A transdermal therapeutic system for the transdermal administration of guanfacine containing guanfacine and monocarboxylic acid.

Abstract

The present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine, comprising guanfacine and a monocarboxylic acid.

Description

[Technical Field]

[0001] The present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of guanfacine into the systemic circulation, as well as a method for manufacturing the same, a therapeutic method, and a use thereof. [Background technology]

[0002] The activator guanfacine (also known as N-(aminoiminomethyl)-2,6-dichlorobenzeneacetamide, C9H9Cl2N3O, CAS registry number 29110-47-2) is a sympathomimetic agent used to treat hypertension and attention deficit hyperactivity disorder (ADHD). It is a centrally acting alpha(2)-adrenergic receptor agonist. It has the following chemical formula: [ka]

[0003] Currently, guanfacine is marketed in the form of immediate-release or controlled-release tablets, for example, containing 1 mg to 4 mg of guanfacine. These tablets are suitable for once-daily administration.

[0004] However, oral administration of active ingredients has disadvantages, for example, from the perspective of patient compliance. Furthermore, once sustained-release tablets are taken orally, it is not possible to quickly discontinue treatment in light of signs of overdose or intolerance.

[0005] Therefore, a transdermal treatment system for the transdermal administration of guanfacine is needed. In particular, a TTS suitable for multi-day treatment with a single application is required, thereby improving patient compliance. [Overview of the project]

[0006] Therefore, an object of the present invention is to provide a TTS for transdermal administration of guanfacine. In particular, an object of the present invention is to provide a TTS for transdermal administration of guanfacine that provides sufficient skin permeability to achieve a therapeutically effective dose.

[0007] A further object of the present invention is to provide a TTS for transdermal administration of guanfacine that provides a therapeutically effective amount of guanfacine for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours. In particular, an object of the present invention is that a therapeutically effective amount is provided over the entire period, where the TTS is applied to the skin and 24-hour treatment is possible by replacing the TTS after a certain application time, for example, at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

[0008] A further object of the present invention is to provide a transdermal transdermal treatment (TTS) for guanfacine that reduces fluctuations in guanfacine plasma concentration compared to oral administration (especially at steady state).

[0009] A further object of the present invention is to provide a TTS for transdermal administration of guanfacine with advanced utilization of the active ingredient.

[0010] Another object of the present invention is to provide a transdermal tethering system (TTS) for guanfacine that is convenient to apply in terms of size and thickness, and / or easy to manufacture and cost-effective.

[0011] A further object of the present invention is to provide a method for preparing TTS.

[0012] The present invention achieves these and other objectives and, according to one embodiment, relates to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure. Herein, the guanfacine-containing layer structure is A) Backing layer, B) A guanfacine-containing layer comprising guanfacine and monocarboxylic acid, Includes.

[0013] The TTS according to the present invention, comprising guanfacine and monocarboxylic acid, has been found to offer advantageous properties in terms of utilization of the active ingredient and constant and continuous delivery of guanfacine. In particular, the TTS according to the present invention provides appropriate permeability and appropriate amount of guanfacine over a period of at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours. According to certain embodiments, the present invention also relates to a transdermal therapeutic system for transdermal administration of guanfacine as described above, wherein the guanfacine-containing layer is i) Guanfacine and monocarboxylic acid, ii) at least one polymer, This is a guanfacine-containing matrix layer.

[0014] In certain preferred embodiments, the present invention relates to the transdermal treatment system described above, where guanfacine and monocarboxylic acid in the guanfacine-containing layer are present in the form of a premixture.

[0015] In a more preferred embodiment, the present invention relates to the transdermal treatment system described above, wherein the guanfacine and monocarboxylic acid in the guanfacine-containing layer are present in the form of a premixture, which can be obtained by dry grinding or slurrying.

[0016] In certain preferred embodiments, at least one polymer is • A mixture of an acrylic polymer and at least one silicone-based polymer, • A mixture of two silicone-acrylic hybrid polymers, or • A mixture of two silicone-based polymers, or • Acrylic polymer, or Acrylic polymer containing -OH groups That is the case.

[0017] In another preferred embodiment, the guanfacine-containing layer further comprises at least one additive, preferably at least two additives, selected from the group consisting of dispersants, permeation enhancers, and solubilizers.

[0018] According to one particular embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) A mixture of an acrylic polymer and at least one silicone-based polymer, wherein, based on the total weight of the guanfacine-containing layer, the acrylic polymer is present in an amount of 20-55% by weight, and the at least one silicone-based polymer is present in an amount of 20-55% by weight, iii) Polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer. 20 -alkyl ether and, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of oleyl alcohol, Includes.

[0019] According to another specific embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of the two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight. iii) Polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer. 20 -alkyl ether and, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of oleyl alcohol, Includes.

[0020] According to a further specific embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising, A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) A mixture of two silicone-based polymers, in which the first silicone-based polymer is present in an amount of 20-55% by weight and the second silicone-based polymer is present in an amount of 20-55% by weight, based on the total weight of the guanfacine-containing layer, iii) Polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer. 20 - Alkyl ether and, based on the total weight of the guanfacine-containing layer, 2-6% by weight of oleyl alcohol, Includes.

[0021] According to another specific embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) Based on the total weight of the guanfacine-containing layer, 65-95% by weight of acrylic polymer, iii) Polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer. 20 -alkyl ether and, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of oleyl alcohol, Includes.

[0022] According to a further specific embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising, A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) Based on the total weight of the guanfacine-containing layer, an acrylic polymer containing 65-95% by weight of -OH groups, iii) Polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer. 20 -alkyl ether and, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of oleyl alcohol, Includes.

[0023] According to certain embodiments of the present invention, the transdermal therapeutic system according to the present invention is for use in a method of treating a human patient, preferably for use in a method of treating a human patient aged 6 to 17 years. In particular, the transdermal therapeutic system according to the present invention is for use in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD), and / or for use as an adjuvant therapy to stimulant drug therapy in a human patient, preferably a human patient aged 5 to 17 years. In connection with these medical uses, the TTS according to the present invention is preferably applied to the skin of the patient for at least 24 hours, more preferably for at least 72 hours, most preferably for about 84 hours.

[0024] According to certain embodiments, the present invention further relates to a method of treating a human patient, preferably a human patient aged 6 to 17 years, by applying the transdermal therapeutic system according to the present invention to the skin of the patient. In particular, the present invention relates to a method of treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient, preferably a human patient aged 6 to 17 years, by applying the transdermal therapeutic system according to the present invention to the skin of the patient. In connection with these methods, the TTS according to the present invention is preferably applied to the skin of the patient for at least 24 hours, more preferably for at least 72 hours, most preferably for about 84 hours.

[0025] According to another embodiment, the present invention has an AUC of about 10 to 600 ng*h / ml, preferably about 20 to 400 ng*h / ml 0-24h and / or an AUC of about 30 to 1800 ng*h / ml, preferably about 60 to 1200 ng*h / ml 0-72h and / or an AUC of about 35 to 2100 ng*h / ml, preferably about 70 to 1400 ng*h / ml 0-84h and / or has a ratio of C to C less than 3.5 max of C 84 and / or has a ratio of C to C less than 3.0 max of C 72 and / or has a ratio of C to C less than 2.0 max of C 24This relates to a transdermal therapeutic system for the transdermal administration of guanfacine as defined above, having a ratio to [a certain value].

[0026] In a further aspect, the present invention relates to a method for producing an active drug-containing layer for use in a transdermal therapy system, the method being 1) At least, ingredients (i) Pharmaceutical activators, (ii) at least one monocarboxylic acid, A step of obtaining a premixture by combining, 2) (i) The premixture from step 1) and (ii) at least one polymer, A step of obtaining a coating composition by combining, 3) A step of coating the coating composition onto a backing layer or release liner to obtain a coated coating composition, 4) A step of drying the coated coating composition to form the active agent-containing layer, Includes.

[0027] In yet another aspect, the present invention relates to a transdermal treatment system obtained by a method according to the present invention.

[0028] definition Within the scope of the present invention, the term “Transdermal Therapy System” (TTS) refers to a system for administering an active agent (e.g., guanfacine) into the systemic circulation via transdermal delivery, and to the entirety of individual dose units applied to the patient’s skin after removal of an optional release liner, the entirety of which dose units comprises a therapeutically effective amount of the active agent in an active agent-containing layer structure and an adhesive overlay which may be added on top of the active agent-containing layer structure. The active agent-containing layer structure may be located on a release liner (a removable protective layer), and thus the TTS may further include a release liner. Within the scope of the present invention, the term “TTS” particularly refers to a system that provides transdermal delivery other than, for example, delivery of an active substance via iontophoresis or microporation. A transdermal therapy system may also be called a transdermal drug delivery system (TDDS) or transdermal delivery system (TDS).

[0029] Within the scope of the present invention, the terms "activator-containing layer structure" or "guanfacine-containing layer structure" refer to a layer structure comprising a backing layer and an activator-containing layer. The activator-containing layer structure contains a therapeutically effective amount of activator. Preferably, the activator-containing layer structure is a self-adhesive layer structure containing an activator. Preferably, the activator is guanfacine.

[0030] Within the scope of the present invention, the term “therapeutic dose” refers to the amount of activator in a TTS that, when administered to a patient by TTS, is sufficient to provide the desired pharmacological effect. With respect to guanfacine, the term “therapeutic dose” refers to the amount of activator in a TTS that, when administered to a patient by TTS, is preferably sufficient to treat, prevent or alleviate hypertension or attention deficit hyperactivity disorder (ADHD), or sufficient as an adjunct therapy to stimulant drug therapy in human patients. TTS typically contains more active substances in the system than are actually delivered to the skin and systemic circulation. This excess amount of activator is usually necessary to provide sufficient driving force for delivery from the TTS to the systemic circulation.

[0031] Within the scope of the present invention, terms such as “active substance” and “activator,” as well as the term “guanfacine,” refer to each activator in any pharmaceutically acceptable chemical and morphological form, and physical state. Preferably, the activators in the present invention exist in the form of a “co-salt” (i.e., the activator (preferably guanfacine) exists in a premixture with at least one monocarboxylic acid) so that, for example, proton transfer or hydrogen bond formation is possible, preferably forming a guanfacine salt of at least partially monocarboxylic acid. In other words, the activator (preferably guanfacine) may exist in at least partially protonated form. Further forms include, but are not limited to, protonated or partially protonated forms, deprotonated or partially deprotonated forms, salts, or cocrystals of the activator. Further pharmaceutically acceptable chemical and morphological forms and physical states include solvates, hydrates, clathrates, complexes, as well as activators in the form of particles (which may be finely ground crystalline and / or amorphous), and any mixture of the aforementioned forms. The activator, when contained in a medium such as a solvent, may be dissolved or dispersed, or partially dissolved and partially dispersed. However, it should be understood that the present invention, relating to the activator (preferably guanfacine) and monocarboxylic acid, encompasses any form obtained in the guanfacine-containing layer based on a premixture of guanfacine and monocarboxylic acid, and that this form includes, for example, the option of guanfacine and monocarboxylic acid coexisting without chemical interaction (i.e., proton transfer or hydrogen bond formation) and the option of co-salt formation as described above. Preferably, the free guanfacine base and monocarboxylic acid may together form a co-salt or any other type of acid addition salt, and as a result, the guanfacine-containing layer preferably contains at least partially a co-salt or any other type of acid addition salt of the free guanfacine base and monocarboxylic acid.In other words, the guanfacine-containing layer preferably comprises guanfacine in at least a partially protonated form and a monocarboxylic acid in at least a partially deprotonated form.

[0032] Where it is mentioned that an activator is used in a particular form in the manufacture of TTS, this does not preclude interactions between this form of the activator and other components of the activator-containing layer structure (which may still be present in the final TTS), such as when the activator is provided as a premixture with a monocarboxylic acid to form a co-salt or any other type of acid addition salt. This means that the activator may be present in the final TTS in a protonated or partially protonated / or deprotonated or partially deprotonated form, or in the form of an acid addition salt, or, if it is included in the form of a salt, a portion of it may be present in the final TTS as a free base. Unless otherwise indicated, the amount of activator in the layer structure, in particular, relates to the amount of activator contained in the TTS during the manufacture of the TTS and is calculated based on the activator itself or a premixture of the activator with a monocarboxylic acid, but not on any other form.

[0033] During the manufacture of TTS, the activator starting material included in TTS may be in the form of particles. The activator may, for example, be present in the form of particles in the activator-containing layer structure and / or be dissolved.

[0034] Within the scope of this invention, the term "particles" refers to particulate materials of a solid that include individual particles, the size of which is negligible compared to the material. In particular, particles are solids including amorphous and crystalline materials, and plastics / deformable solids.

[0035] Within the scope of the present invention, the term “disperse” refers to a step or combination of steps in which the starting material (e.g., guanfacine) is not completely dissolved. Dispersion in the sense of the present invention involves dissolving a portion of the starting material (e.g., guanfacine particles) depending on the solubility of the starting material (e.g., the solubility of guanfacine in the coating composition).

[0036] There are two main types of transdermal therapy systems (TTS) for activator delivery: matrix-type TTS and reservoir-type TTS. In matrix-type TTS, the release of the activator is primarily controlled by a matrix containing the activator itself. In contrast, reservoir-type TTS typically require a rate-controlling membrane to control the release of the activator. In principle, matrix-type TTS may also contain a rate-controlling membrane. However, matrix-type TTS are generally advantageous over reservoir-type TTS in that they do not require a rate-determining membrane and dose dumping due to membrane rupture cannot occur. In summary, matrix-type transdermal therapy systems (TTS) are less complex to manufacture and are easy and convenient for patient use.

[0037] Within the scope of the present invention, “matrix-type TTS” refers to a system or structure in which the active substance is homogeneously dissolved and / or dispersed within a polymer carrier, i.e., a matrix, and together with the activator and optionally residual components, forms a matrix layer. In such a system, the matrix layer controls the release of the activator from the TTS. Preferably, the matrix layer has sufficient cohesiveness to be self-supporting so that sealing between other layers is not required. Thus, in one embodiment of the present invention, the activator-containing layer may be an activator-containing matrix layer in which the activator is homogeneously distributed within the polymer matrix. In certain embodiments, the activator-containing matrix layer may comprise two activator-containing matrix layers that may be laminated together. Matrix-type TTS may also take the form of “drug in adhesive” type TTS, which refers in particular to a system in which the active substance is homogeneously dissolved and / or dispersed within a pressure-sensitive adhesive matrix. In this regard, the activator-containing matrix layer may also be referred to as an activator-containing pressure-sensitive adhesive layer or an activator-containing pressure-sensitive adhesive matrix layer. A TTS containing an activator dissolved and / or dispersed within a polymer gel, e.g., a hydrogel, is also considered matrix-type according to the present invention. It should be understood that a TTS containing an activator-containing matrix layer may also additionally include a skin contact layer.

[0038] A reservoir-type TTS should not be understood as a matrix-type TTS within the scope of the present invention.

[0039] Within the scope of the present invention, the term “activator-containing layer” refers to a layer that contains an activator and provides a release region. The term encompasses activator-containing matrix layers and activator-containing reservoir layers. When the activator-containing layer is an activator-containing matrix layer, the layer is present within a matrix-type TTS. When the polymer is a pressure-sensitive adhesive, the matrix layer may also represent an adhesive layer of the TTS, such that no additional skin contact layer is present. Alternatively, an additional skin contact layer may be present as an adhesive layer, and / or an adhesive overlay is provided. The additional skin contact layer is usually manufactured to be activator-free. However, due to the concentration gradient, the activator migrates from the matrix layer to the additional skin contact layer over time until equilibrium is reached. The additional skin contact layer may be present on the activator-containing matrix layer, or it may be separated from the activator-containing matrix layer by a film, preferably a rate-controlled film. Preferably, the activator-containing matrix layer has sufficient adhesive properties so that no additional skin contact layer is present. If the activator-containing layer is an activator-containing reservoir layer, the layer is located within a reservoir-type TTS, and the layer contains the activator in a liquid reservoir. Furthermore, a skin contact layer may be present to provide adhesive properties. The additional skin contact layer is typically manufactured without the activator. If the skin contact layer is activator-free, the activator migrates from the reservoir layer to the skin contact layer over time due to the concentration gradient until equilibrium is reached. Additionally, an adhesive overlay may be provided.

[0040] As used herein, the activator-containing layer is preferably an activator-containing matrix layer, which is referred to as the final solidified layer. Preferably, the activator-containing matrix layer is obtained after coating with a solvent-containing coating composition as described herein and drying. Alternatively, the activator-containing matrix layer is obtained after melt coating and cooling. The activator-containing matrix layer may also be manufactured by laminating two or more such solidified layers (e.g., dried or cooled layers) of the same composition to provide a desired area weight. Preferably, the matrix layer is a pressure-sensitive adhesive matrix layer. Optionally, an adhesive overlay may be present.

[0041] Within the scope of the present invention, the term “pressure-sensitive adhesive” (also abbreviated as “PSA”) refers to a material that adheres particularly by pressure, is permanently tacky, exhibits strong holding power, and is removable from smooth surfaces without leaving any residue. When in contact with skin, the pressure-sensitive adhesive layer is “self-adhesive,” in other words, it provides adhesion to the skin in such a way that no further assistance is usually required for fixation to the skin. The “self-adhesive” layer structure according to the present invention includes a pressure-sensitive adhesive layer for skin contact, which may be provided in the form of a pressure-sensitive matrix layer or an additional layer, i.e., a pressure-sensitive adhesive skin contact layer. Adhesive overlays may still be employed to improve adhesion. The pressure-sensitive adhesive properties of the pressure-sensitive adhesive depend on the polymer or polymer composition used.

[0042] Within the scope of the present invention, the term “silicone-acrylic hybrid polymer” refers to a polymerization product comprising repeating units of silicone variants and acrylate variants. Thus, a silicone-acrylic hybrid polymer comprises a silicone phase and an acrylic phase. Preferably, a silicone-acrylic hybrid polymer comprises a silicone phase and an acrylate phase, in other words, a silicone variant and an acrylate variant, in a specific weight ratio, e.g., 60:40 to 40:60. The term “silicone-acrylic hybrid” is intended to mean more than a simple blend of silicone-based variants and acrylate-based variants. Instead, the term refers to a polymerization hybrid species comprising a silicone-based variant and an acrylate-based variant polymerized together. In the context of hybrid polymers as used in the present invention, the terms acrylate and acrylic are generally used interchangeably, so a silicone-acrylic hybrid polymer may also be called a “silicone-acrylate hybrid polymer.”

[0043] Within the scope of the present invention, the term “silicone-acrylic hybrid pressure-sensitive adhesive” refers to a silicone-acrylic hybrid polymer in the form of a pressure-sensitive adhesive. Silicone-acrylic hybrid pressure-sensitive adhesives are described, for example, in EP2599847 and WO2016 / 130408. Examples of silicone-acrylic hybrid pressure-sensitive adhesives include the PSA series 7-6100 and 7-6300 (7-610X and 7-630X; X=1 n-heptane-based / X=2 ethyl acetate-based) manufactured and supplied by DuPont® in n-heptane or ethyl acetate. It has been found that the arrangement of the silicone and acrylic phases differs depending on the solvent in which the silicone-acrylic hybrid PSA is supplied, providing a continuous silicone or acrylic outer phase and a corresponding discontinuous internal phase. When the silicone-acrylic hybrid PSA is supplied in n-heptane, the composition contains a continuous silicone outer phase and a discontinuous acrylic internal phase. When the silicone-acrylic hybrid PSA composition is supplied in ethyl acetate, the composition contains a continuous acrylic outer phase and a discontinuous silicone internal phase.

[0044] Within the scope of the present invention, the term “non-hybrid polymer” is used synonymously with a polymer that does not contain hybrid species. Preferably, a non-hybrid polymer is a pressure-sensitive adhesive (e.g., a silicone or acrylate-based pressure-sensitive adhesive). A preferred non-hybrid polymer according to the present invention is a “silicone-based polymer,” which, as used herein, is a polymer obtained by polycondensation of silanol-terminated polydimethylsiloxane with a silicate resin. Another preferred non-hybrid polymer is an acrylate-based polymer, i.e., an acrylic polymer, which, as used herein, is a polymer obtained from one or more monomers selected from acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, butyl methacrylate, t-octylacrylamide, and vinyl acetate.

[0045] As used herein, the activator-containing matrix layer is a layer containing an activator dissolved or dispersed in at least one polymer, or containing an activator dissolved in a solvent to form an activator-solvent mixture dispersed in the form of deposits (particularly droplets) in at least one polymer. Preferably, at least one polymer is a polymer-based pressure-sensitive adhesive (e.g., an acrylic polymer). Within the scope of the present invention, the term “pressure-sensitive adhesive layer” refers to a pressure-sensitive adhesive layer obtained from a solvent-containing adhesive coating composition after coating onto a film and evaporating the solvent.

[0046] Within the scope of the present invention, the term “skin contact layer” refers to a layer included in the activator-containing layer structure that comes into direct contact with the patient’s skin during administration. When the TTS includes a skin contact layer, other layers of the activator-containing layer structure do not come into contact with the skin and do not necessarily possess self-adhesive properties. As outlined above, an additional skin contact layer bound to the activator-containing layer may absorb some of the activator over time. The size of the additional skin contact layer and the activator-containing layer are usually the same and correspond to the release area. However, the area of ​​the skin contact layer may be larger than the area of ​​the activator-containing layer. In such cases, the release area still refers to the area of ​​the activator-containing layer.

[0047] Within the scope of this invention, the term "area weight" means g / m² 2 This refers to the dry weight of a specific layer, such as the matrix layer, provided. Due to manufacturing variations, the area weight value requires a tolerance of ±10%, preferably ±7.5%.

[0048] Unless otherwise indicated, "%" refers to weight percentage (percentage by weight).

[0049] Within the scope of the present invention, the term "polymer" refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, and includes homopolymers consisting of one type of monomer and copolymers consisting of two or more types of monomers. Polymers can have any structure, such as linear polymers, star polymers, comb polymers, brush polymers, etc., and in the case of copolymers, any monomer arrangement, such as alternating, statistical, block copolymers, or graft polymers. The minimum molecular weight varies depending on the type of polymer and is known to those skilled in the art. Polymers can have a molecular weight, for example, greater than 2,000 daltons, preferably greater than 5,000 daltons, and more preferably greater than 10,000 daltons. Correspondingly, compounds having a molecular weight of less than 2,000 daltons, preferably less than 5,000 daltons, or more preferably less than 10,000 daltons are usually referred to as oligomers.

[0050] Within the scope of the present invention, the term "crosslinking agent" refers to a substance that can crosslink functional groups contained within a polymer.

[0051] Within the scope of the present invention, the term “adhesive overlay” refers to a self-adhesive layer structure that does not contain an activator, has a larger surface area than an activator-containing structure, and provides an additional surface area for adhesion to the skin, but does not provide an surface area for activator release. This improves the overall adhesive properties of the TTS. The adhesive overlay comprises a lining layer and an adhesive layer, which may provide closed or open properties. Preferably, the lining layer of the adhesive overlay provides open properties.

[0052] Within the scope of the present invention, the term “backing layer” refers to a layer that supports the activator-containing layer or forms the backing of an adhesive overlay. At least one backing layer in a TTS, and usually the backing layer of the activator-containing layer, is substantially impermeable to the activator contained in the layer during the period of storage and administration, and thus prevents activity loss or cross-contamination in accordance with regulatory requirements. Preferably, the backing layer is also sealed, meaning it is substantially impermeable to water and water vapor. Suitable materials for the backing layer include polyethylene terephthalate (PET), polyethylene (PE), ethylene vinyl acetate copolymer (EVA), polyurethane, and mixtures thereof. Thus, suitable backing layers are, for example, PET laminates, EVA-PET laminates, and PE-PET laminates. Woven or nonwoven backing layers are also suitable.

[0053] The TTS according to the present invention can be characterized by certain parameters measured in an in vitro skin penetration test.

[0054] Generally, in vitro permeability tests are performed in a Franz diffusion cell using a 0.9% sodium chloride solution with 0.1% sodium azide as the antimicrobial agent.

[0055] Furthermore, the in vitro permeability test may be performed in a Franz diffusion cell using human or animal skin, preferably from a Göttinger miniature pig with a skin thickness of about 800 μm and intact epidermis, and using a 0.9% sodium chloride solution (at 32°C with 0.1% azide saline).

[0056] Unless otherwise indicated, in vitro permeability tests are performed using detached Göttinger miniature pig skin approximately 800 μm thick and with intact epidermis, using a 0.9% sodium chloride solution (at 32°C with 0.1% azide saline) as the receptor medium. The amount of active substance permeated into the receptor medium is determined at regular intervals using HPLC with a UV photometric detector by taking sample volumes. The receptor medium is completely or partially replaced with fresh medium when taking sample volumes, and the measured amount of permeated active substance relates to the amount permeated between the last two sample collection points, and not to the total amount permeated up to that point.

[0057] Therefore, within the scope of the present invention, the parameter "transmission amount" is μg / cm³. 2 The amount of active substance that permeated during a sample interval at a specific time interval is provided and relates to the amount of active substance that permeated the receptor medium. For example, in the in vitro permeation test described above, where the amount of active substance that permeated the receptor medium was measured at, for example, 0, 4, 8, 16, 24, 32, 40, 48, 56, 64, 72 and 88 hours, the "permeation amount" of active substance can be given, for example, in the sample interval from 8 hours to 16 hours, corresponding to the measurement result at 16 hours, in which case the receptor medium was completely replaced at 8 hours.

[0058] Furthermore, the amount of permeation can be expressed as a "cumulative permeation amount," which corresponds to the cumulative amount of the active substance that has permeated at a specific point in time. For example, in the in vitro permeation test described above, where the amount of active substance that has permeated the receptor medium is measured at, for example, 0, 4, 8, 16, and 24 hours, the "cumulative permeation amount" of the active substance at 16 hours corresponds to the sum of the permeation amounts from 0 to 4 hours, 4 to 8 hours, and 8 to 16 hours.

[0059] Within the scope of the present invention, the parameter "skin permeability" in a specific sample interval at a specific time interval is defined as μg / (cm³). 2 *h) Provided in the in vitro permeability test as described above, μg / cm³ 2The amount of permeation during the sample interval is calculated by dividing the amount of permeation during the sample interval by the time of the sample interval. For example, in the skin permeation rate in the in vitro permeation test described above, where the amount of active substance that permeated into the receptor medium was measured at, for example, 0, 4, 8, 16, and 24 hours, the "skin permeation rate" at 16 hours is calculated by dividing the amount of permeation during the sample interval from 8 hours to 16 hours by 8 hours.

[0060] "Cumulative skin permeability" can be calculated from each cumulative permeation amount by dividing the cumulative permeation amount by the elapsed time. For example, in the in vitro permeation test described above, where the amount of active substance permeated into the receptor medium is measured at, for example, 0, 4, 8, 16, and 24 hours, the "cumulative skin permeability" at 16 hours is calculated by dividing the cumulative permeation amount at 16 hours (see above) by 16 hours.

[0061] Within the scope of the present invention, the above parameters, "penetration amount" and "skin permeability" (as well as "cumulative penetration amount" and "cumulative skin permeability"), refer to the average values ​​calculated from at least two in vitro permeability test experiments. Unless otherwise indicated, the standard deviation (SD) of these average values ​​is given by the formula:

number

number

number

[0062] The TTS according to the present invention can also be characterized by certain parameters, such as those measured in in vitro clinical studies.

[0063] Within the scope of the present invention, the parameter "average release rate" refers to the average release rate of the activator into the systemic circulation through human skin in μg / h (μg / hour) or mg / day over a period of administration (e.g., 1 to 7 days), based on the AUC obtained over the said administration period during clinical studies.

[0064] Within the scope of the present invention, the term "long period" refers to a period of at least or about 24 hours, at least or about 48 hours, at least or about 84 hours, at least or about 168 hours, at least or about 1 day, at least or about 3.5 days, or at least or about 7 days, or about 24 hours to about 168 hours or 1 to 7 days, or about 24 hours to about 84 hours or 1 to 3.5 days.

[0065] In the case of continuous drug therapy, the frequency of drug administration is preferably kept high enough to maintain therapeutically effective plasma concentrations. In other words, the interval between two dosage forms, also called the dosing interval, needs to be adjusted as appropriate. Within the scope of this invention, the term “doseing interval” refers to the period between two consecutive TTS administrations, i.e., the interval between two consecutive points in time when TTS is applied to the patient’s skin. Once applied, TTS is usually maintained on the patient’s skin throughout the dosing interval and is removed only at the end of the dosing interval, at which point new TTS is applied to the skin. For example, if the dosing interval is 24 hours or 1 day, the TTS is applied to the patient’s skin and maintained for 24 hours or 1 day. After 24 hours or 1 day, the TTS is removed from the skin and new TTS is applied. Thus, a 24-hour or 1-day dosing interval allows for a daily TTS exchange pattern in 24-hour treatment.

[0066] Within the scope of the present invention, the term "room temperature" refers to the unmodified temperature found in the laboratory where the experiment is conducted, which is typically in the range of 15 to 35°C, preferably about 18 to 25°C.

[0067] Within the scope of the present invention, the term "patient" refers to a subject who exhibits clinical signs of one or more specific symptoms that suggest the need for treatment, a subject who is being treated preventively or injunctively for a condition, or a subject who has been diagnosed with a condition that requires treatment.

[0068] Within the scope of the present invention, the term "pharmacokinetic parameters" refers, for example, to plasma curves obtained in clinical studies from single, multiple, or steady-state administration of an activator-containing TTS, e.g., guanfacine-containing TTS, to healthy human subjects, e.g., C max , C t , and AUC t1-t2 This refers to the parameters that describe the pharmacokinetic parameters of individual subjects, such as the arithmetic mean and geometric mean, e.g., mean C. max , average AUC t , and mean AUC INF In addition, additional statistics, such as the respective standard deviation and standard error, minimum value, maximum value, and median value, are used to summarize the list of values ​​if they are ranked. Unless otherwise indicated, in the context of the present invention, pharmacokinetic parameters, for example, C max , C t and AUC t1-t2 This refers to the geometric mean. It cannot be ruled out that the absolute mean obtained for a particular TTS in a clinical study will differ to some extent from study to study. To enable comparison of absolute means between studies, a reference formulation, for example, one of the products based on the present invention in the future, may be used as an internal standard. A correction factor can be obtained by comparing the AUC per release area of ​​each reference product in previous and subsequent studies to take into account the differences between studies.

[0069] The clinical research described herein refers to research conducted in full compliance with the International Conference for Harmonization of Clinical Trials (ICH) and all applicable local Good Clinical Practices (GCP) and regulations.

[0070] Within the scope of the present invention, the term "healthy human subject" refers to a male or female subject having a body weight in the range of 55 kg to 100 kg and a body mass index (BMI) in the range of 18 to 29.4, as well as normal physiological parameters such as blood pressure. Healthy human subjects for the purposes of the present invention are selected according to selection and exclusion criteria based on and in accordance with the recommendations of the ICH.

[0071] Within the scope of the present invention, the term "subject population" refers to at least five, preferably at least ten, individual healthy human subjects.

[0072] Within the scope of this invention, the term "geometric mean" refers to the average of logarithmically transformed data that has been inversely transformed back to its original scale.

[0073] Within the scope of this invention, the term "arithmetic mean" refers to the sum of all observed values ​​divided by the total number of observed values.

[0074] Within the scope of this invention, the parameter "AUC" corresponds to the area under the plasma concentration-time curve. The AUC value is proportional to the total amount of the activator absorbed into the bloodstream and therefore serves as a measure of bioavailability.

[0075] Unless otherwise indicated, "AUC" is used within the meaning of the present invention. t1-t2 The parameter is provided in (ng / ml)h and is calculated using the linear trapezoidal method for the area under the plasma concentration-time curve from t1 to t2. Other calculation methods include, for example, the logarithmic and linear-logarithmic trapezoidal methods.

[0076] Within the meaning of the present invention, "C max The parameter "(ng / ml)" is provided and relates to the observed maximum plasma concentration of the activator.

[0077] Within the meaning of the present invention, "C t The parameter, provided in (ng / ml), relates to the plasma concentration of the activator observed at time t.

[0078] Within the meaning of the present invention, "t max The parameter " is provided in hours, C max Regarding the point in time at which the value is reached. In other words, t max This is the time point at which the maximum plasma concentration was observed.

[0079] Within the scope of the present invention, the term "mean plasma concentration" is provided in (ng / ml) and is the average of the individual plasma concentrations of an activator, e.g., guanfacine, at each time point.

[0080] Within the scope of the present invention, the term "coating composition" refers to a composition containing all the components of a matrix layer in a solvent, which can be coated onto a backing layer or release liner to dry and form a matrix layer.

[0081] Within the scope of the present invention, the term "pressure-sensitive adhesive composition" refers to a pressure-sensitive adhesive mixed with at least a solvent (e.g., n-heptane or ethyl acetate).

[0082] Within the scope of the present invention, the term "dissolve" refers to a process that yields a solution that is transparent to the naked eye and free of any particles.

[0083] Within the scope of the present invention, the term “solvent” preferably refers to any liquid substance that is a volatile organic liquid, such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane, toluene, and mixtures thereof.

[0084] Within the scope of the present invention, the term "monocarboxylic acid" refers to a carboxylic acid containing only one -COOH group.

[0085] Within the scope of the present invention, the term “equomolar” refers to the amount in which two or more components are present. Preferably, “equomolar” means that the components are present in a 1:1 ratio.

[0086] Within the scope of this invention, the term “premixture” refers to a mixture of guanfacine and monocarboxylic acid. The premixture can be obtained by various preparation methods, such as dry grinding or slurry methods. Within the scope of this invention, the premixture obtained by the “slurry method” includes weighing equimolar amounts of guanfacine free base and monocarboxylic acid. A solvent, such as DCM, is added, and the mixture is stirred with a magnetic stirrer at room temperature for at least one day. The white solid is recovered by filtration under vacuum, washed with a solvent, and dried under vacuum at 40°C for 24 hours.

[0087] Within the scope of the present invention, the premixture obtained by the "dry grinding method" refers to guanfacine and monocarboxylic acid obtained by a process that includes milling a mixture of guanfacine base, monocarboxylic acid, and methanol with zirconium oxide milling beads (for example, a Retsch Mixer Mill MM 500 with a bead size of 3 mm) at 35 Hz for about 10 minutes. [Brief explanation of the drawing]

[0088] [Figure 1.1] The cumulative permeation of guanfacine from TTS prepared according to Comparative Examples 1A and 1B is shown. [Figure 1.2] The cumulative permeation amount of guanfacine from TTS prepared according to Comparative Example 1D is shown. [Figure 1.3] The cumulative permeation amount of guanfacine from TTS prepared according to Examples 1A-E and Comparative Example 1C is shown. [Figure 2] The cumulative permeation of guanfacine from TTS prepared according to Examples 2A-C and Comparative Examples 2A and 2B is shown. [Figure 3] The cumulative permeation amount of guanfacine from TTS prepared according to Examples 3A-E and Comparative Example 3 is shown. [Figure 4.1] The cumulative permeation amount of guanfacine from TTS prepared according to Examples 4A-C and Comparative Example 4 is shown. [Figure 4.2]The cumulative permeation of guanfacine in TTS prepared according to Example 4D is shown. [Figure 5.1] The cumulative permeation of guanfacine from TTS prepared according to Examples 5A to 5E is shown. [Figure 5.2] The cumulative permeation amount of guanfacine from TTS prepared according to Example 5F is shown. [Figure 6] The cumulative permeation amount of guanfacine from TTS prepared according to Example 6 and Comparative Example 6 is shown. [Modes for carrying out the invention]

[0089] TTS structure The present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine, comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising a) a backing layer and b) a guanfacine-containing layer comprising guanfacine and monocarboxylic acid. The guanfacine-containing layer structure is preferably a guanfacine-containing self-adhesive layer structure and preferably does not contain an additional skin contact layer. Preferably, the guanfacine-containing layer is a guanfacine-containing matrix layer comprising guanfacine and monocarboxylic acid and at least one polymer. In particular, the at least one polymer present in the transdermal therapeutic system preferably provides adhesive properties. Furthermore, the guanfacine-containing layer structure comprises guanfacine and monocarboxylic acid. Preferably, guanfacine, particularly guanfacine free base and monocarboxylic acid, are pre-mixed before being added to the guanfacine-containing layer.

[0090] The TTS according to the present invention may be a matrix-type TTS or a reservoir-type TTS, and is preferably a matrix-type TTS. In the matrix-type TTS according to the present invention, a premixture of guanfacine and monocarboxylic acid is preferably uniformly dispersed within a polymer carrier (i.e., matrix), and this polymer carrier, together with guanfacine and monocarboxylic acid, and optionally the remaining components, forms a matrix layer. Therefore, in one embodiment of the present invention, the guanfacine-containing layer may be a guanfacine-containing matrix layer in which guanfacine and monocarboxylic acid are uniformly dispersed within the polymer matrix. Preferably, the polymer matrix contains at least one polymer as defined herein. Thus, according to the present invention, it is preferable that the guanfacine-containing matrix layer contains guanfacine, monocarboxylic acid, and at least one polymer present in the TTS. The at least one polymer is selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof. More preferably, according to the present invention, the guanfacine-containing matrix layer comprises guanfacine, a monocarboxylic acid, and at least one polymer, the at least one polymer being selected from a mixture of an acrylic polymer and at least one silicone-based polymer, a mixture of two silicone-acrylic hybrid polymers, a mixture of two silicone-based polymers, an acrylic polymer, and an acrylic polymer containing an OH group. In connection therewith, it is also preferable that the guanfacine-containing matrix layer is self-adhesive so that no additional skin contact layer is present. When the guanfacine-containing matrix layer is prepared by laminating two guanfacine-containing matrix layers of substantially the same composition together, the resulting bilayer is considered to be a single guanfacine-containing matrix layer.

[0091] In a preferred embodiment of the present invention, the guanfacine-containing layer is a guanfacine-containing matrix layer, and this guanfacine-containing matrix layer is i) Guanfacine and monocarboxylic acid, ii) at least one polymer, Includes.

[0092] Therefore, according to one embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, which comprises a guanfacine-containing layer structure, A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Guanfacine and monocarboxylic acid, ii) at least one polymer, Includes.

[0093] The guanfacine-containing layer structure is preferably a guanfacine-containing self-adhesive layer structure. In connection with this, it is also preferable that the guanfacine-containing layer structure does not contain an additional skin contact layer. Instead, it is preferable that the guanfacine-containing layer (preferably the guanfacine-containing matrix layer) is self-adhesive. Therefore, in a preferred embodiment, the guanfacine-containing layer structure is preferably a guanfacine-containing self-adhesive layer structure and does not contain an additional skin contact layer. Alternatively or additionally, it is preferable that the guanfacine-containing layer is directly bonded to the backing layer so that there is no additional layer between the backing layer and the guanfacine-containing layer. As a result, a less complex layer structure is obtained. This is advantageous, for example, in terms of manufacturing costs.

[0094] In particular, the guanfacine-containing layer structure preferably consists of three or fewer layers, more preferably two layers, i.e., preferably only a backing layer and a guanfacine-containing layer. In this case, sufficient adhesion between the guanfacine-containing self-adhesive layer structure during administration and the patient's skin is provided by the guanfacine-containing layer, preferably a guanfacine-containing matrix layer. If an additional skin contact layer is present, for example, as a third layer of the guanfacine-containing layer structure, adhesive properties may be provided by the additional skin contact layer. However, according to the present invention, it is preferable that no additional skin contact layer is present.

[0095] Preferably, the self-adhesive properties of the guanfacine-containing layer structure are provided by at least one polymer present in the TTS, preferably in the guanfacine-containing layer, and more preferably in the guanfacine-containing matrix layer. Therefore, in a preferred embodiment of the present invention, the at least one polymer is a pressure-sensitive adhesive polymer.

[0096] In a preferred embodiment of the present invention, guanfacine and monocarboxylic acid are present in the guanfacine-containing layer in the form of a premixture.

[0097] In a more preferred embodiment of the present invention, guanfacine and monocarboxylic acid in the guanfacine-containing layer exist in the form of a premixture, which can be obtained by dry grinding or slurrying.

[0098] In preferred embodiments of the present invention, at least one polymer is selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof. In more preferred embodiments of the present invention, at least one polymer is selected from a mixture of an acrylic polymer and at least one silicone-based polymer, a mixture of two silicone-acrylic hybrid polymers, a mixture of two silicone-based polymers, an acrylic polymer, and an acrylic polymer containing an -OH group. Further details regarding the at least one polymer according to the present invention are provided below.

[0099] It should be understood that the TTS, preferably a guanfacine-containing layer, more preferably a guanfacine-containing matrix layer, comprises at least two polymers, and these at least two polymers are selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof. Preferably, the TTS, preferably a guanfacine-containing layer, more preferably a guanfacine-containing matrix layer, comprises polymers, and it should be understood that these polymers are selected from a mixture of an acrylic polymer and at least one silicone-based polymer, a mixture of two silicone-acrylic hybrid polymers, or a mixture of two silicone-based polymers. The first polymer may offer advantages, for example, in terms of high flux, while the second polymer may be used, for example, to reduce and / or optimize the flux to obtain a continuous and constant flux. Furthermore, the tackiness of the TTS can be modified by using a combination of at least two polymers. Further details regarding specific polymers and mixtures are provided below.

[0100] It should be understood that the TTS according to the present invention contains at least a therapeutically effective amount of guanfacine. Therefore, in a preferred embodiment of the present invention, the guanfacine-containing layer structure contains a therapeutically effective amount of guanfacine. In the guanfacine-containing layer structure according to the present invention, guanfacine exists together with a monocarboxylic acid, preferably in the form of a co-salt as described in more detail above or below. In a more preferred embodiment of the present invention, guanfacine and the monocarboxylic acid are preferably dispersed in the guanfacine-containing layer. Preferred embodiments relating to guanfacine and monocarboxylic acid in the TTS according to the present invention are further provided below. Furthermore, it should be understood that the presence of guanfacine together with a monocarboxylic acid increases and / or optimizes the flux. In a particularly preferred embodiment of the present invention, guanfacine and sorbic acid are present in the guanfacine-containing layer structure.

[0101] It should be understood that the TTS according to the present invention may contain at least one additive selected from the group consisting of dispersants, permeation enhancers, and / or solubilizers. Additives will be described in more detail below.

[0102] Furthermore, it should be understood that the additives are present within the TTS, preferably within the guanfacine-containing layer structure, more preferably within the guanfacine-containing layer, and especially within the guanfacine-containing matrix layer.

[0103] According to the present invention, the emission area of ​​TTS is 1 to 100 cm². 2 Preferably 2.5 to 50 cm 2 It is preferable that it be within the range of [specify range].

[0104] In preferred embodiments of the present invention, the backing layer is substantially impermeable to a premixture of guanfacine and monocarboxylic acid. In particular, in preferred embodiments of the present invention, the backing layer is substantially impermeable to guanfacine and / or monocarboxylic acid. Furthermore, the backing layer is preferably airtight as outlined above.

[0105] According to certain embodiments of the present invention, the TTS may further include an adhesive overlay. This adhesive overlay is particularly larger in area than the guanfacine-containing layer structure and is bonded to it to improve the adhesive properties of the entire transdermal treatment system. The adhesive overlay includes a backing layer and an adhesive layer. The adhesive overlay provides an additional area for adhesion to the skin, but does not add to the area for guanfacine release. The adhesive overlay includes a self-adhesive polymer or self-adhesive polymer mixture selected from the group consisting of silicone-acrylic hybrid polymers, acrylate polymers, silicone polymers, polyisobutylene, styrene-isoprene-styrene copolymers, and mixtures thereof, which may be identical or different from any polymer or polymer mixture contained in the guanfacine-containing layer structure.

[0106] The guanfacine-containing layer structure according to the present invention, such as a guanfacine-containing self-adhesive layer structure, is typically placed on a removable protective layer (release liner) and removed from this protective layer immediately before application to the patient's skin surface. Thus, the TTS may further include a release liner. The TTS thus protected is typically stored in a blister pack or a seam-sealed pouch. This packaging can be child-safe and / or elderly-friendly.

[0107] Guanfacine-containing layer As outlined in more detail above, the TTS according to the present invention comprises a guanfacine-containing layer structure including a guanfacine-containing layer. Preferably, the guanfacine-containing layer structure is a guanfacine-containing self-adhesive layer structure. Therefore, it is also preferable that the guanfacine-containing layer be a self-adhesive guanfacine-containing layer, and more preferably a self-adhesive guanfacine-containing matrix layer. In a preferred embodiment, the guanfacine-containing layer contains a therapeutically effective amount of guanfacine.

[0108] In one embodiment, the guanfacine-containing layer is a guanfacine-containing matrix layer. In another embodiment, the guanfacine-containing layer is a guanfacine-containing reservoir layer. Preferably, the guanfacine-containing layer is a guanfacine-containing matrix layer.

[0109] In one embodiment, the guanfacine-containing layer is i) Guanfacine and monocarboxylic acid, ii) at least one polymer, It should be understood that at least one polymer contained in the guanfacine-containing layer is at least one polymer contained in the TTS according to the present invention.

[0110] In a preferred embodiment, the guanfacine-containing layer is i) Guanfacine and monocarboxylic acid, ii) at least one polymer, This is a guanfacine-containing matrix layer. It should be understood that at least one polymer contained in the guanfacine-containing layer is at least one polymer contained in the TTS according to the present invention.

[0111] In a preferred embodiment, the guanfacine-containing layer comprises at least one polymer, which is selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof. Preferably, at least one polymer is a pressure-sensitive adhesive. Therefore, the guanfacine-containing layer is preferably a guanfacine-containing matrix layer, and particularly preferably a guanfacine-containing pressure-sensitive adhesive matrix layer.

[0112] In one embodiment of the present invention, the guanfacine-containing layer comprises guanfacine, a monocarboxylic acid, or a salt formed from guanfacine and a monocarboxylic acid. It is preferable that guanfacine and the monocarboxylic acid exist in the form of a co-salt. Furthermore, it should be understood that guanfacine and the monocarboxylic acid are pre-mixed before being added to the guanfacine-containing layer so that a co-salt is formed.

[0113] The premixing of guanfacine and monocarboxylic acid according to the present invention refers to various types of preparation methods for obtaining a premixture of guanfacine and monocarboxylic acid. In one embodiment of the present invention, the premixture of guanfacine and monocarboxylic acid is prepared by a dry milling method, which involves milling a mixture of guanfacine base, monocarboxylic acid, and methanol with zirconium oxide milling beads (e.g., a Retsch Mixer Mill MM 500 with a bead size of 3 mm) at 35 Hz for about 10 minutes. In this regard, it should be understood that the guanfacine base and monocarboxylic acid are present in equimolar amounts, and methanol acts as a catalyst. In another embodiment of the present invention, the guanfacine / monocarboxylic acid premixture is prepared by a slurry method, which involves weighing equimolar amounts of free guanfacine base and monocarboxylic acid. A solvent, e.g., DCM, is added, and the mixture is stirred with a magnetic stirrer at room temperature for at least 1 day. The white solid is collected by filtration under vacuum, washed with a solvent, and dried under vacuum at 40°C for 24 hours.

[0114] Therefore, the guanfacine-containing layer can be obtained by dispersing a guanfacine-monocarboxylic acid premixture, and it is preferable that guanfacine and the monocarboxylic acid exist in the premixture in the form of a co-salt. It should be understood that the guanfacine-monocarboxylic acid premixture is obtained by mixing the free guanfacine base with the monocarboxylic acid as described above. Preferably, the guanfacine in the present invention exists in the form of a "co-salt" (i.e., guanfacine exists in the premixture together with at least one monocarboxylic acid) so that proton transfer is possible, and preferably a guanfacine salt of at least partially monocarboxylic acid is formed. In other words, the activator (preferably guanfacine) may exist in at least partially protonated form. However, it should be understood that the present invention, in relation to the activator (preferably guanfacine) and the monocarboxylic acid, encompasses any form obtained in the guanfacine-containing layer based on a premixture of guanfacine and the monocarboxylic acid, and that this form includes, for example, the option of guanfacine and the monocarboxylic acid coexisting without chemical interaction (i.e., proton transfer), and the option of co-salt formation as described above. Preferably, the free guanfacine base and the monocarboxylic acid may together form a co-salt or any other type of acid addition salt, and as a result, the guanfacine-containing layer preferably contains at least partially a co-salt or any other type of acid addition salt of the free guanfacine base and the monocarboxylic acid. In other words, the guanfacine-containing layer preferably contains guanfacine in at least a partially protonated form and a monocarboxylic acid in at least a partially deprotonated form.

[0115] Therefore, in one embodiment, the guanfacine-containing layer comprises guanfacine, a monocarboxylic acid, or a salt formed from guanfacine and a monocarboxylic acid. In a more preferred embodiment of the present invention, the monocarboxylic acid is sorbic acid. Therefore, in a preferred embodiment of the present invention, the guanfacine-containing layer comprises guanfacine, sorbic acid, or a salt formed from guanfacine and sorbic acid. In relation to the above embodiments, it is surprising that the combination of guanfacine and a monocarboxylic acid, particularly the monocarboxylic acid sorbic acid, enhances the flux and permeation of transdermal treatment systems. In particular, surprisingly, the inventors of the present invention have found that a TTS containing a combination of guanfacine base and sorbic acid in the guanfacine-containing layer exhibits improved cumulative permeation over 88 hours compared to a TTS containing only guanfacine in the form of a free base in the guanfacine-containing layer.

[0116] In one embodiment of the present invention, the guanfacine-containing layer structure of the transdermal treatment system according to the present invention, preferably the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer, contains guanfacine in an amount of 1 to 100 mg / TTS, preferably 3 to 72 mg / TTS. In a preferred embodiment, the guanfacine-containing layer structure, preferably the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer, contains guanfacine in an amount of 3 to 50 mg / TTS. In another preferred embodiment, the guanfacine-containing layer structure, preferably the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer, contains guanfacine in an amount of 3 to 30 mg / TTS. In other words, the total amount of guanfacine in the guanfacine-containing layer structure is in the range of 1 to 100 mg / TTS, preferably 3 to 72 mg / TTS, more preferably 3 to 50 mg / TTS, and even more preferably 3 to 30 mg / TTS. In this regard, it should be understood that this refers to the amount of guanfacine in TTS, and not the amount of the premixture of guanfacine and monocarboxylic acid.

[0117] In another embodiment, the amount of guanfacine loaded in the guanfacine-containing layer structure is 0.4 to 2 mg / cm³. 2 In another embodiment, the amount of guanfacine loaded in the guanfacine-containing layer structure is 0.4 to 0.85 mg / cm³. 2 This is within the range. Furthermore, the TTS emission area is 1 to 100 cm². 2 Preferably 2.5 to 50 cm 2 It is preferable that the range be within this range. It should be understood that this refers to the loading amount of guanfacine, and not the loading amount of the guanfacine-monocarboxylic acid premixture.

[0118] In one embodiment of the present invention, the guanfacine-containing layer contains guanfacine in an amount of 1 to 20% by weight, preferably 2 to 16% by weight, more preferably 4 to 14% by weight, and most preferably 5 to 13% by weight, based on the total weight of the guanfacine-containing layer. Particularly preferably, the guanfacine-containing layer contains guanfacine in an amount of 4 to 8% by weight, preferably 5 to 7% by weight, or 10 to 14% by weight, preferably 11 to 13% by weight, based on the total weight of the guanfacine-containing layer, depending on the desired TTS administration strength.

[0119] In one embodiment of the present invention, the guanfacine-containing layer contains a monocarboxylic acid in an amount of 1 to 20% by weight, more preferably 2 to 16% by weight, based on the total weight of the guanfacine-containing layer. A particularly preferred monocarboxylic acid to be included together with guanfacine in the guanfacine-containing layer is sorbic acid.

[0120] The guanfacine-containing layer structure, preferably the guanfacine-containing layer, comprises at least one polymer. As described above, the at least one polymer is selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof. Preferably, the TTS, preferably the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer, comprises a polymer, and it should be understood that this polymer is selected from a mixture of an acrylic polymer and at least one silicone-based polymer, a mixture of two silicone-acrylic hybrid polymers, two silicone-based polymers, an acrylic polymer, and a mixture of acrylic polymers containing -OH groups.

[0121] In one embodiment of the present invention, the guanfacine-containing layer contains at least one polymer in an amount of 20 to 99% by weight, preferably 30 to 97% by weight, and most preferably 35 to 94% by weight, based on the total weight of the guanfacine-containing layer. It should be understood that the amount of at least one polymer shown above may refer to only one polymer, but may also refer to a combination of polymers as defined herein.

[0122] In a preferred embodiment of the present invention, the guanfacine-containing layer comprises a mixture of an acrylic polymer and at least one silicone-based polymer, wherein the acrylic polymer is present in an amount of 20-55% and the at least one silicone-based polymer is present in an amount of 20-55% by weight, based on the total weight of the activator-containing layer. It should be understood that if more than one silicone-based polymer is present, for example two, the amount of at least one silicone-based polymer refers to the amount of only one silicone-based polymer or the total amount of silicone-based polymers present. Further details regarding the acrylic polymer and silicone-based polymer are provided below.

[0123] In another preferred embodiment of the present invention, the guanfacine-containing layer comprises a mixture of two silicone-acrylic hybrid polymers, in each case, based on the total weight of the guanfacine-containing layer, the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight, preferably the first silicone-acrylic hybrid polymer and the second silicone-acrylic hybrid polymer each contain a silicone phase and an acrylate phase in a weight ratio of 60:40-40:60.

[0124] The silicone-acrylic hybrid polymer defined above comprises a silicone phase and an acrylate phase, preferably in a weight ratio of 60:40 to 40:60, most preferably 50:50. The silicone-acrylic hybrid polymer typically comprises a reaction product of (a) a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, (b) an ethylenically unsaturated monomer, and (c) an initiator. Further details regarding components (a), (b), and (c) are provided below. It should be understood that component (a) mainly forms the silicone phase, and component (b) mainly forms the acrylate phase of the silicone-acrylic hybrid polymer. The acrylate phase affects the tackiness and viscosity of the silicone-acrylic hybrid polymer. Therefore, the ethylenically unsaturated monomer forming the acrylate phase is preferably a combination of 2-ethylhexyl acrylate and methyl acrylate, preferably in a ratio of 40:60 to 70:30. A ratio of 60:40 is preferred in terms of high tackiness, but the viscosity in that case will be lower. From the viewpoint of higher viscosity, a 50:50 ratio is preferred, but in that case, the tackiness decreases. The silicone-acrylic hybrid polymer in the guanfacine-containing layer preferably comprises a continuous acrylic outer phase and a discontinuous silicone inner phase.

[0125] In one embodiment of the present invention, the guanfacine-containing layer contains at least one silicone acrylic hybrid polymer in an amount of 20 to 99% by weight, preferably 30 to 97% by weight, and most preferably 35 to 94% by weight, based on the total weight of the guanfacine-containing layer. In a preferred embodiment, the guanfacine-containing layer contains at least one silicone acrylic hybrid polymer in an amount of 74 to 94% by weight, preferably 74 to 89% by weight, based on the total weight of the guanfacine-containing layer. It should be understood that the amount of at least one silicone acrylic hybrid polymer shown above may refer to a single silicone acrylic hybrid polymer, but may also refer to a combination of silicone acrylic hybrid polymers. Therefore, the given amount refers to the total amount of silicone acrylic hybrid polymer.

[0126] In a preferred embodiment of the present invention, the guanfacine-containing layer contains only one silicone acrylic hybrid polymer in an amount of 60 to 97% by weight, preferably 70 to 94% by weight, based on the total weight of the guanfacine-containing layer.

[0127] In another preferred embodiment of the present invention, the guanfacine-containing layer comprises a first silicone acrylic hybrid polymer and a second silicone acrylic hybrid polymer, wherein the total amount of at least two silicone acrylic hybrid polymers is 35 to 94% by weight, preferably 74 to 94% by weight, based on the total weight of the guanfacine-containing layer. Preferably, the guanfacine-containing layer comprises 60 to 90% by weight of the first silicone acrylic hybrid polymer and 1 to 20% by weight of the second silicone acrylic hybrid polymer, based on the total weight of the guanfacine-containing layer. In a particularly preferred embodiment, the guanfacine-containing layer comprises 70 to 85% by weight, preferably 70 to 78% by weight, of the first silicone acrylic hybrid polymer and 1 to 8% by weight, preferably 3 to 5% by weight, of the second silicone acrylic hybrid polymer, based on the total weight of the guanfacine-containing layer.

[0128] It should be understood that the above-mentioned selections regarding silicone-acrylic hybrid polymers, particularly regarding the weight ratio of acrylate to the silicone phase, the components that form the silicone-acrylic hybrid polymer, the ethylenically unsaturated monomers that form the silicone-acrylic hybrid polymer, and the acrylic outer phase and silicone inner phase, apply to both the first and second silicone-acrylic hybrid polymers. In particular, it is preferable that the weight ratio of the silicone phase to the acrylate phase in the first silicone-acrylic hybrid polymer is 55:45 to 45:55, and that the ethylenically unsaturated monomers forming the acrylate include 2-ethylhexyl acrylate and methyl acrylate in a ratio of 55:45 to 45:55. It is more preferable that the weight ratio of the silicone phase to the acrylate phase in the first silicone-acrylic hybrid polymer is 50:50, and that the ethylenically unsaturated monomers forming the acrylate include 2-ethylhexyl acrylate and methyl acrylate in a ratio of 50:50. On the other hand, it is preferable that the weight ratio of the silicone phase to the acrylate phase in the second silicone-acrylic hybrid polymer is 55:45 to 45:55, and that the ethylenically unsaturated monomers forming the acrylate consist of 2-ethylhexyl acrylate and methyl acrylate in a ratio of 65:35 to 55:45. It is more preferable that the weight ratio of the silicone phase to the acrylate phase in the second silicone-acrylic hybrid polymer is 50:50, and that the ethylenically unsaturated monomers forming the acrylate consist of 2-ethylhexyl acrylate and methyl acrylate in a ratio of 60:40. Furthermore, for both silicone-acrylic hybrid polymers, it is preferable that the silicone phase is the internal phase and the acrylate phase is the external phase.

[0129] In another preferred embodiment of the present invention, the guanfacine-containing layer comprises a mixture of two silicone-based polymers, wherein, based on the total weight of the guanfacine-containing layer, the first silicone-based polymer is present in an amount of 20-55% by weight and the second silicone-based polymer is present in an amount of 20-55% by weight. Further details regarding the silicone-based polymers are provided below.

[0130] In one embodiment of the present invention, the TTS according to the present invention, in particular the guanfacine-containing layer, comprises at least one additive. Suitable additives are described in more detail below, but preferably each is present in an amount of 0.5 to 10% by weight based on the total weight of the guanfacine-containing layer.

[0131] In a preferred embodiment, the guanfacine-containing layer includes at least one additive selected from the group consisting of dispersants, permeation accelerators, and solubilizers. In one preferred embodiment, at least one additive is a dispersant. In another preferred embodiment, at least one additive is a permeation accelerator. In yet another preferred embodiment, at least one additive is a solubilizer. In a particular preferred embodiment, a combination of the aforementioned additives is also preferred. The aforementioned additives are particularly advantageous for providing guanfacine in a uniformly dispersed and releaseable form. It should be understood that dispersants can also act as permeation accelerators, and vice versa. Similarly, solubilizers can also additionally act as dispersants or permeation accelerators. Furthermore, solubilizers may stabilize the guanfacine dispersion in the TTS to avoid crystallization. Moreover, solubilizers may help optimize the cohesiveness of the TTS. In a particular preferred embodiment, the guanfacine-containing layer also includes at least one dispersant and at least one permeation accelerator, and optionally at least one solubilizer.

[0132] In a preferred embodiment, at least one additive is a dispersant and is present in an amount of 1 to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the dispersant is present in an amount of 2 to 6% by weight, more preferably 3 to 5% by weight, based on the total weight of the guanfacine-containing layer.

[0133] In another preferred embodiment, at least one additive is a permeation enhancer, present in an amount of 1 to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the permeation enhancer is present in an amount of 2 to 9% by weight, more preferably 2 to 6% by weight, and even more preferably 3 to 5% by weight, based on the total weight of the guanfacine-containing layer.

[0134] In another embodiment, at least one additive is a solubilizer, present in an amount of 0.5 to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the solubilizer is present in an amount of 0.5 to 5% by weight based on the total weight of the guanfacine-containing layer.

[0135] In one embodiment, the TTS according to the present invention, particularly the guanfacine-containing layer, and more specifically the guanfacine-containing matrix layer, comprises at least two additives selected from the group consisting of dispersants, permeation enhancers, and solubilizers.

[0136] In a preferred embodiment, the transdermal treatment system, particularly the guanfacine-containing layer, more specifically the guanfacine-containing matrix layer, comprises at least two additives, the first of which is a dispersant present in an amount of 1 to 10% by weight based on the total weight of the guanfacine-containing layer, and the second of which is a permeation enhancer present in an amount of 1 to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the dispersant is present in an amount of 1 to 6% by weight and the permeation enhancer is present in an amount of 2 to 9% by weight. More preferably, the dispersant is present in an amount of 2 to 6% by weight and the permeation enhancer is present in an amount of 2 to 6% by weight. Even more preferably, the dispersant is present in an amount of 3 to 5% by weight and the permeation enhancer is present in an amount of 3 to 5% by weight based on the total weight of the guanfacine-containing layer.

[0137] In another preferred embodiment, the transdermal treatment system, particularly the guanfacine-containing layer, more specifically the guanfacine-containing matrix layer, comprises at least two additives, the first of which is a dispersant present in an amount of 1 to 10% by weight based on the total weight of the guanfacine-containing layer, and the second of which is a solubilizer present in an amount of 0.5 to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the dispersant is present in an amount of 1 to 6% by weight and the solubilizer in an amount of 0.5 to 5% by weight. More preferably, the dispersant is present in an amount of 2 to 6% by weight and the solubilizer in an amount of 0.5 to 5% by weight. Even more preferably, the dispersant is present in an amount of 3 to 5% by weight and the solubilizer in an amount of 0.5 to 5% by weight.

[0138] In another preferred embodiment, the transdermal treatment system, particularly the guanfacine-containing layer, more specifically the guanfacine-containing matrix layer, comprises at least two additives, the first of which is a permeation enhancer present in an amount of 1 to 10% by weight based on the total weight of the guanfacine-containing layer, and the second of which is a solubilizer present in an amount of 0.5 to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the permeation enhancer is present in an amount of 2 to 9% by weight and the solubilizer is present in an amount of 0.5 to 5% by weight. Preferably, the permeation enhancer is present in an amount of 2 to 6% by weight and the solubilizer is present in an amount of 0.5 to 5% by weight. More preferably, the permeation enhancer is present in an amount of 3 to 5% by weight and the solubilizer is present in an amount of 0.5 to 5% by weight.

[0139] In a particularly preferred embodiment of the present invention, the TTS according to the present invention, in particular the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer, comprises two additives selected from a dispersant and a permeation enhancer.

[0140] Therefore, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, contains a dispersant present in an amount of 1 to 10% by weight based on the total weight of the guanfacine-containing layer, and a permeation enhancer present in an amount of 1 to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the dispersant is present in an amount of 1 to 6% by weight, and the permeation enhancer is present in an amount of 2 to 9% by weight. More preferably, the dispersant is present in an amount of 2 to 6% by weight, and the permeation enhancer is present in an amount of 2 to 6% by weight. Even more preferably, the dispersant is present in an amount of 3 to 5% by weight, and the permeation enhancer is present in an amount of 3 to 5% by weight based on the total weight of the guanfacine-containing layer.

[0141] In relation to the above embodiments relating to the TTS according to the present invention, particularly the guanfacine-containing layer, and more specifically the number and amount of additives in the guanfacine-containing matrix layer, the following specific additives are preferred.

[0142] In preferred embodiments, the dispersant is selected from the group consisting of esters of fatty acids and polyols, aliphatic alcohols, polyethylene glycol having a number average molecular weight of 300-400, and polyethylene glycol alkyl ethers, and the dispersant is preferably polyethylene glycol C8-C having 2-10 EO units, preferably 2-6 EO units. 20 -Alkyl ethers. Particularly preferred dispersants are polyoxyethylene (4) lauryl ether (C 12 H 25 This is (OCH2CH2)4OH). This dispersant is available from Merck, for example, under the trade name Brij L4(registered trademark).

[0143] In preferred embodiments, the permeation enhancer is selected from the group consisting of diethylene glycol monoethyl ether (Transktol), oleic acid, levulinic acid, caprylic / capric triglyceride, diisopropyl adipate, isopropyl myristart, isopropyl palmitate, lauryl lactate, triacetin, dimethylpropylene urea, oleyl alcohol, oleoyl macrogol-6 glyceride (labrafil MS 1944), and lauroglycol, and is preferably oleyl alcohol, lauroglycol, or oleoyl macrogol-6 glyceride (labrafil MS 1944). Oleyl alcohol is available from BASF, for example, under the trade name Kolliream® OA.

[0144] In preferred embodiments, the solubilizer is selected from the group consisting of copolymers derived from esters of acrylic acid and methacrylic acid, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, preferably polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. A particularly preferred solubilizer is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. A suitable polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is available from BASF, for example, under the trade name Soluplus®, and preferably has the following structural formula, where l, m, and n are selected such that the average molecular weight determined by gel permeation chromatography is in the range of 90,000 to 140,000 g / mol. [ka]

[0145] In certain preferred embodiments, the guanfacine-containing layer comprises, in any case, at least one dispersant in an amount of 2 to 6% by weight, at least one permeation accelerator in an amount of 2 to 9% by weight, and optionally at least one solubilizer in an amount of 0.5 to 5% by weight, based on the total weight of the guanfacine-containing layer. Preferably, the guanfacine-containing layer comprises, in any case, at least one dispersant in an amount of 2 to 6% by weight, at least one permeation accelerator in an amount of 2 to 6% by weight, and optionally at least one solubilizer in an amount of 0.5 to 5% by weight, based on the total weight of the guanfacine-containing layer. More preferably, the guanfacine-containing layer comprises, in any case, at least one dispersant in an amount of 3 to 5% by weight, at least one permeation accelerator in an amount of 3 to 5% by weight, and optionally at least one solubilizer in an amount of 0.5 to 5% by weight, based on the total weight of the guanfacine-containing layer. In relation to the preferred weight percentages above, the preferred dispersants, permeation accelerators and solubilizers are preferred.

[0146] Therefore, in a particularly preferred embodiment, the guanfacine-containing layer is, in any case, based on the total weight of the guanfacine-containing layer, polyethylene glycol C8-C having 2-10 EO units. 20 -Alkyl ether, preferably 2-6% by weight of polyoxyethylene(4) lauryl ether, 2-9% by weight of oleyl alcohol, and optionally, preferably 0.5-5% by weight of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specifically described above. In a more particularly preferred embodiment, the guanfacine-containing layer is, in any case, based on the total weight of the guanfacine-containing layer, polyethylene glycol C8-C having 2-10 EO units. 20-Alkyl ether, preferably 2-6% by weight of polyoxyethylene(4) lauryl ether, 2-6% by weight of oleyl alcohol, and optionally, preferably 0.5-5% by weight of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specifically described above. Most preferably, the guanfacine-containing layer comprises polyethylene glycol C8-C8 having 2-10 EO units, based on the total weight of the guanfacine-containing layer in any case. 20 - It comprises an alkyl ether, preferably 3 to 5% by weight of polyoxyethylene(4) lauryl ether, 3 to 5% by weight of oleyl alcohol, and optionally, preferably 0.5 to 5% by weight of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specifically described above.

[0147] Therefore, in another particularly preferred embodiment, the guanfacine-containing layer is polyethylene glycol C8-C8 having 2-10 EO units, based on the total weight of the guanfacine-containing layer in any case. 20 -Alkyl ether, preferably 2-6% by weight of polyoxyethylene(4) lauryl ether, 2-9% by weight of laurogeniclyl, and optionally, preferably 0.5-5% by weight of polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer as specifically described above. In another, more particularly preferred embodiment, the guanfacine-containing layer comprises polyethylene glycol C8-C8 having 2-10 EO units, based on the total weight of the guanfacine-containing layer in any case. 20-Alkyl ether, preferably 2-6% by weight of polyoxyethylene(4) lauryl ether, 2-6% by weight of laurogenicly soluble, and optionally, preferably 0.5-5% by weight of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specifically described above. Most preferably, the guanfacine-containing layer comprises polyethylene glycol C8-C8 having 2-10 EO units, based on the total weight of the guanfacine-containing layer in any case. 20 - It comprises an alkyl ether, preferably 3 to 5% by weight of polyoxyethylene(4) lauryl ether, 3 to 5% by weight of laurogenicly loic acid, and optionally, preferably 0.5 to 5% by weight of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specifically described above.

[0148] Therefore, in another particularly preferred embodiment, the guanfacine-containing layer is polyethylene glycol C8-C8 having 2-10 EO units, based on the total weight of the guanfacine-containing layer in any case. 20 -Alkyl ether, preferably 2-6% by weight of polyoxyethylene(4) lauryl ether, 2-9% by weight of oleoyl macrogol-6 glyceride (labrafil MS 1944), and optionally, preferably 0.5-5% by weight of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specifically described above. In another, more particularly preferred embodiment, the guanfacine-containing layer comprises polyethylene glycol C8-C8 having 2-10 EO units, based on the total weight of the guanfacine-containing layer in any case. 20-Alkyl ether, preferably 2-6% by weight of polyoxyethylene(4) lauryl ether, 2-6% by weight of oleoyl macrogol-6 glyceride (labrafil MS 1944), and optionally, preferably 0.5-5% by weight of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specifically described above. Most preferably, the guanfacine-containing layer comprises polyethylene glycol C8-C8 having 2-10 EO units, based on the total weight of the guanfacine-containing layer in any case. 20 - comprises an alkyl ether, preferably 3 to 5% by weight of polyoxyethylene (4) lauryl ether, 3 to 5% by weight of oleoyl macrogol-6 glyceride (labrafil MS 1944), and optionally, preferably 0.5 to 5% by weight of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specifically described above.

[0149] In one embodiment of the present invention, the area weight of the guanfacine-containing layer is 40 to 250 g / m². 2 Preferably 50-180 g / m² 2 More preferably 70-180 g / m² 2 For example, 75-150 g / m 2 Or 100-150g / m 2 This range is as follows: In certain preferred embodiments, the area weight is 80-120 g / m². 2 Preferably 90-100 g / m² 2 It is within the range of [the specified range].

[0150] In consideration of the above, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine, wherein the guanfacine-containing layer structure comprises, A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) A mixture of an acrylic polymer and at least one silicone-based polymer, wherein, based on the total weight of the guanfacine-containing layer, the acrylic polymer is present in an amount of 20-55% by weight and the at least one silicone-based polymer is present in an amount of 20-55% by weight, iii) Based on the total weight of the guanfacine-containing layer, at least one dispersant in an amount of 2 to 6% by weight, iv) Based on the total weight of the guanfacine-containing layer, at least one permeation enhancer in an amount of 2 to 6% by weight, This includes. In relation to this embodiment, it is even more preferable that the guanfacine-containing layer structure does not include an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents a skin contact layer and has pressure-sensitive adhesive properties due to at least one polymer which is a mixture of an acrylic polymer and at least one silicone-based polymer. In a preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6-9% by weight of guanfacine and sorbic acid, ii) A mixture of an acrylic polymer and at least one silicone-based polymer, wherein, based on the total weight of the guanfacine-containing layer, the acrylic polymer is present in an amount of 20-55% by weight and the at least one silicone-based polymer is present in an amount of 20-55% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene(4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, 2-6% by weight of oleoyl macrogol-6 glyceride, This includes. In relation to this embodiment, it is even more preferable that the guanfacine-containing layer structure does not include an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents a skin contact layer and has pressure-sensitive adhesive properties due to at least one polymer which is a mixture of an acrylic polymer and at least one silicone-based polymer.

[0151] In a preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of the two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight. iii) Based on the total weight of the guanfacine-containing layer, at least one dispersant in an amount of 2 to 6% by weight, iv) Based on the total weight of the guanfacine-containing layer, at least one permeation enhancer in an amount of 2 to 6% by weight, This includes. In relation to this embodiment, it is even more preferable that the guanfacine-containing layer structure does not include an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents a skin contact layer and has pressure-sensitive adhesive properties due to at least one polymer which is a mixture of two silicone-acrylic hybrid polymers.

[0152] In a preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) A mixture of two silicone-based polymers, in which the first silicone-based polymer is present in an amount of 20-55% by weight and the second silicone-based polymer is present in an amount of 20-55% by weight, based on the total weight of the guanfacine-containing layer, iii) Based on the total weight of the guanfacine-containing layer, at least one dispersant in an amount of 2 to 6% by weight, iv) Based on the total weight of the guanfacine-containing layer, at least one permeation enhancer in an amount of 2 to 6% by weight, This includes. In relation to this embodiment, it is even more preferable that the guanfacine-containing layer structure does not include an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents a skin contact layer and has pressure-sensitive adhesive properties due to at least one polymer which is a mixture of two silicone-based polymers.

[0153] In a preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) Based on the total weight of the guanfacine-containing layer, an acrylic polymer in an amount of 65 to 95% by weight, and iii) Based on the total weight of the guanfacine-containing layer, at least one dispersant in an amount of 2 to 6% by weight, and iv) Based on the total weight of the guanfacine-containing layer, at least one permeation enhancer in an amount of 2 to 6% by weight, and It contains. In connection with this embodiment, it is further preferred that the guanfacine-containing layer structure does not include an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents the skin contact layer and has pressure-sensitive adhesive properties by at least one polymer that is an acrylic polymer.

[0154] In a preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine, which in one embodiment includes a guanfacine-containing layer structure, and the guanfacine-containing layer structure is A) A backing layer, and <> B) A guanfacine-containing layer, preferably a guanfacine-containing matrix layer, and It contains, and the layers are i) Based on the total weight of the guanfacine-containing layer, guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight, and ii) Based on the total weight of the guanfacine-containing layer, an acrylic polymer containing -OH groups in an amount of 65 to 95% by weight, and iii) Based on the total weight of the guanfacine-containing layer, at least one dispersant in an amount of 2 to 6% by weight, and iv) Based on the total weight of the guanfacine-containing layer, at least one permeation enhancer in an amount of 2 to 6% by weight, and It contains. In connection with this embodiment, it is further preferred that the guanfacine-containing layer structure does not include an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents the skin contact layer and has pressure-sensitive adhesive properties by at least one polymer that is an acrylic polymer containing -OH groups.

[0155] In a more preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) A mixture of an acrylic polymer and at least one silicone-based polymer, wherein, based on the total weight of the guanfacine-containing layer, the acrylic polymer is present in an amount of 20-55% by weight and the at least one silicone-based polymer is present in an amount of 20-55% by weight, iii) Polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer. 20 -alkyl ether and, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of oleyl alcohol, This includes. In relation to this embodiment, it is even more preferable that the guanfacine-containing layer structure does not include an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents a skin contact layer and has pressure-sensitive adhesive properties due to at least one polymer which is a mixture of an acrylic polymer and at least one silicone-based polymer.

[0156] In another, more preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of the two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight. iii) Polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer. 20 -alkyl ether and, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of oleyl alcohol, This includes. In relation to this embodiment, it is even more preferable that the guanfacine-containing layer structure does not include an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents a skin contact layer and has pressure-sensitive adhesive properties due to at least one polymer which is a mixture of two silicone-acrylic hybrid polymers.

[0157] In another, more preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) A mixture of two silicone-based polymers, in which the first silicone-based polymer is present in an amount of 20-55% by weight and the second silicone-based polymer is present in an amount of 20-55% by weight, based on the total weight of the guanfacine-containing layer, iii) Polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer. 20 -alkyl ether and, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of oleyl alcohol, This includes. In relation to this embodiment, it is even more preferable that the guanfacine-containing layer structure does not include an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents a skin contact layer and has pressure-sensitive adhesive properties due to at least one polymer which is a mixture of two silicone-based polymers. In a more preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6-9% by weight of guanfacine and sorbic acid, ii) A mixture of two silicone-based polymers, in which the first silicone-based polymer is present in an amount of 20-55% by weight and the second silicone-based polymer is present in an amount of 20-55% by weight, based on the total weight of the guanfacine-containing layer, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene(4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of oleyl alcohol, This includes. In relation to this embodiment, it is even more preferable that the guanfacine-containing layer structure does not include an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents a skin contact layer and has pressure-sensitive adhesive properties due to at least one polymer which is a mixture of two silicone-based polymers.

[0158] In another more preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine, which in one embodiment comprises a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure comprises A) a backing layer, and B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer, and comprising, wherein the layer i) based on the total weight of the guanfacine-containing layer, guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight, and ii) based on the total weight of the guanfacine-containing layer, an acrylic polymer in an amount of 65 to 95% by weight, and iii) based on the total weight of the guanfacine-containing layer, polyethylene glycol C8-C 20 -alkyl ether having from 2 to 10 EO units in an amount of 2 to ⑥% by weight, and iv) based on the total weight of the guanfacine-containing layer, oleyl alcohol in an amount of 2 to 6% by weight, and comprising. In connection with this embodiment, it is further preferred that the guanfacine-containing layer structure does not include an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents the skin contact layer and has pressure-sensitive adhesive properties by at least one polymer that is an acrylic polymer. In an even more preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine, which in one embodiment comprises a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure comprises A) a backing layer, and B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer, and comprising, wherein the layer i) based on the total weight of the guanfacine-containing layer, a total amount of guanfacine and sorbic acid of 6 to 9% by weight, and ii) based on the total weight of the guanfacine-containing layer, an acrylic polymer in an amount of 65 to 95% by weight, and iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene(4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of oleyl alcohol, This includes. In relation to this embodiment, it is even more preferable that the guanfacine-containing layer structure does not include an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents a skin contact layer and has pressure-sensitive adhesive properties due to at least one polymer, which is an acrylic polymer.

[0159] In another, more preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) Based on the weight of the guanfacine-containing layer, an acrylic polymer containing 65-95% by weight of -OH groups, iii) Polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer. 20 -alkyl ether and, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of oleyl alcohol, This includes. In relation to this embodiment, it is even more preferable that the guanfacine-containing layer structure does not include an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents a skin contact layer and has pressure-sensitive adhesive properties due to at least one polymer, which is an acrylic polymer containing an -OH group. In a more preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6-9% by weight of guanfacine and sorbic acid, ii) Based on the total weight of the guanfacine-containing layer, an acrylic polymer containing 65-95% by weight of -OH groups, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene(4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of oleyl alcohol, This includes. In relation to this embodiment, it is even more preferable that the guanfacine-containing layer structure does not include an additional skin contact layer. Therefore, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents a skin contact layer and has pressure-sensitive adhesive properties due to at least one polymer, which is an acrylic polymer containing an -OH group.

[0160] In a particularly preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Guanfacine and sorbic acid, ii) A mixture of two silicone-acrylic hybrid polymers, iii) Polyoxyethylene (4) lauryl ether and iv) A permeation enhancer selected from oleyl alcohol, lauroglycol, and oleoyl macrogol-6 glyceride, Includes.

[0161] In a particularly preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Guanfacine and sorbic acid, ii) A mixture of two silicone-acrylic hybrid polymers, iii) Polyoxyethylene (4) lauryl ether and iv) Oleyl alcohol and, Includes.

[0162] In another particularly preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Guanfacine and sorbic acid, ii) A mixture of two silicone-acrylic hybrid polymers, iii) Polyoxyethylene (4) lauryl ether and iv) Lauroglycol and, Includes.

[0163] In another particularly preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Guanfacine and sorbic acid, ii) A mixture of two silicone-acrylic hybrid polymers, iii) Polyoxyethylene (4) lauryl ether and iv) Oleoyl macrogol-6 glyceride, Includes.

[0164] In a more particularly preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of the two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight. iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene(4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, a permeation enhancer selected from oleyl alcohol, lauroglycol, and oleoyl macrogol-6 glyceride in an amount of 2 to 6% by weight, Includes.

[0165] In another, more particularly preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6-9% by weight of guanfacine and sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of the two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight. iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene(4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, a permeation enhancer selected from oleyl alcohol, lauroglycol, and oleoyl macrogol-6 glyceride in an amount of 2 to 6% by weight, Includes.

[0166] In a more particularly preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of the two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight. iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene(4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of oleyl alcohol, Includes.

[0167] In another, more particularly preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6-9% by weight of guanfacine and sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of the two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight. iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene(4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of oleyl alcohol, Includes.

[0168] In another, more particularly preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of the two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight. iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene(4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of laurglycol, Includes.

[0169] In another, more particularly preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6-9% by weight of guanfacine and sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of the two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight. iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene(4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, add 2-6% by weight of laurglycol, Includes.

[0170] In another, more particularly preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of the two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight. iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene(4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, 2-6% by weight of oleoyl macrogol-6 glyceride, Includes.

[0171] In another, more particularly preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6-9% by weight of guanfacine and sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of the two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight. iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene(4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, 2-6% by weight of oleoyl macrogol-6 glyceride, Includes.

[0172] In the above preferred and more preferred embodiments, the area weight of the guanfacine-containing layer is 50 to 180 g / m². 2 Preferably 75-150 g / m² 2 More preferably 80-120 g / m² 2 It is even more preferable that it be within the range of [a certain range].

[0173] Guanfaxin The TTS according to the present invention comprises a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising A) a backing layer and B) a guanfacine-containing layer containing guanfacine and a monocarboxylic acid. The guanfacine-containing layer is preferably a guanfacine-containing matrix layer, which is described in detail above.

[0174] In one embodiment of the present invention, the guanfacine in the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, is present in a premixture with a monocarboxylic acid. In one embodiment of the present invention, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, contains guanfacine and a monocarboxylic acid, or a salt formed from guanfacine and a monocarboxylic acid. It is preferable that guanfacine and the monocarboxylic acid exist in the form of a co-salt. Furthermore, it should be understood that guanfacine and the monocarboxylic acid are pre-mixed before being added to the guanfacine-containing layer so that a co-salt is formed.

[0175] Preferably, the guanfacine in the present invention exists in the form of a "co-salt" (i.e., guanfacine exists in the premixture together with at least one monocarboxylic acid) so that proton transfer is possible, and preferably a guanfacine salt of at least partially monocarboxylic acid is formed. In other words, the activator (preferably guanfacine) may exist in at least partially protonated form. However, it should be understood that the present invention, in relation to the activator (preferably guanfacine) and the monocarboxylic acid, encompasses any form obtained in the guanfacine-containing layer based on a premixture of guanfacine and the monocarboxylic acid, and that this form includes, for example, the option of guanfacine and the monocarboxylic acid coexisting without chemical interaction (i.e., proton transfer), and the option of co-salt formation as described above. Preferably, the free guanfacine base and the monocarboxylic acid may together form a co-salt or any other type of acid addition salt, and as a result, the guanfacine-containing layer preferably contains at least partially a co-salt of the free guanfacine base and the monocarboxylic acid or any other type of acid addition salt. In other words, the guanfacine-containing layer preferably comprises guanfacine in at least a partially protonated form and a monocarboxylic acid in at least a partially deprotonated form.

[0176] In a preferred embodiment of the present invention, as described above, guanfacine and monocarboxylic acid in the guanfacine-containing layer exist in the form of a premixture.

[0177] In a more preferred embodiment of the present invention, guanfacine and monocarboxylic acid in the guanfacine-containing layer exist in the form of a premixture, which can be obtained by dry grinding or slurrying.

[0178] In a preferred embodiment of the present invention, guanfacine and monocarboxylic acid are present in equimolar amounts in the guanfacine-containing layer. In connection therewith, it should be understood that the guanfacine free base and the monocarboxylic acid added to the premixture are also present in equimolar amounts.

[0179] In a preferred embodiment of the present invention, the guanfacine-containing layer contains a monocarboxylic acid in an amount of 1 to 20% by weight, more preferably 2 to 16% by weight, based on the total weight of the guanfacine-containing layer. A particularly preferred monocarboxylic acid to be included together with guanfacine in the guanfacine-containing layer is sorbic acid.

[0180] In relation to the embodiments described above, it is surprising that the combination of guanfacine and a monocarboxylic acid, particularly sorbic monocarboxylic acid, enhances the flux and permeation of transdermal treatment systems. In particular, the inventors of the present invention have found that a TTS containing a combination of guanfacine base and sorbic acid in the guanfacine-containing layer exhibits improved cumulative permeation over 88 hours compared to a TTS containing only guanfacine in the form of a free base in the guanfacine-containing layer.

[0181] In a preferred embodiment of the present invention, the guanfacine-containing layer structure preferably contains a therapeutically effective amount of guanfacine. More preferably, the therapeutically effective amount of guanfacine is present in the guanfacine-containing layer of the guanfacine-containing layer structure.

[0182] In certain embodiments, the amount of guanfacine in the guanfacine-containing layer is in the range of 1 to 20% by weight, preferably 2 to 16% by weight, most preferably 5 to 13% by weight, for example, 11 to 13% by weight or 5 to 7% by weight, based on the total weight of the guanfacine-containing layer.

[0183] In one embodiment of the present invention, a guanfacine-containing layer can be obtained by dispersing a guanfacine-monocarboxylic acid premixture. When the guanfacine-containing layer is a guanfacine-containing matrix layer, the layer can preferably be obtained by dispersing a guanfacine-monocarboxylic acid premixture in a polymer carrier, which particularly preferably comprises at least one polymer selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers and mixtures thereof, and optionally at least one additive as defined above, particularly at least one dispersant and at least one permeation enhancer.

[0184] In certain embodiments, guanfacine has a purity of at least 95%, preferably at least 98%, and more preferably at least 99%, as measured by quantitative HPLC. Quantitative HPLC may be performed using reverse-phase HPLC with UV detection.

[0185] polymer Silicone acrylic hybrid polymer The TTS according to the present invention comprises at least one polymer, at least one polymer selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof. Further details regarding the polymer mixture are provided below.

[0186] In one embodiment of the present invention, the TTS according to the present invention comprises a silicone-acrylic hybrid polymer. The silicone-acrylic hybrid polymer comprises a polymerized hybrid species including a silicone-based variant and an acrylate-based variant polymerized together. Thus, the silicone-acrylic hybrid polymer comprises a silicone phase and an acrylic phase. Preferably, the silicone-acrylic hybrid polymer is a silicone-acrylic hybrid pressure-sensitive adhesive.

[0187] Silicone-acrylic hybrid pressure-sensitive adhesives are typically supplied and used in solvents such as n-heptane and ethyl acetate. The solids content of pressure-sensitive adhesives is usually between 30% and 80%. Those skilled in the art know that the solids content may be altered by adding a suitable amount of solvent.

[0188] Preferably, the weight ratio of silicone to acrylate in the silicone-acrylic hybrid pressure-sensitive adhesive is 5:95 to 95:5, or 20:80 to 80:20, more preferably 40:60 to 60:40, and most preferably the ratio of silicone to acrylate is about 50:50. Suitable silicone-acrylic hybrid pressure-sensitive adhesives having a weight ratio of 50:50 silicone to acrylate are, for example, the commercially available silicone-acrylic hybrid pressure-sensitive adhesives 7-6102, silicone / acrylate ratio 50 / 50, and 7-6302, silicone / acrylate ratio 50 / 50, supplied by DuPont® in ethyl acetate.

[0189] A preferred silicone-acrylic hybrid pressure-sensitive adhesive according to the present invention is characterized by a solution viscosity at 25°C and with a solids content of about 50% in ethyl acetate, which is preferably greater than about 400 cP, or from about 500 cP to about 3,500 cP, particularly from about 1,000 cP to about 3,000 cP, more preferably from about 1,200 cP to about 1,800 cP, or most preferably about 1,500 cP, or alternatively more preferably from about 2,200 cP to about 2,800 cP, or most preferably about 2,500 cP, as measured using a Brookfield RVT viscometer with spindle number 5 at 50 RPM.

[0190] These silicone-acrylic hybrid pressure-sensitive adhesives may also feature a complex viscosity of 0.1 rad / s at 30°C, which is preferably less than about 1.0e9 poise, or from about 1.0e5 poise to about 9.0e8 poise, more preferably from about 9.0e5 poise to about 1.0e7 poise, or most preferably about 4.0e6 poise, or alternatively more preferably from about 2.0e6 poise to about 9.0e7 poise, or most preferably about 1.0e7 poise, measured using a Rheometrics ARES rheometer with an 8 mm plate and a zero-defined gap.

[0191] To prepare a sample for measuring rheological behavior using a Rheometrics ARES rheometer, 2-3 grams of adhesive solution can be poured onto a SCOTCH-PAK1022 fluoropolymer release liner and allowed to stand for 60 minutes under ambient conditions. To achieve an essentially solvent-free film of the adhesive, it can be left in an oven at 110°C ± 10°C for 60 minutes. After removal from the oven, it is allowed to equilibrate at room temperature. The film can be removed from the release liner, folded, and formed into a square. To remove air bubbles, the film can be compressed using a Carver press. The sample can then be placed between plates and compressed to 1.5 ± 0.1 mm at 30°C. Excess adhesive is trimmed, and the final gap is recorded. A frequency sweep of 0.01-100 rad / s can be performed with the following settings: temperature = 30°C; strain = 0.5-1%, and data can be collected at 3 points / decade.

[0192] Suitable commercially available silicone-acrylic hybrid pressure-sensitive adhesives include the PSA series 7-6100 and 7-6300 (7-610X and 7-630X; X=1 n-heptane-based / X=2 ethyl acetate-based), manufactured and supplied by DuPont® in n-heptane or ethyl acetate. For example, the 7-6102 silicone-acrylic hybrid PSA with a silicone / acrylate ratio of 50 / 50 features a solution viscosity of 2,500 cP at 25°C and with a solids content of approximately 50% in ethyl acetate, and a complex viscosity of 1.0e7 poise at 30°C at 0.1 rad / s. The 7-6302 silicone-acrylic hybrid PSA with a silicone / acrylate ratio of 50 / 50 features a solution viscosity of 1,500 cP at 25°C and with a solids content of approximately 50% in ethyl acetate, and a complex viscosity of 4.0e6 poise at 30°C at 0.1 rad / s.

[0193] Depending on the solvent in which the silicone-acrylic hybrid pressure-sensitive adhesive is supplied, the arrangement of the silicone and acrylic phases differs, providing a continuous silicone or acrylic outer phase and a corresponding discontinuous internal phase. When the silicone-acrylic hybrid pressure-sensitive adhesive is supplied in n-heptane, the composition contains a continuous silicone outer phase and a discontinuous acrylic internal phase. When the silicone-acrylic hybrid pressure-sensitive adhesive is supplied in ethyl acetate, the composition contains a continuous acrylic outer phase and a discontinuous silicone internal phase. After the solvent in which the silicone-acrylic hybrid pressure-sensitive adhesive is supplied is evaporated, the phase arrangement of the resulting pressure-sensitive adhesive film or layer corresponds to the phase arrangement of the solvent-containing adhesive coating composition. For example, if there is no substance that can induce a reversal of the phase arrangement in the silicone-acrylic hybrid pressure-sensitive adhesive composition, a pressure-sensitive adhesive layer prepared from the silicone-acrylic hybrid pressure-sensitive adhesive in n-heptane provides a continuous silicone outer phase and a discontinuous acrylic internal phase, while a pressure-sensitive adhesive layer prepared from the silicone-acrylic hybrid pressure-sensitive adhesive in ethyl acetate provides a continuous acrylic outer phase and a discontinuous silicone internal phase. The phase configuration of the composition can be determined, for example, by a peel force test using a pressure-sensitive adhesive film or layer prepared from a silicone-acrylic hybrid PSA composition attached to a siliconeized release liner. The pressure-sensitive adhesive film contains a continuous silicone outer phase if the siliconeized release liner cannot be removed, or can hardly be removed, from the pressure-sensitive adhesive film (laminated to the backing film) due to blocking of the two silicone surfaces. Blocking results from the adhesion of two silicone layers having similar surface energies. The silicone adhesive exhibits good spreadability on the siliconeized liner and can therefore produce good adhesion to the liner. If the siliconeized release liner can be easily removed, the pressure-sensitive adhesive film contains a continuous acrylic outer phase. The acrylic adhesive does not exhibit good spreadability due to the difference in surface energies and therefore has poor or almost no adhesion to the siliconeized liner.Preferably, according to the present invention, the silicone-acrylic hybrid pressure-sensitive adhesive is provided in ethyl acetate, and the composition contains a continuous acrylic outer phase and a discontinuous silicone inner phase.

[0194] According to a preferred embodiment of the present invention, the silicone-acrylic hybrid polymer is a silicone-acrylic hybrid pressure-sensitive adhesive that can be obtained from a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups. It should be understood that the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups may contain only acrylate functional groups, only methacrylate functional groups, or both acrylate and methacrylate functional groups.

[0195] According to a predetermined embodiment of the present invention, the silicone-acrylic hybrid pressure-sensitive adhesive comprises a reaction product of (a) a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, (b) an ethylenically unsaturated monomer, and (c) an initiator. That is, the silicone-acrylic hybrid pressure-sensitive adhesive is the product of a chemical reaction between these reactants ((a), (b), and (c)). In particular, the silicone-acrylic hybrid pressure-sensitive adhesive comprises a reaction product of (a) a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, (b) an (meth)acrylate monomer, and (c) an initiator (i.e., in the presence of an initiator). That is, the silicone-acrylic hybrid pressure-sensitive adhesive comprises the product of a chemical reaction between these reactants ((a), (b), and (c)).

[0196] The reaction product of (a) a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, (b) an ethylenically unsaturated monomer, and (c) an initiator may contain a continuous silicone outer phase and a discontinuous acrylic inner phase, or the reaction products of (a), (b), and (c) may contain a continuous acrylic outer phase and a discontinuous silicone inner phase.

[0197] A silicon-containing pressure-sensitive adhesive composition (a) containing an acrylate or methacrylate functional group is typically present in the silicone-acrylic hybrid pressure-sensitive adhesive in an amount of 5 to 95 parts by weight, more typically 25 to 75 parts by weight, based on 100 parts by weight of the hybrid pressure-sensitive adhesive.

[0198] Ethylene-unsaturated monomer (b) is typically present in the silicone-acrylic hybrid pressure-sensitive adhesive in an amount of 5 to 95 parts by weight, more typically 25 to 75 parts by weight, based on 100 parts by weight of the hybrid pressure-sensitive adhesive.

[0199] The initiator (c) is typically present in the silicone acrylic hybrid pressure-sensitive adhesive in an amount of 0.005 to 3 parts by weight, more typically 0.01 to 2 parts by weight, based on 100 parts by weight of the hybrid pressure-sensitive adhesive.

[0200] According to a predetermined embodiment of the present invention, a silicon-containing pressure-sensitive adhesive composition (a) containing an acrylate or methacrylate functional group comprises a condensation reaction product of (a1) a silicone resin, (a2) a silicone polymer, and (a3) ​​a silicon-containing encapsulant that provides the acrylate or methacrylate functional group.

[0201] According to a predetermined embodiment of the present invention, a silicon-containing pressure-sensitive adhesive composition (a) comprising an acrylate or methacrylate functional group is (a1) Silicone resin and (a2) Silicone polymer and (a3) A silicon-containing encapsulant that provides the acrylate or methacrylate functional group, The silicon-containing encapsulant comprises a condensation reaction product of the general formula XYR' b SiZ 3-b {In the formula, X is a monovalent group of the general formula AE-, where, E is -O- or -NH-, and A is an acrylic group or a methacrylic group. Y is a divalent alkylene group having 1 to 6 carbon atoms. R' is a methyl or phenyl group. Z is a monovalent hydrolyzable organic group or halogen, b is either 0 or 1. It has, Silicone resins and silicone polymers react to form a pressure-sensitive adhesive, and silicon-containing encapsulants are introduced before, during, or after the reaction of the silicone resins and silicone polymers. After the silicone resin and silicone polymer undergo a condensation reaction to form a pressure-sensitive adhesive, the silicon-containing sealant reacts with the pressure-sensitive adhesive, or Silicon-containing encapsulants react in situ with silicone resins and silicone polymers.

[0202] According to a particular embodiment of the present invention, a silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group comprises a condensation reaction product of a pressure-sensitive adhesive and a silicon-containing encapsulant that provides the acrylate or methacrylate functional group. That is, a silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group is essentially a pressure-sensitive adhesive encapsulated or end-blocked with a silicon-containing encapsulant that provides the acrylate or methacrylate functional group, and the pressure-sensitive adhesive comprises a condensation reaction product of a silicone resin and a silicone polymer. Preferably, the silicone resin reacts in an amount of 30 to 80 parts by weight to form a pressure-sensitive adhesive, and the silicone polymer reacts in an amount of 20 to 70 parts by weight to form a pressure-sensitive adhesive. Both of these parts by weight are based on 100 parts by weight of pressure-sensitive adhesive. Although not essential, the pressure-sensitive adhesive may contain a catalytic amount of a condensation catalyst. A variety of silicone resins and silicone polymers are suitable for constituting the pressure-sensitive adhesive.

[0203] According to a predetermined embodiment of the present invention, the silicone acrylic hybrid pressure-sensitive adhesive is (a) A silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group, wherein the silicon-containing pressure-sensitive adhesive composition is (a1) Silicone resin and (a2) Silicone polymer and (a3) A silicon-containing encapsulant that provides the acrylate or methacrylate functional group, The silicon-containing encapsulant comprises a condensation reaction product of the general formula XYR' b SiZ 3-b {In the formula, X is a monovalent group of the general formula AE-, where, E is -O- or -NH-, and A is an acrylic group or a methacrylic group. Y is a divalent alkylene group having 1 to 6 carbon atoms. R' is a methyl or phenyl group. Z is a monovalent hydrolyzable organic group or halogen, b is either 0 or 1. It has, Silicone resins and silicone polymers react to form a pressure-sensitive adhesive, and silicon-containing encapsulants are introduced before, during, or after the reaction of the silicone resins and silicone polymers. After the silicone resin and silicone polymer undergo a condensation reaction to form a pressure-sensitive adhesive, the silicon-containing sealant reacts with the pressure-sensitive adhesive, or The silicon-containing encapsulant comprises a silicon-containing pressure-sensitive adhesive composition containing a silicone resin and a silicone polymer, and an acrylate or methacrylate functional group that reacts in situ with the silicone resin and silicone polymer. (b) Ethylene unsaturated monomers and (c) Initiator and, It is a reaction product.

[0204] The silicone acrylic hybrid composition used in the present invention is (i) A step of providing a silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group, wherein the silicon-containing pressure-sensitive adhesive composition is Silicone resin and Silicone polymer and A silicon-containing encapsulant providing the acrylate or methacrylate functional group, The silicon-containing encapsulant comprises a condensation reaction product of the general formula XYR' b SiZ3-b {In the formula, X is a monovalent group of the general formula AE-, where, E is -O- or -NH-, and A is an acrylic group or a methacrylic group. Y is a divalent alkylene group having 1 to 6 carbon atoms. R' is a methyl or phenyl group. Z is a monovalent hydrolyzable organic group or halogen, b is either 0 or 1. It has, Silicone resins and silicone polymers react to form a pressure-sensitive adhesive, and silicon-containing encapsulants are introduced before, during, or after the reaction of the silicone resins and silicone polymers. After the silicone resin and silicone polymer undergo a condensation reaction to form a pressure-sensitive adhesive, the silicon-containing sealant reacts with the pressure-sensitive adhesive, or Silicon-containing encapsulants react in situ with silicone resins and silicone polymers. The process of providing, (ii) A step of polymerizing a silicon-containing pressure-sensitive adhesive composition containing an ethylenically unsaturated monomer and the acrylate or methacrylate functional group of step (i) at a temperature of any choice between 50°C and 100°C or 65°C and 90°C in the presence of an initiator to form a silicone acrylic hybrid composition, It may be described as being prepared by a method including the following.

[0205] During the polymerization of silicon-containing pressure-sensitive adhesive compositions comprising ethylenically unsaturated monomers and acrylate or methacrylate functional groups, the ratio of silicone to acrylic can be controlled and optimized as desired. The ratio of silicone to acrylic can be controlled by various mechanisms within and during the process. An exemplary example of such a mechanism is the rate-controlled addition of one or more ethylenically unsaturated monomers to the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups. In certain applications, it may be desirable to have a silicone-based variant or total silicone content that exceeds the acrylate-based variant or the total acrylic content. In other applications, the reverse may be desirable. Independent of the end use, as already described above, it is generally preferred that the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups be present in the silicone-acrylic hybrid composition in an amount of about 5 to about 95 parts by weight, more preferably about 25 to about 75 parts by weight, and even more preferably about 40 to about 60 parts by weight, based on 100 parts by weight of the silicone-acrylic hybrid composition.

[0206] According to a predetermined embodiment of the present invention, the silicone acrylic hybrid composition used in the present invention is (i) A step of providing a silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group, wherein the silicon-containing pressure-sensitive adhesive composition is Silicone resin and Silicone polymer and A silicon-containing encapsulant providing the acrylate or methacrylate functional group, The silicon-containing encapsulant comprises a condensation reaction product of the general formula XYR' b SiZ 3-b {In the formula, X is a monovalent group of the general formula AE-, where, E is -O- or -NH-, and A is an acrylic group or a methacrylic group. Y is a divalent alkylene group having 1 to 6 carbon atoms. R' is a methyl or phenyl group. Z is a monovalent hydrolyzable organic group or halogen, and b is 0 or 1. It has, Silicone resins and silicone polymers react to form a pressure-sensitive adhesive, and silicon-containing encapsulants are introduced before, during, or after the reaction of the silicone resins and silicone polymers. After the silicone resin and silicone polymer undergo a condensation reaction to form a pressure-sensitive adhesive, the silicon-containing sealant reacts with the pressure-sensitive adhesive, or Silicon-containing encapsulants react in situ with silicone resins and silicone polymers. The process of providing, (ii) A step of polymerizing a silicon-containing pressure-sensitive adhesive composition containing an ethylenically unsaturated monomer and the acrylate or methacrylate functional group of step (i) in a first solvent at a temperature of 50°C to 100°C in the presence of an initiator to form a silicone acrylic hybrid composition, (iii) A step of removing the first solvent, (iv) A step of forming a silicone acrylic hybrid composition by adding a second solvent, wherein the phase arrangement of the silicone acrylic hybrid composition is selectively controlled by the selection of the second solvent. It may be described as being prepared by a method including the following.

[0207] The silicone acrylic hybrid PSA composition used in the present invention is also (i) A step of providing a silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group, wherein the silicon-containing pressure-sensitive adhesive composition is Silicone resin and Silicone polymer and A silicon-containing encapsulant providing the acrylate or methacrylate functional group, The silicon-containing encapsulant comprises a condensation reaction product of the general formula XYR' b SiZ 3-b {In the formula, X is a monovalent group of the general formula AE-, where, E is -O- or -NH-, and A is an acrylic group or a methacrylic group. Y is a divalent alkylene group having 1 to 6 carbon atoms. R' is a methyl or phenyl group. Z is a monovalent hydrolyzable organic group or halogen, b is either 0 or 1. It has, Silicone resins and silicone polymers react to form a pressure-sensitive adhesive, and silicon-containing encapsulants are introduced before, during, or after the reaction of the silicone resins and silicone polymers. After the silicone resin and silicone polymer undergo a condensation reaction to form a pressure-sensitive adhesive, the silicon-containing sealant reacts with the pressure-sensitive adhesive, or The silicon-containing encapsulant is provided by a process that involves a reaction in place with a silicone resin and a silicone polymer. (ii) A step of polymerizing a silicon-containing pressure-sensitive adhesive composition containing an ethylenically unsaturated monomer and the acrylate or methacrylate functional group of step (i) in a first solvent at a temperature of 50°C to 100°C in the presence of an initiator to form a silicone acrylic hybrid composition, (iii) A step of adding a processing solvent, wherein the processing solvent has a higher boiling point than the first solvent, (iv) A step of heating at a temperature of 70°C to 150°C so that most of the first solvent is selectively removed, (v) A step to remove the processing solvent, (vi) A step of forming a silicone acrylic hybrid composition by adding a second solvent, wherein the phase arrangement of the silicone acrylic hybrid composition is selectively controlled by the selection of the second solvent. It may be described as being prepared by a method including the following.

[0208] The silicone resin described in the previous paragraph is given by formula R X 3SiO 1 / 2 The triorganosiloxy unit and the formula SiO4 / 2 A copolymer may be contained in which the tetrafunctional siloxy units are present in a ratio of 0.1 to 0.9, preferably about 0.6 to 0.9, of triorganosiloxy units per tetrafunctional siloxy unit. Preferably, each R X This independently represents a monovalent hydrocarbon group, vinyl, hydroxyl, or phenyl group having 1 to 6 carbon atoms.

[0209] The silicone polymer according to the previous paragraph may contain at least one polydiorganosiloxane, which is preferably end-capping (end-blocked) with a functional group selected from the group consisting of hydroxyl groups, alkoxy groups, hydride groups, vinyl groups, or mixtures thereof. The diorgano substituent may be selected from the group consisting of dimethyl, methylvinyl, methylphenyl, diphenyl, methylethyl, (3,3,3-trifluoropropyl)methyl, and mixtures thereof. Preferably, the diorgano substituent contains only a methyl group. The molecular weight of the polydiorganosiloxane is usually in the range of about 50,000 to about 1,000,000, preferably about 80,000 to about 300,000. Preferably, the polydiorganosiloxane is end-blocked TR X ASiO 1 / 2 AR terminated by units X Containing SiO units, the polydiorganosiloxane has a viscosity of approximately 100 centipoise to approximately 30,000,000 centipoise at 25°C, and each A group independently contains R X Alternatively, selected from halohydrocarbon groups having 1 to 6 carbon atoms, each T group independently comprises R X OH, H or OR Y Selected from the group consisting of each R Y These are alkyl groups that independently have 1 to 4 carbon atoms.

[0210] As an example, a certain type of pressure-sensitive adhesive is prepared using preferred forms of silicone resin and preferred silicone polymer as follows: (i) Contains silicon-bonded hydroxyl groups, each SiO present 4 / 2 R with a molar ratio of 0.6 to 0.9 relative to the unit X 3SiO1 / 2 R in units X 3SiO 1 / 2 units and SiO 4 / 2 At least one resin copolymer of 30 to 80 parts by weight (including both ends) consisting essentially of units, and (ii) terminal block TR X ASiO 1 / 2 AR terminated with units X At least one polydiorganosiloxane of about 20 to about 70 parts by weight containing SiO units, the polydiorganosiloxane having a viscosity of about 100 centipoise to about 30,000,000 centipoise at 25°C, each R X is a monovalent organic group selected from the group consisting of hydrocarbon groups having 1 to 6 carbon atoms (including both ends), each A group is R X or independently selected from halo hydrocarbon groups having 1 to 6 carbon atoms (including both ends), each T group is R X OH, H or OR Y independently selected from the group consisting of, each R Y is independently an alkyl group having 1 to 4 carbon atoms (including both ends), a polydiorganosiloxane, (iii) also called a terminal blocking agent throughout, described below, and capable of providing a silanol content or concentration in the range of 5,000 to 15,000, more typically 8,000 to 13,000 ppm of at least one silicon-containing blocking agent in sufficient amount, (iv) if nothing is provided by (ii), an additional catalytic amount of a mild silanol condensation catalyst if desired, and (v) optionally, an effective amount of an organic solvent inert to (i), (ii), (iii) and (iv) to reduce the viscosity of the mixture of (i), (ii), (iii) and (iv), and concentrating the mixture of (i), (ii), (iii) and (iv) until at least a substantial amount of the silicon-containing blocking agent(s) reacts with the silicon-bonded hydroxyl groups and T groups of (i) and (ii). Additional organosilicon terminal blocking agents can be used in combination with the silicon-containing blocking agent(s) (iii) of the present invention.

[0211] The silicon-containing encapsulant according to the previous paragraph may be selected from the group consisting of acrylate-functional silane, acrylate-functional silazane, acrylate-functional disilazane, acrylate-functional disiloxane, methacrylate-functional silane, methacrylate-functional silazane, methacrylate-functional disiloxane, methacrylate-functional disiloxane, and combinations thereof, with the general formula XYR′ b SiZ 3-b It may also be described as follows, where X is a monovalent group of the general formula AE (E is -O- or -NH-, and A is an acrylic group or a methacrylic group), Y is a divalent alkylene group having 1 to 6 carbon atoms, R' is a methyl or phenyl group, Z is a monovalent hydrolyzable organic group or halogen, and b is 0, 1, or 2. Preferably, the monovalent hydrolyzable organic group has the general formula R"0" (R" is an alkylene group). Most preferably, this particular terminal blocking agent is 3-methacryloxypropyldimethylchlorosilane, 3-methacryloxypropyldichlorosilane, 3-methacryloxypropyltrichlorosilane, 3-methacryloxypropyldimethylmethoxysilane, 3-methacryloxypropylmethyldimethoxysilane, 3-methacryloxypropyltrimethoxysilane, 3-methacryloxypropyldimethylethoxysilane, 3-methacryloxypropylmethyldiethoxysilane, 3-methacryloxypropyltriethoxysilane, (methacryloxymethyl)dimethylmethoxysilane, (methacryloxymethyl)methyldimethoxysilane, (methacryloxymethyl)trimethoxy The following are selected from silane, (methacryloxymethyl)dimethylethoxysilane, (methacryloxymethyl)methyldiethoxysilane, methacryloxymethyltriethoxysilane, methacryloxypropyltriisopropoxysilane, 3-methacryloxypropyldimethylsilazane, 3-acryloxypropyldimethylchlorosilane, 3-acryloxypropyldichlorosilane, 3-acryloxypropyltrichlorosilane, 3-acryloxypropyldimethylmethoxysilane, 3-acryloxypropylmethyldimethoxysilane, 3-acryloxypropyltrimethoxysilane, 3-acryloxypropyldimethylsilazane, and combinations thereof.

[0212] The ethylenically unsaturated monomer according to the previous paragraph can be any monomer having at least one carbon-carbon double bond. Preferably, the ethylenically unsaturated monomer according to the previous paragraph may be a compound selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, alicyclic acrylates, alicyclic methacrylates, and combinations thereof. It should be understood that each of these compounds, i.e., aliphatic acrylates, aliphatic methacrylates, alicyclic acrylates, and alicyclic methacrylates, contains an alkyl group. The alkyl group of these compounds may contain up to 20 carbon atoms. Aliphatic acrylates that can be selected as one of the ethylenically unsaturated monomers are selected from the group consisting of methyl acrylate, ethyl acrylate, propyl acrylate, n-butyl acrylate, iso-butyl acrylate, tert-butyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, iso-octyl acrylate, iso-nonyl acrylate, iso-pentyl acrylate, tridecyl acrylate, stearyl acrylate, lauryl acrylate, and mixtures thereof. Aliphatic methacrylates that can be selected as one of the ethylenically unsaturated monomers are selected from the group consisting of methyl methacrylate, ethyl methacrylate, propyl methacrylate, n-butyl methacrylate, iso-butyl methacrylate, tert-butyl methacrylate, hexyl methacrylate, 2-ethylhexyl methacrylate, iso-octyl methacrylate, iso-nonyl methacrylate, iso-pentyl methacrylate, tridecyl methacrylate, stearyl methacrylate, lauryl methacrylate, and mixtures thereof. A cyclohexyl acrylate that can be selected as one of the ethylenically unsaturated monomers is cyclohexyl acrylate, and a cyclohexyl methacrylate that can be selected as one of the ethylenically unsaturated monomers is cyclohexyl methacrylate.

[0213] It should be understood that the ethylenically unsaturated monomers used to prepare the silicone-acrylic hybrid pressure-sensitive adhesive may be multiple ethylenically unsaturated monomers. That is, a combination of ethylenically unsaturated monomers may be polymerized, and more specifically copolymerized, with a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups and an initiator. According to a particular embodiment of the present invention, the silicone-acrylic hybrid pressure-sensitive adhesive is prepared by using at least two different ethylenically unsaturated monomers, preferably selected from the group consisting of 2-ethylhexyl acrylate and methyl acrylate, as acrylic monomers, more preferably in a ratio of 50% 2-ethylhexyl acrylate and 50% methyl acrylate, or 60% 2-ethylhexyl acrylate and 40% methyl acrylate.

[0214] The initiator according to the previous paragraph may be any substance suitable for initiating the polymerization of a silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group and an ethylenically unsaturated monomer to form a silicone-acrylic hybrid. For example, a free radical initiator selected from the group consisting of peroxides, azo compounds, redox initiators, and photoinitiators may be used.

[0215] Further preferred silicone resins, silicone polymers, silicon-containing encapsulants, ethylenically unsaturated monomers, and initiators that may be used in accordance with the preceding paragraph are described in detail in WO2007 / 145996, EP2599847A1, and WO2016 / 130408.

[0216] According to a predetermined embodiment of the present invention, the silicone-acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin, and an acrylic polymer, wherein the acrylic polymer is self-crosslinked by covalent bonds and covalently bonded to the silicone polymer and / or silicone resin.

[0217] According to other predetermined embodiments of the present invention, the silicone-acrylic hybrid polymer comprises a silicone polymer, a silicone resin, and a reaction product of an acrylic polymer, wherein the silicone resin comprises a triorganosiloxy unit R3SiO 1 / 2 (R is an organic group), and the tetrafunctional siloxy unit SiO 4 / 2 each SiO 4 / 2 R3SiO 1 / 2 It is contained in a molar ratio of the unit.

[0218] The acrylic polymer may comprise at least an alkoxysilyl functional monomer, a polysiloxane-containing monomer, a halosilyl functional monomer, or an alkoxyhalosilyl functional monomer. Preferably, the acrylic polymer is prepared from an alkoxysilyl functional monomer selected from the group consisting of trialkoxysilyl (meth)acrylate, dialkoxyalkylsilyl (meth)acrylate, and mixtures thereof, or comprises a terminally encapsulated alkoxysilyl functional group. The alkoxysilyl functional group may preferably be selected from the group consisting of trimethoxysilyl, dimethoxymethylsilyl, triethoxysilyl, diethoxymethylsilyl, and mixtures thereof.

[0219] Acrylic polymers can also be prepared from mixtures containing polysiloxane-containing monomers, preferably mixtures containing polydimethylsiloxane mono(meth)acrylate.

[0220] Silyl functional monomers are typically used in amounts ranging from 0.2 to 20 weight percent of the acrylic polymer, and more preferably, the amount of silyl functional monomers ranges from about 1.5 to about 5 weight percent of the acrylic polymer.

[0221] Polysiloxane-containing monomers are typically used in amounts of 1.5 to 50 weight percent of the acrylic polymer, and more preferably, the amount of polysiloxane-containing monomers is in the range of 5 to 15 weight percent of the acrylic polymer.

[0222] Alternatively, acrylic polymers include block or graft copolymers of acrylic and polysiloxane. An example of a polysiloxane block copolymer is polydimethylsiloxane-acrylic block copolymer. The preferred amount of siloxane block is 10 to 50 weight percent of the total block polymer.

[0223] Acrylic polymers contain alkyl (meth)acrylate monomers. Preferred alkyl (meth)acrylates that can be used have up to about 18 carbon atoms in the alkyl group, preferably 1 to about 12 carbon atoms in the alkyl group. Preferred low glass transition temperature (Tg) alkyl acrylates having a homopolymer Tg of less than about 0°C have about 4 to about 10 carbon atoms in the alkyl group and include butyl acrylate, amyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, octyl acrylate, isooctyl acrylate, decyl acrylate, their isomers, and combinations thereof. Butyl acrylate, 2-ethylhexyl acrylate, and isooctyl acrylate are particularly preferred. The acrylic polymer components may further contain high Tg (meth)acrylate monomers such as methyl acrylate, ethyl acrylate, methyl methacrylate, and isobutyl methacrylate.

[0224] The acrylic polymer component may further contain polyisobutylene groups to improve the low-temperature flow properties of the resulting adhesive.

[0225] Acrylic polymer components may include nitrogen-containing polar monomers. Examples include N-vinylpyrrolidone, N-vinylcaprolactam, N-tertiary octylacrylamide, dimethylacrylamide, diacetoneacrylamide, N-tertiary butylacrylamide, N-isopropylacrylamide, cyanoethyl acrylate, N-vinylacetamide, and N-vinylformamide.

[0226] The acrylic polymer component may contain one or more hydroxyl-containing monomers such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, hydroxypropyl acrylate, and / or hydroxypropyl methacrylate.

[0227] The acrylic polymer component may optionally contain a carboxylic acid-containing monomer. The useful carboxylic acids preferably contain about 3 to about 6 carbon atoms and include, in particular, acrylic acid, methacrylic acid, itaconic acid, and β-carboxyethyl acrylate. Acrylic acid is especially preferred.

[0228] Other useful and well-known comonomers include vinyl acetate, styrene, cyclohexyl acrylate, alkyl di(meth)acrylate, glycidyl methacrylate and allyl glycidyl ether, as well as macromers such as poly(styryl) methacrylate.

[0229] One acrylic polymer component that can be used in carrying out the present invention is an acrylic polymer comprising about 90 to about 99.5% by weight of butyl acrylate and about 0.5 to about 10% by weight of dimethoxymethylsilyl methacrylate.

[0230] According to a particular embodiment of the present invention, a silicone-acrylic hybrid polymer may be prepared by a) reacting a silicone polymer with a silicone resin to form a product, and b) reacting the product obtained as a result of a) with an acrylic polymer containing a reactive functional group, in which case these components are reacted in an organic solvent.

[0231] According to a predetermined embodiment of the present invention, a silicone-acrylic hybrid polymer may be prepared by a) reacting a silicone resin with an acrylic polymer containing reactive functional groups to form a resulting product, and b) reacting the resulting product from a) with a silicone polymer, in which case these components are reacted in an organic solvent.

[0232] According to a particular embodiment of the present invention, a silicone-acrylic hybrid polymer may be prepared by a) reacting a silicone polymer with an acrylic polymer containing reactive functional groups to form a product, and b) reacting the product obtained as a result of a) with a silicone resin, in which case these components are reacted in an organic solvent.

[0233] More suitable acrylic polymers, silicone resins, and silicone polymers that can be used to provide silicone-acrylic hybrid polymers according to the previous paragraph by chemically reacting silicone polymers, silicone resins, and acrylic polymers together are described in detail in WO2010 / 124187.

[0234] Acrylic polymer (non-hybrid) As described above, the TTS according to the present invention contains at least one polymer in the guanfacine-containing layer. According to the present invention, the at least one polymer is selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof. Thus, in one embodiment of the present invention, the TTS according to the present invention contains an acrylic polymer in the guanfacine-containing layer.

[0235] As used herein, the terms acrylic polymer and acrylate polymer are used synonymously. Preferably, the acrylic polymer is an acrylate-based pressure-sensitive adhesive. Alternatively, an acrylate-based pressure-sensitive adhesive may be called an acrylate-based pressure-sensitive adhesive or an acrylate pressure-sensitive adhesive.

[0236] The acrylate-based pressure-sensitive adhesive may be provided in the form of a solution having a solids content between 30% and 60%.

[0237] Acrylate-based pressure-sensitive adhesives may or may not contain functional groups such as hydroxyl groups, carboxylic acid groups, neutralized carboxylic acid groups, and mixtures thereof. Therefore, the term "functional group" refers in particular to hydroxyl groups, carboxylic acid groups, and deprotonated carboxylic acid groups.

[0238] Corresponding commercial products are available, for example, from Henkel under the trade name Duro Tak®. Such acrylate-based pressure-sensitive adhesives are based on monomers selected from one or more of acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, butyl methacrylate, t-octylacrylamide, and vinyl acetate, and are provided in ethyl acetate, heptane, n-heptane, hexane, methanol, ethanol, isopropanol, 2,4-pentanedione, toluene, or xylene, or mixtures thereof.

[0239] Specifically, the following acrylate-based pressure-sensitive adhesives are available. · Duro-Tak® 387-2287 or Duro-Tak® 87-2287 (a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, and glycidyl methacrylate, provided as a solution in ethyl acetate without the use of a crosslinking agent), · Duro-Tak® 387-2516 or Duro-Tak® 87-2516 (a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, and glycidyl methacrylate, provided as a solution in ethyl acetate, ethanol, n-heptane, and methanol using a titanium crosslinking agent), · Duro-Tak® 387-2051 or Duro-Tak® 87-2051 (a copolymer based on acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, and vinyl acetate, provided as a solution in ethyl acetate or heptane without the use of a crosslinking agent), ·Duro-Tak® 387-2353 or Duro-Tak® 87-2353 (a copolymer based on acrylic acid, 2-ethylhexyl acrylate, glycidyl methacrylate, and methyl acrylate, provided as a solution in ethyl acetate and hexane), · Duro-Tak (trademark) 87-4098 (trademark) (a copolymer based on 2-ethylhexyl acrylate and vinyl acetate, provided as a solution in ethyl acetate), · Duro-Tak® 387-2287 or Duro-Tak® 87-2054 (a copolymer based on acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, and vinyl acetate, provided as a solution in ethyl acetate or heptane using a crosslinking agent).

[0240] Preferred acrylate-based pressure-sensitive adhesives according to the present invention are Duro-Tak® 387-2516 or Duro-Tak® 87-2516 (a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, and glycidyl methacrylate, provided as a solution in ethyl acetate, ethanol, n-heptane, and methanol using a titanium crosslinking agent), and Duro-Tak® 87-4098 (a copolymer based on 2-ethylhexyl acrylate and vinyl acetate, provided as a solution in ethyl acetate).

[0241] Additionally, extra polymers may be added to improve cohesiveness and / or adhesion.

[0242] Silicone-based polymer (non-hybrid) As described above, the TTS according to the present invention contains at least one polymer in the guanfacine-containing layer. According to the present invention, the at least one polymer is selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof. Thus, in one embodiment of the present invention, the TTS according to the present invention contains at least one silicone-based polymer in the guanfacine-containing layer, preferably the guanfacine-containing matrix layer.

[0243] As used herein, silicone-based polymers are non-hybrid polymers, i.e., polymers that do not contain hybrid species. Silicone-based polymers are polysiloxane-based. Therefore, they may also be called polysiloxane-based polymers. Preferably, silicone-based polymers are silicone-based pressure-sensitive adhesives, i.e., polysiloxane-based pressure-sensitive adhesives.

[0244] Since silicone-based polymers are preferably non-curable polymers, they are typically supplied and used in solvents such as n-heptane and ethyl acetate. The solids content is usually 30% to 80%.

[0245] Suitable silicone-based polymers are commercially available under the brand name BIO-PSA (pressure-sensitive adhesives based on polysiloxanes).

[0246] Polysiloxane-based pressure-sensitive adhesives offer suitable adhesion and rapid bonding to various skin types, including moist skin, favorable adhesion and tackiness properties, long-lasting adhesion to skin, high flexibility, moisture permeability, and compatibility with many active substances and film substrates. It is possible to provide polysiloxane-based pressure-sensitive adhesives with sufficient amine resistance, and therefore improved stability in the presence of amines. Such pressure-sensitive adhesives are based on the resin-in-polymer concept, where a polysiloxane-based pressure-sensitive adhesive is prepared by a condensation reaction of silanol-terminated polydimethylsiloxane with a silica resin (also called a silicate resin), in which residual silanol functional groups are additionally encapsulated with trimethylsiloxy groups for amine stability. The silanol-terminated polydimethylsiloxane content contributes to the viscous component of the viscoelastic behavior and affects the wetting and spreading properties of the adhesive. The resin functions as a tackifier and reinforcing agent, participating in the elastic component. The correct balance between silanol-terminated polydimethylsiloxane and the resin provides appropriate adhesive properties.

[0247] Considering the above, silicone-based polymers, particularly silicone-based pressure-sensitive adhesives, can generally be obtained by polycondensation of silanol-terminated polydimethylsiloxanes with silicate resins. Amine-compatible silicone-based polymers, particularly amine-compatible silicone-based pressure-sensitive adhesives, can be obtained by reacting the silicone-based polymer, particularly the silicone-based pressure-sensitive adhesive, with trimethylsilyl (e.g., hexamethyldisilazane) to reduce the silanol content of the polymer. As a result, residual silanol functional groups are encapsulated at least partially, preferably mostly or completely, with trimethylsiloxy groups.

[0248] As described above, the tackiness of the silicone-based polymer may be modified by the resin-to-polymer ratio, i.e., the ratio of silanol-terminated polydimethylsiloxane to the silicate resin, preferably in the range of 70:30 to 50:50, more preferably 65:35 to 55:45. Tackiness increases as the amount of polydimethylsiloxane relative to the resin increases. High-tack silicone-based polymers preferably have a resin-to-polymer ratio of 55:45, medium-tack silicone-based polymers preferably have a resin-to-polymer ratio of 60:40, and low-tack silicone-based polymers preferably have a resin-to-polymer ratio of 65:35. High-tack silicone-based polymers exhibit a viscosity of approximately 5 × 10⁻¹⁶ at 0.01 rad / s and 30°C. 6 Preferably, the poise has a complex viscosity, and the medium-tack silicone-based polymer has a viscosity of approximately 5 × 10 at 0.01 rad / s and 30°C. 7 It is preferable that the low-tack silicone-based polymer has a complex viscosity of poise, and at 0.01 rad / s and 30°C, it is about 5 × 10⁻⁶. 8 It is preferable to have a complex viscosity of poise. The highly adhesive amine-compatible silicone-based polymer has a viscosity of approximately 5 × 10 at 0.01 rad / s and 30°C. 6 Preferably having a complex viscosity of poise, the medium-tack amine-compatible silicone-based polymer has a viscosity of approximately 5 × 10 at 0.01 rad / s and 30°C. 8 Preferably having a complex viscosity of poise, the low-tack amine-compatible silicone-based polymer has a viscosity of approximately 5 × 10 at 0.01 rad / s and 30°C. 9 It is preferable that it has a complex viscosity of Poise.

[0249] Examples of commercially available silicone-based PSA compositions include the standard BIO-PSA series (7-4400, 7-4500, and 7-4600 series) and amine-compatible (end-sealed) BIO-PSA series (7-4100, 7-4200, and 7-4300 series) manufactured by DuPont® and typically supplied in n-heptane or ethyl acetate. For example, BIO-PSA 7-4201 has a solution viscosity of 450 mPa·s at 25°C and a solids content of approximately 60% in heptane, and 1 × 10⁻⁶ at 0.01 rad / s at 30°C. 8 It is characterized by the complex viscosity of Poise. BIO-PSA 7-4301 has a solution viscosity of 500 mPa·s at 25°C and in heptane with a solid content of approximately 60%, and 5 × 10⁻⁶ at 0.01 rad / s at 30°C. 6 It has a complex viscosity of Poise. BIO-PSA 7-4202 has a solution viscosity of 800 mPa·s at 25°C and in ethyl acetate with a solid content of approximately 60%, and 1 × 10⁻⁶ at 0.01 rad / s at 30°C. 8 It is characterized by the complex viscosity of Poise. BIO-PSA 7-4302 has a solution viscosity of 1200 mPa·s at 25°C and in ethyl acetate with a solid content of approximately 60%, and 5 × 10⁻⁶ at 0.01 rad / s at 30°C. 6 It has a complex viscosity in Poise.

[0250] Polysiloxane-based pressure-sensitive adhesives are supplied and used in a solvent such as n-heptane, ethyl acetate, or other volatile silicone fluids. The solids content of the polysiloxane-based pressure-sensitive adhesive in the solvent is typically 60–85%, preferably 70–80% or 60–75%. Those skilled in the art know that the solids content may be modified by adding a suitable amount of solvent.

[0251] For example, a polysiloxane-based pressure-sensitive adhesive, available from DuPont®, may be obtained according to the following scheme. [ka] Such polysiloxane-based pressure-sensitive adhesives are available from DuPont® under trade names such as BIO-PSA 7-4401, BIO-PSA-7-4501, or BIO-PSA 7-4601, provided in n-heptane solvent (indicated by the symbol "01"), or under trade names such as BIO-PSA 7-4402, BIO-PSA 7-4502, and BIO 7-4602, provided in ethyl acetate solvent (indicated by the symbol "02"). Typical solids content in the solvent ranges from 60 to 75%. The symbol "44" indicates a resin-to-polymer ratio of 65:35, resulting in low tackiness; the symbol "45" indicates a resin-to-polymer ratio of 60:40, resulting in medium tackiness; and the symbol "46" indicates a resin-to-polymer ratio of 55:45, resulting in high tackiness.

[0252] For example, an amine-compatible polysiloxane-based pressure-sensitive adhesive, available from DuPont®, may be obtained according to the following scheme. [ka] Such amine-compatible polysiloxane-based pressure-sensitive adhesives are available from DuPont® under trade names such as BIO-PSA 7-4101, BIO-PSA-7-4201, or BIO-PSA 7-4301, provided in n-heptane solvent (indicated by the symbol "01"), or under trade names such as BIO-PSA 7-4102, BIO-PSA 7-4202, and BIO 7-4302, provided in ethyl acetate solvent (indicated by the symbol "02"). Typical solids content in the solvent ranges from 60 to 75%. The symbol "41" indicates a resin-to-polymer ratio of 65:35, resulting in low tackiness; the symbol "42" indicates a resin-to-polymer ratio of 60:40, resulting in moderate tackiness; and the symbol "43" indicates a resin-to-polymer ratio of 55:45, resulting in high tackiness.

[0253] Preferred polysiloxane-based pressure-sensitive adhesives according to the present invention are characterized by a solution viscosity at 25°C and a solids content of 60% in n-heptane, which is preferably greater than about 150 mPa·s or between about 200 mPa·s and about 700 mPa·s, measured using a Brookfield RVT viscometer with spindle #5 at 50 rpm. These also have a viscosity of about 1 x 10⁻¹⁶ at 0.01 rad / s at 30°C. 9 Less than poise, or about 1 x 10⁻¹⁰ 5 ~approximately 9x10 8 The complex viscosity of Poise may also be a characteristic feature.

[0254] Polymer mixture The TTS according to the present invention, in particular the guanfacine-containing layer, comprises at least one polymer selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof. In one embodiment of the present invention, the guanfacine-containing layer comprises at least one polymer, and the at least one polymer is A mixture of an acrylic polymer and at least one silicone-based polymer, or • A mixture of two silicone-acrylic hybrid polymers, or • A mixture of two silicone-based polymers, or • Acrylic polymer, or Acrylic polymer containing -OH groups That is the case.

[0255] In this regard, it should be understood that acrylic polymers, silicone-based polymers, and silicone-acrylic hybrid polymers are as defined above.

[0256] In one preferred embodiment of the present invention, at least one polymer is present in an amount of 20 to 99% by weight, preferably 30 to 97% by weight, and most preferably 35 to 94% by weight, based on the total weight of the guanfacine-containing layer.

[0257] In a more preferred embodiment of the present invention, the guanfacine-containing layer comprises a mixture of an acrylic polymer and at least one silicone-based polymer, wherein, based on the total weight of the guanfacine-containing layer, the acrylic polymer is present in an amount of 20-55% by weight and the at least one silicone-based polymer is present in an amount of 20-55% by weight.

[0258] In another more preferred embodiment of the present invention, the guanfacine-containing layer comprises a mixture of two silicone-acrylic hybrid polymers, in either case, based on the total weight of the guanfacine-containing layer, the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight, preferably the first silicone-acrylic hybrid polymer and the second silicone-acrylic hybrid polymer each contain a silicone phase and an acrylate phase in a weight ratio of 60:40-40:60.

[0259] In a more preferred embodiment of the present invention, the guanfacine-containing layer comprises a mixture of two silicone-based polymers, wherein, based on the total weight of the guanfacine-containing layer, the first silicone-based polymer is present in an amount of 20-55% by weight and the second silicone-based polymer is present in an amount of 20-55% by weight.

[0260] In a more preferred embodiment of the present invention, the guanfacine-containing layer comprises a mixture of an acrylic polymer, which is a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, and glycidyl methacrylate, and at least one silicone-based polymer, wherein the at least one silicone-based polymer refers to two silicone-based polymers, the first being BIO-PSA 7-4202 and the second being BIO-PSA 7-4302. In relation to the above more preferred embodiment, it should be understood that, based on the total weight of the guanfacine-containing layer, the acrylic polymer is present in an amount of 20-55% by weight, and the two silicone-based polymers are present in an overall amount of 20-55% by weight. Furthermore, in relation to the above preferred embodiment, it should be understood that the two silicone-based polymers are preferably present in a 1:1 ratio in the guanfacine-containing layer.

[0261] In a more preferred embodiment of the present invention, the guanfacine-containing layer comprises a mixture of an acrylic polymer, which is a copolymer based on 2-ethylhexyl acrylate and vinyl acetate, and at least one silicone-based polymer, wherein the at least one silicone-based polymer refers to two silicone-based polymers, the first being BIO-PSA 7-4202 and the second being BIO-PSA 7-4302. In relation to the above more preferred embodiment, it should be understood that, based on the total weight of the guanfacine-containing layer, the acrylic polymer is present in an amount of 20-55% by weight, and the two silicone-based polymers are present in an overall amount of 20-55% by weight. Furthermore, in relation to the above preferred embodiment, it should be understood that the two silicone-based polymers are preferably present in a 1:1 ratio in the guanfacine-containing layer.

[0262] In relation to the embodiments described above, it should be understood that the amount of at least one silicone-based polymer refers to the total amount of silicone-based polymer present in the guanfacine-containing layer, based on the total weight of the guanfacine-containing layer. In particular, when referring to two silicone-based polymers, it should be understood that the two silicone-based polymers are present in the total amounts defined above.

[0263] In another, more preferred embodiment of the present invention, the guanfacine-containing layer comprises a mixture of two silicone-acrylic hybrid polymers, in each case, based on the total weight of the guanfacine-containing layer, the first silicone-acrylic hybrid polymer is preferably the 7-6102 silicone-acrylic hybrid PSA defined above, present in an amount of 60-90% by weight, and the second silicone-acrylic hybrid polymer is preferably the 7-6302 silicone-acrylic hybrid PSA defined above, present in an amount of 1-20% by weight, and preferably the first silicone-acrylic hybrid polymer and the second silicone-acrylic hybrid polymer comprise a silicone phase and an acrylate phase in a weight ratio of 60:40 to 40:60.

[0264] In a further preferred embodiment of the present invention, the guanfacine-containing layer comprises a mixture of two silicone-based polymers, wherein, based on the total weight of the guanfacine-containing layer, the first silicone-based polymer is BIO-PSA 7-4202 and is present in an amount of 20-55% by weight, and the second silicone-based polymer is BIO-PSA 7-4302 and is present in an amount of 20-55% by weight. In relation to the above preferred embodiment, it should be understood that the two silicone-based polymers are preferably present in a 1:1 ratio in the guanfacine-containing layer.

[0265] Further additives The TTS according to the present invention, in particular the guanfacine-containing layer, may further contain at least one additive or excipient. Particularly preferred additives according to the present invention include dispersants, permeation enhancers, and solubilizers. Further details in this regard are provided above. However, the TTS according to the present invention, in particular the guanfacine-containing layer, may contain further additives or excipients.

[0266] Generally, additives or excipients are preferably selected from the group consisting of dispersants, solubilizers, permeation enhancers, film-forming agents, softeners / plasticizers, tackifiers, skincare substances, pH adjusters, preservatives, stabilizers, and fillers. Such additives may be present in the guanfacine-containing layer in amounts of 0.001 to 15% by weight, for example, 0.5 to 10% by weight or 1 to 10% by weight, or 0.01 to 6% by weight, based on the total weight of the guanfacine-containing layer, where the amount by weight % refers to a single additive.

[0267] It should be noted that in pharmaceutical formulations, formulation components are classified according to their physicochemical and physiological properties, as well as their function. This means, in particular, that a substance or compound classified into one category of formulation components is not excluded from classification into another category. For example, certain polymers can be not only film-forming agents but also tackifiers. Some substances can be, for example, typical emollients and at the same time act as permeability enhancers. Those skilled in the art can, based on general knowledge, determine which category(s) of formulation components a particular substance or compound belongs to. Details of excipients and additives are provided below, but they should not be understood as being mutually exclusive. Other substances not expressly enumerated herein may also be used in accordance with the present invention, and substances and / or compounds expressly enumerated as one category of formulation components are not excluded from use as other formulation components in the sense of the present invention.

[0268] In one embodiment, the guanfacine-containing layer comprises a dispersant as defined above, preferably selected from the group consisting of esters of fatty acids and polyols, aliphatic alcohols, polyethylene glycol having a number average molecular weight of 300-400, and polyethylene glycol alkyl ethers. As described above, the dispersant is preferably polyethylene glycol C8-C having 2-10 EO units. 20 - Alkyl ethers, particularly polyoxyethylene(4) lauryl ether. Alternatively or additionally, silicone polyethers may be used as dispersants. The dispersants help to uniformly disperse guanfacine within the guanfacine-containing layer, particularly the guanfacine-containing matrix layer, thereby improving the release properties of TTS.

[0269] In one embodiment, the guanfacine-containing layer contains a solubilizer. The solubilizer preferably improves the dispersibility of guanfacine in the guanfacine-containing layer and stabilizes the guanfacine-containing layer. Furthermore, the solubilizer may have a positive effect on cohesiveness. Preferred solubilizers include, for example, glycerol esters, polyglycerol esters, propylene glycol esters, and polyoxyethylene esters of medium-chain and / or long-chain fatty acids, such as glyceryl monolinoleate, medium-chain glycerides and medium-chain triglycerides, nonionic solubilizers produced by reacting castor oil with ethylene oxide, and any mixtures thereof which may further contain fatty acids or fatty alcohols; cellulose and methylcellulose, and their derivatives, such as hydroxypropylcellulose and hypromellose acetate succinate; various cyclodextrins and their derivatives; nonionic triblock copolymers known as poloxamers, having a central hydrophobic chain of polyoxypropylene adjacent to two hydrophilic chains of polyoxyethylene; water-soluble derivatives of vitamin E; and medical Pharmaceutical grade or aggregated spherical isomalt; polyester glycol, polyvinyl acetate, and polyvinylcaprolactam graft copolymers, also abbreviated as PVAc-PVCap-PEG and known as Soluplus®; vinylpyrrolidone-vinyl acetate copolymers such as Kollidon® VA64; refined grades of naturally derived castor oil, polyethylene glycol 400, polyoxyethylene sorbitan monooleate (such as polysorbate 80), or propylene glycol; diethylene glycol monoethyl ether; glucono-delta-lactone; corn and potato starch; and any of the soluble polyvinylpyrrolidones listed below, as well as insoluble / crosslinked polyvinylpyrrolidones such as crospovidone.

[0270] However, the permeation enhancers mentioned below can also act as solubilizers. Furthermore, the film-forming agents described below may act simultaneously as solubilizers, and vice versa.

[0271] In one embodiment, the guanfacine-containing layer includes a permeation enhancer. Options in this regard are provided above. A permeation enhancer is a substance that affects the barrier properties of the stratum corneum in the sense that it increases the permeability of the active ingredient. Some examples of permeation enhancers are polyhydric alcohols such as dipropylene glycol, propylene glycol, and polyethylene glycol; oils such as olive oil, squalene, and lanolin; fatty ethers such as cetyl ether and oleyl ether; fatty acid esters such as isopropyl myristate; urea and urea derivatives such as allantoin; polar solvents such as dimethyldecyl phosphooxide, methyl cetyl sulfoxide, dimethyl aurylamine, dodecylpyrrolidone, isosorbitol, dimethyl acetonide, dimethyl sulfoxide, decyl methyl sulfoxide, and dimethylformamide; salicylic acid; amino acids; benzyl nicotinate; and high molecular weight aliphatic surfactants such as lauryl sulfate. Other agents include oleic acid and linoleic acid, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate. If the guanfacine-containing layer contains a permeation enhancer, the permeation enhancer is preferably selected from the group consisting of diethylene glycol monoethyl ether (Transktol), oleic acid, levulinic acid, caprylic / capric triglyceride, diisopropyl adipate, isopropyl myristart, isopropyl palmitate, lauryl lactate, triacetin, dimethylpropylene urea, oleyl alcohol, oleoyl macrogol-6 glyceride (labrafil MS 1944), and lauroglycol, and is preferably oleyl alcohol, lauroglycol, or oleoyl macrogol-6 glyceride (labrafil MS 1944).

[0272] In one embodiment, the guanfacine-containing layer further comprises a film-forming agent. It should be understood that the aforementioned solubilizers, such as Soluplus®, also act as film-forming agents and can control cohesiveness. Suitable examples of further film-forming agents include polyvinylpyrrolidone, vinyl acetate / vinylpyrrolidone copolymers, and cellulose derivatives, preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone.

[0273] It is necessary for the guanfacine-containing layer to have self-adhesive properties, and if one or more polymers are selected that do not provide sufficient self-adhesive properties, a tackifier is added. Preferred tackifiers include migliol, which is a liquid wax ester based on plant-derived long-chain unsaturated even fatty acids and long-chain unsaturated even aliphatic alcohols, and polyethylene glycol. In particular, the tackifier may be selected from polyvinylpyrrolidone (which can maintain the adhesive properties of the matrix layer due to its water-absorbing ability and can therefore be considered a tackifier in a broad sense), triglycerides, polyethylene glycol, dipropylene glycol, resins, resin esters, terpenes and their derivatives, ethylene vinyl acetate adhesives, dimethylpolysiloxane, and polybutene, and preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone. Preferably, the tackifier may be selected from polyvinylpyrrolidone, triglycerides, dipropylene glycol, resins, resin esters, terpenes and their derivatives, ethylene vinyl acetate adhesives, dimethylpolysiloxane, and polybutene, and preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone.

[0274] The term "soluble polyvinylpyrrolidone" refers to polyvinylpyrrolidone (also known as povidone) that is soluble in at least ethanol, preferably more than 10%, in water, diethylene glycol, methanol, n-propanol, 2-propanol, n-butanol, chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2-propylene glycol, 1,4-butanediol, glycerol, triethanolamine, propionic acid, and acetic acid. Examples of commercially available polyvinylpyrrolidones include Kollidon® 12PF, Kollidon® 17PF, Kollidon® 25, Kollidon® 30, and Kollidon® 90F, or povidone K90F, supplied by BASF. Different grades of Kollidon® are defined with respect to the K value, which reflects the average molecular weight of the polyvinylpyrrolidone grade. Kollidon® 12PF features a K-value range of 10.2 to 13.8, corresponding to a nominal K-value of 12. Kollidon® 17PF features a K-value range of 15.3 to 18.4, corresponding to a nominal K-value of 17. Kollidon® 25 features a K-value range of 22.5 to 27.0, corresponding to a nominal K-value of 25, and Kollidon® 30 features a K-value range of 27.0 to 32.4, corresponding to a nominal K-value of 30. Kollidon® 90F features a K-value range of 81.0 to 97.2, corresponding to a nominal K-value of 90. Preferred Kollidon® grades are Kollidon® 12PF, Kollidon® 30, and Kollidon® 90F. Within the scope of the present invention, the term "K value" refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the European Pharmacopoeia (Ph.Eur.) and the USP monograph for "Povidone".

[0275] In one embodiment, the guanfacine-containing layer further comprises a softening agent / plasticizer. Exemplary softening agents / plasticizers include linear or branched saturated or unsaturated alcohols, triglycerides, and polyethylene glycol having 6 to 20 carbon atoms.

[0276] In one embodiment, the guanfacine-containing layer further comprises stabilizers. The stabilizers include tocopherol and its ester derivatives, ascorbic acid and its ester derivatives. Further stabilizers include sodium metabisulfite, ascorbyl esters of fatty acids such as ascorbyl palmitate, ascorbic acid, butylated hydroxytoluene, tocopherol, tocopheryl acetate, and tocopheryl linoleate.

[0277] In one embodiment, the guanfacine-containing layer further comprises a pH adjuster. Suitable pH adjusters include amine derivatives, inorganic alkali derivatives, and weak acids and weak bases, including polymers having basic or acidic functional groups.

[0278] In one embodiment, the guanfacine-containing layer further comprises a preservative. Suitable preservatives include parabens, formaldehyde-releasing agents, isothiazolinone, and phenoxyethanol.

[0279] In one embodiment, the guanfacine-containing layer further comprises a skincare substance. Such a substance may be used to avoid or reduce skin irritation detectable by a skin reaction score. Suitable skincare substances include sterol compounds such as cholesterol, dexpanthenol, α-bisabolol, and antihistamines.

[0280] In one embodiment, the guanfacine-containing layer further comprises a filler. Fillers such as silica gel, titanium dioxide, and zinc oxide may be used in combination with the polymer to influence specific physical parameters such as cohesiveness and bonding strength in a desired manner.

[0281] Release characteristics The TTS according to the present invention is designed to deliver guanfacine transdermally into the systemic circulation for a predetermined period of time, preferably at least 24 hours, more preferably at least 72 hours, and particularly about 84 hours.

[0282] In one embodiment, the TTS according to the present invention provides an average plasma concentration of guanfacine of 1 to 20 ng / ml, preferably 1 to 15 ng / ml, and more preferably 1 to 10 ng / ml, by transdermal delivery in a steady state.

[0283] Preferably, the TTS provides a therapeutically effective plasma concentration of guanfacine within 8 hours, preferably less than 6 hours, and more preferably less than 4 hours, after application of the TTS to the skin. Furthermore, the therapeutically effective plasma concentration is preferably maintained over the entire administration period of at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

[0284] In one embodiment, the TTS according to the present invention has an AUC of 10-600 ng*h / ml, preferably 20-400 ng*h / ml. 0-24h In another embodiment, the TTS according to the present invention has an AUC of 30 to 1800 ng*h / ml, preferably 60 to 1200 ng*h / ml. 0-72h In another embodiment, the TTS according to the present invention has an AUC of 35 to 2100 ng*h / ml, preferably 70 to 1400 ng*h / ml. 0-84h It should be understood that the AUC value preferably refers to the AUC value obtained under steady-state conditions.

[0285] In one embodiment, the TTS according to the present invention has a C of less than 3.5. max vs C 84 Provides a ratio. In another embodiment, the TTS according to the present invention is less than 3.0 C max vs C 72 Provides a ratio. In another embodiment, the TTS according to the present invention is less than 2.0 C max vs C 24 The ratios provided show a flat plasma curve, which is advantageous from the perspective of continuous patient treatment.

[0286] In one embodiment, the TTS according to the present invention provides the following skin permeability of guanfacine, measured using a Franz diffusion cell with human skin samples. That is, 0.01 μg / cm³ in the first 24 hours 2 *h)~8μg / (cm 2 *h), From 24 hours to 88 hours, 0.05 μg / cm³ 2 *h)~10μg / (cm 2 *h). In another embodiment, the TTS according to the present invention provides the following skin permeability of guanfacine as measured in a Franz diffusion cell using human skin scavenged from the skin. That is, 0.01 μg / cm³ in the first 24 hours 2 *h)~8μg / (cm 2 *h), From 24 hours to 88 hours, 0.05 μg / cm³ 2 *h)~8μg / (cm 2 *h).

[0287] In one embodiment, the TTS according to the present invention was measured in a Franz diffusion cell using skin collected from Göttinger miniature pigs, and was 0.01 μg / cm³ in the first 24 hours. 2 *h)~8μg / (cm 2 *h), 0.05 μg / cm³ from 24 hours to 88 hours. 2 *h)~10μg / (cm 2 *h) Provides the following skin permeability of guanfacine.

[0288] In another embodiment, the TTS according to the present invention was measured at 0.01 mg / cm³ over an 88-hour period using a Franz diffusion cell with skin collected from a Göttinger miniature pig. 2 ~0.7 mg / cm³ 2 Preferably 0.05 mg / cm³ 2 ~0.6 mg / cm³ 2 More preferably 0.10 mg / cm³ 2 ~0.5 mg / cm³ 2 This provides the cumulative permeation amount of guanfacine.

[0289] In consideration of the above, the present invention also relates in one aspect to a transdermal therapy system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the transdermal therapy system providing, by transdermal delivery, one or more pharmacokinetic parameters selected from the group consisting of the following: AUC 0-24 10-600 (ng / ml) h, AUC 0-72 30-1800 (ng / ml)h, AUC 0-84 35-2100 (ng / ml)h, C less than 2.0 max vs C 24 ratio, C below 3.0 max vs C 72 Ratio, and C below 3.5 max vs C 84 ratio.

[0290] In a preferred embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the transdermal therapeutic system providing, by transdermal delivery, one or more pharmacokinetic parameters selected from the group consisting of: AUC 0-24 20-400 (ng / ml) h, AUC 0-72 60-1200 (ng / ml) h, AUC 0-84 70-1400 (ng / ml)h, C less than 1.5 max vs C 24 ratio, C less than 2.5 max vs C 72 Ratio, and C below 3.0 max vs C 84 ratio.

[0291] In a particularly preferred embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the transdermal therapeutic system delivers 70-1400 (ng / ml)h AUC by transdermal delivery. 0-84 To provide.

[0292] Treatment method / medical use In one embodiment of the present invention, the TTS according to the present invention is suitable for use in a method of treating human patients, preferably patients aged 6 to 17 years. In particular, the TTS according to the present invention is suitable for use in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD), and / or as an adjunct therapy to stimulant drug therapy in human patients, preferably human patients aged 6 to 17 years.

[0293] In preferred embodiments relating to the above medical applications, TTS is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

[0294] In one embodiment, the present invention relates to a method for treating human patients, preferably human patients aged 6 to 17 years, by applying the transdermal treatment system defined above to the patient's skin. In particular, the present invention relates to a method for treating hypertension or attention deficit hyperactivity disorder (ADHD) in human patients, preferably human patients aged 6 to 17 years, by applying the transdermal treatment system according to the present invention to the patient's skin.

[0295] In a preferred embodiment of the above treatment method, the transdermal treatment system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

[0296] In consideration of the above, the present invention relates in one embodiment to a transdermal therapy system comprising guanfacine and a monocarboxylic acid for use in a method of treating a human patient, preferably a human patient aged 6 to 17 years, by transdermal administration of guanfacine, wherein the transdermal therapy system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours. In a preferred embodiment, the transdermal therapy system is for use in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD), and / or as an adjunct therapy to stimulant drug therapy in human patients. In a more preferred embodiment, the transdermal therapy system is a transdermal therapy system according to the present invention, in particular a transdermal therapy system that provides one or more pharmacokinetic parameters selected from the group consisting of: AUC 0-24 10-600 (ng / ml) h, AUC 0-72 30-1800 (ng / ml)h, AUC 0-84 35-2100 (ng / ml)h, C less than 2.0 max vs C 24 ratio, C below 3.0 max vs C 72 Ratio, and C below 3.5 max vs C 84 ratio. More preferably, the following group is selected: AUC 0-24 20-400 (ng / ml) h, AUC 0-72 60-1200 (ng / ml) h, AUC 0-84 70-1400 (ng / ml)h, C less than 1.5 max vs C 24 ratio, C less than 2.5 max vs C 72 Ratio, and C below 3.0 max vs C 84 ratio.

[0297] In relation to the above-described use and treatment method, the TTS according to the present invention is preferably applied at defined dosing intervals to at least one body surface of a subject, selected from the outer upper arm, upper chest, upper back, or side of the chest.

[0298] The preferred application time for TTS according to the present invention is at least 24 hours (1 day), preferably at least 72 hours (3 days), and more preferably about 84 hours (3.5 days). After this time, the TTS may be removed, or a new TTS may be applied to enable 24-hour treatment.

[0299] Manufacturing method The present invention further relates to a method for producing an active drug-containing layer, preferably an active drug-containing matrix layer, for use in a transdermal therapy system.

[0300] According to the present invention, a method for producing an active drug-containing layer for use in a transdermal treatment system according to the present invention is: 1) At least, ingredients (i) Pharmaceutical activators, (ii) at least one monocarboxylic acid, A step of obtaining a premixture by combining, 2) (i) The premixture from step 1) and (ii) at least one polymer, A step of obtaining a coating composition by combining, 3) A step of coating the coating composition onto a backing layer or release liner to obtain a coated coating composition, 4) A step of drying the coated coating composition to form the active agent-containing layer, Includes.

[0301] In one embodiment of the present invention, the premixture obtained by step 1) of the present method is obtained by combining (i) and (ii) by dry grinding and / or slurry methods.

[0302] In one embodiment of the present invention, the slurry method of the above method is • A step of weighing equimolar amounts of the pharmaceutical activator (i) and the monocarboxylic acid (ii), The step of adding a solvent selected from the group consisting of dichloromethane, methanol, and ethyl acetate, The obtained mixture is stirred using a magnetic stirrer for at least 24 hours, preferably 24 to 36 hours. Includes.

[0303] Therefore, step 1) of the manufacturing method, the slurry method, includes the step of combining equimolar amounts of components (i) and (ii) in at least one solvent selected from the group consisting of dichloromethane, methanol, and ethyl acetate.

[0304] To obtain a premixture of the pharmaceutically active agent and monocarboxylic acid by the slurry method of step 1), the solvent is removed from the mixture obtained above under reduced pressure, and the residue is dried under vacuum for at least 24 hours.

[0305] In step 2) of the above manufacturing method, it is preferable to disperse the premixture obtained in step 1) in at least one polymer to obtain a homogeneous coating composition. In this regard, it should be understood that the premixture obtained in step 1) can be obtained by dry grinding and / or slurry methods.

[0306] It should be understood that in step 2), further components, preferably at least one of the additives defined above, may also be added.

[0307] Preferably, the solvent is added in step 2) of the method and / or the solvent is present because one or more polymers are provided in the form of a solution. The solvent is preferably selected from alcoholic solvents, specifically methanol, ethanol, isopropanol, and mixtures thereof, and non-alcoholic solvents, specifically ethyl acetate, hexane, heptane, petroleum ether, toluene, and mixtures thereof. Preferably, the solvent is selected from non-alcoholic solvents, most preferably ethyl acetate or n-heptane. In a particularly preferred embodiment, the solvent is ethyl acetate.

[0308] In a preferred embodiment, at least one of the polymers defined above, in particular a mixture of the polymers defined above, is provided as a solution, the solvent being ethyl acetate or n-heptane, preferably ethyl acetate.

[0309] In a preferred embodiment, at least one polymer as defined above has a solids content of 40 to 70% by weight.

[0310] In step 3) of the method, the coating composition is applied to the backing layer or release liner. As a result, a coated coating composition is obtained, i.e., a coating composition coated on the backing layer or release liner.

[0311] After the active ingredient-containing layer is formed in step 4), the method may further include the step of applying a release liner or backing layer to the other side of the active ingredient-containing layer.

[0312] In step 4) of the above manufacturing method, drying is preferably carried out at a temperature of 20 to 90°C, more preferably 30 to 70°C.

[0313] In a preferred embodiment of the manufacturing method defined in the above embodiment, the pharmaceutically active agent (i) in the active agent-containing layer is guanfacine.

[0314] In another preferred embodiment of the manufacturing method defined above, monocarboxylic acid(ii) is sorbic acid.

[0315] In relation to the above embodiments of the manufacturing method, it should be understood that at least one polymer, further additives, and the activator-containing layer, preferably the guanfacine-containing layer, are as defined above with respect to TTS. [Examples]

[0316] The present invention will now be described more fully with reference to the attached examples. However, it should be understood that the following description is illustrative only and should not be construed as limiting the present invention. The numerical values ​​provided in the examples regarding the amount or area weight of components in the composition may vary slightly due to manufacturing variations.

[0317] Comparative Examples 1A, 1B, 1C, and 1D Coating composition The formulations of the guanfacine-containing coating compositions of Comparative Examples 1A, 1B, 1C, and 1C are summarized in Tables 1.1 and 1.2 below. The solids content % value refers to the amount in weight % (Amt).

[0318] [Table 1]

[0319] [Table 2]

[0320] Preparation of coating composition The drug substance (sorbic acid, if present) and the accelerator used were dispersed in ethyl acetate solvent and optionally sonicated for about 5 minutes. The adhesive was then added. These two steps can also be performed in the reverse order. The mixture was homogenized using a dissolver stirrer at 2000 rpm for 10 minutes.

[0321] In Comparative Example 1B, a premixture of guanfacine base and polyoxyethylene(4) lauryl ether (Brij L4) in a 1:1 ratio was prepared. The premixture was prepared by dry milling using zirconium oxide milling beads (bead size 1 mm, Retsch mixer mill MM500) at 35 Hz for approximately 1.5 hours, achieving a particle size of approximately 5 μm. To prepare the coating composition, the premixture was stirred, and the accelerator and adhesive used were added. The mixture was homogenized using a dissolver stirrer at 2000 rpm for approximately 10 minutes.

[0322] In Comparative Example 1D, equimolar amounts of guanfacine base and sorbic acid were ground in a mortar for 15 minutes. To prepare the coating composition, the guanfacine base and sorbic acid were dry-ground, the accelerator used was dissolved in ethyl acetate solvent, and sonicated for 5 minutes. The adhesive was then added. The mixture was homogenized using a dissolver stirrer at 2000 rpm for 10 minutes.

[0323] Coating of coating composition Taking into account the desired dry coating weight and according to the solid content of the mixture, the resulting guanfacine-containing coating composition was coated onto a polyethylene terephthalate film (Scotchpak 9755, which can function as a release liner) using, for example, an Eriksen film applicator, and dried at approximately 50°C for approximately 10 minutes. Depending on the area weight of the target, the gap of the corresponding film applicator was between 325 and 350 μm.

[0324] By selecting the coating thickness, the area weight of the guanfacine-containing layer as a result of solution removal is approximately 95 g / m² (Comparative Example 1A). 2 , 96 (Comparative Example 1B) g / m 2 , 95 (Comparative Example 1C) g / m 2 , and 89 (Comparative Example 1D) g / m² 2Next, the dried film was laminated with a backing layer (PET 15 μm [tsp]) to provide a guanfacine-containing self-adhesive layer structure.

[0325] Preparation of TTS (for all examples) Next, individual systems (TTS) were punched out from the guanfacine-containing self-adhesive layer structure obtained as described above. Then, the TTS were sealed in pouches of primary packaging material.

[0326] Measurement of skin permeability The permeation of TTS prepared according to Comparative Examples 1A-D was measured using a 7.0 mL Franz diffusion cell in accordance with OECD guidelines (adopted April 13, 2004). Split-thickness Göttinger miniature pig skin (female) was used. Using a skin harvesting knife, skin with intact epidermis for all TTS was prepared to a thickness of 800 μm. 1.17 cm 2 A die-cut with the specified emission area was punched out from a TTS. The amount of guanfacine permeated into the receptor medium of the Franz diffusion cell (0.9% sodium chloride solution containing 0.1% sodium azide as an antimicrobial agent) was measured at a temperature of 32±1℃, and the corresponding cumulative permeation amount was calculated.

[0327] The results are shown in Tables 1.3 and 1.4, and in Figures 1.1, 1.2, and 1.3.

[0328] [Table 3]

[0329] [Table 4]

[0330] Examples 1A, 1B, 1C, 1D, and 1E Coating composition The formulations of the guanfacine-containing coating compositions of Examples 1A, 1B, 1C, 1D, and 1E are summarized in Tables 1.4, 1.5, and 1.6 below. The solids content % value refers to the amount in weight % (Amt).

[0331] [Table 5-1] [Table 5-2]

[0332] [Table 6-1] [Table 6-2]

[0333] [Table 7]

[0334] Preparation of coating composition A premixture of guanfacine base, sorbic acid, and methanol was prepared. The premixture was prepared by dry milling using zirconium oxide milling beads (bead size 3 mm, Retsch mixer mill MM500) at 35 Hz for approximately 10 minutes. The guanfacine base and sorbic acid were present in a 1:1 ratio. To prepare the coating composition, the premixture and the accelerator used were dispersed in ethyl acetate solvent and sonicated for approximately 5 minutes. The adhesive was then added. These two steps can also be performed in the reverse order. The mixture was homogenized using a dissolver stirrer at 2000 rpm for 10 minutes.

[0335] Coating of coating composition Taking into account the desired dry coating weight and according to the solid content of the mixture, the resulting guanfacine-containing coating composition was coated onto a polyethylene terephthalate film (Scotchpak 9755, which can function as a release liner) using, for example, an Eriksen film applicator, and dried at approximately 50°C for approximately 10 minutes. Depending on the area weight of the target, the gap of the corresponding film applicator was between 300 and 400 μm.

[0336] By selecting the coating thickness, the area weight of the guanfacine-containing layer as a result of solution removal is approximately 100 g / m² (Example 1A). 2 , 94 (Example 1B) g / m 2 , 91 (Example 1C) g / m 2 , 98 (Example 1D) g / m 2 and 81 (Example 1E) g / m 2 Next, the dried film was laminated with a backing layer (PET 15 μm [tsp] or MN19AB I) to provide a guanfacine-containing self-adhesive layer structure.

[0337] Preparation of TTS See Comparative Examples 1A to 1D.

[0338] Measurement of skin permeability The permeation of TTS prepared according to Examples 1A-E was measured using a 7.0 mL Franz diffusion cell in accordance with OECD guidelines (adopted April 13, 2004). Split-thickness Göttinger miniature pig skin (female) was used. Using a skin harvesting knife, skin with intact epidermis for all TTS was prepared to a thickness of 800 μm. 1.17 cm 2 A die-cut with the specified emission area was punched out from a TTS. The amount of guanfacine permeated into the receptor medium of the Franz diffusion cell (0.9% sodium chloride solution containing 0.1% sodium azide as an antimicrobial agent) was measured at a temperature of 32±1℃, and the corresponding cumulative permeation amount was calculated.

[0339] The results are shown in Tables 1.7 and 1.8, and in Figure 1.3.

[0340] [Table 8]

[0341] [Table 9]

[0342] Examples 2A, 2B, 2C and Comparative Examples 2A, 2B Coating composition The formulations of the guanfacine-containing coating compositions for Examples 2A, 2B, and 2C, and Comparative Examples 2A and 2B, are summarized in Tables 2.1, 2.2, and 2.3 below. The solids content % values ​​refer to the amount in weight % (Amt).

[0343] [Table 10]

[0344] [Table 11]

[0345] [Table 12]

[0346] Preparation of coating composition The guanfacine / sorbic acid premixture was prepared according to the slurry method, i.e., following the general procedure outlined below. Free guanfacine base and sorbic acid were weighed in equimolar amounts. A solvent, such as 1 mL of DCM, was added, and the mixture was stirred at room temperature for at least 1 day using a magnetic stirrer. The white solid was collected by filtration under vacuum, washed with solvent (at least 4 mL), and dried under vacuum at 40°C for 24 hours. In Comparative Example 2, a premixture was not prepared, but guanfacine was used in the form of a free base.

[0347] To prepare the coating composition, a guanfacine / sorbic acid premixture or guanfacine free base and the accelerator used were dispersed in ethyl acetate solvent and sonicated for approximately 5 minutes. The adhesive was then added. These two steps can also be performed in the reverse order. The mixture was homogenized using a dissolver stirrer at 2000 rpm for 10 minutes.

[0348] To prepare Comparative Examples 2A and 2B, free guanfacine base and any accelerator used were dispersed in ethyl acetate solvent and sonicated for approximately 5 minutes as needed. The adhesive was then added. These two steps can also be performed in the reverse order. The mixtures were homogenized using a dissolver stirrer at approximately 1500 rpm for 15 minutes.

[0349] Coating of coating composition Taking into account the desired dry coating weight and according to the solid content of the mixture, the resulting guanfacine-containing coating composition was coated onto a polyethylene terephthalate film (Scotchpak 9755, which can function as a release liner) using, for example, an Eriksen film applicator, and dried at approximately 50°C for approximately 10 minutes. Depending on the area weight of the target, the gap of the corresponding film applicator was between 325 and 450 μm.

[0350] By selecting the coating thickness, the area weight of the guanfacine-containing layer resulting from solution removal is approximately 137 g / m² (Example 2A). 2 , 104 (Example 2B) g / m 2 , 102 (Example 2C) g / m 2 , 95 (Comparative Example 2A) g / m 2 , and 95 (Comparative Example 2B) g / m² 2 Next, the dried film was laminated with a backing layer (MN 19 SIL, PET RN15, or PET 15 μm) to provide a guanfacine-containing self-adhesive layer structure.

[0351] Preparation of TTS See Comparative Examples 1A to 1D.

[0352] Measurement of skin permeability The permeation rates of TTS prepared according to Examples 2A-C and Comparative Examples 2A and 2B were measured using a 7.0 mL Franz diffusion cell in accordance with OECD guidelines (adopted April 13, 2004). Split-thickness Göttinger miniature pig skin (female) was used. Using a skin harvesting knife, skin with intact epidermis for all TTS was prepared to a thickness of 800 μm. 1.17 cm 2 A die-cut with the specified emission area was punched out from a TTS. The amount of guanfacine permeated into the receptor medium of the Franz diffusion cell (0.9% sodium chloride solution containing 0.1% sodium azide as an antimicrobial agent) was measured at a temperature of 32±1℃, and the corresponding cumulative permeation amount was calculated.

[0353] The results are shown in Tables 2.4 and 2.5, and in Figure 2.

[0354] [Table 13]

[0355] [Table 14]

[0356] Examples 3A, 3B, 3C, 3D, 3E and Comparative Example 3 Coating composition The formulations of the guanfacine-containing coating compositions of Examples 3A, 3B, 3C, 3D, and 3E, as well as Comparative Example 3, are summarized in Tables 3.1, 3.2, 3.3, and 3.4 below. The solids content % values ​​refer to the amount in weight % (Amt).

[0357] [Table 15]

[0358] [Table 16]

[0359] [Table 17]

[0360] [Table 18]

[0361] Preparation of coating composition The guanfacine / sorbic acid premixture was prepared according to the slurry method, i.e., following the general procedure outlined below. Free guanfacine base and sorbic acid were weighed in equimolar amounts. A solvent, such as 1 mL of DCM, was added, and the mixture was stirred at room temperature for at least 1 day using a magnetic stirrer. The white solid was collected by filtration under vacuum, washed with solvent (at least 4 mL), and dried under vacuum at 40°C for 24 hours. In Comparative Example 3, a premixture was not prepared, but guanfacine was used in the form of a free base.

[0362] To prepare the coating composition, the guanfacine / sorbic acid premixture or guanfacine free base and adhesive were dispersed in ethyl acetate solvent, and the mixture was homogenized at 2000 rpm for about 10 minutes using a dissolver stirrer. In the case of Example 3A, when BIO-PSA 4202 and BIO-PSA 4302 were used together, the adhesive was mixed together with the guanfacine / sorbic acid premixture and stirred at 2000 rpm for about 10 minutes until homogenized.

[0363] Coating of coating composition Taking into account the desired dry coating weight and according to the solid content of the mixture, the resulting guanfacine-containing coating composition was coated onto a polyethylene terephthalate film (Scotchpak 9755, which can function as a release liner) using, for example, an Eriksen film applicator, and dried at approximately 50°C for approximately 10 minutes. Depending on the area weight of the target, the gap of the corresponding film applicator was between 300 and 400 μm.

[0364] By selecting the coating thickness, the area weight of the guanfacine-containing layer resulting from solution removal is approximately 114 g / m² (Example 3A). 2 , 87 (Example 3B) g / m 2 , 102 (Example 3C) g / m 2 , 90 (Example 3D) g / m 2 , 96 (Example 3E) g / m 2 and 95 (Comparative Example 3) g / m 2 Next, the dried film was laminated with a backing layer (MN19SIL or PET 15μm) to provide a guanfacine-containing self-adhesive layer structure.

[0365] Preparation of TTS See Comparative Examples 1A to 1D.

[0366] Measurement of skin permeability The permeation rates of TTS prepared according to Examples 3A-E and Comparative Example 3 were measured using a 7.0 mL Franz diffusion cell in accordance with OECD guidelines (adopted April 13, 2004). Split-thickness Göttinger miniature pig skin (female) was used. Using a skin harvesting knife, skin with intact epidermis for all TTS was prepared to a thickness of 800 μm. 1.17 cm 2 A die-cut with the specified emission area was punched out from a TTS. The amount of guanfacine permeated into the receptor medium of the Franz diffusion cell (0.9% sodium chloride solution containing 0.1% sodium azide as an antimicrobial agent) was measured at a temperature of 32±1℃, and the corresponding cumulative permeation amount was calculated.

[0367] The results are shown in Tables 3.5 and 3.6, and in Figure 3.

[0368] [Table 19]

[0369] [Table 20]

[0370] Examples 4A, 4B, 4C, 4D and Comparative Example 4 Coating composition The formulations of the guanfacine-containing coating compositions of Examples 4A, 4B, 4C, and 4D, and Comparative Example 4, are summarized in Tables 4.1, 4.2, and 4.3 below. The solids content % value refers to the amount in weight % (Amt).

[0371] [Table 21]

[0372] [Table 22]

[0373] [Table 23]

[0374] Preparation of coating composition A guanfacine / sorbic acid premixture was prepared according to the slurry method, i.e., by the following general procedure: Equimolar amounts of free guanfacine base and sorbic acid were weighed. A solvent, e.g., 1 mL of DCM, was added, and the mixture was stirred at room temperature for at least 1 day using a magnetic stirrer. The white solid was collected by filtration under vacuum, washed with solvent (at least 4 mL), and dried under vacuum at 40°C for 24 hours. In Comparative Example 4, no premixture was prepared, but guanfacine was used in the form of a free base.

[0375] To prepare the coating composition, the guanfacine / sorbic acid premixture or guanfacine free base, the accelerator used, and the adhesive were dispersed in ethyl acetate solvent, and the mixture was homogenized at 2000 rpm for approximately 10 minutes using a dissolver stirrer. When used together, the adhesives SilAc6102 and SilAc6302 were mixed together with the guanfacine / sorbic acid premixture and stirred at 2000 rpm for approximately 10 minutes until homogenized.

[0376] In Comparative Example 4, the free guanfacine base and the accelerator used were dissolved in ethyl acetate solvent, and the adhesive was added. The mixture was homogenized using a dissolver stirrer at 2000 rpm for approximately 10 minutes.

[0377] Coating of coating composition Taking into account the desired dry coating weight and according to the solid content of the mixture, the resulting guanfacine-containing coating composition was coated onto a polyethylene terephthalate film (Scotchpak 9755, which can function as a release liner) using, for example, an Eriksen film applicator, and dried at approximately 50°C for approximately 10 minutes. Depending on the area weight of the target, the gap of the corresponding film applicator was between 325 and 350 μm.

[0378] By selecting the coating thickness, the area weight of the guanfacine-containing layer resulting from solution removal is approximately 103 g / m² (Example 4A). 2 , 93 (Example 4B) g / m 2 , 96 (Example 4C) g / m 2 , 100 (Example 4D) g / m 2 and 95 (Comparative Example 4) g / m 2 Next, the dried film was laminated with a backing layer (PET 15 μm) to provide a guanfacine-containing self-adhesive layer structure.

[0379] Preparation of TTS See Comparative Examples 1A to 1D.

[0380] Measurement of skin permeability The permeation rates of TTS prepared according to Examples 4A-D and Comparative Example 4 were measured using a 7.0 mL Franz diffusion cell in accordance with OECD guidelines (adopted April 13, 2004). Split-thickness Göttinger miniature pig skin (female) was used. Using a skin harvesting knife, skin with intact epidermis for all TTS was prepared to a thickness of 800 μm. 1.17 cm 2 A die-cut with the specified emission area was punched out from a TTS. The amount of guanfacine permeated into the receptor medium of the Franz diffusion cell (0.9% sodium chloride solution containing 0.1% sodium azide as an antimicrobial agent) was measured at a temperature of 32±1℃, and the corresponding cumulative permeation amount was calculated.

[0381] The results are shown in Tables 4.3 and 4.4, and in Figures 4.1 and 4.2.

[0382] [Table 24]

[0383] [Table 25]

[0384] Comparative Examples 5A, 5B, 5C, 5D, 5E, and 5F Coating composition The formulations of the guanfacine-containing coating compositions of Comparative Examples 5A, 5B, 5C, 5D, 5E, and 5F are summarized in Tables 5.1, 5.2, 5.3, and 5.4 below. The solids content % value refers to the amount in weight % (Amt).

[0385] [Table 26]

[0386] [Table 27]

[0387] [Table 28]

[0388] [Table 29]

[0389] Preparation of coating composition A premixture of guanfacine base and pimelic acid was prepared. The premixture was prepared by milling the mixture of guanfacine base and pimelic acid using zirconium oxide milling beads (bead size 3 mm, Retsch mixer mill MM500) at 35 Hz for approximately 10 minutes. The guanfacine base and pimelic acid were present in a 1:1 ratio. To prepare the coating composition, the premixture and the accelerator used were dispersed in ethyl acetate solvent and sonicated for approximately 5 minutes. The adhesive was then added. These two steps can also be performed in the reverse order. The mixture was homogenized using a dissolver stirrer at 2000 rpm for 10 minutes. In Comparative Example 5F, a premixture of guanfacine base and pimelic acid was not prepared. Instead, the guanfacine base, pimelic acid, and accelerator used were weighed directly to prepare the coating composition.

[0390] Coating of coating composition Taking into account the desired dry coating weight and according to the solid content of the mixture, the resulting guanfacine-containing coating composition was coated onto a polyethylene terephthalate film (Scotchpak 9755, which can function as a release liner) using, for example, an Eriksen film applicator, and dried at approximately 50°C for approximately 10 minutes. Depending on the area weight of the target, the gap of the corresponding film applicator was between 300 and 525 μm.

[0391] By selecting the coating thickness, the area weight of the guanfacine-containing layer as a result of solution removal is approximately 90 g / m² (Comparative Example 5A). 2 , 96 (Comparative Example 5B) g / m 2 , 112 (Comparative Example 5C) g / m 2 , 107 (Comparative Example 5D) g / m 2 , 99 (Comparative Example 5E) g / m 2 , and 104 (Comparative Example 5F) g / m 2 Next, the dried film was laminated with a backing layer (PET MN 19 AB 1 or PET 15 μm [tsp]) to provide a guanfacine-containing self-adhesive layer structure.

[0392] Preparation of TTS See Comparative Examples 1A to 1D.

[0393] Measurement of skin permeability The permeation of TTS prepared according to Comparative Examples 5A-F was measured using a 7.0 mL Franz diffusion cell in accordance with OECD guidelines (adopted April 13, 2004). Split-thickness Göttinger miniature pig skin (female) was used. Using a skin harvesting knife, skin with intact epidermis for all TTS was prepared to a thickness of 800 μm. 1.17 cm 2 A die-cut with the specified emission area was punched out from a TTS. The amount of guanfacine permeated into the receptor medium of the Franz diffusion cell (0.9% sodium chloride solution containing 0.1% sodium azide as an antimicrobial agent) was measured at a temperature of 32±1℃, and the corresponding cumulative permeation amount was calculated.

[0394] The results are shown in Tables 5.5 and 5.6, and in Figures 5.1 and 5.2.

[0395] [Table 30]

[0396] [Table 31]

[0397] Example 6 and Comparative Example 6 Coating composition The formulations of the guanfacine-containing coating compositions of Example 6 and Comparative Example 6 are summarized in Table 6.1 below. The solids content % value refers to the amount in weight % (Amt).

[0398] [Table 32]

[0399] Preparation of coating composition The guanfacine / sorbic acid premixture of Example 6 and the guanfacine / glutaric acid premixture of Comparative Example 6 were prepared according to the slurry method, i.e., according to the following general procedure. Equimolar amounts of guanfacine free base and each acid were weighed. A solvent, such as 1 mL of DCM or 2 mL of ethyl acetate, was added, and the mixture was stirred at room temperature for at least 1 day using a magnetic stirrer. The white solid was collected by filtration under vacuum, washed with solvent (at least 4 mL), and dried under vacuum at 40°C for 24 hours.

[0400] To prepare the coating composition, a guanfacine / sorbic acid premixture or guanfacine / glutaric acid premixture, the accelerator used, and the adhesive were dispersed in ethyl acetate solvent, and the mixture was homogenized at 1400 rpm for about 15 minutes using a dissolver stirrer.

[0401] Coating of coating composition Taking into account the desired dry coating weight and according to the solid content of the mixture, the resulting guanfacine-containing coating composition was coated onto a polyethylene terephthalate film (Scotchpak 9755, which can function as a release liner) using, for example, an Eriksen film applicator, and dried at approximately 50°C for approximately 15 minutes. Depending on the area weight of the target, the gap of the corresponding film applicator was between 275 and 350 μm.

[0402] By selecting the coating thickness, the area weight of the guanfacine-containing layer as a result of solution removal is approximately 89 g / m² (Example 6). 2 and 94 (Comparative Example 6) g / m 2 Next, the dried film was laminated with a backing layer (PET 15 μm [tsp.]) to provide a guanfacine-containing self-adhesive layer structure.

[0403] Preparation of TTS See Comparative Examples 1A to 1D.

[0404] Measurement of skin permeability The permeation rates of TTS prepared according to Example 6 and Comparative Example 6 were measured according to the OECD guidelines (adopted April 13, 2004) using a 7.0 mL Franz diffusion cell. Split-thickness Göttinger miniature pig skin was used. Using a skin harvesting knife, skin with intact epidermis for all TTS was prepared to a thickness of 800 μm. 1.17 cm 2 A die-cut with the specified emission area was punched out from a TTS. The amount of guanfacine permeated into the receptor medium of the Franz diffusion cell (0.9% sodium chloride solution containing 0.1% sodium azide as an antimicrobial agent) was measured at a temperature of 32±1℃, and the corresponding cumulative permeation amount was calculated.

[0405] The results are shown in Table 6.1 and Figure 6.

[0406] [Table 33]

[0407] The present invention relates in particular to the following further provisions. 1. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) A guanfacine-containing layer comprising guanfacine and monocarboxylic acid, The transdermal treatment system, including the above.

[0408] 2. The guanfacine-containing layer is i) Guanfacine and monocarboxylic acid, ii) at least one polymer, The transdermal treatment system according to Clause 1, comprising a guanfacine-containing matrix layer.

[0409] 3. The transdermal treatment system according to Clause 1 or 2, wherein the monocarboxylic acid is sorbic acid.

[0410] 4. The transdermal treatment system according to any one of the clauses 1 to 3, wherein the guanfacine-containing layer structure is self-adhesive and preferably does not include an additional skin contact layer.

[0411] 5. The transdermal treatment system according to any one of the clauses 1 to 4, wherein the at least one polymer is selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof.

[0412] 6. The at least one polymer is A mixture of an acrylic polymer and at least one silicone-based polymer, or • A mixture of two silicone-acrylic hybrid polymers, or • A mixture of two silicone-based polymers, or • Acrylic polymer, or Acrylic polymer containing -OH groups A percutaneous treatment system as described in any one of clauses 1 to 5.

[0413] 7. The transdermal treatment system according to any one of Clause 5 or 6, wherein the silicone-based polymer is obtained by polycondensation with a silicate resin of silanol-terminated polydimethylsiloxane.

[0414] 8. The transdermal treatment system according to any one of Clauses 5 to 7, wherein the acrylic polymer is selected from copolymers based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, and glycidyl methacrylate, and copolymers based on 2-ethylhexyl acrylate and vinyl acetate.

[0415] 9. The silicone-acrylic hybrid polymer is a silicone-acrylic hybrid pressure-sensitive adhesive, and the silicone-acrylic hybrid pressure-sensitive adhesive is (a) A silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group, and (b) an ethylenically unsaturated monomer, (c) Initiator and, A transdermal treatment system according to any one of clauses 5 to 8, comprising the reaction product thereof.

[0416] 10. The silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group is (a1) Silicone resin and (a2) Silicone polymer and (a3) A silicon-containing encapsulant containing an acrylate or methacrylate functional group, The silicon-containing encapsulant comprises a condensation reaction product of the general formula XYR' b SiZ 3-b {wherein X is a monovalent group of the general formula AE (where E is -O- or -NH-, and A is an acrylic group or a methacrylic group), Y is a divalent alkylene group having 1 to 6 carbon atoms, R' is a methyl or phenyl group, Z is a monovalent hydrolyzable organic group or halogen, and b is 0 or 1}, The silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, and the silicon-containing sealant is introduced before, during, or after the reaction of the silicone resin and the silicone polymer. The transdermal treatment system according to Clause 9, wherein the silicon-containing encapsulant reacts with the pressure-sensitive adhesive after the silicone resin and the silicone polymer undergo a condensation reaction to form the pressure-sensitive adhesive, or the silicon-containing encapsulant reacts in situ with the silicone resin and the silicone polymer.

[0417] 11. The transdermal treatment system according to any one of Clause 9 or 10, wherein the ethylenically unsaturated monomer is selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, alicyclic acrylates, alicyclic methacrylates, and combinations thereof, each of the compounds having up to 20 carbon atoms in the alkyl group, and the ethylenically unsaturated monomer is preferably a combination of 2-ethylhexyl acrylate and methyl acrylate, particularly preferably in a ratio of 40:60 to 70:30.

[0418] 12. (b1) The silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group, (b2) The ethylenically unsaturated monomer and, (b3) The initiator and, The transdermal treatment system according to any one of the clauses 9 to 11, wherein the reaction product comprises a continuous acrylic outer phase and a discontinuous silicone inner phase.

[0419] 13. The transdermal treatment system according to any one of the clauses 1 to 12, wherein the guanfacine-containing layer structure contains guanfacine in an amount of 1 to 100 mg / TTS, preferably 3 to 72 mg / TTS.

[0420] 14. The transdermal treatment system according to any one of the claims 1 to 13, wherein the guanfacine-containing layer contains guanfacine in an amount of 1 to 20% by weight, more preferably 2 to 16% by weight, based on the total weight of the guanfacine-containing layer.

[0421] 15. The transdermal treatment system according to any one of the claims 1 to 14, wherein the guanfacine-containing layer contains the monocarboxylic acid in an amount of 1 to 20% by weight, more preferably 2 to 16% by weight, based on the total weight of the guanfacine-containing layer.

[0422] 16. A transdermal treatment system according to any one of clauses 1 to 15, comprising guanfacine and the monocarboxylic acid in equimolar amounts.

[0423] 17. The transdermal treatment system according to any one of the claims 1 to 16, wherein the guanfacine-containing layer comprises at least one polymer in an amount of 20 to 99% by weight, preferably 30 to 97% by weight, and most preferably 35 to 94% by weight, based on the total weight of the guanfacine-containing layer.

[0424] 18. The transdermal treatment system according to any one of the claims 1 to 17, wherein the guanfacine-containing layer comprises a mixture of an acrylic polymer and at least one silicone-based polymer, and based on the total weight of the guanfacine-containing layer, the acrylic polymer is present in an amount of 20 to 55% by weight and the at least one silicone-based polymer is present in an amount of 20 to 55% by weight.

[0425] 19. The transdermal treatment system according to any one of the claims 1 to 17, wherein the guanfacine-containing layer comprises a mixture of two silicone-acrylic hybrid polymers, in each case, based on the total weight of the guanfacine-containing layer, the first silicone-acrylic hybrid polymer is present in an amount of 60 to 90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1 to 20% by weight, preferably the first silicone-acrylic hybrid polymer and the second silicone-acrylic hybrid polymer comprise a silicone phase and an acrylate phase in a weight ratio of 60:40 to 40:60.

[0426] 20. The transdermal treatment system according to any one of the clauses 1 to 17, wherein the guanfacine-containing layer comprises a mixture of two silicone-based polymers, and based on the total weight of the guanfacine-containing layer, the first silicone-based polymer is present in an amount of 20 to 55% by weight and the second silicone-based polymer is present in an amount of 20 to 55% by weight.

[0427] twenty one. The transdermal treatment system according to any one of the clauses 1 to 20, wherein the guanfacine-containing layer further comprises at least one additive, preferably at least two additives, selected from the group consisting of dispersants, permeation enhancers, and solubilizers.

[0428] twenty two. The dispersant is selected from the group consisting of esters of fatty acids and polyols, aliphatic alcohols, polyethylene glycol having a number average molecular weight of 300 to 400, and polyethylene glycol alkyl ethers. Preferably, the dispersant is polyethylene glycol C8 to C having 2 to 10 EO units. 20 - An alkyl ether, as described in Clause 21, for the transdermal treatment system.

[0429] twenty three. The permeation enhancer is selected from the group consisting of diethylene glycol monoethyl ether (Transktol), oleic acid, levulinic acid, caprylic / capric acid triglyceride, diisopropyl adipate, isopropyl myristart, isopropyl palmitate, lauryl lactate, triacetin, dimethylpropylene urea, oleyl alcohol, oleoyl macrogol-6 glyceride (labrafil MS 1944), and lauroglycol, wherein the permeation enhancer is preferably oleyl alcohol, lauroglycol, or oleoyl macrogol-6 glyceride (labrafil MS 1944), as described in the transdermal treatment system according to Clause 21 or 22.

[0430] twenty four. The transdermal treatment system according to any one of the claims 21 to 23, wherein the solubilizer is selected from the group consisting of copolymers derived from esters of acrylic acid and methacrylic acid, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, preferably polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0431] twenty five. The transdermal treatment system according to any one of the clauses 21 to 24, wherein the guanfacine-containing layer comprises two additives selected from a dispersant and a permeation enhancer.

[0432] 26. The area weight of the guanfacine-containing layer is 40-250 g / m². 2 Preferably, 50-180 g / m² 2 The range is 1 to 100 cm², and / or the emission area is 1 to 100 cm². 2 Preferably, 2.5 to 50 cm 2 A transdermal treatment system described in any one of clauses 1 to 25, which falls within the scope of the system.

[0433] 27. The guanfacine load in the aforementioned transdermal treatment system is 0.4-2 mg / cm³. 2 Preferably, 0.4 to 0.85 mg / cm³ 2 A transdermal treatment system described in any one of clauses 1 to 26, which falls within the scope of the system.

[0434] 28. The transdermal therapy system according to any one of claims 1 to 27, wherein the transdermal therapy system provides a plasma concentration of 1 to 20 ng / ml, preferably 1 to 15 ng / ml of guanfacine by transdermal delivery in a steady state.

[0435] 29. AUC of approximately 10-600 ng*h / ml, preferably approximately 20-400 ng*h / ml 0-24hHaving and / or an AUC of about 30-1800 ng*h / ml, preferably about 60-1200 ng*h / ml 0-72h Having and / or an AUC of about 35-2100 ng*h / ml, preferably about 70-1400 ng*h / ml 0-84h Having and / or less than 3.5 C max C 84 A ratio of less than 3.0 to C max C 72 A ratio of C to and / or less than 2.0 max C 24 A percutaneous treatment system according to any one of clauses 1 to 28, having a ratio to [a certain value].

[0436] 30. Measurements using Franz diffusion cells with skin collected from miniature pigs showed a reading of 0.01 μg / cm³ in the first 24 hours. 2 *h)~8μg / (cm 2 *h), 0.05 μg / cm³ from 24 hours to 88 hours. 2 *h)~10μg / (cm 2 *h) A transdermal treatment system according to any one of clauses 1 to 29 that provides the following skin penetration rates of guanfacine.

[0437] 31. Measurements using Franz diffusion cells with skin collected from miniature pigs showed a concentration of 0.01 mg / cm³ over an 88-hour period. 2 ~0.7 mg / cm³ 2 Preferably 0.05 mg / cm³ 2 ~0.6 mg / cm³ 2 More preferably 0.10 mg / cm³ 2 ~0.5 mg / cm³ 2 A transdermal treatment system according to any one of clauses 1 to 30, which provides a cumulative permeation amount of guanfacine.

[0438] 32. A percutaneous treatment system according to any one of Clauses 1 to 31, for use in a method of treating human patients, preferably human patients aged 6 to 17 years.

[0439] 33. A transdermal treatment system according to any one of Clauses 1 to 31, for use in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD), and / or for use as an adjunct therapy to stimulant drug therapy in human patients, preferably human patients aged 6 to 17 years.

[0440] 34. The transdermal treatment system is a transdermal treatment system for use in accordance with the description in Clause 32 or 33, which is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

[0441] 35. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) A mixture of an acrylic polymer and at least one silicone-based polymer, wherein, based on the total weight of the guanfacine-containing layer, the acrylic polymer is present in an amount of 20-55% by weight and the at least one silicone-based polymer is present in an amount of 20-55% by weight, iii) Based on the total weight of the guanfacine-containing layer, at least one dispersant in an amount of 2 to 6% by weight, iv) Based on the total weight of the guanfacine-containing layer, at least one permeation enhancer in an amount of 2 to 6% by weight, The transdermal treatment system, including the above.

[0442] 36. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight, iii) Based on the total weight of the guanfacine-containing layer, at least one dispersant in an amount of 2 to 6% by weight, iv) Based on the total weight of the guanfacine-containing layer, at least one permeation enhancer in an amount of 2 to 6% by weight, The transdermal treatment system, including the above.

[0443] 37. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) A mixture of two silicone-based polymers, wherein, based on the total weight of the guanfacine-containing layer, the first silicone-based polymer is present in an amount of 20-55% by weight, and the second silicone-based polymer is present in an amount of 20-55% by weight. iii) Based on the total weight of the guanfacine-containing layer, at least one dispersant in an amount of 2 to 6% by weight, iv) Based on the total weight of the guanfacine-containing layer, at least one permeation enhancer in an amount of 2 to 6% by weight, The transdermal treatment system, including the above.

[0444] 38. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) Based on the total weight of the guanfacine-containing layer, an amount of 65-95% by weight of acrylic polymer, iii) Based on the total weight of the guanfacine-containing layer, at least one dispersant in an amount of 2 to 6% by weight, iv) Based on the total weight of the guanfacine-containing layer, at least one permeation enhancer in an amount of 2 to 6% by weight, The transdermal treatment system, including the above.

[0445] 39. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) Based on the total weight of the guanfacine-containing layer, an acrylic polymer containing -OH groups in an amount of 65 to 95% by weight, iii) Based on the total weight of the guanfacine-containing layer, at least one dispersant in an amount of 2 to 6% by weight, iv) Based on the total weight of the guanfacine-containing layer, at least one permeation enhancer in an amount of 2 to 6% by weight, The transdermal treatment system, including the above.

[0446] 40. A transdermal treatment system according to Clause 35, comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) A mixture of an acrylic polymer and at least one silicone-based polymer, wherein, based on the total weight of the guanfacine-containing layer, the acrylic polymer is present in an amount of 20-55% by weight and the at least one silicone-based polymer is present in an amount of 20-55% by weight, iii) Based on the total weight of the guanfacine-containing layer, polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight. 20 -alkyl ether and, iv) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of oleyl alcohol and The transdermal treatment system, including the above.

[0447] 41. A transdermal treatment system according to Clause 36, comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight, iii) Based on the total weight of the guanfacine-containing layer, polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight. 20 -alkyl ether and, iv) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of oleyl alcohol and The transdermal treatment system, including the above.

[0448] 42. A transdermal treatment system according to Clause 37, comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) A mixture of two silicone-based polymers, wherein, based on the total weight of the guanfacine-containing layer, the first silicone-based polymer is present in an amount of 20-55% by weight, and the second silicone-based polymer is present in an amount of 20-55% by weight. iii) Based on the total weight of the guanfacine-containing layer, polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight. 20 -alkyl ether and, iv) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of oleyl alcohol and The transdermal treatment system, including the above.

[0449] 43. A transdermal treatment system according to Clause 38, comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) Based on the total weight of the guanfacine-containing layer, an amount of 65-95% by weight of acrylic polymer, iii) Based on the total weight of the guanfacine-containing layer, polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight. 20 -alkyl ether and, iv) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of oleyl alcohol and The transdermal treatment system, including the above.

[0450] 44. A transdermal treatment system according to Clause 39, comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 3 to 16% by weight of guanfacine and 1 to 7.2% by weight of sorbic acid, ii) Based on the weight of the guanfacine-containing layer, an acrylic polymer containing -OH groups in an amount of 65 to 95% by weight, iii) Based on the total weight of the guanfacine-containing layer, polyethylene glycol C8-C having 2-10 EO units in an amount of 2-6% by weight. 20 -alkyl ether and, iv) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of oleyl alcohol and The transdermal treatment system, including the above.

[0451] 45. A method for producing an active drug-containing layer for use in a transdermal therapy system, 1) At least, ingredients (i) Pharmaceutical activators, (ii) at least one monocarboxylic acid, A step of obtaining a premixture by combining, 2) (i) The premixture from step 1) and (ii) at least one polymer, A step of obtaining a coating composition by combining, 3) A step of coating the coating composition onto a backing layer or release liner to obtain a coated coating composition, 4) A step of drying the coated coating composition to form the active agent-containing layer, The method comprising the above.

[0452] 46. The method according to Clause 45, wherein the premixture obtained by step 1) of the above method is obtained by combining (i) and (ii) by dry grinding and / or slurrying.

[0453] 47. The slurry method according to clause 45 or 46, comprising the step of combining equimolar amounts of components (i) and (ii) in at least one solvent selected from the group consisting of dichloromethane, methanol, and ethyl acetate.

[0454] 48. The slurry method according to any one of the claims 45 to 47, further comprising the step of stirring the solution obtained in step 1) for 24 to 36 hours.

[0455] 49. The solution is preferably stirred for 24 hours, as described in clause 48.

[0456] 50. The aforementioned active agent-containing layer is i) Pharmaceutical active agents and monocarboxylic acids, ii) at least one polymer, The method according to any one of the claims 45 to 49, wherein the matrix layer contains an active drug.

[0457] 51. The method according to any one of the claims 45 to 50, wherein the at least one monocarboxylic acid is sorbic acid.

[0458] 52. The method according to any one of the claims 45 to 51, wherein the pharmaceutically active agent is guanfacine.

[0459] 53. The method according to any one of the claims 45 to 52, wherein the active agent-containing layer structure is self-adhesive and preferably does not include an additional skin contact layer.

[0460] 54. The method according to any one of the claims 45 to 53, wherein the at least one polymer is selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof.

[0461] 55. The at least one polymer is A mixture of an acrylic polymer and at least one silicone-based polymer, or • A mixture of two silicone-acrylic hybrid polymers, or • A mixture of two silicone-based polymers, or • Acrylic polymer, or Acrylic polymer containing -OH groups The method described in any one of the clauses 45 to 54.

[0462] 56. The method according to any one of the claims 45 to 55, wherein the silicone-based polymer is obtained by polycondensation of a silicate resin of silanol-terminated polydimethylsiloxane.

[0463] 57. The method according to any one of claims 45 to 56, wherein the acrylic polymer is selected from copolymers based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, and glycidyl methacrylate, and copolymers based on 2-ethylhexyl acrylate and vinyl acetate.

[0464] 58. The silicone-acrylic hybrid polymer is a silicone-acrylic hybrid pressure-sensitive adhesive, and the silicone-acrylic hybrid pressure-sensitive adhesive is (a) A silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group, and (b) an ethylenically unsaturated monomer, (c) Initiator and, The method according to any one of the claims 45 to 57, comprising the reaction product thereof.

[0465] 59. The silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group is (a1) Silicone resin and (a2) Silicone polymer and (a3) A silicon-containing encapsulant containing an acrylate or methacrylate functional group, The silicon-containing encapsulant comprises a condensation reaction product of the general formula XYR' b SiZ 3-b {wherein X is a monovalent group of the general formula AE (where E is -O- or -NH-, and A is an acrylic group or a methacrylic group), Y is a divalent alkylene group having 1 to 6 carbon atoms, R' is a methyl or phenyl group, Z is a monovalent hydrolyzable organic group or halogen, and b is 0 or 1}, The silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, and the silicon-containing sealant is introduced before, during, or after the reaction of the silicone resin and the silicone polymer. The method according to Clause 58, wherein the silicon-containing encapsulant reacts with the pressure-sensitive adhesive after the silicone resin and the silicone polymer undergo a condensation reaction to form the pressure-sensitive adhesive, or the silicon-containing encapsulant reacts in situ with the silicone resin and the silicone polymer.

[0466] 60. The method according to clause 58 or 59, wherein the ethylenically unsaturated monomer is selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, alicyclic acrylates, alicyclic methacrylates, and combinations thereof, each of the compounds having up to 20 carbon atoms in the alkyl group, and the ethylenically unsaturated monomer is preferably a combination of 2-ethylhexyl acrylate and methyl acrylate, particularly preferably in a ratio of 40:60 to 70:30.

[0467] 61. (b1) The silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group, (b2) The ethylenically unsaturated monomer and, (b3) The initiator and, The method according to any one of the claims 58 to 60, wherein the reaction product comprises a continuous acrylic outer phase and a discontinuous silicone inner phase.

[0468] 62. The method according to any one of the claims 45 to 61, wherein the active agent-containing layer structure comprises the pharmaceutically active agent in an amount of 1 to 100 mg / TTS, preferably 3 to 72 mg / TTS.

[0469] 63. The method according to any one of claims 45 to 62, wherein the active agent-containing layer contains the pharmaceutically active agent in an amount of 1 to 20% by weight, more preferably 3 to 16% by weight, based on the total weight of the active agent-containing layer.

[0470] 64. The method according to any one of claims 45 to 63, comprising the pharmaceutically active agent and the monocarboxylic acid in equimolar amounts.

[0471] 65. The method according to any one of claims 45 to 64, wherein the active agent-containing layer comprises the at least one polymer in an amount of 20 to 99% by weight, preferably 30 to 97% by weight, and most preferably 35 to 94% by weight, based on the total weight of the active agent-containing layer.

[0472] 66. The method according to any one of claims 45 to 65, wherein the activator-containing layer comprises a mixture of an acrylic polymer and at least one silicone-based polymer, and based on the total weight of the activator-containing layer, the acrylic polymer is present in an amount of 20 to 55% by weight and the at least one silicone-based polymer is present in an amount of 20 to 55% by weight.

[0473] 67. The method according to any one of claims 45 to 65, wherein the activator-containing layer comprises a mixture of two silicone-acrylic hybrid polymers, in each case, based on the total weight of the activator-containing layer, the first silicone-acrylic hybrid polymer is present in an amount of 60 to 90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1 to 20% by weight, preferably the first silicone-acrylic hybrid polymer and the second silicone-acrylic hybrid polymer comprise a silicone phase and an acrylate phase in a weight ratio of 60:40 to 40:60.

[0474] 68. The method according to any one of claims 45 to 65, wherein the active agent-containing layer comprises a mixture of two silicone-based polymers, wherein, based on the total weight of the active agent-containing layer, the first silicone-based polymer is present in an amount of 20 to 55% by weight and the second silicone-based polymer is present in an amount of 20 to 55% by weight.

[0475] 69. The method according to any one of the claims 45 to 68, wherein the active agent-containing layer further comprises at least one additive selected from the group consisting of dispersants, permeation enhancers, and solubilizers, preferably at least two additives.

[0476] 70. The dispersant is selected from the group consisting of esters of fatty acids and polyols, aliphatic alcohols, polyethylene glycol having a number average molecular weight of 300 to 400, and polyethylene glycol alkyl ethers. Preferably, the dispersant is polyethylene glycol C8 to C having 2 to 10 EO units. 20 -The method according to clause 69, wherein the alkyl ether is used.

[0477] 71. The method according to clause 69 or 70, wherein the permeation enhancer is selected from the group consisting of diethylene glycol monoethyl ether (Transktol), oleic acid, levulinic acid, caprylic / capric triglyceride, diisopropyl adipate, isopropyl myristart, isopropyl palmitate, lauryl lactate, triacetin, dimethylpropylene urea, oleyl alcohol, oleoyl macrogol-6 glyceride (labrafil MS 1944), and lauroglycol, and the permeation enhancer is preferably oleyl alcohol, lauroglycol, or oleoyl macrogol-6 glyceride (labrafil MS 1944).

[0478] 72. The method according to any one of claims 69 to 71, wherein the solubilizer is selected from the group consisting of copolymers derived from esters of acrylic acid and methacrylic acid, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, preferably polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0479] 73. The method according to any one of the claims 69 to 72, wherein the active agent-containing layer comprises two additives selected from a dispersant and a permeation enhancer.

[0480] 74. A percutaneous treatment system obtained by the method described in any one of the clauses 45 to 73.

[0481] 75. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6 to 9% by weight of guanfacine and sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, a permeation enhancer selected from oleyl alcohol, lauroglycol, and oleoyl macrogol-6 glyceride in an amount of 2 to 6% by weight, The transdermal treatment system, including the above.

[0482] 76. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6 to 9% by weight of guanfacine and sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of oleyl alcohol and The transdermal treatment system, including the above.

[0483] 77. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6 to 9% by weight of guanfacine and sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, a laurogenic glycol in an amount of 2 to 6% by weight, The transdermal treatment system, including the above.

[0484] 78. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6 to 9% by weight of guanfacine and sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, an amount of 2 to 6% by weight of oleoyl macrogol-6 glyceride, The transdermal treatment system, including the above.

[0485] 79. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6 to 9% by weight of guanfacine and sorbic acid, ii) A mixture of two silicone-based polymers, wherein, based on the total weight of the guanfacine-containing layer, the first silicone-based polymer is present in an amount of 20-55% by weight, and the second silicone-based polymer is present in an amount of 20-55% by weight. iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of oleyl alcohol and The transdermal treatment system, including the above.

[0486] 80. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6 to 9% by weight of guanfacine and sorbic acid, ii) Based on the total weight of the guanfacine-containing layer, an amount of 65-95% by weight of acrylic polymer, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of oleyl alcohol and The transdermal treatment system, including the above.

[0487] 81. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6 to 9% by weight of guanfacine and sorbic acid, ii) Based on the total weight of the guanfacine-containing layer, an acrylic polymer containing -OH groups in an amount of 65 to 95% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of oleyl alcohol and The transdermal treatment system, including the above.

[0488] 82. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6 to 9% by weight of guanfacine and sorbic acid, ii) A mixture of an acrylic polymer and at least one silicone-based polymer, wherein, based on the total weight of the guanfacine-containing layer, the acrylic polymer is present in an amount of 20-55% by weight and the at least one silicone-based polymer is present in an amount of 20-55% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, an amount of 2 to 6% by weight of oleoyl macrogol-6 glyceride, The transdermal treatment system, including the above.

[0489] Furthermore, the present invention relates to the following provisions. 1. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) A guanfacine-containing layer comprising guanfacine and monocarboxylic acid, The transdermal treatment system, including the above.

[0490] 2. The guanfacine-containing layer is i) Guanfacine and monocarboxylic acid, ii) at least one polymer, The transdermal treatment system according to Clause 1, comprising a guanfacine-containing matrix layer.

[0491] 3. The transdermal treatment system according to Clause 1 or 2, wherein the monocarboxylic acid is sorbic acid.

[0492] 4. The transdermal treatment system according to any one of the clauses 1 to 3, wherein the guanfacine-containing layer structure is self-adhesive and preferably does not include an additional skin contact layer.

[0493] 5. The transdermal treatment system according to any one of the clauses 1 to 4, wherein the at least one polymer is selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof.

[0494] 6. The at least one polymer is • A mixture of an acrylic polymer and at least one silicone-based polymer, • A mixture of two silicone-acrylic hybrid polymers, or • A mixture of two silicone-based polymers, or • Acrylic polymer, or Acrylic polymer containing -OH groups A percutaneous treatment system as described in any one of clauses 1 to 5.

[0495] 7. The transdermal treatment system according to any one of Clause 5 or 6, wherein the silicone-based polymer is obtained by polycondensation with a silicate resin of silanol-terminated polydimethylsiloxane.

[0496] 8. The transdermal treatment system according to any one of Clauses 5 to 7, wherein the acrylic polymer is selected from copolymers based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, and glycidyl methacrylate, and copolymers based on 2-ethylhexyl acrylate and vinyl acetate.

[0497] 9. The silicone-acrylic hybrid polymer is a silicone-acrylic hybrid pressure-sensitive adhesive, and the silicone-acrylic hybrid pressure-sensitive adhesive is (a) A silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group, and (b) an ethylenically unsaturated monomer, (c) Initiator and, A transdermal treatment system according to any one of clauses 5 to 8, comprising the reaction product thereof.

[0498] 10. The silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group is (a1) Silicone resin and (a2) Silicone polymer and (a3) A silicon-containing encapsulant containing an acrylate or methacrylate functional group, The silicon-containing encapsulant comprises a condensation reaction product of the general formula XYR' b SiZ 3-b {wherein X is a monovalent group of the general formula AE (where E is -O- or -NH-, and A is an acrylic group or a methacrylic group), Y is a divalent alkylene group having 1 to 6 carbon atoms, R' is a methyl or phenyl group, Z is a monovalent hydrolyzable organic group or halogen, and b is 0 or 1}, The silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, and the silicon-containing sealant is introduced before, during, or after the reaction of the silicone resin and the silicone polymer. The transdermal treatment system according to Clause 9, wherein the silicon-containing encapsulant reacts with the pressure-sensitive adhesive after the silicone resin and the silicone polymer undergo a condensation reaction to form the pressure-sensitive adhesive, or the silicon-containing encapsulant reacts in situ with the silicone resin and the silicone polymer.

[0499] 11. The transdermal treatment system according to either item 9 or 10, wherein the ethylenically unsaturated monomer is selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, alicyclic acrylates, alicyclic methacrylates, and combinations thereof, each of the compounds having up to 20 carbon atoms in the alkyl group, and the ethylenically unsaturated monomer is preferably a combination of 2-ethylhexyl acrylate and methyl acrylate, particularly preferably in a ratio of 40:60 to 70:30.

[0500] 12. The transdermal treatment system according to any one of the clauses 1 to 11, wherein the guanfacine-containing layer structure contains guanfacine in an amount of 1 to 100 mg / TTS, preferably 3 to 72 mg / TTS.

[0501] 13. The transdermal treatment system according to any one of the clauses 1 to 12, wherein the guanfacine-containing layer contains guanfacine in an amount of 1 to 20% by weight, more preferably 3 to 16% by weight, based on the total weight of the guanfacine-containing layer.

[0502] 14. A transdermal treatment system according to any one of the clauses 1 to 13, comprising guanfacine and the monocarboxylic acid in equimolar amounts.

[0503] 15. The transdermal treatment system according to any one of the claims 1 to 14, wherein the guanfacine-containing layer comprises at least one polymer in an amount of 20 to 99% by weight, preferably 30 to 97% by weight, and most preferably 35 to 94% by weight, based on the total weight of the guanfacine-containing layer.

[0504] 16. The transdermal treatment system according to any one of the claims 1 to 15, wherein the guanfacine-containing layer further comprises at least one additive, preferably at least two additives, selected from the group consisting of dispersants, permeation enhancers, and solubilizers.

[0505] 17. The area weight of the guanfacine-containing layer is 40-250 g / m². 2 Preferably, 50-180 g / m² 2 The range is 1 to 100 cm², and / or the emission area is 1 to 100 cm². 2 Preferably, 2.5 to 50 cm 2 A transdermal treatment system described in any one of clauses 1 to 16, which falls within the scope of the system.

[0506] 18. A percutaneous treatment system according to any one of Clauses 1 to 17, for use in a method of treating human patients, preferably human patients aged 6 to 17 years.

[0507] 19. A transdermal treatment system according to any one of Clauses 1 to 17, for use in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD), and / or for use as an adjunct therapy to stimulant drug therapy in human patients, preferably human patients aged 6 to 17 years.

[0508] 20. The transdermal treatment system is a transdermal treatment system for use in accordance with the description in Clause 18 or 19, which is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

[0509] twenty one. A method for producing an active drug-containing layer for use in a transdermal therapy system, 1) At least, ingredients (i) Pharmaceutical activators, (ii) at least one monocarboxylic acid, A step of obtaining a premixture by combining, 2) (i) The premixture from step 1) and (ii) at least one polymer, A step of obtaining a coating composition by combining, 3) A step of coating the coating composition onto a backing layer or release liner to obtain a coated coating composition, 4) A step of drying the coated coating composition to form the active agent-containing layer, The method comprising the above.

[0510] twenty two. The method according to clause 21, wherein the pharmaceutically active agent is guanfacine.

[0511] twenty three. The method according to clause 21 or 22, wherein the premixture obtained by step 1) of the method is obtained by combining (i) and (ii) by dry grinding and / or slurrying.

[0512] twenty four. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6 to 9% by weight of guanfacine and sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, a permeation enhancer selected from oleyl alcohol, lauroglycol, and macrogol-6 glyceride in an amount of 2 to 6% by weight, The transdermal treatment system, including the above.

[0513] twenty five. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6 to 9% by weight of guanfacine and sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of oleyl alcohol and The transdermal treatment system, including the above.

[0514] 26. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6 to 9% by weight of guanfacine and sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, a laurogenic glycol in an amount of 2 to 6% by weight, The transdermal treatment system, including the above.

[0515] 27. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing layer, preferably a guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, 6 to 9% by weight of guanfacine and sorbic acid, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1-20% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of macrogol-6 glyceride and The transdermal treatment system, including the above.

Claims

1. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) A guanfacine-containing layer comprising guanfacine and monocarboxylic acid, Includes, The transdermal treatment system wherein the monocarboxylic acid is sorbic acid.

2. The guanfacine-containing layer is i) Guanfacine and monocarboxylic acid, ii) at least one polymer, The transdermal treatment system according to claim 1, comprising a guanfacine-containing matrix layer, wherein the monocarboxylic acid is sorbic acid.

3. The transdermal treatment system according to claim 1 or 2, wherein the guanfacine and the monocarboxylic acid in the guanfacine-containing layer are present in the form of a premixture.

4. The transdermal treatment system according to any one of claims 1 to 3, wherein the guanfacine and the monocarboxylic acid in the guanfacine-containing layer exist in the form of a premixture, and the premixture can be obtained by a dry grinding method or a slurry method.

5. The transdermal treatment system according to any one of claims 1 to 4, wherein the guanfacine-containing layer structure is self-adhesive and does not include an additional skin contact layer.

6. The transdermal treatment system according to any one of claims 1 to 5, wherein the at least one polymer is selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof.

7. The at least one polymer is A mixture of an acrylic polymer and at least one silicone-based polymer. A mixture of two silicone-acrylic hybrid polymers, or - A mixture of two silicone-based polymers, or ・Acrylic polymer, or - Acrylic polymer containing -OH groups The transdermal treatment system according to any one of claims 1 to 6.

8. The transdermal treatment system according to claim 6 or 7, wherein the silicone-based polymer is obtained by polycondensation with a silicate resin of silanol-terminated polydimethylsiloxane.

9. The transdermal treatment system according to any one of claims 6 to 8, wherein the acrylic polymer is selected from a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, and glycidyl methacrylate, and a copolymer based on 2-ethylhexyl acrylate and vinyl acetate.

10. The silicone-acrylic hybrid polymer is a silicone-acrylic hybrid pressure-sensitive adhesive, and the silicone-acrylic hybrid pressure-sensitive adhesive is (a) A silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group, and (b) an ethylenically unsaturated monomer, (c) Initiator and A transdermal treatment system according to any one of claims 6 to 9, comprising the reaction product of the following:

11. The silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group comprises (a1) a silicone resin and (a2) Silicone polymer and (a3) A silicon-containing encapsulant containing an acrylate or methacrylate functional group, The silicon-containing encapsulant contains a condensation reaction product of the general formula XYR' ｂ SiZ ３－ｂ {wherein X is a monovalent group of the general formula AE (where E is -O- or -NH-, and A is an acrylic group or a methacrylic group), Y is a divalent alkylene group having 1 to 6 carbon atoms, R' is a methyl or phenyl group, Z is a monovalent hydrolyzable organic group or halogen, and b is 0 or 1}, The silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, and the silicon-containing sealant is introduced before, during, or after the reaction of the silicone resin and the silicone polymer. The transdermal treatment system according to claim 10, wherein the silicon-containing encapsulant reacts with the pressure-sensitive adhesive after the silicone resin and the silicone polymer undergo a condensation reaction to form the pressure-sensitive adhesive, or the silicon-containing encapsulant reacts in situ with the silicone resin and the silicone polymer.

12. The transdermal treatment system according to claim 10 or 11, wherein the ethylenically unsaturated monomer is selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, alicyclic acrylates, alicyclic methacrylates, and combinations thereof, each of the compounds having up to 20 carbon atoms in the alkyl group, and the ethylenically unsaturated monomer is a combination of 2-ethylhexyl acrylate and methyl acrylate in a ratio of 40:60 to 70:

30.

13. The transdermal treatment system according to any one of claims 1 to 12, wherein the guanfacine-containing layer structure contains guanfacine in an amount of 1 to 100 mg / TTS or 3 to 72 mg / TTS.

14. The transdermal treatment system according to any one of claims 1 to 13, wherein the guanfacine-containing layer contains guanfacine in an amount of 1 to 20% by weight or in an amount of 3 to 16% by weight, based on the total weight of the guanfacine-containing layer.

15. A transdermal treatment system according to any one of claims 1 to 14, comprising guanfacine and the monocarboxylic acid in equimolar amounts.

16. The transdermal treatment system according to any one of claims 1 to 15, wherein the guanfacine-containing layer contains at least one polymer in an amount of 20 to 99% by weight, or 30 to 97% by weight, or 35 to 94% by weight, based on the total weight of the guanfacine-containing layer.

17. The transdermal treatment system according to any one of claims 1 to 16, wherein the guanfacine-containing layer further comprises at least one additive selected from the group consisting of dispersants, permeation enhancers, and solubilizers, or at least two additives.

18. The area weight of the guanfacine-containing layer is 40 to 250 g / m². ２ , or 50-180 g / m ２ The range is 1 to 100 cm², and / or the emission area is 1 to 100 cm². ２ , or 2.5 to 50 cm ２ A transdermal treatment system according to any one of claims 1 to 17, which falls within the range of [the specified range].

19. A percutaneous treatment system according to any one of claims 1 to 18, for use in a method of treating a human patient aged 6 to 17 years.

20. A transdermal therapy system according to any one of claims 1 to 18, for use in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD), and / or for use as an adjunct therapy to stimulant drug therapy in human patients aged 6 to 17 years.

21. The transdermal treatment system is applied to the patient's skin for at least 24 hours, at least 72 hours, or about 84 hours, and is used in accordance with claim 19 or 20.

22. A method for producing an active drug-containing layer for use in a transdermal therapy system, 1) At least, components (i) Pharmaceutical activators and (ii) at least one monocarboxylic acid, A step of obtaining a premixture by combining, ２） (i) The premixture from step 1) and (ii) at least one polymer, A step of obtaining a coating composition by combining, 3) A step of coating the coating composition onto a backing layer or release liner to obtain a coated coating composition, 4) A step of drying the coated coating composition to form the active agent-containing layer, Includes, The method wherein the pharmaceutically active agent is guanfacine and the monocarboxylic acid is sorbic acid.

23. The method according to claim 22, wherein the premixture obtained by step 1) of the above method is obtained by a step of combining (i) and (ii) by dry grinding and / or slurrying.

24. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, a total amount of guanfacine and sorbic acid in an amount of 6 to 9% by weight, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60 to 90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1 to 20% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) A permeation enhancer selected from oleyl alcohol, lauroglycol and oleoyl macrogol-6 glyceride in an amount of 2 to 6% by weight, based on the total weight of the guanfacine-containing layer, The transdermal treatment system, including the above.

25. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, a total amount of guanfacine and sorbic acid in an amount of 6 to 9% by weight, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60 to 90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1 to 20% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, an amount of oleyl alcohol of 2 to 6% by weight, The transdermal treatment system, including the above.

26. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, a total amount of guanfacine and sorbic acid in an amount of 6 to 9% by weight, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60 to 90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1 to 20% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, a lauroglycol in an amount of 2 to 6% by weight, The transdermal treatment system, including the above.

27. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure is A) Backing layer, B) Guanfacine-containing matrix layer, The layer includes, i) Based on the total weight of the guanfacine-containing layer, a total amount of guanfacine and sorbic acid in an amount of 6 to 9% by weight, ii) In either case, based on the total weight of the guanfacine-containing layer, the mixture of two silicone-acrylic hybrid polymers is such that the first silicone-acrylic hybrid polymer is present in an amount of 60 to 90% by weight and the second silicone-acrylic hybrid polymer is present in an amount of 1 to 20% by weight, iii) Based on the total weight of the guanfacine-containing layer, 2 to 6% by weight of polyoxyethylene (4) lauryl ether, iv) Based on the total weight of the guanfacine-containing layer, an amount of 2 to 6% by weight of oleoyl macrogol-6 glyceride, The transdermal treatment system, including the above.

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