisingly discovered that by adding a small amount of paraffin to the matrix layer (2), despite the simultaneous use of a non-amine-resistant silicone adhesive and the active ingredient rotigotine in the matrix layer (2), a significant improvement in adhesiveness and adhesion, as well as improved storage stability, can be achieved compared to transdermal treatment systems using amine-resistant silicone adhesives and rotigotine, particularly in terms of adhesiveness and adhesion.

[0049] As used herein, the terms “total weight” and “total amount” refer to dry weight in their respective contexts, that is, the weight of the components involved in a ready-to-use transdermal therapy system in the appropriate context, unless otherwise expressly stated.

[0050] The term "pressure-sensitive adhesive" in a transdermal therapy system, or a layer of a transdermal therapy system, such as the matrix layer (2) and / or at least one additional initially non-active pressure-sensitive adhesive layer (3), refers in the sense of this invention all those components, particularly polymeric adhesives, that are added to the transdermal therapy system or its layers as pressure-sensitive adhesive promoters / adhesives due to their inherent properties. Such pressure-sensitive adhesives are known to those skilled in the art. Therefore, active ingredients, paraffin wax, crystallization inhibitors such as polyvinylpyrrolidone, penetration promoters, and other additives such as plasticizers and antioxidants are not included in the category of pressure-sensitive adhesives. As used herein, the terms "silicone adhesive" and "pressure-sensitive silicone adhesive" are interchangeable.

[0051] The matrix layer (2) of the transdermal therapeutic system according to the present invention comprises more than 50% by weight of one or more non-amine-resistant silicone adhesives, based on the total weight of the pressure-sensitive adhesives in the matrix layer (2). That is, the matrix layer (2) may comprise one, two, three, four, or other non-amine-resistant silicone adhesives.

[0052] Those skilled in the art are familiar with the terms "non-amine-resistant" silicone adhesives and "amine-resistant" silicone adhesives. Amine-resistant silicone adhesives or methods for preparing such adhesives are described, for example, in U.S. patent specifications USRE 35,474 and US 4,591,622. For example, a "non-amine-resistant" silicone adhesive is characterized by being a pressure-sensitive silicone adhesive, unlike "amine-resistant" adhesives, having a relevant amount of free silanol groups (OH groups unprotected by protecting groups), thus posing a risk of interaction with amine-containing active ingredients under normal circumstances. Incomplete protection (so-called end-capping or (terminal) closure) or only partial removal of said free silanol groups results in so-called silanol-reduced silicone adhesives. Silanol-reduced non-amine-resistant silicone adhesives and methods for preparing such silanol-reduced non-amine-resistant silicone adhesives are known to those skilled in the art and are described, for example, in U.S. patent specification US 6,337,086. They still belong to the category of non-amine-resistant silicone adhesives.

[0053] Preferably, in the context of this invention, the term "non-amine-resistant" silicone adhesive refers to a pressure-sensitive silicone adhesive whose content of free silanol groups (the content of free OH groups or the content of hydroxyl groups bonded to silicon) is, for example, at least 7700 ppm or more, preferably at least about 8000 ppm or more, and preferably not more than 13000 ppm. The content (or concentration) of free silanol groups in the silicone adhesive can be measured by methods familiar to those skilled in the art, for example by nuclear magnetic resonance spectroscopy (NMR spectroscopy) and / or Fourier transform infrared spectroscopy (FTIR spectroscopy) (see, for example, US 6,337,086). Here, it can be measured by...29 Si nuclear magnetic resonance spectrum ( 29 Si-NMR spectroscopy and the correlation of data with standardized reference samples are used to determine silanol content, while FTIR spectroscopy directly provides the ratio of free to protected silanol functionality.

[0054] Therefore, as described in, for example, US 6,337,086, the silanol content can be calculated by FTIR spectroscopy using the peak area ratio A1 / (A2*100), where the A1 area corresponds to the dimerization expansion mode peak of the OH bond from the silanol group, and the A2 area corresponds to the area of ​​the deformed overtone peak of the hydrogen of the methyl group in polydimethylsiloxane (PDMS). In this embodiment, the non-amine-resistant silicone adhesive is characterized by a ratio of unprotected silanol functional groups to protected silanol functional groups, for example, greater than 0.45, preferably at least 0.46, more preferably at least 0.5 or greater.

[0055] In a preferred embodiment of the invention, the non-amine-resistant silicone adhesive is characterized in that, after reacting with the active ingredient rotigotine at about 50°C for at least 2 hours, preferably 2 to 4 hours, in a suitable solvent and at a silicone adhesive to rotigotine mixing ratio of, for example, 20:1 to 4:1, preferably, for example, 10:1, a non-negligible portion of rotigotine, for example, at least 0.5% by weight, preferably at least 1.0% by weight, preferably at least 2.5% by weight, reacts with the silicone adhesive and is thus degraded or transformed. Suitable solvents are known to those skilled in the art and are particularly dependent on the silicone adhesive; for example, heptane, ethanol, and ethyl acetate. The proportion of degraded or transformed rotigotine can be determined in a manner known to those skilled in the art.

[0056] This invention does not impose any particular limitation on the selection of one or more non-amine-resistant silicone adhesives. Non-amine-resistant silicone adhesives are known in the prior art.

[0057] In embodiments of the present invention, one or more non-amine-resistant pressure-sensitive silicone adhesives are selected from non-amine-resistant pressure-sensitive silicone adhesives with moderate adhesive strength, such as Dow. BIO-PSA 7-4501, Dow BIO-PSA 7-4502, Dow BIO-PSA SRS7-4501, Dow BIO-PSA SRS7-4502, a high-adhesion, non-amine-resistant pressure-sensitive silicone adhesive such as Dow BIO-PSA 7-4601, Dow BIO-PSA 7-4602, Dow BIO-PSA SRS7-4601, Dow BIO-PSA SRS7-4602 and combinations thereof. These adhesives are also chemically referred to as dimethylsiloxane alcohol trimethylsiloxysilicate crosslinking polymers. In another embodiment of the invention, one or more non-amine-resistant pressure-sensitive silicone adhesives are selected from medium-tack non-silanol-reduced non-amine-resistant pressure-sensitive silicone adhesives, high-tack non-silanol-reduced non-amine-resistant pressure-sensitive silicone adhesives, medium-tack silanol-reduced non-amine-resistant pressure-sensitive silicone adhesives, high-tack silanol-reduced non-amine-resistant pressure-sensitive silicone adhesives, and combinations thereof. In the context of the invention, a preferred example of a non-amine-resistant pressure-sensitive silicone adhesive is Dow... BIO-PSA 7-4501, Dow BIO-PSA 7-4601, Dow BIO-PSASRS7-4501, Dow BIO-PSA SRS7-4601 and its combinations.

[0058] The matrix layer (2) of the transdermal therapeutic system according to the present invention comprises more than 50% by weight of one or more non-amine-resistant pressure-sensitive silicone adhesives, based on the total weight of the pressure-sensitive adhesives in the matrix layer (2). That is, the total weight percentage of the non-amine-resistant pressure-sensitive silicone adhesives contained in the matrix layer (2) is greater than 50% by weight, based on the total weight of the pressure-sensitive adhesives in the matrix layer (2).

[0059] In a preferred embodiment of the invention, the matrix layer (2) of the transdermal treatment system comprises more than 60% by weight, preferably more than 70% by weight, more preferably more than 75% by weight, more preferably more than 80% by weight, more preferably more than 85% by weight, more preferably more than 90% by weight, further preferably more than 93% by weight, further preferably more than 95% by weight, and further preferably at least 99% by weight, based on the total weight of the pressure-sensitive adhesive in the matrix layer (2). In a further preferred embodiment of the invention, the matrix layer (2) of the transdermal treatment system comprises only non-amine-resistant pressure-sensitive silicone adhesive as the pressure-sensitive adhesive; that is, in particular, the matrix layer (2) does not contain other polymer adhesives, but only non-amine-resistant pressure-sensitive silicone adhesive.

[0060] When exactly one non-amine-resistant silicone adhesive is contained in one or more pressure-sensitive adhesive layers of the TTS (e.g., matrix layer (2) or another initially non-active pressure-sensitive adhesive (3)), the weight percentage of the non-amine-resistant silicone adhesive is greater than 50% by weight, based on the total weight of the pressure-sensitive adhesives in one or more pressure-sensitive adhesive layers of the TTS; when exactly two non-amine-resistant silicone adhesives are contained in one or more pressure-sensitive adhesive layers of the TTS, the total weight percentage of the two non-amine-resistant silicone adhesives is greater than 50% by weight, based on the total weight of the pressure-sensitive adhesives in one or more pressure-sensitive adhesive layers of the TTS; and so on. In the case of multiple pressure-sensitive adhesive layers, each of these layers contains a weight percentage greater than 50% by weight, based on the total weight of the pressure-sensitive adhesives in the respective layer.

[0061] The matrix layer (2) of the transdermal therapeutic system according to the invention comprises at least 0.1% by weight of paraffin, also known as white oil, based on the total weight of the matrix layer (2). Specifically, two types of paraffin are known: one is viscous paraffin, referred to as paraffin, liquid paraffin, or paraffin liquid in Ph.Eur., as mineral oil in USP, as liquid paraffin in JP, and also as paraffin subliquid in common literature, and representing a range of 0.827 to 0.890 according to Ph.Eur (Method 2.2.5) and a range of 0.845 to 0.905 according to USP (Method 2.2.5). <841> According to JP, the relative density is in the range of 0.860 to 0.890; according to Ph.Eur., it is in the range of 110-230 mPas (Method 2.2.9); according to USP, it is in the range of 34.5 to 150.0 mm. 2 *s -1 Within the scope (method) <911> Capillary viscometer (at 40±0.1°) and according to JP at not less than 37 mm 2 Oily liquids with a viscosity in the range of / s (Method 1, 37.8℃).

[0062] On the other hand, low-viscosity paraffins are known, referred to as paraffin, light liquid paraffin, or super-liquid paraffin in Ph.Eur, as light mineral oil in USP, and as light liquid paraffin in JP, and represent a viscosity range of 0.810 to 0.875 according to Ph.Eur (Method 2.2.5) and a viscosity range of 0.818 to 0.880 according to USP (Method 2.2.5). <841> Densities in the range of 0.830 to 0.870 according to JP; in the range of 25-80 mPas according to Ph.Eur. (Method 2.2.9); and in the range of 3.0 to 34.4 mm according to USP. 2 *s -1Within the scope (method) <911> Capillary viscometer (at 40 ± 0.1°) and according to JP at less than 37 mm 2 An oily liquid with a viscosity in the range of / s (Method 1, 37.8℃).

[0063] A viscous paraffin is preferred. In another embodiment, the paraffin is a low-viscosity paraffin.

[0064] The amount of paraffin in the matrix layer (2) of the transdermal therapeutic system according to the present invention may be, for example, up to 50% by weight, preferably up to 40% by weight, more preferably up to 30% by weight, more preferably up to 20% by weight, more preferably up to 15% by weight, more preferably up to 10% by weight, based on the total weight of the matrix layer (2) of the transdermal therapeutic system according to the present invention.

[0065] In a preferred embodiment of the invention, the amount of paraffin in the matrix layer (2) is at least 0.2% by weight, preferably at least 0.3% by weight, more preferably at least 0.5% by weight, more preferably at least 0.8% by weight, and more preferably at least 1.0% by weight, based on the total weight of the matrix layer (2). In another preferred embodiment of the invention, paraffin is present in the matrix layer (2) in an amount of at least 0.1-30.0% by weight, preferably 0.1-20.0% by weight, more preferably 0.2-20.0% by weight, more preferably 0.5-10.0% by weight, more preferably 0.8-5.0% by weight, more preferably 1.0-5.0% by weight, and more preferably 1.0-3.0% by weight, based on the total weight of the matrix layer (2).

[0066] Since the matrix layer in the transdermal therapeutic system according to the invention is adhesive, it is generally not necessary for an additional adhesive layer to be present on the matrix layer (2), as required in WO 2012 / 072650. However, the invention does not preclude the provision of at least one additional initially non-active pressure-sensitive adhesive layer (3), for example, to improve adhesion and tackiness. In a preferred embodiment of the invention, the transdermal therapeutic system according to the invention does not contain an additional initially non-active pressure-sensitive adhesive layer (3) between the matrix layer (2) and the protective foil (4) to be removed before use. According to the embodiment, the matrix layer (2) has sufficient adhesiveness to ensure favorable adhesion to the skin during the desired application.

[0067] In another preferred embodiment of the invention, the transdermal therapeutic system according to the invention comprises at least one additional initially non-active pressure-sensitive adhesive layer (3) between the matrix layer (2) and the protective foil (4) to be removed before use (see...). Figure 1B). At least one additional initially non-active pressure-sensitive adhesive layer (3), especially in the case of a multiphase matrix layer (2), can lead to greater robustness to the distribution of different sphere sizes of the active-containing internal phase during in vitro dissolution, because the diffusion distance from the active-containing matrix layer (2) to the skin through at least one initially non-active pressure-sensitive adhesive layer (3) reaches a fixed layer thickness.

[0068] In a further preferred embodiment, the transdermal therapeutic system according to the invention therefore includes at least one additional initially non-active pressure-sensitive adhesive layer (3) between the matrix layer (2) and the protective foil (4) to be removed before use, wherein the at least one additional initially non-active pressure-sensitive adhesive layer (3) comprises one or more non-amine-resistant pressure-sensitive silicone adhesives in an amount exceeding 50% based on the total weight of the pressure-sensitive adhesives in the at least one additional initially non-active pressure-sensitive adhesive layer (3); and at least 0.1% by weight, preferably 0.2-20.0% by weight, more preferably 1.0-5.0% by weight, of paraffin based on the total weight of the at least one additional initially non-active pressure-sensitive adhesive layer (3). That is, the at least one additional initially non-active pressure-sensitive adhesive layer (3) may comprise one, two, three, four, or other non-amine-resistant silicone adhesives.

[0069] In another preferred embodiment of the invention, at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) of the transdermal therapeutic system has a weight percentage of more than 60%, preferably more than 70% by weight, more preferably more than 75% by weight, more preferably more than 80% by weight, more preferably more than 85% by weight, more preferably more than 90% by weight, further preferably more than 93% by weight, further preferably more than 95% by weight, and further preferably at least 99% by weight, based on the total weight of the pressure-sensitive adhesive in at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3). In another embodiment of the invention, at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) of the transdermal therapeutic system has only a non-amine-resistant pressure-sensitive silicone adhesive as the pressure-sensitive adhesive; that is, in particular, at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) does not contain any additional polymer adhesive, but only contains a non-amine-resistant pressure-sensitive silicone adhesive.

[0070] In a further preferred embodiment, the transdermal therapeutic system according to the invention has a weight percentage of more than 50%, preferably more than 60% by weight, more preferably more than 70% by weight, more preferably more than 75% by weight, more preferably more than 80% by weight, more preferably more than 85% by weight, more preferably more than 90% by weight, more preferably more than 93% by weight, more preferably more than 95% by weight, and more preferably at least 99% by weight, based on the total weight of the pressure-sensitive adhesives in the transdermal therapeutic system (wherein the transdermal therapeutic system may have a single non-amine-resistant pressure-sensitive silicone adhesive, or a mixture of two, three, four, or other non-amine-resistant silicone adhesives). In another embodiment, the transdermal therapeutic system has only a non-amine-resistant pressure-sensitive silicone adhesive as a pressure-sensitive adhesive; that is, in particular, the transdermal therapeutic system does not contain any additional polymer adhesives, but only contains a non-amine-resistant pressure-sensitive silicone adhesive.

[0071] In a further preferred embodiment, the transdermal treatment system has at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3), wherein the at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3) or matrix layer (2) and at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3) have a weight percentage of more than 60% by weight, more preferably more than 70% by weight, more preferably more than 75% by weight, more preferably more than 80% by weight, more preferably more than 85% by weight, more preferably more than 90% by weight, more preferably more than 93% by weight, more preferably greater than 95% by weight, more preferably at least 99% by weight, based on the total weight of the pressure-sensitive adhesive of the at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3), or based on the pressure-sensitive adhesive of the matrix layer (2) and at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3).

[0072] The basis weight (weight per unit area) of the matrix layer (2) in the transdermal therapy system according to the present invention is not particularly limited. In a general embodiment of the present invention, the basis weight of the matrix layer (2) is 30-70 g / m². 2 Preferred concentration: 30-60g / m 2 The term “weight per unit area” in relation to the layers of the transdermal therapeutic system according to the invention, such as the matrix layer (2) or at least one other initially non-active pressure-sensitive adhesive layer (3), refers to the weight per unit area of ​​the dried layer, i.e., the weight per unit area of ​​the layer after the solvent has been removed by drying during the preparation of the TTS.

[0073] In a preferred embodiment where the transdermal therapy system does not include any pressure-sensitive adhesive layer other than the matrix layer (2), the matrix layer (2) has a density of 40-70 g / m³. 2 Preferred size: 45-65g / m 2More preferably, about 50-60g / m 2 More preferably 50-60g / m 2 The weight per unit area. In a further preferred embodiment in which the transdermal treatment system does not contain any pressure-sensitive adhesive layers other than the matrix layer (2), the matrix layer (2) has approximately 50 g / m². 2 or about 60g / m 2 Weight per unit area.

[0074] The term “about” as used here before numerical values ​​and numerical ranges means that the value or range specified by it also includes all values ​​within ±10% of the given value or range, or within ±5% of the value or range, or in some embodiments within ±1% of the value or range.

[0075] In an embodiment of the present invention, the transdermal therapeutic system comprises at least one additional pressure-sensitive adhesive layer (3) initially free of active ingredients, in addition to the matrix layer (2), the matrix layer (2) has a content of 30-70 g / m³. 2 More preferably 40-70g / m 2 More preferably 45-65g / m 2 More preferably, about 50-60g / m 2 More preferably 50-60g / m 2 For example, approximately 50g / m 2 or about 60g / m 2 The unit area weight; and at least one additional initially non-active pressure-sensitive adhesive layer (3) has 15-40 g / m². 2 Preferred concentration: 20-40g / m 2 More preferably 20-35g / m 2 More preferably 25-35g / m 2 Further optimization to approximately 30g / m 2 Weight per unit area.

[0076] In the transdermal therapeutic system according to the invention, the matrix layer (2), if at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3) is present, comprises one or more of more than 50% by weight of non-amine-resistant pressure-sensitive silicone adhesive, based on the total weight of the pressure-sensitive adhesive in the matrix layer (2), and if at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3) is present, the total weight of the pressure-sensitive adhesive in the matrix layer (2) or based on the total weight of the pressure-sensitive adhesive in the at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3).

[0077] In a preferred embodiment, the matrix layer (1) and / or at least one additional initially non-active pressure-sensitive adhesive layer (3), if present, has exactly one non-amine-resistant pressure-sensitive silicone adhesive. That is, in this embodiment, the matrix layer (2), at least one additional initially non-active pressure-sensitive adhesive layer (3), or the matrix layer (2) and at least one additional initially non-active pressure-sensitive adhesive layer (3) contain exactly one non-amine-resistant pressure-sensitive silicone adhesive. In a further preferred embodiment, the pressure-sensitive adhesive of the matrix layer (2) and / or at least one additional initially non-active pressure-sensitive adhesive layer (3), if present, consists only of exactly one non-amine-resistant pressure-sensitive silicone adhesive.

[0078] In a further preferred embodiment, the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) is present) comprises one or more different non-amine-resistant pressure-sensitive silicone adhesives, or three or more different non-amine-resistant pressure-sensitive silicone adhesives, wherein, preferably, at least one (i.e., one or more) non-amine-resistant pressure-sensitive silicone adhesives have medium tack and at least one (i.e., one or more) non-amine-resistant pressure-sensitive silicone adhesives have high tack. In a further preferred embodiment, the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3)) comprises exactly two, exactly three, or exactly four different non-amine-resistant pressure-sensitive silicone adhesives. In yet another preferred embodiment, the matrix layer (2) comprises exactly one, and at least one additional pressure-sensitive adhesive layer (3) (if present) initially without active ingredients comprises exactly two non-amine-resistant pressure-sensitive silicone adhesives.

[0079] In yet another preferred embodiment, the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) is present) comprises one or more non-amine-resistant pressure-sensitive silicone adhesives having at least two, at least three, at least four, etc., different molecular weights of non-amine-resistant pressure-sensitive silicone adhesives.

[0080] In a preferred embodiment of the transdermal therapy system of the present invention, one or more non-amine-resistant pressure-sensitive silicone adhesives of the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if present) comprise at least one non-amine-resistant pressure-sensitive silicone adhesive with moderate adhesiveness, such as Dow BIO-PSA 7-4501 and at least one non-amine-resistant pressure-sensitive silicone adhesive with high adhesiveness, such as Dow A mixture of BIO-PSA 7-4601. In a further preferred embodiment of the transdermal therapeutic system of the present invention, one or more non-amine-resistant pressure-sensitive silicone adhesives of the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if present) are made of a non-amine-resistant pressure-sensitive silicone adhesive with moderate adhesiveness, such as Dow BIO-PSA7-4501 and non-amine-resistant pressure-sensitive silicone adhesives with high adhesiveness, such as Dow The mixture composition of BIO-PSA 7-4601.

[0081] In a preferred variant of the above embodiments of the present invention, one or more non-amine-resistant pressure-sensitive silicone adhesives of the matrix layer (2) and / or at least one additional initially non-active-ingredient pressure-sensitive adhesive layer (3) (if present) are made of a non-amine-resistant pressure-sensitive silicone adhesive with moderate adhesiveness, such as Dow BIO-PSA 7-4501 and non-amine-resistant pressure-sensitive silicone adhesives with high adhesiveness, such as Dow The mixture of BIO-PSA 7-4601 comprises a matrix layer (2) and / or at least one additional initially non-active pressure-sensitive adhesive layer (3) (if present) without additional pressure-sensitive adhesive.

[0082] In a preferred embodiment of the present invention, wherein the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) comprises a mixture of at least one non-amine-resistant pressure-sensitive silicone adhesive having moderate adhesiveness and at least one non-amine-resistant pressure-sensitive silicone adhesive having high adhesiveness, or a mixture thereof, the non-amine-resistant pressure-sensitive silicone adhesive having moderate adhesiveness is preferably 0.0-55.0% by weight, more preferably 0.0-45.0% by weight, and more preferably... Preferably, the non-amine-resistant pressure-sensitive silicone adhesive with high adhesiveness is present in a weight range of about 0.0-35.0% by weight, more preferably 0.0-25.0% by weight, and in a weight range of preferably 45.0-100.0% by weight, more preferably 55.0-100.0% by weight, more preferably 65.0-100.0% by weight, more preferably 75.0-100.0% by weight, based on the total weight of the silicone adhesive in the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if present). Here, if the matrix layer (2) and at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) are present in the TTS, the weight ratio of the non-amine-resistant silicone adhesive with medium adhesiveness to the non-amine-resistant silicone adhesive with high adhesiveness may be the same or different in the two layers.

[0083] The non-amine-resistant silicone adhesive in this invention can be a non-silanol-reduced silicone adhesive (i.e., a non-amine-resistant silicone adhesive where the silanol groups are not protected by protecting groups) or a silanol-reduced silicone adhesive (i.e., a non-amine-resistant silicone adhesive where the silanol groups are only partially protected by protecting groups). Such non-silanol-reduced or only partially silanol-reduced silicone adhesives are known in the prior art. Preferred non-amine-resistant silicone adhesives are non-silanol-reduced non-amine-resistant silicone adhesives, such as Dow... BIO-PSA 7-4501, Dow BIO-PSA7-4601, Dow BIO-PSA 7-4502, Dow BIO-PSA 7-4602, or non-amine-resistant silicone adhesives with reduced silanol content, are still classified as non-amine-resistant silicone adhesives due to their low silanol reduction, such as Dow BIO-PSA SRS7-4501 and Dow BIO-PSA SRS7-4601. The following non-amine-resistant silicone adhesive, Dow, is particularly preferred. BIO-PSA7-4501, Dow BIO-PSA 7-4601, Dow BIO-PSA SRS7-4501 and Dow BIO-PSA SRS7-4601, Dow is preferred BIO-PSA SRS7-4501 and Dow BIO-PSA SRS7-4601.

[0084] Furthermore, the inventors of this invention have surprisingly discovered that the adhesive strength of the resulting transdermal therapeutic system can be improved by using a silanol-reduced non-amine-resistant silicone adhesive instead of a non-silanol-reduced non-amine-resistant silicone adhesive. In the context of this invention, the term "silanol-reduced" refers to a so-called non-amine-resistant silicone adhesive in which a portion of the silanol groups are protected by protecting groups; that is, such a silanol-reduced silicone adhesive is still a non-amine-resistant silicone adhesive in the context of this invention. Silanol-reduced non-amine-resistant silicone adhesives are known in the prior art and are described, for example, in U.S. publication US6,337,086. BIO-PSA SRS7-4501, Dow BIO-PSA SRS7-4601, Dow BIO-PSA SRS7-4502, Dow BIO-PSA SRS7-4602 is an example of a silanol-reduced, non-amine-resistant silicone adhesive. Preferably, the silanol-reduced, non-amine-resistant silicone adhesive is a Dow... BIO-PSA SRS7-4501 and Dow BIO-PSA SRS7-4601. According to a preferred embodiment of the invention, the silanol content of the silanol-reduced non-amine-resistant silicone adhesive, expressed in ppm, is preferably between about 8000 ppm and 13000 ppm, and the silanol content of the non-silanol-reduced non-amine-resistant silicone adhesive is preferably greater than 13000 ppm, and, for example, as described in US6,337,086, can be achieved through, for example... 29 Si-NMR spectroscopy and / or FTIR spectroscopy determination.

[0085] In a preferred embodiment of the invention, one or more non-amine-resistant silicone adhesives of the matrix layer (2) comprise one or more silanol-reduced non-amine-resistant silicone adhesives, preferably having a weight percentage of more than 50% by weight, more preferably more than 60% by weight, more preferably more than 75% by weight, more preferably more than 85% by weight, more preferably more than 90% by weight, more preferably more than 95% by weight, and more preferably at least 99% by weight of silanol-reduced non-amine-resistant silicone adhesives based on the total weight of the non-amine-resistant silicone adhesives of the matrix layer (2).

[0086] In a preferred embodiment of the invention, in which the transdermal therapeutic system comprises at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3), one or more non-amine-resistant silicone adhesives in the at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3) comprise one or more silanol-reduced non-amine-resistant silicone adhesives, preferably having a weight percentage of more than 50 wt%, more preferably more than 60 wt%, more preferably more than 75 wt%, more preferably more than 85 wt%, more preferably more than 90 wt%, more preferably more than 95 wt%, more preferably at least 99 wt% of silanol-reduced non-amine-resistant silicone adhesives based on the total weight of the non-amine-resistant silicone adhesives in the at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3).

[0087] For example, one or more non-amine-resistant silicone adhesives of the matrix layer (2) may also include two, three, or four types of silanol-reduced non-amine-resistant silicone adhesives, preferably in the weight percentage of the total weight of the non-amine-resistant silicone adhesives of the matrix layer (2). Similarly, one or more non-amine-resistant silicone adhesives of at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) may also include two, three, or four types of silanol-reduced non-amine-resistant silicone adhesives, preferably in the weight percentage of the above, but based on the total weight of the non-amine-resistant silicone adhesives of at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3).

[0088] As observed by the inventors of this invention, even when using a protective foil (4) made of fluorosilicone foil, such as Scotchpak 9709 (3M Corporation), the use of non-amine-resistant silicone adhesives with high adhesiveness, such as Dow, reduces the use of silanols. BIO-PSA SRS7-4601 can also lead to a significant increase in separation force during storage. Surprisingly, the inventors have discovered that the use of silanols with moderate adhesiveness, such as Dow, reduces the effectiveness of non-amine-resistant silicone adhesives. BIO-PSA SRS7-4501 and non-amine-resistant silicone adhesives with high adhesiveness and reduced silanol content, such as Dow BIO-PSA SRS7-4601 can significantly reduce this increase in separation force during storage.

[0089] Therefore, in embodiments of the present invention, the matrix layer (2) comprises one or more non-amine-resistant silicone adhesives of reduced silanol content or consisting only of such adhesives. The matrix layer (2) preferably comprises one or more non-amine-resistant pressure-sensitive silicone adhesives of reduced silanol content, such as Dow. BIO-PSA SRS7-4501 and one or more silanol-reduced non-amine-resistant pressure-sensitive silicone adhesives with high adhesiveness, such as Dow A mixture of BIO-PSA SRS7-4601.

[0090] In another embodiment of the invention, the transdermal therapeutic system comprises at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3), and at least one or more non-amine-resistant silicone adhesives of the at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3) comprise silanol-reduced non-amine-resistant silicone adhesives or consist only of such adhesives. The at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3) preferably comprises one or more silanol-reduced non-amine-resistant pressure-sensitive silicone adhesives with moderate adhesiveness, such as Dow. BIO-PSA SRS7-4501 and one or more silanol-reduced non-amine-resistant pressure-sensitive silicone adhesives with high adhesiveness, such as Dow A mixture of BIO-PSA SRS7-4601.

[0091] In a preferred embodiment of the invention, wherein the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if present) comprises one or more non-amine-resistant silicone adhesives with medium tack and a mixture of one or more silanol-reduced non-amine-resistant silicone adhesives with high tack, or a mixture thereof, the silanol-reduced non-amine-resistant silicone adhesive with medium tack is preferably 10.0-40.0% by weight, more preferably 15.0-35% by weight. The silanol-reduced non-amine-resistant silicone adhesive with high adhesiveness is present in a weight range of approximately 17.5-30.0% by weight, more preferably 17.5-30.0% by weight, and more preferably in a weight range of approximately 70.0-82.5% by weight, based on the total weight of the silicone adhesive in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if present) that is initially free of active ingredients. Here, if the matrix layer (2) and at least one additional pressure-sensitive adhesive layer (3) that is initially free of active ingredients are present in the TTS, the weight ratio of the silanol-reduced non-amine-resistant silicone adhesive with medium adhesiveness to the silanol-reduced non-amine-resistant silicone adhesive with high adhesiveness may be the same or different in the two layers.

[0092] In a preferred variant of the above-described embodiment of the transdermal therapeutic system having a silanol-reduced, non-amine-resistant pressure-sensitive silicone adhesive, one or more non-amine-resistant pressure-sensitive silicone adhesives of the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if present) consist solely of a silanol-reduced, non-amine-resistant pressure-sensitive silicone adhesive. In a further preferred variant of the above-described embodiment, the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if present) have only a silanol-reduced, non-amine-resistant pressure-sensitive silicone adhesive as the pressure-sensitive adhesive.

[0093] In another preferred variant of the above-described embodiment of the transdermal therapeutic system with a silanol-reduced, non-amine-resistant pressure-sensitive silicone adhesive, the pressure-sensitive adhesive of the matrix layer (2) and / or at least one additional initially non-active-ingredient pressure-sensitive adhesive layer (3) (if present) is made solely of a silanol-reduced, non-amine-resistant pressure-sensitive silicone adhesive, such as Dow, with moderate adhesive strength. BIO-PSA SRS7-4501 and non-amine-resistant pressure-sensitive silicone adhesives with high adhesiveness and reduced silanol content, such as Dow The mixture composition of BIO-PSA SRS7-4601.

[0094] In a preferred embodiment of the bilayer formulation according to the invention, one or more non-amine-resistant silicone adhesives of the matrix layer (2) are reduced only by a non-amine-resistant pressure-sensitive silicone adhesive such as Dow, which has a moderate adhesiveness. BIO-PSA SRS7-4501, and at least one additional initial pressure-sensitive adhesive layer (3) consisting of one or more non-amine-resistant silicone adhesives made solely of non-amine-resistant silicone adhesives such as Dow, which are reduced only by silanols with moderate adhesiveness. BIO-PSA SRS7-4501 and non-amine-resistant silicone adhesives with high adhesiveness and reduced silanol content, such as Dow The mixture comprises BIO-PSA SRS7-4601. In another preferred embodiment of the bilayer formulation according to the invention, the pressure-sensitive adhesive of the matrix layer (2) consists only of a silanol-reduced non-amine-resistant silicone adhesive with medium tack, and the pressure-sensitive adhesive of at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) consists only of a mixture of a silanol-reduced non-amine-resistant silicone adhesive with medium tack and a silanol-reduced non-amine-resistant silicone adhesive with high tack.

[0095] In a preferred variant of the above-described embodiments having one or more silanol-reduced non-amine-resistant silicone adhesives, one or more non-silanol-reduced non-amine-resistant silicone adhesives are used instead of one or more silanol-reduced non-amine-resistant silicone adhesives. That is, for example, in a preferred embodiment of the invention, one or more non-amine-resistant silicone adhesives of the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if present) contain one or more non-silanol-reduced non-amine-resistant silicone adhesives, preferably at a weight percentage of more than 50% by weight, more preferably more than 60% by weight, more preferably more than 75% by weight, more preferably more than 85% by weight, more preferably more than 90% by weight, more preferably more than 95% by weight, more preferably at least 99% by weight, based on the total weight of the non-amine-resistant silicone adhesives of the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if present). Alternatively, for example, in a preferred variant of the above embodiments, one or more non-amine-resistant pressure-sensitive silicone adhesives of the matrix layer (2) and / or at least one additional initially non-active-ingredient pressure-sensitive adhesive layer (3) (if present) consist only of non-amine-resistant silicone adhesives with reduced non-silanol content.

[0096] For example, one or more non-amine-resistant silicone adhesives based on a matrix layer (2) and / or at least one additional initially non-active pressure-sensitive adhesive layer (3) (if at least one such initially non-active pressure-sensitive adhesive layer (3) is present) may also contain two, three, four, or other non-silanol-reduced non-amine-resistant silicone adhesives, preferably in the aforementioned weight percentage of the total weight of the non-amine-resistant silicone adhesives of the matrix layer (2) or at least one additional initially non-active pressure-sensitive adhesive layer (3). Non-silanol-reduced non-amine-resistant silicone adhesives are known to those skilled in the art. Preferred non-silanol-reduced non-amine-resistant silicone adhesives are Dow BIO-PSA 7-4501, Dow BIO-PSA 7-4601, Dow BIO-PSA 7-4502 and Dow BIO-PSA 7-4602.

[0097] All of the above embodiments are preferably designed such that the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if present) and / or the entire transdermal treatment system contain only silicone adhesives as pressure-sensitive adhesives. Furthermore, all of the above embodiments are preferably designed such that the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if present) and / or the entire transdermal treatment system contain only non-amine-resistant pressure-sensitive silicone adhesives as pressure-sensitive silicone adhesives; that is, in particular, the matrix layer (2) and / or at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) (if present) and / or the entire transdermal treatment system do not contain amine-resistant pressure-sensitive silicone adhesives, but are limited to non-amine-resistant pressure-sensitive silicone adhesives.

[0098] The preferred administration period for the transdermal therapeutic system according to the invention is one day, i.e., the transdermal therapeutic system according to the invention is removed from the skin after one day. Since the transdermal therapeutic system according to the invention is typically used for long-term treatment (months or even years), the novel transdermal therapeutic system according to the invention is adhered to the skin after removal of the transdermal therapeutic system after one day.

[0099] However, the transdermal therapy system of the present invention can also be used for more than one day, for example, two or three days. In these cases, the transdermal therapy system according to the present invention is replaced by a new transdermal therapy system after two or three days, respectively.

[0100] The adhesive matrix has a backing layer (1) on the side facing away from human skin during use. In a more preferred embodiment, the backing layer (1) is sealed to the active ingredient, i.e., impermeable. It is also particularly preferred that the backing layer is largely opaque. In one embodiment, such a backing layer may be composed of polyester, polyolefin, particularly polyethylene or polyurethane. It is also advantageous to use a backing layer comprising a variety of different polymers disposed on top of each other. Preferably, the backing layer has high water vapor impermeability.

[0101] Preferred materials for the backing layer are polyesters, for example, in the form of composite foils having an inner polyester, a central aluminum barrier layer, and an outer colored polyethylene. Particularly preferred backing layers are, for example, polyester-based foils sold by 3M under the names Scotchpak 1109 or Scotchpak 9738, or those from Mitsubishi Polyester Film under the name... MN19 MN 19Med and Polyester-based foils are available for sale; for single-layer formulations, Scotchpak 9738 is particularly preferred, and for double-layer formulations, for example... MN19Med.

[0102] Other suitable materials include cellophane, cellulose acetate, ethyl cellulose, vinyl acetate-vinyl chloride copolymer with plasticizer, ethylene-vinyl acetate copolymer, polyethylene terephthalate, nylon, polyethylene, polypropylene, polyvinylidene chloride, ethylene-methyl methacrylate copolymer, optionally coated paper, textile fabrics such as polyethylene terephthalate foil, aluminum foil, and polymeric metal composites.

[0103] The thickness of the backing layer (1) of the transdermal therapeutic system according to the present invention is not particularly limited. In a preferred embodiment, the backing layer (1) comprises polyester foil, preferably with a thickness of less than 35 μm, more preferably 5-30 μm, more preferably 10-25 μm, and particularly preferably 15-23 μm. In another embodiment, the backing layer (1) is composed of polyester foil, preferably with a thickness of less than 70 μm, more preferably 15-65 μm, more preferably 25-60 μm, particularly preferably 30-60 μm, or particularly preferably 49-60 μm, or even more preferably 31-37 μm.

[0104] A cover layer may also be present on the backing layer (1) of the patch, particularly to prevent the patch from adhering to the packaging in the event of a small amount of matrix material escaping. The cover layer is preferably located on the backing layer and held in place by electrostatic forces. This type of cover layer is known in the prior art, for example from EP 1 097 090, which is fully referenced in all respects. The cover layer is coated with an anti-stick coating, for example, fluorinated or fluorosilicone coated, at least on the side located on the backing layer.

[0105] Furthermore, the transdermal therapeutic system according to the invention includes a protective foil (4) (isolation liner) to be removed prior to use. The protective foil (4) follows the matrix layer (2), or, if present, at least one additional pressure-sensitive adhesive layer (3) initially without active ingredients (see, for example...). Figure 1(A) and (B)). Here, the protective foil (4) to be removed before use is preferably the outer layer of the TTS, such that one side of the protective foil (4) to be removed before use forms the outer side. If there is no additional initial pressure-sensitive adhesive layer (3) without active ingredients, the protective foil (4) to be removed before use is preferably in direct contact with the substrate layer (2), such that the opposite side of the protective foil (4) to be removed before use represents the outer layer of the TTS. If there is an additional initial pressure-sensitive adhesive layer (3) without active ingredients, the additional initial pressure-sensitive adhesive layer (3) without active ingredients is located between the substrate layer (2) and the protective foil (4) to be removed before use, and preferably in direct contact with the substrate layer (2) and / or the protective foil (4) to be removed before use. If there is more than one additional initial non-active pressure-sensitive adhesive layer (3), the additional additional initial non-active pressure-sensitive adhesive layers (3) are located between the substrate layer (2) and the protective foil (4) to be removed before use, such that the protective foil (4) to be removed before use is preferably in direct contact with the additional initial non-active pressure-sensitive adhesive layer (3) furthest from the substrate layer (2).

[0106] The protective foil (4) to be removed before use is preferably made of a polymer material, which may optionally be metallized. Examples of preferred polymer materials are polyester, polyurethane, polyvinyl acetate, polyvinylidene chloride, polypropylene, polycarbonate, polystyrene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, and paper optionally coated with the corresponding polymer. Preferably, it is a protective foil (4) that is fluorosilicone-coated on one or both sides. Commercially available fluorosilicone-coated polyester foils are particularly preferred, such as the fluorosilicone-coated trade product Scotchpak 9709 (3M). In a preferred embodiment, the transdermal treatment system further includes a protective foil (4) to be removed before use, which consists of a fluorosilicone-coated foil and preferably a fluorosilicone-coated polyester foil.

[0107] In a preferred embodiment, the transdermal treatment system according to the invention comprises a backing layer (1); a matrix layer (2) situated on the backing layer; and a protective foil (4) to be removed upon use, situated on the matrix layer. In a further preferred embodiment, the transdermal treatment system comprises a backing layer (1); a matrix layer (2) situated on the backing layer; at least one additional initially non-active pressure-sensitive adhesive layer (3) situated between the matrix layer and the protective foil (4) to be removed upon use; and a protective foil (4) to be removed upon use, situated on at least one additional initially non-active pressure-sensitive adhesive layer (3).

[0108] According to the invention, the active ingredient is in the matrix layer (2). The active ingredient is rotigotine or a pharmaceutically acceptable salt of rotigotine, preferably rotigotine. The invention is not limited by the polymorphic forms of rotigotine that can be used; however, for stability reasons, polymorph II rotigotine as described in WO 2009 / 068520 is preferred. For the preparation and characterization of polymorph II rotigotine, please refer fully to WO 2009 / 068520.

[0109] Preferably, the active ingredient is present in the matrix layer (adhesive matrix) in a completely dissolved form, i.e., the matrix layer preferably does not contain solid active ingredient particles. The content of rotigotine in the matrix layer (2) is preferably in the range of 5% to 25% by weight, more preferably in the range of 6% to 20% by weight, more preferably in the range of 6% to 15% by weight, and even more preferably in the range of 6.5% to 11.5% by weight, for example 6.875-9% by weight, especially about 7.5-9% by weight of rotigotine, based on the total weight of the matrix layer (2).

[0110] According to the invention, the active ingredient is present in the matrix layer (adhesive matrix), preferably in the dispersed phase of a substantially amorphous solid dispersion, wherein one or more non-amine-resistant silicone adhesives and possibly other polymeric adhesives preferably form a dispersant. In a preferred embodiment, in addition to amorphous rotigotine, the dispersed phase also comprises polyvinylpyrrolidone. In this document, "substantially" means more than 50%, especially more than 90%, particularly preferably more than 99%, or completely.

[0111] Rotigotine has poor solubility in silicone adhesives, but excellent solubility in crystallization inhibitors such as polyvinylpyrrolidone. In a preferred embodiment of the transdermal therapeutic system according to the invention, the matrix layer (2) therefore contains polyvinylpyrrolidone dispersed therein in addition to an amine-resistant silicone adhesive. Rotigotine is preferably completely dissolved in the matrix layer, i.e., the amount of rotigotine in the silicone adhesive is so small that preferably no rotigotine precipitation / crystallization is observed, and the major portion of rotigotine is preferably dissolved (or at least in a non-crystalline form) in the dispersed polyvinylpyrrolidone.

[0112] Polyvinylpyrrolidone (PVP) is a polymer formed from N-vinylpyrrolidone monomers. It is known to increase the cohesive strength of silicone adhesives. PVP also acts as a crystallization inhibitor for the active ingredient rotigotine. The molecular weight of PVP ranges from 2,000 to 2,500,000 Daltons (g / mol) (by average weight), preferably from 700,000 to 1,500,000 Daltons, and more preferably from 900,000 to 1,500,000 Daltons. Various PVP grades are available. Commercially available, for example from BASF AG, Ludwigshafen, Germany, and under the name Kollidon. For example, the following Kollidon grades are water-soluble forms of PVP: K-12PF (molecular weight = 2,000-3,000 Daltons); K-17PF (molecular weight = 7,000-11,000 Daltons); K-25 (molecular weight = 28,000-34,000 Daltons); K-30 (molecular weight = 44,000-54,000 Daltons); and K-90 (molecular weight = 900,000-1,500,000 Daltons). In a preferred embodiment, the molecular weight of polyvinylpyrrolidone is in the range of 28,000 to 1,500,000 Daltons (g / mol).

[0113] The inventors have surprisingly discovered that in transdermal therapeutic systems in which the active ingredient rotigotine and one or more non-amine-resistant silicone adhesives are present in a matrix layer in an amount exceeding 50% by weight (based on the total weight of the pressure-sensitive adhesives in the matrix layer (2)), when rotigotine and polyvinylpyrrolidone are used in the matrix layer, crystallization does not occur even after prolonged storage at 25°C or higher in a solid dispersion phase with a weight ratio of 9:6.4, particularly 9:7 or lower. On the other hand, at a larger weight ratio of rotigotine to polyvinylpyrrolidone, for example 9:5 or higher, crystallization can occur after prolonged storage at 25°C or higher. Therefore, according to the present invention, such a high weight ratio of rotigotine to polyvinylpyrrolidone is certainly possible, but not preferred.

[0114] Therefore, in a preferred embodiment of the transdermal therapeutic system according to the invention, rotigotine in the matrix layer exists substantially in a non-crystalline form within the dispersed phase of a solid dispersion comprising polyvinylpyrrolidone (PVP), wherein the weight ratio of rotigotine to PVP is at most 9:6.4, more preferably at most 9:6.5, and especially at most 9:7. The weight ratio of rotigotine to PVP is preferably at least 9:11, more preferably at least 9:10, and especially at least 9:9. Preferably, this ratio is in the range of 9:7 to 9:10. At such weight ratios, the matrix layer may contain, for example, 5.14-12.86 wt% rotigotine and 4-10 wt% PVP, or 6.88-9 wt% rotigotine and 5.35-7 wt% PVP, based on the total weight of the matrix layer. In a further preferred embodiment of the invention, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 90 wt%, at least 95 wt%, and at least 97.5 wt% of rotigotine in the matrix layer are present in a non-crystalline form in the dispersed phase of the solid dispersion comprising polyvinylpyrrolidone (PVP).

[0115] Suitable polyvinylpyrrolidones (PVPs) for use in the matrix layer of transdermal therapeutic systems in combination with rotigotine are known in the prior art. Such PPVs are described, for example, in WO2011 / 076879. For the purposes of this invention, a preferred PPV is PVP K90 (BASF SE). Particularly preferred is the K-90 type PPV (PVP K90).

[0116] The matrix layer (2) and / or at least one additional initially non-active pressure-sensitive adhesive layer (3) may contain other polymeric adhesives (i.e., pressure-sensitive adhesives) that are not non-amine-resistant silicone adhesives. The weight fraction of other polymeric adhesives that are not non-amine-resistant silicone adhesives in the matrix layer (2) is less than 50% by weight, preferably less than 40% by weight, more preferably less than 30% by weight, preferably less than 20% by weight, more preferably less than 10% by weight, more preferably less than 5% by weight, based on the total weight of the pressure-sensitive adhesives in the matrix layer (2). If an additional initially non-active pressure-sensitive adhesive layer (3) is present in the TTS, the weight fraction of other polymeric adhesives (not non-amine-resistant silicone adhesives) in the additional initially non-active pressure-sensitive adhesive layer (3) is less than 50% by weight, preferably less than 40% by weight, more preferably less than 30% by weight, more preferably less than 20% by weight, more preferably less than 10% by weight, and more preferably less than 5% by weight, based on the total weight of at least one additional initially non-active pressure-sensitive adhesive layer (3). Such additional polymeric adhesives are, for example, polyacrylates, polymethacrylates, SBS block copolymers, and polyisobutylene.

[0117] Polyacrylates and polymethacrylates are known in the art (see, for example, US2002 / 0077437) and are used in various ways in transdermal therapeutic systems. Polyacrylates are typically prepared by free radical polymerization of acrylic acid or methacrylic acid derivatives, particularly acrylic acid or methacrylates, wherein other suitable compounds, such as vinyl acetate, may be copolymerized as additional monomers. The properties of polyacrylates or polymethacrylates can be modified, for example, by crosslinking with polyvalent metal ions. Both crosslinked and uncrosslinked polyacrylates or polymethacrylates are commercially available, with one of the major suppliers being Henkel (or National Starch), which sells polyacrylates and polymethacrylates under the name "DURO-TAK".

[0118] Examples are, for instance, polyacrylate or polymethacrylate copolymers or terpolymers selected from monomers such as: acrylic acid, methacrylic acid, methoxyethyl acrylate, ethyl acrylate, ethyl methacrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, methyl acrylate, methyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate, methoxyethyl methacrylate, etc. Optionally, acrylamide, dimethylamide, acrylonitrile, and vinyl acetate may be used as comonomers. Other examples of suitable acrylic adhesives are mentioned, for example, in Satas, Acrylic Adhesives, Handbook of Pressure Sensitive Adhesives Technology, 2nd edition, pp. 396-456 (D. Satas, editor) van Nostrand Reinhold, New York (1989). When polyacrylates are mentioned herein, the corresponding polymethacrylates are also referred to.

[0119] Polyisobutylene is known in the art and is commercially available. For example, BASF, Ludwigshafen, Germany sells Oppanol. Suitable polyisobutylenes include, for example, Oppanol B50, N50, B80, N80, B100, N100, B150, N150, B200, and N200, or Oppanol B10SFN or Oppanol B15SFN B10, B15. For example, a mixture of polyisobutylene selected from, for example, Oppanol B80, Oppanol B100, Oppanol B150, and Oppanol B200, preferably Oppanol B80 or Oppanol B100, with a second polyisobutylene selected from Oppanol B10SFN and Oppanol B15SFN can also be used.

[0120] With respect to the molecular weight of the polymer as referred to in the context of this invention, it is always the weight-average molecular weight M. w Unless otherwise expressly stated or clear from the context, the weight-average molecular weight M is as known to those skilled in the art. wFor example, it can be determined through GPC.

[0121] In the transdermal therapeutic system according to the invention, in addition to the pressure-sensitive adhesive, rotigotine, and optionally polyvinylpyrrolidone mentioned above, the matrix layer containing the active ingredient may contain additional components if necessary.

[0122] For example, a penetration enhancer can be added to the matrix layer to ensure that the active ingredient fully penetrates the skin. Suitable penetration enhancers are known. Examples include fatty alcohols, fatty acids, fatty acid esters, fatty acid amides, glycerol and glycerol derivatives, n-methylpyrrolidone, terpenes and terpene derivatives, such as D-limonene, α-pinene, α-terpineol, carvone, carvacrol, limonene oxide, pinene oxide, and 1,8-cineole. However, preferably, the transdermal therapeutic system according to the invention does not contain such a penetration enhancer.

[0123] In addition, one or more plasticizers may optionally be added to the matrix layer (2). Suitable plasticizers are also known in the prior art, and examples of plasticizers based on mineral oil or polybutene may be mentioned herein. In one embodiment, the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if present) that is initially free of active ingredients contains one or more additives, preferably plasticizers.

[0124] In a preferred embodiment of the invention, the matrix layer (2) further comprises one or more additives to improve the chemical stability of rotigotine, such as antioxidants, such as tocopherol and its derivatives, especially esters, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid and its derivatives, especially esters, and / or sodium metabisulfite. In one embodiment, the matrix layer (2) comprises tocopherol, ascorbyl palmitate, and sodium metabisulfite, for example, about 0.05-0.125% by weight of tocopherol, 0.0-0.1% by weight of ascorbyl palmitate, and 0.0-0.0021% by weight of sodium metabisulfite, based on the total weight of the matrix layer (2). Preferably, antioxidants or sodium metabisulfite are not added to at least one additional pressure-sensitive adhesive layer (3) that is initially free of active ingredients.

[0125] The transdermal therapeutic system according to the present invention can be used to treat all diseases requiring administration of the active ingredient rotigotine. However, the transdermal therapeutic system according to the present invention is particularly preferred for the treatment of Parkinson's disease.

[0126] The transdermal therapeutic system according to the invention can be prepared in a manner known per se. For example, for a monolayer formulation, all components of the matrix layer of the transdermal therapeutic system are added to a suitable solvent and stirred until the desired homogeneity is achieved. Subsequently, a homogenized coating material is applied to the backing layer (1) or preferably to the protective foil (4), and the solvent is removed by drying. Finally, the remaining layer, i.e., the protective foil (4) or preferably the backing layer (1), is laminated onto the matrix layer (2), and a transdermal therapeutic system of suitable size is stamped out.

[0127] Therefore, the present invention according to the preferred embodiment further relates to a method for preparing a transdermal therapeutic system as a single-layer formulation of one of the above embodiments of the transdermal therapeutic system according to the present invention, comprising a) preparing a homogenized coating material (coating material) by adding all components of the matrix layer (2) of the transdermal therapeutic system together to a suitable solvent and mixing to the desired homogeneity; b) applying the homogenized coating material to a backing layer (1) or preferably to a protective foil (4) and removing the solvent by drying; c) laminating the remaining layer, i.e., the protective foil (4) or preferably the backing layer (1), onto the matrix layer (2) and stamping out a transdermal therapeutic system of appropriate size.

[0128] For two-layer or multi-layer formulations, for example, all components of the active ingredient-containing matrix layer (2) of the transdermal therapy system are added together to a suitable solvent and stirred until the desired homogeneity is achieved. Subsequently, the first stirred or homogenized coating material is applied to the backing layer (1), or preferably to a temporary protective foil (4), and the solvent is removed by drying. Finally, the remaining layer, i.e., the temporary protective foil (4) or preferably the backing layer (1), is laminated onto the matrix layer (2) (the first precursor of the TTS). Then, the components of at least one additional initially non-active ingredient-free pressure-sensitive adhesive layer (3) of the transdermal therapy system are added together to a suitable solvent and stirred until the desired homogeneity is achieved. Subsequently, the additional coating material is applied to the protective foil (4) and the solvent is removed by drying (the second precursor of the TTS). Finally, the first precursor of TTS peels off the temporary protective foil (4) and laminates it together with at least one additional initial non-active ingredient pressure-sensitive adhesive layer (3) and the protective foil (4) (the second precursor of TTS) into a monolithic laminate material, which sequentially comprises or consists of: a backing layer (1), an active ingredient matrix layer (2), at least one additional initial non-active ingredient pressure-sensitive adhesive layer (3) and the protective foil (4), and the monolithic laminate material is stamped to form a transdermal treatment system of appropriate size.

[0129] Therefore, the present invention according to the second preferred embodiment further relates to a method for preparing a transdermal therapeutic system, comprising a) preparing a first precursor of the transdermal therapeutic system: comprising a1) preparing a first homogenized coating material by adding all components of the matrix layer (2) together to a suitable solvent and mixing to the desired homogeneity; a2) applying the first homogenized coating material to a backing layer (1), or preferably to a temporary protective foil (4), and removing the solvent by drying; and a3) laminating the remaining layer, i.e., the temporary protective foil (4) or preferably the backing layer (1), onto the matrix layer (2); b) preparing a second precursor of the transdermal therapeutic system, comprising: b1) by adding at least one additional initially non-active... a) Add all components of the pressure-sensitive adhesive layer (3) of the active ingredient to a suitable solvent and mix to the desired homogeneity to prepare an additional homogenized coating material; b2) Apply the additional homogenized coating material to the protective foil (4) and remove the solvent by drying; and c) Remove the temporary protective foil (4) from the first precursor of the transdermal treatment system from a), and laminate the first and second precursors of the transdermal treatment system into a monolithic laminate material, which sequentially comprises or consists of: a backing layer (1), a matrix layer (2) containing active ingredients, at least one additional initially non-active ingredient pressure-sensitive adhesive layer (3) and a protective foil (4); and stamp the transdermal treatment system of appropriate size from the monolithic laminate material.

[0130] In the above-described method for preparing a transdermal therapeutic system, additional layers can be inserted in a manner known per se through other intermediate process steps. For example, a membrane for controlling the release of the active ingredient can be inserted between a matrix layer and at least one additional pressure-sensitive adhesive layer (3) initially free of active ingredients. Alternatively, for example, a TTS comprising at least two additional pressure-sensitive adhesive layers (3) initially free of active ingredients can be prepared, for example, by removing the protective foil (4) from a bilayer formulation of a TTS prepared according to the second preferred method of the above-described method for preparing a TTS according to the invention, and laminating the bilayer formulation with, for example, an additional second precursor of the TTS in step b) (the second preferred embodiment of the above-described method for preparing a TTS according to the invention) into a monolithic laminate material, the monolithic laminate material sequentially comprising: a backing layer (1), a matrix layer (2) containing the active ingredient, first and second additional pressure-sensitive adhesive layers (3) initially free of active ingredients, and a protective foil (4); and stamping out a transdermal therapeutic system of suitable size. In this way, additional layers can be inserted into the TTS.

[0131] The following examples illustrate the invention. Percentages always refer to weight percentages.

[0132] Example 1a: Monolayer (Preparation of test formulation using 616ROTTS as an example)

[0133]

[0134] Prepare a 1% (wt%) sodium metabisulfite aqueous solution. Prepare a 25% (wt%) ethanol solution of PVP K90. In a suitable glass container, add the corresponding amount of sodium metabisulfite solution to the corresponding amount of PVP solution and stir for about 15 minutes. Add ascorbate palmitate and tocopherol and stir. Then, slowly add the active ingredient rotigotine while stirring, and heat in a water bath while stirring at about 60°C until completely dissolved. After the material cools again, add the silicone adhesive sequentially and stir briefly. Then, add the equilibration solvent heptane and stir. Finally, add paraffin. Stir the coating material until all materials are visually uniformly distributed. Subsequently, treat the coating material at about 10,000 rpm for about 3 minutes using a suitable dispersing instrument (Ultra-Turrax). Spread the thus homogenized coating material as a thin film onto a fluorinated foil such as Scotchpak. TM Apply 9709 / 1022 / 9744, then heat at, for example, 85°C for 10 minutes to almost completely remove the solvent. The dried matrix is ​​approximately 60 g / m³. 2 It is laminated together with a protective foil, such as polyethylene terephthalate (PET) or aluminum polyethylene polyester with a thickness of 19 μm.

[0135] Example 1b: Monolayer (Preparation of test formulation using IMPD 631ROTTDS as an example)

[0136]

[0137]

[0138] Prepare a 1% (wt%) sodium metabisulfite aqueous solution. Prepare a 25% (wt%) ethanol solution of PVP K90. In a suitable glass container, add the corresponding amount of sodium metabisulfite solution to the corresponding amount of PVP solution and stir for about 30 minutes. Add ascorbate palmitate and tocopherol and stir. Then, under stirring and heating in a water bath, slowly add the active ingredient rotigotine and stir at about 60°C until completely dissolved. After the material cools again, add the silicone adhesive sequentially and stir briefly. Then, add the equilibrium solvent heptane and stir. Finally, add paraffin. Stir the coating material until all materials are visually uniformly distributed. Subsequently, treat the coating material at about 10,000 rpm for about 3 minutes using a suitable dispersing instrument (Ultra-Turrax). Spread the thus homogenized coating material as a thin film on a fluorinated foil such as Scotchpak. TM9709, and subsequently heated at rates of approximately 0.16 m / min at 45, 60, 80, and 99 °C respectively in a drying tunnel of approximately 52 cm in length with four separate sections, to almost completely remove the solvent. The dried matrix was approximately 50 g / m³. 2 It is laminated together with a protective foil, such as polyethylene terephthalate (PET) with a thickness of 19 μm.

[0139] Example 2a: Bilayer (Preparation of test formulation using 618-617 ROTTDS as an example)

[0140]

[0141]

[0142] First, the matrix layer (2) is prepared. For this purpose, a 1% (wt%) aqueous solution of sodium metabisulfite and a 25% (wt%) ethanol solution of PVP K90 are prepared. In a suitable glass container, the appropriate amount of sodium metabisulfite solution is added to the appropriate amount of PVP solution and stirred for at least 15 minutes. Ascorbate palmitate and tocopherol are added and stirred. Then, the active ingredient rotigotine is slowly added under stirring and heating in a water bath, and stirred at approximately 60°C until completely dissolved. After the material cools again, the silicone adhesive is added sequentially and stirred briefly. Then, the equilibration solvent heptane is added and stirred. The coating material is stirred until all materials are visually uniformly distributed. Subsequently, the coating material is spread as a thin film onto a fluorinated foil such as Scotchpak. TM 9709 / 1022 / 9744 and then, for example, heated at 85°C for 10 minutes to almost completely remove the solvent. The dried matrix is ​​approximately 50 g / m³. 2 It is laminated together with a protective foil, such as polyethylene terephthalate (PET) with a thickness of 19 μm.

[0143] For the preparation of an initial adhesive layer (3) without active ingredients, silicone adhesive is added to a suitable glass container and briefly stirred. Then, paraffin and the equilibration solvent heptane are added sequentially and stirred. The coating material is stirred until all materials are visually uniformly distributed. Subsequently, the coating material is spread as a thin film onto a fluorinated foil such as Scotchpak. TM On 9709 / 1022 / 9744, then heat at, for example, 85°C for 10 minutes to almost completely remove the solvent. The matrix weight of the dried, initially non-active adhesive layer (3) is 25-30 g / m². 3 And, in the case of peeling off its release liner, it is laminated together with the matrix layer onto the open matrix of the initially non-active adhesive layer (3).

[0144] Example 2b: Bilayer (Preparation of test formulation using 629_628ROTTDS as an example)

[0145]

[0146]

[0147] First, the matrix layer (2) was prepared. For this purpose, a 1% (wt%) aqueous solution of sodium metabisulfite and a 25% (wt%) ethanol solution of PVP K90 were prepared. In a suitable glass container, the appropriate amount of sodium metabisulfite solution was added to the appropriate amount of PVP solution and stirred for approximately 30 minutes. Ascorbate palmitate and tocopherol were added and stirred. Then, the active ingredient rotigotine was slowly added under stirring and heating in a water bath, and stirred at approximately 60°C until completely dissolved. After the material cooled again, the silicone adhesive was added sequentially and stirred briefly. Then, the equilibration solvent heptane was added and stirred. The coating material was stirred until all materials were visually uniformly distributed. Subsequently, the coating material was spread as a thin film onto a fluorinated foil such as Scotchpak. TM The substrate was then heated in a drying tunnel of approximately 52 cm in length, consisting of four sections, at rates of approximately 0.16 m / min at 45, 60, 80, and 99 °C respectively, until the solvent was almost completely removed. The dried substrate yielded approximately 50 g / m³. 2 It is laminated together with a protective foil, such as polyethylene terephthalate (PET) with a thickness of 19 μm.

[0148] For the preparation of an initial adhesive layer (3) without active ingredients, silicone adhesive is added to a suitable glass container and briefly stirred. Then, paraffin and the equilibration solvent heptane are added sequentially and stirred. The coating material is stirred until all materials are visually uniformly distributed. Subsequently, the coating material is spread as a thin film onto a fluorinated foil such as Scotchpak. TM 9709, then heated, for example, at 80°C for 5 minutes, to almost completely remove the solvent. The matrix weight of the dried, initially non-active adhesive layer (3) is 25-30 g / m². 2 And, in the case of peeling off its release liner, it is laminated together with the matrix layer onto the open matrix of the initially non-active adhesive layer (3).

[0149] FG[g / m 2 Weight per unit area

[0150] PVP K90: Polyvinylpyrrolidone K-90 (BASF SE)

[0151] rh: Relative humidity

[0152] RSD: Relative Standard Deviation

[0153] RS: Matrix layer

[0154] HS: Initial adhesive layer without active ingredients

[0155] mon: month

[0156] RT: Room temperature

[0157] The transdermal therapy system prepared in this way has, for example, the following general composition:

[0158] A monolayer formulation having a matrix layer containing active ingredients, including rotigotine and PVP K90 in a certain weight ratio and weight percentage based on the total weight of the matrix layer; 0-3% by weight of viscous paraffin; one or two non-silanol-reduced or silanol-reduced non-amine-resistant silicone adhesives (Dow Various combinations thereof; at least one antioxidant, such as 0.05-0.1% by weight of tocopherol, 0.02-0.1% by weight of ascorbate palmitate and 0.0006-0.0021% by weight of sodium metabisulfite; and a matrix weight of about 50-60 g / m³. 2 .

[0159] Bilayer formulations with a matrix layer containing active ingredients, including rotigotine and PVP K90 in a specific weight ratio and weight percentage based on the total weight of the matrix layer; non-silanol reduced or silanol reduced non-amine-resistant silicone adhesives BIO-PSA 7-4501 or BIO-PSA SRS7-4501 (Dow ); at least one antioxidant, such as 0.05-0.1% by weight of tocopherol and / or 0.02-0.1% by weight of ascorbate palmitate and 0.0006-0.0021% by weight of sodium metabisulfite; the matrix weight is about 2550 g / m 2 ; and an additional initial pressure-sensitive adhesive layer (3) without active ingredients, comprising one or two non-amine-resistant silicone adhesives (Dow) without silanol. Various combinations of 0-3% by weight of viscous paraffin.

[0160] The following specific monolayer and bilayer formulations have been prepared:

[0161] A) Paraffin-free single-layer formulations with varying proportions of non-amine-resistant silicone adhesives.

[0162] Various paraffin-free monolayer formulations were prepared, with different mixing ratios of BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601, and BIO-PSA 7-4501 and BIO-PSA 7-4601 in the matrix layer. For these monolayer formulations, Scotchpak 1109 (3M Corporation) as a backing layer was used. Various combinations of MN19 (Mitsubishi Polyester Film) and protective foils Scotchpak 1022, Scotchpak 9744, and Scotchpak 9709 (3M Corporation) were used. The resulting TTS were stored at 25°C and 40°C for different time periods, and their separation force, adhesion force, and tackiness (adhesion) were investigated. Furthermore, the in vitro permeability of some formulations to human thermally separated epidermis (HSE) was determined.

[0163] The separation force can be determined as the force required to separate the sample from its peeling liner at a specified angle and rate. For its determination, a TDS of a defined size is stamped out, for example, 10 cm. 2 The conditions were adjusted to 23±1℃ and 50±5% RH. A guide strip with the width of the TDS was attached to the TDS. The TDS with the peeling pad facing down was then secured to the tool holder using double-sided tape. It was placed in a tensile testing instrument, such as the Texture Analyzerplus from Stable Micro Systems, to peel the TDS at a 90° angle. Typically, measurements were taken at a rate of 300±30 mm / min at 23±1℃ and 50±5% RH. The separation force is the average force normalized to a 25 mm [N / 25 mm] sample width and measured along the separation path.

[0164] Adhesive force (adhesive strength) can be defined as the force required to separate a sample from a suitable carrier at a specified angle and rate. For the determination of adhesive force, a defined dimension is stamped out, for example, 10 cm. 2The TDS is measured and conditioned at 23±1℃ and 50±5% RH. A guide strip, for example made of double-sided tape, with the width of the TDS is attached. The TDS is adhered to a test plate, for example made of steel, while its release liner is peeled off, and then pressed between two glass plates with a 2kg weight for, for example, 1 minute. The test plate is vertically attached to a tensile testing instrument, such as the Stable Micro Systems TextureAnalyzer plus, and the guide strip is clamped, causing the TDS to peel off at a 90° angle. Typically, measurements are taken at a specified rate of 300±30 mm / min at 23±1℃ and 50±5% RH. The adhesive force is the average force normalized to a 25mm [N / 25mm] sample width and measured over the entire path.

[0165] Adhesion is defined as the maximum force required to completely separate the stainless steel specimen from the adhesive layer of TDS. To determine adhesion, a plaster or laminate is conditioned at 23±1°C and 50±5% RH and then fixed to a perforated support plate with an open adhesive matrix while its release liner is peeled off. The plate is attached to a tensile testing instrument such as the Stable MicroSystems Texture Analyzer plus. Typically, the test piece is pressed against the top of the sample at 23±1°C and 50±5% RH and peeled off after a specified contact time of typically 2 seconds. A series of measurements after peeling the release liner from the first sample should be completed within 30 minutes. The maximum force (adhesion; [N]) used to separate the bond between the test piece and the adhesive layer is determined.

[0166] Table 1: Paraffin-free single-layer formulations

[0167]

[0168]

[0169] B) Single-layer formulations of non-amine-resistant silicone adhesives and paraffin wax with different mixing ratios

[0170] Similar to A), various monolayer formulations containing small amounts of paraffin were prepared, including BIO-PSA SRS7-4501 with BIO-PSA SRS7-4601 and BIO-PSA 7-4501 with BIO-PSA 7-4601 (Dow The mixing ratios in the matrix layer differ. For these monolayer formulations, Scotchpak 1109 (3M Corporation) backing layer has been used. Various combinations of MN19 (Mitsubishi Polyester Film) and protective foils Scotchpak 9744 and Scotchpak 9709 (3M Corporation) were used. The resulting TTS were stored at 25°C and 40°C for different time periods, and their separation force, adhesion force, and tackiness (adhesion) were investigated. Furthermore, the in vitro permeability of some formulations to human thermally separated epidermis (HSE) was determined.

[0171] Table 2: Single-layer formulations containing paraffin

[0172]

[0173] C) Two-layer formulations with and without paraffin, containing different mixing ratios of non-amine-resistant silicone adhesives.

[0174] Different amounts of rotigotine and BIO-PSA SRS7-4501 or BIO-PSA 7-4501 (Dow) were prepared in the matrix layer. Various two-layer formulations. The two-layer formulation also has an additional, initially non-active pressure-sensitive adhesive layer on the side of the matrix layer opposite to the contact backing layer. This additional, initially non-active pressure-sensitive adhesive layer is made with or without a small amount of paraffin and a certain amount of BIO-PSA SRS7-4501 and / or BIO-PSA SRS7-4601 or BIO-PSA7-4501 (Dow) Prepared.

[0175] Here, a ratio of silicone adhesive with medium tack and silicone adhesive with high tack is selected to result in good adhesion and tack (adhesion) as well as the lowest possible cold flow and sufficiently high cohesion.

[0176] The backing layer used was Scotchpak 1109 (3M Corporation) and Various combinations of MN19 (Mitsubishi Polyester Film) and protective foils Scotchpak 9744, Scotchpak 1022, and Scotchpak 9709 (3M Corporation) and Primeliner 100μm 78BT and Primeliner 75μm 78HL (Loparex International BV) were used. The resulting TTS were stored at 25°C and 40°C for different time periods, and their separation force, adhesion force, and tackiness (adhesion) were investigated. Furthermore, the in vitro permeability of some formulations to human thermally separated epidermis (HSE) was determined.

[0177] In bilayer formulations, the effects of an additional, initially non-active pressure-sensitive adhesive layer on separation force, bond strength, tackiness, and in vitro permeability should be investigated.

[0178] Table 3: Two-layer formulations with and without paraffin

[0179]

[0180]

[0181] D) Monolayer formulations containing non-amine-resistant silicone adhesives and different concentrations of polyvinylpyrrolidone.

[0182] Various monolayer formulations with different amounts of PVP K90 were prepared, with rotigotine immobilization at 9%, based on the total weight of the matrix layer and the amounts of BIO-PSA SRS7-450 and BIO-PSA SRS7-4601 (Dow) in the matrix layer. The mixing ratio of ) is 1:1.

[0183] Scotchpak 1109 (3M Corporation) was used as the backing layer, and Scotchpak 9744 as the protective foil. The resulting TTS were stored at 25°C and 40°C for different time periods, and their appearance was studied. Furthermore, the in vitro permeability of some formulations to human thermally separated epidermis (HSE) was determined. The aim was to investigate the effect of PVP K90 dosage on the recrystallization and in vitro permeability of rotigotine.

[0184] Table 4: Monolayer formulations of rotigotine with different amounts of PVP K90 and a constant amount of 9% by weight.

[0185]

[0186]

[0187] Example 2 (Separation force, adhesion force, and adhesiveness)

[0188] The aim was to study the non-amine-resistant silicone adhesives BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601, and BIO-PSA 7-4501 and BIO-PSA 7-4601 (Dow) The study aimed to determine the effect of the mixing ratio of paraffin on separation force, adhesion, and adhesiveness, thereby enabling the determination of the optimal mixing ratio for the matrix layer. The study also aimed to investigate the effect of paraffin on separation force, adhesion, and adhesiveness.

[0189] A) Separation force

[0190] From Table 5 and Figure 2It is clear that the following TTS formulations resulted in a significant increase in separation force during storage: a combination of rotigotine in a matrix layer of a monolayer formulation with one or more silicone adhesives (non-amine-resistant silicone adhesives) primarily having free silanol groups, and a protective foil coated with a fluoropolymer such as Scotchpak 1022 or Scotchpak 9744 (3M Corporation). In placebo formulations without rotigotine, no increase in separation force was observed when using silicone adhesives with still-free silanol groups and the same type of protective foil.

[0191] When using rotigotine and one or more silicone adhesives that still have free silanol groups, protective foils coated with fluorosilicone, such as Scotchpak 9709 (3M Corporation), show a significantly lower increase in separation force for the same or similar formulations (see [link]). Figure 2 (and Table 5).

[0192] Table 5: Separation power of silicone adhesive formulations, with or without paraffin, with different polymer adhesive mixing ratios, including silicone adhesives with reduced non-silanol content and non-amine-resistant silicone adhesives with reduced silanol content, stored at 40°C / 75% RH for 0–3 months.

[0193]

[0194]

[0195] Surprisingly, compared to the non-amine-resistant silicone adhesive BIO-PSA SRS7-4601 (Dow) with only silanol reduction, Compared to rotigotine, the non-amine-resistant silicone adhesives BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 (Dow) have reduced silanol content. The mixture of ) and formulations of rotigotine also showed a lower increase in separation power. Non-silanol reduced non-amine-resistant silicone adhesives BIO-PSA 7-4501 and BIO-PSA 7-4601 (Dow It also showed reduced non-amine-resistant silicone adhesive BIO-PSA 7-4601 (Dow) compared to non-silanol alone. Lower separation force increases.

[0196] B) Adhesion

[0197] Furthermore, the adhesive strength of various TTS formulations, including different non-amine-resistant silicone adhesives and adhesive mixtures, as well as rotigotine, after storage of 0 to 3 months has been compared with placebo formulations and commercially available formulations. A comparison was made between TTS and other media platforms.

[0198] From Table 6 and Figure 3 It can be clearly seen that rotigotine with one or more non-silanol-reduced silicone adhesives (BIO-PSA 7-4501 and BIO-PSA 7-4601; Dow) The TTS formulation, consisting of a combination of (non-silanol reduced non-amine-resistant silicone adhesives), results in relatively low adhesive strength. This relatively low adhesive strength decreases sharply even with storage times of 1 and 3 months at 40°C / 75% RH, thus resulting in lower adhesive strength than [previous formulation] after 1 month of storage. The product exhibits lower adhesion strength. For the placebo formulation, despite the use of non-amine-resistant silicone adhesives, adhesion strength was not reduced.

[0199] Surprisingly, silanols reduce the effectiveness of non-amine-resistant silicone adhesives (Dow). Formulations of BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 with rotigotine, despite having fewer free silanol groups and therefore less interaction with surfaces compared to non-silanol silicone adhesives, exhibited significantly higher adhesive strength and lower adhesive strength-related degradation, resulting in absolute adhesive strength values ​​still higher than those of rotigotine after 0 to 3 months of storage at 40°C / 75% RH. Product details.

[0200] Furthermore, formulations containing approximately 17.5-30.0 wt% BIO-PSA SRS7-4501 and 82.5-70.0 wt% BIO-PSA SRS7-4601 (based on the total share of silicone adhesives BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601) exhibit high adhesive strength and are compatible with formulations containing only BIO-PSA SRS7-4601 (Dow (See formulation) Figure 3 Compared to this, it does not lead to a related increase in separation force (see...). Figure 4 (and Table 6).

[0201] Surprisingly, adding a small amount of paraffin, approximately 1-3% by weight, to the formulation resulted in a significant increase in adhesive strength, with only a slight decrease in adhesive strength during 1-3 months of storage (see [link]). Figure 3 (and Table 6).

[0202] Therefore, the presence of paraffin according to the invention also allows for the use of non-silanol-reduced, non-amine-resistant silicone adhesives. Compared to other products, these silicone adhesives offer improved adhesion, although not as strong as those using non-amine-resistant silicone adhesives with reduced silanol content. Therefore, the use of non-amine-resistant silicone adhesives with reduced silanol content is preferred.

[0203] Table 6: Adhesive strength (bond strength) of silicone adhesive formulations with or without paraffin, using different polymer adhesive mixing ratios, with and without non-silanol reduced silicone adhesives and with silanol reduced silicone adhesives, stored at 40°C / 75% RH for 0–3 months.

[0204]

[0205]

[0206] C) Adhesiveness

[0207] Finally, the adhesive properties of various TTS formulations, including different non-amine-resistant silicone adhesives and adhesive mixtures, as well as rotigotine, were compared with placebo formulations and commercially available formulations after 0 to 3 months of storage. A comparison was made.

[0208] From Table 7 and Figure 5 It can be clearly seen that silicone adhesives with reduced rotigotine and one or more non-silanols having still free silanol groups (Dow) The TTS formulation of the combination of BIO-PSA7-4501 and BIO-PSA7-4601 (non-silanol reduced non-amine resistant silicone adhesives) results in a higher performance than... The product has low adhesiveness (tackiness).

[0209] Surprisingly, the adhesive strength of non-amine-resistant silicone adhesives using silanol-reduced adhesives was significantly higher, showing only a slight decrease after one month of storage at 40°C / 75% RH, and then stabilizing after three months. Furthermore, the adhesive strength could be increased to above [a certain level] by adding a small amount of paraffin. The product has good adhesive properties, and surprisingly, when a small amount of paraffin (about 2% by weight) is used, the adhesive properties decrease only slightly during storage.

[0210] Table 7: Adhesive properties (tackiness) of silicone adhesive formulations with or without paraffin, using different polymer adhesive mixing ratios, including silicone adhesives with and without silanol reduction and those with silanol reduction, stored at 40°C / 75% RH for 0–3 months.

[0211]

[0212] Example 3 (Recrystallization during storage)

[0213] The aim was to investigate the effect of the amount of PVP K90 on the recrystallization and penetration of rotigotine. When the non-amine-resistant silicone adhesives BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 (Dow) are present in the matrix layer... When the mixture of rotigotine and PVP K90 was used together, crystallization was observed after storage at 25°C and 40°C at a rotigotine:PVP K90 weight ratio in the range of 9:3.2 to 9:5.

[0214] Surprisingly, the non-amine-resistant silicone adhesives BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 (Dow) in the matrix layer... The same mixture, when used with rotigotine and PVP K90 at a rotigotine:PVP K90 weight ratio of 9:7 or lower, prevented crystallization at the same storage temperature.

[0215] Table 8: Recrystallization during storage at 2-8℃, 25℃ / 60% RH, or 40℃ / 75% RH

[0216]

[0217] Example 4 (In vitro permeation and dissolution)

[0218] Description of in vitro dissolution test

[0219] Not available in a specific size (e.g., 10cm) 2 The samples of the peeling liner were prepared according to Ph.Eur 2.9.4 (Method 3) or USP. <724> Apparatus 6 (cylinder with adapter) was exposed via a rotating drum. 900 mL of 50 mM phosphate buffer (pH 4.5) was used as the exposure medium for each sample. The exposure temperature was 32 °C, and the drum rotation speed was 50 rpm. Sampling was performed according to the formulation to be studied, for example, 0.25; 0.5; 0.75; 1; 1.5; 2; 2.5; and 3 hours (monolayer), and for example, 0.5; 1; 1.5; 2; 2.5; 3; 4; and 6 hours (bilayer). Sample solutions were analyzed directly by RP-HPLC, as briefly described below:

[0220] Stationary phase: C18 (e.g., 50x3mm, 5μm particle size, 35°C oven temperature). Mobile phase: 70mM phosphate buffer (pH 5.0 / methanol; 55 / 45 (v / v), flow rate 0.6mL / min). Injection volume: 20μL, detection wavelength: 223nm, rotigotine residence time: approximately 3–6 min, run time: 8 min (isoclimate). Evaluation was performed using an external standard solution via 1-point calibration. Cumulative release [%] was calculated based on the average concentration in the sample solution.

[0221] Description of rotigotine's in vitro skin penetration

[0222] Using NovoCell The skin absorption device was used for in vitro skin absorption studies according to OECD (2004) Test Guideline 428 "Skin absorption: In vitro Method & Series on testing and assessment", and Guideline document 28 "Guidance document for the conduct of skin absorption studies". Throughout the measurement process, the measuring unit was tempered to 32±1°C. The measuring unit consists of donor and acceptor chambers, which are located on a cellulose membrane with a diameter of 1.05 cm. 2 The effective penetration surface of the human skin is achieved by thermally separating the epidermis from each other. The substrate of the patch to be tested (approximately 1.2 cm) 2 The sample (of various sizes) adheres to the stratum corneum, with the surface area to be exposed facing the receptor chamber. The total volume of the measuring unit is 15 mL, filled with physiological phosphate buffer, pH 5.5. At specified time points (e.g., 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24 hours), aliquots are removed from the receptor chamber as samples. The concentration of rotigotine is determined by RP-HPLC analysis, and the aliquots are immediately replaced with fresh buffer. A uniform temperature and concentration distribution of rotigotine is ensured by an integrated magnetic stirring system within the receptor chamber.

[0223] The method for performing RP-HPLC analysis and calculating sample concentrations is the same as for in vitro dissolution (see above). Subsequently, the cumulative permeate at each time point is calculated and plotted against time in a graph, and then the steady-state flux [μg / cm³] is calculated. 2 / h).

[0224] A) Single layer: The ratio of rotigotine to PVP K90 and the effect of paraffin on permeation

[0225] Skin permeability was investigated by applying the test formulation to human thermally separated epidermis (HSE). Various weight ratios of rotigotine to PVP K90, with or without paraffin as a substance to enhance adhesion and adhesiveness, were tested here.

[0226] Previous single-layer formulations included polyacrylate adhesives, mixtures of silicone adhesives and polyacrylates, polyisobutylene / polybutene, styrene-butadiene, or styrene-isoprene / resin formulations, and bilayer formulations using an initially non-active pressure-sensitive adhesive layer with said adhesive. In contrast, when applied to human thermally separated skin (HSE), it invariably results in relatively low permeability.

[0227] When the monolayer test formulation was applied to human HSE (thermally separated epidermis), the effect of different rotigotine:PVP ratios on in vitro permeability was investigated at a fixed rotigotine content of 9%.

[0228] like Figure 6 As shown in A), the amount of PVP K90 used in the range of 6.4-9.0% had no relevant effect on in vitro permeation at the rotigotine:PVP K90 ratio used. Furthermore, with... In comparison, monolayer formulations exhibit similar, or even minimally, higher / more effective, permeability.

[0229] When the monolayer test formulation was applied to human HSE (thermal separation of epidermis), the effect of different mixing ratios of BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 on in vitro permeability was investigated at fixed rotigotine content (9 wt%) and PVP K90 content (7 wt%).

[0230] like Figure 6 As shown in B), in the case of monolayer formulations, when the test formulation was applied to human HSE (thermally separated epidermis), the mixing ratios of BIO-PSA SRS7-4501 to SRS7-4601 used at 1:1, 1:1.5, 1:2, and 1:3 had no relevant effect on in vitro permeability. Furthermore, monolayer formulations with mixing ratios of BIO-PSA SRS7-4501 to SRS7-4601 ranging from 1:1 to 1:3 exhibited similar characteristics to... Similar, but with a minimum higher / more effective penetration.

[0231] Finally, the effect of small amounts of paraffin on in vitro permeation was investigated when the monolayer test formulation was applied to human HSE (thermally separated epidermis).

[0232] In the case of a single-layer formulation of the non-amine-resistant silicone adhesive BIO-PSA SRS7-4501 with reduced silanol content, a positive effect on in vitro permeation was observed for 2% paraffin, where... Compared to the previous method, penetration is slightly increased / more effective. Figure 7 A).

[0233] In the case of monolayer formulations with non-silanol-reduced, non-amine-resistant silicone adhesives BIO-PSA 7-4501 and / or BIO-PSA 7-4601, a positive effect on in vitro permeation has been shown for paraffin content of 1-2% by weight. Compared to other products, the penetrability is slightly higher / more effective. Furthermore, the formulation improved with paraffin exhibits higher penetrability than these paraffin-free formulations with reduced non-silanol, non-amine-resistant silicone adhesives. Figure 7 B).

[0234] B) Double layer: The effect of various pressure-sensitive adhesive layers without active ingredients on penetration.

[0235] The study investigated the effects of various combinations (bilayer formulations) of initial non-active pressure-sensitive adhesive layers and active silicone adhesive-based matrix layers based on different adhesive systems on human HSE (thermal separation of the epidermis). Compared to its effect on in vitro permeation.

[0236] Apply to a coating of approximately 30 g / m 2 Initially non-active pressure-sensitive adhesive layers based on polyacrylate adhesives, polyisobutylene / polybutene, or mixtures of styrene-isobutylene, resin, and paraffin are significantly less effective than bilayer formulations based on non-active pressure-sensitive adhesive layers made from the non-amine-resistant silicone adhesive SRS7-4601 (see [link to bilayer formulation]). Figure 8 A). In all formulations, the same matrix layer was used, comprising 15 wt% rotigotine, 8.5 wt% PVP K90, and 76.5 wt% BIO-PSA SRS7-4501 adhesive, with a coating weight of approximately 30 g / m². 2 Furthermore, with In comparison, the bilayer with an initial pressure-sensitive adhesive layer containing no active ingredients and a non-amine-resistant silicone adhesive in the matrix layer exhibits increased / improved permeability.

[0237] C) In vitro dissolution

[0238] like Figure 8 As shown in B), the mixing ratios of BIO-PSA SRS7-4501 and SRS7-4601 at 1:1 and 1:3 had no relevant effect on in vitro release, as 538ROTTDS and 539ROTTDS behaved almost identically. However, formulations with 9 wt% rotigotine and 7 wt% PVP K90 showed better performance than... The slightly faster in vitro release is likely due to the higher content of PVP K90.

[0239] Figure 9 The cumulative release of rotigotine over 6 hours via in vitro dissolution in the case of a bilayer formulation is shown, with approximately 50 g / m² in the corresponding coating. 2 The materials in the matrix layer (2) containing the active ingredients were previously stirred only, and then coated to a depth of 50 g / m. 2The same material was previously homogenized separately. Then, two matrix layers (2) containing active ingredients were laminated with the same initial adhesive layer (3) without active ingredients. For further comparison, a monolayer formulation was similarly treated without laminating the initial adhesive layer (3) without active ingredients. Slow stirring alone resulted in larger spheres with a wider size distribution compared to subsequent additional homogenization. Both exhibited the same release process.

Claims

1. Transdermal therapeutic system, comprising a) a backing layer (1), b) a matrix layer (2) comprising a drug, and c) a protective foil (4) to be removed before use, wherein the drug is rotigotine, wherein the matrix layer (2) comprises one or more non-amine-resistant pressure sensitive silicone adhesives in an amount of more than 50% by weight based on the total weight of pressure sensitive adhesives of the matrix layer (2) and paraffin in an amount of 1.0 to 5.0% by weight based on the total weight of the matrix layer (2), and rotigotine in the matrix layer (2) is present in a non-crystalline form in a dispersed phase of a solid dispersion comprising polyvinylpyrrolidone, wherein the weight ratio of rotigotine to polyvinylpyrrolidone is at most 9:6.

4.

2. Transdermal therapeutic system according to claim 1, wherein the matrix layer (2) comprises paraffin in an amount of 1.0 to 3.0% by weight based on the total weight of the matrix layer (2).

4. Transdermal therapeutic system according to claim 1, wherein at least one further initial active ingredient-free pressure sensitive adhesive layer (3) is located between the matrix layer (2) and the protective foil (4) to be removed before use, wherein the at least one further initial active ingredient-free pressure sensitive adhesive layer (3) comprises one or more non-amine-resistant pressure sensitive silicone adhesives in an amount of more than 50% by weight based on the total weight of pressure sensitive adhesives of the at least one further initial active ingredient-free pressure sensitive adhesive layer (3) and paraffin in an amount of 1.0 to 5.0% by weight based on the total weight of the at least one further initial active ingredient-free pressure sensitive adhesive layer (3).

6. Transdermal therapeutic system according to claim 1, wherein the matrix layer (2) has a weight fraction of non-amine-resistant pressure sensitive silicone adhesives of more than 75% by weight based on the total weight of pressure sensitive adhesives of the matrix layer (2).

7. Transdermal therapeutic system according to claim 4, wherein the at least one further initial active ingredient-free pressure sensitive adhesive layer (3) has a weight fraction of non-amine-resistant pressure sensitive silicone adhesives of more than 75% by weight based on the total weight of pressure sensitive adhesives of the at least one further initial active ingredient-free pressure sensitive adhesive layer (3).

8. Transdermal therapeutic system according to claim 1, wherein the matrix layer (2) has only non-amine-resistant pressure sensitive silicone adhesives as pressure sensitive adhesives.

9. Transdermal therapeutic system according to claim 4, wherein the matrix layer (2) and the at least one further initial active ingredient-free pressure sensitive adhesive layer (3) have only non-amine-resistant pressure sensitive silicone adhesives as pressure sensitive adhesives.

3. Transdermal therapeutic system according to claim 1, wherein the matrix layer (2) has a weight per unit area of 40 to 70 g / m2. 2 of 40 to 70 g / m2.

10. Transdermal therapeutic system according to claim 1, wherein the non-amine-resistant pressure sensitive silicone adhesives are silanol-reduced silicone adhesives.

5. Transdermal therapeutic system according to claim 4, wherein the at least one further pressure sensitive adhesive layer (3) initially free of active ingredient has an areal weight of 20 to 40 g / m2. 2 of 20 to 40 g / m2.

11. Transdermal therapeutic system according to claim 10, wherein the weight ratio of rotigotine to polyvinylpyrrolidone is 9:7 to 9:

10.

12. Transdermal therapeutic system according to claim 1, wherein the drug content in the matrix layer (2) is in the range of 6% to 20% by weight based on the total weight of the matrix layer (2). ​ ​ ​ ​ ​ 13. The transdermal therapeutic system according to claim 1, wherein the one or more non-amine-resistant pressure sensitive silicone adhesives of the matrix layer (2) comprise two or more non-amine-resistant pressure sensitive silicone adhesives, wherein one or more of the non-amine-resistant pressure sensitive silicone adhesives has a medium adhesion and one or more of the non-amine-resistant pressure sensitive silicone adhesives has a high adhesion.

14. The transdermal therapeutic system according to claim 4, wherein the one or more non-amine-resistant pressure sensitive silicone adhesives of the at least one further initial active ingredient-free pressure sensitive adhesive layer (3) comprise two or more non-amine-resistant pressure sensitive silicone adhesives, wherein one or more of the non-amine-resistant pressure sensitive silicone adhesives has a medium adhesion and one or more of the non-amine-resistant pressure sensitive silicone adhesives has a high adhesion.

15. The transdermal therapeutic system according to claim 1, wherein the one or more non-amine-resistant pressure sensitive silicone adhesives of the matrix layer (2) consist only of a silanol-reduced non-amine-resistant pressure sensitive silicone adhesive.

16. The transdermal therapeutic system according to claim 4, wherein the one or more non-amine-resistant pressure sensitive silicone adhesives of the at least one further initial active ingredient-free pressure sensitive adhesive layer (3) consist only of a silanol-reduced non-amine-resistant pressure sensitive silicone adhesive.

17. The transdermal therapeutic system according to claim 1, wherein the matrix layer (2) comprises one or more antioxidants.

18. The transdermal therapeutic system according to claim 1, wherein the matrix layer (2) comprises sodium metabisulfite.

19. A method of preparing a transdermal therapeutic system according to one of claims 1-3, 6, 8, 10-13, 15, 17 and 18 as a single layer formulation, comprising the following steps: a) preparing a homogenized coating material by adding all components of the matrix layer (2) together to a suitable solvent and mixing to the desired homogeneity; b) applying the homogenized coating material to the backing layer (1), or to a protective foil (4), and removing the solvent by drying; and c) laminating the remaining layer, i.e. the protective foil (4) or the backing layer (1), to the matrix layer (2), and punching out the transdermal therapeutic system in the appropriate size.

20. A method of preparing a transdermal therapeutic system according to one of claims 4-5, 7, 9, 14 and 16, comprising the following steps: a) preparing a first precursor of the transdermal therapeutic system comprising a1) preparing a first homogenized coating material by adding all components of the matrix layer (2) together to a suitable solvent and mixing to the desired homogeneity; a2) applying the first homogenized coating material to the backing layer (1), or to a temporary protective foil, and removing the solvent by drying; and a3) laminating the remaining layer, i.e. the temporary protective foil or the backing layer (1), to the matrix layer (2); b) preparing a second precursor of the transdermal therapeutic system comprising: b1 ) preparing a further homogenized coating material by adding all components of at least one further initially active ingredient-free pressure sensitive adhesive layer (3) to a suitable solvent and mixing to the desired homogeneity; b2) applying the further homogenized coating material to the protective foil (4) and removing the solvent by drying; and c) removing the temporary protective foil from the first precursor of the transdermal therapeutic system from a), laminating the first precursor of the transdermal therapeutic system and the second precursor to an integral laminate, which integral laminate comprises in the following layer order: backing layer (1 ), active ingredient-containing matrix layer (2), at least one further initially active ingredient-free pressure sensitive adhesive layer (3) and protective foil (4); and punching out the transdermal therapeutic system of suitable size.

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