A transdermal treatment system comprising rotigotine as the active ingredient and at least one non-amine-resistant silicone adhesive.

Abstract

The present invention relates to a transdermal therapeutic system (TTS) for administering rotigotine as an active ingredient, comprising a matrix layer containing rotigotine, the matrix layer further comprising one or more non-amine-resistant silicone adhesives in an amount of more than 50% by weight, based on the total weight of the pressure-sensitive adhesives contained in the matrix layer, and paraffin, and to a method for preparing the same. The transdermal therapeutic system of the present invention is particularly suitable for the treatment of Parkinson's disease.

Description

[Technical Field]

[0001] The present invention relates to a transdermal therapy system (TTS) for administering rotigotine as an active ingredient, comprising one or more non-amine-resistant silicone adhesives, and a method for preparing the transdermal therapy system. The transdermal therapy system of the present invention is particularly suitable for the treatment of Parkinson's disease. [Background technology]

[0002] Rotigotine is the international common name for the compound (-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-1-naphthalenol, which is represented by the following structural formula. [ka]

[0003] Rotigotine is currently known to exist in two crystalline forms: polymorph I and polymorph II (WO2009 / 068520). Polymorph I and polymorph II can be distinguished by physicochemical parameters such as powder X-ray diffraction diffractograms, Raman spectra, and melting points. As described in WO2009 / 068520, polymorph II is considered to be more thermodynamically stable and has better processing properties than polymorph I.

[0004] Rotigotine is known as a dopamine receptor agonist and has been successful in the treatment of Parkinson's disease. The pharmacological efficacy of rotigotine and the diseases for which its use is preferable are described, for example, in WO2002 / 089777, WO2005 / 092331, WO2005 / 009424, WO2003 / 092677 and WO2005 / 063237.

[0005] Rotigotine has a short half-life and a high first-pass effect, making oral administration problematic. Therefore, transdermal administration of rotigotine has been proposed in numerous publications, and a drug called Neupro® has been launched for transdermal administration.

[0006] A transdermal therapy system for rotigotine administration was reported early on in WO94 / 07468. In this patent document, the transdermal therapy system contains rotigotine hydrochloride in a two-phase matrix, the majority of which is formed of a hydrophobic polymer material as a continuous phase with dispersed hydrated silicate to adsorb the hydrophilic salt of the drug. However, the transdermal therapy system described in this patent document is difficult to prepare, and there are various problems in getting the active ingredient to penetrate the skin from this transdermal therapy system. For these reasons, the transdermal therapy system described in WO94 / 07468 has not been brought to market.

[0007] Improved transdermal treatment systems have been reported in numerous publications. For example, WO99 / 49852 discloses a transdermal treatment system having a matrix with an adhesive system made of a non-aqueous polymer using acrylic acid or silicone, which is substantially free of inorganic silicate particles. In the simplest embodiment of this matrix system, a single-phase matrix system is shown. This matrix is ​​substantially composed of an acrylic acid-based adhesive or a silicone-based adhesive. In the case of a matrix made of a silicone-based adhesive, this matrix may further include, for example, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, glycerin, glycerin fatty acid ester, or ethylene-vinyl acetate copolymer.

[0008] In WO2004 / 012730, WO2004 / 012719 and WO2004 / 058247, transdermal therapeutic systems for rotigotine administration are disclosed. These transdermal therapeutic systems comprise a self-adhesive matrix filled with an active ingredient, and this active ingredient is contained as a number of microreservoirs or amorphous particles. This self-adhesive matrix is a self-adhesive matrix using a silicone-based adhesive.

[0009] A transdermal therapeutic system for rotigotine administration using a silicone matrix is also disclosed in WO02 / 089778. In this patent document, it is stated that the surface area of this transdermal therapeutic system is 10 - 40 cm 2 and it is essential to contain 0.1 - 3.15 mg / cm 2 of rotigotine as the active ingredient.

[0010] Regarding the formulation of a transdermal therapeutic system containing rotigotine as the active ingredient, an important aspect is that it is necessary to avoid crystallization of the active ingredient contained in the transdermal therapeutic system. Crystallization of the active ingredient may cause various problems. For example, the administration rate may be affected or the adhesiveness of the adhesive matrix may be adversely affected. Unfortunately, in the prior art, crystallization of the active ingredient is cited as a problem often seen in rotigotine. Currently, in the formulation "Neupro" of UCB, which is the only transdermal therapeutic system on the market, rotigotine is embedded in a polymer matrix. However, the stability of this first marketed formulation has not been proven, and in fact, crystals were formed in the formulation, resulting in the product being subject to recall.

[0011] Based on this, in WO2012 / 072650, it is proposed to introduce the active ingredient into a non-adhesive matrix and provide an adhesive layer on this non-adhesive matrix. This adhesive layer is preferably self-adhesive, preferably composed of a "pressure-sensitive adhesive", and preferably a silicone-based adhesive resistant to amines.

[0012] Furthermore, WO2012 / 084969 also proposes a transdermal treatment system for rotigotine administration, characterized in that it contains rotigotine as an active ingredient and at least one cross-linked polyvinylpyrrolidone or vinylpyrrolidone-vinyl acetate copolymer in an adhesive matrix made of polystyrene, polyisobutylene, or a mixture thereof.

[0013] WO2011 / 076879 states that polyvinylpyrrolidone and rotigotine must be used in a specific weight ratio. Unexpectedly, this specific weight ratio can stabilize the amorphous form of rotigotine, preventing its recrystallization in solid dispersions such as self-adhesive matrices in transdermal treatment systems. Therefore, WO2011 / 076879 proposes using polyvinylpyrrolidone to stabilize amorphous rotigotine contained in the dispersant of a solid dispersion, preferably containing at least one silicone-based pressure-sensitive adhesive, with a weight ratio of rotigotine to polyvinylpyrrolidone of approximately 9:3.5 to approximately 9:6.

[0014] Furthermore, WO2011 / 057714 describes a method for preventing crystallization of agents contained in polymer films. The polymer films described in WO2011 / 057714 are suitable for the preparation of transdermal treatment systems and the like, and rotigotine is described as one of two preferred agents. In the preparation process of this polymer film, a solvent-containing coating solution containing a polymer or polymer mixture constituting the matrix and at least one agent is applied, and the coating solution is dried at a temperature which may be at least 10°C higher than the melting temperature of the agent in the coating solution.

[0015] Another important aspect of the formulation of transdermal treatment systems is the selection of a pressure-sensitive adhesive. When selecting a pressure-sensitive adhesive, various factors must be considered, particularly ensuring optimal adhesion, peel strength, and tack, sustained release of the active ingredient, and storage stability, while minimizing adhesive residue and irritation to the skin. Furthermore, the pressure-sensitive adhesive must not react with the active ingredient.

[0016] "Adhesion" (or "adhesion strength") refers to the force required to peel the transdermal treatment system from the test surface to which it is attached, i.e., its resistance to peeling from the surface. "Peel force" refers to the force required to peel the transdermal treatment system from the release liner (4). "Tack" refers to the property of adhering to a solid surface, i.e., the property of adhering to a solid surface with short contact time and very light pressure.

[0017] Prior art has proposed various pressure-sensitive adhesives for use in transdermal treatment systems containing rotigotine as the active ingredient. Specifically, in addition to silicone-based adhesives, polyacrylic acid-based polymer adhesives, polyisobutylene-based polymer adhesives, and polystyrene-based polymer adhesives have been proposed.

[0018] For example, WO2012 / 084969 describes the use of polyisobutylene, polystyrene, and mixtures thereof in transdermal therapeutic systems for rotigotine administration. Polyisobutylene typically has inferior solution properties compared to various pharmaceutical active ingredients, can only exhibit sufficient tack in the form of low molecular weight polyisobutylene mixtures, and suffers from the disadvantage of high so-called cold flow. Styrene, on the other hand, typically requires large amounts of plasticizers and tackifiers.

[0019] On the other hand, silicone-based pressure-sensitive adhesives are characterized by high flexibility, low surface tension, and virtually no change in properties over a wide temperature range. Furthermore, silicone-based adhesives have high breathability and moisture permeability, are gentle on the skin, and possess durability against various external influences (moisture, ultraviolet light, and stability under acidic or alkaline conditions).

[0020] Silicone-based pressure-sensitive adhesives for transdermal treatment systems can generally be classified into two types: "non-amine-resistant" silicone-based adhesives and "amine-resistant" silicone-based adhesives. "Non-amine-resistant" silicone-based adhesives contain free silanol groups. These free silanol groups interact slightly with amine groups contained in active ingredients such as rotigotine, which can result in the formation of degradation products of the active ingredients. Furthermore, this reaction can significantly impair the properties of the adhesive layer in the transdermal treatment system, for example, causing a decrease in tack during storage and / or complete drying (see, for example, U.S. Patent Reissue No. 35,474 and U.S. Patent Publication No. 4,591,622).

[0021] For these reasons, prior art relating to transdermal treatment systems containing rotigotine as an active ingredient and using silicone adhesives typically uses only amine-resistant silicone adhesives, and not non-amine-resistant silicone adhesives. In "amine-resistant" silicone adhesives, the silanol group is protected by a protecting group such as a trimethylsilyl (TMS) group.

[0022] Therefore, for example, in Neupro, the only transdermal treatment system currently on the market, only amine-resistant silicone adhesives are used. Neupro is a monolayer thin film composed of a two-phase matrix layer in the form of a solid dispersion, which consists of an inner phase consisting of an active ingredient dissolved in a polymer and an outer phase consisting of an amine-resistant silicone adhesive as a dispersant.

[0023] Similarly, in WO99 / 49852, amine-resistant adhesives are used in silicone adhesives containing rotigotine, based on the basic properties of rotigotine. As described in this patent document, amine-resistant silicone adhesives are characterized by not containing free silanol functional groups (i.e., silanol groups).

[0024] The silicone-based transdermal treatment systems disclosed in WO02 / 089778 must include at least one amine-resistant silicone compound as a major component. This silicone compound is typically a pressure-sensitive adhesive or a mixture thereof, forming a matrix into which the other components of the transdermal treatment system are embedded.

[0025] According to WO2004 / 012730 (and WO2004 / 012719 and WO2011 / 076879), pressure-sensitive adhesives particularly preferred for use in transdermal treatment systems disclosed in this patent document are pressure-sensitive adhesives that form a soluble polycondensed polydimethylsiloxane (PDMS) / resin network in which hydroxyl groups are protected, for example, with trimethylsilyl (TMS) groups.

[0026] In one preferred embodiment of WO2004 / 058247, the matrix polymer is preferably a silicone, and more preferably an amine-resistant silicone or a mixture thereof. In this patent document as well, for the same reasons mentioned above, an amine-resistant silicone or a mixture thereof is used as the matrix polymer. Furthermore, according to WO2011 / 057714, an amine-resistant polysiloxane is particularly preferred.

[0027] On the other hand, amine-resistant silicone adhesives, such as those used in commercially available products like NewPro, often lack sufficient tack and adhesive strength.

[0028] Therefore, although various transdermal therapy systems containing rotigotine as the active ingredient are known, there is a need for a transdermal therapy system for administering rotigotine as the active ingredient that possesses sufficient adhesion and tack, as well as excellent storage stability (i.e., the property of not crystallizing the active ingredient during storage). Furthermore, such a transdermal therapy system must be able to sufficiently penetrate the skin with the active ingredient, be manufactured using the simplest possible method, and be able to administer the active ingredient for the desired duration of administration within at least one day. In addition, taking into account cost and the requirements of national drug regulatory authorities (e.g., requirements to prevent abuse), it is desirable that the amount of active ingredient remaining in the transdermal therapy system after use not be too high. [Overview of the project] [Problems that the invention aims to solve]

[0029] In order to solve the above problems, the present invention proposes a transdermal treatment system as defined in the claims.

[0030] To our surprise, the inventors discovered that by adding a small amount of paraffin to the matrix layer of a transdermal treatment system (TTS) containing rotigotine as the active ingredient, the properties of the TTS improved compared to a transdermal treatment system using an amine-resistant silicone adhesive, even when using a silicone adhesive containing a significant amount of free silanol groups (i.e., a non-amine-resistant silicone adhesive). In particular, the adhesive strength and tack were significantly increased, and storage stability was improved.

[0031] Furthermore, the inventors have found that in a transdermal treatment system comprising rotigotine as an active ingredient and one or more non-amine-resistant silicone adhesives in an amount exceeding 50% by weight relative to the total weight of the pressure-sensitive adhesive contained in the matrix layer (2), the active ingredient does not crystallize when the weight ratio of rotigotine to polyvinylpyrrolidone in the dispersed phase of the solid dispersion in the matrix layer is 9:6.4, and in particular when the rotigotine content is 9:7 or less when expressed as the weight ratio of rotigotine to polyvinylpyrrolidone. On the other hand, if the weight ratio of rotigotine to polyvinylpyrrolidone is greater than this, for example, when the rotigotine content is 9:5 or more when expressed as the weight ratio of rotigotine to polyvinylpyrrolidone, there is a risk of crystallization when stored for a long period of time at a temperature of 25°C or higher. Therefore, although it is possible to increase the weight ratio of rotigotine to polyvinylpyrrolidone in this way according to the present invention, it is not desirable.

[0032] Furthermore, the inventors have surprisingly found that, in the transdermal treatment system of the present invention, it is not necessary to dry the system after application at a temperature at least 10°C higher than the melting point of rotigotine in order to prevent crystallization of rotigotine after preparation of the transdermal treatment system. [Means for solving the problem]

[0033] Therefore, the present invention is a transdermal treatment system, Backing layer (1), A matrix layer containing the drug (2), and Release liner (4) to be removed before use Includes, The aforementioned drug is rotigotine, and The present invention provides a transdermal treatment system characterized in that the matrix layer (2) contains more than 50% by weight of one or more non-amine-resistant silicone-based pressure-sensitive adhesives relative to the total weight of the pressure-sensitive adhesives contained in the matrix layer (2), and at least 0.1% by weight of paraffin relative to the total weight of the matrix layer (2).

[0034] Furthermore, the present invention relates to the use of a transdermal therapy system for treating diseases to which transdermal administration of rotigotine is applied, particularly Parkinson's disease. Moreover, the present invention relates to a method for preparing the transdermal therapy system of the present invention. [Brief explanation of the drawing]

[0035] [Figure 1] (A) Shows a transdermal treatment system in the form of a single-layer formulation having a backing layer (1), a matrix layer (2), and a release liner (4). (B) Shows a transdermal treatment system in the form of a two-layer formulation having a backing layer (1), a matrix layer (2), at least one additional pressure-sensitive adhesive layer (3) which does not initially contain the active ingredient, and a release liner (4). [Figure 2] This shows the peeling strength of various single-layer and double-layer formulations when stored at 40°C / 75%rh (relative humidity) for 0 to 3 months. [Figure 3] This shows the adhesive strength of various single-layer and double-layer formulations when stored for 0 to 3 months at 40°C / 75%rh (relative humidity). [Figure 4] (A) This shows that the optimal ratio of BIO-PSA SRS7-4501 (medium tack) and BIO-PSA SRS7-4601 (high tack), which are silicone-based adhesives with reduced silanol content, was determined taking into account peel force, adhesive strength, and tack. (B) This shows that the optimal ratio of BIO-PSA 7-4501 (medium tack) and BIO-PSA 7-4601 (high tack), which are silicone-based adhesives with unreduced silanol content, was determined taking into account peel force, adhesive strength, and tack. [Figure 5] This shows the tack of various single-layer and double-layer formulations when stored for 0 to 3 months at 40°C / 75%rh (relative humidity). [Figure 6]A) Shows the cumulative rotigotine permeation over 24 hours for a monolayer formulation containing a fixed amount of rotigotine and various amounts of PVP K90. B) Shows the cumulative rotigotine permeation over 24 hours for monolayer formulations with constant rotigotine and PVP K90 content, and varying mixing ratios of BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 (Dow Corning®). [Figure 7] (A) Shows the cumulative rotigotine permeation over 24 hours for a monolayer formulation containing a non-amine-resistant silicone adhesive with reduced silanol content and 2% by weight of paraffin. (B) Shows the cumulative rotigotine permeation over 24 hours for a monolayer formulation containing a non-amine-resistant silicone adhesive with unreduced silanol content and 1-2% by weight of paraffin. [Figure 8] A) Shows the cumulative permeation of rotigotine over 24 hours for the two-layer formulation. B) Shows the cumulative release of rotigotine over 6 hours for the single-layer formulation. [Figure 9] This shows the cumulative release of rotigotine from a two-layer formulation over 6 hours in an in vitro dissolution test (release of the active ingredient in vitro). In this dissolution test, the matrix layer (2) containing the active ingredient was prepared by either stirring the coating solution and then applying it to a thickness of approximately 50 g / m2, or by stirring and further homogenizing before applying it to a thickness of approximately 50 g / m2. 618_617ROTTDS: Two-layer formulation; 589ROTTDS: Single-layer formulation; "Stirring": Stirring only; "Homogenization": Stirring and homogenization. [Modes for carrying out the invention]

[0036] The transdermal treatment system of the present invention, in its simplest design, includes a backing layer (1), a matrix layer (2) containing an active ingredient placed on the backing layer (1), and a release liner (4) placed on the matrix layer (2) that is removed before use (see Figure 1(A)). One or more additional layers may be placed between each layer of the transdermal treatment system of the present invention, i.e., between the backing layer (1) and the matrix layer (2), and / or between the matrix layer (2) and the release liner (4). For example, in a preferred embodiment of the present invention, at least one additional pressure-sensitive adhesive layer (3) which does not initially contain an active ingredient may be placed between the matrix layer (2) and the release liner (4).

[0037] The matrix layer (2) of the transdermal treatment system of the present invention is a pressure-sensitive adhesive layer containing rotigotine as an active ingredient. According to the present invention, this pressure-sensitive adhesive layer must contain one or more non-amine-resistant silicone-based pressure-sensitive adhesives in an amount exceeding 50% by weight relative to the total weight of the pressure-sensitive adhesives contained in the matrix layer (2), and at least 0.1% by weight of paraffin relative to the total weight of the matrix layer (2).

[0038] The inventors have surprisingly discovered that by adding a small amount of paraffin to the matrix layer (2), the adhesive strength and tack can be significantly increased, and storage stability can be improved. In particular, they have found that even when a non-amine-resistant silicone adhesive and rotigotine as the active ingredient are used simultaneously in the matrix layer (2), the adhesive strength and tack can be increased compared to other transdermal treatment systems using an amine-resistant silicone adhesive and rotigotine.

[0039] In this specification, unless otherwise specified, the terms “total weight” and “total volume” refer to dry weight, i.e., the weight of the components referred to by the terms “total weight” or “total volume” in descriptions of ready-to-use transdermal treatment systems.

[0040] In the present invention, the terms “pressure-sensitive adhesive” and “pressure-sensitive adhesive” layer (e.g., matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) that initially does not contain the active ingredient) of the transdermal treatment system both refer to these components, and specifically refer to polymer-based adhesives that are added to the transdermal treatment system or its layers in order to possess properties as pressure-sensitive adhesive promoters / pressure-sensitive adhesives. Such pressure-sensitive adhesives are known to those skilled in the art. These pressure-sensitive adhesives do not contain active ingredients, paraffins, crystallization inhibitors (e.g., polyvinylpyrrolidone), transdermal absorption enhancers, or other additives (e.g., plasticizers and antioxidants). In this specification, the terms “silicone-based adhesive” and “silicone-based pressure-sensitive adhesive” are used interchangeably.

[0041] The matrix layer (2) of the transdermal treatment system of the present invention contains one or more non-amine-resistant silicone adhesives in an amount exceeding 50% by weight relative to the total weight of the pressure-sensitive adhesive contained in the matrix layer (2). That is, the matrix layer (2) may contain one, two, three, four or more types of non-amine-resistant silicone adhesives.

[0042] Non-amine-resistant and amine-resistant silicone adhesives are known to those skilled in the art. An amine-resistant silicone adhesive is described, for example, in U.S. Provisional Patent No. 35,474, and a method for preparing an amine-resistant silicone adhesive is described, for example, in U.S. Patent No. 4,591,622. For example, a non-amine-resistant silicone adhesive, unlike an amine-resistant silicone adhesive, is a pressure-sensitive silicone adhesive containing a considerable amount of free silanol groups (OH groups not protected by a protecting group), which may interact with amine-containing active ingredients under normal circumstances. By performing incomplete protection, such as so-called capping or (end) blocking, or partial removal of free silanol groups, a silicone adhesive known as a silicone adhesive with reduced silanol content can be obtained. A non-amine-resistant silicone adhesive with reduced silanol content and a method for preparing it are known to those skilled in the art and are described, for example, in U.S. Published Patent No. 6,337,086. Such non-amine-resistant silicone adhesives with reduced silanol content are classified as non-amine-resistant silicone adhesives.

[0043] In this specification, “non-amine-resistant” silicone adhesives preferably refer to silicone pressure-sensitive adhesives containing, for example, at least 7,700 ppm, preferably at least about 8,000 ppm, and preferably 13,000 ppm or less of free silanol groups (free OH groups or silicon-bonded hydroxyl groups). The content (or concentration) of free silanol groups in a silicone adhesive can be measured by methods known to those skilled in the art, for example, by nuclear magnetic resonance spectroscopy (NMR) and / or Fourier transform infrared spectroscopy (FTIR) (see, for example, U.S. Patent Publication No. 6,337,086). 29 Si nuclear magnetic resonance spectroscopy measurement method ( 29 In Si-NMR measurement, the silanol group content can be measured by normalizing the data against a standard reference sample, while FTIR spectroscopy directly provides the ratio of free silanol groups to protected silanol groups.

[0044] For example, as described in U.S. Patent Publication No. 6,337,086, the silanol group content measured by FTIR spectroscopy can be calculated from the peak area ratio obtained by A1 / (A2 × 100). Here, area A1 is the area of ​​the peaks of the two stretching vibrations of the OH bond derived from the silanol group, and area A2 is the area of ​​the peak of the harmonic component of the bending vibration of the hydrogen of the polydimethylsiloxane (PDMS) methyl group. In this embodiment, the non-amine-resistant silicone adhesive is characterized in that the ratio of unprotected silanol groups to protected silanol groups is, for example, greater than 0.45, preferably at least 0.46, and more preferably at least 0.5.

[0045] In a preferred embodiment of the present invention, a non-amine-resistant silicone adhesive is characterized in that, when the non-amine-resistant silicone adhesive is reacted with rotigotine, which is the active ingredient, in a suitable solvent at a mixing ratio of, for example, 20:1 to 4:1, preferably 10:1, at about 50°C for at least 2 hours, preferably 2 to 4 hours, it reacts with a considerable amount of rotigotine (for example, at least 0.5% by weight, preferably at least 1.0% by weight, preferably at least 2.5% by weight of rotigotine) to decompose or convert the rotigotine. Suitable solvents are known to those skilled in the art and are selected according to the type of non-amine-resistant silicone adhesive. Examples of suitable solvents include heptane, ethanol, and ethyl acetate. The proportion of rotigotine decomposed or converted can be measured by methods known to those skilled in the art.

[0046] In the present invention, the selection of one or more non-amine-resistant silicone adhesives is not particularly limited. Non-amine-resistant silicone adhesives are known in the prior art.

[0047] In one embodiment of the present invention, one or more non-amine-resistant silicone pressure-sensitive adhesives must be selected from the group including, for example, non-amine-resistant silicone pressure-sensitive adhesives having a moderate tack, such as Dow Corning's BIO-PSA 7-4501, Dow Corning's BIO-PSA 7-4502, Dow Corning's BIO-PSA SRS7-4501, and Dow Corning's BIO-PSA SRS7-4502; non-amine-resistant silicone pressure-sensitive adhesives having a high tack, such as Dow Corning's BIO-PSA 7-4601, Dow Corning's BIO-PSA 7-4602, Dow Corning's BIO-PSA SRS7-4601, and Dow Corning's BIO-PSA SRS7-4602; and combinations thereof. These adhesives are also known by the chemical name dimethiconol trimethylsiloxysilicate crosspolymer. In another embodiment of the present invention, one or more non-amine-resistant silicone pressure-sensitive adhesives must be selected from the group including: a non-amine-resistant silicone pressure-sensitive adhesive having moderate tack and no reduced silanol content; a non-amine-resistant silicone pressure-sensitive adhesive having high tack and no reduced silanol content; a non-amine-resistant silicone pressure-sensitive adhesive having moderate tack and reduced silanol content; a non-amine-resistant silicone pressure-sensitive adhesive having high tack and reduced silanol content; and combinations thereof. Examples of preferred non-amine-resistant silicone pressure-sensitive adhesives in the present invention include Dow Corning's BIO-PSA 7-4501, Dow Corning's BIO-PSA 7-4601, Dow Corning's BIO-PSA SRS7-4501, Dow Corning's BIO-PSA SRS7-4601, and combinations thereof.

[0048] The matrix layer (2) of the transdermal treatment system of the present invention contains one or more non-amine-resistant silicone-based pressure-sensitive adhesives in an amount exceeding 50% by weight of the total weight of the pressure-sensitive adhesives contained in the matrix layer (2). That is, the total weight percentage of the non-amine-resistant silicone-based pressure-sensitive adhesives contained in the matrix layer (2) exceeds 50% by weight of the total weight of the pressure-sensitive adhesives contained in the matrix layer (2).

[0049] In a preferred embodiment of the present invention, the amount of non-amine-resistant silicone pressure-sensitive adhesive contained in the matrix layer (2) of the transdermal treatment system is more than 60% by weight of the total weight of the pressure-sensitive adhesive contained in the matrix layer (2), 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, even more preferably more than 93% by weight, even more preferably more than 95% by weight, and even more preferably at least 99% by weight. In a further preferred embodiment of the present invention, in the transdermal treatment system, the matrix layer (2) that functions as a pressure-sensitive adhesive contains only a non-amine-resistant silicone pressure-sensitive adhesive, that is, the matrix layer (2) does not contain any other polymer-based adhesives and contains only a non-amine-resistant silicone pressure-sensitive adhesive.

[0050] If one or more pressure-sensitive adhesive layers in a transdermal treatment system (e.g., a matrix layer (2) or an additional pressure-sensitive adhesive layer (3) that initially does not contain an active ingredient) contain only one type of non-amine-resistant silicone adhesive, the content of this non-amine-resistant silicone adhesive is, for example, more than 50% by weight of the total weight of the pressure-sensitive adhesive in one or more pressure-sensitive adhesive layers in the transdermal treatment system. If one or more pressure-sensitive adhesive layers in a transdermal treatment system contain two types of non-amine-resistant silicone adhesives, the combined content of these two types of non-amine-resistant silicone adhesives is, for example, more than 50% by weight of the total weight of the pressure-sensitive adhesive in one or more pressure-sensitive adhesive layers in the transdermal treatment system. If there are several pressure-sensitive adhesive layers, the content of non-amine-resistant silicone adhesive in each layer must be more than 50% by weight of the total weight of the pressure-sensitive adhesive in each layer.

[0051] The matrix layer (2) of the transdermal treatment system of the present invention contains at least 0.1% by weight of paraffin (also called white oil) relative to the total weight of the matrix layer (2). In particular, two types of paraffin are known. One of them is liquid paraffin, also called liquid paraffin or paraffinum liquidum in the European Pharmacopoeia, called mineral oil in the United States Pharmacopoeia, called liquid paraffin in the Japanese Pharmacopoeia, and also called viscous paraffin in general academic literature. The relative density of liquid paraffin is 0.827 to 0.890 when measured according to the European Pharmacopoeia (Method 2.2.5), and the United States Pharmacopoeia (Method 2.2.5) <841> When measured according to the (Method 2.2.9), the viscosity was 0.845-0.905, and when measured according to the Japanese Pharmacopoeia, it was 0.860-0.890, and when measured according to the European Pharmacopoeia (Method 2.2.9), it was 110-230 mPas, and according to the United States Pharmacopoeia (Method 2.2.9), <911> When measured according to the method (measured by capillary viscometer at 40±0.1℃), the values ​​were 34.5~150.0 mm. 2 The value is / s, and when measured according to the Japanese Pharmacopoeia (Method 1, 37.8℃), it is 37 mm 2 It is an oily liquid with a viscosity of 1 / s or more.

[0052] Another type of paraffin known is low-viscosity paraffin. Low-viscosity paraffin is also called light liquid paraffin or paraffinum perliquidum in the European Pharmacopoeia, light mineral oil in the United States Pharmacopoeia, and light liquid paraffin in the Japanese Pharmacopoeia. Low-viscosity paraffin has a density of 0.810–0.875 when measured according to the European Pharmacopoeia (Method 2.2.5), and according to the United States Pharmacopoeia (Method 2.2.5). <841> When measured according to the (Method 2.2.9), the viscosity was 0.818-0.880, and when measured according to the Japanese Pharmacopoeia, it was 0.830-0.870, and when measured according to the European Pharmacopoeia (Method 2.2.9), it was 25-80 mPas, and according to the United States Pharmacopoeia (Method 2.2.9), <911> When measured according to the method (measured by capillary viscometer at 40±0.1℃), the values ​​were 3.0~34.4mm. 2 The value is / s, and when measured according to the Japanese Pharmacopoeia (Method 1, 37.8℃), it is 37 mm 2It is an oily liquid with a viscosity of less than / s.

[0053] Liquid paraffin is preferred. In another embodiment, the paraffin is low-viscosity paraffin.

[0054] The paraffin content in the matrix layer (2) of the transdermal treatment system of the present invention may be, for example, 50% by weight or less, preferably 40% by weight or less, preferably 30% by weight or less, more preferably 20% by weight or less, more preferably 15% by weight or less, and more preferably 10% by weight or less, relative to the total weight of the matrix layer (2) of the transdermal treatment system of the present invention.

[0055] In a preferred embodiment of the present invention, the paraffin content 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 a further preferred embodiment of the present invention, the paraffin content in the matrix layer (2) is at least 0.1 to 30.0% by weight, preferably 0.1 to 20.0% by weight, more preferably 0.2 to 20.0% by weight, more preferably 0.5 to 10.0% by weight, more preferably 0.8 to 5.0% by weight, more preferably 1.0 to 5.0% by weight, and more preferably 1.0 to 3.0% by weight, based on the total weight of the matrix layer (2).

[0056] Since the matrix layer of the transdermal treatment system of the present invention is self-adhesive, it is not necessary to place an additional self-adhesive layer on the matrix layer (2), as is usually required in matrix layers such as those described in WO2012 / 072650. However, according to the present invention, at least one additional pressure-sensitive adhesive layer (3) which does not initially contain an active ingredient may be provided, for example, to improve adhesion and tack. In one preferred embodiment of the present invention, the transdermal treatment system of the present invention does not have an additional pressure-sensitive adhesive layer (3) which does not initially contain an active ingredient between the matrix layer (2) and the release liner (4) which is removed before use. According to this embodiment, the matrix layer (2) has sufficient adhesion to adhere well to the skin for a desired period of time.

[0057] In a more preferred embodiment of the present invention, the transdermal treatment system includes at least one additional pressure-sensitive adhesive layer (3) between the matrix layer (2) and a peel-off liner (4) that is removed before use, which initially does not contain the active ingredient (see Figure 1B). In particular, when the matrix layer (2) consists of several phases, providing at least one additional pressure-sensitive adhesive layer (3) which initially does not contain the active ingredient ensures that the distance over which the active ingredient diffuses from the matrix layer (2) containing the active ingredient through this at least one additional pressure-sensitive adhesive layer (3) to the skin is a constant layer thickness, thereby further improving the distribution of various particle sizes in the internal phase containing the active ingredient when eluting the active ingredient in vitro.

[0058] Therefore, in a more preferred embodiment, the transdermal treatment system of the present invention comprises at least one additional pressure-sensitive adhesive layer (3) between the matrix layer (2) and a peel-off liner (4) that is removed before use, wherein the pressure-sensitive adhesive layer (3) comprises one or more non-amine-resistant silicone-based pressure-sensitive adhesives in an amount exceeding 50% by weight of the total weight of the pressure-sensitive adhesives contained in the pressure-sensitive adhesive layer (3), and at least 0.1% by weight, preferably 0.2 to 20.0% by weight, and more preferably 1.0 to 5.0% by weight of paraffin, based on the total weight of the pressure-sensitive adhesive layer (3). That is, the at least one additional pressure-sensitive adhesive layer (3) that initially does not contain the active ingredient may contain one, two, three, four or more types of non-amine-resistant silicone-based adhesives.

[0059] In a more preferred embodiment of the present invention, the content of non-amine-resistant silicone pressure-sensitive adhesive in the at least one additional pressure-sensitive adhesive layer (3) that initially does not contain an active ingredient in the transdermal treatment system is more than 60% by weight of the total weight of the pressure-sensitive adhesive in the pressure-sensitive adhesive layer (3), 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, even more preferably more than 93% by weight, even more preferably more than 95% by weight, and even more preferably at least 99% by weight. In another embodiment of the present invention, the at least one additional pressure-sensitive adhesive layer (3) that initially does not contain an active ingredient in the transdermal treatment system comprises only a non-amine-resistant silicone pressure-sensitive adhesive as a pressure-sensitive adhesive, that is, the at least one additional pressure-sensitive adhesive layer (3) that initially does not contain an active ingredient comprises only a non-amine-resistant silicone pressure-sensitive adhesive and does not contain any other polymer-based adhesives.

[0060] In a further preferred embodiment, the content of the non-amine-resistant silicone pressure-sensitive adhesive in the transdermal treatment system of the present invention is more than 50% by weight of the total weight of the pressure-sensitive adhesives contained in the transdermal treatment system, 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, even more preferably more than 93% by weight, even more preferably more than 95% by weight, and even more preferably at least 99% by weight (the transdermal treatment system may contain one type of non-amine-resistant silicone pressure-sensitive adhesive, or a mixture of two, three, four or more types of non-amine-resistant silicone pressure-sensitive adhesives). In another embodiment, the transdermal treatment system contains only a non-amine-resistant silicone pressure-sensitive adhesive as the pressure-sensitive adhesive, that is, the transdermal treatment system does not contain any other polymer-based adhesives and contains only a non-amine-resistant silicone pressure-sensitive adhesive.

[0061] In a more preferred embodiment, the transdermal treatment system comprises at least one additional pressure-sensitive adhesive layer (3) which initially does not contain an active ingredient, wherein the content of non-amine-resistant silicone pressure-sensitive adhesive in the pressure-sensitive adhesive layer (3), or the content of non-amine-resistant silicone pressure-sensitive adhesive in the matrix layer (2) and the pressure-sensitive adhesive layer (3), is 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, even more preferably more than 93% by weight, even more preferably more than 95% by weight, and even more preferably at least 99% by weight.

[0062] The weight per unit area of the matrix layer (2) of the transdermal therapeutic system of the present invention is not particularly limited. In general embodiments of the present invention, the weight per unit area of the matrix layer (2) is 30 to 70 g / m 2 and preferably 30 to 60 g / m 2 For example, the "weight per unit area" described for the layers constituting the transdermal therapeutic system of the present invention, such as the matrix layer (2) and at least one additional pressure-sensitive adhesive layer (3) that initially does not contain an active ingredient, refers to the weight per unit area of the dried layer, that is, in the preparation process of the transdermal therapeutic system, the weight per unit area of each layer after drying to remove the solvent.

[0063] In a preferred embodiment where the transdermal therapeutic system does not have a pressure-sensitive adhesive layer other than the matrix layer (2), the weight per unit area of the matrix layer (2) is 40 to 70 g / m 2 and preferably 45 to 65 g / m 2 more preferably about 50 to 60 g / m 2 and even more preferably 50 to 60 g / m 2 In an even more preferred embodiment where the transdermal therapeutic system does not have a pressure-sensitive adhesive layer other than the matrix layer (2), the weight per unit area of the matrix layer (2) is about 50 g / m 2 or about 60 g / m 2 or about 60 g / m.

[0064] <000029​​​​In one embodiment of the transdermal treatment system, the transdermal treatment system comprises a matrix layer (2) and at least one additional pressure-sensitive adhesive layer (3) which initially does not contain an active ingredient, wherein the weight per unit area of ​​the matrix layer (2) is 30-70 g / m². 2 It is 40-70g / m 2 It is more preferable that the amount be 45-65 g / m². 2 It is more preferable that the amount be approximately 50-60 g / m 2 It is more preferable that the amount be 50-60 g / m². 2 It is more preferable that it be approximately 50 g / m² 2 Or approximately 60g / m 2 Therefore, the weight per unit area of ​​at least one additional pressure-sensitive adhesive layer (3) that does not initially contain the active ingredient is 15-40 g / m². 2 It is 20-40 g / m 2 Preferably, it is 20-35 g / m 2 It is more preferable that the amount be 25-35 g / m². 2 It is more preferable that it be approximately 30 g / m 2 It is even more preferable that this be the case.

[0066] In the transdermal treatment system of the present invention, the matrix layer (2) and at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain an active ingredient contain one or more non-amine-resistant silicone-based pressure-sensitive adhesives in an amount exceeding 50% by weight relative to the total weight of the pressure-sensitive adhesive contained in the matrix layer (2), or relative to the total weight of the pressure-sensitive adhesive contained in the matrix layer (2) and the total weight of at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain an active ingredient.

[0067] In one preferred embodiment, the matrix layer (1) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain an active ingredient, comprises only one type of non-amine-resistant silicone pressure-sensitive adhesive. That is, in this embodiment, the matrix layer (2) comprises only one type of non-amine-resistant silicone pressure-sensitive adhesive, or at least one additional pressure-sensitive adhesive layer (3) which initially does not contain an active ingredient comprises only one type of non-amine-resistant silicone pressure-sensitive adhesive, or both the matrix layer (2) and at least one additional pressure-sensitive adhesive layer (3) which initially does not contain an active ingredient comprises only one type of non-amine-resistant silicone pressure-sensitive adhesive. In a further preferred embodiment, the pressure-sensitive adhesive contained in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain an active ingredient consists of only one type of non-amine-resistant silicone pressure-sensitive adhesive.

[0068] In a further preferred embodiment, the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain an active ingredient comprises one or more non-amine-resistant silicone-based pressure-sensitive adhesives of two or more, three or more, four or more types, preferably at least one (i.e., one or more) of these non-amine-resistant silicone-based pressure-sensitive adhesives having a moderate tack and at least one (i.e., one or more) having a high tack. In a further preferred embodiment, the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain an active ingredient comprises only two, three, four or more types of non-amine-resistant silicone-based pressure-sensitive adhesives. In another further preferred embodiment, the matrix layer (2) comprises only one type of non-amine-resistant silicone-based pressure-sensitive adhesive, and the at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain an active ingredient comprises only two types of non-amine-resistant silicone-based pressure-sensitive adhesives.

[0069] In a further preferred embodiment, one or more non-amine-resistant silicone pressure-sensitive adhesives included in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, include at least two, at least three, at least four or more types, or two, three, four or more types, of non-amine-resistant silicone pressure-sensitive adhesives with different molecular weights.

[0070] In a preferred embodiment of the transdermal treatment system of the present invention, one or more non-amine-resistant silicone adhesives included in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, include a mixture of at least one non-amine-resistant silicone pressure-sensitive adhesive having a moderate tack (e.g., Dow Corning's BIO-PSA 7-4501) and at least one non-amine-resistant silicone pressure-sensitive adhesive having a high tack (e.g., Dow Corning's BIO-PSA 7-4601). In a more preferred embodiment of the transdermal treatment system of the present invention, one or more non-amine-resistant silicone adhesives included in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, consist of a mixture of a non-amine-resistant silicone pressure-sensitive adhesive having moderate tack (e.g., Dow Corning's BIO-PSA 7-4501) and a non-amine-resistant silicone pressure-sensitive adhesive having high tack (e.g., Dow Corning's BIO-PSA 7-4601).

[0071] In one preferred modification of the above embodiment of the present invention, one or more non-amine-resistant silicone adhesives included in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, consist of a mixture of a non-amine-resistant silicone pressure-sensitive adhesive having moderate tack (e.g., Dow Corning's BIO-PSA 7-4501) and a non-amine-resistant silicone pressure-sensitive adhesive having high tack (e.g., Dow Corning's BIO-PSA 7-4601), and the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, do not contain any other pressure-sensitive adhesives.

[0072] In a preferred embodiment of the present invention, one or more non-amine-resistant silicone adhesives contained in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, include a mixture of at least one non-amine-resistant silicone pressure-sensitive adhesive having moderate tack and at least one non-amine-resistant silicone pressure-sensitive adhesive having high tack, or a mixture thereof, the content of the non-amine-resistant silicone adhesive having moderate tack relative to the total weight of the silicone adhesives contained in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient. The content of a non-amine-resistant silicone adhesive having high tack is preferably 0.0 to 55.0% by weight, more preferably 0.0 to 45.0% by weight, more preferably about 0.0 to 35.0% by weight, more preferably 0.0 to 25.0% by weight, and is preferably 45.0 to 100.0% by weight, more preferably 55.0 to 100.0% by weight, more preferably 65.0 to 100.0% by weight, and more preferably 75.0 to 100.0% by weight, relative to the total weight of the silicone adhesive contained in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient. If the transdermal treatment system includes a matrix layer (2) and at least one additional pressure-sensitive adhesive layer (3) that does not initially contain an active ingredient, the weight ratio of a non-amine-resistant silicone adhesive having moderate tack to a non-amine-resistant silicone adhesive having high tack may be the same or different in these layers.

[0073] The non-amine-resistant silicone adhesive in the present invention may be a silicone adhesive in which the silanol content has not been reduced (i.e., a non-amine-resistant silicone adhesive in which the silanol groups are not protected by protecting groups), or a silicone adhesive in which the silanol content has been reduced (i.e., a non-amine-resistant silicone adhesive in which only some of the silanol groups are protected by protecting groups). Such silicone adhesives in which the silanol content has not been reduced, and silicone adhesives in which the silanol content has been partially reduced, are known in the prior art. As non-amine-resistant silicone adhesives, for example, non-amine-resistant silicone adhesives with a silanol content that has not been reduced, such as Dow Corning's BIO-PSA 7-4501, Dow Corning's BIO-PSA 7-4601, Dow Corning's BIO-PSA 7-4502, and Dow Corning's BIO-PSA 7-4602, are preferred. Alternatively, non-amine-resistant silicone adhesives with a reduced silanol content that are classified as non-amine-resistant silicone adhesives even if the silanol content is partially reduced, such as Dow Corning's BIO-PSA SRS7-4501 and Dow Corning's BIO-PSA SRS7-4601, are preferred because the silanol content has not been reduced to a significant extent. In particular, Dow Corning's BIO-PSA 7-4501, Dow Corning's BIO-PSA 7-4601, Dow Corning's BIO-PSA SRS7-4501, and Dow Corning's BIO-PSA SRS7-4601 are preferred as non-amine-resistant silicone adhesives, with Dow Corning's BIO-PSA SRS7-4501 and Dow Corning's BIO-PSA SRS7-4601 being more preferred.

[0074] Furthermore, the inventors have surprisingly found that using a non-amine-resistant silicone adhesive with reduced silanol content instead of a non-amine-resistant silicone adhesive with unreduced silanol content can increase the adhesion of transdermal treatment systems. In the present invention, "reduced silanol content" means that in a so-called non-amine-resistant silicone adhesive, some of the silanol groups are protected by protecting groups; that is, in the present invention, such a silicone adhesive with reduced silanol content is classified as a non-amine-resistant silicone adhesive even if some of the silanol groups are protected by protecting groups. Non-amine-resistant silicone adhesives with reduced silanol content are known in the prior art, for example, as described in U.S. Patent Publication No. 6,337,086. Examples of non-amine-resistant silicone adhesives with reduced silanol content include Dow Corning's BIO-PSA SRS7-4501, BIO-PSA SRS7-4601, BIO-PSA SRS7-4502, and BIO-PSA SRS7-4602. Dow Corning's BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 are preferred as non-amine-resistant silicone adhesives with reduced silanol content. According to a preferred embodiment of the present invention, the silanol content (ppm) in a non-amine-resistant silicone adhesive with reduced silanol content is preferably about 8000 ppm to 13000 ppm, and the silanol content in a non-amine-resistant silicone adhesive without reduced silanol content is preferably more than 13000 ppm. The silanol content in these non-amine-resistant silicone adhesives is, for example, as described in U.S. Patent Publication No. 6,337,086, for example, 29 It can be measured by Si-NMR and / or FTIR spectroscopy.

[0075] In a preferred embodiment of the present invention, the matrix layer (2) comprises one or more non-amine-resistant silicone adhesives, the silanol content of which is reduced, and the content is preferably more than 50% by weight of the total weight of the non-amine-resistant silicone adhesives in the matrix layer (2), 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.

[0076] In a preferred embodiment of the present invention, the transdermal treatment system initially comprises at least one additional pressure-sensitive adhesive layer (3) which does not initially contain an active ingredient, wherein one or more non-amine-resistant silicone adhesives contained in the at least one additional pressure-sensitive adhesive layer (3) which does not initially contain an active ingredient comprises one or more non-amine-resistant silicone adhesives with reduced silanol content, wherein the content is preferably 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 at least 99% by weight, relative to the total weight of the non-amine-resistant silicone adhesives contained in the at least one additional pressure-sensitive adhesive layer (3) which does not initially contain an active ingredient.

[0077] For example, the matrix layer (2) may contain one or more non-amine-resistant silicone adhesives, each of two, three, four or more types of non-amine-resistant silicone adhesives with reduced silanol content, and the content is preferably the aforementioned weight ratio to the total weight of the non-amine-resistant silicone adhesives contained in the matrix layer (2). Similarly, for example, the one or more non-amine-resistant silicone adhesives contained in at least one additional pressure-sensitive adhesive layer (3) that initially does not contain an active ingredient may also contain two, three, four or more types of non-amine-resistant silicone adhesives with reduced silanol content, and the content is preferably the aforementioned weight ratio to the total weight of the non-amine-resistant silicone adhesives contained in at least one additional pressure-sensitive adhesive layer (3) that initially does not contain an active ingredient.

[0078] Experiments conducted by the inventors revealed that using a non-amine-resistant silicone adhesive with high tack and reduced silanol content (e.g., Dow Corning's BIO-PSA SRS7-4601) can significantly increase the peel force during storage, even when using a release liner (4) made of fluorosilicone-coated foil (e.g., Scotchpak 9709 (3M)). Surprisingly, the inventors found that using a mixture of a non-amine-resistant silicone adhesive with moderate tack and reduced silanol content (e.g., Dow Corning's BIO-PSA SRS7-4501) and a non-amine-resistant silicone adhesive with high tack and reduced silanol content (e.g., Dow Corning's BIO-PSA SRS7-4601) can significantly reduce the increase in peel force during storage.

[0079] Therefore, in one embodiment of the present invention, in which the matrix layer (2) contains one or more non-amine-resistant silicone adhesives, one includes a non-amine-resistant silicone adhesive with reduced silanol content, or consists only of a non-amine-resistant silicone adhesive with reduced silanol content, it is preferable that the matrix layer (2) contains a mixture of one or more non-amine-resistant silicone pressure-sensitive adhesives with reduced silanol content having moderate tack (e.g., Dow Corning's BIO-PSA SRS7-4501) and one or more non-amine-resistant silicone pressure-sensitive adhesives with reduced silanol content having high tack (e.g., Dow Corning's BIO-PSA SRS7-4601).

[0080] In another embodiment of the present invention, the transdermal treatment system comprises at least one additional pressure-sensitive adhesive layer (3) which initially does not contain an active ingredient, and one or more non-amine-resistant silicone adhesives contained in the at least one additional pressure-sensitive adhesive layer (3) which initially does not contain an active ingredient comprises a non-amine-resistant silicone adhesive with reduced silanol content, or consists solely of a non-amine-resistant silicone adhesive with reduced silanol content, wherein the at least one additional pressure-sensitive adhesive layer (3) which initially does not contain an active ingredient preferably comprises a mixture of one or more non-amine-resistant silicone pressure-sensitive adhesives with reduced silanol content having a moderate tack (e.g., Dow Corning's BIO-PSA SRS7-4501) and one or more non-amine-resistant silicone pressure-sensitive adhesives with reduced silanol content having a high tack (e.g., Dow Corning's BIO-PSA SRS7-4601).

[0081] In a preferred embodiment of the present invention, one or more non-amine-resistant silicone adhesives contained in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, include a mixture of one or more non-amine-resistant silicone pressure-sensitive adhesives with a moderate tack and a reduced silanol content, and one or more non-amine-resistant silicone pressure-sensitive adhesives with a high tack and a reduced silanol content, or a mixture thereof, wherein the content of the non-amine-resistant silicone adhesive with a moderate tack and a reduced silanol content is the same as the content of the silanol-resistant silicone adhesive contained in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient. The content of the non-amine-resistant silicone adhesive with reduced silanol content having high tack is preferably 10.0 to 40.0% by weight, more preferably 15.0 to 35.0% by weight, more preferably about 17.5 to 30.0% by weight, and more preferably 17.5 to 30.0% by weight, relative to the total weight of the silicone adhesive in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, is preferably 60.0 to 90.0% by weight, more preferably 65.0 to 85.0% by weight, more preferably about 70.0 to 82.5% by weight, and more preferably 70.0 to 82.5% by weight, relative to the total weight of the silicone adhesive in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient. If the transdermal treatment system includes a matrix layer (2) and at least one additional pressure-sensitive adhesive layer (3) that initially does not contain an active ingredient, the weight ratio of a silanol-reduced non-amine-resistant silicone adhesive having moderate tack to a silanol-reduced non-amine-resistant silicone adhesive having high tack may be the same or different in these layers.

[0082] In one preferred modification of the above embodiment of a transdermal treatment system comprising a non-amine-resistant silicone pressure-sensitive adhesive with reduced silanol content, one or more non-amine-resistant silicone pressure-sensitive adhesives included in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, consist solely of a non-amine-resistant silicone pressure-sensitive adhesive with reduced silanol content. In one even more preferred modification of this embodiment, the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, consist solely of a non-amine-resistant silicone pressure-sensitive adhesive with reduced silanol content as the pressure-sensitive adhesive.

[0083] In another more preferred variation of the above embodiment of a transdermal treatment system comprising a non-amine-resistant silicone pressure-sensitive adhesive with reduced silanol content, the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, consists solely of a mixture of a non-amine-resistant silicone pressure-sensitive adhesive with reduced silanol content having moderate tack (e.g., Dow Corning's BIO-PSA SRS7-4501) and a non-amine-resistant silicone pressure-sensitive adhesive with reduced silanol content having high tack (e.g., Dow Corning's BIO-PSA SRS7-4601).

[0084] In a preferred embodiment of the two-layer formulation of the present invention, the matrix layer (2) consists of only one or more non-amine-resistant silicone adhesives having a moderate tack and reduced silanol content (e.g., Dow Corning's BIO-PSA SRS7-4501), and the at least one additional pressure-sensitive adhesive layer (3), which initially does not contain the active ingredient, consists of only a mixture of a non-amine-resistant silicone pressure-sensitive adhesive having a moderate tack and reduced silanol content (e.g., Dow Corning's BIO-PSA SRS7-4501) and a non-amine-resistant silicone pressure-sensitive adhesive having a high tack and reduced silanol content (e.g., Dow Corning's BIO-PSA SRS7-4601). In a more preferred embodiment of the two-layer formulation of the present invention, the pressure-sensitive adhesive contained in the matrix layer (2) consists solely of a non-amine-resistant silicone pressure-sensitive adhesive with a reduced silanol content having moderate tack, and the pressure-sensitive adhesive contained in at least one additional pressure-sensitive adhesive layer (3), which initially does not contain the active ingredient, consists solely of a mixture of a non-amine-resistant silicone pressure-sensitive adhesive with a reduced silanol content having moderate tack and a non-amine-resistant silicone pressure-sensitive adhesive with a reduced silanol content having high tack.

[0085] In a preferred modification of the above embodiment, which includes one or more non-amine-resistant silicone adhesives with reduced silanol content, one or more non-amine-resistant silicone adhesives with unreduced silanol content are used instead of the one or more non-amine-resistant silicone adhesives with reduced silanol content. That is, for example, in a preferred embodiment of the present invention, one or more non-amine-resistant silicone adhesives contained in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, include one or more non-amine-resistant silicone adhesives whose silanol content has not been reduced, and the content thereof is preferably 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 at least 99% by weight, based on the total weight of the non-amine-resistant silicone adhesives contained in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient. In another embodiment, for example, in a preferred modification of the above embodiment, one or more non-amine-resistant silicone pressure-sensitive adhesives included in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, consist only of non-amine-resistant silicone pressure-sensitive adhesives whose silanol content has not been reduced.

[0086] For example, one or more non-amine-resistant silicone pressure-sensitive adhesives contained in the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient may further contain two, three, four or more types of non-amine-resistant silicone adhesives with unreduced silanol content, the content of which is preferably in the aforementioned weight ratio with respect to the total weight of the non-amine-resistant silicone adhesives contained in the matrix layer (2) or at least one additional pressure-sensitive adhesive layer (3) which initially does not contain the active ingredient. Non-amine-resistant silicone adhesives with unreduced silanol content are known to those skilled in the art. Preferred non-amine-resistant silicone adhesives with unreduced silanol content include Dow Corning's BIO-PSA 7-4501, Dow Corning's BIO-PSA 7-4601, Dow Corning's BIO-PSA 7-4502, and Dow Corning's BIO-PSA 7-4602.

[0087] In any of the above embodiments, the matrix layer (2) of the transdermal treatment system and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) that initially does not contain an active ingredient, and / or the entire transdermal treatment system, may be preferably designed to contain only a silicone-based adhesive as the pressure-sensitive adhesive. Furthermore, in any of the above embodiments, the matrix layer (2) of the transdermal treatment system and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) that initially does not contain an active ingredient, and / or the entire transdermal treatment system, may be preferably designed to contain only a non-amine-resistant silicone-based pressure-sensitive adhesive as the silicone-based pressure-sensitive adhesive; that is, the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) that initially does not contain an active ingredient, and / or the entire transdermal treatment system, may be preferably designed to contain only a non-amine-resistant silicone-based pressure-sensitive adhesive and not an amine-resistant silicone-based pressure-sensitive adhesive.

[0088] The application period for the transdermal treatment system of the present invention is preferably one day; that is, it is preferable to remove the transdermal treatment system of the present invention from the skin after one day. Since the transdermal treatment system of the present invention is usually used for long-term therapy (several months, or even several years), after removing the transdermal treatment system after one day, a new transdermal treatment system according to the present invention is applied to the skin.

[0089] However, the transdermal treatment system of the present invention may be used for a period longer than one day, for example, over two or three days. In this case, after two or three days, the transdermal treatment system of the present invention is replaced with another new transdermal treatment system.

[0090] The adhesive matrix layer has a backing layer (1) on the side opposite to human skin during use, but in a more preferred embodiment, this backing layer (1) blocks the active ingredient, i.e., does not allow the active ingredient to pass through. It is also particularly preferable that the backing layer does not transmit most light. In one embodiment, such a backing layer may be made of polyester, polyolefin (particularly polyethylene), or polyurethane. It is also advantageous to use a backing layer laminated with multiple different polymers. It is preferable that the backing layer has high impermeability to water vapor.

[0091] Polyester is preferred as the backing layer material, and for example, it is preferable that it be in the form of a composite foil in which the inner layer is made of polyester, the intermediate layer is an aluminum barrier layer, and the outer layer is made of colored polyethylene. Particularly preferred as the backing layer is a polyester foil sold by 3M under the trade names Scotchpak 1109 or Scotchpak 9738, or a polyester foil sold by Mitsubishi Polyester Film Co., Ltd. under the trade names Hostafan® MN 19, Hostafan MN 19 Med, or Hostafan MN 15 Med. For single-layer formulations, for example, Scotchpak 9738 is particularly preferred, and for double-layer formulations, for example, Hostafan MN 19 Med is particularly preferred.

[0092] Other suitable materials include cellophane, cellulose acetate, ethylcellulose, vinyl acetate-vinyl chloride copolymers containing plasticizers, ethylene-vinyl acetate copolymers, polyethylene terephthalate, nylon, polyethylene, polypropylene, polyvinylidene chloride, ethylene-methacrylate copolymers, possibly coated papers, fabrics such as polyethylene terephthalate foil, aluminum foil, and polymer-metal composite materials.

[0093] The thickness of the backing layer (1) of the transdermal treatment system of the present invention is not particularly limited. In one preferred embodiment, the backing layer (1) comprises polyester foil, and its thickness is preferably less than 35 μm, more preferably 5 to 30 μm, more preferably 10 to 25 μm, and particularly preferably 15 to 23 μm. In another embodiment, the backing layer (1) consists of polyester foil, and its thickness is preferably less than 70 μm, more preferably 15 to 65 μm, more preferably 25 to 60 μm, particularly preferably 30 to 60 μm, particularly preferably 49 to 60 μm, and even more particularly preferably 31 to 37 μm.

[0094] The backing layer (1) of the adhesive patch of the present invention may be provided with a cover layer to prevent the patch from sticking to the packaging in the event of leakage of a small amount of matrix material. The cover layer is preferably loosely positioned on the backing layer and held in place by electrostatic force. Such cover layers are known in the prior art, for example, described in European Patent Publication 1 097 090 (this document is incorporated in whole in this regard). The cover layer is non-adhesive at least on the surface that is positioned on the backing layer and is coated with, for example, fluorine or fluorosilicone.

[0095] The transdermal treatment system of the present invention further includes a release liner (4) that is removed before use. The release liner (4) is positioned on the matrix layer (2), and if there is at least one additional pressure-sensitive adhesive layer (3) which does not initially contain an active ingredient, it is positioned on this at least one additional pressure-sensitive adhesive layer (3) (see, for example, Figures 1(A) and 1(B), respectively). In this embodiment, it is preferable that the release liner (4) to be removed before use is positioned on the outermost layer of the transdermal treatment system, with one side of the release liner (4) constituting the outer surface of the transdermal treatment system. If there is no additional pressure-sensitive adhesive layer (3) which does not initially contain an active ingredient, it is preferable that the release liner (4) to be removed before use is in direct contact with the matrix layer (2), with the opposite side of the release liner (4) constituting the outer surface of the transdermal treatment system. If an additional pressure-sensitive adhesive layer (3) that does not initially contain an active ingredient is provided, it is preferable that this additional pressure-sensitive adhesive layer (3) is positioned between the matrix layer (2) and the release liner (4) that is removed before use, and is in direct contact with the matrix layer (2) and / or the release liner (4). If two or more additional pressure-sensitive adhesive layers (3) that do not initially contain an active ingredient are provided, it is preferable that some of them are positioned between the matrix layer (2) and the release liner (4) that is removed before use, and that the pressure-sensitive adhesive layer (3) furthest from the matrix layer (2) is in direct contact with the release liner (4).

[0096] The release liner (4), which is removed before use, is preferably made of a polymer material which may be coated with metal. Preferred polymer materials for use as a release liner include polyester, polyurethane, polyvinyl acetate, polyvinylidene chloride, polypropylene, polycarbonate, polystyrene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, and papers which may have their surfaces coated with such polymers. The release liner (4) is preferably coated with fluorosilicone on one or both sides. Commercially available polyester foil coated with fluorosilicone is particularly preferred, for example, Scotchpak 9709 (3M), which is a fluorosilicone-coated product. In a preferred embodiment, the transdermal treatment system further includes a release liner (4), which is removed before use, which consists of a foil coated with fluorosilicone, preferably a polyester foil coated with fluorosilicone.

[0097] In a preferred embodiment, the transdermal treatment system of the present invention comprises a backing layer (1), a matrix layer (2) disposed on the backing layer, and a peel-off liner (4) disposed on the matrix layer that is removed before use.

[0098] In a more preferred embodiment, the transdermal treatment system of the present invention comprises: a backing layer (1); a matrix layer (2) disposed on the backing layer; at least one additional pressure-sensitive adhesive layer (3) which initially does not contain an active ingredient and is disposed between the matrix layer and a release liner (4) which is removed before use; and a release liner (4) which is disposed on the at least one additional pressure-sensitive adhesive layer which is removed before use.

[0099] According to the present invention, the active ingredient is contained in the matrix layer (2). The active ingredient is rotigotine or a pharmaceutically acceptable salt thereof, and rotigotine is preferred. In the present invention, polymorphs of rotigotine may also be used, and the polymorphs of rotigotine are not particularly limited, but for reasons of stability, polymorph II rotigotine described in WO2009 / 068520 is preferred. For details on the preparation and characterization of polymorph II rotigotine, please refer to WO2009 / 068520.

[0100] The active ingredient is preferably completely dissolved in the matrix layer (adhesive matrix), that is, the matrix layer preferably does not contain solid particles of the active ingredient. The rotigotine content 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, more preferably in the range of 6.5% to 11.5% by weight, for example, 6.875% to 9% by weight, and particularly more preferably about 7.5% to 9% by weight.

[0101] According to the present invention, the active ingredient is contained in a matrix layer (adhesive matrix) and preferably in a substantially amorphous form in the dispersion phase of a solid dispersion contained in the matrix layer, wherein the dispersant in this dispersion phase preferably comprises one or more non-amine-resistant silicone adhesives and any other polymer adhesive. In a preferred embodiment, the dispersion phase contains polyvinylpyrrolidone in addition to rotigotine in an amorphous form. In this specification, "substantially" means more than 50%, particularly more than 90%, and particularly preferably more than 99% or 100%.

[0102] Rotigotine is hardly soluble in silicone-based adhesives, but it is well soluble in crystallization inhibitors such as polyvinylpyrrolidone. Therefore, in a preferred embodiment of the transdermal treatment system of the present invention, the matrix layer (2) further comprises polyvinylpyrrolidone dispersed in the matrix layer in addition to a non-amine-resistant silicone-based adhesive. It is preferable that rotigotine is completely dissolved in the matrix layer, that is, it is preferable that the content of rotigotine in the silicone-based adhesive is low enough not to cause precipitation or crystallization, and that most of the rotigotine is dissolved in the dispersed polyvinylpyrrolidone (or exists in at least an amorphous form).

[0103] Polyvinylpyrrolidone (PVP) is a polymer composed of N-vinylpyrrolidone monomer units. Polyvinylpyrrolidone is known to enhance the cohesive force of silicone adhesives. Furthermore, polyvinylpyrrolidone can also function as a crystallization inhibitor for rotigotine, the active ingredient. The molecular weight (as average weight molecular weight) of polyvinylpyrrolidone may be 2,000 to 2,500,000 daltons (g / mol), preferably 700,000 to 1,500,000 daltons, and more preferably 900,000 to 1,500,000 daltons. Various qualities of PVP are available, for example, from BASF AG (Ludwigshafen, Germany), which sells it under the product name Coridon. For example, examples of water-soluble PVPs (polyvinylpyrrolidones) include K-12 PF (molecular weight = 2,000-3,000 daltons), K-17 PF (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 28,000-1,500,000 daltons (g / mol).

[0104] The inventors have surprisingly found that in a transdermal treatment system in which the matrix layer contains one or more non-amine-resistant silicone adhesives in an amount exceeding 50% by weight relative to the total weight of the pressure-sensitive adhesive of the matrix layer (2), and rotigotine as an active ingredient, when rotigotine and polyvinylpyrrolidone are contained in the dispersed phase of the solid dispersion in the matrix layer in a weight ratio of 9:6.4, and especially when rotigotine is contained in a ratio of 9:7 or less as expressed as the weight ratio of rotigotine to polyvinylpyrrolidone, crystallization does not occur even when stored for a long period of time at a temperature of 25°C or higher. On the other hand, when the weight ratio of rotigotine to polyvinylpyrrolidone is large, for example, when the rotigotine content is expressed as a weight ratio of 9:5 or more as expressed as the weight ratio of rotigotine to polyvinylpyrrolidone, there is a risk of crystallization occurring when stored for a long period of time at a temperature of 25°C or higher. Therefore, although it is possible to increase the weight ratio of rotigotine to polyvinylpyrrolidone according to the present invention, it is not desirable.

[0105] Therefore, in a preferred embodiment of the transdermal treatment system of the present invention, rotigotine is contained in a solid dispersion in the matrix layer in a substantially amorphous form within a dispersed phase containing polyvinylpyrrolidone (PVP), and the rotigotine content is 9:6.4 or less, preferably 9:6.5 or less, and particularly preferably 9:7 or less, when expressed as a weight ratio of rotigotine to polyvinylpyrrolidone. The weight ratio of rotigotine to polyvinylpyrrolidone is preferably at least 9:11, more preferably at least 9:10, and particularly preferably at least 9:9. The weight ratio of rotigotine to polyvinylpyrrolidone is preferably in the range of 9:7 to 9:10. In such weight ratios, the matrix layer may contain, for example, 5.14–12.86% by weight of rotigotine and 4–10% by weight of polyvinylpyrrolidone, or 6.88–9% by weight of rotigotine and 5.35–7% by weight of polyvinylpyrrolidone, relative to its total weight. In a more preferred embodiment of the present invention, in the solid dispersion in the matrix layer, the content of amorphous rotigotine in the dispersed phase containing polyvinylpyrrolidone (PVP) is at least 70% by weight, at least 80% by weight, at least 85% by weight, at least 90% by weight, at least 95% by weight, or at least 97.5% by weight.

[0106] Polyvinylpyrrolidones suitable for use in combination with rotigotine in the matrix layer of transdermal treatment systems are known in the prior art. Such polyvinylpyrrolidones are described, for example, in WO2011 / 076879. The preferred polyvinylpyrrolidone in the present invention is PVP K90 (BASF SE). Polyvinylpyrrolidone K-90 (PVP K90) is particularly preferred.

[0107] The matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) which initially does not contain the active ingredient may contain another type of polymer adhesive (i.e., pressure-sensitive adhesive) other than the non-amine-resistant silicone adhesive. The weight percentage of the other type of polymer adhesive other than the non-amine-resistant silicone adhesive in the matrix layer (2) 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, relative to the total weight of the pressure-sensitive adhesive contained in the matrix layer (2). If the transdermal treatment system is provided with at least one additional pressure-sensitive adhesive layer (3) that does not initially contain the active ingredient, the weight percentage of another type of polymer-based adhesive other than the non-amine-resistant silicone-based adhesive in this 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, relative to the total weight of this pressure-sensitive adhesive layer (3). Such another type of polymer-based adhesive is, for example, polyacrylic acid, polymethacrylic acid, SBS block copolymer, or polyisobutylene.

[0108] Polyacrylic acid and polymethacrylic acid are known in the prior art (see, for example, U.S. Patent Publication No. 2002 / 0077437) and are used in various applications in transdermal therapeutic systems. Polyacrylic acid and polymethacrylic acid are typically prepared by radical polymerization of acrylic acid derivatives or methacrylic acid derivatives (particularly acrylic acid esters or methacrylic acid esters), respectively. Other suitable compounds, such as vinyl acetate, can also be further copolymerized as additional monomers. The properties of polyacrylic acid or polymethacrylic acid can be altered by crosslinking, for example, with polyvalent metal ions. Crosslinked or uncrosslinked polyacrylic acid or polymethacrylic acid are commercially available, supplied by Henkel (or National Starch), which sells polyacrylic acid and polymethacrylic acid under the trade name "DURO-TAK".

[0109] Examples of polyacrylic acid or polymethacrylic acid include copolymers or terpolymers of monomers selected from 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, and others. As comonomers, acrylamide, dimethylamide, acrylonitrile, or vinyl acetate may be used. Further examples of suitable acrylic adhesives are described, for example, in the literature by Satas (Acrylic Adhesives, Handbook of Pressure Sensitive Adhesives Technology, 2nd edition, pages 396-456 (D. Satas, ed.), van Nostrand Reinhold, New York (1989)). In this specification, when polyacrylic acid is mentioned, the corresponding polymethacrylic acid is also referred to.

[0110] Polyisobutylene is known in the prior art and is commercially available. For example, Opanol is a product sold by BASF (Ludwigshafen, Germany). Suitable polyisobutylenes include, for example, Opanol B50, Opanol N50, Opanol B80, Opanol N80, Opanol B100, Opanol N100, Opanol B150, Opanol N150, Opanol B200 and Opanol N200; Opanol B10 SFN or Opanol B15 SFN; and Opanol B10 and Opanol B15. For example, a mixture of polyisobutylene selected from Opanol B80, Opanol B100, Opanol B150, and Opanol B200, and preferably Opanol B80 and Opanol B100, and a second polyisobutylene selected from Opanol B10 SFN and Opanol B15 SFN can also be used.

[0111] Unless otherwise explicitly stated or evident from the context, the molecular weight of the polymers described in this invention is always the weight-average molecular weight (M w This refers to the weight-average molecular weight (M). As those skilled in the art are well aware, w This can be measured, for example, by GPC.

[0112] In the transdermal treatment system of the present invention, the matrix layer, which contains rotigotine as an active ingredient and the aforementioned pressure-sensitive adhesive, and optionally contains polyvinylpyrrolidone, may contain other components as needed.

[0113] For example, by adding a transdermal absorption enhancer to the matrix layer, the active ingredient can be sufficiently permeated through the skin. Suitable transdermal absorption enhancers are known. Examples of suitable transdermal absorption enhancers include aliphatic alcohols, fatty acids, fatty acid esters, fatty acid amides, glycerin and glycerin derivatives, n-methylpyrrolidone, and terpenes and terpene derivatives (e.g., D-limonene, α-pinene, α-terpineol, carvone, carveol, limonene oxide, pinene oxide, 1,8-eucalyptol, etc.). However, it is preferable that the transdermal treatment system of the present invention does not contain such transdermal absorption enhancers.

[0114] Furthermore, one or more plasticizers can be added to the matrix layer (2). Suitable plasticizers are also known in the prior art, for example, mineral oil and polybutene-based plasticizers. In one embodiment, the matrix layer (2) and / or at least one additional pressure-sensitive adhesive layer (3) (if provided) which initially does not contain the active ingredient, contain one or more additives, preferably a plasticizer.

[0115] In one preferred embodiment of the present invention, the matrix layer (2) further comprises one or more additives that improve the chemical stability of rotigotine, such additives include, for example, antioxidants, specifically tocopherol and its derivatives (especially esters), butylhydroxytoluol (BHT), butylhydroxyanisole (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 to 0.125% by weight of tocopherol, 0.0 to 0.1% by weight of ascorbyl palmitate, and 0.0 to 0.0021% by weight of sodium metabisulfite based on the total weight of the matrix layer (2). It is preferable that antioxidants and sodium metabisulfite are not added to at least one additional pressure-sensitive adhesive layer (3) that initially does not contain the active ingredient.

[0116] The transdermal therapy system of the present invention can be used to treat any disease in which rotigotine is administered as an active ingredient. However, the transdermal therapy system of the present invention is particularly preferred for use in the treatment of Parkinson's disease.

[0117] The percutaneous treatment system of the present invention can be prepared by methods known to the present. For example, in the preparation of a single-layer formulation, all the components of the matrix layer of the percutaneous treatment system are added simultaneously to a suitable solvent and stirred to obtain a homogeneous coating solution. Next, this homogeneous coating solution is applied to a backing layer (1) or preferably a release liner (4) and dried to remove the solvent. Then, the other layers, namely the release liner (4) or preferably the backing layer (1), are laminated on the obtained matrix layer (2) and punched out to an appropriate size to obtain a percutaneous treatment system.

[0118] Therefore, according to one preferred embodiment, the present invention further provides a method for preparing a transdermal treatment system as a monolayer formulation according to any of the above embodiments of the transdermal treatment system of the present invention, a) A step of preparing a homogeneous coating solution by simultaneously adding all the components of the matrix layer (2) of the transdermal treatment system to a suitable solvent and mixing them to achieve the desired homogeneity; b) A step of applying the homogeneous coating liquid to the backing layer (1) or preferably the release liner (4), drying it, and removing the solvent; and c) Laminating another layer, namely a release liner (4) or preferably a backing layer (1), onto the obtained matrix layer (2), punching it out to an appropriate size, to obtain a transdermal treatment system. Regarding methods including

[0119] In the preparation of a two-layer or multi-layer formulation, for example, all components of the active ingredient-containing matrix layer (2) of the transdermal treatment system are added simultaneously to a suitable solvent and stirred to obtain a first homogeneous coating solution. Next, this stirred and homogenized first coating solution is applied to a backing layer (1) or preferably a temporary release liner (4) and dried to remove the solvent. Then, the other layers, i.e., the temporary release liner (4) or preferably the backing layer (1), are laminated on the obtained matrix layer (2) (a first precursor of the transdermal treatment system is obtained). Next, all components of at least one additional pressure-sensitive adhesive layer (3), which initially does not contain the active ingredient, are added simultaneously to a suitable solvent and stirred to obtain another coating solution. Next, this other coating solution is applied to a release liner (4) and dried to remove the solvent (a second precursor of the transdermal treatment system is obtained). Finally, the temporary release liner (4) is peeled off the first precursor of the transdermal treatment system and laminated onto a precursor (second precursor of the transdermal treatment system) consisting of at least one additional pressure-sensitive adhesive layer (3) which does not initially contain the active ingredient and the release liner (4), to obtain a laminate containing a backing layer (1), a matrix layer (2) containing the active ingredient, at least one additional pressure-sensitive adhesive layer (3) which does not initially contain the active ingredient, and the release liner (4) in this order, or a laminate consisting of these layers laminated in this order, and the transdermal treatment system is obtained by punching out this laminate to an appropriate size.

[0120] Therefore, according to a second preferred embodiment, the present invention further relates to a method for preparing a transdermal treatment system, a) As a step to prepare the first precursor of the transdermal treatment system, a1) A step of preparing a first homogeneous coating solution by simultaneously adding all the components of the matrix layer (2) to a suitable solvent and mixing them to achieve the desired homogeneity; a2) Applying a first homogeneous coating liquid to a backing layer (1) or preferably a temporary release liner (4), and drying it to remove the solvent; and a3) Laminating another layer, namely a temporary release liner (4) or preferably a backing layer (1), onto the obtained matrix layer (2). Includes, b) As a step of preparing the second precursor of the transdermal treatment system, b1) The step of preparing another homogeneous coating solution by simultaneously adding all the components of at least one additional pressure-sensitive adhesive layer (3), which initially does not contain the active ingredient, to a suitable solvent and mixing them to have the desired homogeneity; and b2) The process of applying the other homogeneous coating liquid to the release liner (4) and drying it to remove the solvent. Includes, c) a) step of removing the temporary fixing release liner (4) from the first precursor of a); A step of laminating a first precursor and a second precursor to obtain a laminate comprising, in this order, the backing layer (1), the matrix layer (2) containing the active ingredient, the at least one additional pressure-sensitive adhesive layer (3) which initially does not contain the active ingredient, and the release liner (4), or a laminate consisting of these layers laminated in this order; and The process of punching out the laminate to an appropriate size to obtain a transdermal treatment system. Regarding methods including

[0121] In the method for preparing the transdermal treatment system described above, additional layers can be inserted by carrying out intermediate manufacturing steps by methods known to the present invention. For example, a membrane for controlling the release of the active ingredient can be inserted between the matrix layer and at least one additional pressure-sensitive adhesive layer (3) which initially does not contain the active ingredient. Alternatively, for example, a transdermal treatment system may be prepared that includes at least two additional pressure-sensitive adhesive layers (3) which initially do not contain the active ingredient. This transdermal treatment system can be prepared, for example, by removing the release liner (4) from a transdermal treatment system in the form of a two-layer formulation prepared according to a second preferred embodiment of the method for preparing the transdermal treatment system of the present invention, and further laminating a second precursor prepared according to step b) (of the second preferred embodiment of the method for preparing the transdermal treatment system of the present invention), for example, to this two-layer formulation to obtain a laminate containing a backing layer (1), a matrix layer (2) containing the active ingredient, first and second additional pressure-sensitive adhesive layers (3) which initially do not contain the active ingredient, and a release liner (4) in this order, and then punching out this laminate to an appropriate size to obtain the transdermal treatment system. In this way, an additional layer can be inserted into the percutaneous treatment system. [Examples]

[0122] The present invention will be illustrated by the following examples. "%" always means "weight percent".

[0123] Example 1a: Monolayer formulation (Preparation of test formulation using 616ROTTS as an example) [Table 1]

[0124] A 1% (w / w%) aqueous solution of sodium metabisulfite was prepared. Next, a 25% (w / w%) ethanol solution of PVP K90 was prepared. The PVP solution was placed in a suitable glass container, a corresponding amount of sodium metabisulfite solution was added, and the mixture was stirred for about 15 minutes. Ascorbyl palmitate and tocopherol were added and the mixture was stirred. Next, the resulting mixture was heated in a water bath and rotigotine as the active ingredient was gradually added while stirring, and the mixture was stirred at about 60°C until the rotigotine was completely dissolved. After the mixture cooled, several types of silicone-based adhesives were added in succession and stirred for a short time. Next, heptane as the solvent was added to adjust the total volume and the mixture was stirred. Finally, paraffin was added. The resulting coating solution was stirred until it was visually confirmed that all components were homogeneously dispersed. Next, the coating solution was homogenized using a suitable disperser (Ultra-Turrax), for example, at about 10,000 rpm for about 3 minutes. The homogenized coating solution is then applied to a fluorine-coated foil (for example, Scotchpak TM The material (9709 / 1022 / 9744) was applied to form a thin film, which was then heated, for example, at 85°C for 10 minutes to almost completely remove the solvent. The weight per unit area of ​​the dried matrix was approximately 60 g / m². 2 This was the matrix. A release liner (for example, a release liner made of polyethylene terephthalate (PET) with a thickness of 19 μm, or a release liner made of polyethylene, aluminum, and polyester) was laminated onto this matrix.

[0125] Example 1b: Monolayer formulation (Preparation of test formulations using IMPD 631ROTTDS as an example) [Table 2]

[0126] A 1% (w / w%) aqueous solution of sodium metabisulfite was prepared. Next, a 25% (w / w%) ethanol solution of PVP K90 was prepared. The PVP solution was placed in a suitable glass container, a corresponding amount of sodium metabisulfite solution was added, and the mixture was stirred for about 30 minutes. Ascorbyl palmitate and tocopherol were added and the mixture was stirred. Next, the resulting mixture was heated in a water bath and rotigotine as the active ingredient was gradually added while stirring, and the mixture was stirred at about 60°C until the rotigotine was completely dissolved. After the mixture cooled, several types of silicone-based adhesives were added in succession and stirred for a short time. Next, heptane as the solvent was added to adjust the total volume and the mixture was stirred. Finally, paraffin was added. The resulting coating solution was stirred until it was visually confirmed that all components were homogeneously dispersed. Next, the coating solution was homogenized using a suitable disperser (Ultra-Turrax), for example, at about 10,000 rpm for about 3 minutes. The homogenized coating solution is then applied to a fluorine-coated foil (for example, Scotchpak TM The material was applied to 9709) to form a thin film, and the solvent was almost completely removed by heating at a rate of approximately 0.16 m / min in a tunnel dryer approximately 52 cm long with four compartments at approximately 45°C, 60°C, 80°C, or 99°C. The weight per unit area of ​​the dried matrix was approximately 50 g / m². 2 This was the matrix. A release liner (for example, a release liner made of polyethylene terephthalate (PET) with a thickness of 19 μm) was laminated onto this matrix.

[0127] Example 2a: Two-layer formulation (Preparation of a test formulation using 618_617ROTTDS as an example) [Table 3]

[0128] First, the matrix layer (2) was prepared. To prepare the matrix layer (2), a 1% (w / w%) aqueous solution of sodium metabisulfite and a 25% (w / w%) ethanol solution of PVP K90 were prepared. The PVP solution was placed in a suitable glass container, a corresponding amount of sodium metabisulfite solution was added, and the mixture was stirred for at least about 15 minutes. Ascorbyl palmitate and tocopherol were added and stirred. Next, the resulting mixture was heated in a water bath and rotigotine as the active ingredient was gradually added while stirring, and the mixture was stirred at about 60°C until the rotigotine was completely dissolved. After the mixture cooled, several types of silicone-based adhesives were added in succession and stirred for a short time. Next, heptane as the solvent was added to adjust the total volume and stirred. The resulting coating solution was stirred until it could be visually confirmed that all components were homogeneously dispersed. Next, a fluorine-coated foil (e.g., Scotchpak) was used. TM A coating solution was applied to the matrix (9709 / 1022 / 9744) to form a thin film, and the solvent was almost completely removed by heating, for example, at 85°C for 10 minutes. The weight per unit area of ​​the dried matrix was approximately 50 g / m². 2 This was the matrix. A release liner (for example, a release liner made of polyethylene terephthalate (PET) with a thickness of 19 μm) was laminated onto this matrix.

[0129] Next, to prepare an adhesive layer (3) that initially does not contain any active ingredients, several types of silicone-based adhesives were added to a suitable glass container and stirred for a short time. Then, paraffin and heptane as a solvent to adjust the overall volume were added in sequence and stirred. The resulting coating solution was stirred until it was visually confirmed that all components were homogeneously dispersed. Next, a fluorine-coated foil (e.g., Scotchpak) was added. TM A coating solution was applied to (9709 / 1022 / 9744) to form a thin film, and the solvent was almost completely removed by heating, for example, at 85°C for 10 minutes. The weight per unit volume of the matrix of the dried adhesive layer (3) was 25-30 g / m². 3Initially, the release liner of the adhesive layer (3), which does not contain the active ingredient, was peeled off to expose the matrix of the adhesive layer (3), and the matrix layer was then laminated onto the exposed matrix of the adhesive layer (3).

[0130] Example 2b: Two-layer formulation (Preparation of test formulation using 629_628ROTTDS as an example) [Table 4]

[0131] First, the matrix layer (2) was prepared. To prepare the matrix layer (2), a 1% (w / w%) aqueous solution of sodium metabisulfite and a 25% (w / w%) ethanol solution of PVP K90 were prepared. The PVP solution was placed in a suitable glass container, a corresponding amount of sodium metabisulfite solution was added, and the mixture was stirred for about 30 minutes. Ascorbyl palmitate and tocopherol were added and the mixture was stirred. Next, the resulting mixture was heated in a water bath and stirred while gradually adding rotigotine as the active ingredient, stirring at about 60°C until the rotigotine was completely dissolved. After the mixture cooled, several types of silicone-based adhesives were added in succession and stirred for a short time. Next, heptane was added as the solvent to adjust the total volume and the mixture was stirred. The resulting coating solution was stirred until it could be visually confirmed that all components were homogeneously dispersed. Next, a fluorine-coated foil (e.g., Scotchpak) was used. TM A coating solution was applied to 9709) to form a thin film, and the solvent was almost completely removed by heating at a rate of approximately 0.16 m / min in a tunnel dryer approximately 52 cm long with four compartments at approximately 45°C, 60°C, 80°C, or 99°C. The weight per unit area of ​​the dried matrix was approximately 50 g / m². 2 This was the matrix. A release liner (for example, a release liner made of polyethylene terephthalate (PET) with a thickness of 19 μm) was laminated onto this matrix.

[0132] Next, to prepare an adhesive layer (3) that initially does not contain any active ingredients, several types of silicone-based adhesives were added to a suitable glass container and stirred for a short time. Then, paraffin and heptane as a solvent to adjust the overall volume were added in sequence and stirred. The resulting coating solution was stirred until it was visually confirmed that all components were homogeneously dispersed. Next, a fluorine-coated foil (e.g., Scotchpak) was added. TM A coating solution was applied to 9709) to form a thin film, and the solvent was almost completely removed by heating, for example, at 85°C for 5 minutes. The weight per unit area of ​​the matrix of the dried adhesive layer (3) was 25-30 g / m². 2 Initially, the release liner of the adhesive layer (3), which does not contain the active ingredient, was peeled off to expose the matrix of the adhesive layer (3), and the matrix layer was then laminated onto the exposed matrix of the adhesive layer (3). WpUA [g / m 2 ]: Weight per unit area PVP K90: Polyvinylpyrrolidone K-90 (BASF SE) rh: Relative humidity RSD: Relative Standard Deviation RS: Matrix Layer HS: Initially, the adhesive layer does not contain any active ingredients. mon: number of months RT: room temperature

[0133] The percutaneous treatment system prepared in this manner generally has the following composition, for example:

[0134] A monolayer formulation comprising a matrix layer containing an active ingredient, wherein the matrix layer comprises rotigotine and PVP K90 in specific weight ratios and weight percentages relative to the total weight of the matrix layer; 0-3% by weight of liquid paraffin; various combinations of one or two non-amine-resistant silicone adhesives with unreduced silanol content or non-amine-resistant silicone adhesives with reduced silanol content (Dow Corning); and at least one antioxidant (e.g., 0.05-0.1% by weight of tocopherol, 0.02-0.1% by weight of ascorbyl palmitate, and 0.0006-0.0021% by weight of sodium metabisulfite), and the weight of the matrix per unit area is approximately 50-60 g / m². 2 A single-layer formulation characterized by the following:

[0135] A two-layer formulation comprising a matrix layer containing an active ingredient and an additional pressure-sensitive adhesive layer (3) that initially does not contain the active ingredient, wherein the matrix layer contains rotigotine and PVP K90 in specific weight ratios and weight percentages relative to the total weight of the matrix layer; a non-amine-resistant silicone adhesive with unreduced silanol content (BIO-PSA 7-4501) or a non-amine-resistant silicone adhesive with reduced silanol content (BIO-PSA SRS7-4501) (Dow Corning); and at least one antioxidant (e.g., 0.05-0.1% by weight of tocopherol and / or 0.02-0.1% by weight of ascorbyl palmitate and 0.0006-0.0021% by weight of sodium metabisulfite), and the weight per unit area of ​​the matrix is ​​approximately 2550 g / m² 2 The two-layer formulation is characterized in that the pressure-sensitive adhesive layer (3) comprises one or two types of silanol-free, non-amine-resistant silicone adhesives (Dow Corning) in various combinations, and 0 to 3% by weight of liquid paraffin.

[0136] The following specific monolayer and bilayer formulations were prepared.

[0137] A) Paraffin-free monolayer formulation containing multiple types of non-amine-resistant silicone adhesives in various mixing ratios. Various monolayer formulations were prepared that contained BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 in various mixing ratios, or BIO-PSA 7-4501 and BIO-PSA 7-4601 in various mixing ratios, without paraffin. These monolayer formulations used various combinations of Scotchpak 1109 (3M) or Hostafan MN 19 (Mitsubishi Polyester Films) as the backing layer, and Scotchpak 1022, Scotchpak 9744, or Scotchpak 9709 (3M) as the release liner. The prepared transdermal treatment systems were stored at 25°C or 40°C for various periods, and peel strength, adhesion, and tack were examined. Furthermore, for some formulations, in vitro permeability was measured using heat-separated epidermis (HSE) prepared by heat separation.

[0138] The peeling force can be measured as the force required to peel the sample from the peeling liner at a predetermined angle and speed. To measure the peeling force, a predetermined size (e.g., 10 cm) is used. 2 The transdermal delivery system is punched out and left at 23±1°C and 50±5% relative humidity. A narrow guide liner of the same width as the transdermal delivery system is attached to the transdermal delivery system. Next, with the guide release liner facing downwards, the transdermal delivery system is fixed to a fixture with double-sided tape and set on a tensile testing machine (e.g., Stable Micro Systems' Texture Analyzer plus), and the transdermal delivery system is peeled off at a 90° angle. Generally, measurements are taken at a speed of 300±30 mm / min under conditions of 23±1°C and 50±5% relative humidity. The peel force is defined as the average adhesive force over the peeled length, normalized by the width of the sample piece (25 mm) [N / 25 mm].

[0139] Adhesion can be measured as the force required to peel a sample from a suitable jig at a predetermined angle and speed. To measure adhesion, a predetermined size (e.g., 10 cm) is used. 2The transdermal delivery system is punched out and left at 23±1°C and 50±5% relative humidity. A narrow guide liner (e.g., double-sided tape) the same width as the transdermal delivery system is attached. One side of this release liner is peeled off and the transdermal delivery system is attached to a test plate (e.g., made of steel), sandwiched between two glass plates, and pressed with a weight of, for example, 2 kg for 1 minute. The test plate is mounted horizontally on a tensile testing machine (e.g., Stable Micro Systems' Texture Analyzer plus), the guide liner is clamped, and the transdermal delivery system is peeled off at a 90° angle. Generally, measurements are taken at a predetermined speed of 300±30 mm / min, usually at 23±1°C and 50±5% relative humidity. The adhesive strength is defined as the average adhesive strength over the peeled length, standardized by the width of the sample piece (25 mm) [N / 25 mm].

[0140] Tack can be measured as the maximum force required to completely separate a stainless steel specimen from the adhesive layer of a transdermal delivery system. To measure tack, the adhesive or laminate is left to stand at 23±1°C and 50±5% relative humidity, then the release liner is peeled off, and the exposed adhesive matrix is ​​fixed to a porous support plate. This porous support plate is then placed in a tensile testing machine (e.g., Stable Micro Systems' Texture Analyzer plus). Typically, at 23±1°C and 50±5% relative humidity, a stainless steel specimen is pressed against the top surface of the sample (matrix), and after a predetermined contact time of typically 2 seconds, the specimen is peeled off. The entire measurement procedure must be completed within 30 minutes after peeling the release liner off the first sample. Determine the maximum force (tack; [N]) required to separate the adhesion between the specimen and the adhesive layer (matrix).

[0141] [Table 5] TIFF0007835678000007.tif189166

[0142] B) Paraffin-containing monolayer formulations containing multiple types of non-amine-resistant silicone adhesives in various mixing ratios. Various monolayer formulations were prepared in the same manner as in A) above, either by containing BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 (Dow Corning) in various mixing ratios in the matrix layer, or by containing BIO-PSA 7-4501 and BIO-PSA 7-4601 (Dow Corning) in various mixing ratios, with paraffin further added to the matrix layer. These monolayer formulations were used in various combinations of Scotchpak 1109 (3M) or Hostafan MN 19 (Mitsubishi Polyester Films) as the backing layer and Scotchpak 9744 or Scotchpak 9709 (3M) as the release liner. The prepared transdermal treatment systems were stored at 25°C or 40°C for various periods, and the peel force, adhesive force, and tack were examined. Furthermore, for some formulations, in vitro permeability was measured using human epidermis prepared by a heat separation method.

[0143] [Table 6]

[0144] C) Paraffin-containing or paraffin-free bilayer formulations containing multiple types of non-amine-resistant silicone adhesives in various mixing ratios. Various two-layer formulations were prepared, each containing a matrix layer in varying amounts of BIO-PSA SRS7-4501 or BIO-PSA 7-4501 (Dow Corning) and rotigotine. These two-layer formulations further included an additional pressure-sensitive adhesive layer, initially without the active ingredient, on the matrix layer side opposite to the side in contact with the backing layer. This additional pressure-sensitive adhesive layer, initially without the active ingredient, was prepared using varying amounts of BIO-PSA SRS7-4501 and / or BIO-PSA SRS7-4601 or BIO-PSA 7-4501 (Dow Corning), with or without the addition of a small amount of paraffin.

[0145] In these two-layer formulations, it was necessary to select the ratio of silicone-based adhesives with moderate tack and silicone-based adhesives with high tack to achieve good adhesion and tack, minimize cold flow, and obtain sufficiently high cohesive force.

[0146] Furthermore, these two-layer formulations were used in various combinations of Scotchpak 1109 (3M) or Hostafan MN 19 (Mitsubishi Polyester Films) as the backing layer and Scotchpak 9744, Scotchpak 1022, Scotchpak 9709 (3M), Primeliner 100μm 78BT, and Primeliner 75μm 78HL (Loparex International BV) as the release liner. The prepared transdermal treatment systems were stored at 25°C or 40°C for various periods, and the peel force, adhesion, and tack were examined. In addition, for some formulations, in vitro permeability was measured using human epidermis prepared by a heat separation method.

[0147] In these two-layer formulations, the effect of an additional pressure-sensitive adhesive layer, which initially did not contain the active ingredient, on peel strength, tack, and in vitro permeability was investigated.

[0148] [Table 7]

[0149] D) Monolayer formulations containing a non-amine-resistant silicone adhesive and polyvinylpyrrolidone in various concentrations. Various monolayer formulations were prepared, each containing different amounts of PVP K90 and rotigotine (fixed at 9% by weight) relative to the total weight of the matrix layer, and containing BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 (Dow Corning) in a 1:1 mixture ratio within the matrix layer.

[0150] Scotchpak 1109 (3M) was used as the backing layer, and Scotchpak 9744 was used as the release liner. The resulting transdermal treatment systems were stored at 25°C or 40°C for various periods, and their appearance was examined. Furthermore, for some formulations, in vitro permeability was measured using human epidermis (HSE) prepared by heat separation. This example aimed to investigate the effects of varying amounts of PVP K90 on rotigotine recrystallization and in vitro permeability.

[0151] [Table 8]

[0152] Example 2 (Peel strength, adhesive strength, and tack) This example aimed to investigate the effects of the mixing ratio of non-amine-resistant silicone adhesives BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 (Dow Corning), or the mixing ratio of BIO-PSA 7-4501 and BIO-PSA 7-4601 (Dow Corning), on peel strength, tack, and other properties, and to determine the optimal mixing ratio for the matrix layer based on the results. For another purpose, the effects of paraffin on peel strength, tack, and other properties were also investigated.

[0153] A) Peeling force As is evident from Table 5 and Figure 2, a transdermal treatment system in the form of a rotigotine-containing monolayer formulation, stored using a release liner coated with a fluoropolymer (e.g., Scotchpak 1022 or Scotchpak 9744 (3M)) containing one or more silicone-based adhesives (non-amine-resistant silicone-based adhesives) primarily containing free silanol groups in the matrix layer, showed a significant increase in peel force. No increase in peel force was observed with a rotigotine-free placebo formulation using the same release liner as with a silicone-based adhesive containing free silanol groups.

[0154] When a release liner coated with a fluorosilicone such as Scotchpak 9709 (3M) was used with the same or similar formulations using one or more silicone-based adhesives containing free silanol groups and rotigotine, the increase in peel force was significantly less (see Figure 2 and Table 5).

[0155] [Table 9]

[0156] Surprisingly, rotigotine formulations containing a mixture of BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 (Dow Corning), both non-amine-resistant silicone adhesives with reduced silanol content, showed less increase in peel force compared to rotigotine formulations containing only BIO-PSA SRS7-4601 (Dow Corning), a non-amine-resistant silicone adhesive with reduced silanol content. Furthermore, rotigotine formulations containing a mixture of BIO-PSA 7-4501 and BIO-PSA 7-4601 (Dow Corning), both non-amine-resistant silicone adhesives with unreduced silanol content, also showed less increase in peel force compared to rotigotine formulations containing only BIO-PSA 7-4601 (Dow Corning), a non-amine-resistant silicone adhesive with unreduced silanol content.

[0157] B) Adhesive strength Furthermore, various types of non-amine-resistant silicone adhesives or mixtures thereof, along with various transdermal treatment system formulations containing rotigotine, were stored for 0 to 3 months, and their adhesive strength was compared to a placebo formulation and a commercially available Neupro transdermal treatment system.

[0158] As is evident from Table 6 and Figure 3, the adhesion strength of transdermal treatment system formulations containing rotigotine and one or more silicone-based adhesives with unreduced silanol content (BIO-PSA 7-4501 and / or BIO-PSA 7-4601; Dow Corning) (non-amine-resistant silicone-based adhesives with unreduced silanol content) was relatively low. This relatively low adhesion strength decreased even more significantly after storage for one or three months at 40°C / 75% relative humidity, becoming lower than that of commercially available Neupro after one month of storage. No decrease in adhesion strength was observed in the placebo formulation, even when using non-amine-resistant silicone-based adhesives.

[0159] Surprisingly, despite having fewer free silanol groups and therefore less interaction with the surface than silicone adhesives with a reduced silanol content, formulations containing rotigotine and reduced silanol-containing non-amine-resistant silicone adhesives (Dow Corning's BIO-PSA SRS7-4501 and / or BIO-PSA SRS7-4601) exhibited significantly higher adhesion and less degradation. Even after storage at 40°C / 75% relative humidity for 0-3 months, the absolute adhesion remained higher than that of commercially available Neupro.

[0160] Furthermore, formulations containing BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 as silicone adhesives in a ratio of approximately 17.5-30.0% by weight and approximately 82.5-70.0% by weight relative to their combined proportion exhibited higher adhesive strength compared to formulations using only BIO-PSA SRS7-4601 (Dow Corning) (see Figure 3), but no corresponding increase in peeling force was observed (see Figure 4 and Table 6).

[0161] Surprisingly, adding a small amount of paraffin, approximately 1-3% by weight, to the formulation resulted in significantly higher tackiness, with only a slight decrease observed during storage for 1-3 months (see Figure 3 and Table 6).

[0162] Therefore, it has been shown that adding paraffin to the formulation of the present invention also has the effect of enabling the use of non-amine-resistant silicone adhesives with unreduced silanol content. The adhesive strength when using a non-amine-resistant silicone adhesive with unreduced silanol content is not as strong as when using a non-amine-resistant silicone adhesive with reduced silanol content, but it is superior to commercially available Neupro, and is therefore preferable.

[0163] [Table 10]

[0164] C) Tuck Furthermore, various types of non-amine-resistant silicone adhesives or mixtures thereof, along with various transdermal treatment system formulations containing rotigotine, were stored for 0 to 3 months, and their tack was compared to a placebo formulation and the commercially available Neupro.

[0165] As is clear from Table 7 and Figure 5, the tack of transdermal treatment system formulations containing rotigotine and one or more silicone adhesives containing free silanol groups (Dow Corning's BIO-PSA 7-4501 and / or BIO-PSA 7-4601) (non-amine-resistant silicone adhesives with unreduced silanol content) was lower than that of commercially available Neupro, due to the lack of reduced silanol content.

[0166] Surprisingly, the tack was significantly higher when using a non-amine-resistant silicone adhesive with reduced silanol content, and it only decreased slightly after one month of storage at 40°C / 75% relative humidity, remaining stable even after three months. Furthermore, the addition of a small amount of paraffin resulted in a higher tack than commercially available Neupro, and surprisingly, the decrease in tack during storage was not significant when using a small amount of paraffin (approximately 2% by weight).

[0167] [Table 11]

[0168] Example 3 (Recrystallization during storage) This example aimed to investigate the effects of varying the amount of PVP K90 on the recrystallization and permeability of rotigotine. A mixture of non-amine-resistant silicone adhesives, BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 (Dow Corning), along with rotigotine and PVP K90, was used as the matrix layer. When the weight ratio of rotigotine to PVP K90 was 9:3.2 to 9:5, crystallization was observed when stored at 25°C or 40°C.

[0169] Surprisingly, when the matrix layer was made using the same mixture consisting of non-amine-resistant silicone adhesives BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 (Dow Corning), along with rotigotine and PVP K90, and the rotigotine content was kept at a weight ratio of 9:7 or less for rotigotine to PVP K90, crystallization could be prevented even when stored at the same temperature.

[0170] [Table 12]

[0171] Example 4 (Permeability and elution in vitro) Explanation of in vitro dissolution experiments A specific size (e.g., 10cm) without a release liner. 2The test formulation of ) is compared with the European Pharmacopoeia 2.9.4 (Method 3) or the United States Pharmacopoeia. <724> The active ingredient was released by attaching the formulation to a rotary cylinder according to apparatus 6 (cylinder with adapter). 900 mL of 50 mM phosphate buffer (pH 4.5) was used as the eluate for each test formulation. The elution temperature was 32°C, and the cylinder rotation speed was 50 rpm. Samples were collected according to the formulation under test. For single-layer formulations, samples were collected at, for example, 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, and 3 hours. For two-layer formulations, samples were collected at, for example, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, and 6 hours. The collected sample solutions were directly analyzed by RP-HPLC, which is outlined below.

[0172] Stationary phase: C18 (e.g., 50 x 3 mm, particle size 5 μm, oven temperature 35°C). Mobile phase: 70 mM phosphate buffer (pH 5.0) / methanol = 55% / 45% (v / v) at a flow rate of 0.6 mL / min. Injection volume: 20μL. Detection wavelength: 223 nm. The retention time for rotigotine is approximately 3 to 6 minutes. Measurement time: 8 minutes (isocratic). External standard solutions were analyzed, and a single-check concentration curve was constructed for evaluation. The cumulative release concentration [%] was calculated based on the average concentration in the sample solution.

[0173] Description of the in vitro skin permeability test of rotigotine In vitro skin permeability studies were conducted using a NovoCell Schonbach skin permeability tester, in accordance with the Organisation for Economic Co-operation and Development (OECD) (2004) Guideline 428, "Skin absorption: In vitro Method & Series on testing and assessment," specifically document No. 28, "Guidance document for the conduct of skin absorption studies." During measurement, the test cell was set to 32±1°C. The test cell consisted of a donor chamber and an acceptor chamber, with human skin prepared by a heat separation method sandwiched between them. The effective permeability area of ​​this human skin was 1.05 cm². 2 It is supported by a cellulose membrane. With the surface from which the active ingredient is released facing the acceptor chamber, the test patch (approximately 1.2 cm) is placed. 2 A matrix of a certain size was attached to the stratum corneum. The volume of the measurement cell was 15 mL and it was filled with pH 5.5 phosphate physiological buffer. Samples were taken from the acceptor chamber at predetermined times (e.g., 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 15 hours, 18 hours, 21 hours, and 24 hours), and the rotigotine concentration was measured by RP-HPLC analysis. When taking samples, the same amount of fresh buffer as the sample was immediately added to the acceptor chamber. A magnetic stirrer incorporated into the acceptor chamber was used to ensure uniformity of temperature and rotigotine concentration.

[0174] RP-HPLC analysis was performed in the same manner as in the in vitro elution experiment (see above), and the sample concentration was calculated. Next, the cumulative permeation amount at each time point was calculated, plotted against time to create a graph, and the steady-state permeation flux was calculated [μg / cm²]. 2 / h].

[0175] A) Monolayer formulation: Effect of the ratio of rotigotine to PVP K90 and the addition of paraffin on permeability Skin permeability was investigated by applying the test formulation to human epidermis (HSE) prepared by a heat separation method. In this experiment, the weight ratio of rotigotine to PVP K90 was varied, and tests were conducted with and without the addition of paraffin as an ingredient to increase adhesion and tack.

[0176] The aforementioned single-layer formulations, prepared using polyacrylic acid-based adhesives, mixtures of polyacrylic acid and silicone-based adhesives, polyisobutylene / polybutylene, styrene-butadiene, or mixtures of styrene-isoprene and resin, and two-layer formulations, prepared using a pressure-sensitive adhesive layer initially without the active ingredient and one of the aforementioned adhesives, showed significantly lower permeability of the active ingredient compared to Neupro when applied to human epidermis (HSE) prepared by the heat separation method.

[0177] The effect on in vitro permeability was investigated by fixing the rotigotine content at 9% and varying the ratio of rotigotine to PVP, by applying a test monolayer formulation to human epidermis prepared by a heat separation method.

[0178] As can be seen in Figure 6A), when the ratio of rotigotine to PVP K90 used was set to 6.4-9.0% PVP K90, no effect on in vitro permeability was observed. Furthermore, the permeability of all tested monolayer formulations was similar, showing slightly higher or slightly more effective permeability than Neupro.

[0179] The effects on in vitro permeability were investigated by fixing the rotigotine content (9% by weight) and PVP K90 content (7% by weight) and varying the mixing ratio of BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601, by applying test monolayer formulations to human epidermis prepared by a heat separation method.

[0180] As can be seen in Figure 6B), when test monolayer formulations of BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 mixed in a ratio of 1:1, 1:1.5, 1:2, or 1:3 were applied to human epidermis prepared by the heat separation method and tested, no effect on in vitro permeability was observed. Furthermore, the permeability of monolayer formulations of BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 mixed in a ratio of 1:1 to 1:3 was all about the same, showing slightly higher or slightly more effective permeability than Neupro.

[0181] Furthermore, the effect of adding a small amount of paraffin on in vitro permeability was investigated by applying a test monolayer formulation to human epidermis prepared by a heat separation method.

[0182] In the case of a monolayer formulation using BIO-PSA SRS7-4501, a non-amine-resistant silicone adhesive with reduced silanol content, and 2% by weight of paraffin, an improvement in in vitro permeability was observed, showing slightly higher or slightly more effective permeability than Neupro (Figure 7A).

[0183] Even with monolayer formulations using BIO-PSA 7-4501 and / or BIO-PSA 7-4601, which are non-amine-resistant silicone adhesives with unreduced silanol content, the addition of 1-2% by weight of paraffin improved in vitro permeability. The permeability was slightly higher or slightly more effective than that of Neupro. Furthermore, the paraffin-improved formulations showed higher permeability than paraffin-free formulations using non-amine-resistant silicone adhesives with unreduced silanol content (Figure 7B).

[0184] B) Two-layer formulation: Effect on the permeability of various pressure-sensitive adhesive layers that do not contain active ingredients. The effect on in vitro permeability of a two-layer formulation (a combination of various pressure-sensitive adhesive layers, initially without active ingredients, prepared using different adhesive systems, and an active ingredient-containing matrix layer using a silicone-based adhesive) was investigated by applying the formulation to human epidermis prepared by a heat separation method and comparing it with Neupro.

[0185] Initially, the pressure-sensitive adhesive layer, which does not contain any active ingredients, is prepared using a polyacrylic acid-based adhesive, polyisobutylene / polybutylene, or a mixture of styrene-isobutadiene and resin, along with paraffin, at a density of approximately 30 g / m². 2 The adhesive was applied to a thickness of [thickness]. The two-layer formulation using this pressure-sensitive adhesive layer had significantly lower permeability than the two-layer formulation using a pressure-sensitive adhesive layer without the active ingredient, which consists of the non-amine-resistant silicone adhesive SRS7-4601 (see Figure 8A). In both formulations, approximately 30 g / m was used, with 15% by weight of rotigotine, 8.5% by weight of PVP K90, and 76.5% by weight of BIO-PSA SRS7-4501 adhesive. 2 A matrix layer of the same composition, prepared by coating to a certain thickness, was used. On the other hand, a two-layer formulation using a pressure-sensitive adhesive layer (which initially did not contain the active ingredient) and a non-amine-resistant silicone adhesive in the matrix layer showed higher or improved permeability than Neupro.

[0186] C) Elution in vitro As shown in Figure 8B), even when the mixing ratio of BIO-PSA SRS7-4501 and BIO-PSA SRS7-4601 was 1:1 or 1:3, 538ROTTDS and 539ROTTDS exhibited almost identical release behavior, indicating no effect on in vitro release. On the other hand, these formulations contained 9% by weight of rotigotine and 7% by weight of PVP K90, and presumably due to the higher PVP K90 content, the initial in vitro release was slightly faster than that of Neupro.

[0187] Figure 9 shows the cumulative release of rotigotine from the two-layer formulation over 6 hours. In an in vitro dissolution test from the two-layer formulation, approximately 50 g / m² was released after stirring the coating solution of the matrix layer (2) containing the active ingredient. 2 Either apply to a thickness to prepare the matrix layer (2), or add to the mixture to further homogenize it, then apply at approximately 50 g / m². 2 A matrix layer (2) was prepared by coating it to a certain thickness. Next, these active ingredient-containing matrix layers (2) were laminated onto an adhesive layer (3) of the same composition, which initially did not contain the active ingredient. For further comparison, a single-layer formulation was processed in the same manner, and initially, the adhesive layer (3) which did not contain the active ingredient was not laminated. When gently stirred, the particle size increased and the particle size distribution widened compared to when further homogenization was performed. No change was observed in the release process whether stirring alone or stirring and homogenization were performed.

Claims

1. It is a transdermal treatment system, a) Backing layer (1), b) A matrix layer containing the drug (2), and c) Release liner to be removed before use (4) Includes, The aforementioned drug is rotigotine, and The matrix layer (2) comprises one or more non-amine-resistant silicone-based pressure-sensitive adhesives in an amount exceeding 50% by weight relative to the total weight of the pressure-sensitive adhesives contained in the matrix layer (2), and paraffin in an amount of 1 to 3% by weight relative to the total weight of the matrix layer (2), wherein the non-amine-resistant silicone-based pressure-sensitive adhesives comprise a mixture of one or more non-amine-resistant silicone-based pressure-sensitive adhesives having a moderate tack and reduced silanol content, and one or more non-amine-resistant silicone-based pressure-sensitive adhesives having a high tack and reduced silanol content. The dispersed phase of the solid dispersion in the matrix layer (2) contains polyvinylpyrrolidone, and the rotigotine content is 9:7 or less in weight ratio of rotigotine to polyvinylpyrrolidone. A transdermal treatment system characterized by [feature].

2. The weight per unit area of ​​the matrix layer (2) is 40 to 70 g / m². 2 The transdermal treatment system according to claim 1.

3. A transdermal treatment system according to claim 1 or 2, wherein between the matrix layer (2) and the release liner (4) which is removed before use, there is at least one additional pressure-sensitive adhesive layer (3) which initially does not contain an active ingredient, and the pressure-sensitive adhesive layer (3) contains one or more non-amine-resistant silicone-based pressure-sensitive adhesives in an amount exceeding 50% by weight of the total weight of the pressure-sensitive adhesives contained in the pressure-sensitive adhesive layer (3), and 1 to 3% by weight of paraffin in relation to the total weight of the pressure-sensitive adhesive layer (3).

4. Initially, the weight per unit area of ​​the at least one additional pressure-sensitive adhesive layer (3) that does not contain the active ingredient is 20–40 g / m². 2 The transdermal treatment system according to claim 3.

5. The transdermal treatment system according to any one of claims 1 to 4, wherein the amount of the non-amine-resistant silicone pressure-sensitive adhesive in the matrix layer (2) is greater than 75% by weight of the total weight of the pressure-sensitive adhesive contained in the matrix layer (2).

6. The transdermal treatment system according to any one of claims 3 to 5, wherein the amount of the non-amine-resistant silicone pressure-sensitive adhesive in the at least one additional pressure-sensitive adhesive layer (3) that does not initially contain the active ingredient is greater than 75% by weight of the total weight of the pressure-sensitive adhesive contained in the pressure-sensitive adhesive layer (3).

7. The transdermal treatment system according to any one of claims 3 to 6, wherein the matrix layer (2) and the at least one additional pressure-sensitive adhesive layer (3), which initially does not contain an active ingredient, each contain only a non-amine-resistant silicone-based pressure-sensitive adhesive as the pressure-sensitive adhesive.

8. The transdermal treatment system according to any one of claims 1 to 7, wherein the non-amine-resistant silicone pressure-sensitive adhesive is a silicone adhesive with reduced silanol content.

9. The transdermal treatment system according to any one of claims 1 to 7, wherein the majority of rotigotine in the matrix layer (2) exists in an amorphous form in the dispersed phase of a solid dispersion, and the dispersed phase contains polyvinylpyrrolidone.

10. The transdermal treatment system according to any one of claims 1 to 9, wherein the content of rotigotine is expressed as a weight ratio of rotigotine to polyvinylpyrrolidone of 9:7 to 9:

10.

11. The transdermal treatment system according to any one of claims 3 to 10, wherein the content of the active ingredient in the matrix layer (2) is in the range of 6 to 20% by weight relative to the total weight of the matrix layer (2).

12. The transdermal treatment system according to any one of claims 3 to 11, wherein the one or more non-amine-resistant silicone pressure-sensitive adhesives contained in the matrix layer (2) and / or the at least one additional pressure-sensitive adhesive layer (3) which initially does not contain an active ingredient, comprises two or more non-amine-resistant silicone pressure-sensitive adhesives.

13. The transdermal treatment system according to any one of claims 3 to 12, wherein the one or more non-amine-resistant silicone pressure-sensitive adhesives contained in the matrix layer (2) and / or the at least one additional pressure-sensitive adhesive layer (3) which initially does not contain an active ingredient, consist only of non-amine-resistant silicone pressure-sensitive adhesives with reduced silanol content.

14. The transdermal treatment system according to any one of claims 1 to 13, wherein the matrix layer (2) contains one or more antioxidants and / or sodium metabisulfite.

15. A percutaneous treatment system according to any one of claims 1 to 14, for use in the treatment of Parkinson's disease.

16. A method for preparing a transdermal treatment system according to any one of claims 1 to 15 as a monolayer formulation, a) A step of preparing a homogeneous coating solution by simultaneously adding all the components of the matrix layer (2) to a suitable solvent and mixing them to achieve the desired homogeneity; b) A step of applying the homogeneous coating liquid to the backing layer (1) or preferably the release liner (4), drying it, and removing the solvent; and c) Laminating another layer, namely a release liner (4) or preferably a backing layer (1), onto the obtained matrix layer (2), punching it out to an appropriate size, to obtain a transdermal treatment system. A method that includes this.

17. A method for preparing a transdermal treatment system according to any one of claims 3 to 16, a) As a step of preparing the first precursor of the transdermal treatment system, a1) A step of preparing a first homogeneous coating solution by simultaneously adding all the components of the matrix layer (2) to a suitable solvent and mixing them to achieve the desired homogeneity; a2) Applying a first homogeneous coating solution to a backing layer (1) or preferably a temporary release liner (4), and drying it to remove the solvent; and a3) Laminating another layer, namely a temporary release liner (4) or preferably a backing layer (1), onto the obtained matrix layer (2). Includes, b) As a step of preparing a second precursor of the transdermal treatment system, b1) A step of preparing a homogeneous coating solution by simultaneously adding all the components of at least one additional pressure-sensitive adhesive layer (3), which initially does not contain the active ingredient, to a suitable solvent and mixing them to achieve the desired homogeneity; and b2) The process of applying the homogeneous coating liquid to the release liner (4) and drying it to remove the solvent. Includes, c) A step of removing the temporary fixing release liner (4) from the first precursor of a); A step of laminating a first precursor and a second precursor to obtain a laminate comprising, in this order, the backing layer (1), the matrix layer (2) containing the active ingredient, the at least one additional pressure-sensitive adhesive layer (3) which initially does not contain the active ingredient, and the release liner (4); and The process of punching out the laminate to an appropriate size to obtain a transdermal treatment system. A method that includes this.

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